Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:27][CH:28]([F:31])[CH2:29]I.C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[N:24]([CH2:29][CH:28]([F:31])[F:27])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Reactant: FC(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1CC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (100 mg, 0.271 mmol) was suspended in acetonitrile (5 ml). 1,1-Difluoro-2-iodoethane (0.053 ml, 116 mg) and cesium carbonate (124 mg, 0.380 mmol) were added and the resulting mixture was stirred overnight at RT. Next day 2 ml of THF and 50 μl of 1,1-difluoro-2-iodoethane was added and the stirring was continued for three more nights. Another 0.2 ml of 1,1-difluoro-2-iodoethane was added and the reaction mixture was stirred overnight. The reaction mixture was evaporated. 3 ml of N,N-dimethyl formamide was added and the mixture filtered. Filtrate was purified with LC/MS-trigger. Yield 27.4%. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 2.44 (s, 3H), 4.19-4.33 (m, 3H), 4.39 (dd, 1H), 4.51-4.62 (m, 1H), 5.82-6.13 (m, 1H), 6.61 (d, 1H), 7.49 (d, 1H), 7.52 (s, 1H), 7.64-7.71 (m, 2H), 7.85 (dd, 1H), 8.00 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1CS(N)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][N:14]2[CH:15]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:40]5[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[C:38]([NH:8][S:25]([CH3:28])(=[O:27])=[O:26])[CH:39]=5)[CH:3]=4)[N:8]([S:25]([C:28]4[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=4)(=[O:26])=[O:27])[CH:9]=3)[CH:12]=[N:13]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccc(F)cc4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(CCc4ccc(F)cc4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 29.41 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(4-fluorophenethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (70 mg, 0.129 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (Intermediate 17) (50 mg, 0.155 mmol) using sodium carbonate (41 mg, 0.387 mmol) and Pd(PPh3)2Cl2 (4 mg, 0.0064 mmol) in DME/water (10/1 ml). This afforded 25 mg (29.41% yield) after purification by column (Silica gel 60/120) using 30% ethyl acetate in hexane as eluent. MS: m/z=660.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:10]#[N:11])=[C:4]([NH:8][CH3:9])[S:5][C:6]=1[CH3:7].[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:10]([C:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][C:4]=1[N:8]([CH3:9])[C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:22])#[N:11]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CNc1sc(C)c(C)c1C#N
Product: Cc1sc(N(C)C(=O)NC(=O)c2ccccc2)c(C#N)c1C

Procedure:
Prepared as in Example 1a from 4,5-dimethyl-2-(methylamino)thiophene-3-carbonitrile (Example 22b) and benzoyl isocyanate. MS 314 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH:9]=S)=[CH:7][N:6]=[C:5](C)[N:4]=1.[NH2:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1.C1(C)C=C[C:23]([S:26](O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][CH2:9][C:8]1[C:3]([NH:2][CH3:1])=[N:4][C:5]([S:26][CH3:23])=[N:6][CH:7]=1
Reactant: Cc1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CNc1nc(C)ncc1C=S
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CNc1nc(SC)ncc1CNc1ccccc1C
Temperature: 70 °C
Yield: 230.8 %

Procedure:
A mixture of 300 mg (1.6 mmol) of 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde, 0.20 ml (1.8 mmol) of o-toluidine and 59 mg (0.3 mmol) of 4-toluenesulfonic acid in 50 ml of toluene was heated at reflux with azeotropic removal of water for 18 hours. The mixture was cooled and evaporated. The residue was dissolved in 40 ml of ethanol and heated to 70° C. 300 mg (8 mmol) of sodium borohydride were added cautiously and the mixture was heated at 70° C. for 2 hours. A further 300 mg (0.8 mmol) of sodium borohydride were added cautiously and the heating was continued for a further hour. The mixture was cooled and then evaporated. The residue was partitioned between 50 ml of 2M aqueous sodium hydroxide solution and 50 ml of ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel using diethyl ether/hexane (1:1) for the elution. Product-containing fractions were combined and evaporated to give 190 mg (43%) of 5-(2-methylphenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine as a white solid. [Mass spectrum (ESI) MH+ =275].
Reaction SMILES: [CH3:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]1.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.[Br:35]N1C(=O)CCC1=O.ClC1C=CC=CC=1>O>[Br:35][CH2:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]1
Reactant: CSc1cccc(-n2nnn(C)c2=O)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: O
Solvent: Clc1ccccc1
Product: CSc1cccc(-n2nnn(C)c2=O)c1CBr
Yield: 20 %

