Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:2].[H][H]>[Pd].CO>[NH2:14][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=1
Reactant: CCOc1cc([N+](=O)[O-])ccc1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(N)ccc1C(=O)OC
Yield: 94.6 %

Procedure:
A mixture of methyl 2-ethoxy-4-nitrobenzoate (2.038 g, 9.05 mmol) and palladium on carbon (583 mg, 10 wt %, Aldrich) in methanol (62 ml) was reacted with hydrogen at 40 psi for 18 hrs on the PARR shaker. It was filtered through celite and washed with methanol under N2 and the filtrate was concentrated to give methyl 4-amino-2-ethoxybenzoate (1.672 g, 94%) as a light brown solid.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:7]1(=[O:23])=[O:22].[CH3:24][NH2:25].Cl>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5]/[CH:4]=[CH:3]/[CH2:2][NH:25][CH3:24])[S:7]1(=[O:23])=[O:22]
Reactant: O=S1(=O)N(C/C=C/CBr)c2ccccc2N1c1ccccc1F
Reactant: CN
Agent: Cl
Product: CNC/C=C/CN1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[(2E)-4-bromobut-2-en-1-yl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.13 g, 0.33 mmol) was treated with methyl amine to give (2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbut-2-en-1-amine (105 mg) after treatment with HCl.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][N:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:14]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C[O:29][C:30](=[O:41])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][CH2:39]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][N:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]([CH:22]4[CH2:23][CH2:24][N:25]([CH2:39][CH2:38][O:37][C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[C:30]([OH:41])=[O:29])[CH2:26][CH2:27]4)=[CH:14]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCOc1ccc2c(c1)OCO2
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCOc3ccc4c(c3)OCO4)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 2.3 g (6.2 mmol) of 1-[2-(benzo[1,3]dioxol-5-yloxy)-ethyl]-3-piperidin-4-yl-1H-indole and 1.5 g (7.1 mmol) of 2-(2-chloroethoxy)-benzoic acid methyl ester. After standard work-up and recrystallisation with methanol, 1.6 g (49% of yield) of the expected acid were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][C:16]3([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(O)CC.O>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][C:16]3([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC1(O)CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCCO
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4ccc(F)cc4)cnc3c2n1CC1(O)CCCC1
Temperature: 25 °C
Yield: 57 %

Procedure:
1-{[4-Amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}cyclopentanol (1.13 g, 2.7 mmol), 4-fluorobenzeneboronic acid (0.43 g, 3.1 mmol), triphenylphosphine (6.3 mg, 0.024 mmol), and 5:1 (v/v) 1-propanol/water (6.6 mL) were combined under a nitrogen atmosphere. A 5 mg/mL solution of palladium (II) acetate (1.8 mg, 0.008 mmol) in toluene and aqueous sodium carbonate (1.8 mL of 2 M) were sequentially added. The reaction mixture was heated at reflux for two hours, allowed to cool to room temperature, and partitioned between chloroform (75 mL) and brine (20 mL). The organic fraction was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (1.27 g) was purified by trituration with acetonitrile at 98° C. followed by recrystallization from chloroform/hexane. The crystals were dried in a vacuum oven at 110 C for two hours to provide 0.67 g of 1-{[4-amino-2-(ethoxymethyl)-7-(4-fluorophenyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}cyclopentanol as a steel-gray solid, mp 212-212.5° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([CH:16]=O)=[CH:14][N:13]([CH3:18])[N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:19]([N:26]([CH3:31])[CH2:27][CH2:28][NH:29][CH3:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH3-]C#N.[Na+].O>CO.[Cl-].[Cl-].[Zn+2]>[CH2:19]([N:26]([CH3:31])[CH2:27][CH2:28][N:29]([CH2:16][C:15]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[N:12][N:13]([CH3:18])[CH:14]=1)[CH3:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CNCCN(C)Cc1ccccc1
Reactant: CC(C)Oc1ccc(-c2nn(C)cc2C=O)cc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc(-c2nn(C)cc2CN(C)CCN(C)Cc2ccccc2)cc1
Reaction time: 0.75 h
Yield: 47.7 %

