Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][S:7](Cl)(=[O:9])=[O:8])(=[O:4])=[O:3].[CH3:11][NH2:12]>C(Cl)(Cl)Cl.O>[CH3:11][NH:12][S:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)CCS(=O)(=O)Cl
Reactant: CN
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNS(=O)(=O)CCS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a stirred mixture of 2-(methylsulfonyl)ethanesulfonyl chloride in 50 ml chloroform, 15.5 g (0.2 mole) 40% methylamine in water were added slowly. The reaction mixture was stirred one hour and then filtered. The filtrate was washed with water. The organic phase was separated and then stripped. Cold ether was added to the residue; the resulting mixture was stirred. Filtration of the ether mixture gave 11.0 g of the above-identified product as a white solid, mp. 116°-117° C.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([C@@:9]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[CH:23]=[CH:22]2)(C2C=CC=CC=2)[C@H:10]([OH:14])[CH2:11][NH:12][CH3:13])[CH:6]=[CH:7][CH:8]=1.COC1C=C2C(C=CN2[C@@H](C2C=CC=C(F)C=2)[C@H](O)COS(C2C=CC(C)=CC=2)(=O)=O)=CC=1.CN>>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([C@H:9]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[CH:23]=[CH:22]2)[C@H:10]([OH:14])[CH2:11][NH:12][CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CNC[C@@H](O)[C@](c1ccccc1)(c1cccc(F)c1)n1ccc2ccc(OC)cc21
Agent: CN
Agent: COc1ccc2ccn([C@@H](c3cccc(F)c3)[C@H](O)COS(=O)(=O)c3ccc(C)cc3)c2c1
Agent: Cl
Product: CNC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccc(OC)cc21

Procedure:
In an analogous manner to EXAMPLE 5, (1S,2R)-1-(3-fluorophenyl)-1-(6-methoxy-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid 3-(6-methoxy-indol-1-yl)-2-hydroxy-3-(3-fluorophenyl)-propyl ester and methylamine as a white solid. MS (ES) m/z 329.2; HRMS: calcd for C19H21FN2O2+H+, 329.16598; found (ESI, [M+H]+), 329.1663.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](Cl)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([CH:24]=[N+:25]=[N-:26])(C)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:18])[CH:24]=[N+:25]=[N-:26])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Product: [N-]=[N+]=CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.1 %

Procedure:
4-Chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (43 g, 0.15 mol) in dichloromethane (300 mL) was treated with (trimethylsilyl)diazomethane (2.0 M in hexanes, 150 mL, 0.31 mol) over 15 min. The reaction mixture was stirred at ambient temperature for 18 hours and the mixture was concentrated to afford crude 4-(2-diazo-acetyl)-piperidine-1-carboxylic acid benzyl ester (44 g), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1OS(C1C=CC(C)=CC=1)(=O)=O)=[O:4].[CH:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CCCCCCC.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4]
Reactant: C#CCCCCC
Reactant: COC(=O)c1sccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCCCCC#Cc1ccsc1C(=O)OC

Procedure:
This product was prepared from 3-(toluene-4-sulfonyloxy)-thiophene-2-carboxylic acid methyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (71 mg, 60%); 1H NMR δ (CDCl3): 7.32 (d, J=5.03 Hz, 1H), 7.01 (d, J=5.10 Hz, 1H), 3.81 (s, 3H), 2.42 (t, J=7.25 Hz, 2H), 1.57 (p, J=7.19 Hz, 2H), 1.45-1.26 (m, 4H), 0.87 (t, J=7.2 Hz, 3H); LCMS m/z: 236.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[CH:12]=[C:13]([C:17]([O:19]C(C)C)=[O:18])[CH:14]=[CH:15][C:16]=3[C:8]=2[N:7]=[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:5]=1)(=[O:3])[NH2:2].CO.[OH-].[Na+]>C1COCC1>[C:1]([C:4]1[C:9]2[NH:10][C:11]3[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][C:16]=3[C:8]=2[N:7]=[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CC(C)OC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccccc3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A solution of isopropyl 4-carbamoyl-2-phenyl-5H-pyrido[3,2-b]indole-7-carboxylate (2 g, 5.36 mmol) in a mixture of THF (36 ml), MeOH (15 ml) and 1 N aqueous NaOH (12 ml, 120 mmol) was stirred at 25° C. overnight. The organic solvents were removed and the residue was dissolved in water, washed with DCM (20 mL), and acidified to about pH 3 with 1 N aqueous HCl to give a yellow gel-like precipitate. This was chilled in an ice bath and the precipitate was collected by filtration, washed with water, and dried to leave 4-carbamoyl-2-phenyl-5H-pyrido[3,2-b]indole-7-carboxylic acid (2.1 g, 5.1 mmol, 95% yield). MS (ESI) m/z 332.00 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.67 (1H, d, J=8.55 Hz), 8.58-8.64 (1H, m), 8.54 (1H, s), 8.03-8.17 (3H, m), 7.67-7.79 (3H, m).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([CH:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[CH3:9].CC[O-].[Na+].I[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:24]=1>C(O)C>[CH2:8]([CH:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[CH3:9].[C:1]([O:7][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:24]=1)(=[O:6])[CH2:2][C:3]([O-:5])=[O:4]
Reactant: CCCCCCCC(=O)c1ccc(CCI)cc1
Reactant: O=C(O)CC(=O)O
Agent: CCC(CC)C(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCC(=O)c1ccc(CCOC(=O)CC(=O)[O-])cc1
Yield: 50.2 %

