Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:15])[CH:6]=1)=[S:4].[OH-].[Na+].Cl>CO>[CH3:15][C:7]1[CH:6]=[C:5]([C:3]([OH:2])=[S:4])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: COC(=S)c1cc(C)nc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(O)=S)c2ccccc2n1
Yield: 104.2 %

Procedure:
2-Methylthioquinoline-4-carboxylic acid methyl ester (0.40 g) in methanol:2N sodium hydroxide (2:1, 45 ml) was heated at 60° C. until all solid had dissolved. Volume of solvent was reduced to (15 ml) at reduced pressure and acidified with 2N HCl (16 ml). The precipitated solid was separated by filtration and dried to give the title compound (0.39 g). 1H NMR δ: 2.68 (3H, s), 7.56 (1H, m), 7.75-7.80 (2H, m), 7.96 (1H, d, J=8.2 Hz), 8.55 (1H, d), 13.91 (1H, brs).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]#[N:10].NC1C(C)=CC=CC=1.[ClH:19].[CH3:20][C:21]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:22]=1[NH2:23]>ClC1C=CC=CC=1>[ClH:19].[CH3:20][C:21]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:22]=1[NH:23][C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[NH:10]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: Cc1ccccc1NC#N
Agent: Cl
Solvent: Cc1ccccc1N
Solvent: Clc1ccccc1
Product: Cc1ccccc1NC(=N)Nc1ccc([N+](=O)[O-])cc1C
Yield: 91 %

Procedure:
A vigorously stirred mixture of 2-methylphenyl-cyanamide [1.107 g, 0.380 mmol, prepared from o-toluidine by the method of Safter et al. (1948)] and 2-methyl-4-nitroaniline hydrochloride in chlorobenzene (45 ml) was heated at 90° for 3 h and then allowed to cool to 25°. The resulting pale yellow precipitate was collected, washed with CH2Cl2, and dried, giving 2.284 g (91%) of the hydrochloride of the desired product (pure by NMR). A 681 mg sample was recrystallized twice from absolute EtOH to give 600 mg (88%) of the desired product as pale yellow microcrystals suitable for the next reaction: mp 196-200; (CD3OD, 300 MHz) 2.37 (s, 3), 2.47 (s, 3), 7.33-7.40 (m, 4), 7.59 (d, 1), 8.18 (dd, 1), 8.27 (d, 1). A 473 mg sample of the hydrochloride was dissolved in 50 ml of hot water, filtered, cooled to 25°, and treated with 5 ml of 5 N NaOH. The resulting bright yellow precipitate of the title compound (free base) was dried (403 mg, 92%) and then recrystallized twice from 95% EtOH to give the analytical sample as yellow platelets: mp 177-179; (DC3OD, 300 MHz) 2.31 (s, 6), 7.01-7.35 (m, 5), 7.98 (dd, 1), 8.06 (d, 1). Analysis calculated for C15H16N4O2 :C, 63.37; H, 5.67; N, 19.71. Found: C, 63.41; H, 5.42; N, 19.90.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[CH2:10][NH:11][C:12]([C:14]2[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[C:1]1([CH:7]2[CH2:9][CH:8]2[CH2:10][NH:11][C:12]([C:14]2[N:15]=[N:16][C:17]([N:24]3[CH2:25][CH2:26][N:21]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:36])[F:37])[CH2:22][CH2:23]3)=[CH:18][CH:19]=2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCC1CC1c1ccccc1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCC1CC1c1ccccc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-phenylcyclopropylmethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (25% yield). 1H NMR (400 MHz, CDCl3) δ 8.09-8.03, 7.76, 7.64, 7.57, 7.36, 7.28-7.21, 7.17-7.12, 7.07-6.96, 4.09-3.32, 1.92-1.86, 1.47-1.38, 1.01-0.96. MS (ES+) m/z 510.4 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:62])=[C:25]([N:27]2[C:31](=[O:32])[N:30]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[S:46](=[O:56])(=[O:55])[NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:36][C:35]=3[F:57])[C:29]([CH2:58][CH2:59][CH2:60][CH3:61])=[N:28]2)[CH:26]=1.N12CCCN=C1CCCCC2>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:51]([O:50][C:48]([NH:47][S:46]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:30]2[C:29]([CH2:58][CH2:59][CH2:60][CH3:61])=[N:28][N:27]([C:25]3[CH:26]=[C:21]([NH:20][C:5](=[O:7])[CH2:4][O:3][CH2:1][CH3:2])[CH:22]=[CH:23][C:24]=3[Cl:62])[C:31]2=[O:32])=[C:35]([F:57])[CH:36]=1)(=[O:55])=[O:56])=[O:49])([CH3:52])([CH3:53])[CH3:54]
Reactant: CCOCC(=O)O
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc(NC(=O)COCC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 19.8 %

