Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[Si:20]([N:27]1[CH:30]([CH2:31][CH:32]=[O:33])[CH:29]([N:34]=[N+:35]=[N-:36])[C:28]1=[O:37])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>O1CCCC1>[Si:20]([N:27]1[CH:30]([CH2:31][CH:32]([OH:33])[CH2:2][C:1]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH:29]([N:34]=[N+:35]=[N-:36])[C:28]1=[O:37])([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CC=O
Reactant: CC(=O)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CC(O)CC(=O)OCc1ccccc1
Temperature: -78 °C

Procedure:
A solution of benzyl acetate (0.011 mol) in anhydrous tetrahydrofuran (5 ml) is added dropwise to solution of lithium diisopropylamide (0.011 mol) in anhydrous tetrahydrofuran (20 ml) at -78° C. After stirring 15 more min at -78° C. the reaction mixture is treated dropwise with a solution of N-(t-butyldimethylsilyl)-3-azido-4-(2-oxoethyl)-azetidin-2-one (0.01 mol) in tetrahydrofuran (10 ml). The mixture is stirred at -78° an additional 15 min and then quenched with 2.5 N hydrochloric acid (10 ml). The mixture is diluted with ethyl acetate, washed with water, 5% sodium bicarbonate solution, and brine, dried with magnesium sulfate, and evaporated under vacuum to afford N-(t-butyldimethylsilyl)-3-azido-4-(3-benzyloxycarbonyl 2-hydroxypropyl)-azetidin-2-one.
Reaction SMILES: [Li+].[BH4-].CO.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:19]2[C:27]3[C:22](=[C:23]([N:28](COCC[Si](C)(C)C)[S:29]([CH3:32])(=[O:31])=[O:30])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[N:20]2)([CH2:17][CH3:18])[C:13](OC)=O)=[CH:8][CH:7]=1>C1COCC1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([N:19]2[C:27]3[C:22](=[C:23]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[N:20]2)([CH:13]2[CH2:8][CH:9]2[C:12]#[N:19])[CH2:17][CH3:18])=[CH:10][CH:11]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(c1ccc(Cl)cc1)(C1CC1C#N)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of LiBH4 (120 mg, 5.43 mmol) in THF (5 mL) was added MeOH (174 mg, 5.43 mmol) and a solution of methyl 2-(4-chlorophenyl)-2-(4-(N-((2-(trimethylsilyl)ethoxy)methyl)methylsulfonamido)-1H-indazol-1-yl)butanoate (600 mg, 1.09 mmol) in THF (8 mL) followed. The mixture was stirred at room temperature for 2 h. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=3/1) to afford the title compound as a pale yellow solid. LC/MS m/z=524.2 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([SH:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[CH3:15][O-].[Na+].IC>CO>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14][CH3:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(=O)N1CCc2ccc(S)cc2C1
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1ccc2c(c1)CN(C(C)=O)CC2
Temperature: 25 °C

Procedure:
A suspension of N-acetyl-7-mercapto-1,2,3,4-tetrahydroisoquinoline (1.0 gm., 0.0048 m.) in 20 ml. of methanol was stirred in a nitrogen atmosphere. Sodium methoxide (0.3 gm., 0.0055 m.) and 5 ml. of iodomethane were added to the suspension. The mixture was stirred at 25° C. for thirty minutes, evaporated and partitioned between chloroform and water. The chloroform layer was washed, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluted with ethyl acetate to give pure N-acetyl-7-methylthio-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[CH:10]([NH:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH2:24])[CH:20]=4)[N:15]=3)[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4]1[C:9]2[CH:10]([NH:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:33](=[O:34])[CH2:32][N:29]5[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]5)[CH:20]=4)[N:15]=3)[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CO2
Reactant: CN1CCN(CC(=O)O)CC1
Product: CCOc1cccc2c1C(Nc1ccc3cc(NC(=O)CN4CCN(C)CC4)ccc3n1)CO2

