Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:3]=12.Cl[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:3]=12
Reactant: CSc1nc(Cl)c2c(-c3ccccc3Cl)n[nH]c2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2c(-c3ccccc3Cl)nn(COCC[Si](C)(C)C)c2n1
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
4-Chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (10.0 g, 0.032 mol) was added to 100 mL of dry DMF, and the resulting solution was cooled to 0° C. (2-Chloromethoxy-ethyl)-trimethyl-silane (6.8 mL, 0.038 mol) was added dropwise, and the reaction mixture was stirred for five minutes. Sodium hydride (1.40 g, 0.0333 mol) was then added, and the reaction mixture was stirred for 30 minutes at 0° C. The reaction mixture was partitioned between water and ethyl acetate. The layers were separated, and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with brine, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0% to 10% hexanes in EtOAc) to afford 8.55 g of 4-Chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=[O:24].N12CCN(CC1)CC2>CN(C)C=O>[F:18][C:16]([F:19])([F:17])[C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:23](=[O:24])[N:22]([CH3:21])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:7][CH:6]=2)=[O:20])=[CH:15][CH:14]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(C(F)(F)F)cc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(NC(=O)c2ccc(C(F)(F)F)cc2)cn1)c1ccccc1
Yield: 64.5 %

Procedure:
A solution of N-(6-hydroxy-pyridin-3-yl)-4-trifluoromethyl-benzamide (1.41 g, 5.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.85 g, 5.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.56 g, 5.00 mmol) in dimethylformamide (10 mL) was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50) yielding the title compound (1.34 g, 64% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([N+:11]([O-])=O)[CH:10]=[C:4]2[CH2:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[CH:10]=[C:4]2[CH2:3]1
Reactant: CN1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CN1CCn2nc(N)cc2C1
Reaction time: 8 h
Yield: 102 %

Procedure:
A solution of 5-methyl-2-nitro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (1.6 g, 8.7 mmol) in ethanol (20 mL) was treated with palladium on carbon (10%, 300 mg) and flushed with argon. The resulting mixture was stirred under a hydrogen (1 atm) overnight. The reaction mixture was filtered through a celite pad, and the pad washed with ethanol. The filtrate was concentrated in vacuo to give 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (1.35 g, quantitative) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.30 (s, 3 H) 2.71 (t, J=5.67 Hz, 2 H) 3.37 (s, 2 H) 3.74 (t, J=5.67 Hz, 2 H) 4.46 (s, 2 H) 5.14 (s, 1 H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[CH:17](=O)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+]>CO.O>[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8]2
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Reactant: O=CCCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(CCCc1ccccc1)CC2
Reaction time: 6 h
Yield: 93.3 %

Procedure:
A solution of the product from Example 5 (1 g, 3.24 mmol) and hydrocinnamaldehyde (0.94 g, 7 mmol) in 2:1 MeOH/H2O (50 mL) was treated with sodium cyanoborohydride (0.56 g, 9 mmol) portionwise under nitrogen and stirred for six hours. The solvent was decanted and the semi-solid was dissolved in dichloromethane, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude compound was chromatographed on silica gel (eluted with 25% ethyl acetate in hexane) to give the title compound (1.18 g, 94% yield) as a brown oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([CH3:22])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.[Cl:23][C:24]1[C:25]([C:30](O)=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:22][C:5]1[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)=[CH:7][N:8]=[CH:9][C:4]=1[CH2:3][NH:2][C:30]([C:25]1[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:31]
Reactant: O=C(O)c1ncccc1Cl
Reactant: Cc1c(CN)cncc1-c1ccc2c(c1)CCC(=O)N2C
Agent: Cl
Product: Cc1c(CNC(=O)c2ncccc2Cl)cncc1-c1ccc2c(c1)CCC(=O)N2C

