Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH2:5][C:6]1[NH:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([CH3:16])[C:7]=1[C:17](=O)[CH3:18])(=O)C.[C:20]([C:25]1[CH:29]=[CH:28][NH:27][C:26]=1[CH3:30])([O:22][CH2:23][CH3:24])=[O:21].C(OCC)(=O)C>ClCCCl.ClCCl>[CH3:16][C:8]1[C:7]2[C:6](=[CH:5][C:29]3[C:25]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:26]([CH3:30])[NH:27][C:28]=3[C:17]=2[CH3:18])[NH:10][C:9]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1[nH]c(COC(C)=O)c(C(C)=O)c1C
Reactant: CCOC(=O)c1cc[nH]c1C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1[nH]c2cc3c(C(=O)OCC)c(C)[nH]c3c(C)c2c1C
Yield: 6.1 %

Procedure:
A solution of ethyl 5-acetoxymethyl-4-acetyl-3-methylpyrrole-2-carboxylate (0.267 g, 1.0 mmol) and 3-carbethoxy-2-methylpyrrole (0.153 g, 1.0 mmol) in 1,2-dichloroethane (10 cm3) was heated at reflux and stirred with Montmorillonite clay (1 g) for 18 h. After filtration from clay and washing well with 1,2-dichloroethane, evaporation of the combined filtrates under reduced pressure gave an oil. This oil was submitted to flash chromatography on silica eluting with (0-20%) ethyl acetate in dichloromethane to give the starting 3-carbethoxy-2-methylpyrrole (0.045 g, 29.4%) and diethyl 1,5-dihydro-3,4,6-trimethylpyrrolo[2,3-f]indole-2,7-dicarboxylate as a colourless solid (0.021 g, 6.14%) m.p. 269° C. (decomp); δH ([2H6]-DMSO)11.34 (1H, s, 5-NH), 11.00 (1H, s, 1-NH), 7.80 (1H, s, 8-H), 4.33 (2H, q, 7-OCH2CH3), 4.26 (2H, q, 2-OCH2CH3), 2.85 (6H, s, 3-CH3 and 4-CH3), 2.69 (3H, s, 6-CH3), 1.39 (3H, t, 7-OCH2CH3), and 1.37 (3H, t, 2-OCH2CH3); saturation of the singlet 8-H at δ 7.80 enhanced the signal due to 1-NH at δ 11.00 (2.3%); m/z (%) 342 (75,M+), 296 (100), 268 (6), 223 (7) and 195 (5) (Found: M+ 342.1580. C19H22N2O4 requires M, 342.1579; λ max EtOH/nm (log ε max.dm3 mol−1 cm−1 378 (3.56), 365 sh (353), 329 (3.83), 3.04 (3.99) and 259 (3.74). Further elution gave diethyl 1,7-dihydro-3,4,6-trimethylpyrrolo[3,2-f]indole-2,5-dicarboxylate as a colourless solid (0.048 g, 14%) m.p. 216-216.5° C. (Found: C, 66.82; H, 6.68; N, 8.17. C19H22N2O4 requires C, 66.65; H, 6.48, N, 8.18%); δ ([2H6]-DMSO) 11.30 (1H, s, 7-NH), 10.91 (1H, s, 1N-H), 7.12 (1H, s, 8-11), 4.35 (2H, q, 5-OCH2CH3), 4.28 (2H, q, 2-OCH2CH3), 2.90 (3H, s, 4-CH3), 2.87 (3H, s, 3-CH3, 2.54 (3H, s, 6-CH3), 1.36 (3H, t, 5-OCH2CH3) and 1.34 (3H, t, 2-OCH2CH3); saturation of the 8-H proton at δ 7.12 enhanced the signals due to 7-NH at δ 11.30 (2.4%) and 1-NH at δ 10.91 (1.8%); m/z (%) 342 (64, M+), 296 (100), 250(5), and 194(9); λ max (EtOH)/nm (log ε max/dm3 mol−1 cm−1) 340 (4.10), 327.5 (4.53) and 270 (4.46), and the starting 5-acetoxymethyl-4-acetylpyrrole (0.029 g, 10.9%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:8]=2[CH:24]=1)(O)=[O:2].[CH2:25]([S:30]([NH2:33])(=[O:32])=[O:31])[CH2:26][CH2:27][CH2:28][CH3:29]>CN(C)C=O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[C:14]([CH2:13][N:9]2[C:8]3[CH:24]=[C:4]([C:1](=[O:2])[NH:33][S:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31])[CH:5]=[CH:6][C:7]=3[N:11]=[C:10]2[CH3:12])[N:15]=1
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1cc2ccccc2cn1
Reactant: CCCCCS(N)(=O)=O
Solvent: CN(C)C=O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3cc4ccccc4cn3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.2 %