Procedure:
To a mixture of 1-(2-methyl-3-methylsulfanylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 15) 1.50 g, 1,1′-azobis(cyclohexane-1-carbonitrile) 0.620 g, N-bromosuccinimide 1.30 g and chlorobenzene 15 ml was stirred with heating under reflux for four hours. After cooling the mixture, to the reaction solutions was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(2-bromomethyl-3-methylthiophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 0.400 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:35])[C:33]=1[F:34])[C:28](Cl)=[O:29]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:28](=[O:29])[C:27]5[CH:31]=[C:32]([F:35])[C:33]([F:34])=[C:25]([F:24])[CH:26]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cc(F)c(F)c(F)c4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3,4,5-trifluoro-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.80 mmol) and 3,4,5-trifluorobenzoyl chloride (116 μl, 0.88 mmol). The title compound was obtained as white powder (86 mg, 23%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([O:11][CH2:12][C:13]1[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I>C1COCC1>[CH2:1]([N:8]([CH3:30])[C:9]([O:11][CH2:12][C:13]1[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)c1sc(COC(=O)NCc2ccccc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sc(COC(=O)N(C)Cc2ccccc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.2 %

Procedure:
To a solution of 170 (0.620 g, 1.625 mmol) in 10 mL of THF was added NaH (0.098 g, 2.438 mmol) and stirred at room temperature for 20 min. Then MeI (0.5 ml, 8.00 mmol) was added and stirred for an additional 2 hours at 50° C. The reaction mixture was cooled down at room temperature, quenched with 2 mL of MeOH, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by ISCO (40 g column, 5%-30% ethyl acetate in hexanes) to yield in 53% (342 mg) compound 171 as colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[C:3]([N:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]3)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=2[CH3:8])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccccc3)cc2)c1N1CCC(C)(C)CC1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.514 g, 1.129 mmol), (4-(benzyloxy)phenyl)boronic acid (0.515 g, 2.257 mmol) and 2M Na2CO3 (1.693 ml, 3.39 mmol) in DMF (10 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (0.065 g, 0.056 mmol) was added, degassed for 5 min and placed in a pre-heated oil bath at 110° C. After 2 h, cooled, diluted with ether (50 mL), washed with water (4×10 mL), brine (10 mL), dried (MgSO4), filtered, concentrated and purified by flash chromatography using 10, 20 and 30% EtOAc/Hex to afford (S)-ethyl 2-(5-(4-(benzyloxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.4345 g, 0.778 mmol, 68.9% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.48-7.51 (m, 2H), 7.40-7.45 (m, 2H), 7.34-7.38 (m, 1H), 7.16-7.20 (m, 1H), 7.04-7.10 (m, 3H), 6.09 (s, 1H), 5.13-5.20 (m, 2H), 4.26 (qd, J=7.1, 10.7 Hz, 1H), 4.17 (qd, J=7.1, 10.7 Hz, 1H), 3.18 (d, J=11.8 Hz, 1H), 2.87 (t, J=11.8 Hz, 1H), 2.27 (d, J=11.8 Hz, 1H), 2.21 (s, 3H), 2.05 (t, J=11.7 Hz, 1H), 1.56 (dt, J=4.6, 12.9 Hz, 2H), 1.32-1.41 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.18 (br. s., 1H), 1.05-1.11 (m, 1H), 0.91 (s, 3H), 0.64 (s, 3H). LCMS (M+H) 559.5.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl.CCOCC>O1CCOCC1>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccc(N3CCOCC3)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1cc(OC[C@@H]2CCCN2)ccc1Cc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a 20 mL vial which contained a solution of (S)-2-[4-(4-morpholin-4-yl-benzyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.2 mmol) in dioxane (1 mL) was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. the resulting solid was filtered out and dried under vacuo to yield the title product (70 mg, 80%); LCMS; 90%, ESI+ Calcd: 352.5, found m/z: 353.7 (M+1); 1H NMR (400 MHz, DMSO-d6); δ 1.66-1.76 (m, 1H), 1.84-2.02 (m, 2H), 2.04-2.14 (m, 1H), 3.05-3.24 (m, 4H), 3.73-4.12 (m, 10H), 4.19 (dd, J1=10.8 Hz, J2=3.6 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 7.20 (m, 6H):
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[CH:7]1)[CH2:3][OH:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[CH:7]1)[CH:3]=[O:4]
Reactant: CC(C)(CO)Cn1cnc(-c2cccnc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C=O)Cn1cnc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propanol (11 mg) in CH2Cl2 was added Dess-Martin periodinane (41 mg) and the resulting solution was stirred at room temperature for 15 minutes. Saturated NaHCO3 was added, the aqueous layer was extracted with CHCl3, the combined organic layers were washed with brine, dired over Na2SO4 and evaporated in vacuo to afford the title compound as a slightly yellow oil.
Reaction SMILES: [OH-].[Na+:2].[C:3]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[N:34]/[O:35][CH3:36])/[CH2:12][O:13][C:14]2[CH:33]=[CH:32][C:17]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:28][CH:27]4[C:29]([OH:31])=[O:30])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)#[N:4]>>[C:3]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[N:34]/[O:35][CH3:36])/[CH2:12][O:13][C:14]2[CH:33]=[CH:32][C:17]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:28][CH:27]4[C:29]([O-:31])=[O:30])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)#[N:4].[Na+:2]
Reactant: CO/N=C(\COc1ccc(COc2ccc(C3CC3C(=O)O)cc2)cc1)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO/N=C(\COc1ccc(COc2ccc(C3CC3C(=O)[O-])cc2)cc1)c1ccc(C#N)cc1
Yield: 72.4 %

