Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12]([OH:15])(=[O:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O.C([O-])(O)=O.[Na+]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][S:12]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:14])=[O:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCS(=O)(=O)O)cc1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=[N+]([O-])c1ccc(CCS(=O)(=O)N2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
A flask was charged with 491 mg (2.12 mmol) of solid 2-(4-nitro-phenyl)-ethanesulfonic acid (as prepared in the previous step), which was treated with 3.10 mL (42.4 mmol) of thionyl chloride and heated to 80° C. for 7 h. The volatile components were removed in vacuo, the residue was taken up in THF (20 mL), and 927 μL (10.6 mmol) of morpholine was added. The mixture was stirred at RT for 16 h, diluted with water (15 mL) and saturated aqueous NaHCO3 (15 mL) and extracted with EtOAc (2×70 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 370 mg (52%) of the title compound as a pale yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 8.20 (d, 2H, J=8.8 Hz), 7.40 (d, 2H, J=8.8 Hz), 3.79-3.73 (m, 4H), 3.31-3.23 (m, 6H), 3.21-3.14 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[S:22]1[CH:26]=[CH:25][N:24]=[C:23]1[NH2:27]>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:15])(=[O:16])[N:4]([CH3:17])[C:3]=1[C:18]([NH:27][C:23]1[S:22][CH:26]=[CH:25][N:24]=1)=[O:19]
Reactant: Nc1nccs1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2sc3ccccc3c2S1(=O)=O

Procedure:
25.0 gm (0.0768 mol) of methyl 4-hydroxy-2-methyl-2H-[1]benzothieno-[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 10.0 gm (0.12 mol) of 2-thiazolamine were refluxed for 16 hours in 300 cc of anhydrous xylene in an atmosphere of nitrogen. The released methanol was removed by means of 4 A-molecular sieve filled in a Soxhlet apparatus. After cooling and standing for several hours, the reaction product was filtered off. After recrystallization from a mixture of dimethylformamide and 1,2-dichloroethane 19.9 gm (66% of theory) of light-yellow 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-[1]benzothieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide were obtained.
Reaction SMILES: C[O:2][C:3]1[C:4]([C:13]2[C:22]([O:23][CH3:24])=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.Br.[K+].[Br-].OC1C2C(=CC=CC=2)C=NC=1C1N=CC2C(C=1O)=CC=CC=2>C(O)(=O)C.O.C(Cl)(Cl)Cl>[OH:2][C:3]1[C:4]([C:13]2[C:22]([O:23][CH3:24])=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1cc2ccccc2nc1-c1nc2ccccc2cc1OC
Agent: Br
Agent: Oc1c(-c2ncc3ccccc3c2O)ncc2ccccc12
Agent: [Br-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc2ccccc2nc1-c1nc2ccccc2cc1O
Reaction time: 8 h

Procedure:
240 mg (0.75 mmol) of 3,3'-dimethoxy-2,2'-biquinoline are suspended in 15 ml of 30 percent strength HBr in glacial acetic acid. In the course of heating, the educt soon dissolves. After as little as about 1 hour, the first crystals of the hydrobromide precipitate. The reaction solution is constantly refluxed. After 8 hours, another 5 ml of 30 percent strength HBr in glacial acetic acid are added. The reaction is stopped after 24 hours. The reaction mixture is diluted to 100 ml with water. This dissolves the precipitate formed. The aqueous phase is brought to a pH of 11 with solid sodium hydroxy [sic] pellets and extracted with 50 ml of chloroform. The aqueous phase is then brought to a pH of 6 with concentrated hydrochloric acid and extracted with 250 ml of chloroform (5×50 ml). The chloroform phase is dried over CaCl2 and evaporated on a rotary evaporator (beige crude product). The crude product is purified on a column (silica gel/chloroform). Finally, the product is recrystallized from 10 ml of toluene, giving colorless crystals of pure substance. Yield 0.19 g (86.4%)--melting point 255° C. dec.--RF (silica gel/toluene:glacial acetic acid=4:1)=0.26.--IR (KBr):ν=3422 cm-1 (m), 3066 (m), 2938 (m), 2842 (m), 3010-2280 (m, OH), 1576 (m), 1501 (m), 1465 (m), 1424 (w), 1375 (w), 1332 (m), 1309 (s), 1279 (s), 1241 (m), 1214 (w, C--O), 1200 (w), 1161 (w, C--O), 1143 (s), 1061 (w), 995 (w), 758 (s).--UV (chloroform): λmax (ε)=335 nm (8326), 327 (8062), 298 (6134).--1H-NMR ((D6 ) DMSO/TMS): δ=3.90 (s, 3H, OCH3), 7.00-7.70 (m, 6H, 5-H, 5'-H, 6-H, 6'-H, 7-H, 7'-H), 8.18 (d. J8,7 =J8',7' =8.0 Hz, 2H, 8-H, 8'-H), 8.90 (s, 1H, 4'-H) 9.03 (s, 1H, 4-H).--MS (70 eV): m/z (5)=303 (18) M+ +1, 302 (100) M+, 301 (9), 288 (8), 287 (46) M+CH3, 286 (6), 271 (4), 259 (11), 258 (5), 242 (5), 241 (5), 231 (13), 230 (5), 229 (4), 204 (7), 203 (10), 177 (4), 176 (10), 88 (5), 57 (5), 43 (5), 41 (6).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]([N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:1][CH2:2][CH2:3][CH:4]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:5][C:6]([N:8]([CH3:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)CC(CCO)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccccc1)c1ccccc1
Yield: 100.3 %

