Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[O:13]1[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][CH2:20][CH:21]=O)[CH2:14]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:12][C:11]1[C:2]([NH:1][CH2:21][CH2:20][CH2:19][CH:15]2[CH2:16][CH2:17][CH2:18][O:13][CH2:14]2)=[CH:3][C:4]2[O:8][C:7](=[O:9])[NH:6][C:5]=2[CH:10]=1
Reactant: O=CCCC1CCCOC1
Reactant: Nc1cc2oc(=O)[nH]c2cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]c2cc(F)c(NCCCC3CCCOC3)cc2o1
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a solution of 6-amino-5-fluoro-benzoxazolin-2-one (2.1 g, 12.5 mmole) in methanol (80 ml) were added 3-(tetrahydro-2H-pyran-3-yl) propanal (1.95 g, 13.7 mmole) and acetic acid (1 ml) at room temperature, and then the mixture was stirred for 1 hour. Sodium cyanoborohydride (0.867 g, 13.7 mmole) was combined and stirring continued for 17 hours at room temperature. The reaction mixture was concentrated in vacuo, and the residue was treated with aqueous ammonium chloride solution. The organic substance was extracted with ethyl acetate/tetrahydrofuran. The extracts were washed with brine, dried over magnesium sulfate, and concentrated to afford crude product. This crude product was recrystallized from methanol to give 1.40 g of the title compound: m.p. 144°-145° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][CH2:25][CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:21]([Cl:32])=[CH:20][N:19]=1>>[Cl:32][C:21]1[C:22]([NH:24][CH2:25][CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)NCCNc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(NCCNS(C)(=O)=O)n3)cc2CC1

Procedure:
N-(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-ethyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-ethyl]-methanesulfonamide in an analogous manner to Example 298. Product isolated as a white solid (34 mg, 21%). m.p.=92-95° C.; LCMS (m/e) 469 (M+1); 1H-NMR (d6-DMSO, 400 MHz) δ 9.06 (s, 1H), 7.93 (s, 1H), 7.45-7.39 (m, 2H), 7.17-7.07 (m, 2H), 6.97 (d, 1H, J=8.6 Hz), 3.58-3.49 (m, 2H), 3.47-3.40 (m, 2H), 3.23 (s, 3H), 3.24-3.17 (m, 2H), 2.89 (s, 3H) 2.79-2.71 (m, 4H), 2.65-2.54 (m, 6H).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[N:11]([CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[CH3:32])[N:25]([CH3:33])[CH:24]=2)[C:10]1=[O:34])[CH2:5][CH2:6][CH2:7][CH3:8]>O1CCOCC1.O>[CH3:33][N:25]1[C:26]2[C:31](=[C:30]([CH3:32])[CH:29]=[CH:28][CH:27]=2)[C:23]([CH2:22][N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:20][CH3:21])=[CH:14][CH:13]=3)[C:18](=[O:19])[N:9]([C@@H:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:3]([OH:35])=[O:2])[C:10]2=[O:34])=[CH:24]1
Reactant: CCCC[C@@H](C(=O)OC)n1c(=O)c2cc(OC)ccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Solvent: O
Solvent: C1COCCO1
Product: CCCC[C@@H](C(=O)O)n1c(=O)c2cc(OC)ccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-6-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-hexanoic acid methyl ester (124 mg, 0.26 mmol) in dioxane (2.5 ml) is added a solution of LiOH monohydrate (50 mg, 1.19 mmol) in H2O (2.5 mL). The solution is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, quenched with 4M HCl in dioxane (500 μL) and concentrated. The resulting residue is triturated with H2O and MeOH to afford the title compound. LCMS (ESMS): m/z 464.87 (M+H+)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=[C:4]([NH:16][C:17]([CH3:23])([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1.[CH:24]12[CH2:32][CH2:31][CH:28]([CH2:29][CH2:30]1)[CH2:27][NH:26][CH2:25]2>COCCOCCOC>[CH3:22][C:17]([NH:16][C:4]1[N:5]=[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=[C:2]([N:26]2[CH2:27][CH:28]3[CH2:31][CH2:32][CH:24]([CH2:30][CH2:29]3)[CH2:25]2)[N:3]=1)([CH3:23])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C1CC2CCC1CNC2
Reactant: CC(C)(C)C(C)(C)Nc1nc(Cl)nc(NC(C)(C)C(C)(C)C)n1
Solvent: COCCOCCOC
Product: CC(C)(C)C(C)(C)Nc1nc(NC(C)(C)C(C)(C)C)nc(N2CC3CCC(CC3)C2)n1