Procedure:
N,N′-carbonyldiimidazole (0.324 g) was added to a solution of 6-carboxy-1-(isoquinolin-3-ylmethyl)-2-methylbenzimidazole (0.413 g) as obtained in Production Example 5 in N,N-dimethylformamide (10 ml) all at once and the mixture was stirred at room temperature for 1.5 hour. Then, 1-pentanesulfonamide (0.302 g) and diazabicyclo-undecene (0.304 g) were added thereto, and the resulting mixture was stirred at 100° C. for 6.5 hour. The reaction solution was concentrated, brine was added to the concentrate, and the mixture was extracted with chloroform. The organic layer was concentrated and the residue was purified by silica gel column chromatography (eluate: methanol/chloroform=1/19) followed by recrystallization from hexane/ethyl acetate (2/3) to yield the desired compound, 1-(isoquinolin-3-ylmethyl)-2-methyl-6-(1-pentanesulfonyl-carbamoyl)benzimidazole (13) (0.142 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:49])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@@H:14]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([O:38]CC3C=CC(OC)=CC=3)([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])=[CH:25][C:24]=2[CH3:48])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:49])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C@@H:14]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:38])([C:30]([F:33])([F:32])[F:31])[C:34]([F:35])([F:36])[F:37])=[CH:25][C:24]=2[CH3:48])[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCc1ccc(OC[C@H](Cc2ccccc2)Oc2ccc(C(OCc3ccc(OC)cc3)(C(F)(F)F)C(F)(F)F)cc2C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(OC[C@H](Cc2ccccc2)Oc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2C)cc1
Yield: 40.7 %

Procedure:
330 mg (0.5 mmol) of 3-[4-((S)-2-{2-methyl-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-3-phenyl-propoxy)-phenyl]-propionic acid methyl ester in 10 mL of EtOAc were hydrogenated in the presence of 200 mg of 10% Pd/C. After removal of the catalyst and evaporation of the solvent, the residue was purified by column chromatography on silica gel with EtOAc/n-heptane 1:4 to yield 116 mg (42%) of 3-(4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-3-phenyl-propoxy}-phenyl)-propionic acid methyl ester as a light yellow oil, MS: 569 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].C(N(CC)CC)C.[CH:26]1([CH2:29][NH:30][CH2:31][CH3:32])[CH2:28][CH2:27]1>C(COC)OC>[CH:26]1([CH2:29][N:30]([CH2:31][CH3:32])[C:6]2[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([C:15]([F:18])([F:17])[F:16])=[C:2]([Cl:1])[C:7]=2[N+:8]([O-:10])=[O:9])[CH2:28][CH2:27]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCNCC1CC1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCN(CC1CC1)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Yield: 69.9 %