Procedure:
To a solution of 3-(4-isopropoxyphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (82 mg, 0.32 mmol) in methanol (2 mL) was added TEA (129 mg, 1.2 mmol). ZnCl2 (5 mg, 0.05 mmol) and N-benzyl-N,N′-dimethylethane-1,2-diamine (71 mg, 0.38 mmol) were added at rt and stirred for 45 min. NaCNBH3 (87 mg, 1.2 mmol) was added and stirred for 2 h at rt. The reaction was poured into water (100 mL), extracted with EtOAc (50 mL×2). The combined extracts was washed with brine (100 mL), dried and concentrated under vacuum. The residue was purified by SGC using DCM: MeOH (0%-4%) as eluent to obtain N1-benzyl-N2-((3-(4-isopropoxyphenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-N1,N2-dimethylethane-1,2-diamine (62 mg, Yield: 45%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>C(Cl)Cl>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN(C)CCN
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 107 %

Procedure:
3-Nitrobenzoyl chloride (2 g, 10.77 mmol) was loaded into a round bottomed flask, placed under a N2 atmosphere and dissolved in anhydrous DCM (10 mL). The mixture was cooled to 0° C. and N,N-dimethylethylenediamine (0.98 mL, 8.98 mmol) was added to the reaction. The reaction was allowed to warm to RT and left to stir for 18 h. After 18 h the reaction had given a precipitate which was isolated by filtration and washed with DCM to give 2.28 g of a white solid, which was partitioned between DCM and a saturated aqueous NaHCO3 solution. The organic layer was removed under reduced pressure and the aqueous layer was then re-extracted DCM. The organic layers were combined, dried over Na2SO4 and the solvent was removed under reduced pressure to afford the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:19])[CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:22]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:19])[CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:22])[C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(F)cccc2c1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cc1c(Br)cccc1-n1c(=O)c2cccc(F)c2n(C)c1=O
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A solution of 3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione [Intermediate 1] (4.80 g, 13.8 mmol) in DMF (25 mL) was treated with Cs2CO3 (13.4 g, 41.2 mmol). The suspension was stirred at room temperature and treated dropwise (but quickly) with iodomethane (4.30 mL, 68.7 mmol) and stirred rapidly at room temperature for 1 h. The mixture was diluted with EtOAc and water (200 mL). The organic phase was separated and washed sequentially with water and brine, then was dried and concentrated to provide 3-(3-bromo-2-methylphenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione as a tan glassy foam (4.80 g, 96% yield). Mass spectrum m/z 363, 365 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:16][CH3:17])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([NH2:15])=O)[N:12]=2)[C:8]=1[CH3:9])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>O1CCCC1>[CH2:1]([C:3]1[C:4]([O:16][CH3:17])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13](=[S:27])[NH2:15])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCc1c(OC)nc2nc(C(N)=O)cn2c1C
Solvent: C1CCOC1
Product: CCc1c(OC)nc2nc(C(N)=S)cn2c1C
Yield: 76595.1 %

Procedure:
A mixture of 20.0 g (0.0854 mmol) of 6-ethyl-7-methoxy-5-methylimidazo-[1,2-a]pyrimidine-2-carboxamide and 25.4 g (0.0629 mmol) of Lawesson's Reagent in 470 ml of tetrahydrofuran (THF) was refluxed for 4 hours. The mixture was then cooled, and the product was filtered and washed with THF, then ether to obtain 12.06 g (56%) of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-thiocarboxamide as a yellow solid melting at 248°-259° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([O:29]C)=[O:28])=[CH:20][C:19]=3[CH:31]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20][C:19]=3[CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(CCCOc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1ccc(CCCOc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 60 °C
Reaction time: 18.5 h
Yield: 36.7 %

Procedure:
To methyl 7-[3-(4-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (937 mg) dissolved in THF-methanol (15-7.5 ml) was added a 2 M aqueous solution (1.5 ml) of potassium carbonate, and the resulting mixture was stirred at 60° C. for 18.5 hours. The reaction mixture was treated with 1 N hydrochloric acid to bring the pH to 2. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. After evaporation under reduced pressure to remove the solvent, the precipitated crystals were washed with hexane-ethyl acetate to obtain 7-[3-(4-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (333 mg) as white crystals.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)[O:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[K+]>C(O)C.O>[Cl:21][C:13]1[CH:12]=[C:11]([CH:4]([O:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(OC2CCCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
A solution of rac-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetic acid methyl ester (395 mg, 1.14 mmol) in ethanol (15 mL) at 25° C. was treated with a solution of potassium hydroxide (320 mg, 5.69 mmol) in water (3 mL) and the mixture was stirred at 25° C. After 3 h, the reaction was diluted with water and evaporated under reduced pressure. The concentrate was acidified to pH 2 with an aqueous solution of 1N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated in vacuo. The residual oil was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate plus 1% acetic acid) to furnish rac-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetic acid (364 mg, 96% yield) as a colorless oil: EI-HRMS m/e calcd for C14H17ClSO5 (M+) 332.0485, found 332.0486.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([O:22][CH2:23][CH3:24])[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)O)[CH3:2].COC(=O)C(OC)=CC1C=CC=C(OCC2C=CC=CC=2)C=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:22][CH2:23][CH3:24])=[CH:6][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(OCC)C(O)c1cccc(OCc2ccccc2)c1
Agent: COC(=O)C(=Cc1cccc(OCc2ccccc2)c1)OC
Product: CCOC(=O)C(=Cc1cccc(OCc2ccccc2)c1)OCC