Procedure:
A 10.25 g. portion of 2-chloro-4,6-bis[(1,1,2,2-tetramethylpropyl)amino]-s-triazine and 7.65 g. of 3-azabicyclo[3.2.2]nonane in 50 ml. of diglyme is heated at reflux for 3 hours and then cooled, giving a pink solid. This solid is collected, washed with diglyme, suspended in 500 ml. of water, stirred, filtered and washed with water giving a pink solid. This solid is recrystallized from ethanol (charcoal being employed in decolorization) to give the desired product m.p. 282°-284° C.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[CH3:21][N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=1[C:32]([F:35])([F:34])[F:33])[CH3:23]>C(Cl)Cl.CO>[CH3:23][N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:17](=[O:19])[CH2:16][C:13]2[CH:14]=[CH:15][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:11][C:12]=2[CH3:20])=[CH:27][C:26]=1[C:32]([F:33])([F:35])[F:34])[CH3:21]
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Reactant: CN(C)Cc1ccc(N)cc1C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)Nc1ccc(CN(C)C)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (disclosed in WO2005/051366). Title compound: ES-MS: 468.2 [M+H]+; tR=2.97 min (System 1); Rf=0.37 (CH2Cl2/MeOH, 9:1+0.1% NH3aq).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([CH:14]([O:17][CH3:18])[O:15][CH3:16])=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]([OH:29])[N:8]([C:20]([CH3:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])[C:9]2=[O:19].CN(CCN(C)C)C.[I:38]I>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([CH:14]([O:15][CH3:16])[O:17][CH3:18])=[CH:12][C:11]([I:38])=[C:10]2[C:6]=1[CH:7]([OH:29])[N:8]([C:20]([CH3:21])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:28])[C:9]2=[O:19]
Reactant: COCOc1c(C(OC)OC)ccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Reactant: II
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1c(C(OC)OC)cc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 51.1 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-methoxymethoxy-5-dimethoxymethyl-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (3.34 g, 8.31 mmol) was dissolved in THF (100 mL), and the solution was treated with TMEDA (4.00 mL, 27.0 mmol), sec-butyl lithium-hexane solution (1.03 mol/L, 25.8 mL, 26.6 mmol) and iodine (3.16 g, 12.5 mmol), followed by purification by slurry using methanol and diisopropylether to obtain 4-methoxymethoxy-5-dimethoxymethyl-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (2.24 g, yield 51%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:13][CH:14]=1>C1(C)C=CC=CC=1>[CH2:24]([Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[C:11]1[CH:10]=[C:9]([NH:8][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])[CH:14]=[CH:13][CH:12]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(N)c1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(NC(=O)/C=C\C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Maleic anhydride (0.18 g, 1.8 mmol) was dissolved in toluene (2 mL). m-Aminophenyltributylstannane as described above (0.70 g, 1.8 mmol) in toluene (4 mL) was added dropwise over a 5 minute period. After the addition was complete, the reaction mixture was stirred for 15 minutes at room temperature then cooled in an ice-water bath. The precipitaed yellow product N-(m-tri-n-butylstannylphenyl)maleamic acid was collected by vacuum filtration, recrystallized from toluene and dried overnight in a vacuum dessicator (0.75 g, 85%): mp. 130°-131° C. 1H NMR (Me2SO-d6, δ); 10.4 (singlet, 1H, OH); 7.6 (singlet, 2H, aryl C2-H and aryl C6-H); 7.3 (triplet, 1H, aryl C5-H); 7.2 (doublet, 1H, aryl C4-H); 6.4 (doublet of doublets, 2H AB, J=12 Hz, 2 CHC=O); 0.9-1.6 (muliplets, 27H, 3× n-C4H9).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:23]([C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=1)(=[O:24])=[O:25]
Reactant: Fc1cc(Br)c2cc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)n2ccc3c(Br)cc(F)cc32)cc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 4-bromo-6-fluoro-1H-indole (2 g) in DMF (5 ml) was added sodium hydride (60% in mineral oil) (0.448 g). The reaction was stirred at 20° C. for 10 min. 4-Nitrobenzenesulfonyl chloride (2.278 g) was added and the reaction was stirred at 20° C. for 1 h. The mixture was poured onto water (100 ml), and extracted with DCM (50 ml) which was separated by hydrophobic frit. Purification by silica (2×100 g) on Flashmaster II using a gradient of DCM and cyclohexane gave the title compound as a pale yellow solid, 1.54 g.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C(F)(F)F)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].Br[C:14]1[C:19]([O:20][CH2:21][CH2:22][CH3:23])=[CH:18][CH:17]=[C:16]([I:24])[N:15]=1.O>CN(C)C=O>[I:24][C:16]1[N:15]=[C:14]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:19]([O:20][CH2:21][CH2:22][CH3:23])=[CH:18][CH:17]=1
Reactant: CCCOc1ccc(I)nc1Br
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(I)nc1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Methoxybenzyl alcohol (689 mg) was added to a solution of sodium hydride (200 mg) in N,N-dimethylformamide (4 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. A solution of 2-bromo-6-iodo-3-propoxypyridine in N,N-dimethylformamide (2 mL) was added thereto, and the mixture was stirred at 85° C. for six hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→1:1) to give the title compound as a colorless powder (670 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:13][C:14]1[CH:22]=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[CH2:8][CH2:9][CH2:10][NH:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[N:29]=[C:28](Cl)[S:27][N:26]=1.CS(C)=O>O>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:13][C:14]1[CH:22]=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[CH2:8][CH2:9][CH2:10][N:11]([C:28]1[S:27][N:26]=[C:25]([Cl:24])[N:29]=1)[CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNCCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C
Reactant: Clc1nsc(Cl)n1
Solvent: O
Solvent: CS(C)=O
Product: CN(CCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C)c1nc(Cl)ns1
Yield: 69 %