Procedure:
4′-(2-Iodoethyl)octanophenone (175 g) prepared in the step D-3 was dissolved in anhydrous tetrahydrofuran (700 ml) to obtain 4′-(2-iodoethyl)octanophenone solution. Diethyl acetamide malonate (320 g) and sodium ethylate (100 g) was dissolved in anhydrous ethanol (1050 ml), and the 4′-(2-iodoethyl)octanophenone (175 g) solution was added, and the solution was heated to reflux for 7 hours. Tetrahydrofuran was removed by distillation from the solution. The solution was poured into ice water to obtain a precipitate which was recrystallized from hexane-ethyl acetate (40:1) to obtain diethyl acetamide-2-(4-octanoyl phenyl)ethyl malonate (110 g) in the form of colorless crystal.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]([CH2:21][CH3:22])=[C:5]([CH3:23])[N:4]=1.Cl.N1C=CC=CC=1.Cl>O>[C:11]1([NH:10][CH2:9][C:8]2[C:3](=[O:2])[NH:4][C:5]([CH3:23])=[C:6]([CH2:21][CH3:22])[CH:7]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCc1cc(CNc2cccc3ccccc23)c(OC)nc1C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCc1cc(CNc2cccc3ccccc23)c(=O)[nH]c1C
Yield: 15.8 %

Procedure:
A mixture of 2-methoxy-3-{[1-naphthylamino]-methyl}-5-ethyl-6-methylpyridine (125 mg, 0.41 mmol) and pyridine hydrochloride (500 mg, 4.3 mmol) was warmed at 145°-160° C. for 20 minutes. The reaction mixture was then cooled, water added, and the mixture made acidic with dilute aqueous hydrochloride acid. The product was then extracted into chloroform. Chloroform extracts were concentrated and the residue flash chromatographed on silica gel eluting with 5% methanol/95% chloroform. Appropriate fractions were combined and evaporated. The residue was triturated with diethyl ether to give 18.9 mg (15%) of product, m.p. 165°-167° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[CH:10]=1)=[O:8].Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([CH3:17])[CH:10]=1)=[O:8]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CCOC(=O)CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1c(C)cc(C=O)cc1C
Temperature: 110 °C

Procedure:
Potassium tert-butoxide (2.1 g, mw 112.2, 18 mmol) was added to a solution of 4-formyl-2,6-dimethylphenol (2.5 g, mw 150.2, 17 mmol) in dry DMF (15 mL) and the resultant suspension stirred under N2 at 25° C. for 5 minutes. Ethyl 5-bromovalerate (2.8 mL, mw 209.1, ρ 1.32, 18 mmol) dissolved in dry DMF (15 mL) was added, and the reaction heated at 110° C. for 5 hours, following which DMF was removed at 60° C. and 2 mm Hg. The residue was taken up in ethyl acetate (125 mL), washed with water (25 mL), 1 N aqueous NaOH (25 mL), and brine (75 mL), dried over Na2SO4, filtered, and concentrated to yield 4.47 g (97%) of NMR and TLC (Rf 0.58, CHCl3-methanol, 99:1) pure title product as an amber oil.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[C:1]([N:5]([C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=1)[NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccccn1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccn1)C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Reaction time: 4 h
Yield: 79.1 %