Procedure:
The title compound was prepared from rac-N2-(4-ethoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine (Example 175) (200 mg, 0.49 mmol) and commercially available (4-methyl-piperazin-1-yl)-acetic acid (74 mg, 0.65 mmol) in accordance with the general method 14 described in example 119 and was obtained as an off-white solid (200 mg, 93%); MS: m/e=462.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:8](=[O:13])C(Cl)(Cl)Cl)[N:5]([CH3:7])[CH:6]=1.[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][C:8]([C:4]1[N:5]([CH3:7])[CH:6]=[C:2]([Br:1])[N:3]=1)=[O:13]
Reactant: Cn1cc(Br)nc1C(=O)C(Cl)(Cl)Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc(Br)cn1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 337.7 %

Procedure:
To the solution of 1.18 g of 1-(-4-bromo-1-methyl-1H-imidazol-2-yl)-2,2,2-trichloroethanone in 10 mL of methanol was added 42 mg of sodium methoxide and the resulting mixture was stirred at 25° C. for 20 min. TLC showed completion of the reaction. The solution was evaporated, redissolved in 30 mL of DCM, washed with water (15 mL×2) and brine (15 mL). The solution was dried over anhydrous sodium sulfate and filtered. The residue was purified by silica gel column (DCM/MeOH=60/1) to give 4-bromo-1-methyl-1H-imidazole-2-carboxylic acid methyl ester (0.575 g, yield 68%). 1H NMR (300 MHz, CDCl3) δ 7.02 (s, 1H), 4.00 (s, 3H). 3.93 (s, 3H). LC-MS calcd for C6H7BrN2O2 (m/e) 217.97, obsd 219 and 221 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[NH2:27][CH:28]([C:34]([CH3:36])=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>ClCCl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]1[O:8][C:34]([CH3:36])=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:27]=1
Reactant: O=C(O)C=Cc1ccccc1Cl
Reactant: CCOC(=O)C(N)C(C)=O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nc(C=Cc2ccccc2Cl)oc1C
Temperature: 25 °C

Procedure:
To a suspension of o-chlorocinnamic acid (9.1 g) in dichloromethane (200 ml) was added triethylamine (21 ml) for dissolution. With cooling with ice-sodium chloride and stirring, ethyl chlorocarbonate (5.0 ml) was added dropwise to the above-obtained solution, and the mixture was further stirred for 10 minutes. To the resulting mixed acid anhydride solution was added portionwise ethyl 2-aminoacetoacetate hydrochloride (9.05 g) and the mixture was stirred under cooling for 20 minutes and at room temperature for 40 minutes. The reaction mixture was washed with diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate and water in that order and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was dissolved in toluene (100 ml). Phosphorus oxychloride (14 ml) was added and the mixture was refluxed for an hour. The solvent and phosphorus oxychloride were distilled off under reduced pressure, and the residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was treated with isopropyl ether to give ethyl 2-(2- chlorostyryl)-5-methyl-4-oxazolecarboxylate as crystals; yield 6.4 g (44.1%). Recrystallization from ethanol gave yellow prisms melting at 99°-100° C.
Reaction SMILES: [I:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.C(O)(=O)C>[OH-].[Na+].C(OCC)(=O)C>[I:1][C:2]1[N:3]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1
Yield: 86.9 %

