Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:4]=1[CH3:14])=O.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=[O:24].[OH-].[Na+]>O>[CH3:8][C:6]1[NH:7][C:3]([CH:1]=[C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:15][C:16]2=[O:24])=[C:4]([CH3:14])[C:5]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: O=C1Cc2ccccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]c(C=C2C(=O)Nc3ccccc32)c(C)c1CCC(=O)O
Temperature: 50 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
Alternatively, a mixture of 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (10 g, 51 mmol), 2-oxindole (6.5 g, 49 mmol) and sodium hydroxide (40 g, 58 mmol) dissolved in 50 ml of water was stirred at 50° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate acidified with to pH 3 with 12 N hydrochloric acid. The solid which precipitated was collected by vacuum filtration, washed with 10 ml of water and dried under vacuum overnight. The crude solid slurry washed with hot ethanol twice. The solid was then collected by vacuum filtration, washed with 10 ml of ethanol and dried under vacuum to give 13.8 g (91%) of 3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid.
Reaction SMILES: [CH3:1][O-:2].[K+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7](F)[CH:6]=1>O1CCCC1>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:2][CH3:1])[CH:6]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A suspension of potassium methoxide (4.24 g, 60.0 mmol) in tetrahydrofuran (40 mL) was added in portions to a solution of 4-Bromo-2-fluorobenzonitrile (8.0 g, 40.0 mmol) in tetrahydrofuran (50 mL) at −50° C. After one hour, the dry ice bath was removed and the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 6 hours. The reaction mixture was poured onto water (250 mL) and the solid was collected by filtration to give 4-bromo-2-methoxybenzonitrile (7.85 g, 92%). 1H NMR (DMSO-d6) δ 3.94 (s, 3H), 7.32 (d, J=8.23 Hz, 1H), 7.15 (s, 1H), 7.69 (d, J=8.23 Hz, 1H).
Reaction SMILES: [C:1]([C:3]([CH3:12])([CH3:11])[CH:4]([OH:10])[CH2:5][C:6](OC)=[O:7])#[N:2].CO.[BH4-].[Na+].Cl>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]([CH3:12])([CH3:11])[CH:4]([OH:10])[CH2:5][CH2:6][OH:7])#[N:2]
Reactant: COC(=O)CC(O)C(C)(C)C#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C#N)C(O)CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
Optically active methyl 4-cyano-3-hydroxy-4-methylpentanoate (2 g, 11.7 mmol) was dissolved in THF (10 mL) and methanol (5 mL) was added. An aqueous sodium borohydride (885 mg, 23.4 mmol) solution (5 mL) was dropwise added at room temperature. The mixture was stirred at room temperature for 3 hr and then 2N aqueous hydrochloric acid solution (15 mL) was dropwise added at 0° C. Ethyl acetate (20 mL) was added and the mixture was stirred vigorously. An organic layer was extracted. Ethyl acetate (20 mL) was further added to the aqueous layer and the mixture was stirred vigorously. The organic layer was extracted again. This step was repeated three times and the obtained organic layer was dried over anhydrous magnesium sulfate (2 g) and concentrated under reduced pressure to give optically active 4-cyano-4-methyl-3-hydroxy-1-pentanol (1.12 g, 7.84 mmol) (yield relative to optically active methyl 4-cyano-3-hydroxy-4-methylpentanoate: 67%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:13]Br>C(O)(=O)C.O>[Br:13][C:7]1[C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[C:10]([O:11][CH3:12])=[CH:9][CH:8]=1
Reactant: COc1cccc(C(=O)O)c1F
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)c(C(=O)O)c1F
Temperature: 60 °C
Yield: 83.9 %

Procedure:
To the suspension of 2-fluoro-3-methoxybenzoic acid (20 g, 118 mmol) in Acetic Acid (100 mL) and water (100 mL) at RT, bromine (12.05 mL, 235 mmol) was added dropwise. The reaction mixture was heated for 1 h at 60° C. The reaction was then cooled to RT and white precipitate was filtered. The solid was washed with excess water and dried to give 6-bromo-2-fluoro-3-methoxybenzoic acid (24.68 g, 99 mmol) as a white solid.
Reaction SMILES: Br[C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:6][C:5]1[C:4]([CH3:10])=[CH:3][C:2]([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[C:8]([Cl:9])[CH:7]=1
Reactant: Cc1cc(Br)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c(Cl)cc1N
Temperature: 100 °C

