Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]1([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[S:47][C:46](Cl)=[N:45][CH:44]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C.O>[C:33]1([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[S:47][C:46]([C:20]3[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:32])=[CH:22][CH:21]=3)=[N:45][CH:44]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Nc1ccccc1)OCc1cnc(Cl)s1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(COC(=O)Nc3ccccc3)s2)cc1

Procedure:
Using an analogous procedure to that described in Method 4, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with (2-chloro-1,3-thiazol-5-yl)methyl N-phenylcarbamate (136 mg, 0.5 mmol). The crude residue stirred in ethyl acetate/water for 16 hours before being filtered, and the aqueous removed using a Varian Chem Elut Column (CE1010). The resulting solution was concentrated and purified by flash chromatography on silica, eluting with methanol/dichloromethane (0-30%) to give the title compound; Mass Spectrum: M+H+-Boc 489.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:25]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)=[CH:24][C:21]=2[C:22]#[N:23])[CH2:14][CH2:13]1>ClCCl>[C:1]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:25]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)=[CH:24][C:21]=2[C:22]#[N:23])[CH2:14][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC1(C)OB(c2ccc(OCC3CCNCC3)c(C#N)c2)OC1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C#N)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 134.6 %

Procedure:
Glacial acetic acid (2.1 g, 0.035 mol), triethylamine (3.5 g, 0.035 mol) and 1-propanephosphonic anhydride (60% w/w in ethyl acetate) (11 ml, 0.0174 mol) are added to a solution of 2-(piperidin-4-ylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (4.0 g, 0.0116 mol) in dichloromethane (40 ml) at 0° C. under nitrogen. The reaction is stirred at room temperature for 15 h. The solution is evaporated and poured into water (200 ml). The mixture is extracted with dichloromethane (100 ml×2) and evaporated in a rotary evaporator. The crude product is purified by chromatography, giving 6.0 g of the desired product as colourless oil;
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]([C:13]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC(C)C)=O)=C(C)[NH:17][C:18]=1[CH3:19])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[O:1]([CH2:8][CH2:9][O:10][C:11](=[O:12])/[CH:13]=[C:18](\[NH2:17])/[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C(C(=O)OCCOc2ccccc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCCOc1ccccc1
Yield: 70 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid isopropyl ester and 75 mmols of β-aminocrotonic acid 2-phenoxyethyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 2-phenoxyethyl ester of melting point 110° C (from ethanol).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15]([C:17]1[S:21][CH:20]=[N:19][CH:18]=1)=[O:16]>C(Cl)Cl>[CH3:7][N:6]1[C:2]([C:15]([C:17]2[S:21][CH:20]=[N:19][CH:18]=2)=[O:16])=[CH:3][N:4]=[CH:5]1
Reactant: CON(C)C(=O)c1cncs1
Reactant: Cn1cncc1Br
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1cncs1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-1-methyl-1H-imidazole (1.14 g, 7.11 mmol) in DCM was added ethyl magnesium bromide (2.34 mL, 7.11 mmol; 3.0 M in diethyl ether) dropwise over a 10 minute period. The resulting pale yellow solution was stirred at room temperature for 15 minutes, cooled in an ice bath to 0° C. and N-methoxy-N-methylthiazole-5-carboxamide (1.02 g, 5.92 mmol, Intermediate 11: step a) dissolved in DCM (3 mL) was added dropwise. The cold bath was removed and the reaction mixture stirred at room temperature for 48 hours. To the resulting yellow suspension was added water followed by 6 M aqueous HCl to a neutral pH (pH=6-7). The aqueous mixture was extracted with DCM, dried over Na2SO4, filtered and concentrated. Et2O was added and the mixture sonicated. The precipitate was collected by filtration and dried to provide the title compound as a tan solid.
Reaction SMILES: ClC1C=C(N2CCN(CCC3C=CC=CC=3)CC2)C=CC=1OCOC.[Cl:26][C:27]1[CH:28]=[C:29]([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][C:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:45])[CH2:39][CH2:38]2)[CH:30]=[CH:31][C:32]=1[O:33]COC>>[Cl:26][C:27]1[CH:28]=[C:29]([N:37]2[CH2:38][CH2:39][N:40]([CH2:43][C:44]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)=[O:45])[CH2:41][CH2:42]2)[CH:30]=[CH:31][C:32]=1[OH:33]
Reactant: COCOc1ccc(N2CCN(CC(=O)c3ccccc3)CC2)cc1Cl
Agent: COCOc1ccc(N2CCN(CCc3ccccc3)CC2)cc1Cl
Product: O=C(CN1CCN(c2ccc(O)c(Cl)c2)CC1)c1ccccc1
Yield: 13.3 %

