Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:19][CH:20]=[CH2:21])[C@@:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([NH2:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH3:26][C:27]([CH3:29])=O.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:19][CH:20]=[CH2:21])[C@@:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)([NH:11][CH:27]([CH3:29])[CH3:26])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: C=CC[C@H](c1cccc(Cl)c1)[C@](C)(N)c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CC[C@H](c1cccc(Cl)c1)[C@](C)(NC(C)C)c1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
A mixture of (2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)hex-5-en-2-amine (Example 418, Step D) (270 mg, 0.843 mmol), acetic acid (0.243 mL, 4.22 mmol), acetone (3.10 mL, 42.2 mmol) and sodium cyanoborohydride (0.442 mL, 8.43 mmol) in methanol (4 mL) was heated to 65° C. overnight. After sixteen hours, an additional ten equivalents of sodium cyanoborohydride were added and heating continued for another five hours then equilibrated to room temperature and concentrated under reduced pressure. The concentrate was partitioned between aqueous sodium hydroxide solution and ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to afford a yellow oil. The crude product was adsorbed onto silica and purified by chromatography (24 g RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.)) eluting with 30 to 100% ethyl acetate gradient in hexane. Fractions containing product were combined and concentrated to afford the title compound as a colorless glass.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH-].[Na+].[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11].Cl>C1COCC1.O>[CH3:1][S:2]([NH:8][C@@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:14]([OH:16])=[O:15])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[C@H](NS(C)(=O)=O)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 30.6 %

Procedure:
A solution of methanesulfonyl chloride (0.593 mL, 7.62 mmol) in 1M NaOH (7.60 mL, 15.2 mmol) and THF (10 mL) was added drop wise to a stirred mixture of (L)-tert-leucine (1.0 g, 7.6 mmol), dissolved in THF (7.6 mL) and H2O (12 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and then at room temperature overnight. The mixture was acidified with 4M HCl and extracted with EtOAc. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give (2S)-2-methanesulphonylamino-3,3-dimethyl-butyric acid (0.486 g, 30%), which was analyzed by NMR and then used without further purification. The general procedure for the preparation of hydrazides described above was then followed using the crude (2S)-2-methanesulfonylamino-3,3-dimethyl-butyric acid (0.476 g, 2.27 mmol), EDAC (0.481 g, 2.51 mmol), HOBT (0.338 g, 2.50 mmol), NMM (0.275 mL, 2.50 mmol), benzylhydrazine×2HCl (0.489 g, 2.51 mmol) and Et3N (0.700 mL, 4.98 mmol) which gave the title compound (0.416 g, 58%) as a white solid.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:21]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:21]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncc1F)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)c(F)cn3)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(5-fluoro-2-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)pyridin-4-yl)propanoate (379 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at 50° C. for 20 min. To the reaction mixture was added 1N hydrochloric acid (2.0 mL) at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (330 mg) as a white amorphous solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][C:22](=[O:24])[CH3:23])[N:18]=[C:17]([Cl:25])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)C.Cl.O1CCOCC1>[ClH:25].[ClH:25].[Cl:25][C:17]1[N:18]=[C:19]([NH:21][C:22](=[O:24])[CH3:23])[CH:20]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:16]=1
Reactant: CC(=O)Nc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(NC2CCNCC2)nc(Cl)n1

Procedure:
A solution of 4-(6-acetylamino-2-chloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.27 mmol) in ethanol (2 mL) and 4 M HCl in dioxane (2 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 270.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:65][O:66][C:67]1[CH:72]=[CH:71][C:70]([SH:73])=[CH:69][CH:68]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.CO>[CH2:11]([N:10]1[C:3]2[C:2]([S:73][C:70]3[CH:71]=[CH:72][C:67]([O:66][CH3:65])=[CH:68][CH:69]=3)=[CH:7][N:6]=[CH:5][C:4]=2[N:8]=[C:9]1[C:13]1[C:14]([NH2:18])=[N:15][O:16][N:17]=1)[CH3:12]
Reactant: COc1ccc(S)cc1
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCn1c(-c2nonc2N)nc2cncc(Sc3ccc(OC)cc3)c21
Temperature: 175 °C
Yield: 0 %