Procedure:
To a mixture of 4-bromo-5-chloro-2-methylaniline (500 mg, 2.27 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (840 mg, 3.73 mmol) and sodium carbonate (2.52 g, 15.9 mmol) in DMF/H2O (20/5 mL) was added tetrakis(triphenylphosphine) palladium (0) (131 mg, 5 mol %). The reaction tube was sealed, the mixture was purged with N2 for 3 min and then heated at 100° C. under N2 for overnight. The reaction was cooled to room temperature and poured into saturated aqueous ammonia chloride solution. The crude reaction mixture was extracted with ethyl acetate (3×15 mL). The organic extracts were combined, washed with brine and concentrated. The crude product was purified with silica chromatography (80% ethyl acetate in hexanes) to afford tert-butyl 4-(4-amino-2-chloro-5-methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate as a yellow solid. This obtained product (322 mg, 1 mmol) was dissolved in dioxane/NMP (anhydrous, 4 mL, 3/1). To this solution was added tributyl(vinyl)stannane (380 mg, 1.2 mmol), cesium fluoride (304 mg, 2 mmol) and palladium bis(tri-tert-butyl-phosphine) (51 mg, 10 mol %). This mixture was purged with N2 for 3 minutes and then heated in a sealed tube at 120° C. for overnight. The mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was sequentially washed with saturated aqueous ammonium chloride and brine, and finally dried over sodium sulfate. After concentration, the crude product was purified via silica chromatography (10% ethyl acetate in hexanes) to afford tert-butyl 4-(4-amino-5-methyl-2-vinylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate as a light yellow oil; ESMS m/z 215.2 (M−Boc+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([CH:27]=[CH2:28])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([CH2:27][CH3:28])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cncc2cccc(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)c12
Agent: [Pd]
Solvent: CCO
Product: CCc1cncc2cccc(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 161.7 %

Procedure:
A solution of Intermediate 6 (120 mg) obtained in Example 9, Step A in ethanol (2 ml) is added with 10% palladium/activated carbon (90 mg, Wako Pure Chemical Industries), and the mixture is stirred at room temperature for 72 hours under a hydrogen gas atmosphere. The atmosphere is replaced with nitrogen gas, and then the insoluble matters are removed by filtration through Celite. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (195 mg (predictive yield)).
Reaction SMILES: [ClH:1].[SH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.CS[C:9]1[S:10][CH2:11][CH2:12][N:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[ClH:1].[SH:2][CH:3]1[CH2:6][N:5]([C:9]2[S:10][CH2:11][CH2:12][N:13]=2)[CH2:4]1
Reactant: SC1CNC1
Reactant: CSC1=NCCS1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: SC1CN(C2=NCCS2)C1
Yield: 76.4 %

Procedure:
To a solution of 22.7 mg of 3-mercaptoazetidine hydrochloride (12) obtained in the above Example 11 dissolved in 95% methanol (including 1 ml of water), there were added 26.6 mg of 2-(methylthio)-1,3-thiazoline and 5.2 mg of triphenylphosphine, and the resulting solution was subjected to heating and reflux for six hours. After the reaction was over, the solvent was evaporated in a vacuum, and the obtained residue was dissolved in a 0.1N hydrochloric acid, and the resulting mixture was washed with ethylacetate. The solvent in the obtained aqueous layer was evaporated in a vacuum, and the obtained residue was separated and purified by high performance liquid chromatography, and, thus, there was produced 29.1 mg (yield: 73.4%) of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine hydrochloride (8) in the form of colorless needle crystal.
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]1[CH:10]2[C:6]3([C:12]4[O:13][C:14](=O)[C:15]5[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=5[N:17]=4)[CH2:7][CH:8]([CH2:11][CH:4]1[CH2:5]3)[CH2:9]2>C1(C)C=CC=CC=1>[NH2:1][N:2]1[C:14](=[O:13])[C:15]2[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:17]=[C:12]1[C:6]12[CH2:7][CH:8]3[CH2:11][CH:4]([CH2:3][CH:10]1[CH2:9]3)[CH2:5]2
Reactant: NN
Reactant: O=c1oc(C23CC4CC(CC2C4)C3)nc2ccccc12
Solvent: Cc1ccccc1
Product: Nn1c(C23CC4CC(CC2C4)C3)nc2ccccc2c1=O
Temperature: 22.5 °C
Reaction time: 10 h
Yield: 99.9 %