Procedure:
A solution of benzo[1,3]dioxol-5-ylmethyl-(3-methylamino-propyl)-carbamic acid tert-butyl ester (10 g, 46 mmol), 3,5-dichloro-1,2,4-thiadiazole (7.1 g, 46 mmol), DMSO (20 mL) and TEA (20 mL) was stirred at r.t. for 20 min. Water (150 mL) was added and the solution was extracted with ethyl acetate (2×150 mL), washed with brine and dried over Na2SO4. Evaporation of the solvent gave 14 g (69%) of benzo[1,3]dioxol-5-ylmethyl-{3-[(3-chloro-[1,2,4]thiadiazol-5-yl)-methyl-amino]-propyl}-carbamic acid tert-butyl ester as a clear gum. The product was used directly in the next step. 1H-NMR (400 MHz, CD3OD) δ 6.77 (m, 3H), 5.96 (s, 2H), 4.35 (s, 2H), 3.4-3.0 (m, 6H), 1.84 (br s, 3H), 1.50 (s, 9H).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16]Cl>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: CN(C)CCCCl
Reactant: O=Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1ccccc1C=O
Yield: 76.7 %

Procedure:
The reaction between 100 g (0.82 mole) of salicylaldehyde, 40 g (0.82 mole) of 50% NaH, and 650 ml (1.2 mole) of 1.89 N 3-dimethylaminopropyl chloride in toluene in a procedure described in Example 2, part A, gives 130.4 g (77%) of yellow product, bp 125°-130°/0.5 mm.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[OH:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>C(O)(=O)C>[OH:12][C:13]1[CH:14]=[C:15]([N:16]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cccc(O)c1

