Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC2(CC1)CNc1cc(Cl)ccc12
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1cc(Cl)ccc12
Reaction time: 16 h

Procedure:
A mixture of 2.4 g of 6-chloro-1'-methylspiro[indoline-3,4'-piperidine], Example 23b, 5.4 g of 2-fluoronitrobenzene and 1.0 g of sodium bicarbonate is stirred at 160°-165° C. under nitrogen, for 16 hours. Thereafter, the mixture is permitted to cool before sequentially being quenched with water and extracted thrice with ether. The combined ether extracts are shaken with a large excess of 1 N hydrochloric acid. The acidified layer is basified providing a reddish oil which upon drying over magnesium sulfate and then cooling leaves an orange solid. The solid is recrystallized from an etherpentane mixture to provide prisms, mp 130°-131° C. of 6-chloro-1'-methyl-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:14]1[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]1.O.NN>CO>[CH3:22][CH:20]([N:17]1[CH2:18][CH2:19][N:14]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([NH2:9])=[C:6]([O:12][CH3:13])[CH:5]=2)[CH2:15][CH2:16]1)[CH3:21]
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1N1CCN(C(C)C)CC1
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(N2CCN(C(C)C)CC2)c(OC)cc1N
Yield: 63.5 %

Procedure:
A solution of 1-[2,5-bis(methyloxy)-4-nitrophenyl]-4-(1-methylethyl)piperazine (3.50 g, 11.3 mmol), FeCl3 (0.550 g, 3.4 mmol), activated carbon (4.0 g), and hydrazine hydrate (3.6 mL, 113 mmol) was heated in methanol (50 mL) for 3 hours. The mixture was filtered over celite and concentrated to give 4-[4-(1-methylethyl)-1-piperazinyl]-2,5-bis(methyloxy)aniline as a grey solid (2.00 g, 7.17 mmol, 63% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.10 (d, J=6.60 Hz, 6 H), 2.72 (s, 5 H), 3.03 (s, 4H), 3.59 (s, 2 H), 3.78 (s, 3 H), 3.79 (s, 3 H), 6.34 (s, 1 H), 6.57 (s, 1 H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([C:17](OCC)=[O:18])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>O1CCCC1>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCC2(CC1)OCCO2
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (8.19 g) in tetrahydrofuran (400 mL) was added slowly dropwise a solution of EXAMPLE 445A (37.8 g) in tetrahydrofuran (75 mL). The mixture was then heated at reflux for 2 hours. The reaction mixture was cooled in an ice bath and quenched very slowly with water (8 mL). Then added sequentially were 4N sodium hydroxide (8 mL), ether (200 mL), water (24 mL), ether (500 mL) and anhydrous sodium sulfate (250 g). The resulting mixture was stirred rapidly for 2 hours and then filtered. The title compound was isolated by concentration of the filtrate.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([CH3:36])=[C:8]([NH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2[S:22]([N:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[C:30]=2[CH3:35])COC)(=[O:24])=[O:23])=[O:16])[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])(=[O:3])[CH3:2]>C(O)(=O)C.O.S(=O)(=O)(O)O>[C:1]([O:4][CH2:5][C:6]1[C:7]([CH3:36])=[C:8]([NH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2[S:22](=[O:24])(=[O:23])[NH:25][C:29]2[O:33][N:32]=[C:31]([CH3:34])[C:30]=2[CH3:35])=[O:16])[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])(=[O:3])[CH3:2]
Reactant: COCN(c1onc(C)c1C)S(=O)(=O)c1ccsc1C(=O)Nc1c(C)cc(C)c(COC(C)=O)c1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCc1c(C)cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2C)c1C
Temperature: 80 °C
Yield: 27.9 %

Procedure:
