Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C@:16]12[CH2:33][CH2:32][C@H:31]3[C@@H:21]([CH2:22][CH2:23][C:24]4[C@:29]3([CH3:30])[CH2:28][CH2:27][C:26](=[O:34])[CH:25]=4)[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[C:35](O)=[O:36].C(N(CC)CC)C.CS(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][C:35]([C@H:17]2[CH2:18][CH2:19][C@H:20]3[C@H:21]4[C@H:31]([CH2:32][CH2:33][C@:16]23[CH3:15])[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH2:27][CH2:28]2)[CH2:23][CH2:22]4)=[O:36])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 74 %

Procedure:
0.108 ml of benzhydrylamine was added to a solution of 100 mg of androsta-4-ene-3-one-17β-carboxylic acid, a catalytic amount of 4-dimethylaminopyridine and 0.132 ml of triethylamine in 4 ml of methylene chloride. 0.037 ml of methanesulfonyl chloride was divided into three portions and added to this reaction mixture at intervals of 30 minutes at room temperature, whilst stirring. One hour after finishing the addition of methanesulfonyl chloride, the reaction mixture was diluted with methylene chloride, washed with 1N aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was crystallized from acetone to give 113.2 mg (yield 74%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH:8]1[C:17](=O)[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1.[OH-].[K+].O.NN>C(O)CO.O>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1[nH]cnc1CC1CCc2cccnc2C1=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1[nH]cnc1CC1CCc2cccnc2C1
Temperature: 120 °C
Reaction time: 4 h
Yield: 0.7 %

Procedure:
A mixture of (5) (0.83 g, 344 mmol), potassium hydroxide (0.782 g, 13.9 mmol), and hydrazine hydrate (0.77 mL, 24.7 mmol) in ethylene glycol (20 mL) was heated at 120° C. in an apparatus fitted with a Dean Stark trap for 1 h, and at 180° C. for 4 hours. The reaction was cooled to rt, and diluted with water. The aqueous medium was extracted three times with chloroform/isopropanol (3:1, 200 mL). The pooled organic layers were dried over magnesium sulfate. The mixture was filtered and the solvents were removed under vacuum. The residue was purified by chromatography on silica gel with 2 to 3% ammonia saturated methanol in dichloromethane to give 7-(5-methyl-1H-imidazol-4-ylmethyl)-5,6,7,8-tetrahydro-quinoline (6) as a foam (0.544 g, 2.40 mmol, 70% yield). 1H NMR (300 MHz, CDCl3): δ 8.30 (d, J=3.90 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J=7.50 Hz, 1H), 7.03 (dd, J=7.50, 4.80 Hz, 1H), 2.99-2.91 (m, 1H), 2.84-2.76 (m, 2H), 2.70-2.50 (m, 3H), 2.24-2.14 (m, 1H), 2.15 (s, 3H), 2.04-1.96 (m, 1H), 1.54-1.40 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][C:12]([CH3:20])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[H-].[Na+].CI.[CH3:25]CCCCC>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([CH3:25])[CH:9]2[CH2:10][CH2:11][C:12]([CH3:20])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:3]=1
Reactant: CCOC(=O)C1(C)CCC(Nc2ncc(Br)cn2)CC1
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCC(N(C)c2ncc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To an ice-cold solution of ethyl 4-(5-bromopyrimidin-2-ylamino)-1-methylcyclohexanecarboxylate (0.30 g, 0.88 mmol) in THF (10 mL) was added NaH (0.053 g, 1.32 mmol, 60% dispersion in mineral oil) portion wise and the mixture stirred at 0° C. for 10 min followed by drop wise addition of MeI (0.066 ml, 1.06 mmol). The mixture was heated up to 65° C. for 6-8 h. After completion (by TLC), the reaction was cooled up to 0° C. and quenched with ice-cold water (20 mL), extracted with EtOAc (2×50 mL) and the combined organics washed with water, brine and dried over Na2SO4. The crude residue was purified over 100-200 M silica-gel using 2% EtOAc:hexane to obtain the desired product as a yellow liquid (0.074 g, 24% yield). 1H NMR (DMSO-d6): δ 8.42 (s, 2H), 4.51 (m, 1H), 4.15 (q, J=6.80 Hz, 2H), 2.85 (s, 3H), 2.15 (m, 2H), 1.52 (m, 4H), 1.36 (m, 2H), 1.29 (t, J=6.80 Hz, 3H) and 1.21 (s, 3H).
