Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[OH:29])=[CH:24][C:23]=1[OH:31].C([O-])(O)=O.[Na+]>CC#N>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[OH:29])=[CH:24][C:23]=4[OH:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(O)c1ccc(OCCCCl)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(O)c1
Yield: 106.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.3 g, 19.5 mmol), 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzenemethanol (4.5 g, 19.5 mmol), KI (200 mg), NaHCO3 (1.8 g, 21.5 mmol) and CH3CN (125 ml) was stirred at reflux under nitrogen for 24 hours. The cooled reaction was filtered and the filter cake was washed with CH3CN. The filtrate was concentrated to afford an oily residue, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4, and concentrated to yield 8.6 g of a dark oil. The oil was purified by preparative HPLC (Waters Associates prep LC/system 500) to yield 5.0 g. The compound was recrystallized twice from ethanol to provide 3.9 g (49%) of 4-[3-4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-hydroxy-α-methyl-benzene methanol as a light beige solid, m.p.=142°-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[Li]CCCC.[CH3:17][O:18]C=O>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[CH:17]=[O:18]
Reactant: COC=O
Reactant: FC(F)(F)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1c(Cl)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-3-trifluoromethylbenzene (1.0 g, 5.54 mmol) in THF (15 mL) cooled to −78° C., under N2 protection was added dropwise n-BuLi (3.81 mL of a 1.6 M solution in hexane, 6.1 mmol). After an hour, formic acid methyl ester (664.8 mg, 11.08 mmol) was added slowly to the solution. After the addition, the solution was warmed to ambient temperature slowly and stirred for 30 min. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (15:1) as eluent to give 2-chloro-6-trifluoromethylbenzaldehyde as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]([CH3:23])[C:7](=[O:22])[CH2:8][NH:9][C:10]([CH3:21])([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:21][C:10]([N:9]([CH2:8][C:7](=[O:22])[CH:6]([CH3:5])[CH3:23])[C:1](=[O:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH3:11]
Reactant: CC(=O)Cl
Reactant: CC(C)C(=O)CNC(C)(C)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CC(=O)C(C)C)C(C)(C)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 89.2 %

Procedure:
Acetyl chloride (0.24 mL, 3.4 mmol) was added to an ice-cooled solution of 3-methyl-1-[1-methyl-1-(3-nitro-phenyl)-ethylamino]-butan-2-one (600 mg, 2.27 mmol) and triethylamine (0.79 mL, 5.6 mmol) in DCM (10 mL). The mixture was maintained between 0 and 5° C. for 30 min. then concentrated in vacuo. The residue was redissolved in ethyl acetate, washed with water then brine and dried over sodium sulfate. Concentration afforded N-[1-methyl-1-(3-nitro-phenyl)-ethyl]-N-(3-methyl-2-oxo-butyl)-acetamide (620 mg, 89%) as an oil.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:11][CH2:12][C:13]([OH:15])=[O:14]>>[C:13]([CH2:12][CH2:11][N:1]1[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:6][CH2:5][N:4]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:3][CH2:2]1)([OH:15])=[O:14]
Reactant: O=C(O)CCCl
Reactant: C1CNCCNCCN1
Product: O=C(O)CCN1CCN(CCC(=O)O)CCN(CCC(=O)O)CC1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), 3-chloropropionic acid and base.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][C:12](=[O:14])[CH3:13].[CH3:15][O:16][CH2:17][C:18]1[O:23][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([F:32])([F:31])[F:30])[C:20]=2[N:19]=1.Cl>O1CCCC1.CCCCCC>[CH3:15][O:16][CH2:17][C:18]([NH:19][C:20]1[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](=[O:24])[CH2:13][C:12]([NH:11][C:7]1[S:6][CH:10]=[CH:9][N:8]=1)=[O:14])=[O:23]
Reactant: COCc1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CC(=O)Nc1nccs1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCC(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
150 ml of a solution of 1.5 moles of butyllithium per liter of hexane were added over 20 minutes at 0° C. to a solution of 15.73 g of N-(2-thiazolyl)-acetamide in 550 ml of tetrahydrofuran and the mixture was stirred at 0° C. for 10 minutes and was cooled to -70° C. A solution of 14.4 g of the product of Step A in 165 ml of tetrahydrofuran was added at -70° C. over 15 minutes to the mixture which was then stirred at -70° C. for 30 minutes and poured into a mixture of ice and N hydrochloric acid. The mixture was extracted with ether and the combined organic phases were washed successively with hydrochloric acid and water, dried and evaporated to dryness under reduced pressure at 20° to 30° C. The residue was empasted with 250 ml of ether and was vacuum filtered. The product was washed with ether and dried under reduced pressure at 20° C. to obtain 15 g of 2-methoxyacetamido-β-oxo-N-(2-thiazolyl)-3-trifluoromethyl-benzene-propanamide melting at 152° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH:4]=[N:3][CH:2]=1.O.NN>C(O)C>[N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:4]=[N:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCc1cncnc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCCc1cncnc1
Yield: 89.3 %