Procedure:
To a stirred solution of 15.0 grams (0.05 mole) of 2,4-dichloro-3,5-dinitrobenzotrifluoride and 4.97 grams (0.05 mole) of triethylamine in 200 ml. of dimethoxyethane was added, dropwise, 4.28 grams (0.05 mole) of N-cyclopropylmethyl-N-ethylamine at room temperature over a period of 2.5 hours. The resultant mixture was then heated under reflux for 16 hours. The solvent was removed by evaporation under reduced pressure and the residue then dissolved in a mixture of chloroform and water. The organic layer was separated and was washed with water, dilute hydrochloric acid, dilute sodium bicarbonate, and then water. After drying over anhydrous sodium sulfate, the organic solution was evaporated to dryness. The residue was dissolved in hexane and filtered and then evaporated to dryness to give 12.85 grams of the product as as dark, viscous amber liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Li+].[Br:13][C:14]1[C:27]2=[N:28][O:29][C:25]3=[C:26]2[C:17]([C:18](=[O:30])[C:19]2[C:24]3=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:16](Br)[CH:15]=1.CC(OC)(C)C>CC(N(C)C)=O>[Br:13][C:14]1[C:27]2=[N:28][O:29][C:25]3=[C:26]2[C:17]([C:18](=[O:30])[C:19]2[C:24]3=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:16]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:15]=1
Reactant: O=C1c2ccccc2-c2onc3c(Br)cc(Br)c1c23
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(Nc2cc(Br)c3noc4c3c2C(=O)c2ccccc2-4)cc1
Temperature: 5 °C
Reaction time: 19 h
Yield: 60.1 %

Procedure:
About 70 g of 4-amino benzoic acid and 22 g of lithium hydroxide were mixed in 800 mL of DMAc. Then 100 g of 3,5-dibromo-6H-anthra[1,9-cd]isoxazol-6-one was dissolved in the pre-mixed solution. Nitrogen protection was applied to the reaction mixture at 45-55° C. for about 18-20 hours. After reaction completion was confirmed by HPLC, 30 mL of MTBE was slowly added to the reactor. Reaction mixture was then slowly cooled to 0-10° C. under nitrogen protection. Centrifuged the solid and washed with 18 mL of MTBE. Dried the wet cake under 25-30° C. to obtain about 69 g of 4-((3-bromo-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23]C(O)=O)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([Cl:28])=[N:8]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.[CH2:35]([O:37][C:38]([CH:40]1[CH2:45][CH2:44]C(O)[CH2:42][CH2:41]1)=[O:39])[CH3:36]>>[CH2:35]([O:37][C:38]([CH:40]1[CH2:45][CH2:44][CH:23]([N:19]2[C:18](=[O:27])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:29]=[CH:30][C:2]([Cl:1])=[CH:3][C:4]=3[C:31]([F:34])([F:33])[F:32])[N:8]=[C:9]4[Cl:28])/[S:21][C:20]2=[O:22])[CH2:42][CH2:41]1)=[O:39])[CH3:36]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(c2)c(Cl)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O
Product: CCOC(=O)C1CCC(N2C(=O)S/C(=C\c3ccc4c(c3)c(Cl)nn4Cc3ccc(Cl)cc3C(F)(F)F)C2=O)CC1

Procedure:
4-[(5Z)-5-({3-Chloro-1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]cyclohexanecarboxylic acid ethyl ester was prepared from [(5Z)-5-({3-chloro-1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 287) and 4-hydroxycyclohexanecarboxylic acid ethyl ester following General Procedure J.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][NH:30][CH3:31]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:13])[N:30]([CH2:29][CH2:28][N:27]([CH3:32])[CH3:26])[CH3:31])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with N,N,N′-trimethylethylenediamine gives “A90”; method 2: HPLC/MS: 1.55 min, [M+H]419;
Reaction SMILES: OO.[C:3]([O:8][CH2:9][CH3:10])(=[O:7])[C:4]([CH3:6])=O.[C:11]([C:14]1C=C[N:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].S(=O)(=O)(O)O>O.ClCCl>[C:11]([C:14]1[CH:15]=[CH:16][N:17]=[C:4]([C:3]([O:8][CH2:9][CH3:10])=[O:7])[CH:6]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1ccncc1
Reactant: CCOC(=O)C(C)=O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)=O)ccn1
Yield: 24.2 %