Procedure:
Anhydrous hydrazine (0.30 mL, 9.56 mmol) was added to a solution of the product of Example 2A (0.79 g, 2.81 mmol) in toluene (10 mL). The solution was stirred at 20-25° C. for 10 hours, then diluted with toluene (15 mL) and heated at reflux under a Dean-Stark trap for 33 hours. The solution was cooled to room temperature and concentrated under vacuum to leave a white solid residue. The residue was purified by flash chromatography (silica gel, eluted with hexanes-EtOAc 70:30-50:50) to provide the title compound as a white solid (0.79 g, 72% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.64-1.78 (m, 4H), 2.05 (dd, J=10.5, 2.7 Hz, 2H), 2.08-2.18 (m, 2H), 2.40 (br s, 2H), 2.45-2.55 (m, 2H), 2.96 (t, J=6.6 Hz, 1H), 4.73 (s, 2H), 7.44 (ddd, J=8.1, 6.4, 1.7 Hz, 1H), 7.66-7.77 (m, 2H), 8.24 (ddd, J=8.0, 1.4, 0.7 Hz, 1H); MS (DCI) m/z 282 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]([CH2:28][C:29]#[C:30][CH3:31])[C:17](=[O:27])[N:18]3CCC#N)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].O.Cl>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]([CH2:28][C:29]#[C:30][CH3:31])[C:17](=[O:27])[NH:18]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCn1c(=O)n(CCC#N)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC#CCn1c(=O)[nH]c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 117.1 %

Procedure:
4-[7-(2-Butynyl)-9-(2-cyano-ethyl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazine-1-carboxylic acid t-butyl ester (1.22 g) was dissolved in ethanol (20 mL). Sodium hydride (60%, in oil) (344 mg) was then added slowly to this solution. After stirring the reaction solution at room temperature for 72 hours, water (50 mL) and 1 N hydrochloric acid (10 mL) were added to the reaction solution, and this was extracted using ethyl acetate. The obtained organic layer was washed with water and saturated brine. The obtained organic layer was then dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.25 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:5][CH:4]=1)#[N:2].CN(C)C=O.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.[CH:39]1[CH:44]=[CH:43][C:42]([CH:45]([NH2:50])[CH2:46][C:47]([OH:49])=[O:48])=[CH:41][CH:40]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:50][CH:45]([C:42]2[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=2)[CH2:46][C:47]([OH:49])=[O:48])=[O:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CCCCC(=O)O)cc1
Reactant: NC(CC(=O)O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#Cc1ccc(CCCCC(=O)NC(CC(=O)O)c2ccccc2)cc1
Reaction time: 5 h
Yield: 49.2 %

Procedure:
To a solution of 5-(p-cyanophenyl)pentanoic acid (1.00g, 4.93 mmol), dimethylformamide (10 mL), and pyridine (2 mL) was added N,N'-disuccinimidylcarbonate (1.24 g, 4.85 mmol) and 4-dimethylaminopyridine (60 mg, 0.493 mmol) under an argon atmosphere at 23° C. After 5 h, DL-3-amino-3-phenylpropionic acid (0.814 g, 4.93 mmol) was added as a solid, followed immediately by N,N'-diisopropylethyl amine (0.627 g, 4.85 mmol). After 20 h at 23° C., the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (300 mL), washed with KHSO4 (2×50 mL), washed with brine (1×50 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (2 liters ethyl acetate: chloroform:acetic acid 50:50:0.5 followed by 2 liters of ethyl acetate:methanol:acetic acid 89:10:1) to afford 850 mg (50%) of the title compound (compound 6 of Scheme D). The product was verified by C NMR (CDCl3) delta 24.9, 29.9, 35.3, 35.7, 40.5, 49.7, 109.1, 118.9, 126.1, 127.4, 128.5, 129.0, 131.9, 140.5, 147.8, 173.4, 176.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].[F:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([F:39])[C:36]=1[CH2:37]O)[O:30][CH2:31][C:32]#[N:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:37][C:36]3[C:35]([F:39])=[CH:34][C:29]([O:30][CH2:31][C:32]#[N:33])=[CH:28][C:27]=3[F:26])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: N#CCOc1cc(F)c(CO)c(F)c1
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCC#N)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Yield: 38.5 %