Procedure:
Under Ar, a solution of the product from Example 100 (53.2 mg, 172 mol) in 1,4-dioxane (1 ml) and toluene (1.5 ml) was treated with Tris(dibenzylidene-acetone)dipalladium (15 mg, 17 mol), racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (20 mg, 34 mol), 4-methoxybenzenethiol (26 l, 206 mol), and sodium tert-butoxide (23.5 mg, 241 mol). This mixture was then heated to 175° C. by microwave for 1 h. After cooled to ambient temperture, the reaction mixture was diluted with ethyl acetate (30 ml) and methanol (30 ml), filtered though a celite pad and then the filtrate was concentrated in vacuo. The residue was purified with flash chromatography (hexanes/ethyl acetate 2:1), to afford the title compound, (35.6 mg, 56%); MS (ES+) m/e 369 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]=O>>[CH2:1]([N:8]([CH3:25])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: NC(=O)OCc1cc(-c2ccc(NCc3ccccc3)cc2)no1
Product: CN(Cc1ccccc1)c1ccc(-c2cc(COC(N)=O)on2)cc1

Procedure:
An experiment was performed using carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester (150 mg, 0.46 mmol) in Example 74 as a starting material and formaldehyde (20 μl, 0.70 mmol) in the same manner as in Example 74.4 to obtain carbamic acid 3-[4-(benzyl-methyl-amino)-phenyl]-isoxazol-5-ylmethyl ester.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[C:11]([F:17])[CH:10]=1)CCC.[OH-].[Na+]>CO.O>[F:15][C:13]1[CH:14]=[C:9]([CH2:8][CH2:7][C:6]([OH:18])=[O:5])[CH:10]=[C:11]([F:17])[C:12]=1[CH3:16]
Reactant: CCCCOC(=O)CCc1cc(F)c(C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(F)cc(CCC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(3,5-difluoro-4-methyl-phenyl)-propionic acid butyl ester (6.960 g; 27.157 mmol) in MeOH (150 ml) and water (25 ml) was added at rt aq. 1N NaOH (68 ml; 68 mmol). The resulting solution was further stirred at rt for 1 h. MeOH was then removed under reduced pressure. Water (25 ml) was added, and the mixture was acidified with aq. 1N HCl (68 ml) in order to reach pH=2. DCM (150 ml) was added, and the layers were shaken and separated. The aq. layer was further extracted with DCM (50 ml). The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The product 3-(3,5-difluoro-4-methyl-phenyl)-propionic acid was obtained as a pale yellow solid which was further dried under HV (5.090 g; 94%). LC-MS: tR=0.86 min.; [M+H]+: no ionisation.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](O)(=[O:13])=[O:12])=[CH:7][CH:6]=1>N1C=CC=CC=1>[F:1][CH2:2][CH2:3][O:4][S:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: OCCF
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCF)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
1g (15.6 mmol) of 2-fluoroethanol was dissolved in pyridine (15 mL), and 6.5 g (34.1 mmol) of p-toluenesulfonic acid was added thereto over a period of 30 minutes while stirring on ice. The mixture was stirred at 0° C. under nitrogen atmosphere for 3 hours, and after adding 35 mL of ice water to the reaction mixture, extraction was performed with 30 mL of ethyl acetate. The obtained organic layer was washed three times with 30 mL of 1N hydrochloric acid, and then further washed with sodium carbonate solution and saturated saline. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure to yield the title compound (3.19 g, 94%) as a colorless oil.
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[Cl:4][C:5]1[C:14]([CH:15]=[N:16][OH:17])=[C:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C([O-])(=O)C.[Na+].Cl[O-].[Na+]>ClCCl>[Cl:4][C:5]1[C:14]([C:15]2[CH2:1][CH:2]([CH3:3])[O:17][N:16]=2)=[C:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Reactant: C=CC
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(C)C2)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
At room temperature, propene was introduced into a solution of 15.0 g (52 mmol) of methyl 2-chloro-3-hydroxyiminomethyl-4-methylsulfonylbenzoate and 200 ml of dichloromethane for 30 minutes. After the addition of 1.6 g of sodium acetate, 42.8 ml of sodium hypochlorite solution were added dropwise, with the simultaneous introduction of propene. At room temperature, propene was subsequently introduced into the mixture for a further 15 minutes. The mixture was heated for 3 hours under reflux and then stirred for 12 hours at room temperature, propene was introduced once more under reflux for 5 hours and the mixture was stirred at room temperature for another 12 hours. The phases were separated and the organic phase was washed with water, dried and concentrated. 15.5 g (89% of theory) of methyl 2-chloro-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[S:43](=[O:45])(=[O:44])[NH:42][C:41](=[O:46])[CH2:40]2)=[C:35](Br)[CH:34]=1)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:22]=1[C:23]([O:25]C)=[O:24])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48]1(B(O)O)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.O.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>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:32][C:33]1[CH:34]=[C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:36]([CH:39]2[S:43](=[O:45])(=[O:44])[NH:42][C:41](=[O:46])[CH2:40]2)=[CH:37][CH:38]=1)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:22]=1[C:23]([OH:25])=[O:24])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
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: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)NCCCCOc3cccc(O)c3C(=O)O)cc2-c2ccccc2)S(=O)(=O)N1
Temperature: 100 °C
Yield: 33.2 %