Procedure:
Beta-(2-hydroxyethyl)-N-methyl-N-phenylbenzenepropanamide (5.0 g) in CH2Cl2 (100 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (2.23 g), and methanesulfonyl chloride (2.53 g). After two hours the reaction mixture was washed with water(3×50 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (6.4 g).
Reaction SMILES: [CH:1]12[NH:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:7]2[CH:4]3[CH2:5][CH2:6][CH:1]2[CH:2]([NH:8][C:9]2[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]4)[CH2:3]3)=[CH:22][CH:21]=1
Reactant: COc1ccc(C=O)cc1
Reactant: c1cc2[nH]ncc2cc1NC1CC2CCC1N2
Product: COc1ccc(CN2C3CCC2C(Nc2ccc4[nH]ncc4c2)C3)cc1

Procedure:
Reaction of Intermediate 24 with 4-methoxybenzaldehyde affords the title compound.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:26]=[CH:25][C:22]([CH2:23][N:27]3[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH2:31][CH2:32]3)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:2])[CH3:3]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(C=O)cc2)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CN3CCC(NC(=O)OC(C)(C)C)CC3)cc2)n1

Procedure:
Title compound was prepared as a white solid (32 mg, 59% yield), with procedures similar to those used to prepare Intermediate 128, but utilizing 4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzaldehyde and tert-butyl piperidin-4-ylcarbamate. MS m/z 539.4 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:21](=[N:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:13]1([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:12]2.C(N(CC)CC)C.[N:32]1([C:36](OC2C=CC=CC=2)=[O:37])[CH2:35][CH2:34][CH2:33]1>CS(C)=O>[N:32]1([C:36]([N:16]2[CH2:17][CH2:18][C:13]3([CH2:12][C:11]4[C:21](=[N:22][CH:23]=[C:9]([Br:8])[CH:10]=4)[NH:20][C:19]3=[O:24])[CH2:14][CH2:15]2)=[O:37])[CH2:35][CH2:34][CH2:33]1
Reactant: O=C1Nc2ncc(Br)cc2CC12CCNCC2
Reactant: O=C(Oc1ccccc1)N1CCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCC1)N1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Temperature: 27.5 °C
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
To a stirred solution of 6-bromo-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one 2,2,2-trifluoroacetate (Intermediate-14) (600 mg, 1.47 mmol) in DMSO (5 mL) was added triethylamine (0.60 mL, 4.40 mmol) at 0° C. and the mixture was stirred at the same temperature for 15 min. Then phenyl azetidine-1-carboxylate (J) (520 mg, 2.93 mmol) was added and the reaction mixture was allowed to stir at 100° C. for 24 h. The reaction mixture was cooled to 20-35° C., diluted with ice cold water (30 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue; which was purified by column chromatography using mixture of 3% MeOH/DCM as an eluent to get the desired compound as a brown solid (180 mg, 32%); 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.22 (d. J=1.5 Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 3.86 (t, J=7.8 Hz, 4H), 3.43-3.36 (m, 2H), 3.21-3.13 (m, 2H), 2.96 (s, 2H), 2.18-2.10 (m, 2H), 1.73-1.67 (m, 2H), 1.34-1.23 (m, 2H).
Reaction SMILES: C([O-])(=O)C.[Na+].[SH2:6].[C:7]([C:10]([C:12]([CH3:14])=[CH2:13])=[O:11])([CH3:9])=[CH2:8]>C(O)C>[CH3:13][CH:12]1[C:10](=[O:11])[CH:7]([CH3:9])[CH2:8][S:6][CH2:14]1