Procedure:
A mixture of 12 μL (13.2 mg, 0.127 mmol) of ethoxyacetic acid, 20.6 mg (0.127 mmol) of 1,1'-carbonyldiimidazole (CDI), and 1 mL of dry THF was stirred at 60° C. for 4 hours. To this solution was then added 40 mg (0.0635 mmol) of 2-(5-amino2-chlorophenyl)-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step C) dissolved in THF, followed by 19 μL (19.3 mg, 0.127 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After being stirred overnight at 60° C., the reaction mixture was diluted with 5% citric acid (aqueous) and extracted 2× with ethyl acetate. The combined organic fractions were washed twice with water, then with brine, and dried over Na2SO4. The filtered solution was concentrated, and the residue was flash chromatographed on silica gel (gradient elution with 0.5-2% MeOH in CH2Cl2), yielding 9 mg (20%) of the title compound as a white, glassy solid, mp 100°-102° C.; satisfactory purity by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 622 (M+Li)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]3)=[O:15])[C:10]([CH3:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][CH:28]([CH3:31])[C:29]#[CH:30]>>[CH2:22]([N:21]([CH2:24][CH3:25])[CH:18]1[CH2:19][CH2:20][N:16]([C:14]([C:11]2[C:10]([CH3:26])=[N:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:30]#[C:29][CH:28]([CH3:31])[CH3:27])[CH:3]=3)[C:12]=2[CH3:13])=[O:15])[CH2:17]1)[CH3:23]
Reactant: C#CC(C)C
Reactant: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(Br)c3)c2C)C1
Product: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(C#CC(C)C)c3)c2C)C1

Procedure:
In analogy to the procedure described in Example 31F], [1-(3-bromo-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone (1 eq) (Example 28A]) and 3-methyl-1-butyne (1.2 eq) gave the title compound in 90% yield yellow viscous oil. MS: 407.4 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].N1CCOCC1.C[O:14][CH:15](OC)[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.Cl.CCOCC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)(C)(C)C.C1COCC1>[N:22]1([C:19]2[CH:18]=[CH:17][C:16]([CH:15]=[O:14])=[CH:21][CH:20]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: COC(OC)c1ccc(N2CCOCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(N2CCOCC2)cc1
Temperature: 110 °C
Reaction time: 28 h
Yield: 75 %

Procedure:
A solution of 4-iodobenzaldehyde (1 g, 4.31 mmol) in MeOH (50 mL) was mixed with trimethyl orthoformate (4 mL, 36.10 mmol) and p-toluenesulfonic acid (5 mg). The reaction was stirred at room temperature for 3 h and then quenched by adding excess of sodium bicarbonate solid and stirred for 1 h. The solid was removed by filtration and the filtrate was concentrated to yield 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 100%). A mixture of 1-dimethoxymethyl-4-ido-benzene (1.2 g, 4.31 mmol), cesium carbonate (1.4 g, 4.31 mmol), morpholine (0.375 g, 4.31 mmol), and palladium tetrakis(triphenyl)phosphine (0.25 g, 0.216 mmol) in toluene (60 mL) and tert-butanol (10 mL) was thoroughly degassed and stirred at 110° C. for 28 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), concentrated to afford a solid residue. Purification by column chromatography left 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 60%). A solution of 4-(4-dimethoxyrnethyl-phenyl)-morpholine (0.61 g, 2.58 mmol) in THF (20 mL) was mixed with HCl in ether (10 mL, 10 mmol) and stirred at room temperature for 2 h. The reaction mixture was then neutralized with 1 N sodium bicarbonate aqueous to pH 9 and extracted with DCM (3×100 mL), to afford 4-morpholin-4-yl-benzaldehyde (0.37 g, 75%).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH2:3]1.[Br:17][CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:17][CH2:18][CH2:19][O:20][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH2:3]1
Reactant: OCCBr
Reactant: ClC1Cc2ccccc2Sc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: BrCCOC1Cc2ccccc2Sc2ccccc21
Temperature: 50 °C
Reaction time: 6 h
Yield: 100.4 %

Procedure:
10-Chloro-10,11-dihydrodibenzo[b,f]thiepine (10 g, 0.041 mol, prepared as described in Monatshefte 96, 182, 1965) was slowly added to a mixture of 2-bromoethanol (44 g, 0.35 mol) and powdered potassium carbonate (10 g, 0.072 mol) at room temperature. After stirring for 6 h, dichloromethane (15 ml) was added, and the reaction mixture was heated at 50° C. for 3 h. After cooling, dichloromethane (35 ml) was added and the mixture was filtered. The dichloromethane was evaporated and excess of 2-bromoethanol was distilled off in vacuo. The oily residue was dissolved in benzene (100 ml), washed with water (3×70 ml), dried (K2CO3) and the solvent was evaporated to give 13.8 g of crude 10-(2-bromoethoxy)-10,11-dihydrodibenzo[b,f]thiepine as an oil.
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([Cl:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:15]1[CH:14]=[C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Reactant: Cc1ccc(Oc2ccc(CCOC(=N)N)cc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc(CCOc3nc(=O)c(Cc4cnn(C)c4)c[nH]3)cc2)cc1Cl
Temperature: 130 °C
Yield: 14.8 %