Procedure:
Compound 51 was synthesized from sodium hydroxide (0.04 g, 0.96 mmol) and 2-{4-[(4-{[(2Z)-2-(4-cyanophenyl)-2-(methoxyimino)ethyl]oxy}benzyl)oxy]phenyl}cyclopropanecarboxylic acid (0.22 g, 0.48 mmol) by following the procedure described in scheme 12 (0.15 g, yield: 72.40%); Purity: 90.60%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21](Cl)[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:29]=3[O:28][CH3:27])[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc(Cl)n1
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CNc2nc(C)cc(NCC3CCN(C(=O)OCc4ccccc4)CC3)n2)c(OC)c1
Temperature: 25 °C

Procedure:
A stirred solution of 4-[(2-chloro-6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 57, 0.5 g, 1.33 mmol) in 2,4-dimethoxybenzylamine (1.00 mL, 6.67 mmol) was heated at 100° C. for 6 h, then cooled to rt and purified by silica gel chromatography [1-10 (10% NH4OH in MeOH)/99-90 CH2Cl2)] to give 4-{[2-(2,4-dimethoxy-benzylamino)-6-methyl-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):506.46
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([OH:11])=[C:5](O)[C:6]([CH3:9])=[N:7][CH:8]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=1.[C:22](=[O:25])([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][O:11][C:4]1[C:3]([CH2:2][OH:1])=[CH:8][N:7]=[C:6]([CH3:9])[C:5]=1[O:25][CH2:22][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[C:20]#[N:21])#[N:21]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1ncc(CO)c(O)c1O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ncc(CO)c(OCc2cccc(C#N)c2)c1OCc1cccc(C#N)c1
Yield: 23.2 %

Procedure:
A mixture of 5-hydroxymethyl-2-methyl-pyridine-3,4-diol (4.0 g, 35.8 mmol), α-bromo-m-tolunitrile (8.8 g, 44.8 mmol) and cesium carbonate (15.6 g, 47.8 mmol) was stirred in DMF (20 mL) for 150 minutes. The reaction mixture was evaporated to dryness, and the crude product purified by column chromatography on silica gel using a gradient of dichloromethane:methyl alcohol (1:0 to 19:1) as eluant to give product 3-[4-(3-cyano-benzyloxy)-5-hydroxymethyl-2-methyl-pyridin-3-yloxymethyl]-benzonitrile (161) (2 g, 20% yield).
Reaction SMILES: C[O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=[C:5]([CH3:21])[N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.C(#N)C>O>[CH3:21][C:5]1[NH:4][C:3](=[O:2])[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]=1[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]
Reactant: COc1nc(C)c(-c2cccc(C#N)c2)c2c1CCCC2
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1[nH]c(=O)c2c(c1-c1cccc(C#N)c1)CCCC2
Yield: 85.1 %

