Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36]C)=[O:35])=[CH:29][CH:28]=3)[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:41])([F:40])[F:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].[CH:44](O)=[O:45]>C(OC(=O)C)(=O)C>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:29][CH:28]=3)[CH:44]=[O:45])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:39])([F:40])[F:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: COC(=O)Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=CN(Cc1ccc(CC(=O)O)cc1)c1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
A mixture of methyl {4-[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amino)methyl]phenyl}acetate (0.05 g, 0.09 mmol) in 5 mL of 96% of formic acid and 1 mL of acetic anhydride was heated under reflux for 1 h. Removal of solvent under reduced pressure gave a crude product that was used for the LiOH hydrolysis as described in Example 66. 35 Mg (68%) of the title compound was obtained as a pale yellow solid. MS (ESI) m/z 569; HRMS: calcd for C33H23F3N2O4, 568.1610; found (ESI, [M−H]−), 567.1543.
Reaction SMILES: [O:1]=[C:2]([N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)/[CH:3]=[CH:4]/[C:5]1[C:13]2[C:8](=[CH:9][C:10](/[CH:14]=[CH:15]/[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:12]=2)[N:7]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][C:25]=2[O:33][CH3:34])[CH:6]=1.[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47]([NH2:50])(=[O:49])=[O:48]>>[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47]([NH:50][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([CH2:23][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]([N:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)=[O:17])[CH:9]=3)[C:5](/[CH:4]=[CH:3]/[C:2](=[O:1])[N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:6]2)=[C:25]([O:33][CH3:34])[CH:26]=1)(=[O:49])=[O:48]
Reactant: COc1cc(C(=O)O)ccc1Cn1cc(/C=C/C(=O)N2CCCC2)c2ccc(/C=C/C(=O)N3CCCC3)cc21
Reactant: NS(=O)(=O)c1ccccc1Cl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2Cl)ccc1Cn1cc(/C=C/C(=O)N2CCCC2)c2ccc(/C=C/C(=O)N3CCCC3)cc21

Procedure:
Using a similar procedure to that described in Example 32, except starting from E,E-4-[3,6-di-(3oxo-3-pyrrolidino-1-propenyl)indol-1-ylmethyl]- 3-methoxybenzoic acid, and using 2-chlorobenzenesulfonamide, title compound was obtained (87%) as powder, mp 291°-293°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.[O:14]([C:21]1[N:26]=[C:25]([CH2:27][CH2:28][C:29](OC)=[O:30])[CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:29](=[O:30])[CH2:28][CH2:27][C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:26]=2)[C:12]#[N:13])=[CH:7][CH:6]=1
Reactant: COC(=O)CCc1cccc(Oc2ccccc2)n1
Reactant: COc1ccc(CC#N)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)C(=O)CCc2cccc(Oc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.6 %

Procedure:
Under a nitrogen atmosphere, 235 mg of sodium hydride (60% oil dispersion) were added to 50 ml of dry tetrahydrofuran, and the mixture was heated to 50° C. to 60° C. A solution of 864 mg of 4-methoxyphenylacetonitrile and 1.51 g of methyl 3-(6-phenoxypyridin-2-yl)propionate in 10 ml of dry tetrahydrofuran were added dropwise thereto over 5 minutes. After dropwise addition, the reaction solution was heated under reflux for 2 hours, cooled with ice, poured into ice water, neutralized to a pH of 7 with aqueous dilute hydrochloric acid and extracted twice with ethyl acetate. The ethyl acetate layers were combined and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue crystallized, so that the crystal was washed with a little diethyl ether, filtered and dried to obtain 0.91 g of the desired 2-(4-methoxyphenyl)-3-oxo-5-(6-phenoxypyridin-2-yl)valeronitrile [corresponding to the compound represented by the foregoing general formula (X) wherein R1 is a methoxy group, R2, R5 and R6 are a hydrogen atom] as a crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(CN2CCCCC2)C1
Yield: 50 %

Procedure:
To a suspension of 3-methanesulfonyloxymethylazetidine-1-carboxylic acid tert-butyl ester (0.36 g, 1.40 mmol) in toluene (2 mL) was added piperidine (0.7 mL, 7.00 mmol) and the resultant mixture was heated to 110° C. in a sealed tube for 18 h. The solution was concentrated in vacuo, the crude residue dissolved in DCM and washed with 0.5 N KOH (aq.) (1×) and brine (1×). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The resultant oil was purified by chromatography on silica gel with MeOH:DCM (1:19, v/v) as eluent to afford 3-piperidin-1-ylmethylazetidine-1-carboxylic acid tert-butyl ester (180 mg, 0.70 mmol, 50%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C@@H:13]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)=[O:15]>>[CH2:22]([N:19]1[CH2:20][CH2:21][C@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([NH:12][C:10]([NH:9][C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[O:11])[C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:18]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)[C@H](N)C(=O)N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C=Nc1cc(F)ccc1F
Product: CC(C)(C)[C@H](NC(=O)Nc1cc(F)ccc1F)C(=O)N[C@H]1CCN(Cc2ccccc2)C1