Procedure:
In a similar manner 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (227 mg, 0.60 mmol), 2-(3,5-difluoro-4-(hydroxymethyl)phenoxy)acetonitrile (156 mg, 0.78 mmol), PPh3 (173 mg, 0.66 mmol) and DIAD (137 μL, 0.66 mmol) in THF (0.8 mL) were reacted, processed and purified by flash chromatography (80% EtOAc/Hex) to provide 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)acetonitrile (129 mg, 39%). MS (EI) m/z 558.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].O1CCCC1.B>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Br)c(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-bromo-5-nitrobenzoic acid (5 g, 20 mmol) at 0° C. was added borane tetrahydrofuran complex (1M in THF; 200 mL, 200 mmol), and the reaction was stirred at room temperature overnight. The mixture was quenched with 1N aqueous HCl to give the title compound.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[N:10]=[CH:9]1)(OC(C)(C)C)=O.Br[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH2:19][N:17]([CH2:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[C:15]2[CH:14]=[CH:13][C:12]3[NH:8][CH:9]=[N:10][C:11]=3[CH:16]=2)=[CH:21][CH:22]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)n1cnc2cc(N)ccc21
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(CN(Cc2ccc(C#N)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N1-Boc-benzimidazol-5-amine (233 mg; 1 mmol; 1 eq.), 4-bromomethylbenzonitrile (490 mg; 2.5 mmol; 2.5 eq.) and K2CO3 (345 mg; 2.5 mmol; 2.5 eq.) according to method 4; Yield: 0.176 g (48.4%); MS m/z: 364.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.80 (s, 4H); 6.66-6.68 (m, 2H); 7.34 (d, 1H, 3J=8.7 Hz); 7.47 (d, 4H, 3J=8.3 Hz); 7.78 (d, 4H, 3J=8.3 Hz); 7.92 (s, 1H); 11.95 (br s, 1H); HPLC (METHOD [A]): rt 13.50 min (100%)
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[NH:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[F:24][C:23]([F:26])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([C:16]2[S:37][C:2]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:3]=3[N:15]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(NC(=O)c2ccc(C(F)(F)F)cc2)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C1
Yield: 91 %

Procedure:
0.40 g (1.0 mmol) of t-butyl 4-oxo-3-{[4-(trifluoromethyl)benzoyl]amino}piperidin-1-carboxylate (product of step 2) was dissolved in 0.47 g (1.2 mmol) of Lawesson's reagent, and the resulting solution was stirred under refluxing of 30 mL of toluene for 4 hours and distilled off under reduced pressure. The residue was purified by column chromatography to give 0.30 g (0.91 mmol) of the title compound in a total yield of 91%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:14])[CH3:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Na+].[I-:16].Cl>CC#N>[I:16][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:14])[CH3:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)(C)c1ccc(Cl)nc1
Reactant: [I-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)NC(C)(C)c1ccc(I)nc1