Reaction SMILES: O.[Li+:2].[OH-].[N:4]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:8]([C:9]([O:11]C)=[O:10])[CH2:7][CH:6]=[N:5]1.Cl.O>CO>[C:16]([O:15][C:13]([N:4]1[C@H:8]([C:9]([O-:11])=[O:10])[CH2:7][CH2:6][NH:5]1)=[O:14])([CH3:19])([CH3:17])[CH3:18].[Li+:2]
Reactant: COC(=O)[C@@H]1CC=NN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1NCC[C@H]1C(=O)[O-]
Reaction time: 7 h

Procedure:
A water (5 mL) solution of LiOH (0.146 g, 6.09 mmol) was added to a methanol (5 mL) solution of (S)-1-tert-butyl 5-methyl 1H-pyrazole-1,5(4H,5H)-dicarboxylate (0.76 g, 3.11 mmol), and stirred at ambient conditions for ˜7 h. The reaction mixture was cooled with an ice-water bath, and HCl/H2O (3 mL of 1.00 N; 3.0 mmol) was added dropwise and stirred for a few minutes. Then, the volatile component was removed in vacuo and the resultant viscous oil was exposed to high vacuum to afford lithium (S)-2-(tert-butoxycarbonyl)pyrazolidine-3-carboxylate as a white foam, which was used without further purification. 1H NMR (DMSO-d6, δ=2.50 ppm, 400 MHz) for crude sample: 3.98 (dd, J=8.5, 6.3, 1H), 2.86-2.74 (m, 2H), 2.45 (s, 3H), 2.25-2.17 (m, 1H), 2.10-2.02 (m, 1H), 1.35 (s, 9H). LC-MS: Anal. Calcd. for [M+H]+ C10H19N2O4: 231.13. found 231.21.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)=[CH:13][C:12]([C:27]#[N:28])=[CH:11][CH:10]=2)=[O:5])C.C1COCC1.[OH-].[Na+].Cl>C(O)C.CO>[Cl:26][C:20]1[CH:19]=[C:18]([CH2:17][NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:27]#[N:28])[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([OH:5])=[O:3])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CCOC(=O)c1cnc2ccc(C#N)cc2c1NCc1ccc(OC)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: COc1ccc(CNc2c(C(=O)O)cnc3ccc(C#N)cc23)cc1Cl
Reaction time: 1 h
Yield: 100 %

Procedure:
To 8.0 g (20 mmol) 4-(3-Chloro-4 -methoxyphenylmethylamino)-6 -cyanoquinoline-3-carboxylic acid ethyl ester was added 100 mL THF, 100 mL MeOH and 100 mL 1M NaOH, and the resulting mixture was stirred well. The solids gradually dissolved as the reaction progressed. After 1 h, the THF and most of the MeOH was evaporated under reduced pressure to leave an aqueous slurry of a white solid. The slurry was acidified to pH 1.5 with HCl, stirred well for 1 h, and then filtered and washed well with water to give 7.5 g (20 mmol, ˜100% yield) of a white chalky solid. Codistilling twice to dryness with absolute ethanol afforded the title compound: LC/MS: M/Z 368 (M+H) observed, 90+% purity; mp: decomposed 255-260° C. LC 2.93′.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[N:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][N:6]=1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>C(Cl)Cl>[CH2:13]([O:12][C:10]([C:8]1[N:9]=[C:5]2[CH2:4][C:3]3[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=3[NH:1][C:19](=[O:20])[N:6]2[N:7]=1)=[O:11])[CH3:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)c1nc(Cc2ccccc2N)n[nH]1
Solvent: ClCCl
Product: CCOC(=O)c1nc2n(n1)C(=O)Nc1ccccc1C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 13.96 g of 3-(o-aminobenzyl)-5-ethoxycarbonyl-1,2,4-triazole, 410 ml of methylene chloride and 9.19 g of 1,1'-carbonyldimidazole is stirred at room temperature for 2 days and filtered. The filtrate is washed with water, dried over magnesium sulfate, decolorized with charcoal, evaporated to a small volume and diluted with ether. The product is filtered off and recrystallized from tetrahydrofuran to give 2-ethoxycarbonyl-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine-5(6H)-one, m.p. 216°-220° (intermediate 6/b).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[C:4]=2[CH:3]=C1.C([OH:25])C>>[CH:3]([C:4]1[C:5]([OH:1])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)=[O:25]