Procedure:
30% Hydrogen peroxide (130 ml) was added to ethyl pyruvate (216 g) at -5° to 5° C. with stirring. This solution was then added to a mixture of 4-acetylpyridine (15.0 g), concentrated sulfuric acid (12.4 g), ferrous sulfate heptahydrate (345 g), dichloromethane (1.5 l) and water (100 ml) at the same temperature with stirring. After further stirring for 30 minutes, the resulting organic layer was separated. The solution was washed with aqueous sodium sulfite and then water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography by eluting with a mixture of ethyl acetate and toluene (1:20) to give ethyl 4-acetyl-2-pyridinecarboxylate (5.79 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[Li]CCCC.[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+]([O-])=O)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15]>C1COCC1.CCCCCC>[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15]
Reactant: OCC1CCOCC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1c(OCC2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of tetrahydropyran-4-methanol (782 mg, 6.73 mmol) in THF (25 mL), was added slowly 1.38M nBuLi (4.13 mL, 5.70 mmol) in hexane at −78° C. under nitrogen. At one hour a solution of 2,6-dinitrobenzonitrile (1.00 g, 5.18 mmol) in THF (25 mL) was added. The reaction was stirred under N2 overnight at rt, then was quenched with water (100 mL). The precipitate was collected by filtration to provide 2-nitro-6-((tetrahydro-2H-pyran-4-yl)methoxy)benzonitrile (1.13 g, 83%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 1.68 (m, 2H), 2.06 (br, 1H), 3.33 (m, 2H), 3.88 (m, 2H), 4.11 (d, J=6.0 Hz, 2H), 7.72 (d, J=6.0 Hz, 1H), 7.89-7.85 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: N#CC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.5 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and piperidine-4-carbonitrile (880 mg, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 18 h. The reaction mixture was evaporated in vacuo and the residue partitioned between saturated sodium bicarbonate solution (100 mL) and dichloromethane (100 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, Biotage 50 g column, 0-100% ethyl acetate in cyclohexane) to afford the title compound (1.10 g, 99%). 1H NMR (CDCl3, 300 MHz): 7.46-7.41 (m, 2H); 7.21-7.15 (m, 2H); 3.44 (s, 2H); 2.70-2.57 (m, 3H); 2.38-2.22 (m, 2H); 1.99-1.74 (m, 4H). LCMS (Method B): RT=1.82 min, M+H+=280.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][CH:11]2[CH2:13][C:12]2([F:15])[F:14])=[CH:7][C:5]([NH2:6])=[C:4]([F:16])[CH:3]=1.[N:17]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[OH-].[Na+]>O.Cl>[Cl:1][C:2]1[C:8]([O:9][CH2:10][CH:11]2[CH2:13][C:12]2([F:14])[F:15])=[CH:7][C:5]([NH:6][NH2:17])=[C:4]([F:16])[CH:3]=1
Reactant: Nc1cc(OCC2CC2(F)F)c(Cl)cc1F
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(OCC2CC2(F)F)c(Cl)cc1F
Temperature: -10 °C
Reaction time: 3 h