Procedure:
A stirred mixture of 3-(1-methoxy-3-methyl-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (56 mg, 0.2 mmol), sodium iodide (60 mg, 0.4 mmol), chlorotrimethylsilane (51 μL, 0.4 mL) and acetonitrile (3 mL) is heated at reflux temperature for 1.5 hr. The cooled reaction mixture is diluted with water (5 mL) and the solids are collected by filtration to give 3-(3-methyl-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl)benzonitrile (45 mg, 87%) as a beige solid. LC/MS: MS m/e=265 (M+H); RT 2.97 min.
Reaction SMILES: C(OC([NH:7][CH2:8][CH:9]([C:18]1[CH2:24][C@H:23]2[N:20]([C:21](=[O:28])[C@@H:22]2[C@H](O)C)[C:19]=1[C:29]([O:31]CC=C)=[O:30])[CH2:10][NH:11][C:12](OCC=C)=O)=O)C=C.[C:35]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:36]=1.[C:54]([OH:57])(=[O:56])[CH3:55].C([SnH](CCCC)CCCC)CCC>O1CCCC1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH2:35]([O:56][C:54]([CH2:55][C:12]1[NH:11][CH2:10][CH:9]([C:18]2[CH2:24][CH:23]3[N:20]([C:21](=[O:28])[CH2:22]3)[C:19]=2[C:29]([OH:31])=[O:30])[CH2:8][N:7]=1)=[O:57])[CH3:36]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=CCOC(=O)NCC(CNC(=O)OCC=C)C1=C(C(=O)OCC=C)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Reactant: CC(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC1=NCC(C2=C(C(=O)O)N3C(=O)CC3C2)CN1
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
To a solution of allyl (5R,6S)-3-[2-allyloxycarbonylamino-1-(N-allyloxycarbonylaminomethyl)ethyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (858 mg) in tetrahydrofuran (12 ml) and ethanol (4 ml) were added successively triphenylphosphine (0.19 g), acetic acid (0.10 ml) and tetrakis(triphenylphosphine)palladium (0.16 g) at room temperature under nitrogen. The temperature was raised to 30° C. and after all components were dissolved, tributyltin hydride (1.94 ml) was added dropwise. After stirring for 15 minutes at room temperature, ethyl acetate (50 ml) was added. After 30 minutes, the precipitate was filtrated and washed with ethyl acetate and dichloromethane under nitrogen, and dissolved in buffer solution (68 ml, pH 6.86). Ethyl 2-ethoxycarbonylacetoimidate hydrochloride (599 mg) was added to the solution at pH 8.5. After stirring for 30 minutes at pH 8.5. The mixture was stirred for 30 minutes at pH 7. After the starting material disappeared, the reaction mixture was washed five times with ethyl acetate-tetrahydrofuran (7:3, V/V, 70 ml) at pH 7. The aqueous layer was evaporated and the residue was purified by Diaion HP-20 column chromatography (eluent:acetonitrile-water=4:96, V/V) and silica gel column chlomatorgaphy (eluent:acetonitrile-water=100:00-85:15, V/V) to give (5R,6S)-6-[1R)-1-hydroxyethyl]-3-[2-(ethoxycarbonylmethyl)-3,4,5,6-tetrahydropyrimidin-5-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (56.4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=[N:12]O)[S:10][C:3]=12.CCOC(C)=O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]#[N:12])[S:10][C:3]=12
Reactant: ON=Cc1cc2nccc(Cl)c2s1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc2nccc(Cl)c2s1
Reaction time: 48 h
Yield: 71.1 %

Procedure:
A solution of the oxime 125 (100 mg, 0.47 mmol) in acetic anhydride (2 ml) was set to reflux for 3 h and then at 90° C. for 48 h. The acetic anhydride was removed under reduced pressure and the residue was partitioned between a cold aqueous K2CO3 solution and EtOAc. The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness and remained solid was purified by column chromatography, eluents 25% EtOAc/hexane (25:75), then 100% EtOAc, to afford the title compound 126 (65 mg, 71% yield). MS (m/z) 195.1/197.1 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20](S(C)(=O)=O)[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.C[N:28]1C(C2SC3N=CN=C(S(C)(=O)=O)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:28])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: Cn1cnc(-c2cccc(I)c2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1cnc(-c2cccc(I)c2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[4-(3-Iodophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 55) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). White solid (136 mg, 78%);
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][C:13]([CH3:20])=[CH:12]2>CCOCC>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][C:13]([CH3:20])=[C:12]2[C:1](=[O:5])[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc2cc(C)[nH]c2cc1OC
Solvent: CCOCC
Product: COc1cc2[nH]c(C)c(C(=O)C(=O)Cl)c2cc1OC
Reaction time: 0.17 h

Procedure:
8.7 g of oxalyl chloride are added dropwise to a stirring solution, cooled to about -10° C., of 12.0 g of 5,6-dimethoxy-2-methylindole in 250 ml of ether. After addition is complete, the mixture is stirred for 10 minutes, producing a bright orange precipitate of 5,6-dimethoxy-2-methyl-3-indole glyoxylyl chloride which is immediately used for the next step.