Procedure:
The title compound was prepared from 3-(3-benzyloxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethyl ester (Example 378, Step 1) via the same procedure used for the preparation of 3-(3-benzyloxy-phenyl)-2-methoxy-acrylic acid methyl ester (Example 291, Step 2) to afford the title compound as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1)=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>O1CCCC1.O>[OH:16][N:15]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=NO)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A solution of methyl 4-formyl-2-methylbenzoate (1.3 g) in tetrahydrofuran (50 mL) was added dropwise to a solution of hydroxylamine hydrochloride (1.0 g), sodium acetate (1.2 g) in tetrahydrofuran (50 mL) and water (50 mL) under ice cooling, and after finishing the dropwise addition, the mixture was stirred for one hour at room temperature. The reaction mixture was diluted with water and then extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of methyl 4-[(hydroxyimino)methyl]-2-methylbenzoate (1.3 g).
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[C:21](C)[C:20]([NH2:24])=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:4][N:3]=[N:2]1.N1C(NC(C2C(=O)N3[C:36]([S:37]C4C=C(CCC)C(N)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(OC)C(N)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(OCC)C(N)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(O)C(N)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(Cl)C(N)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(F)C(N)=CC=43)=NC=2)=O)=NN=N1>>[NH:4]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[C:21]([S:37][CH3:36])[C:20]([NH2:24])=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:1][N:2]=[N:3]1
Reactant: Cc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1N
Reactant: CCCc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1N
Agent: CCOc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1N
Agent: COc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1N
Agent: Nc1cc2c(cc1Cl)sc1ncc(C(=O)Nc3nnn[nH]3)c(=O)n12
Product: CSc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1N

Procedure:
N-(5-tetrazolyl)-7-amino-8-methyl-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-amino-8-n-propyl-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-amino-8-methoxy-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-amino-8-ethoxy-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-amino-8-hydroxy-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-amino-8-chloro-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; and N-(5-tetrazolyl)-7-amino-8-fluoro-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]#[CH:11])=[CH:4][N+:5]([O-:7])=[O:6].[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1)[CH3:14]>>[N+:5]([CH:4]=[C:3]([NH:8][CH2:9][C:10]#[CH:11])[NH:25][CH2:24][CH2:23][S:22][CH2:21][C:19]1[O:20][C:16]([CH2:15][N:13]([CH3:14])[CH3:12])=[CH:17][CH:18]=1)([O-:7])=[O:6]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: C#CCNC(=C[N+](=O)[O-])SC
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1

Procedure:
A solution of the product of Step A is reacted with about an equimolar amount of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine to give, after workup and chromatography as in Example 1, the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:23]=[N:22][CH:21]=[CH:20][C:11]=1[C:12]([NH:14][NH:15][C:16]([NH:18][CH3:19])=[O:17])=O.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:23]=[N:22][CH:21]=[CH:20][C:11]=1[C:12]1[N:18]([CH3:19])[C:16](=[O:17])[NH:15][N:14]=1
Reactant: CNC(=O)NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(-c2ccncc2Nc2ccc(I)cc2F)n[nH]c1=O
Temperature: 120 °C
Yield: 6.4 %