Procedure:
Production Example 28 was repeated except that 1-(3-chloro-4-methoxymethoxyphenyl)-4-phenethylpiperazine was replaced with 2-[4-(3-chloro-4-methoxymethoxyphenyl)piperazin-1-yl]-1-phenylethan-1-one (221 mg). Thus obtained crude product was purified on TLC (developer, chloroform: acetone=6:1) to provide 2-[4-(3-chloro-4-hydroxyphenyl)piperazin-1-yl]-1-phenylethan-1-one (26 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][C:6]2[CH2:7][C:8](=[O:26])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:25])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21](N)=[CH:20][CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.N([O-])=O.[Na+].[ClH:35]>>[ClH:35].[ClH:35].[CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][C:6]2[CH2:7][C:8](=[O:26])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:25])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:35])=[CH:20][CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1ccc(N)cc1)CC2
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1ccc(Cl)cc1)CC2
Temperature: 55 °C

Procedure:
1.01 gm (0.00245 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2{4-amino-phenyl}-ethyl)-amino]-propane were dissolved in 5 ml of semi-concentrated hydrochloric acid, and the solution was diazotized with 0.17 gm (0.00245 of sodium nitrite. Subsequently, the solution was stirred at 55° C. until no more nitrogen escaped. The solution was made weakly alkline and extracted with methylene chloride. After drying and evaporating in vacuo, the residueal oil was purified on aluminum oxide (200 gm, neutral, activity II; eluant: methylene chloride +2% of ethanol) and the dihydrochloride was precipitated from acetone with ethereal hydrochloric acid.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([OH:15])=O)[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.[NH:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].Cl.CN(C=O)C>C1COCC1>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([N:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])=[O:15])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.8 %

Procedure:
BOC-Thr(Bzl)-OH (32.88 g, 0.15 M) was dissolved in THF (100 ml). HOBT (20.94 g, 0.155 M) and H-Pro-OBzl.HCl (37.47 g, 0.155 M) were added thereto, and DMF (200 ml) was added to prepare a solution. WSCI (28.37 ml, 0.155 M) was added dropwise during 10 minutes while cooling with a freezing mixture, then the mixture was stirred at room temperature overnight. The solvent was distilled off in vacuo. Ethyl acetate (500 ml) was added to the residue, which was then washed with 5% aqueous sodium bicarbonate (twice), saturated sodium chloride solution, 1 N HCl (twice), saturated sodium chloride (twice) and water, in that order. After drying with anhydrous sodium sulfate, the solvent was distilled off and the mixture was concentrated in vacuo to obtain oil substance [5] (57.41 g, yield: 77.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:35]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:35][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CCC2
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 505.23 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 4 was performed using 3-chloro-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7](Cl)[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:4]=1.Cl>O1CCCC1>[NH2:1][C:7]1[C:8]([N+:9]([O-:11])=[O:10])=[C:3]([Cl:2])[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:6]=1
Reactant: O=[N+]([O-])c1c(Cl)nc(-c2ccc(F)cc2)nc1Cl
Reactant: N
Agent: Cl
Solvent: C1CCOC1
Product: Nc1nc(-c2ccc(F)cc2)nc(Cl)c1[N+](=O)[O-]
Yield: 87 %

Procedure:
28% aqueous ammonia (3.1 mL) was added to a solution of 4,6-dichloro-2-(4-fluorophenyl)-5-nitropyrimidine (5.0 g, 17.4 mmol) in tetrahydrofuran (50 mL) at −50° C. until the starting material disappeared. After addition of 3N hydrochloric acid (5 mL) to the reaction solution at the same temperature, the reaction temperature was raised and then the mixture was concentrated in vacuo. Water was added to the residue, and the resulting suspension was filtered, then dried to give the objective compound as a solid (4.05 g, 87%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:4][C:3]=1[C:16]#[N:17].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1.CC([O-])(C)C.[K+]>CS(C)=O>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:24][C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)=[C:3]([C:16]#[N:17])[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cccnc1
Reactant: COc1cccc(-c2ccc(F)c(C#N)c2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cccc(-c2ccc(Nc3cccnc3)c(C#N)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.6 %