Procedure:
A solution of 23.2 g of 2-[6-(5-pyrimidinyl)hexyl]-1H-isoindole-1,3-(2H)-dione and 14.6 ml of hydrazine hydrate in 320 ml of ethanol was heated to reflux for 3 hours. The cooled mixture was filtered and the filtrate was concentrated and dissolved in dichloromethne. The solution was washed with 5% sodium hydroxide, dried and evaporated to an oil which was evaportively distilled to yield 12.0 g (90%) of 5-pyrimidinehexanamine, bp 120°-128° C./0.6 mm.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14]>CO>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[O:9][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]2=[O:14]
Reactant: Oc1ccc(Br)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: [Na]
Solvent: CO
Product: O=c1c2cc(Br)ccc2oc2ncccc12
Temperature: 130 °C
Yield: 2.3 %

Procedure:
Sodium metal (2.30 g, 100 mmol) was added to ice-cooled methanol (75 mL) with stirring under nitrogen. After the sodium had reacted completely, a slurry of 4-bromophenol (8.65 g, 50 mmol) and 2-chloronicotinic acid (7.88 g, 50 mmol) in methanol (50 mL) was added. The resulting light yellow solution was concentrated under vacuum, and the solid residue was taken up in DMF (50 mL) and heated to 130° C. for 18 h. The mixture was cooled, concentrated under vacuum, and the residue was diluted with water (50 mL) and extracted with ether (2×50 mL). The aqueous phase was acidified with 5% sulfuric acid (60 mL) to pH ˜3, and the slurry was stirred for 1 h and the precipitate was isolated by filtration and dried at 50° C. The tan solid (3.48 g), a 3:2 mixture of 2-(4-bromophenoxy)nicotinic acid and 2-chloronicotinic acid, was used directly for the cyclization. The solid (1.0 g) was added in one portion to a solution of phosphorous pentoxide (2.6 g) in methanesulfonic acid (27 g) at 80° C. The brownish solution was heated at 80° C. for 15 h, then cooled and poured onto ice (100 g). The mixture was brought to pH>9 by addition of 50% NaOH (17 mL) and extracted with dichloromethane (2×40 mL). The organic extract was dried (MgSO4) and concentrated to provide the title compound as a white solid (0.32 g, 8% from 4-bromophenol). 1H NMR (300 MHz, CD3OD) δ ppm 7.59 (dd, J=8, 5 Hz, 1H), 7.64 (d, J=8 Hz, 1H), 8.00 (dd, J=9, 3 Hz, 1H), 8.36 (d, J=2 Hz, 1H), 8.73 (dd, J=8, 2 Hz, 1H), 8.78 ppm (dd, J=5, 2 Hz, 1H); MS (DCI/NH3) m/z 276/278 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([C:29]1[S:30][CH:31]=[C:32]([C:34]([OH:36])=O)[N:33]=1)[CH2:26][CH2:27][CH3:28].[Si:37]([O:44][CH2:45][CH2:46][C:47]1[C:48]([F:65])=[C:49]([CH:62]=[CH:63][CH:64]=1)[CH2:50][N:51]1[CH2:61][CH2:60][C:54]2([O:59][CH2:58][CH2:57][NH:56][CH2:55]2)[CH2:53][CH2:52]1)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].C(N(CC)CC)C>CN(C=O)C>[Si:37]([O:44][CH2:45][CH2:46][C:47]1[C:48]([F:65])=[C:49]([CH:62]=[CH:63][CH:64]=1)[CH2:50][N:51]1[CH2:52][CH2:53][C:54]2([O:59][CH2:58][CH2:57][N:56]([C:34]([C:32]3[N:33]=[C:29]([CH2:25][CH2:26][CH2:27][CH3:28])[S:30][CH:31]=3)=[O:36])[CH2:55]2)[CH2:60][CH2:61]1)([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: CCCCc1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO[Si](C)(C)C(C)(C)C)c4F)CC3)C2)cs1
Reaction time: 1 h