Reactant: CCOC(=O)c1ccc(COc2cccc3occc23)cc1
Reactant: CCO
Product: CCOC(=O)c1ccc(COc2cccc(O)c2C=O)cc1
Temperature: -65 °C

Procedure:
Ethyl 4-(4-benzofuranyloxymethyl)benzoate (1.84 g, 0.004 M) was dissolved in absolute ethanol (180 ml) and cooled to -65° C. with stirring and exclusion of moisture. Ozonised air was bubbled through the solution at a rate of 20 liters/hr for 1 hr. Nitrogen was then bubbled through the solution (5 mins) to remove excess ozone before the addition of dimethyl sulphide (1.2 ml). The mixture was allowed to warm to room temperature overnight (16 hr.). The solvent was removed in vacuo and the residue recrystallised from ethyl acetate-petrol to give ethyl 4-(2-formyl-3-hydroxyphenoxymethyl)benzoate, m.p. 105°-107° C. (Found: C, 67.59; H, 5.21. C17H16O5 requires C, 67.99; H, 5.37%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]([O:12][CH2:13][CH2:14][OH:15])(=[O:11])[CH:9]=[CH2:10].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[Cl-].C[N+](C)(C)C>[C:8]([O:12][CH2:13][CH2:14][O:15][C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])(=[O:11])[CH:9]=[CH2:10]
Reactant: O=C1CCC(=O)O1
Reactant: C=CC(=O)OCCO
Agent: C[N+](C)(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Product: C=CC(=O)OCCOC(=O)CCC(=O)O
Temperature: 90 °C

Procedure:
A mixture of succinic anhydride (30.0 g), 2-hydroxyethyl acrylate (34.2 g), tetramethylammonium chloride (0.2 g), and 2,6-di-tert. butyl-4-methyl phenol (0.15 g) is heated at 90° C. for 3 hours, by which time the infra-red spectrum of the mixture shows that almost all of the anhydride has reacted. The mixture is cooled to give the desired acid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH2:4][N:3]1[NH:8][C:9]([NH:11][CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([O:15]CC)=[O:14])=[O:10].[OH-].[Na+]>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH2:4][N:3]1[NH:8][C:9]([NH:11][CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([OH:15])=[O:14])=[O:10]
Reactant: CCOC(=O)C(NC(=O)NN1CC(=O)NC1=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1CN(NC(=O)NC(C(=O)O)c2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
29.4 g. of α-[[[(2,4-dioxo-1-imidazolidinyl)amino]carbonyl]amino]benzeneacetic acid, ethyl ester are added to 138 ml. of 2N sodium hydroxide solution with stirring. The substance goes quickly into solution upon slight heating. The mixture is stirred for 2 hours at room temperature, filtered and the clean filtrate is acidified to pH 1 with concentrated hydrochloric acid. Upon rubbing, α-[[[(2,4-dioxo-1-imidazolidinyl)amino]carbonyl]amino]benzene acetic acid crystallizes out. The mixture is let stand in the refrigerator overnight and then filtered under suction, yield 21.9 g., m.p. 139°-143°.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CC[CH2:48][C@H:47]1[CH2:51]N>>[CH3:37][C@H:36]([NH:35][CH2:34][C:32]1[CH:33]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:15][CH2:14][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:18][CH2:17]2)[CH:29]=[C:30]([F:42])[CH:31]=1)[CH:47]([CH3:51])[CH3:48]
Reactant: NC[C@@H]1CCCO1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CN[C@@H](C)C(C)C)c4)cc23)CC1