Procedure:
A solution of N'-t-butyl-N-(2-pyridinecarbonyl)hydrazine (0.5 g) in 10 ml of toluene was treated with 50% sodium hydroxide (0.61 g). 3,4-dichlorobenzoyl chloride (0.6 g) was added and the mixture was stirred rapidly for 4 hours at 23° C. and then was allowed to stand for 48 hours. The solids were removed by filtration and washed with water to afford 0.75 g of N'-t-butyl-N-(2-pyridinecarbonyl)-N'-(3,4-dichlorobenzoyl)hydrazine as a white solid. m.p. 175°-178° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)O)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: OC(c1cn(-c2ccccc2)nc1OCc1ccccc1)C1CCCCC1
Product: O=C(O)CCNC(=O)c1ccc(NC(c2cn(-c3ccccc3)nc2OCc2ccccc2)C2CCCCC2)cc1
Yield: 42.8 %

Procedure:
Using [3-(benzyloxy)-1-phenyl-1H-pyrazol-4-yl](cyclohexyl)methanol (0.79 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.51 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.51 g, 43%) was obtained as a white solid.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:4]=2[C:3]1=O.[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[F:13][C:11]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][CH2:8][C:2]3[S:17][C:16]([NH2:18])=[N:15][C:3]=3[C:4]=2[CH:12]=1
Reactant: O=C1c2cc(F)ccc2CCCC1Br
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc2c(s1)CCCc1ccc(F)cc1-2

Procedure:
6-Bromo-3-fluoro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (1.0 g, 3.89 mmole) was mixed with thiourea (355 mg, 4.66 mmole) in 20 ml of ethanol and heated at reflux temperature for 16 hours. The reaction mixture was cooled and filtered to give a solid (m.p. 270° C.). The filtrate was concentrated and then partitioned between ethyl acetate and saturated sodium carbonate solution. The organic extract was concentrated and chromatographed (silica, ethyl acetate/hexanes) to give the desired product as a yellow solid (m.p. 142-144° C., 34%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:77][CH:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:77][CH:78]5[CH2:83][CH2:82][O:81][CH2:80][CH2:79]5)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCOCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
To a mixture of 0.0651 g (0.141 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 4 mL of dimethylformamide was added 0.0309 g (0.229 mmole) of 1-hydroxybenzotriazole, 0.0825 g (0.229 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1113 g (0.862 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0213 g (0.211 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0631 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-217).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[OH:19][CH2:20][CH2:21][CH:22]1[CH2:28][CH:27]2[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]([CH2:25][CH2:26]2)[CH2:23]1.C(Cl)Cl>C(Cl)(Cl)Cl.O>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:19][CH2:20][CH2:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(CCO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCC2CC3CCC(C2)N3C(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 77.9 %

Procedure:
Triethylamine (0.27 mL) and p-toluenesulfonyl chloride (269 mg) were added to a mixture of tert-butyl 3-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (300 mg) and CH2Cl2 (6 mL) at room temperature, and the mixture was stirred at the same temperature overnight. After CHCl3 and water were added to the reaction mixture, extraction thereof was performed using CHCl3, and the extract was washed with water. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=95:5 to 70:30), whereby tert-butyl 3-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (375 mg) was obtained as a light brown oil.
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[CH2:28]([S:35][CH:36]([CH:39]([O:42][CH3:43])[O:40][CH3:41])[CH2:37][NH2:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.CN(C)C=O>[CH2:28]([S:35][CH:36]([CH:39]([O:40][CH3:41])[O:42][CH3:43])[CH2:37][NH:38][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][C:5]([O:15][C:16]([F:17])([F:19])[F:18])=[CH:4][C:3]=2[N:2]([CH3:1])[S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:22])=[O:13])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(OC)C(CN)SCc1ccccc1
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(OC)C(CNC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Reaction time: 60 h
Yield: 65.3 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylic acid (600 mg), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (410 mg), diisopropylethylamine (450 mg) and N,N-dimethylformamide (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 720 mg) at room temperature, and the mixture was stirred for 2.5 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-2:1, volume ratio) to give the title compound (600 mg, yield 67%) as a colorless amorphous solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].[C:15]1([S:21]([O-:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+]>C(#N)C>[OH:13][C:12]1[C:3]([CH2:2][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6][CH2:5]2
Reactant: O=S([O-])c1ccccc1
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Agent: [Na+]
Solvent: CC#N
Product: O=C1CCCc2c1ccc(O)c2CS(=O)(=O)c1ccccc1
Yield: 84 %