Procedure:
To a solution of N-(2-(6-chloropyridin-3-yl)propan-2-yl)acetamide, 33-c, (25 g, 0.12 mol) in MeCN (400 ml) was added NaI (353 g, 2.35 mol) and concentrated HCl (48 ml, 0.59 mol). The reaction mixture was then refluxed for 60 hours. Product conversion was monitored by LC-MS. The reaction mixture was filtered and the cake was washed with MeCN. The filtrate was concentrated under vacuo and the residue was diluted with ethyl acetate, washed with saturated aqueous Na2S203 and brine, dried and concentrated to give the product, 33-d, as a white solid (22 g, 61%).
Reaction SMILES: N#N.[NH2:3][C:4]1[NH:9][C:8]2[NH:10][CH:11]=[C:12]([CH2:13][CH2:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[C:7]=2[C:6](=[O:24])[N:5]=1.CN1CCOCC1.ClC1C(OC)=NN=NC=1OC.[CH2:43]([O:45][C:46](=[O:56])[C@H:47]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[NH2:48])[CH3:44].[C:57]1([CH3:67])[CH:62]=[CH:61][C:60]([S:63]([OH:66])(=[O:65])=[O:64])=[CH:59][CH:58]=1>C(Cl)Cl.O.C(O)(=O)C.C(#N)C.CN(C)C=O>[C:57]1([CH3:67])[CH:58]=[CH:59][C:60]([S:63]([OH:66])(=[O:64])=[O:65])=[CH:61][CH:62]=1.[CH2:43]([O:45][C:46](=[O:56])[C@H:47]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[NH:48][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([CH2:14][CH2:13][C:12]2[C:7]3[C:6](=[O:24])[N:5]=[C:4]([NH2:3])[NH:9][C:8]=3[NH:10][CH:11]=2)=[CH:16][CH:17]=1)[CH3:44]
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)O)cc3)c[nH]c2[nH]1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: COc1nnnc(OC)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2c[nH]c3[nH]c(N)nc(=O)c23)cc1)C(=O)OCC
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
A 50 mL flask with mechanical stirrer, thermometer and N2 adapter was charged with 1.93 g (corrected for assay) of 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid (2.5 g, potency 77%) and 13.5 mL of dimethylformamide. The slurry was stirred 15 minutes and 1.94 grams of N-methylmorpholine (2.9 eq) was added. The mixture was cooled to 5° C. with an ice/water bath and chlorodimethoxytriazine (1.46 grams, 1.28 eq.) was added all at once. The mixture was stirred 40 minutes before L-glutamic acid diethyl ester (1.99 g, 1.28 eq) was added all at once. The reaction was allowed to warm to ambient temperature. The reaction was monitored by HPLC (reverse phase, gradient 20% to 46% acetonitrile:0.5% acetic acid buffer) and was complete in 1 hour at 23° C. The reaction mixture was transferred to a 250 mL Erlenmeyer flask containing 36 mL of deionized water and 18 mL of methylene chloride. The reaction flask was rinsed with 18 mL of methylene chloride which was added to the Erlenmeyer flask. The mixture was stirred 15 minutes and the layers were allowed to separate. The methylene chloride layer was concentrated from 46 grams to 13 grams using a rotary evaporator at reduced pressure at a bath temperature at 45° C. The concentrate was diluted with 55 mL of 3A alcohol, and concentrated again to 10 grams to remove methylene chloride. The concentrate was diluted to a total volume of 60 mL with 3A alcohol and the resulting solution was heated to 70° C. to 75° C. p-Toluenesulfonic acid (3.16 g, 2.57 eq.) dissolved in 55 mL of 3A alcohol were added over 30-90 minutes. The resulting slurry was refluxed for an hour. The slurry was cooled to ambient temperature and filtered using a 7 cm Buchner funnel. The wet cake was washed with 25 mL ethanol and dried in vacuo at 50° C. overnight to yield 3.66 grams of the title compound. Potency 95%
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23](C(OC(C)(C)C)=O)[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[N:22]1
Reactant: CC(C)(C)OC(=O)n1nc(Cl)c2ccccc21
Reactant: CN1CCC(c2c[nH]c3ccc(B(O)O)cc23)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CCC(c2c[nH]c3ccc(-c4n[nH]c5ccccc45)cc23)CC1

Procedure:
The title compound was prepared by the procedure of Example 14, beginning with 3-(1-methylpiperidin-4-yl)-1H-indole-5-boronic acid (0.250 g, 0.97 mmol), 3-chloro-1-(tert-butoxycarbonyl)indazole (0.230 g, 0.92 mmol), Pd(dppf)Cl2 CH2Cl2 (0.023 g, 0.028 mmol), and 2M aqueous sodium carbonate solution (2 mL) in 6 mL of tetrahydrofuran to give 0.197 g (47%) of 5-(3-[1-tert-butoxycarbonyl]indazolyl)-3-(1-methylpiperidin-4-yl)-1H-indole as an amorphous tan solid, which was dissolved in 3 mL of tetrahydrofuran, followed by the addition of sodium methoxide (0.074 g, 1.38 mmol) in 1 mL of methanol, and the mixture was allowed to stir at room temperature for 0.5 hours, followed by extractive work-up and silica gel chromatography to give 0.062 g (54%) of the title compound as an amorphous off-white solid. FDMS m/e=330 (M+). EA calculated for C21H22N4.½ H2O C, 74.31; H, 6.83; N, 16.50. Found: C, 74.52; H, 6.96; N, 15.95.