Procedure:
To a solution of 4-fluoro-3′-methoxybiphenyl-3-carbonitrile (0.60 g, 2.64 mmol, Example 203A) in DMSO (4 mL) was added pyridine-3-amine (0.27 g, 2.90 mmol) and KOtBu (0.15 g, 1.38 mmol). The reaction stirred under nitrogen at room temperature 12 h. The reaction mixture was partitioned between water and ethyl acetate, the layers were separated, the organics were washed with water, brine solution, dried over Na2SO4 and concentrated to give the crude product. The crude material was purified by silica gel column chromatography (DCM/(2M)NH4-MeOH=100/0−95/5) to afford 0.53 g of 3′-methoxy-4-(pyridine-3-ylamino)biphenyl-3-carbonitrile. MS (ESI) m/z 302.2 (M+H). 1H NMR (MeOD) d ppm 8.43 (1H, d, J=2.75 Hz), 8.19 (1H, dd, J=4.88, 1.22 Hz), 7.91 (1H, d, J=2.14 Hz), 7.81 (1H, dd, J=8.70, 2.29 Hz), 7.56-7.73 (1H, m), 7.32-7.47 (3H, m), 7.11-7.23(2H, m), 6.94(1H, dd, J=8.24, 2.44 Hz), 3.87 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Br:18]Br.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.Br.C(O)(=O)C>[Br:18][CH2:16][C:15]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: COc1cc(C(C)=O)ccc1-c1ccccn1
Reactant: BrBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (400 mg, 1.7 mmol) in benzene (6 mL) and 30% HBr/Acetic acid (6 mL) was cooled to 0° C. and was treated with a solution of bromine (0.086 mL, 1.67 mmol) in benzene (1 mL) over 1 h. The reaction was stirred for an additional 30 min, then poured into an iced solution of saturated aqueous NaHCO3 (100 mL), and the product was extracted into ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated to afford 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[N:22]/[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:7][CH:6]=1.O.Cl>O1CCCC1.CO>[Cl:4][C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[N:22]/[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:10]=1
Reactant: COC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCCCC(=O)O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
Lithium hydroxide monohydrate (160 mg) was added to a solution of methyl E-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate (730 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 3 hours. 1N hydrochloric acid (3.9 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoic acid (632 mg, yield 89%) as colorless crystals. m.p. 90-91° C.
Reaction SMILES: [F:1][CH:2]([F:40])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1.[H-].[Na+].I[CH3:44].O>CN(C=O)C.C(Cl)Cl.C(Cl)Cl.CCOC(C)=O>[F:40][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH3:44])[CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1
Reactant: CI
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(C)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 93 %

Procedure:
A solution of 0.30 g (5.4 mmol) of tert-butyl 4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate in 10 mL of DMF was treated sequentially with excess NaH and iodomethane at room temperature for 2 hrs. Dilution with water and workup in CH2Cl2, followed by chromatography on silica eluting with CH2Cl2/EtOAc (4:1) gave 0.286 g (93% yield) of tert-butyl 4-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](methyl)amino]-1-piperidinecarboxylate: mp (MeOH/CH2Cl2) 200-202° C.; 1H NMR (CDCl3) (rotamer mixture; ratio ca. 3:2) δ 7.98 and 7.91 (2d, J=8.4 Hz, 1H), 7.57 and 7.47 (2t, JHF=53.5 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 4.82 and 4.70 (2m, 1H), 4.29 (m, 2H), 4.05 (s, 3H), 3.88 (m, 4H), 3.79 (m, 4H), 3.10 and 3.05 (2s, 3H), 2.84 (m, 2H), 1.73 (m, 4H), 1.49 (s, 9H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H, 6.3; N, 19.5. Found: C, 56.6; H, 6.4; N, 19.6%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[CH:5]=2.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>>[C:15]([C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc2cc(C)[nH]c2c1
Product: COC(=O)c1ccc2c(C(=O)C(C)C)c(C)[nH]c2c1

Procedure:
Methyl 3-isobutyryl-2-methylindole-6-carboxylate (142 mg) was prepared from methyl 2-methylindole-6-carboxylate (305 mg) and isobutyryl chloride (0.47 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCCC1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[C:25](#[N:29])[C:26]([CH3:28])=[CH2:27]>C1(C)C=CC=CC=1.C(O)C.C(O)(=O)C>[C:25]([CH:26]([CH3:28])[CH2:27][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]1=[O:8])#[N:29]
Reactant: O=C1CCCCCC1
Reactant: C=C(C)C#N
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C#N)CC1CCCCCC1=O