Procedure:
A suspension of 2-iodo-4-(methoxycarbonyl)-1-triphenylmethylimidazole (1.978 g, 4 mmol) in 6N sodium hydroxide (15 mL) was heated at reflux for 4 hours. The resulting suspension was diluted with ethyl acetate (20 mL) and then slightly acidified with acetic acid. The resulting clear solution was extracted three times with ethyl acetate (20 mL) and the combined extracts were dried (magnesium sulfate) and concentrated in vacuo. Residual acetic acid was removed under high vacuum to give 2-iodo-1-triphenylmethylimidazole-4-carboxylic acid (1.67 g, 87%) as a white solid, mp 203-205° C.: 1H NMR (CDCl3) δ 7.60 (s, 1H), 7.38-7.20 (m, 9H), 7.18-7.09 (m, 6H).
Reaction SMILES: S(=O)(=O)(O)O.COCCOC[O:12][CH:13]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:14][CH2:15][S:16]([C:19]1[S:23][C:22]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>O.CO>[OH:12][CH:13]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:14][CH2:15][S:16]([C:19]1[S:23][C:22]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: COCCOCOC(CCS(=O)(=O)c1ccc(S(N)(=O)=O)s1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: NS(=O)(=O)c1ccc(S(=O)(=O)CCC(O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
To a solution of sulfuric acid (76.7 ml) in water (76.7 ml), cooled to 0° C. was added a solution of compound from Step F (5.2 g, 11.5 mmol) in methanol (76.7 ml) and the reaction mixture was stirred at room temperature for 1 hour. Water was added, extracted with ethyl acetate and the organic layers were washed with saturated NaaHCO3 solution and brine. Drying and solvent evaporation gave an oil (4.4 g) and column chromatography (silica gel, 40% ethyl acetate-hexane) gave a solid product (2.3 g, 56%); m.p. 119°-121° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11]C2C#N)=[O:7].S(=O)(=O)(O)O.[C:24]([OH:27])(=[O:26])[CH3:25]>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][CH:25]2[C:24]([OH:27])=[O:26])=[O:7]
Reactant: CC(=O)O
Reactant: N#CC1CCc2c(C(=O)c3cccs3)cccc21
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(c1cccs1)c1cccc2c1CCC2C(=O)O

Procedure:
To 2.5 g of 4-(2-thienylcarbonyl)-1-indancarbonitrile is added 20 ml of 60% sulfuric acid together with 10 ml of acetic acid. The mixture is refluxed in argon gas for 2.5 hours. After cooling, water is added to the reaction mixture which is then extracted with benzene. The benzene layer is washed with water and extracted with a 5% aqueous solution of potassium carbonate. The extract is made acidic with hydrochloric acid and the precipitate is extracted with benzene. The benzene layer is washed with water, dried and decolorized with activated carbon. The solvent is then distilled off under reduced pressure and the residue is crystallized from benzene-cyclohexane (1:2). By the above procedure is obtained 4-(2-thienylcarbonyl)-1-indancarboxylic acid as crystals melting at 121.5°-123.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][C:20]([O:23]CC4C=CC=CC=4)=[CH:21]3)=[C:16]([O:31][CH3:32])[C:15]=2[CH3:33])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+].C(OC(C)C)(C)C>CN(C)C=O.[Pd]>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][C:20]([OH:23])=[CH:21]3)=[C:16]([O:31][CH3:32])[C:15]=2[CH3:33])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3ccc(OCc4ccccc4)cn23)ccc1N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3ccc(O)cn23)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
The mixture of 0.95 g (2.14 mmol) of methyl 2-amino-5-[(6-benzyloxy-1-methoxy-2-methylindolizin-3-yl)carbonyl]benzoate, 0.21 g (3.21 mmol) of ammonium formate and 0.19 g of palladium-on-charcoal at 10% in 12 ml of N,N-dimethylformamide is stirred for 4 hours at ambient temperature. It is then filtered and concentrated to dryness. The solid obtained is taken up with diisopropyl ether and then filtered, to give 0.64 g (85%) of a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([F:8])=[CH:6][CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CCN(CC)CC>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5]([F:8])=[CH:6][CH:7]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 97 %

Procedure:
A solution of 3-amino-6-fluorobenzotrifluoride (2.0 g, 11.17 mmol, Aldrich) in acetic anhydride (10 mL) and Et3N (1 mL) was stirred at room temperature for 24 h, and then most of the acetic anhydride was removed. The white needle crystals were collected by filtration and washed with water (2×2 mL), affording 2.4 g (97%) of 3-acetamido-6-fluorobenzotrifluoride. 1H NMR (CDCl3): δ 2.184 (s, 3H); 7.136 (t, 1H, J=9.9 Hz); 7.733 (m, 3H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1ccccc1Cl
Product: Clc1ccccc1CNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-chlorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (EI): m/e 335.0 (M+). 1H NMR (500 MHz, CDCl3): δ partial 8.60 (s, 1H); 8.43 (d, J=3.9 Hz, 1H); 8.02 (br s, 1H); 7.85 (m, 1H); 7.37 (m, 2H); 6.85 (d, J=5.5 Hz, 1H); 5.93 (br s, 1H); 4.85 (d, J=6.2 Hz, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=3)[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][O:34]C4CCCCO4)[CH:26]=3)[C:12](=[O:41])[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CO>[OH:34][CH2:33][CH2:32][O:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[CH:16][CH:15]=2)[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=2)=[N:11][C:12]1=[O:41]
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(OCCOC2CCCCO2)c1
Solvent: CO
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(OCCO)c1
Reaction time: 72 h