Procedure:
In analogy to the procedure described for the preparation of example 75, 6-(5-aminomethyl-4-methyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 222) has been coupled with 3-chloro-pyridine-2-carboxylic acid to give the title compound as a colorless solid. MS: 421.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2OS(C(F)(F)F)(=O)=O.[CH2:21]([O:28][C:29](=[O:35])[NH:30][CH:31]1[CH2:34][NH:33][CH2:32]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOCC>[CH2:21]([O:28][C:29](=[O:35])[NH:30][CH:31]1[CH2:34][N:33]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:32]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: O=C(NC1CNC1)OCc1ccccc1
Solvent: CCOCC
Product: COc1ccc2nccc(N3CC(NC(=O)OCc4ccccc4)C3)c2n1

Procedure:
According to procedure F and starting from trifluoromethanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-yl ester (prepared according to WO 02/008224) and azetidin-3-yl-carbamic acid benzyl ester the desired intermediate was isolated after trituration with ether as a colorless solid (5.05 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[C:7]([CH:13]=[N:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=2)[C:3]=1[C:4](O)=[O:5].[CH3:26][Li].Cl>C1COCC1>[Cl:1][C:2]1[C:3]2[C:4](=[O:5])[N:14]([CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:13]([CH3:26])[C:7]=2[C:8]([F:12])=[C:9]([Cl:11])[N:10]=1
Reactant: COc1cc(CN=Cc2c(F)c(Cl)nc(Cl)c2C(=O)O)cc(OC)c1
Reactant: [Li]C
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CN2C(=O)c3c(Cl)nc(Cl)c(F)c3C2C)cc(OC)c1
Reaction time: 2 h
Yield: 9.5 %

Procedure:
To a mixture of 2,6-dichloro-4-((3,5-dimethoxybenzylimino)methyl)-5-fluoronicotinic acid (5.8 g, 25.3 mmol) in THF (120 mL) was added methyl-lithium (60.0 mL, 126.6 mmol) drop wise at −78° C. After the addition was completed, the mixture was stirred for an additional 2 h. The reaction mixture was acidified with 1N HCl to pH 7 and THF was removed under reduced pressure. The mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and purified by silica gel chromatography eluting with PE-EtOAc (5:1) to give the title compound as a white solid (0.93 g, 16%). 1H-NMR (CDCl3, 400 MHz) δ 1.58 (d, J=6.8 Hz, 3 H), 3.79 (s, 3 H), 3.84 (s, 3 H), 4.35 (d, J=14.4 Hz, 1 H), 4.52 (q, J=6.8 Hz, 1 H), 5.07 (d, J=14.4 Hz, 1 H), 6.43-6.45 (m, 2 H), 7.28 (d, J=9.2 Hz, 1 H). [M+H] calc'd for C17H15Cl2FN2O3, 386; found, 385.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:10]1(O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.S(=O)(=O)(O)O>>[C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Oc1ccccc1
Reactant: CCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCC(=O)Oc1ccccc1
Temperature: 131 °C