Procedure:
To the solution of 2-{4-[(3-chloro-4-methylphenyl)oxy]phenyl}ethyl imidocarbamate (150 mg, 0.359 mmol) and methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (85 mg, 0.431 mmol) in NMP (2 mL), was added K2CO3 (198 mg, 1.436 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (24 mg, 14.82% yield). LCMS: rt=3.35 min, [M+H+]=451
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10]C(C)=O)[CH:5]=[CH:4][C:3]=1[O:14][C:15]([CH3:17])=[O:16].CO.C([O-])([O-])=O.[K+].[K+].Cl>ClCCl>[C:15]([O:14][C:3]1[CH:4]=[CH:5][C:6]([OH:10])=[C:7]([C:8]#[N:9])[C:2]=1[Br:1])(=[O:16])[CH3:17]
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(C#N)c1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Oc1ccc(O)c(C#N)c1Br
Reaction time: 8 h
Yield: 62.5 %

Procedure:
12C (15 g, 0.05 mol) was added to MeOH (52 ml) and dichloromethane (52 mL). To the mixture was added K2CO3 (7 g, 0.05 mol) in batches at room temperature. The reaction mixture was stirred overnight at room temperture, then neutralized with diluted hydrochloric acid to pH=6˜7, extracted with dichloromethane, dried over anhydrous Na2SO4 and concentrated to give 12D (8 g, 62.1% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:16]1[C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=[C:12]([O:11][C:9]([O:1][CH2:2][C:3]2[S:7][CH:6]=[N:5][CH:4]=2)=[O:10])[CH:17]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1cncs1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of 3.11 g (27 mmol) of 5-(hydroxymethyl)thiazole and excess N-methyl morphcline in 100 ml of methylene chloride was cooled to 0° C. and treated with 8.2 g (41 mmol) of 4-nitrophenyl chloroformate. After being stirred for 1 h, the reaction mixture was diluted with CHCl3, washed successively with 1N HCl, saturated aqueous NaHCO3, and saturated brine, dried over NaSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2, 1-2% MeOH/CHCl3, Rf=0.5 in 4% MeOH/CHCl3) to yield 5.9 g (78%) of the desired compound as a yellow solid. NMR (CDCl3) δ5.53 (s, 2H), 7.39 (dt, J=9, 3 Hz, 2H), 8.01 (s, 1H), 8.29 (dt, J=9, 3 Hz, 2H), 8.90 (s, 1H). Mass spectrum: (M+H)+ =281.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[O:13][CH2:12][C@@H:11]([S:14]C(=O)C)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CO.Cl.C(O)(C)C>O1CCCC1>[O:1]([CH2:8][C@@H:9]1[O:13][CH2:12][C@@H:11]([SH:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)S[C@@H]1CO[C@@H](COc2ccccc2)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Solvent: C1CCOC1
Product: S[C@@H]1CO[C@@H](COc2ccccc2)C1
Yield: 70.1 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.532 g of product from Example 23, 506 microliter of 25% sodium methoxide/methyl alcohol, 7.5 ml of tetrahydrofuran, and 1.18 ml of 1.86N hydrochloric acid/isopropyl alcohol to give 0.311 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:40]1([CH3:49])[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([C:43]3[CH:44]=[CH:45][C:40]([CH3:49])=[CH:41][CH:42]=3)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: Cc1ccc(B(O)O)cc1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-c3ccc(C)cc3)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and 4-tolylboronic acid replacing phenylboronic acid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:14]3[C:26]4[NH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]=4[CH2:17][CH2:16][N:15]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Br[CH2:35][C:36]#[N:37].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:14]3[C:26]4[N:25]([CH2:35][C:36]#[N:37])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]=4[CH2:17][CH2:16][N:15]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1C1(c2ccc(Cl)cc2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC#N)c3ccccc23)C1C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
60% Sodium hydride suspension in mineral oil (0.412 g, 10.3 mmol) in dry dimethylformamide (25 mL) was stirred at room temperature under an atmosphere of nitrogen. tert-Butyl 1-[1-(4-chlorophenyl)cyclobutyl]-1,3,4,9-tetrahydro-2H-b-carboline-2-carboxylate (3.0 g, 6.87 mmol) was added in small portions. After 30 min stirring at room temperature 2-bromoacetonitrile (1.235 g, 10.3 mmol) in dimethylformamide (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for two days. Water was added (1 mL). The reaction mixture was concentrated in vacuo, dichloromethane (100 mL) was added and the organic solution successively washed with water (50 mL), saturated NaHCO3 solution (30 mL) and water (30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane). Yield: 2.7 g (83%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[S:26][C:27]([C:31]([NH2:33])=O)=[C:28]([CH3:30])[N:29]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.CN(C)C=O>O>[C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[S:26][C:27]([C:31]#[N:33])=[C:28]([CH3:30])[N:29]=1)=[CH:14][CH:13]=2)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)sc1C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)sc1C#N
Yield: 94.6 %