Procedure:
2-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.378 g) was added to a stirred solution of 2-butylthiazole-4-carboxylic acid (example 78, step g) (0.193 g), 9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 78, step d) (0.4 g), and triethylamine (0.383 g) in DMF (4 mL). After 1 h, the reaction mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water and brine, dried over magnesium sulphate, filtered and evaporated in vacuo. Purification by silica gel chromatography eluting with 7:1:0.5, isohexane:ethyl acetate:triethylamine gave the subtitled compound as a gum. Yield 0.35 g.
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:12][C:6]=2[N:5]=1.Cl.Cl[CH2:20][C:21]1[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N:22]=1>C(O)C>[CH3:29][O:28][C:25]1[C:24]([CH3:30])=[CH:23][N:22]=[C:21]([CH2:20][S:3][C:4]2[NH:8][C:7]3[CH:9]=[CH:10][C:11]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:12][C:6]=3[N:5]=2)[C:26]=1[CH3:27]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: FC(F)(F)Oc1ccc2[nH]c(S)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)cnc(CSc2nc3cc(OC(F)(F)F)ccc3[nH]2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
5 ml of 4M sodium hydroxide solution are added dropwise to a mixture of 2.34 g of 2-mercapto-5-trifluromethoxy-1H-benzimidazole and 2.2 g of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride in 50 ml of ethanol at room temperature and the mixture is stirred overnight at room temperature. The solvent is distilled off in vacuo, water is added, the mixture is extracted with ethyl acetate, the solution is dried and 4.3 g (95%) of the dihydrochloride of the title compound are precipitated with 4M hydrogen chloride in ether. The salt is dissolved in water and the base is precipitated with dilute sodium carbonate solution at pH 8 and recrystallized from diisopropyl ether. 3.0 g (78%) of the title compound of m.p. 152°-154° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4](C)[CH:3]=1.[CH3:11]O.O>>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: CO
Reactant: Cc1cc(Cl)sc1C(=O)O
Solvent: O
Product: Cc1cc(C(=O)O)sc1Cl

Procedure:
5-Chloro-3-methyl-thiophene-2-carboxylic acid, melting point (methanol/H2O) 149°-152° C. (90%).
Reaction SMILES: [Br:1][C:2]1[S:14][C:5]2=[N:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[C:9]([OH:10])=[C:4]2[CH:3]=1.[OH-].[K+].S(OC)(O[CH3:21])(=O)=O>>[Br:1][C:2]1[S:14][C:5]2[N:6]([CH3:21])[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1cnc2sc(Br)cc2c1O
Agent: [K+]
Agent: [OH-]
Product: Cn1cc(C(=O)O)c(=O)c2cc(Br)sc21

Procedure:
To a solution of 0.274 part of 2-bromo-4-hydroxythieno[2,3-b]pyridine-5-carboxylic acid in 3 parts by volume of a 2N aqueous solution of potassium hydroxide is added 0.24 part by volume of dimethyl sulfate. Treatment of the mixture in the manner described in Example 20 gives 2-bromo-4,7-dihydro-7-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylic acid as crystals. Recrystallization from dimethylformamide-water gives colorless needles melting at 288°-290°C.
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](O)=[O:16])=[CH:10][CH:9]=1.C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:6][C:15](=[O:16])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)[CH:2]=[CH:3][CH2:4][CH3:5]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC/C=C/CO
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC=CCOC(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 116.8 %