Procedure:
Cycloheptanone was converted to an enamine by reaction with pyrrolidine in toluene solvent and in the presence of toluenesulphonic acid. The enamine was alkylated with methacrylonitrile in ethanol solvent and hydrolysed using acetic acid according to the procedure of Stark et al, J. Amer. Chem, Soc., 85, 207 (1963) to give 2-(2-cyanopropyl)cycloheptanone (bp 100° C./0.02 mmHg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>ClCCl.O.CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([NH:33][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([Cl:27])=[CH:29][CH:30]=2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1cc(Br)cc(C)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)cc(C)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a stirred solution of 4-bromo-2-methoxy-6-methyl-benzoic acid (1.2 g, 4.89 mmol) in dichloromethane (10 ml) are added oxalyl chloride (0.52 ml, 5.86 mmol) and dimethylformamide (catalytic amount) at 0° C. The reaction mixture is stirred for 30 min at RT. Excess oxalyl chloride is distilled off under nitrogen. The residue is dissolved in dichloromethane (10 ml), cooled to 0° C. followed by the addition of triethylamine (1.7 ml, 12.2 mmol) and 4-chlorobenzylamine (0.71 ml, 5.86 mmol). The reaction mixture is stirred for 1 h at RT. After completion of the reaction (monitored by TLC) the mixture is diluted with water (50 ml) and extracted with dichloromethane (3×50 ml). The organic layer is washed with water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 15% ethyl acetate/hexane) to yield 4-bromo-N-[(4-chlorophenyl)-methyl]-2-methoxy-6-methyl-benzamide (1.67 g, 4.53 mmol, 92%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1.[H-].[Na+].[N:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=1>C(OCC)(=O)C>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:12]2([CH2:22][C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)[C:13]3[C:5](=[N:4][CH:3]=[CH:2][CH:1]=3)[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:18][CH:17]=1
Reactant: c1ccc2c(c1)Cc1cccnc1-2
Reactant: ClCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)-c1ncccc1C2(Cc1ccncc1)Cc1ccncc1
Yield: 45.4 %

Procedure:
Following the procedure described in Example 608, Part D, alkylation of 2.1 g (12.6 mmole) of 4-azafluorene, in the presence of 1.51 g (31.45 mmole) of 50% sodium hydride with 5.0 g (30.4 mmole) of 4-picolyl-chloride yielded 2.8 g. Flash chromatography with ethyl acetate yielded 2.0 g of material containing a small amount of color. Recrystallization from butyl chloride yielded 1.5 g of pure compound, m.p. 163-4°.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH2:26]>>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH:26][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: NCc1ccco1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccco3)s2)c(C)[nH]c1=O
Yield: 78 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (furan-2-yl)methylamine as described in Step 5, Example 24 to give the title compound as a light orange solid (78% yield). LC/MS: RT 2.75 min; m/e 379 (M+H); 1H NMR (δ, ppm): 11.3 (1H, s), 8.42 (1H, t), 7.54 (1H, s), 7.50 (1H, t), 7.30 (1H, s), 7.11 (1H, d), 6.35 (1H, d), 6.22 (1H, s), 4.12 (2H, d), 2.41 (2H, q), 2.30 (3H, s), 1.10 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3Cl)[CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:31][N:32]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C(=O)C.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]>[NH2:1][C:2]1[C:3]([C:8]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[C:35]2[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=2)[CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Cn1cc(B(O)O)cn1
Reactant: C[C@H](NC(=O)c1nccnc1N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: C[C@H](NC(=O)c1nccnc1N)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-3-amino-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazine-2-carboxamide (4) (100 mg, 0.24 mmol) in anhydrous N,N-dimethylacetamide (6 mL), 1-methyl-1H-pyrazol-4-ylboronic acid (78 mg, 0.4762 mmol), PdCl2(dppf) (16 mg, 0.019 mmol) and aqueous Na2CO3 solution (1.0 M, 0.72 mL, 0.72 mmol) were added sequentially. The resulting mixture was purged with argon and then stirred at 120° C. under argon for 17 h. The mixture was allowed to cool to RT and ice-water was added. The precipitate was collected by filtration, rinsed with water and dried in vacuo. The solid collected was further purified by ISCO column chromatography (silica gel cartridge, 0-8% MeOH/DCM) to afford the product (S)-3-amino-N-(1-(8-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazine-2-carboxamide (compound 54). ESI-MS m/z: 466.2 [M+H]+.