Procedure:
To a solution of methyl 2-[4-((2S)-2-[(benzyloxy)carbonyl]amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoylamino)butoxy]-6-hydroxybenzoate (12.0 mg, 0.0164 mmol) in toluene (0.4 mL) and 1,4-dioxane (0.4 mL) was added phenylboronic acid (2.40 mg, 0.0196 mmol) and 2 M sodium carbonate in water (0.049 mL). The resulting mixture was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.95 mg, 0.82 μmol) was then added to reaction mixture and heated at 100° C. overnight. The reaction mixture was filtered and purified by preparative LCMS to afford a white solid (3.9 mg, 33%). 1H NMR (400 MHz, CD3OD): δ 7.59 (m, 1H), 7.36 (m, 13H), 6.57 (m, 2H), 5.04 (m, 3H), 4.36 (m, 1H), 4.11 (m, 2H), 3.22 (m, 5H), 2.96 (m, 1H),1.78 (m, 2H), 1.59 (m, 2H). LCMS found for C37H378N3O10S (M+H)+: m/z=716.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[NH2:14].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:21][O:20][C:16]1[CH:15]=[C:13]([N:14]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:12]=[C:11]([O:10][CH3:9])[C:17]=1[O:18][CH3:19]
Reactant: ClCCNCCCl
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(N2CCNCC2)cc(OC)c1OC
Reaction time: 16 h
Yield: 37.4 %

Procedure:
A solution of 44.3 g (0.25 mol) of bis(2-chloroethyl)amine hydrochloride and 45.5 g (0.25 mol) of 3,4,5-trimethoxyaniline in 550 mL of absolute ethanol was heated at reflux for 16 h under a nitrogen atmosphere. The mixture was cooled and 50.0 g (0.36 mol) of potassium carbonate was added and heating was continued for 16 h. The hot mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was triturated with ethyl acetate. The collected solid was re-crystallized from 2-propanol/methanol. The solid was dissolved in 5.9N sodium hydroxide and the solution was continuously extracted with chloroform for 5 h. The organic layer was dried (MgSO4), concentrated under reduced pressure, and the residue was triturated with cyclohexane/petroleum ether (30°-60°) to give 23.6 g (38%) of white solid, mp 73°-77° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9]O)=[C:5]([Cl:11])[C:4]([Cl:12])=[N:3]1.S(Cl)([Cl:15])=O>C(Cl)Cl.N1C=CC=CC=1.CCOCC>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][Cl:15])=[C:5]([Cl:11])[C:4]([Cl:12])=[N:3]1
Reactant: Cn1nc(Cl)c(Cl)c1SCCO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1nc(Cl)c(Cl)c1SCCCl