Procedure:
To a solution of 76 mg (0.14 mmol) of 4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1-{3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzyl}-1H-quinazolin-2-one (Example RT-6) in MeOH (10 ml) is added 10 wt % Dowex-50 and the mixture is stirred vigorously for 3 days. The reaction mixture is filtered and the solvent is removed in vacuo. The residue is dissolved in CH2Cl2 and extracted with water and then brine, dried (MgSO4), filtered and evaporated in vacuo to provide a yellow oil which is purified by preparative TLC of silica gel using dichloromethane/ether (1:1) to provide the title compound as a yellow oil. Yield: 11 mg (17%).
Reaction SMILES: C([C@@H:8]1[CH2:12][O:11]C(=O)N1)C1C=CC=CC=1.C([Li])CCC.[N:19]([CH:22]([C:24]1[CH:25]=[C:26]([C:30](=[O:32])[CH3:31])[CH:27]=[CH:28][CH:29]=1)C)=C=O>C1COCC1>[CH3:31][C:30]1([C:26]2[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=2)[C:22]#[N:19])[O:32][CH2:8][CH2:12][O:11]1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CC(=O)c1cccc(C(C)N=C=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(c2cccc(C#N)c2)OCCO1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 155.4 %

Procedure:
(R)-4-benzyloxazolidin-2-one 18 (212.6 mg, 1.19 mmol) was dissolved in dried 100 mL round-bottom flask containing anhydrous THF (8 mL) under N2 atmosphere. Cooled to −78° C. 2.5M solution of n-butyl lithium in hexanes (0.9 mL, 1.2 mmol) was added dropwise. Continuing the same temperature, 16 (2.4 mmol) was added to the reaction mixture and allowed to stir for 15 min. Then reaction mixture was warmed from −78° C. to 0° C. and allowed to stir for 30 min. The reaction mixture was quenched with aq. NH4Cl. The solvent was removed in vacuo, extracted with DCM and washed with brine, dried (MgSO4), filtered, and concentrated. The crude product was isolated by column chromatography eluting with (EtOAC/n-hexane, 20:80) to yield 19 (350 mg, 80%) as a brown semisolid. 1H NMR (CDCl3, 400 MHz) δ 2.77 (t, J=12 Hz, 1H), 3.29 (d, J=12.8 Hz, 1H), 4.23 (m, 2H), 4.35 (d, J=18.4 Hz, 1H), 4.47 (d, J=18.4 Hz, 1H), 4.67 (m, 1H), 7.16-7.30 (m, 7H), 7.40 (dd, J, =4 Hz, J2=2.4 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[C:11]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20]([O:22][CH3:23])=[O:21])[C@@H:15]([CH3:24])[CH2:14][CH2:13]4)[CH:7]=[N:6]2)[CH2:2]1.C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][C:11]2[C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:3]4[CH2:2][N:1]([CH3:35])[CH2:4]4)[CH:9]=3)=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C@H:15]([CH3:24])[N:16]3[C:20]([O:22][CH3:23])=[O:21])=[CH:31][CH:30]=1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CNC4)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1c2ccc(-c3cnn(C4CN(C)C4)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
Methyl (S)-6-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (105 mg, 0.241 mmol) was dissolved in methanol and formaldehyde (179 μL, 2.41 mmol) was added. The reaction was stirred for 4 h at ambient temperature and then cooled to 0° C. Sodium triacetoxyborohydride (0.102 g, 0.481 mmol) was added and the reaction was slowly warmed to ambient temperature. After 16 h the reaction was complete, and the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl (S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.086 g, 79%) as a pale orange oil. 1H NMR (300 MHz, CDCl3) δ ppm 1.13 (d, J=6.45 Hz, 3H) 1.18-1.20 (m, 1H) 1.20-1.33 (m, 1H) 1.55 (br dd, J=13.34, 5.42 Hz, 1H) 1.94-2.18 (m, 4H) 2.22-2.49 (m, 1H) 2.49-2.69 (m, 1H) 3.81 (s, 3H) 4.26 (br s, 