Procedure:
Heptanoic acid (180.9 g; 1.39 mol), phenol (180.69 g; 1.92 mol), toluene (216.5; 2.35 mol) and sulfuric acid (5.04 g; 0.0514 mol) were charged to a 2-liter, 3-necked round bottom flask equipped with a thermometer, a magnetic stirrer and an 8" Vigreux column equipped with a Dean-Stark trap. The reaction mixture was heated to 131° C. and maintained at that temperature for five hours to give 74 weight percent phenyl heptanoate. The reaction product was washed once with a solution of 0.08 mol Na2CO3 in 4.5 mol water. Phase separation occurred after approximately 20 minutes. The organic layer was fractionally distilled at atmospheric pressure using a 20-plate Oldershaw column to remove phenol and toluene. The remaining liquid was then distilled through a 10-plate Oldershaw column at 50 torr to give a center cut fraction of 154.4 g (54% yield) of pure phenyl heptanoate.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@H:19]3[C@@H:23]4[O:24]C(C)(C)[O:26][C@@H:22]4[C@@H:21](/[CH:29]=[CH:30]/[P:31](=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])[O:20]3)[N:17]=[CH:18][C:11]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O>[C:1]([NH:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@@H:19]3[O:20][C@H:21](/[CH:29]=[CH:30]/[P:31](=[O:38])([O:32][CH2:33][CH3:34])[O:35][CH2:36][CH3:37])[C@@H:22]([OH:26])[C@H:23]3[OH:24])[N:17]=[CH:18][C:11]=12)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(/C=C/[C@H]1O[C@@H](n2ncc3c(NC(=O)c4ccccc4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOP(=O)(/C=C/[C@H]1O[C@@H](n2ncc3c(NC(=O)c4ccccc4)ncnc32)[C@H](O)[C@@H]1O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
Compound 22.4 (163 mg, 0.299 mmol) was treated with TFA (1000 μL) and H2O (100 μL) and stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was subjected to a silica gel column chromatography eluting with 0-20% MeOH—CH2Cl2 to afford compound 25.1 (65 mg, 43% yield) as a white solid: 1H NMR (CDCl3, 300 MHz) 9.51 (br s, 1H), 8.65 (s, 1H), 8.47 (s, 1H), 7.90 (d, J=7.5 Hz, 2H), 7.51 (t, J=7.5 Hz, 1H), 7.43 (t, J=7.5 Hz, 2H), 6.88 (m, 1H), 6.61 (s, 1H), 5.98 (m, 1H), 4.85 (m, 1H), 4.67 (m, 1H), 4.60 (m, 1H), 3.89 (m, 4H), 1.20 (t, 6H); 31P NMR (CDCl3, 121.4 MHz) 16.6; MS (ESI) m/z 504 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([NH2:15])=[O:14].C(N(CC)CC)C>C(#N)C>[C:13]([CH2:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)(=[O:14])[NH2:15]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: NC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)COC(=O)c1ccc(O)cc1
Yield: 59.4 %

Procedure:
10 g of p-hydroxybenzoic acid and 10 g of α-bromoacetamide were dissolved in 150 ml of acetonitrile, and 7 g of triethylamine was added to the solution. The resulting mixture was refluxed for 7 hours followed by concentrating under reduced pressure. Water was then added to the residue to obtain 8.4 g of crystals of the above-titled compound having a melting point of 250°-255° C.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]2[C:3]=1[C@@:4]1([CH3:26])[C@H:13]([CH2:14][S:15]2(=[O:22])=[O:21])[C@:12]2([CH3:23])[C@H:7]([C:8]([CH3:25])([CH3:24])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1.[CH3:27][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[OH:1][C:2]1[CH:19]=[C:18]([O:20][CH3:27])[CH:17]=[C:16]2[C:3]=1[C@@:4]1([CH3:26])[C@H:13]([CH2:14][S:15]2(=[O:22])=[O:21])[C@:12]2([CH3:23])[C@H:7]([C:8]([CH3:25])([CH3:24])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(O)c4[C@]3(C)CC[C@@H]12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(O)c2c(c1)S(=O)(=O)C[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
To a solution of (1R,10R,11S,16S)-3,5-dihydroxy-1,11,15,15-tetramethyl-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (28) (8.0 g, 21 mmol) in CH2Cl2 (192 mL) and methanol (64 mL), (trimethylsilyl)diazomethane (2 M in diethyl ether, 16.9 mL, 33.8 mmol) was added in 2 mL increments every hour at room temperature under N2. The mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography on silica gel (Hexanes/EtOAc, 2:1) to yield (1R,10R,11S,16S)-3-hydroxy-5-methoxy-1,11,15,15-tetramethyl-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (30) (4.9 g, 58%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([S:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([S:9][C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc2nc(Sc3ccc(Cl)cc3)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Sc2nc3ccc(OCCCCBr)cc3s2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.74 g (2.5 mmol) of 6-hydroxy-2-(4-chlorophenylmercapto)-benzothiazole are dissolved in 20 ml of dimethylformamide and after the addition of 2.16 g (10 mmol) of 1.4-dibromobutane and 2.07 g (15 mmol) of potassium carbonate the resulting mixture is stirred for 20 hours at ambient temperature. The mixture is then added to water and extracted with ethyl acetate. The extracts are dried and evaporated down. The evaporation residue is purified by column chromatography on silica gel (eluant: petroleum ether/ethyl acetate=4:1). Yield: 0.85 g (79.3% of theory), oil.
Reaction SMILES: Br[CH:2]([CH3:8])[CH:3]([O:6][CH3:7])[O:4][CH3:5].O.[NH2:10][NH2:11]>>[CH3:5][O:4][CH:3]([O:6][CH3:7])[CH:2]([NH:10][NH2:11])[CH3:8]
Reactant: COC(OC)C(C)Br
Reactant: NN
Solvent: O
Product: COC(OC)C(C)NN
Temperature: 140 °C