Procedure:
Compound 3c was prepared from 2,5-difluorophenyl isocyanate and compound 2b, using the method described in Example 9. MS (EI)=444 (M+).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-].[Na+].OO.C([O-])(O)=[O:24].[Na+]>C1COCC1>[OH:24][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[C:7]1[C:8]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:9]=2[NH:10][CH:11]=1
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc2[nH]cc(C3=CCCCC3)c2s1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]cc(C3CCCCC3O)c2s1
Temperature: 25 °C
Reaction time: 7 h
Yield: 56 %

Procedure:
A 2M solution in THF of borane dimethylsulfide complex (1.5 eq.) was added at 0° C. to a 0.1M solution of methyl 6-cyclohex-1-en-1-yl-4H-thieno[3,2-b]pyrrole-2-carboxylate in dry THF, and the mixture was stirred at RT for 7 h. After cooling to 0° C., the mixture was treated with 3M aq. NaOH (3 eq.) and 35% hydrogen peroxide (4 eq.). The mixture was allowed to warm to RT overnight. Aq. NaHCO3-solution was added and the mixture was extracted with EtOAc; the organic layer was washed with water and brine, dried over Na2SO4 and concentrated. Chromatography (PE/EtOAc) afforded the title compound (56%). 1H-NMR (300 MHz, CDCl3, 300 K, δ) 8.30 (bs, 1H), 7.68 (s, 1H), 7.08 (d, 1H, J 2.0), 3.89 (s, 3H), 3.70-3.65 (m, 1H), 2.58-2.49 (m, 1H), 2.16-2.12 (m, 1H), 1.98-1.65 (m, 4H), 1.47-1.23 (m, 3H); MS (ES+) m/z 280 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=O)=[CH:4][C:3]=1[O:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21].C(=O)(O)[O-].[Na+].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=[S:37])=[CH:4][C:3]=1[O:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21]
Reactant: CC(C)=CCOc1cc(NC(=O)c2ccoc2C)ccc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)=CCOc1cc(NC(=S)c2ccoc2C)ccc1Cl
Temperature: 85 °C

Procedure:
A reaction mixture of N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarboxamide (4 g), sodium bicarbonate (7.4 g) and Lawesson's reagent (3.6 g) in toluene (168 mL) was gradually heated to 85° C. over 1 1/2 hours and then held at this temperature for a further 2 1/2 hours. The reaction mixture was then cooled and filtered through a plug of neutral aluminum oxide and eluted with ether:petroleum ether (1:1). Evaporation of the solvent gave the product, N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide, 2.6 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[OH-].[Na+].[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1>O.CC(C)=O>[Cl:13][C:14]1[N:19]=[C:18]([O:9][C:5]2[C:4]([CH3:10])=[CH:3][C:2]([NH2:1])=[C:7]([CH3:8])[CH:6]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: Clc1ccnc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(Oc2ccnc(Cl)n2)c(C)cc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 7.55 g (55 mmol) 4-amino-2,5-dimethylphenol and 2.4 g NaOH (2M) in 30 ml water were added dropwise to a solution of 7.45 g (50.0 mmol) of 2,4-dichloropyrimidine in 50 ml of acetone. The reaction mixture was stirred for 20 h at ambient temperature. After concentration in vacuo and addition of 150 ml water the formed precipitate was filtered by suction. Yield 10.6 g (75%) with a purity of 88% log P (pH=2.3)=1.37.
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][CH2:9][CH2:10]C(=O)CCCC>>[CH:8]#[C:9][CH2:10][CH:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC=O
Reactant: CCCCC(=O)CCC
Product: C#CCC(O)CCCCC