Yield: 42 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (2S)-3-methyl-2-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 19.3 mg of the title compound (42%).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)cc2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 80.0 mg (0.173 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-(1,1-dimethylethyl)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 6) and 18.1 mg (0.432 mmol) of LiOH—H2O in 6 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the remaining aqueous layer acidified with 1M HCl, and then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ7.82 (2H, d, J=8.2 Hz), 7.44 (6H, m), 7.25 (2H, d, J=8.3 Hz), 7.02 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.32 (2H, d, J=4.7 Hz), 1.32 (9H, s), 1.29 (6H, s).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[C:21]([C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=1)#[N:22]
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(C#N)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(C#N)c2)=CC1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution containing (S)-2-[4-(3-cyano-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (2.20 g, 0.007 mol) in tetrahydrofuran (35 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 28 mL, 0.014 mol). The mixture was stirred at 20° C. for 2 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(3-cyano-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1.80 g, 85%) as an off-white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)(=O)[C:19]([Cl:21])=[O:20].[Cl-].[Ca+2].[Cl-]>C(Cl)Cl.O>[O:17]=[C:14]1[CH2:15][CH2:16][CH:11]([C:5]2[CH:10]=[CH:9][C:8]([C:19]([Cl:21])=[O:20])=[CH:7][CH:6]=2)[CH2:12][CH2:13]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: [Al+3]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C1CCC(c2ccc(C(=O)Cl)cc2)CC1
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
A suspension of 133.3 g of aluminium chloride in 250 ml of methylene chloride was treated dropwise at 20° C. while cooling and gassing with nitrogen with a solution of 174.2 g of 4-phenylcyclohexanone in 250 ml of methylene chloride. The reaction mixture was stirred for a further 30 minutes until a clear solution was obtained. In the meanwhile, a suspension of 133.3 g of aluminium chloride in 500 ml of methylene chloride was treated with 172 ml of oxalyl chloride while gassing with nitrogen. This mixture was subsequently treated dropwise at 20°-25° C. within 1 hour with the above solution of the 4-phenylcyclohexanone-aluminium chloride complex. The reaction mixture was stirred for a further 30 minutes, then cooled to 2° C. and added dropwise within 20 minutes while stirring to a solution of 300 g of calcium chloride in 1 l of water. The mixture was stirred at room temperature for a further 1.5 hours and then poured on to 500 ml of ice/water. The organic phase was separated and washed with 500 ml of semi-saturated sodium chloride solution. The aqueous phases were back-extracted twice with 500 ml of methylene chloride each time. The combined organic phase was dried over sodium sulfate, filtered and concentrated. The oily 4-(4-oxocyclohexyl)benzoyl chloride obtained was dissolved in 400 ml of toluene and this solution was added dropwise to a mixture of 150 ml of methanol, 200 ml of pyridine and 1 l of toluene. The reaction mixture was left to stand overnight and then washed in succession with water, 3N hydrochloric acid, semi-saturated sodium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated. Recrystallization of the residue from toluene at -25° C. gave 128 g of pure methyl 4-(4-oxocyclohexyl)-benzoate with m.p. 91°-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]#[C:10][C:11](O)([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(NCC)C.C([OH:23])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:15][C:11]([CH3:12])([CH3:13])[C:10](=[O:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CC(C)(O)C#CC(=O)c1ccc(Cl)cc1
Solvent: CCNCC