Procedure:
6.25 g (34.1 mmol) of 2-bromo-1,1-dimethoxypropane and 6.65 ml (137 mmol) of hydrazine hydrate were stirred under reflux in an oil bath at 140° C. for 6 h. After cooling, the two-phase reaction mixture was extracted with 50 ml of tert-butyl methyl ether. The organic phase was filtered, the filtrate was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 1.89 g (21% of theory) of a pale yellow oil which was reacted directly, without further purification, in the subsequent reaction.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[N:18]=[CH:17]3)[CH2:10][C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.Br[CH2:40][CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:25])[CH3:26])[N:18]=[CH:17]3)[CH:10]([CH2:40][CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(N3CCN(Cc4ccccc4)C(=O)C3)ccc21
Reactant: BrCC1CCOCC1
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(N3CCN(Cc4ccccc4)C(=O)C3CC3CCOCC3)ccc21
Temperature: 25 °C
Yield: 57.7 %

Procedure:
To a solution of 1-benzyl-4-(1-triisopropylsilanyl-1H-indazol-5-yl)-piperazin-2-one (0.78 g, 1.7 mmol) in 8.5 mL THF at −78° C. was added sec-butyllitium (1.3 mL, 1.9 mmol) drop-wise over 5 minutes. After 30 minutes 4-bromomethyl-tetrahydropyran (0.36 g, 2.0 mmol) was added in one portion and mixture was warmed to room temperature. After 18 hours H2O was added and the mixture was extracted with ethyl acetate. The combined organic layerss were washed with H2O, brine, dried over NaSO4, filtered and concentrated in vacuo. Purification via flash chromatography afforded 1-benzyl-3-(tetrahydro-pyran-4-ylmethyl)-4-(1-triisopropylsilanyl-1H-indazol-5-yl)-piperazin-2-one (0.55g, 90%) as a white foam.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH2:6]([N:13]([CH2:20][CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.OS(O)(=O)=O.O=S(=O)=O>O>[CH2:20]([N:13]([CH2:6][C:7]1[C:8]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:21]
Reactant: O=S(=O)(O)O
Reactant: CCN(Cc1ccccc1)c1ccccc1
Agent: O=S(=O)=O
Solvent: O
Product: CCN(Cc1ccccc1S(=O)(=O)O)c1ccccc1
Temperature: 60 °C

Procedure:
To a 30.0 g. of 100% sulfuric acid is added N-benzyl-N-ethylaniline (30.0 g.) dropwise below about 50° C. To this solution is added, at 50°-60° C., 60% oleum (30.0 g.) with good stirring. The mixture is stirred and heated at about 60° C. for three hours and then drowned into 200 ml. of water. The free sulfonic acid which is mostly the meta isomer with a small amount of para, precipitates on standing and is collected by filtration, washed with water, and dried. N-Benzylines containing groups such as alkyl, alkoxy, and halogen in the ortho, meta, or para positions of the benzyl group may also be sulfonated by this procedure. The exact location of the sulfonic acid group in these cases is often not known and mixtures usually are produced.
Reaction SMILES: [CH2:1]([O:3]CC)C.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](Cl)=[O:11]>CO>[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([O:3][CH3:1])=[O:11]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CCOCC
Solvent: CO
Product: COC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a 1-liter flask fitted with a stirrer, addition funnel, condenser, and drying tube containing diethyl ether (200 ml) and methanol (anhd.; 64 g,; 2.0 moles) is added dropwise m-fluorobenzoyl chloride (317 g,; 2.0 moles) at room temperature over a 3 hour period. Additional methanol (10 ml) is added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is then filtered through a bed of silicic acid and the solvent removed under vacuum to afford 285 grams of methyl 3-fluorobenzoate (92.5% yield). This was identical to the product prepared in Example 2A.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]=[O:14])=[CH:7][CH:6]=1)=[O:4].[CH3:15][Si:16]([CH3:19])([CH3:18])Cl.C(N(CC)CC)C>CN(C)C=O.C(=O)(O)[O-]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[CH:13][O:14][Si:16]([CH3:19])([CH3:18])[CH3:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(CCC=O)cc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC=CO[Si](C)(C)C)cc1