Procedure:
To a stirred mixture of 48.4 g (0.213 moles) 1-methyl-3,4-dichloro-5-(2-hydroxyethylthio)pyrazole and 50 ml thionyl chloride in 200 ml methylene chloride, about 1 ml pyridine was added. The reaction mixture was heated at reflux for about 12 hours over 2 days time. The solvent was stripped, and the residue was taken up in ether. The etheral solution was washed 5 times with water and then dried over magnesium sulfate. Stripping of the ether gave 52.2 g of the product as a brown-red oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:21]#[C:22][CH2:23][CH2:24][CH2:25][OH:26].C(N(C(C)C)CC)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].Cl>C(Cl)Cl.CCOCC>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:21]#[C:22][CH2:23][CH2:24][CH2:25][O:26][S:37]([CH3:36])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)N2CCc3cc(C#CCCCO)c(F)cc32)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCc3cc(C#CCCCOS(C)(=O)=O)c(F)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
A solution of 50 mg (0.141 mmol) of 5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-yn-1-ol and 0.072 ml (0.42 mmol) diisopropyl ethylamine in 2 ml CH2Cl2 was treated at 0° C. with 0.033 ml (0.42 mmol) methanesulfonylchloride and stirred at room temperature for one hour. Addition of aqueous 0.1M HCl, extraction with Et2O, drying of the organic layer with MgSO4, and evaporation of the solvent gave 60 mg of Methanesulfonic acid 5-[6-fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynyl ester as brown oil of which 12 mg were dissolved in 0.5 ml DMF, treated with 0.043 ml (0.053 mmol) 2-(methylamino)ethanol and stirred at 80° C. during 2 hours. Evaporation of the solvent and excess 2-(methylamino)ethanol and chromatography on silica gel with EtOAc/MeOH/NEt3 10:1:0.1 gave 10 mg (82%) of 2-({5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynyl}-methyl-amino)-ethanol as a light yellow oil, MS: 431 (MH+).
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3].[NH3:18]>C(Cl)Cl.C(OCC)(=O)C>[NH2:18][S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3]
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Reactant: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H](CS(N)(=O)=O)C(=O)OCc1ccccc1
Temperature: -78 °C

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 1.22 g of benzyl 3-chlorosulfonyl-2(R)-methylpropionate in 15 mL CH2Cl2 and cooled to −78° C. To this solution was added to 10 mL of liquid ammonia at −78° C. After 20 minutes the reaction was warmed to room temperature, concentrated in vacuo to afford a white solid. The solid was slurried in ethyl acetate, filtered to remove inorganic salts and concentrated in vacuo to afford 1.08 g of benzyl 3-aminosulfonyl-2(R)-methylpropionate as a clear yellow oil. The crude product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Na].[Cl:26][C:27]1[N:32]=[C:31]([NH:33][CH:34]([CH2:42][CH3:43])[C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[CH:30]=[C:29]([CH2:44][CH3:45])[N:28]=1.[F:46][C:47]([F:51])=[C:48]([F:50])[F:49].O.C1(C)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:26][C:27]1[N:32]=[C:31]([NH:33][CH:34]([CH2:42][CH3:43])[C:35]2[CH:40]=[CH:39][C:38]([O:41][C:48]([F:50])([F:49])[CH:47]([F:51])[F:46])=[CH:37][CH:36]=2)[CH:30]=[C:29]([CH2:44][CH3:45])[N:28]=1
Reactant: CCc1cc(NC(CC)c2ccc(O)cc2)nc(Cl)n1
Reactant: FC(F)=C(F)F
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(NC(CC)c2ccc(OC(F)(F)C(F)F)cc2)nc(Cl)n1
Yield: 33.5 %

