Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCOCC1.Cl.C(OC([N:15]1[CH2:19][C@@H:18]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:17][C@H:16]1[C:30](=[O:33])[NH:31][CH3:32])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][S:20][C@@H:18]2[CH2:19][NH:15][C@H:16]([C:30](=[O:33])[NH:31][CH3:32])[CH2:17]2)=[CH:27][CH:26]=1
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
52.5 ml of a 4N dioxane solution of hydrogen chloride were added, whilst ice-cooling, to a solution of 4.00 g of (2S, 4S)-1-(t-butoxycarbonyl)-4-(4-methoxybenzylthio)-2-methylcarbamoylpyrrolidine [prepared as described in step (3) above] dissolved in 50 ml of ethyl acetate. The mixture was stirred at 0° to 50° C. for 30 minutes and then at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate to make it weakly basic, and it was then extracted with ethyl acetate. The aqueous layer was saturated with ammonium chloride and then extracted with tetrahydrofuran. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 5:1 mixture by volume of ethyl acetate and methanol), to afford 2.34 g of the title compound as colorless crystals, melting at 53°-54° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(O)[CH2:4][CH2:3]1.Cl>>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(O)(c2ccccc2)CC1
Agent: Cl
Product: CN1CC=C(c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (60.0 g, 0.314 moles, described in Example 1) in concentrated hydrochloric acid (180 ml, 2.16 moles) is heated with stirring at 100° C. for 4 hours. The resulting brown solution is evaporated to dryness and the buff residue is crystallized from isopropanol to give the title compound as the hydrochloride salt, mp 250°-252° C. (S. M. Elvain and J. C. Safranski, Jr., supra, reported mp 248°-250° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=O.[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20].C(=O)(O)[O-].[Na+]>C1COCC1.[Cl-].[Na+].O.C(O[Ti](OCC)(OCC)OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1/[C:5]/2=[N:24]/[S@@:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Agent: CCO[Ti](OCC)(OCC)OCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@@](=O)/N=c1\c2cc(Br)ccc2oc2cnc(Cl)cc12
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (5.0 g, 48.3 mmol), (R)-2-methylpropane-2-sulfinamide (5.85 g, 48.3 mmol), and tetraethoxytitanium (10.00 mL, 48.3 mmol) in dry THF (100 mL) was heated at 75° C. for 24 hours. The solution was cooled to RT and slowly poured into a 2 L flask containing 0.35 L of brine and 0.35 L of saturated sodium bicarbonate. The resulting mixture was stirred vigorously for 15 minutes before being filtered through a pad of celite. The pad was washed with EtOAc. The filtrate was poured into a separatory funnel and the aqueous layer was extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide an orange solid. This solid was purified by silica gel chromatography using 0-15% Hexane/EtOAC to provide (R,E)-N-(7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide as an orange solid. M+H=415.0@2.90 min.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])C.[OH-].[K+]>CO>[F:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:4]([OH:24])=[O:3])[CH:15]=1
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C(=O)O)C(F)(F)F
Yield: 88.6 %

Procedure:
1.9 g of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester is refluxed with 40 ml of potassium hydroxide in methanol (10%) for 2 hours. After the solvent is concentrated by evaporation in a vacuum, water is added, extracted with hexane, and the separated water phase is acidified with 6N hydrochloric acid. After extraction with ethyl acetate, the ethyl acetate phase is washed with water, dried (Na2SO4) and concentrated by evaporation. The residue is crystallized from hexane. 1.55 g of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid, flash point 102-104° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([F:16])([F:15])[CH3:14])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[Li+].[BH4-].CO>CCOCC>[Cl:1][C:2]1[CH:12]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[C:13]([F:15])([F:16])[CH3:14]
Reactant: CCOC(=O)c1cnc(C(C)(F)F)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: CC(F)(F)c1ncc(CO)cc1Cl
Temperature: 40 °C
Yield: 95.1 %