Procedure:
When 1-hexanal is substituted for 4-octanone in Example 27, there is obtained the title product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)[C:43]([CH3:58])=[CH:42][C:40]=1[NH2:41])[CH3:37].Cl>FC(F)(F)CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[C:43]([CH3:58])[C:44]([N:46]4[CH2:51][CH2:50][CH:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH2:36][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: Cl
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 85 °C
Yield: 56.9 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (19.7 g, 39.9 mmol) and 2-(ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (13.6 g, 39.9 mmol) in 2,2,2-trifluoroethanol (200 mL) was added HCl (4M in dioxane) (19.97 mL, 80 mmol). The reaction mixture was heated at 85° C. for 2 days. The reaction was determined to be complete by LCMS. The reaction was cooled and quenched with solid NaOMe. The suspension was concentrated. Purification by flash chromatography, followed by trituration with EtOH provided the title compound of Step H (18.1 g, 22.7 mmol, 57% yield). Alternatively, this reaction can be effected using microwave irradiation. Additionally, further purification of the title compound can be effected by recrystallization from equal parts DCM and EtOH. 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.37 (d, J=6.0 Hz, 1H), 8.38 (s, 1H), 8.27 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.64-7.83 (m, 2H), 7.55 (s, 1H), 7.35-7.52 (m, 2H), 7.29 (d, J=8.6 Hz, 1H), 7.20 (t, J=8.0 Hz, 2H), 6.96 (t, J=6.6 Hz, 1H), 6.75 (s, 1H), 6.59 (d, J=5.0 Hz, 1H), 3.92-4.15 (m, 5H), 3.11-3.27 (m, 2H), 2.91-3.11 (m, 5H), 2.61 (t, 2H), 2.15 (s, 3H), 1.62-1.87 (m, 4H), 1.42-1.57 (m, 1H), 1.21-1.42 (m, 5H). MS (M+H, ES+) 796.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=5[OH:33])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(O[C:50]1(C)[CH2:55][CH2:54]N(C2N3C=C(C4C=C(C5C=C(C)C=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)[CH2:52][CH2:51]1)C=C>>[CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=5[O:33][C@H:55]([CH2:50][CH:51]=[CH2:52])[CH3:54])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O[C@@H](C)CC=C)c4)cn23)CC1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cccc(F)c5O)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cccc(F)c5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 70 %

Procedure:
Prepared from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3′-fluoro-2′-hydroxy-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate in 70% yield following the same procedure as (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-7-methyl-2-(5′-methyl-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)imidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 684.20.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([SH:11])=[C:4]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:3]=1.Br[C:17]1C(C(C)C)=CC(S)=C(C(C)C)C=1>>[CH3:17][S:11][C:5]1[CH:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[C:2]([Br:1])=[CH:3][C:4]=1[CH:12]([CH2:14][CH3:15])[CH3:13]
Reactant: CC(C)c1cc(Br)c(C(C)C)cc1S
Reactant: CCC(C)c1cc(Br)c(C(C)C)cc1S
Product: CCC(C)c1cc(Br)c(C(C)C)cc1SC

Procedure:
4-Bromo-2-sec-butyl-5-isopropylphenyl methyl sulfide was prepared using the procedure of Example 1C except that 4-bromo-2-sec-butyl-5-isopropylbenzenethiol was substituted for the 4-bromo-2,5-diisopropylbenzenethiol. The resulting product had a boiling point of 111°C at 0.3 mm Hg.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:32][CH2:33][CH3:34])[N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:11]=1[C:12]#[N:13])[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-:35].[Na+]>C(O)C>[OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:32][CH2:33][CH3:34])[N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:11]=1[C:12]([NH2:13])=[O:35])[C:3]([CH3:6])([CH3:4])[CH3:5]
Reactant: [OH-]
Reactant: CCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of 0.70 g of 4-(1-hydroxy-2,2-dimethylpropyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (c) above] in 14 ml of 1N aqueous sodium hydroxide and 7 ml of ethanol was heated under reflux for 2 hours. At the end of this time, the ethanol in the reaction mixture was removed by evaporation under reduced pressure, and ethyl acetate and 14 ml of 1N aqueous hydrochloric acid were added to the residue. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 0.45 g of the title compound as a powder, melting at 174°-176° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:23].FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:7])=[CH:4][C:3]=1[F:23]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)c(F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C(=O)N2CCNCC2)cc1F

Procedure:
tert-Butyl 4-(4-amino-3-fluorobenzoyl)piperazine-1-carboxylate (0.649 mmol, 210 mg) was stirred with dichloromethane (˜2 mL) and trifluoroacetic acid (˜0.5 mL) overnight. The mixture was purified by SCX chromatography to give the intermediate (4-amino-3-fluorophenyl)(piperazin-1-yl)methanone. 2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.649 mmol, 219 mg), potassium carbonate (0.649 mmol, 90 mg) and acetonitrile (5 mL) were added to the intermediate (4-amino-3-fluorophenyl)(piperazin-1-yl)methanone and the mixture was stirred for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was stirred in dichloromethane, filtered and the filtrate was purified by silica chromatography (eluting with dichloromethane increasing to ethyl acetate) to afford the title compound (46 mg).
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23](O)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23]([NH:37][CH2:31][C:32]4[O:36][CH:35]=[CH:34][CH:33]=4)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCc1ccco1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccn1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)NCc2ccco2)ccn1
Yield: 63 %