Procedure:
9.61 g (50 mmol) 3-(4-Methoxycarbonylphenyl)propanal are dissolved, together with 8.3 ml (68 mmol) of trimethylchlorosilane and 18.1 ml (0.13 mol) of triethylamine, in 15 ml of absolute dimethyl formamide and the solution is heated under reflux for 2 hours under nitrogen. After cooling, the reaction mixture is diluted with a saturated bicarbonate solution and extracted with petroleum ether. The organic phase is washed 3 times with a saturated bicarbonate solution, dried with sodium sulphate and concentrated by evaporation. The residue is distilled under a high vacuum (distillation apparatus silylated). 11.06 g of a pale yellow, oily product are thus obtained in the form of a mixture of the cis- and trans-isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(OC([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:33](=[O:34])[C:32]2[CH:31]=[CH:30][C:29]([CH2:28][CH:25]3[CH2:24][CH2:23][NH:22][CH2:27][CH2:26]3)=[CH:37][CH:36]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C(=O)O)cc2)CC1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CC2CCNCC2)cc1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 125 mg of 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)benzoic acid via Procedure G. The crude product was treated with 4N HCl in Dioxane, evaporated and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(piperidin-4-ylmethyl)benzamide. MS (Q1) 406.1 (M)+.
Reaction SMILES: CON(C)[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:7][CH:6]=1.[CH3:19][Mg]Br.C(=O)([O-])O.[Na+]>O1CCCC1>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][C:8]1[N:7]=[CH:6][C:5]([C:4](=[O:17])[CH3:19])=[CH:10][CH:9]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(OCC(F)(F)F)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
To a stirred solution of N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (6.54 g, 24.8 mmol, Step-2) in tetrahydrofuran (80 mL) is added dropwise 1.06M methylmagnesium bromide (46.7 mL, 49.5 mmol) at 0° C. The reaction mixture is stirred at room temperature for 1.5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (100 mL) and extracted with ethyl acetate (300 mL). The organic layer is washed with water (100 mL×2) and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (1:1) to give 4.51 g (83% yield) of the title compound as colorless oil.
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:41](=[O:42])[N:40]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)[CH2:39][C:17]=2[C:18]([O:25][S:26]([C:29]2[S:33][C:32]([NH:34][C:35](=[O:37])[CH3:36])=[N:31][C:30]=2[CH3:38])(=[O:28])=[O:27])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].C([SiH](CC)CC)C>ClCCl>[F:50][C:47]1[CH:48]=[CH:49][C:44]([CH2:43][N:40]2[C:41](=[O:42])[C:16]3[C:15]([OH:14])=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[N:23]4)=[C:18]([O:25][S:26]([C:29]4[S:33][C:32]([NH:34][C:35](=[O:37])[CH3:36])=[N:31][C:30]=4[CH3:38])(=[O:28])=[O:27])[C:17]=3[CH2:39]2)=[CH:45][CH:46]=1.[C:53]([OH:55])([C:52]([F:57])([F:56])[F:51])=[O:54]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Oc2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)Oc2c3c(c(O)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 272 (18.9 mg, 0.027 mmol) dissolved in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was triturated with diethyl ether/hexane (1/1) to afford 2-acetylamino-4-methyl-thiazole-5-sulfonic acid 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 273, TFA salt, (13.2 mg, 74%) as a yellow solid: 1H NMR (CD3OD) δ 8.9 (d, 1H), 8.2 (d, 1H), 7.6 (m, 1H), 7.4 (m, 2H), 7.1 (t, 2H), 4.7 (s, 2H), 4.4 (s, 2H), 2.23 (s, 3H), 2.21 (s, 3H); MS: 543 (M+1).