Procedure:
A mixture of 3,4,5,6-tetrahydrophthalic anhydride, 3-hydroxyaniline and a glacial acetic acid was heated to obtain N-(3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (m.p.: 199° to 201° C.) and 40.6 g. of the product was dissolved into 600 ml. of glacial acetic acid and 27.2 g. of bromine was added dropwise at 30° to 40° C. and the mixture was stirred at a room temperature for 5 hours to precipitate a crystal. The crystal was separated by a filtration and washed with methanol and recrystallized from benzene-tetrahydrofuran to obtain N-(4-bromo-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (m.p.: 247°-248° C.; yellow crystal) (yield: 88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(I)c(C(F)(F)F)cc2C1
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N1Cc2cc(N3CCOCC3)c(C(F)(F)F)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A35(d)) and morpholine. White solid. MS (m/e): 373.0 ([M+H]+, 100%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:47][O:48][C:49]1[N:54]=[C:53]([CH2:55]O)[CH:52]=[CH:51][CH:50]=1>ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:55][C:53]1[CH:52]=[CH:51][CH:50]=[C:49]([O:48][CH3:47])[N:54]=1
Reactant: Oc1ccc2c(nnn2CC2CC2)c1Br
Reactant: COc1cccc(CO)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(COc2ccc3c(nnn3CC3CC3)c2Br)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-Bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-ol (25 mg, 0.093 mmol) and triphenylphosphine (32 mg, 0.12 mmol, 1.3 equiv) were dissolved in dichloromethane (0.5 mL). To the stirring mixture was added diethyl diazene-1,2-dicarboxylate (25 mg, 0.12 mmol, 1.3 equiv), followed by (6-methoxypyridin-2-yl)methanol (16 mg, 0.11 mmol, 1.2 equiv) and the mixture stirred at ambient temperature for 14 hours. The mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (5: 95 to 95:5; acetonitrile:water containing 0.1% trifluoroacetic acid), providing the title compound as a clear oil: 1H-NMR (400 MHz, d6-DMSO) δ 7.94 (1H, d, J=9.1 Hz), 7.76 (1H, t, J=7.7 Hz), 7.60 (1H, d, J=8.9 Hz), 7.21 (1H, d, J=7.9 Hz), 6.77 (1H, d, J=7.9 Hz), 5.32, (2H, s), 4.59 (2H, d, J=7.31 Hz), 3.84 (3H, s), 1.40-1.32 (1H, m), 0.56-0.53 (2H, m), 0.48-0.44 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 389.0617 [(M+H)+; calculated for C17H17BrN4O2: 389.0607].
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH3:20])([CH3:19])[C:5](=[O:18])[C:6]([C:13](OCC)=[O:14])=[C:7]2[OH:12].C(N(C(C)C)C(C)C)C.Cl.[NH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>O1CCOCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH3:19])([CH3:20])[C:5](=[O:18])[C:6]([C:13]([NH:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:14])=[C:7]2[OH:12]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cccc(F)c2C(C)(C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccc(F)c2C(C)(C)C1=O
Temperature: 80 °C
Yield: 61.2 %

Procedure:
To a solution of ethyl 5-fluoro-1-hydroxy-4,4-dimethyl-3-oxo-3,4-dihydronaphthalene-2-carboxylate (2.0 g, 7.2 mmol) in 1,4-dioxane (15 mL), was added N-ethyl-N-isopropylpropan-2-amine (2.3 mL, 13 mmol) and tert-butyl 2-aminoacetate hydrochloride (1.6 g, 9.3 mmol). After heating at 80° C. for 12 hours, the solvent was removed in vacuo, and the residue was purified using flash chromatography (15% EtOAc/hexane) to afford the product as a white solid (1.6 g). MS (m/z)=362 (M+H)+.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2.[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:18][N:19]([CH3:24])[S:20]([N:3]([CH3:2])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2)(=[O:22])=[O:21]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CNc1cccc2cc(-c3nccs3)[nH]c12
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of N-methyl-2-(1,3-thiazol-2-yl)-1H-indole-7-amine hydrochloride (100 mg) in pyridine (3 mL) was added dimethylsulfamoyl chloride (200 μL). The reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give. the title compound (88 mg, yield 69%) as yellow crystals. melting point 123° C.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)=[CH:14][CH:15]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(N2CCC(N3CCCCC3)CC2)cc1
Product: c1cc(N2CCC(N3CCCCC3)CC2)ccc1CN1CCCCC1