To a solution of N2-(3-acetoxymethyl-2,4,6-trimethylphenyl)-3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarboxamide (0.78 g, 1.46 mmol) in acetic acid (7 mL) and water (3 mL) was added 2N sulfuric acid (3 drops). The reaction was heated at 80° C. for 4 hours, then allowed to cool to room temperature. The mixture was poured into ice water (50 mL), extracted with ethyl acetate (3×50 mL), washed with saturated sodium chloride (50 mL), dried (MgSO4), then concentrated. The residue was purified by reverse-phase HPLC (20-80% acetonitrile in water) which gave N2-(3-acetoxymethyl-2,4,6-trimethylphenyl)-3-[(3,4-dimethyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxamide (0.2 g, 28%) as an off-white powder, mp 75-77° C. 1H NMR (400 MHZ, DMSO-d6δ7.84 (d, J=5.12 Hz, 1H), 7.34 (d, J=5.12 Hz, 1H), 7.00 (s, 1H), 5.12 (s, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 1.65 (s, 3H) IR (KBr) 3458, 1738, 1646, 1356, 1181 cm−1. And N2-(3-hydroxymethyl-2,4,6-trimethylphenyl)-3-[(3,4-dimethyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxamide (45 mg, 6.9%), ratio 4:1 respectively, as a white powder, mp 100-115° C. 1H NMR (400 MHZ, DMSO-d6δ7.84 (3, J=5.12 Hz, 1H), 7.34 (d, J=5.16 Hz, 1H), 6.92 (s, 1H), 4.48 (s, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H), 2.07 (s, 3H), 1.65 (s, 3H) IR (KBr) 3439, 1651, 1341, 1181 cm−1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8]C=[CH:10][N:11]=2)[CH:2]=1.[Cl:12]N1C(=O)CCC1=O.[CH:20]([Cl:23])(Cl)Cl>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:20]([Cl:23])=[C:10]([Cl:12])[N:11]=2)[CH:2]=1
Reactant: c1cncc(-c2ncc[nH]2)c1
Reactant: ClC(Cl)Cl
Reactant: O=C1CCC(=O)N1Cl
Product: Clc1nc(-c2cccnc2)[nH]c1Cl
Reaction time: 1 h

Procedure:
To a suspension of 2-(3-pyridyl)-imidazole (1.5 g., 0.01 moles) in chloroform (150 ml.) is added dropwise with stirring over one hour at reflux N-chlorosuccinimide (2.6 g., 0.02 moles). The reaction mixture is heated three hours at reflux. After cooling, the solvent is removed at 20 mm. and the residue triturated with water while heating on a steam bath. The resulting solid is filtered and after recrystallization from acetonitrile 400 mg. of 2-(3-pyridyl)-4,5-dichloroimidazole is obtained, m.p. 237°-238° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:17]=[C:18]([CH:39]=[CH:40][CH:41]=1)[O:19][C:20]1[S:24][C:23]([CH2:25][NH:26][C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][CH:33]=[CH:32]3)=[O:28])=[CH:22][CH:21]=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(SC)C=CC=CC=1>[OH:15][C:16]1[CH:17]=[C:18]([CH:39]=[CH:40][CH:41]=1)[O:19][C:20]1[S:24][C:23]([CH2:25][NH:26][C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][CH:33]=[CH:32]3)=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(NCc1ccc(Oc2cccc(OCc3ccccc3)c2)s1)c1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Oc2cccc(O)c2)s1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Trifluoroacetic acid (1.0 mL) and thioanisole (100 μl) were added to the resulting quinoline-6-carboxylic acid (5-(3-benzyloxy-phenoxy)-thiophene-2-ylmethyl)-amide (73 mg, 0.156 mmol), and the solution was stirred for 30 minutes at room temperature. The reaction solution was neutralized with an aqueous solution of saturated sodium bicarbonate, then, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol), and the title compound (47 mg, 80%) was obtained as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].IC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[C:4]([CH3:9])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)ccc1O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1C
Temperature: 25 °C
Yield: 67 %

Procedure:
Under nitrogen, to a stirred suspension of 38.9 g (208 mmol) of 4-bromo-2-methylphenol and 43.1 g (312 mmol) of K2CO3 powder in 300 mL of THF was added 39 mL (624 mmol) of iodomethane. The mixture was heated to reflux overnight, and cooled to ambient temperature. The inorganic salts were removed by filtration, and the organic solvent was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, and dried over MgSO4. Purification by silica gel plug with ethyl acetate/hexane (5:95) gave 28 g (67%) of 4-bromo-2-methylanisole as a colorless solid: mp 65.0-66.0° C.; NMR (CDCl3) δ 2.18 (s, 3H), 3.80 (s, 3H), 6.67 (d, J=9 Hz, 1H), 7.22-7.28 (m, 2H).