Procedure:
29.3 g 4-Chloro-2-fluoro-5-(2,2-difluorocyclopropylmethoxy)aniline was treated first with 45 ml half concentrated hydrochloric acid and then with 273 ml concentrated hydrochloric acid. It was then cooled to -10° C. and treated dropwise with a solution of 8.3 g sodium nitrite in 17 ml water at a such rate that the temperature of the reaction mixture did not rise above -5° C. It was stirred for 3 hours at -5° C. and the at -15° C., a solution of tin (II) chloride dihydrate in 34 ml concentrated hydrochloric acid added dropwise at such a rate that the temperature of the reaction mixture did not exceed -10° C. It was warmed at room temperature overnight. For the work-up, it was cooled to 0° C. and slowly neutralised with with 430 ml 32% caustic soda solution. The precipitated tin hydroxide slurry was separated by filtration through Celite and the filter cake washed with ether and the aqueous mother liquor extracted with ether. The combined organic phases were dried over magnesium sulphate and the solvent removed.
Reaction SMILES: C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+].[O:41]1[CH2:46][CH2:45][N:44]([C:47]2[CH:52]=[C:51]3[NH:53][CH2:54][C:55]4([CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[C:50]3=[CH:49][CH:48]=2)[CH2:43][CH2:42]1.Cl[C:62]1[C:71]2[C:66](=[CH:67][C:68]([F:72])=[CH:69][CH:70]=2)[N:65]=[C:64]([C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([S:79]([CH3:82])(=[O:81])=[O:80])[CH:74]=2)[C:63]=1[CH3:83]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:72][C:68]1[CH:67]=[C:66]2[C:71]([C:62]([N:53]3[C:51]4[C:50](=[CH:49][CH:48]=[C:47]([N:44]5[CH2:43][CH2:42][O:41][CH2:46][CH2:45]5)[CH:52]=4)[C:55]4([CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[CH2:54]3)=[C:63]([CH3:83])[C:64]([C:73]3[CH:78]=[CH:77][CH:76]=[C:75]([S:79]([CH3:82])(=[O:80])=[O:81])[CH:74]=3)=[N:65]2)=[CH:70][CH:69]=1
Reactant: Cc1c(-c2cccc(S(C)(=O)=O)c2)nc2cc(F)ccc2c1Cl
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc(S(C)(=O)=O)c2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(dicyclohexylphosphino)-2,4,6-tri-i-propyl-1,1-biphenyl (24.5 mg, 0.051 mmol), Pd2dba3 (23.6 mg, 0.026 mmol), sodium tert-butoxide (49.5 mg, 0.52 mmol), 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (47.1 mg, 0.17 mmol) (described herein), and 4-chloro-7-fluoro-3-methyl-2-(3-(methylsulfonyl)phenyl)quinoline (60 mg, 0.17 mmol) (described herein) in toluene (1.7 mL) was stirred at 100° C. for 60 min, then cooled to rt and concentrated. The resulting residue was taken up in EtOAc, washed with saturated aqueous sodium bicarbonate solution, 1M NaOH, and brine, then the organic layer dried (MgSO4) and concentrated. Column chromatography afforded 1-(7-fluoro-3-methyl-2-(3-(methylsulfonyl)phenyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran] as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.24 (1H, d, J=2.0 Hz), 8.07 (1H, d), 7.96 (1H, d), 7.76 (3H, m), 7.31 (1H, m), 7.15 (1H, d, J=8.2 Hz), 6.36 (1H, d), 5.59 (1H, s), 4.01-4.10 (2H, m), 3.91-4.01 (2H, m), 3.69-3.82 (4H, m), 3.51-3.63 (2H, m), 3.11-3.19 (3H, m), 2.97 (4H, d, J=4.7 Hz), 2.25-2.33 (3H, m), 2.10-2.24 (2H, m), 1.89 (1H, d), 1.80 (1H, d). Mass Spectrum (ESI) m/e=588 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+:42]>C(O)C.O>[OH:37]/[N:36]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][C@H:11]([C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]([O-:33])=[O:32])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[Na+:42]
Reactant: NO
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(N2CCC(C(=O)O)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(N2CCC(C(=O)[O-])CC2)cc1
Temperature: 120 °C
Yield: 61.1 %