Procedure:
To solution of 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid (40 mg, 0.098 mmol), furfuryl amine (19.11 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.4 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:1) to afford 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-furan-2-ylmethyl-isonicotinamide as a colorless solid (30 mg, 63% yield).
Reaction SMILES: [C:1]([CH:3]([C:13](=O)[CH2:14][CH3:15])[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)#[N:2].[NH2:17][NH2:18]>CCO>[NH2:2][C:1]1[NH:18][N:17]=[C:13]([CH2:14][CH3:15])[C:3]=1[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: NN
Reactant: CCC(=O)C(C#N)Cc1ccc(C#N)cc1
Solvent: CCO
Product: CCc1n[nH]c(N)c1Cc1ccc(C#N)cc1
Reaction time: 0.5 h

Procedure:
To a 500 ml, four-necked flask equipped with an overhead stirrer, a thermocouple and a condenser was charged 4-(2-cyano-3-oxopentyl)benzonitrile (25) (5 g, 23.6 mmol) and 50 ml of EtOH. The solution was stirred and hydrazine (1.65 g, 33 mmol, 64%, 1.4 eq) was added. The batch was stirred at 65° C. for 3 hours. The solvent was concentrated by vacuum and the residue was slurried with 50 ml of MTBE at room temperature for 30 min. The precipitate was collected by vacuum filtration and the solid was washed with MTBE to give product 26 as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2>CO>[C:1]([C:22]1[CH:23]=[C:15]([Cl:14])[CH:16]=[C:17]2[C:21]=1[NH:20][C:19](=[O:24])[CH2:18]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Product: O=C1Cc2cc(Cl)cc(C(=O)c3ccccc3)c2N1

Procedure:
A mixture of 162.5 g. (1.08 mole) of benzoyl chloride and 260 g. of aluminum chloride (1.80 mole) heated to 200°C. with stirring was treated with 65 g. (0.360 mole) of recrystallized 5-chloroindolin-2-one. This mixture was stirred 15 min. and poured over ice. The resulting precipitate was triturated with boiling water and then chloroform. The chloroform solution was washed with 5% sodium bicarbonate, water, dried over sodium sulfate, and stripped to yield approximately 55 g. of a glossy solid. This material was then triturated with hot methanol and the methanol evaporated under vacuum to yield approximately 20 g. of a solid yellow material. Extraction of a benzene solution of this material with conc. hydrochloric acid removed unreacted 5-chloroindolin-2-one and the benzene solution after washing with water and drying yielded on evaporation 3 g. of a blue-gray material. Trituration of this material with room temperature methanol gave a residue which on recrystallization from methanol yielded 2.5 g. of a tan solid identified as product, m.p. 186°-187°C.
Reaction SMILES: [Li+:1].[CH3:2][CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].[SH:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.[CH3:15][C:16](=[O:19])[CH2:17][CH3:18]>C1COCC1.CCOCC>[Li+:1].[CH3:2][CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].[SH:9][C:10]1[S:11][C:12]([C:16]([OH:19])([CH2:17][CH3:18])[CH3:15])=[CH:13][N:14]=1
Reactant: CCC(C)=O
Reactant: Sc1nccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(C)(O)c1cnc(S)s1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of LDA (59 mmol) in THF was prepared at −10° C. and cooled to −78° C. To the LDA was added a solution of 2-mercaptothiazole (3.00 g, 25.6 mmol) in 5 mL of THF. After 15-20 min of stirring a solution of 2-butanone (2.23 mL, 38.4 mmol) was added, and the reaction mixture was stirred at −78° C. for 2 h. The reaction mixture was diluted with ether and washed successively with aq. 2N HCl, H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was washed with Et2O to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11]([CH3:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:18]1(C)[CH:23]=CC(S(O)(=O)=O)=C[CH:19]=1>C(O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17][CH2:19][CH2:18][CH3:23])=[O:16])[C:11]([CH3:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ncc(-c2ccc(Cl)cc2)cc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Product: CCCOC(=O)c1cc(-c2ccc(Cl)cc2)cnc1C
Yield: 28.2 %

Procedure:
5-(p-Chlorophenyl)-2-methyl-3-pyridine carboxylic acid (2 gm) and p-toluenesulphonic acid (1.69 g) in n-propanol (125 ml) was refluxed for 15 hours. The solution was concentrated and the residue partitioned between methylene dichloride and aqueous sodium carbonate. The organic phase was separated, washed with water, dried and concentrated to an oil which slowly crystallised to give the title compound (0.66 g), m.p. 54°-7°.