Procedure:
To a solution of ethyl 5-chloro-6-(1,1-difluoroethyl)nicotinate (2.68 g, 10.74 mmol) in Et2O (40 mL) was added LiBH4 (0.351 g, 16.10 mmol), followed by dropwise addition of methanol (0.653 mL, 16.10 mmol). The reaction was refluxed at 40° C. for one hour. The reaction mixture was then cooled to 0° C., and quenched with HCl (1M) until pH=2 for aqueous layer. The phases were separated and the aqueous layer was extracted with DCM (3×50 mL). The organic was then dried (Na2SO4) and concentrated under reduced pressure to give final crude product (2.12 g). LCMS m/z 208.0 (M+H)+, Rt 0.63 min.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][NH:13][N:14]=2)[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1.[OH-].[Na+].Cl>CO>[C@@H:16]([NH:15][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]2[N:11]=[N:12][NH:13][N:14]=2)[N:7]=1)[C:3]([OH:20])=[O:2])([CH2:18][CH3:19])[CH3:17]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nn[nH]n2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(-c2nn[nH]n2)n1
Reaction time: 8 h

Procedure:
Treat a solution of (S)-2-sec-butylamino-6-(2H-tetrazol-5-yl)-isonicotinic acid methyl ester (250 mg, 0.91 mmol) in methanol (4 mL)at room temperature with 2 N NaOH (1.36 mL, 2.72 mmol). Stir overnight, acidify with 1 N HCl to about pH=3, concentrate and lyophilize to give the title compound.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:19](OCC)(OCC)(OCC)[CH3:20]>>[CH3:19][C:20]1[N:4]2[CH:5]=[CH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)=[N:8][C:3]2=[N:1][N:2]=1
Reactant: NNc1nccc(-c2cccc(C(F)(F)F)c2)n1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc2nc(-c3cccc(C(F)(F)F)c3)ccn12

Procedure:
A mixture of 1.0 g. of 2-hydrazino-4-(m-trifluoromethylphenyl)pyrimidine and 25 ml. of triethyl orthoacetate is refluxed for 12 hours. On cooling the desired compound is isolated by filtration, m.p. 232°-234° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].O1CCCC1.Cl>O.C(O)C>[F:25][C:2]([F:1])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cccc(-c2ccc(-c3ccc(C(F)(F)F)cc3)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(-c2ccc(-c3ccc(C(F)(F)F)cc3)o2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of ethyl 3-[5-(4-trifluoromethylphenyl)-2-furyl]benzoate (1.62 g), 1 M aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (50 ml) and ethanol (50 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (20 ml) was added. Crystals were collected by filtration and recrystallized from ethanol to give 3-[5-(4-trifluoromethylphenyl)-2-furyl]benzoic acid (1.41 g, yield 95%) as a pale-yellow crystalline powder. melting point: 271–272° C.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH2:12]([NH:14][C:15](=[O:17])[O-:16])[CH3:13].[OH:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:23]([CH3:31])[CH:24]3[CH2:28][NH:27][CH2:26][CH:25]3[C:29]=2[CH:30]=1>CC#N.O.C(Cl)Cl>[CH2:12]([NH:14][C:15](=[O:16])[O-:17])[CH3:13].[CH:5]1([CH2:4][O:18][C:19]2[CH:20]=[CH:21][C:22]3[CH:23]([CH3:31])[CH:24]4[CH2:28][NH:27][CH2:26][CH:25]4[C:29]=3[CH:30]=2)[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: CC1c2ccc(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC1c2ccc(OCC3CC3)cc2C2CNCC12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(Bromomethyl)cyclopropane (13 mg, 0.09 mmol) and K2CO3 (24 mg, 0.17 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (23 mg, 0.09 mmol) in CH3CN, and stirred overnight at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The subtitle compound was obtained without further purification. MS calculated for C19H25NO3+H: 316, observed: 316.
Reaction SMILES: [N+](=[CH2:3])=[N-].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=2)[CH:6]=[CH:5]1>C(OCC)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:3])=[O:14])[CH:11]=2)[CH:6]=[CH:5]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccc2cc[nH]c2c1

Procedure:
An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (−15° C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at −15° C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using MDC as eluant.
Reaction SMILES: [N+:1]([C:4]1[C:5](N)=[C:6]([Cl:13])[C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].N(OS(=O)(=O)O)=O.O[PH2]=O.CCOC(C)=O>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:5]=[C:6]([Cl:13])[C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-:3])=[O:2]
Reactant: Nc1c([N+](=O)[O-])cc2ncsc2c1Cl
Agent: O=NOS(=O)(=O)O
Agent: O=S(=O)(O)O
Agent: O=[PH2]O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Cl)c2scnc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.5 %

