Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:26])=[N:4][C:5]([C:8]2[N:9]=[C:10]([C:21]3([CH3:25])[CH2:24][O:23][CH2:22]3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:6][CH:7]=1.[N:27]([C@@H:30]([CH3:35])[CH2:31][CH2:32][O:33][CH3:34])=[C:28]=S.C(N=C=NC(C)C)(C)C>C(O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:12]1[NH:11][C:10]([C:21]2([CH3:25])[CH2:22][O:23][CH2:24]2)=[N:9][C:8]=1[C:5]1[N:4]=[C:3]2[O:26][C:28]([NH:27][C@@H:30]([CH3:35])[CH2:31][CH2:32][O:33][CH3:34])=[N:1][C:2]2=[CH:7][CH:6]=1
Reactant: COCC[C@H](C)N=C=S
Reactant: CC1(c2nc(-c3ccc(N)c(O)n3)c(-c3ccc(F)cc3F)[nH]2)COC1
Agent: CC(C)N=C=NC(C)C
Solvent: CCO
Product: COCC[C@H](C)Nc1nc2ccc(-c3nc(C4(C)COC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 85 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
A KIMAX® tube is charged with 3-amino-6-[5-(2,4-difluorophenyl)-2-(3-methyloxetan-3-yl)-1H-imidazol-4-yl]pyridin-2-ol (2.28 g, 6.36 mmol) and ethanol (18 mL). (3S)-3-Isothiocyanato-1-methoxy-butane (1.39 g, 9.54 mmol) is added, the flask sealed, and the mixture is heated to 85° C. After 16 h, (3S)-3-isothiocyanato-1-methoxy-butane (700 mg) is added and the mixture is stirred for 48 h at 85° C. in the sealed tube. N,N′-diisopropylcarbodiimide (1.04 g) is added and the mixture is stirred 3 h at 85° C. in the sealed tube. The crude reaction mixture is concentrated under reduced pressure and the residue purified by normal phase chromatography (120 g silica-gel cartridge, hexane-ethanol). The desired compound elutes at 3% of ethanol to give the title compound as a brown solid (2.61 g, 87%). LC-ES/MS m/z 470 (M+1); [α]D22+42.2°, (c=0.50, methanol).
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].P(Br)(Br)[Br:17]>CCOCC.N1C=CC=CC=1>[Br:17][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC/C=C\CCCCC#CCO
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCC/C=C\CCCCC#CCBr
Yield: 219.3 %

Procedure:
By the procedure of example 14, 3.82 g (18.34 mmol) of (Z)-8-tetradecen-2-yn-1-ol, 72 mg of dry pyridine, and 1.66 g (6.12 mmol) of phosphorous tribromide were reacted in 20 ml of ether under reflux for 2.0 h. It was worked up as described in example 14 to give 3.83 g of crude product. It was purified by evaporative distillation at 105° C.-120° C./0.25 mm to yield 3.64 g (73% by weight yield) of (Z)-1-bromo-8-tetradecen-2-yne as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C(N(CC)CC)C.[CH3:20][N:21]=[C:22]=[O:23]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:22](=[O:23])[NH:21][CH3:20])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)N1C(=O)C(=O)c2cc(F)ccc21
Yield: 74.5 %

Procedure:
A mixture of 5-fluoroisatin (9.9 g), triethylamine (1 ml) and dimethylformamide (30 ml) is stirred under ice-cooling, and thereto is added dropwise methyl isocyanate (3 g) at the same temperature. The mixture is stirred at room temperature for 30 minutes, and the precipitates are taken by filtration to give 5-fluoro-1-methylcarbamoylisatin (8.7 g). M.p. 230°-232° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.CCCCCC.C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[C:4]=2[N:5]=[C:6]([S:8]([CH3:9])=[O:31])[N:7]=1