1H) 4.61-4.89 (m, 2H) 5.13-5.32 (m, 1H) 6.63-6.82 (m, 2H) 6.83-7.01 (m, 2H) 7.40 (d, J=8.79 Hz, 1H) 7.54-7.67 (m, 2H) 7.79-8.02 (m, 1H). MS (ESI, pos. ion) m/z 451 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:43][OH:44])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([C:32]5[CH:33]=[N:34][C:35]([O:38][CH2:39][CH3:40])=[CH:36][CH:37]=5)=[CH:30][CH:31]=[C:26]4[C:25]([C:41]#[N:42])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:47])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:43][OH:44])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([C:32]5[CH:33]=[N:34][C:35]([O:38][CH2:39][CH3:40])=[CH:36][CH:37]=5)=[CH:30][CH:31]=[C:26]4[C:25]([C:41]([NH2:42])=[O:47])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCO
Reactant: CCOc1ccc(-c2ccc3c(C#N)cn(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)c3n2)cn1
Solvent: O
Product: CCOc1ccc(-c2ccc3c(C(N)=O)cn(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)c3n2)cn1
Temperature: 45 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(6-ethoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (36 mg, 61.2 μmol) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (263 μg, 0.612 μmol, Eq: 0.01) were combined with ethanol (480 μl) and water (480 μl) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo. Mixture was diluted with acetonitrile and water and filtered. The resultant filtrate was lyophilized to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(6-ethoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (31 mg, 84%, [M+H]+ 607).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Reactant: Oc1ccccc1
Product: CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method 15, Step 2 to afford 4-(4-(N-methylsulfamoyl)phenoxy)benzene. 4-(4-(N-Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-(N-Methylsulfamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(4-N-methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.
Reaction SMILES: [CH:1](N1C(N)=CC(C2C=CN=CC=2)=N1)([CH3:3])[CH3:2].[NH2:16][C@@H:17]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:18]([NH:20][C:21]1[NH:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[CH:27]=2)[CH:22]=1)=[O:19]>>[NH2:16][C@@H:17]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=1)[C:18]([NH:20][C:21]1[N:25]([CH:1]([CH3:3])[CH3:2])[N:24]=[C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[CH:27]=2)[CH:22]=1)=[O:19]
Reactant: CC(C)n1nc(-c2ccncc2)cc1N
Reactant: CNc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)[nH]n2)ccn1
Product: CNc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)n(C(C)C)n2)ccn1
Yield: 75 %

Procedure:
This title compound was prepared starting from 29.A according the procedure described above for conversion of 18.0 to 18.E. The crude product was purified by flash chromatography on silica gel using 0-15% MeOH/CH2Cl2 for elution to provide 43.1 (510 mg, 75%). MS ESI (positive.) m/e: 397.1 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1.[Br:10]N1C(=O)CCC1=O>C(#N)C>[Br:10][C:8]1[S:7][C:6]([NH2:9])=[N:5][C:4]=1[CH2:3][O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCc1csc(N)n1
Solvent: CC#N
Product: COCc1nc(N)sc1Br
Reaction time: 2 h

Procedure:
4-Methoxymethyl-thiazol-2-ylamine (170 mg, 1.1 mmol) is dissolved in acetonitrile and N-bromosuccinimide. (231 mg, 1.3 mmol, 1.1 equiv.) was added in one portion. The mixture was stirred at room temp. for 2 hours, then filtered and the filtrate was evaporated. After purification on silica-gel with ethyl acetate/n-heptane as eluent, 260 mg of a light red solid were obtained: MS: m/e 222.8 (M+H).