Reaction SMILES: [S:1]([O-:6])(O[O-])(=O)=[O:2].[K+].[K+].[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12](SC)[CH:11]=1.[CH3:21]O>O>[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:1]([CH3:21])(=[O:6])=[O:2])[CH:11]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: CSc1cc(C)ccc1C(=O)O
Reactant: CO
Agent: [K+]
Solvent: O
Product: Cc1ccc(C(=O)O)c(S(C)(=O)=O)c1
Reaction time: 5 h

Procedure:
A solution of potassium peroxymonosulphate (23.8 g) in water was added to a solution of 4-methyl-2-methylsulphenylbenzoic acid (4.7 g) in methanol. The mixture was stirred for 5 hours and left to stand overnight at room temperature. The methanol was removed by evaporation and the resulting suspension was diluted with water and extracted with chloroform. The organic layer was dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was triturated with a mixture of ether and cyclohexane to give 4-methyl-2-methylsulphonylbenzoic acid (4.4 g) as a cream solid, m.p. 174°-174.5° C.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1)#[N:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.Cl>ClC(Cl)C.CCOC(C)=O>[CH2:33]1[CH:28]([C:22]2[C:21]3[CH:20]=[C:19]([C:17]#[N:18])[CH:27]=[CH:26][C:25]=3[NH:24][CH:23]=2)[CH2:29][CH2:30][CH:31]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[N:12][C:13]=4[CH:14]=[CH:15][CH:16]=3)[CH2:6][CH2:5]2)[CH2:32]1
Reactant: c1cc(N2CCNCC2)c2cccnc2c1
Reactant: N#Cc1ccc2[nH]cc(C3CCC(=O)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: N#Cc1ccc2[nH]cc(C3CCC(N4CCN(c5cccc6ncccc56)CC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(1-piperazinyl)-quinoline (500 mg, 2.35 mmol), 4-(5-cyano-1H-3-indolyl)-cyclohexanone (540 mg, 2.35 mmol), and sodium triacetoxyborohydride (740 mg, 3.5 mmol) in dichloroethane (20 mL) was added acetic acid (0.27 mL, 4.7 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (50 mL) and extracted in CH2Cl (3×100 mL). The organic fractions were combined, dried over Na2SO4, concentrated, filtered and chromatographed (5% MeOH/EtOAc) yielding 410 mg (41%) of the cis isomer as a white solid. The HCl salt was generated from EtOAc yielding a white solid: mp 220-223° C. Elemental Analysis for C28H29N5.HCl.1H2O; Calc'd C, 68.62; H, 6.58; N, 14.29; Found C, 68.99; H, 6.54; N, 14.06.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[C:12]([CH3:24])=[N:13][N:14](COCC[Si](C)(C)C)[CH:15]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][C:32]([F:35])([F:34])[F:33].NC1N=C(NC(C2C(C)N(COCC[Si](C)(C)C)NC=2)=O)C=CC=1C1C=CC=CC=1OC(F)(F)F.Cl>CO.O.O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[C:12]([CH3:24])=[N:13][NH:14][CH:15]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][C:32]([F:33])([F:35])[F:34]
Reactant: Cc1nn(COCC[Si](C)(C)C)cc1C(=O)Nc1ccc(-c2ccccc2OC(F)(F)F)c(N)n1
Agent: CC1C(C(=O)Nc2ccc(-c3ccccc3OC(F)(F)F)c(N)n2)=CNN1COCC[Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1n[nH]cc1C(=O)Nc1ccc(-c2ccccc2OC(F)(F)F)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
A mixture of N-{6-amino-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}-3-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide and N-{6-amino-5-[2-(trifluoromethoxy)phenyl]pyridin-2-yl}-3-methyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (Preparation 18 as a mixture of regioisomers, 0.050 g, 0.1 mmol) was stirred in methanol (1 ml) and water (0.5 ml). To this was added HCl in 1,4-dioxane (1 ml). The reaction was stirred at room temperature for 18 hours. A further 1 ml of HCl in 1,4-dioxane was added and the reaction stirred for a further 72 hours at room temperature before concentrating in vacuo. The residue was partitioned between ethyl acetate and water. The organic extract was dried over MgSO4 and concentrated in vacuo to yield a gum. The gum was purified by trituration with diethyl ether to afford the title compound as a white solid (0.012 g, 32% yield).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:28][CH:27]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclopropylmethyl)(propyl)amino]pyrimidine-4-carboxylic acid (Intermediate 21) and 4-(methylsulfonyl)aniline (Enamine), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][CH2:29][O:30][C:31]([C:33]1[CH:44]=[C:36]2[C:37]([C:41]([OH:43])=O)=[CH:38][CH:39]=[CH:40][N:35]2[N:34]=1)=[O:32].[C:45]12([CH2:55][NH2:56])[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:53][CH:47]([CH2:48]3)[CH2:46]1)[CH2:52]2.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[CH2:29]([O:30][C:31]([C:33]1[CH:44]=[C:36]2[C:37]([C:41](=[O:43])[NH:56][CH2:55][C:45]34[CH2:54][CH:49]5[CH2:48][CH:47]([CH2:53][CH:51]([CH2:50]5)[CH2:52]3)[CH2:46]4)=[CH:38][CH:39]=[CH:40][N:35]2[N:34]=1)=[O:32])[CH3:28]