Procedure:
To a solution of 5-nitro-6-amino-7-chlorobenzothiazole (0.21 g, 0.91 mmol) in 4 mL of sulfuric acid was added nitrososulfuric acid (0.20 g, 1.6 mmol) in a portion. The resulting reaction mixture was stirred for 12 h at 25° C. It was then cooled to 0° C. and 0.3 mL of H3PO2 was added into the mixture. Reaction mixture was stirred for another 12 h at 25° C. and for 2 h at 50° C., poured into EtOAc and washed with aq. NaHCO3. Organic layer was dried over Na2SO4 and concentrated in vacuo to provide an oil, which was purified on column chromatography (EtOAc, neat) to produce the desired product (0.12 g, 0.56 mmol, 62%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH:15]([CH3:17])[CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C1CN(Cc2ccccc2)CCC1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)C1CNCCC1O

Procedure:
A mixture of 1-benzyl-4-hydroxy-3-isopropylpiperidine (2.9 g, 12.44 mmole) and 20% palladium hydroxide (0.25 g) in methanol (25 ml) was stirred in hydrogen atmosphere (1 atm.) for 24 hr at 30° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 4-hydroxy-3-isopropylpiperidine as oil. Yield 1.6 g (80%), C8H17NO, m/z 144 (M+1) PMR (CDCl3): 0.9 (6H, m, 2×CH3), 1.1-1.64 (2H, m, CH & H3), 1.66-2.42 (3H, m, H5, & OH, D2O exchangeable), 2.62 (1H, m, H2), 3.02 (2H, m, H6), 3.45 (1H, bs, NH, D2O exchangeable), 3.54 (1H, m, H6), 4.18 (1H, m, H4).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([CH:33]([N+:35]([O-:37])=[O:36])[CH3:34])[CH:29]=3)[CH:24]=2)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].[C:38]([O:42][CH3:43])(=[O:41])[CH:39]=[CH2:40].[Cl-].[NH4+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OC(=O)C)C.O>[C:12]([C@H:16]1[CH2:21][CH2:20][C@H:19]([O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[C:28]([C:33]([N+:35]([O-:37])=[O:36])([CH3:34])[CH2:40][CH2:39][C:38]([O:42][CH3:43])=[O:41])[CH:27]=[CH:26]3)[CH2:18][CH2:17]1)([CH3:13])([CH3:14])[CH3:15]
Reactant: C=CC(=O)OC
Reactant: CC(c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CCC(C)(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a mixture of potassium carbonate (0.1783 g, 1.290 mmol), tetrabutylammonium hydrogen sulfate (0.005110 g, 0.01505 mmol) and N,N-dimethylformamide (3.00 mL, 38.7 mmol) was added 2-(4-tert-butyl-cyclohexyloxy)-6-(1-nitro-ethyl)-naphthalene (0.3821 g, 1.075 mmol). The mixture was stirred for 15 minutes, then methyl acrylate (0.1162 mL, 1.290 mmol) was added while maintaining the temperature at 20° C. (cool water bath). The mixture was stirred and allowed to reach room temperature. Stirring was continued (in slightly below room temperature water bath) for 2 hours and the reaction was monitored by HPLC. Ethylacetate and saturated aq. ammonium chloride were added and the layers were separated. The combined organic layer was dried over MgSO4, filtered, concentrated and purified by flash chromatography (0-20% EtOAc in hexanes) to give the title compound in 72% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C:31]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38](=[O:50])[O:39][CH:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][NH:48][CH3:49])[CH2:42][CH2:41]1>C(Cl)Cl>[C:31]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38](=[O:50])[O:39][CH:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][N:48]([C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:49])[CH2:42][CH2:41]1
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
6-[(tert-Butoxycarbonyl)amino]hexanoic acid (720 mg, 3.11 mmol) was dissolved in methylene chloride (14 mL), triethylamine (0.590 mL, 4.25 mmol) and pivaloyl chloride (0.418 mL, 3.40 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. 1-[2-(Methylamino)ethyl]piperidin-4-yl biphenyl-2-ylcarbamate (1.00 g, 2.83 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1→4 0:100, v/v) to give the title compound (1.59 g; yield, 99%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH2:18])=[O:5].[CH:24](N)=[O:25]>C(O)=O>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][CH:24]=[O:25])=[O:5]
Reactant: NC=O
Reactant: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Solvent: O=CO
Product: O=CNNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (200 mg) in formic acid (4 ml) was added formamide (26 mg), and the mixture was stirred at ambient temperature for 3 hours. The solvent was azeotropically removed with toluene. The residue was diluted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residual solid was treated with hot ethanol (2 ml), allowed to cool to ambient temperature, filtered and washed with ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(2-formylhydrazino)quinoline (180 mg) as pale yellow crystal.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[Cl-].[Li+].CS([Cl:34])(=O)=O.Cl>ClCCl.C(N(CC)CC)C>[Cl:34][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(CO)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CCl)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of N-[4—(hydroxymethyl)phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (566 mg), lithium chloride (135 mg), triethylamine (446 μl) and dichloromethane (50 ml) was added methanesulfonyl chloride (172 μl), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added dilute hydrochloric acid. The organic layer was separated, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-[4—(chloromethyl)phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (494 mg) as colorless crystals.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][C:28]([NH2:32])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.O>CC(C)=O.CC#N>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][C:28]([NH:32][S:2]([C:5]4[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=4)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CC#N
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(Cn2ccc3cc(NS(=O)(=O)c4cccc(C(=O)O)c4)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3-chlorosulfonyl-benzoic acid (0.80 g, 0.36 mmol) was added in one portion to 1-(4-tert-butylbenzyl)-5-amino-1H-indole (0.30 g, 1.08 mmol) and diisopropylethylamine (0.25 g, 0.90 mmol) in acetone (25 ml) at 0° C. under a nitrogen atmosphere. The resulting yellow solution was stirred at 0° C. for 5 minutes and then stirred for 3 hours at room temperature. The reaction was quenched with water (2 ml) and concentrated in vacuo to a brown powder. The powder was partitioned between EtOAc (15 ml) and std NaHCO3 (10 ml). All organics were combined, extracted with water (10 ml) and brine (10 ml), dried with MgSO4, filtered and concentrated in vacuo to afford a brown powder. This brown powder was subjected to gradient RP-HPLC (H2O: CH3CN) and the title compound was isolated as a brown powder (0.36 g, 8.6% yield): MS (ESI) m/z 463, MS (ESI) m/z 461.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:24])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:10][CH:9]=2)=[O:4].[C:25]([Si:29]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][CH2:31]O)([CH3:28])([CH3:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:24])[S:7][C:8]2[C:13]([C:14]=1[O:15][CH2:31][CH2:30][Si:29]([C:25]([CH3:26])([CH3:28])[CH3:27])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:12][C:11]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(OCc3ccccc3)ccc2sc1=O
Reactant: CC(C)(C)[Si](CCO)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(OCC[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2cc(OCc3ccccc3)ccc2sc1=O
Yield: 66.2 %