Reactant: C=C(C)C(=O)C(=C)C
Reactant: S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1CSCC(C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2 g. of sodium acetate and 25 ml. of ethanol was saturated with hydrogen sulfide gas. To this was added 7.0 g. (0.063 mole) diisopropenylketone while cooling in an ice bath until the reaction was no longer exothermic. The mixture was stirred at room temperature while passing hydrogen sulfide through the mixture for four hours then allowed to stand overnight. The ethanol and excess H2S were evaporated in vacuo and the residue taken up in ethyl ether, washed in turn with water, potassium carbonate solution, dilute hydrochloric acid, and water again. The ether extracts were dried (Na2SO4) and evaporated to provide 6.8 g. of oil. This was distilled in vacuo through a 10 cm. Vigreaux column to provide 1.67 g. of product, B.P. 83°-86° C./9 mm. which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][N:23]=3)=[N:16][NH:17]2)=[CH:13][CH:12]=1.[OH-].[Na+].[NH4+].[Cl-]>CO.C1COCC1.O>[CH2:28]([C:25]1[CH:26]=[CH:27][C:22]([CH:21]=[CH:20][C:15]2[C:14]3[C:18](=[CH:19][C:11]([NH:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:30])=[O:2])=[CH:12][CH:13]=3)[NH:17][N:16]=2)=[N:23][CH:24]=1)[CH3:29]
Reactant: CCc1ccc(C=Cc2n[nH]c3cc(Nc4ccccc4C(=O)OC)ccc23)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(C=Cc2n[nH]c3cc(Nc4ccccc4C(=O)O)ccc23)nc1

Procedure:
To a solution of 2-{3-[2-(5-Ethyl-pyridin-2-yl)-vinyl]-1H-indazol-6-ylamino}-benzoic acid methyl ester (50 mg, 0.104 mmol) in methanol (0.42 mL) and THF (0.10 mL) was added a solution of sodium hydroxide (12 mg, 0.311 mmol) in water (0.05 mL). The solution was heated to 60 degrees Celsius for 3.5 hours and then neutralized with saturated NH4Cl. The reaction was diluted with water (20 mL), and then extracted with EtOAc (2×20 mL). The combined extracts were first dried over Na2SO4, and then the solids were removed by filtration. The desired product (48.7 mg, 100%) was recovered after rotary evaporation to remove the solvents.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:23][NH:24][O:25][CH3:26]>C(Cl)Cl>[CH3:26][O:25][N:24]([CH3:23])[C:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[O:9]
Reactant: O=C(O)c1ccncc1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a suspension of 4-pyridinecarboxylic acid (12.3 g, 100 mmol) over CH2Cl2 (200 mL) a solution of CDI (18.0 g, 111 mmol) in CH2Cl2 (200 mL) was added. After addition, the mixture was stirred for 2 h at room temperature. Following this, N,O-dimethylhydroxyl-amine hydrochloride (13.9 g, 145 mmol) was added and the mixture was stirred overnight. The reaction mixture was quenched with 1N NaOH and the phases separated. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (PE/EtOAc=1:1) to give the title compound as orange oil (10.1 g, 61% yield). LC-MS (Method A): m/z 167 (M+H)+, Rt: 0.49 min. 1H NMR (400 MHz, CDCl3): δ=8.64 (d, J=6.0 Hz, 2H), 7.46 (d, J=6.0 Hz, 2H), 3.47 (s, 3H), 3.30 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[CH3:23])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(Br)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2=O)c(C)c1