Procedure:
Into a solution of 1.6 g of dl-5-chloro-6-ethyl-4-(α-ethyl-4-hydroxybenzyl)aminopyrimidine sodium salt dissolved in 30 ml of N,N-dimethylformamide was gradually bubbled about 2.2 g of tetrafluoroethylene at 80° C. under nitrogen atmosphere while stirring. After completion of the bubbling, the mixture was stirred for 2 hours, and the reaction mixture was charged into water and separated oily product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and ethyl acetate was distilled off under reduced pressure. The oily product obtained was isolated by column chromatography (Wako Gel C-200, trade name, eluted with toluene:ethyl acetate=7:1) to give 0.6 g of the desired product as pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH2:15])=[S:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH:17]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:28]([C:17]1[S:14][C:13]([CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:15][C:18]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc(C(=O)C(Br)Cc2ccccc2)cc1
Reactant: COc1ccc(CCC(N)=S)cc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc(CCc3ccc(OC)c(OC)c3)sc2Cc2ccccc2)cc1
Yield: 71.6 %

Procedure:
To a 50 ml eggplant-shaped bottle were added 0.12 g (0.533 mmol) 3-(3,4-dimethoxy-phenyl)-thiopropanamide prepared in the step 3, 0.17 g (0.533 mmol) 2-bromo-1-(4-methoxy-phenyl)-3-phenyl-propan-1-one prepared in the step 3 of Example 1, 0.04 g (0.533 mmol) anhydrous sodium acetate and 20 ml anhydrous ethanol. The resulting mixture was refluxed for 4 hours, when TLC showed the completion of the reaction, and concentrated under a reduced pressure. The reaction mixture was partitioned between water and ethyl acetate each 20 ml, the ethyl acetate layer was washed with saturated brine 2×10 ml, dried over anhydrous Na2SO4, filtered and concentrated to give a solid crude product which was recrystallized with petroleum ether and ethyl acetate to obtain a 0.17 g product as a thick liquid in a yield of 70.8%. 1H-NMR (CDCl3, 400 MHz) δ: 3.06 (2H, t, J=8.40 Hz, CH2), 3.25 (2H, t, J=8.40 Hz, CH2), 3.83 (3H, s, CH3O), 3.84 (3H, s, CH3O), 3.86 (3H, s, CH3O), 4.20 (2H, s, CH2), 6.70˜6.80 (3H, m, ArH), 6.95 (2H, d, J=8.80 Hz, ArH), 7.15˜7.35 (5H, m, ArH), 7.54 (2H, d, J=8.80 Hz, ArH); EI-MS m/e (%): 445.1 (M, 100), 151.1 (93); HREI-MS Calcd. for C27H27NO3S: 445.1712. found: 445.1716.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C@H:8]2[CH2:25][C@@:24]3([CH3:26])[C@@H:11]([CH2:12][CH2:13][C@@H:14]4[C@@H:23]3[CH2:22][CH2:21][C@@:19]3([CH3:20])[C@H:15]4[CH2:16][C@H:17]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[C@@H:18]3[OH:27])[CH2:10][C@@H:9]2[OH:34])[CH2:4][CH2:3]1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C@H:8]2[CH2:25][C@@:24]3([CH3:26])[C@@H:11]([CH2:12][CH2:13][C@@H:14]4[C@@H:23]3[CH2:22][CH2:21][C@@:19]3([CH3:20])[C@H:15]4[CH2:16][C@H:17]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[C@@H:18]3[O:27][C:18](=[O:27])[CH3:17])[CH2:10][C@@H:9]2[O:34][C:9](=[O:34])[CH3:8])[CH2:4][CH2:3]1
Reactant: CN1CCN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](O)[C@@H](N5CCCCC5)C[C@@H]43)C[C@@H]2O)CC1
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@@]4(C)[C@H]3C[C@H](N3CCCCC3)[C@@H]4OC(C)=O)[C@@]2(C)C[C@@H]1N1CCN(C)CC1
Yield: 72 %

Procedure:
The compound is prepared by acylation of 2β-N-methyl-piperazino-16β-piperidino-3α,17β-dihydroxy-5α-androstane according to the method described in Example 12. Yield: 72.0% [α]D25 = +29.4° (c = 1 in chloroform).