Procedure:
A solution of tert-butyl{6-[5-(aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.16 g, 0.3 mmol) and cyanuric chloride (0.17 g, 0.9 mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. The resulting reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(5-cyano-4-methyl-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.15 g, 93.8%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:23])=[CH:5][C:6]=1[C:7]1[CH:22]=[C:10]2[NH:11][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]3)=[N:13][CH:14]=[C:9]2[N:8]=1.CC[O:26]C(C)=O.[ClH:30]>CO>[OH2:26].[ClH:30].[CH3:1][C:2]1[S:3][C:4]([CH3:23])=[CH:5][C:6]=1[C:7]1[CH:22]=[C:10]2[NH:11][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]3)=[N:13][CH:14]=[C:9]2[N:8]=1
Reactant: CCOC(C)=O
Agent: Cc1cc(-c2cc3[nH]c(C4CCNC(C)C4)ncc-3n2)c(C)s1
Agent: Cl
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing 2,5-dimethyl-3-(1-pyrrolidinylvinyl)thiophene (freshly prepared before use) (1.40 g, 6.76 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.40 g, 6.76 mmol), N,N-diisopropyl ethyl amine (Aldrich Chemical Company) (1.2 mL, 6.76 mmol), piperidine (Aldrich Chemical Company) (1.1 mL, 10.8 mmol), NEt3 (Aldrich Chemical Company) (1.0 mL) and SnCl2 (20 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 335 mg (15%) of the free base as a beige colored solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.63 (br s, 6), 2.40 (s, 3), 2.42 (s, 3), 2.50 (s, 3), 3.70 (br s, 4), 6.36 (s, 1), 7.04 (s, 1), 10.82 (s, 1). MS m/z: 327 (M+1). To a hot solution of 2,5-dimethyl-3-(2-methyl-4-piperidyl pyrrolo[4,5-d]pyrimidin-6-yl)thiophene (0.35 g, 1.02 mmol) in 5:1 EtOAc:MeOH (40 mL) was added 1M etheral HCl (Aldrich Chemical Company) (1.00 mL, 1.00 mmol). Crystallization occurred as the mixture cooled and the precipitate was collected by filtration, washed with Et2O (2×5 mL) and dried under vacuum to give 222 mg (60%) of the title compound as a beige colored solid. Mp: 240-241.5° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.70 (br s, 6), 2.44 (s, 3), 2.50 (s, 3), 2.55 (s, 3), 4.02 (br s, 4), 6.54 (s, 1), 7.06 (s, 1), 11.89 (s, 1), 14.15 (s, 1). MS m/z: 327 (M+1). Anal. Calcd for C18H22N4S.HCl.1.5H2O: C, 55.53; H, 6.68; N, 14.40; Cl, 9.00; S, 8.23. Found C, 55.62; H, 6.66; N, 14.31; Cl, 9.31; S, 8.28.
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.[O:17]1CCCC1>O.CCOCC.[B-](F)(F)(F)F.[Ag+]>[OH:17][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: C1CCOC1
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: O
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 56.0 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 8) in 400 ml. of tetrahydrofuran and 133 ml. of water at 3° C. is added 44.1 g. (0.226 moles) of silver fluoborate during 25 minutes. The mixture is stirred at 0°-5° C. for 60 minutes, diluted with water and ether, and filtered. The aqueous portion of the filtrate is saturated with solid sodium chloride and extracted with additional ether. The combined organic phases are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue gives the subject compound as a mixture with 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one, NMR(CDCl3) 3.60 (multiplet, O-methylene hydrogens) and 4.60 (multiplet, O-methine hydrogen).
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.O.[OH-].[Li+].Cl>O1CCOCC1.O>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:21]2[N:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:39])=[O:3])=[CH:6][CH:7]=3)=[O:38])[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To the solution of 4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-benzoic acid ethyl ester (intermediate d) in 25 ml dioxan, 25 ml water and 0.57 g (13.6 mmol) lithium hydroxide monohydrate were added. The solution was stirred for 2 h at 100° C. After cooling to room temperature, 16 ml 1M aqueous hydrochloric acid were added upon stirring. The suspension was filtered, the filter cake washed with water and dried under high vacuum to give 2.46 g (99%) of the desired compound as colorless solid.