Product: CC1(C)OC(c2ccc(Cl)cc2)=CC1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-4-hydroxy-4-methylpent-2-yn-1-one (2.4 g, 10.70 mmol) in ethanol (20 mL), a solution of diethyl amine (1.34 mL, 12.90 mmol) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 30 min. The ethanol was then removed and the mixture was diluted with EtOAc (50 mL). The combined organic layers were then washed with water (10 mL), and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 5-(4-chlorophenyl)-2,2-dimethylfuran-3(2H)-one (2.1 g) as a light green gummy oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)=[O:33])=[CH:4][N:3]=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][N:37]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:36]2)=[O:33])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(-c2csc3c(C(=O)NC4CCCNC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2csc3c(C(=O)NC4CCCN(S(C)(=O)=O)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-piperidin-3-ylthieno[3,2-c]pyridine-7-carboxamide (150 mg, 0.270 mmol), methanesulfonyl chloride (26 μL, 0.32 mmol) and N,N-diisopropylethyl amine (0.15 mL, 0.81 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. Saturated sodium bicarbonate (2 mL) was added. The layers were separated and the organic solvent was removed. The residue was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (28-30% solution) (90:10:0.05) mixture as the mobile phase to give the title compound. 1H NMR (DMSO, d6) δ 1.58 (m, 2H), 1.91 (m, 2H), 2.58 (m, 1H), 2.71 (m, 1H), 3.50 (m, 1H), 3.73 (m, 1H), 3.91 (s, 3H), 3.99 (m, 1H), 4.04 (m, 3H), 7.07 (d, 1H), 7.15 (t, 1H), 7.19 (s, 1H), 7.33 (t, 1H), 7.35 (s, 1H), 7.58 (m, 2H), 7.71 (d, 1H), 7.99 (d, 1H), 8.34 (d, 1H), 8.61 (s, 1H), 9.50 (s, 1H). LCMS (Conditions a) Rt=3.22 min., 633.0 (MHO.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]4[O:35][CH2:34][CH2:33][C:32]=4[CH:36]=3)=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:42]>C(O)C>[ClH:42].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]3[O:35][CH2:34][CH2:33][C:32]=3[CH:36]=2)=[C:20]([C:37]([F:40])([F:38])[F:39])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc4c(c3)CCO4)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc3c(c2)CCO3)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 76-3 (740 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (500 mg) as a white powder.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([CH3:30])[CH:20]=1)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([CH3:30])[CH:20]=3)[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: Cc1cc(C(C)N)ccc1C(C)(C)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(C(C)NC(=O)Cn2cnc3cccc(C#N)c32)ccc1C(C)(C)C#N
Yield: 74.2 %

Procedure:
To a solution of (7-cyano-1H-benzimidazol-1-yl)acetic acid (100 mg, 0.50 mmol) prepared according to scheme 3, 2-{4-[1-aminoethyl]-2-methylphenyl}-2-methylpropanenitrile (101 mg, 0.50 mmol) prepared according to scheme 16 and DMAP (120 mg, 1.00 mmol) stirred in anhydrous DMF (2.0 mL) is added HATU (189 mg, 0.50 mmol) after 18 hours of stirring, the mixture is diluted with Methanol (200 μL) the solution is purified directly on a preparative on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-2-(7-Cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-methylphenyl]ethyl}acetamide (143 mg, 75%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.49 (d, J=7.03 Hz, 3H) 1.75 (s, 6H) 2.61 (s, 3H) 4.99 (q, J=7.03 Hz, 1H) 5.28-5.40 (m, 2H) 7.21-7.29 (m, 2H) 7.33 (d, J=8.20 Hz, 1H) 7.37-7.44 (m, 1H) 7.69 (dd, J=7.42, 0.78 Hz, 1H) 7.98 (dd, J=8.20, 1.17 Hz, 1H) 8.27 (s, 1H) MS [M+H], calcd: 386.2. found: 386.2.