Procedure:
To a mixture of 3-oxopiperazine-1-carboxylic acid tert-butyl ester (5 g), 1-bromo-2,4-dimethylbenzene (3.4 mL), potassium carbonate (10.6 g) and copper (I) iodide (952 mg) were added toluene (25 mL) and N,N′-dimethylethylenediamine (1.1 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give 4-(2,4-dimethylphenyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester. The obtained 4-(2,4-dimethylphenyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester was dissolved in chloroform (10 mL), 4N hydrogen chloride/ethyl acetate (10 mL) was added, and the mixture was stirred at room temperature for 3 hr. The precipitate was collected by filtration to give 1-(2,4-dimethylphenyl)piperazin-2-one hydrochloride (3 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:29]1[CH2:32][CH:31]([N:33]2[CH2:38][CH2:37][O:36][C:35]([CH3:40])([CH3:39])[CH2:34]2)[CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:39][C:35]1([CH3:40])[O:36][CH2:37][CH2:38][N:33]([CH:31]2[CH2:30][N:29]([CH2:11][C:10]3[N:2]([CH3:1])[C:3]4[C:8]([N:9]=3)=[C:7]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:6]=[C:5]([N:19]3[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[C:20]3[CH3:28])[N:4]=4)[CH2:32]2)[CH2:34]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC1(C)CN(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOC(C)(C)C4)C3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), 4-azetidin-3-yl-2,2-dimethylmorpholine (54 mg, 0.32 mmol) and 4A powdered molecular sieves (200 mg) in DCE (5 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (112 mg, 0.53 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 353 as a white solid (113 mg, 82%). LCMS (Method G): RT 6.47 min [M+H]+ 532.3. 1H NMR (CDCl3, 400 MHz): δ 8.10-8.05 (m, 1 H); 7.73-7.69 (m, 1 H); 7.29-7.24 (m, 2 H); 4.35 (m, 4 H); 3.89-3.83 (m, 9H); 3.73 (m, 2 H); 3.55 (t, J=6.5 Hz, 2 H); 3.08 (t, J=6.8 Hz, 2 H); 3.01-2.90 (m, 4 H); 2.24 (m, 2 H); 2.07 (s, 2 H) and 1.25 (s, 6 H)
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:24])[CH2:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:25])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:24])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc3nc(-c4ccc([N+](=O)[O-])cc4)[nH]c3cc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(N)cc4)[nH]c3cc21

Procedure:
13 g. 8,8-dimethyl-2-(4-nitrophenyl)-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]quinolin-6-one (see Example 30i)) were hydrogenated in methanol in the presence of palladium/charcoal. After filtering off the catalyst, the filtrate was evaporated and the residue recrystallized from 2N hydrochloric acid/ethanol (1:1 v/v) to give 7.8 g. of the title compound in the form of its hydrochloride; m.p. 305°-308° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[C:30]([F:33])([F:32])[F:31]>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:10][CH2:11][C:12]([N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])=[O:13])=[C:2]([NH:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:30]([F:33])([F:31])[F:32])[CH:22]=2)(=[O:28])=[O:27])[CH:7]=1
Reactant: CCN(CC)C(=O)CCSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CCN(CC)C(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 85 %

Procedure:
Following General Procedure B, the title compound (999 mg, 85%) was prepared from 3-((2-amino-4-chlorophenyl)thio)-N,N-diethylpropanamide (635 mg, 2.22 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (619 mg, 2.22 mmol) in pyridine (6 ml).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[O:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][O:18][C:19]([C:21]1[CH:22]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[Cl:40])[C:23]([C:29]([O:31][CH3:32])=[O:30])=[C:24]([CH3:28])[NH:25][C:26]=1[CH3:27])=[O:20]>C(Cl)Cl>[O:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][O:18][C:19]([C:21]1[C:22]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[Cl:40])=[C:23]([C:29]([O:31][CH3:32])=[O:30])[C:24]([CH3:28])=[N:25][C:26]=1[CH3:27])=[O:20]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCCO2)C1c1cccc(Cl)c1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1c(C)nc(C)c(C(=O)OCC2CCCO2)c1-c1cccc(Cl)c1Cl
Reaction time: 7 h
Yield: 87 %