Procedure:
Prepared from the product of Example 5 and piperidine.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:28])[C@H:7]([CH3:27])[NH:8][CH2:9][C:10]([NH:12][C:13]1[C:14]2[C:19]([N:20]=[C:21]3[C:26]=1[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])C.Cl>>[CH2:25]1[C:26]2[C:21](=[N:20][C:19]3[C:14]([C:13]=2[NH:12][C:10]([CH2:9][NH:8][C@H:7]([C:6]([OH:28])=[O:5])[CH3:27])=[O:11])=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:22][CH2:23][CH2:24]1
Reactant: CCOC(=O)[C@H](C)NCC(=O)Nc1c2c(nc3ccccc13)CCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NCC(=O)Nc1c2c(nc3ccccc13)CCCC2)C(=O)O
Reaction time: 2 h
Yield: 77.1 %

Procedure:
Into 12 ml of 1N aqueous solution of sodium hydroxide, was added 2 g of the compound obtained in Example 38 at room temperature, and the reaction was continued for 2 hours. To the reaction mixture, was added 15 ml of 1N hydrochloric acid at a temperature not higher than 15° C. to precipitate white crystals. The crystals were collected by filtration, washed with water and dried to obtain 1.42 g of the titled compound having the melting point of 238° to 242° C. (decomposed).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:16]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:17]=2[N:18]=[C:19]([C:21]([O:23]CC)=[CH2:22])[CH:20]=1)=[O:14].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[C:21]([C:19]1[CH:20]=[C:15]([C:13]([NH:12][CH2:11][C:4]2[C:5](=[O:10])[NH:6][C:7]([CH3:9])=[CH:8][C:3]=2[CH3:2])=[O:14])[C:16]2[CH:28]=[N:27][N:26]([CH:29]([CH3:30])[CH3:31])[C:17]=2[N:18]=1)(=[O:23])[CH3:22]
Reactant: C=C(OCC)c1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
35% HCl (4 mL) was added to the N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(1-ethoxyvinyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.12 g, 0.293 mmol) at 0° C. and stirred it at room temperature for 1 h. After completion of reaction, saturated NaHCO3 solution was added to it and extraction was carried out by using 5% MeOH/DCM, the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired compound (90% yield). LCMS: 382.10 (M+1)+; HPLC: 99.55% (@ 254 nm) (Rt; 6.316); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 9.09 (bs, 1H), 8.48 (s, 1H), 8.14 (s, 1H), 5.89 (s, 1H), 5.35-5.29 (m, 1H), 4.36 (d, 2H, J=4.0 Hz), 2.75 (s, 3H), 2.21 (s, 3H), 2.12 (s, 3H), 1.56 (d, 6H, J=6.8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[N:9]=[C:10](Cl)[C:11]([C:29]#[N:30])=[C:12]3[C:17]=2[C:16]=1[NH:15][C:14](=[O:18])[N:13]3[C:19]1[C:27]2[O:26][CH2:25][O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[Cl:28])=[O:5])[CH3:2].[CH3:32][Sn](C)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[N:9]=[C:10]([CH3:32])[C:11]([C:29]#[N:30])=[C:12]3[C:17]=2[C:16]=1[NH:15][C:14](=[O:18])[N:13]3[C:19]1[C:27]2[O:26][CH2:25][O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[Cl:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc2nc(Cl)c(C#N)c3c2c1NC(=O)N3c1c(Cl)ccc2c1OCO2
Reactant: C[Sn](C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2nc(C)c(C#N)c3c2c1NC(=O)N3c1c(Cl)ccc2c1OCO2
Temperature: 150 °C

Procedure:
7-chloro-5-(5-chloro-benzo[1,3]dioxol-4-yl)-6-cyano-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triaza-acenaphthylene-2-carboxylic acid ethyl ester Compound 1g (115 mg, 0.242 mmol) was combined with 95% tetramethyltin (0.039 ml, 0.266 mmol), PdCl2(Ph3P)2 (17 mg, 0.024 mmol) and DMF (3 mL) in a sealed microwave vessel. The mixture was heated to 150° C. for 15 mins. The reaction mixture was diluted with 0.5 M NaH2PO4 and extracted with EtOAc, then dried (MgSO4) and evaporated. The resulting residue was purified by flash chromatography (30 to 50% EtOAc/hexane/1% Et3N) to give 5-(5-chloro-benzo[1,3]dioxol-4-yl)-6-cyano-7-methyl-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triaza-acenaphthylene-2-carboxylic acid ethyl ester Compound 2a (57 mg) as a white solid. LC/MS 457 (MH+).