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
To the compound 4-chloro-8-(2,6-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1.70 g, 5.0 mmol) in dichloromethane (100 mL) was added mCPBA (1.16 g, 7.5 mmol). The mixture was stirred at rt for 10 min. Chromatography with hexane/ethyl acetate afforded the title compound (1.59 g, 89%). LC-MS m/z 356 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[NH2:8].C([O-])([O-])=O.[K+].[K+].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CCOC(C)=O.CC(O)=O.CC#N.O>O>[CH2:21]([O:20][C:18]([NH:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1cccs1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(NC(Cc1cccs1)C(=O)O)OCc1ccccc1
Reaction time: 1 h
Yield: 98 %

Procedure:
Into a 500 ml flask was placed 3.0 g of 3-(2-Thienyl)-D,L-alanine (optically active material in the L-form is available from Aldrich or SIGMA and could be used to obtain an optically active product) in 75 ml H2O/60 ml dioxane, and 5.6 g K2CO3 was added, followed by 2.85 ml of carbobenzyloxy chloride. The mixture was stirred rapidly for 1 hour. TLC (21/7/7/9, EtOAc/AcOH/CH3CN/H2O) showed that the starting material was gone. A new higher Rf product was seen. The dioxane was concentrated off and the aqueous layer was-washed with Et2O (75 ml). The aqueous layer was mixed with CH2Cl2 (150 ml) and acidified to pH=2.0 with 5N HCl. The desired N-(Benzyloxycarbonyl)-3-(2-thienyl)-D,L-alanine was extracted with CH2Cl2. The organic layer was separated and dried with Na2So4, filtered, and concentrated to give 5.05 g of desired N-(Benzyloxycarbonyl)-3-(2-thienyl)-D,L-alanine (98% yield).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CC[O:27][CH2:26][CH2:25]1.[CH:30]1([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH:42]([C:50]3[NH:54][C:53]([C:55]4[N:60]=[CH:59][C:58]([CH2:61][N:62]5[CH2:67][CH2:66][NH:65][C@@H:64]([CH3:68])[CH2:63]5)=[CH:57][CH:56]=4)=[CH:52][CH:51]=3)[CH2:43][CH:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:32][CH2:31]1>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[C:26]([N:65]1[CH2:66][CH2:67][N:62]([CH2:61][C:58]2[CH:59]=[N:60][C:55]([C:53]3[NH:54][C:50]([CH:42]([C:39]4[CH:38]=[CH:37][C:36]([S:33]([CH:30]5[CH2:32][CH2:31]5)(=[O:34])=[O:35])=[CH:41][CH:40]=4)[CH2:43][CH:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[CH:51][CH:52]=3)=[CH:56][CH:57]=2)[CH2:63][C@@H:64]1[CH3:68])(=[O:27])[CH3:25]
Reactant: CN1CCOCC1
Reactant: C[C@H]1CN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of acetic acid (5.6 μL) in tetrahydrofuran (2 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25.0 mg), 1-hydroxybenzotriazole (18.0 mg) and N-methylmorpholine (30 μL), and the mixture was stirred at room temperature for 30 min. To to the reaction mixture was added a solution of (3S)-1-{[6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]methyl}-3-methylpiperazine (45.0 mg) in tetrahydrofuran (1 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (43.0 mg, yield 90%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 591 (MH+).