Procedure:
Trans-2-penten-1-ol (49.6 ml; 487.6 mmol) and (4-chloro-phenyl)-acetic acid (83.2 g; 487.6 mmol) were dissolved in 1200 ml of dichloromethane. After addition of EDC (140.2 g, 731 mmol) and DMAP (11.9 g, 97.5 mmol), the reaction mixture was stirred for 18 hours at room temperature. After evaporation under reduced pressure, the residue was dissolved with diethyl ether, washed with water, brine and dried over anhydrous sodium sulfate. Evaporation gave 136 g of an yellow oil, which was further purified by flash-chromatography (silica gel; hexane/ethyl acetate 9:1). Yield: 68 g (59%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:30])=[C:11]([N:14]4[CH2:17][C:16]([CH2:19][NH:20][CH2:21][CH2:22]NC(=O)C(F)(F)F)([CH3:18])[CH2:15]4)[CH:12]=3)[C:7](=[O:31])[C:6]([C:32]([OH:34])=[O:33])=[CH:5]2)[CH2:3][CH2:2]1>[Na]>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:30])=[C:11]([N:14]4[CH2:17][C:16]([CH2:19][NH:20][CH2:21][CH3:22])([CH3:18])[CH2:15]4)[CH:12]=3)[C:7](=[O:31])[C:6]([C:32]([OH:34])=[O:33])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1(CNCCNC(=O)C(F)(F)F)CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Agent: [Na]
Product: CCNCC1(C)CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 30.6 %

Procedure:
A solution of 0.78 g (3.5 mmoles) of 1-cyclopropyl-6-fluoro-7-(3-trifluoroacetamidoethylaminomethyl-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (example 31) is heated under reflux for 3 hours in 15 ml of sodium hydroxyde 1N and 6 ml of ethanol then evaporated under vacuum. The mixture is cooled, acetic acid is added, filtrated and washed with water to obtain 0.4 g (65%) of 1-cyclopropyl-6-fluoro-7-(-3-ethylaminomethyl-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid melting at 221°-6° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=1)[O:15][C@@H:16]([CH3:23])[C:17]([O:19]CC=C)=[O:18])=[CH:8][C:7]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:6][CH:5]=2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:42](Cl)(=[O:51])[C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1>O1CCCC1>[CH3:50][O:49][C:46]1[CH:47]=[CH:48][C:43]([C:42]([N:3]2[C:4]3[C:9](=[CH:8][C:7]([O:27][C:28]([F:30])([F:29])[F:31])=[CH:6][CH:5]=3)[C:10]([CH2:11][C:12]3[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=3)[O:15][C@@H:16]([CH3:23])[C:17]([OH:19])=[O:18])=[C:2]2[CH3:1])=[O:51])=[CH:44][CH:45]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: C=CCOC(=O)[C@H](C)Oc1cccc(Cc2c(C)[nH]c3ccc(OC(F)(F)F)cc23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)n2c(C)c(Cc3cccc(O[C@@H](C)C(=O)O)c3)c3cc(OC(F)(F)F)ccc32)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Compound 5 (467 mg, 1.1 mmole) was dissolved in tetrahydrofuran (11 mL) and cooled to −78° C. Sodium bis(trimethylsilyl)amide 1.3 mL of a 1.0N solution in THF) was added and the reaction mixture was stirred for 10 minutes. p-Anisoyl chloride (221 mg, 1.3 mmole) was then added. The reaction was warmed to 0° C. then quenched with saturated ammonium chloride and diluted with ether (100 ml). The ether layer was washed with water (2×), brine (1×) and dried over sodium sulfate followed by filtration and evaporation of the filtrate giving the title compound after silica gel chromatography (490 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:4]3[CH2:3][C:2]([CH3:20])([CH3:1])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=4)[NH:5]3)[CH:14]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(=O)(=O)c3ccc(F)cc3)c1)N2
Yield: 42.1 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.56 mmol) and pyridine (90 mg, 1.14 mmol) in dichloromethane (6 mL) was added 4-fluoro-benzenesulfonyl chloride (120 mg, 0.62 mmol) under nitrogen. The resultant mixture was stirred overnight. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether: ethyl acetate=10:1) to afford 100 mg of 4-fluoro-N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide as yellow solid (Yield: 42%). MS (ESI+APCI) M+1=425.2.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][O:33][NH2:34]>C(Cl)Cl.CO>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]=[N:34][O:33][CH3:32])=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CON
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Solvent: CO
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=NOC)cc4)cc23)CC1
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol) in DCM (1.5 mL) and MeOH (1.5 mL) was added O-methylhydroxylamine (114 mg, 1.71 mmol). The reaction was stirred overnight. The solvent was then concentrated and purified by Gilson Preparatory HPLC to give 38 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)imino]methyl}phenyl)-1H-indole-7-carboxamide (76%).
Reaction SMILES: I[CH3:2].[N:3]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[H-].[Na+]>CN(C=O)C>[CH3:2][N:20]([C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[C:9]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=[O:10])[S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: CI
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1cc([N+](=O)[O-])ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
Iodomethane (0.040 mL, 0.643 mmol) was added to a solution of N-(2-(morpholine-4-carbonyl)-5-nitrophenyl)methanesulfonamide (108 mg, 0.321 mmol) and 60% suspension of NaH (16.5 mg, 0.413 mmol) in DMF (0.5 mL) at room temperature. After 1.5 h at room temperature, the mixture was carefully quenched with water (10 mL) and extracted with EtOAc (3×4 mL). The combined EtOAc phase was concentrated, purified by silica gel chromatography, and eluted with 10-100% EtOAc in hexanes to give a yellow oil (101.3 mg, 92% yield). LCMS: (M+H)+=344.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (1H, d, J=2.26 Hz), 8.27 (1H, dd, J=8.53, 2.26 Hz), 7.71 (1H, d, J=8.53 Hz), 3.69-3.78 (2H, m), 3.47-3.61 (4H, m), 3.10-3.30 (2H, m), 3.21 (3H, s), 3.17 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([O:22]CC)=[O:21])[NH:8]2)=[CH:4][CH:3]=1.CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([OH:22])=[O:21])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(C)c(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2cc(C(=O)O)[nH]c2c1NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88 %