Procedure:
To a microwave vial was added (R)-1-(4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)phenyl)piperidine-4-carboxylic acid (100 mg, 218 μmol), hydroxylamine hydrochloride (45.5 mg, 654 μmol) and sodium hydrogencarbonate (91.6 mg, 1.09 mmol) in ethanol (2 mL) and water (0.2 mL). The vial was capped and heated at 120° C. for 15 min, then hydroxylamine hydrochloride (45.5 mg, 654 μmol) and sodium hydrogencarbonate (91.6 mg, 1.09 mmol) were added again. The vial was capped and heated at 120° C. for 10 min, then the reaction mixture was evaporated. The residue was washed with dichloromethane, then suspended in dichloromethane/methanol 9:1 and filtered. The filtrate was concentrated and purified by chromatography (SiO2; gradient dichloromethane/methanol 19:1 to dichloro-methane/methanol 4:1) to afford the title compound (66 mg, 61%). Light brown solid, MS (ESI−): m/z=472.4 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([CH3:11])[C:2]([Cl:1])=[N:3][CH:4]=1)[CH3:18]
Reactant: Cc1cc(C(=O)O)cnc1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnc(Cl)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 6-chloro-5-methyl-nicotinic acid (13.85 g, 80.75 mmol) in dry ethanol (200 mL) containing some drops of concentrated H2SO4 is stirred at reflux for 2 days. The solution is cooled to rt, the solvent evaporated, the residue dissolved in EA (200 mL) and washed with a solution of sat. aq. Na2CO3 (2×80 mL), 1M aq. KHSO4 (2×80 mL) and brine (50 mL). The org. phase is dried over MgSO4, filtered and evaporated to give 6-chloro-5-methyl-nicotinic acid ethyl ester (12.65 g) as a solid; LC-MS: tR=0.92 min; [M+1]+=200.10; 1H NMR (CDCl3) δ 1.43 (t, J=7.0 Hz, 3H), 2.46 (s, 3H), 4.43 (q, J=7.3 Hz, 2H), 8.16 (m, 1H), 8.84 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=C(c2c[nH]cn2)c2ccccc2C1Cc1ccccc1
Solvent: CCO
Product: c1ccc(CC2CC(c3c[nH]cn3)c3ccccc32)cc1

Procedure:
4-(3-benzyl-3H-inden-1-yl)-1H-imidazole was hydrogenated in ethanol using 10% palladium on charcoal as a catalyst. The mixture was filtered through Celite, and the solvent was evaporated. The crude 4-(3-benzyl-2,3-dihydro-1H-inden-1-yl)-1H-imidazole which was the mixture of the cis and trans diastereomers (the ratio 94:6) was purified by flash chromatography (elution with a dichloromethane—methanol gradient).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(Cl)([Cl:13])=O>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:8]([Cl:13])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1nc(C)c(C(=O)Cl)s1

Procedure:
In a 300-ml three-neck flask, 7.9 g (0.5) mole) of 2,4-dimethylthiazole-5carboxylic acid were suspended in 200 ml of xylene and under heating and reflux, phosgene was blown at a flow rate of 340 ml/hr for 12 hours (0.18 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 8.2 g of 2,4-dimethylthiazole-5-carboxylic acid chloride. Its purity and yield were 95.0% and 98.0%, respectively.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:25])([F:24])[CH2:9][NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:15]=1>C1COCC1>[F:25][C:8]([F:7])([F:24])[CH2:9][NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:20][NH2:21])=[CH:22][CH:23]=2)[N:15]=1
Reactant: N#Cc1ccc(-c2csc(NCC(F)(F)F)n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(-c2csc(NCC(F)(F)F)n2)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Add lithium aluminum hydride (402 mg, 10.6 mmol) portionwise over 3 min to a solution of 4-[2-(2,2,2-trifluoroethylamino)-thiazol-4-yl]-benzonitrile (1.0 g, 3.5 mmol) in THF (40 mL) at room temperature under a nitrogen atmosphere. Stir the mixture for 1 h at 55° C. Cool the mixture to room temperature, quench slowly with water (0.4 mL) and 1N NaOH (0.4 mL). Add sodium sulfate to absorb residual water, filter through Celite®, wash with DCM (50 mL) and concentrate in vacuo. Purify the residue by SCX chromatography to obtain the desired intermediate (902 mg, 90%). MS (ES+) m/z: 288 (M+H)+.