Procedure:
To a suspension of 82 g (0.068 mol) of pyridinium chlorochromate on alumina in 230 ml of CH2Cl2, 10 g (0.023 mol) of 4-(2,3-dichlorophenyl)-2,6-dimethyl 1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester were added, and the mixture was maintained with strong stirring during 7 hours. The insoluble solid was filtered and the remaining liquid was washed with water (3×250 ml), dried with anh. Na2SO4 and concentrated at low pressure. Finally, the product was obtained as an oil, with a yield of 87%.
Reaction SMILES: [C:1]1([CH:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=[C:25]=[N:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)CC1.C1C=CC2N(O)N=NC=2C=1.CN1CCCC(O)CC1>C1COCC1>[CH3:25][N:26]1[CH2:27][CH2:32][CH2:31][CH:30]([O:9][C:8](=[O:10])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:29][CH2:28]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)C(Nc1ccccc1)c1ccccc1
Agent: CN1CCCC(O)CC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN1CCCC(OC(=O)C(Nc2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
A mixture of 2-phenyl-2-(phenylamino)acetic acid (I1) (175 mg, 0.77 mmol), DCC (192 mg, 0.92 mmol), HOBt (124 mg, 0.92 mmol) and 1-methyl-azepan-4-ol (100 mg, 0.77 mmol) in dry THF (100 mL) is stirred at RT overnight under nitrogen flowstream (UPLC-MS monitoring: complete conversion). The solvent is evaporated and the residue is taken up with aq. HCl and washed with EtOAc. The aqueous phase is basified with NaHCO3 and extracted with DCM (three times). The organic layers are combined, dried over Na2SO4, filtered and evaporated to dryness. The resulting crude is first purified by flash chromatography (DCM to DCM/MeOH=95/5) and then by preparative LC-MS. The purified compound is partitioned between sat. NaHCO3 and DCM, the organic phase is dried over Na2SO4, filtered and evaporated under vacuum to give 53 mg of the title compound as brown oil (20% yield, mixture of diastereoisomers).
Reaction SMILES: C([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]([CH3:22])[CH:11]=1)(=O)C1C=CC=CC=1.N1CCCCC1>ClCCl>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([OH:9])=[CH:11][N:12]2[CH3:22])=[CH:17][CH:16]=1
Reactant: Cn1cc(OC(=O)c2ccccc2)c(=O)c2ccc(Cl)cc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cn1cc(O)c(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 7-chloro-1-methyl-4-oxo-1,4-dihydro-quinol-3-yl benzoate (3.45 g), piperidine (1.2 ml) and dichloromethane (100 ml) was stirred at ambient temperature for 2.5 days. The solvent was removed by distillation and the residue triturated with diethyl ether (100 ml) to give the novel compound 7-chloro-3-hydroxy-1-methyl-4-quinolone, m.p. 225°-228°.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:25][C:26]([OH:45])([CH2:31][C:32]([C:35]2[C:43]3[O:42][CH2:41][CH2:40][C:39]=3[CH:38]=[C:37]([F:44])[CH:36]=2)([CH3:34])[CH3:33])[C:27]([F:30])([F:29])[F:28])(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:30][C:27]([F:28])([F:29])[C:26]([CH2:25][C:11]1[NH:10][C:18]2[C:13]([CH:12]=1)=[CH:14][C:15]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:17]=2)([OH:45])[CH2:31][C:32]([C:35]1[C:43]2[O:42][CH2:41][CH2:40][C:39]=2[CH:38]=[C:37]([F:44])[CH:36]=1)([CH3:34])[CH3:33]
Reactant: CC(C)(CC(O)(Cc1cc2cc(-c3cccnc3)ccc2n1S(=O)(=O)c1ccccc1)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(CC(O)(Cc1cc2cc(-c3cccnc3)ccc2[nH]1)C(F)(F)F)c1cc(F)cc2c1OCC2
Temperature: 80 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
To a solution of the above 2-(1-benzenesulfonyl-5-pyridin-3-yl-1H-indol-2-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methylpentan-2-ol (71 mg, 0.11 mmol) in 5 mL of THF was added a I M solution of tetrabutylammonium fluoride (0.5 mL, 0.5 mmol) in THF and the mixture was warmed at 80° C. After 18 hours, the mixture was concentrated in vacuo and diluted with 1 N aqueous sodium hydroxide solution and extracted with three 5 mL portions of ethyl acetate. The combined organic layers were washed with two 5 mL portions of 1 N aqueous sodium hydroxide solution, 5 mL of brine, three 5 mL portions of saturated aqueous ammonium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified on silica gel eluting with methanol-dichloromethane (0:100, then 0.5:99.5, then 1:99) to afford 46 mg (83% yield) of the title compound.