Procedure:
To a suspension of 2-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}-N-methylhydrazinecarboxamide (165 mg; 0.38 mmol) in water (3 mL) was added 1N NaOH (3 mL). The mixture became homogeneous. The reaction mixture was heated at 120° C. for 3 days. The progress of the reaction was monitored by LCMS. Concentration of the solvent and repeated purifications gave 10 mg of 5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-4-methyl-2,4-dihydro-[1,2,4]triazol-3-one
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C@H:16]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:17]3[CH2:28][CH2:29][CH2:30][OH:31])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C)=O.C(N(CC)CC)C.O>ClCCl>[N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C@H:16]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C@@H:17]3[CH2:28][CH2:29][CH:30]=[O:31])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)cc(N3CCCCCC3)n2)[C@H]1CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)cc(N3CCCCCC3)n2)[C@H]1CCC=O
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of the compound 39 (174 mg), dimethylsulphoxide (3 mL) and triethylamine (1.5 mL) in dichloromethane (3 mL) with stirring, sulfur trioxide pyridine complex (212 mg) was added into the solution at room temperature. The reaction solution was stirred for 2 hours, added water and extracted with a mixture solution of hexane/ethyl acetate. The extract was washed with water, aqueous 5% potassium bisulfate solution, water and saturated brine, dried over anhydrous magnesium sulfate, concentrated and obtained the title compound (171 mg) having the following physical properties.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:24]=[O:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH:26]([Mg]Cl)([CH3:28])[CH3:27]>C1COCC1>[CH3:27][CH:26]([CH3:28])[CH:24]([C:22]1[CH:21]=[N:20][CH:19]=[C:18]([C:14]2[CH:15]=[N:16][C:17]3[NH:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:23]=1)[OH:25]
Reactant: CC(C)[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(C=O)c3)cnc21
Solvent: C1CCOC1
Product: CC(C)C(O)c1cncc(-c2cnc3c(c2)CCCN3)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) suspension of 6-(5-formyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (125 mg, 0.37 mmol) in THF (1 mL) is added a solution of isopropylmagnesium chloride in THF (1.3M, 850 μL, 1.1 mmol). The resultant mixture is stirred warming to room temperature for 3 h. The reaction is quenched with saturated aqueous ammonium chloride solution and is extracted with EtOAc. The combined organic extracts are washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue is taken up in MeOH (1 mL) and 4N HCl in 1,4-dioxane (1 mL) is added. The reaction is stirred at room temperature for 16 h then is concentrated to provide 2-methyl-1-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-propan-1-ol (124 mg) as the dihydrochloride salt.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]3[O:19][CH2:20][C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[CH:23](O)[C:17]=3[CH:16]=1)[CH:7]=[CH:6]2)[CH3:2].[SH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35]>>[C:34]([CH2:33][CH2:32][S:31][CH:23]1[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[CH2:20][O:19][C:18]2[CH:29]=[CH:30][C:15]([O:14][CH2:13][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][CH3:2])[CH:4]=4)[N:9]=3)=[CH:16][C:17]1=2)([OH:36])=[O:35]
Reactant: O=C(O)CCS
Reactant: CCc1ccc2nc(COc3ccc4c(c3)C(O)c3ccccc3CO4)ccc2c1
Product: CCc1ccc2nc(COc3ccc4c(c3)C(SCCC(=O)O)c3ccccc3CO4)ccc2c1

Procedure:
2-(6-Ethylquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: N[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([Br:17])=[CH:15][N:14]=[C:13]3[NH:18][CH:19]=[C:20]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=4)[C:12]=23)[CH2:7][CH2:6]1)=[O:4].[C:30]([O:34][C:35]([NH:37][CH2:38]CC(O)=O)=[O:36])([CH3:33])([CH3:32])[CH3:31].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:17][C:16]1[C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][CH2:38][NH:37][C:35](=[O:36])[O:34][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:6][CH2:7]2)=[C:12]2[C:20]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)=[CH:19][NH:18][C:13]2=[N:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Reaction time: 5 h
Yield: 21 %

Procedure:
Crude N-(5-bromo-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.200 g, 0.498 mmol, see Example 61), 3-(tert-butoxycarbonylamino)propanoic acid (0.189 g, 0.997 mmol), HOBT-H2O (0.107 g, 0.698 mmol) and EDCI (0.124 g, 0.648 mmol) were placed in DCM (5 mL) at room temperature. DIEA (d 0.742; 0.434 mL, 2.49 mmol) was then added, and the reaction was allowed to stir for 5 hours. The reaction was then poured into saturated Na2CO3 and extracted into DCM. The organic fractions were combined, dried, filtered, and concentrated to give the crude residue. Purification by column chromatography (500:15 to 500:25 D CM: MeOH) gave tert-butyl 3-(4-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (0.060 g, 21.0% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:18])[F:17])=[CH:10][C:9]2[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH:33]=[CH:32][N:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M53) (0.29 g, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (143 mg, 64%).