Reactant: CCOC(=O)c1cc2c(C(=O)O)cccn2n1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Reaction time: 15 h

Procedure:
BOP (11 g, 24 mmol) is added to a slurry of pyrazolo[1,5-a]pyridine-2,4-dicarboxylic acid 2-ethyl ester (5.6 g, 24 mmol), adamantan-1-ylmethylamine (4.4 g, 27 mmol), iPr2NEt (21 mL, 120 mmol), and DMF (240 mL) under N2. The reaction vessel is sealed and the mixture is left to stir for 15 h. EtOAc (200 mL) is added. The solution is washed with 50% sat. aq. NH4Cl (2×500 mL). The aqueous phases are extracted with EtOAc (3×200 mL). The combined organics are dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (2:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) affords the title compound as a tan solid. 1H NMR (400 MHz, CDCl3) δ: 8.62 (d, 1H), 7.60 (d, 1H), 7.44 (s, 1H), 7.00 (t, 1H), 6.23 (bs, 1H), 4.48 (q, 2H), 3.23 (d, 2H), 1.98-2.07 (m, 3H), 1.57-1.78 (m, 12H), 1.45 (t, 3H). LC-MS m/z (M+H+): 382.2; RT=1.09 min.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[C:13]([NH:19][CH:20]=[O:21])(C(OCC)=O)[CH2:12][C:11]2=[CH:22][CH:23]=[CH:24][C:9]3=[C:10]2[N:5]1[CH2:6][CH2:7][CH2:8]3.Cl>CO>[O:3]=[C:4]1[CH:13]([NH:19][CH:20]=[O:21])[CH2:12][C:11]2=[CH:22][CH:23]=[CH:24][C:9]3=[C:10]2[N:5]1[CH2:6][CH2:7][CH2:8]3
Reactant: CCOC(=O)C1(NC=O)Cc2cccc3c2N(CCC3)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=CNC1Cc2cccc3c2N(CCC3)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.2 %

Procedure:
Sodium hydroxide solution (5.0 mL of 4.0 N, 20 mmol) was slowly added to ethyl 2,3,6,7-tetrahydro-3-oxo-2-(formylamino)-1H,5H-benzo(ij)quinolizine-2-carboxylate (3.04 g, 10.0 mmol) in methanol (25 mL). After stirring at room temperature for 30 min, hydrochloric acid (5.0 mL of 4.0 N) was added and the precipitate was filtered off, washed with water and air dried to give 2.4 g of N-(2,3,6,7-tetrahydro-3-oxo-1H,5H-benzo(ij)quinolizin-2-yl)formamide, mp 149°-152° C. A portion of the product was recrystallized from ethyl acetate for analysis; mp 140°-143°. Anal. Calcd. for C13H14N2O2 : C, 67.81; H, 6.13; N, 12.17. Found: C, 67.67; H, 6.07; N, 11.94.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]([C:7]1[N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:9]=[C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])[N:11]=1)=[O:6].C(N(CC)CC)C.[Br:42][CH2:43][C:44](Cl)=[O:45].C(=O)(O)[O-].[Na+]>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:42][CH2:43][C:44]([O:1][CH2:2][CH2:3][O:4][C:5]([C:7]1[N:8]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=2)[CH:9]=[C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])[N:11]=1)=[O:6])=[O:45]
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)OCCO)n1
Reactant: O=C(Cl)CBr
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)OCCOC(=O)CBr)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1 g (2 mmol) of 2-hydroxyethyl-4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylate (Example 125) are dissolved in a mixture of 25 ml of dichloromethane and 12 ml of DMF, and 1570 μl (1.14 g, 11.2 mmol) of triethylamine are added. While cooling in ice, 804 μl (1.52 g, 9.6 mmol) of bromoacetyl chloride and a catalytic amount of DMAP are added. After stirring at RT for 16 h, a further 0.57 g (5.6 mmol) of triethylamine, 0.76 g (4.8 mmol) of bromoacetyl chloride and a few crystals of DMAP are added while cooling in ice. The reaction mixture is stirred at RT for 2.5 h, poured into saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined extracts are washed twice with water and once with saturated sodium chloride solution, dried with magnesium sulphate and evaporated in vacuo. The residue from evaporation is purified by chromatography on silica gel with dichloromethane/methanol as eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][C:17]#[N:18])[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1.