Procedure:
To a mixture of 6-benzyloxy-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Compound 62 (h), 591 mg, 1.73 mmol) and 2-(tert-Butyl-diphenyl-silanyl)-ethanol (687 mg, 2.42 mmol) (prepared according to the procedure published in J. Org. Chem. 2005, 70(4), 1467-1470) in THF (7 mL) was added triphenylphosphine (634 mg, 2.42 mmol), and DIAD (489 mg, 2.42 mmol). The resultant mixture was stirred at rt for 3.5 h. After concentration, the crude residue was purified by silica gel chromatography (eluting with 0-75% EtOAc/hexanes) to provide the title compound (697 mg). 1H NMR (200 MHz, CDCl3): δ (ppm)=7.69-7.14 (m, 18H), 5.83 (s, 2H), 4.25-4.09 (m, 2H), 3.49 (s, 3H), 1.89-1.81 (m, 2H), 1.08 (s, 9H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([C:1]#[C:2][CH2:3][CH2:4][CH3:5])([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C#CCCC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC#CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 17 h
Yield: 77.6 %

Procedure:
To a solution of 5.47 g (80.3 mmol) of 1-pentyne in 65 mL THF at −78° C. was added 32.1 ml n-butyl lithium (80.3 mmol; 2.5M in hexanes). After the addition was complete the reaction mixture was warmed to 0° C. and a solution of 8.44 g (44.6 mmol) of 1-benzyl-4-piperidone and 40 mL of THF was added dropwise. The cooling bath was removed and the reaction mixture was stirred at ambient temperature. After 17 h, the reaction was quenched by addition of saturated ammonium chloride and diluted with EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated to afford a reddish-gold oil. The crude product was purified by flash chromatography on silica gel (EtOAc/hexane 1:1→65:35). The light gold oil was dried over sodium sulfate to afford 8.91 g (78%) of 1-benzyl-4-pentynyl-4-piperidinol: ms (ESI) [M+H]+=258.