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].C[Si](C)(C)C.[NH2:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:26])[C:15]=1[F:27].CO>O1CCCC1>[CH3:2][O:19][C:18](=[O:20])[C:17]1[CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:14]([NH2:13])=[C:15]([F:27])[C:16]=1[F:26]
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C[Si](C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2 M solution of tetramethylsilane (TMS) diazomethane in hexanes (6.88 ml, 13.75 mmol) was added to a suspension of 4-amino-2,3-difluoro-5-nitrobenzoic acid (2.00 g, 9.17 mmol) in 25 ml of 4:1 Tetrahydrofuran (THF):MeOH at 0° C. under nitrogen atmosphere. Upon completion of addition, reaction mixture was warmed to room temperature. After 0.5 hours, excess TMS diazomethane was destroyed by the careful addition of acetic acid. The reaction was then concentrated under reduced pressure and dried in vacuo 1.95 g (92%) of pure desired product: MS APCI (−) m/z 231 (M−1) detected.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13]([C:15]1[S:19][N:18]=[CH:17][CH:16]=1)=O)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].N1C=CC=CC=1.Cl.[NH2:27][OH:28]>C(O)C>[CH2:1]([N:4]([CH2:12][C:13](=[N:27][OH:28])[C:15]1[S:19][N:18]=[CH:17][CH:16]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)c1ccns1)C(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C=CCN(CC(=NO)c1ccns1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a room temperature solution of tert-butyl N-allyl-N-(2-isothiazol-5-yl-2-oxo-ethyl)carbamate (5.93 g, 21.00 mmol) in ethanol (70 mL) is added pyridine (5.94 mL, 73.50 mmol) and hydroxylamine hydrochloride (3.65 g, 52.50 mmol). The mixture is heated to reflux for 4 hours. The mixture is allowed to cool to room temperature and is then concentrated under reduced pressure. The resulting crude product is diluted with ethyl acetate (200 mL) and washed with saturated sodium bicarbonate (150 mL). The aqueous layer is re-extracted with ethyl acetate (2×100 mL). The combined organic layers are dried over sodium sulfate, filtered, and the solvent is removed under vacuum. The crude product is purified by silica gel column chromatography using a 15 minute, 0% to 20% ethyl acetate in dichloromethane gradient, to give the title compound as a mixture of E and Z isomers (5.62 g, 18.90 mmol, 90%). ES/MS (m/e): 298 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)=[O:9])=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][N:3]=1.CO.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CCOC(C)=O>[C:18]1([C:5]2[CH:6]=[C:7]3[C:8](=[O:9])[C:10]4[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=4[CH:12]=[CH:1][C:2]3=[N:3][CH:4]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ncc(-c2ccccc2)cc1C(=O)c1ccccc1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=c1c2ccccc2ccc2ncc(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
A flask was charged with 2-[(2-methyl-5-phenylpyridin-3-yl)carbonyl]benzaldehyde (6.2 mg, 0.02 mmol) and MeOH (1 mL). LiHMDS (25 μl, 1.0 M in THF) was added and the vessel was heated in the Biotage Initiator series microwave for 30 min. at 100° C. The mixture was then diluted with EtOAc, washed with water and brine, then dried over Na2SO4. The solution was concentrated in vacuo and purified by reverse phase HPLC (0-100% CH3CN/water with a 0.1% TFA modifier) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 9.15 (d, 1H), 8.76 (d, 1H), 8.25 (d, 1H), 7.77 (m, 4H), 7.66 (t, 1H), 7.54 (t, 2H), 7.45 (m, 2H0, 7.36 (d, 1H). LRMS (APCI) calculated for C20H14NO [M+H]+, 284.1; found 283.8
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]5([C:30]#[N:31])[CH2:29][CH2:28]5)[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C.[OH-].[Na+]>>[C:30]([C:27]1([C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[C:20]([NH:19][C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:37](=[O:36])[CH2:38][OH:39])[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:32])[CH2:29][CH2:28]1)#[N:31]
Reactant: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Reactant: CC(=O)OCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)CO)sc2c1