[C:19]1(=[O:29])[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[C:19]([C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH2:15][CH2:16][C:17]#[N:18])[C:12]3[C:4]([C:5]=2[CH:6]=1)=[CH:3][C:2]([CH3:1])=[CH:14][CH:13]=3)=[O:29])([OH:24])=[O:23]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccc2c(c1)c1ccccc1n2CCC#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)c1cc(C(=O)c3ccccc3C(=O)O)ccc1n2CCC#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of the compound prepared in step (a) (0.03 mole), phthalic anhydride (0.03 mole) and 50 ml. of benzene were stirred in an ice bath. Aluminum chloride (0.065 mole) was slowly added to the mixture, and after addition, the mixture was stirred for 30 minutes at 0°C. and then warmed to 50°C. and stirred for 3 hours. After cooling, 3N hydrochloric acid was added to decompose the aluminum complex. The yellow solid that formed was filtered and stirred in warm dilute ammonium hydroxide. The hydroxide solution was filtered, and the filtrate was neutralized with dilute hydrochloric acid. The solid obtained upon neutralization was recrystallized from xylene to give 3-(o-carboxybenzoyl)-6-methyl-9-cyanoethylcarbazole as white crystals, melting point 190°C.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([OH:17])[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2].[N+](=[CH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[N-]>ClCCl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[C:31]([O:30][C:28](=[O:29])[CH2:27][O:17][C@H:13]1[C@H:12]2[CH2:16][C@H:15]([C@@H:10]([C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:3]3[C:1]#[N:2])=[O:9])[N:11]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)N1CCC[C@H]1C#N
Reactant: CC(C)(C)OC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CO[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 (322 mg) in dichloromethane (6 mL), were added rhodium acetate dimer (4.24 mg) and tert-butyl diazoacetate (0.27 mL). The mixture was stirred at room temperature for 4 hrs. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound (236 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:10]=1[C:26]([OH:28])=[O:27])=[O:8].OS(O)(=O)=O.I[CH:39]([CH3:41])[CH3:40].[C:42]([O-])([O-])=O.[K+].[K+]>CO.CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:39]([CH3:41])[CH3:40])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:10]=1[C:26]([O:28][CH3:42])=[O:27])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CC(C)I
Reactant: O=C(NCc1ccc(F)c(F)c1)c1c(C(=O)O)n(Cc2ccccn2)c2cc(O)ccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(C)C)cc2n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(3,4-difluorobenzylcarbamoyl)-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylic acid (Compound 225, crude 6.5 g) and concentrated H2SO4 (0.1 ml, catalytic amount) in MeOH (100 ml) was heated to 90° C. for 16 h. The mixture was cooled and the suspension was filtered. The filtrate was concentrated, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo to give a pale brown solid as the crude product. General Procedure N. To a solution of the crude product in DMF (10 ml) was added 2-iodopropane (2.2 ml, 22 mmol) and K2CO3 (1.8 g, 13.2 mmol). The reaction was stirred at room temperature for 16 h and was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[CH:12]1(N=C=NC2CCCCC2)CCCCC1>CO>[CH3:12][O:7][C:6](=[O:8])[C:5]1[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=1)[OH:11]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Cc1ccc(C(=O)O)c(O)c1
Solvent: CO
Product: COC(=O)c1ccc(C)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-methylsalicylic acid (75 g, 0.49 mmol) in MeOH (500 mL) at 0° C. was treated with dicyclohexylcarbodiimide (101 g, 0.49 mmol) and the mixture was stirred at room temperature for 2 h. The precipitated dicyclohexylurea was removed by filtration and the filtrate was concentrated in vacuo. The crude residue was purified by distillation (110° C. bath temp, 0.5 mm Hg) to afford 4-methylsalicylic acid methyl ester