Procedure:
A mixture of 5-(chloromethyl)-6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (10.0 g, 48 mmol), sodium phenylsulfinate (23.4 g, 142 mmol) and acetonitrile (100 mL) was stirred at reflux under nitrogen overnight. The mixture was poured onto ice. The precipitate was isolated by filtration, air dried, and crystallized from methanol-dichloromethane-ethyl acetate to give 6-hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone as a cream solid, 12.16 g, 84% yield. NMR spectrum was consistent with structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:9]2)=[CH:4][C:3]=1[F:30].[C:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])[CH3:32].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C(O)C>[C:31]([C:34]1[CH:39]=[C:38]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[Cl:19])[N:11]=[C:10]([C:20]([C:22]([F:25])([F:24])[F:23])([C:26]([F:29])([F:28])[F:27])[OH:21])[CH2:9]3)=[CH:4][C:3]=2[F:30])[CH:37]=[CH:36][CH:35]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(Br)c(F)c2)C1)(C(F)(F)F)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2F)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
5-(4-bromo-3-fluoro-phenyl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (30.0 mg, 0.056 mmol) prepared in Step 5 of Preparation 21, 3-acetylphenylboronic acid (10.4 mg, 0.064 mmol), Pd(PPh3)4 (6.7 mg, 0.006 mmol), and a 2N sodium carbonate solution (145.0 uL) were added to a mixed solvent of 1,2-dimethoxyethane (2.0 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 90° C. for 3 hours and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>>[CH2:3]([C:2]1[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:1]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C#CCCCCCCCC
Product: CCCCCCCCC1=CC1C(=O)OCC

Procedure:
Ethyl 2-octylcycloprop-2-ene-1-carboxylate was prepared from 1-decyne and ethyl diazoacetate by the method of Mueller, P.; Pautex, N.; Helv. Chim Acta 1990, 73,1233.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:15][N:14]1[C:10]([CH2:9][CH2:8][NH2:7])=[N:11][N:12]=[N:13]1
Reactant: Cn1nnnc1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1nnnc1CCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[2-(1-Methyl-1H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (0.204 g, 0.9 mmol) is dissolved in DCM (3.5 ml). To this solution is added 4M HCl in dioxane (0.9 ml, 3.6 mmol) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo to afford the title compound as the hydrochloride salt.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([CH:33]=[CH2:34])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.CO>CO>[C:24]1([C:23]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)=[N:19][C:20]3[N:21]([C:30]([CH:33]=[CH2:34])=[CH:31][N:32]=3)[CH:22]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=Cc1cnc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cn12
Agent: Cl
Solvent: CO
Product: C=Cc1cnc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 4-5 (47 mg, 0.1 mmol) in 1 mL of MeOH was added 4M HCl/MeOH (2 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 4-6.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[O:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:26])[CH3:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:2]([CH:4]1[C:13]2([CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[O:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:26])(=[O:1])[CH3:3]
Reactant: CC(O)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
A mixture of tert-butyl 3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (600 mg, 1.66 mmol) and Dess-Martin periodinane (8.3 mL of 0.30 M, 2.5 mmol) was stirred at 25° C. for 5 h. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous NaHCO3 (2×), 5% Na2S2O3 (2×), brine, dried over MgSO4, filtered and concentrated to dryness. Purification by silica gel chromatography provided tert-butyl 3-acetyl-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (435 mg, 73%). ESI-MS m/z calc. 359.2. found 360.4 (M+1)+; Retention time: 2.84 minutes (4 min run). 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J=7.8, 1.5 Hz, 1H), 7.60-7.52 (m, 1H), 7.07-7.01 (m, 2H), 4.10-3.79 (m, 2H), 3.76 (s, 1H), 3.29-3.03 (m, 2H), 2.27 (s, 3H), 2.10-1.85 (m, 3H), 1.68-1.58 (m, 1H), 1.47 (s, 9H).