Procedure:
To a mixed solution of ethyl 6-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.48 g) in tetrahydrofuran (10 mL)-methanol (10 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (0.35 g), and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (390 mg, yield 88%) as pale-yellow prism crystals. melting point>280° C. (decomposition).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16]2)=[C:9]([CH:13]=1)[C:10](N)=[O:11].Cl.S(Cl)([Cl:24])=O.C(N(CC)CC)C>O>[Cl:24][CH2:18][CH2:19][CH:15]1[CH2:16][N:17]([CH3:20])[C:10](=[O:11])[C:9]2[CH:13]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]=2[O:14]1
Reactant: COc1ccc(OC2CCN(C)C2)c(C(N)=O)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(=O)N(C)CC(CCCl)O2
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a solution of 19.2 g (0.48 mole) of sodium hydroxide in 500 ml of water was added 60 g (0.24 mole) of 5-methoxy-2-[(1-methyl-3-pyrrolidinyl)oxy]-benzamide and the mixture was heated at reflux for 24 hr. The reaction mixture was cooled and the pH adjusted to 6.8 with concentrated hydrochloric acid. The mixture was concentrated under reduced pressure and the residue was boiled in isopropyl alcohol for 1 hour. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in 500 ml of chloroform and to this solution was added 114 g (0.96 mole) of thionyl chloride. The mixture was heated at reflux for 48 hr, then cooled with an ice/acetone bath. To the mixture was added dropwise 97 g (0.96 mole) of triethylamine at such a rate that the temperature did not exceed 25° C. The reaction solution was washed in sequence with water, 3N hydrochloric acid solution, water, 15% aqueous sodium hydroxide and water and finally dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a black solid. The solid was purified on a silica gel column using ethyl acetate as the eluting solvent to give on isolation 15 g (23%) of beige colored product, m.p. 98°-100° C.