Yield: 13.6 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (0.11 g, 0.25 mmol) produced in Example A35(iv), 2-chloro-2-oxoethyl acetate (0.27 g, 2.0 mmol), and 8N aqueous sodium hydroxide solution (1 mL), and in the same manner as in Example A30, the title compound (17 mg, 14%) was obtained as a pale-yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:27])[NH:16][CH:17]3[CH:24]4[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:29][C:30](OCC)=[O:31].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15]([NH:16][CH:17]3[CH:24]4[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)=[O:27])[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:29][CH2:30][OH:31]
Reactant: CCOC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CC(CCO)c1cccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
To a solution of (±)-ethyl 2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate (300 mg, 0.566 mmol) in THF (5 mL) was added LiAlH4 (65 mg, 1.132 mmol) at 0° C. under N2. The mixture was stirred overnight at rt. The mixture was separated by preparative TLC to give the crude product, which was purified by preparative HPLC to afford (±)-7-bromo-N-(2-adamantyl)-3-(2-hydroxyethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (26 mg, 10%). LC-MS Method 5 tR=1.467 min, m/z=489.1; 1H NMR: (400 MHz, CDCl3): δ=1.38 (m, 2H), 1.62 (m. 5H), 1.71 (m, 5H), 1.75-1.88 (m, 9H), 2.19 (m, 2H), 2.21-2.49 (m, 5H), 2.52 (m, 1H), 2.95-3.12 (m, 3H), 3.21 (m, 1H), 3.78 (m, 2H), 3.82 (m, 3H), 7.03 (m, 1H), 7.08 (m, 1H), 7.32 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=1[CH3:35]>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([CH3:35])[CH:30]=2)=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Cc1cc(O)ccc1F
Product: Cc1cc(Oc2ncc(Cl)cc2C(=O)N[C@@H](C)c2ccc(C(=O)OC(C)(C)C)cc2)ccc1F

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-fluoro-3-methylphenol: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.6 Hz), 8.23–8.10 (2H, m), 7.96 (2H, d, J=8.4 Hz), 7.41 (2H, d, J=8.4 Hz), 7.15–6.90 (3H, m), 5.50–5.30 (1H, m), 2.32 (3H, s), 1.65–1.55 (3H, m), 1.58 (9H, s); MS (ESI) m/z 485 (M+H)+, 483 (M−H)−.
Reaction SMILES: [CH2:1](S(C1N(C2C=CC=CC=2)N=NN=1)(=O)=O)[CH2:2][CH2:3][CH3:4].[K].C[Si](C)(C)N[Si](C)(C)C.[CH:29]([C@@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:33][CH2:32]1)=O.O>COCCOC>[CH:29](/[C@@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:33][CH2:32]1)=[CH:1]\[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C=O)CC1
Reactant: CCCCS(=O)(=O)c1nnnn1-c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: O
Solvent: COCCOC
Product: CCC/C=C/[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To a mixture of 5-butylsulfonyl-1-phenyl-1H-tetrazole (3.54 g) and anhydrous ethylene glycol dimethyl ether (60 ml) at −60° C. was added 0.5 M hexamethyldisilazane potassium solution (in toluene, 26.6 ml), and the mixture was stirred for 20 minutes. Under the same condition, a solution of t-butyl cis-4-formylcyclohexylcarbamate (3.02 g) in anhydrous ethylene glycol dimethyl ether (15 ml) was added to the mixture. And the reaction mixture was gradually warmed to 25° C. and stirred overnight. To the reaction mixture was added water, and the mixture was stirred for 1 hour, then extracted with diethyl ether, and the organic layer was washed with brine, dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 2.38 g of t-butyl cis-{4-[(E)-1-pentenyl]cyclohexyl}carbamate.
Reaction SMILES: OC[C@@H:3]1[CH2:8][C@H:7]2[CH2:9][C@@:6]32[C@H:10]2[C@H:19]([CH2:20][CH2:21][C@:4]13[CH3:5])[C@@H:18]1[C:13](=[CH:14][C:15](=[O:22])[CH2:16][CH2:17]1)[CH2:12][C@H:11]2[CH3:23].N1C=CC=CC=1.C(OC(=O)C)(=O)C>O1CCCC1>[CH3:23][CH:11]1[CH2:12][C:13]2[C@H:18]([CH2:17][CH2:16][C:15](=[O:22])[CH:14]=2)[C@@H:19]2[C@@H:10]1[C@:6]13[CH2:9][CH:7]1[CH2:8][CH2:3][C@:4]3([CH2:21][CH2:20]2)[CH3:5]
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@H](CO)C[C@H]4C[C@]43[C@@H]21
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)CCC4C[C@@]43[C@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.6 %

Procedure:
A solution of (7α,14β,15β,17α)-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one (Example 1, 0.20 g) in a mixture of dry pyridine (1.76 ml) and dry tetrahydrofuran (8.8 ml) was treated with acetic anhydride (1.06 ml). The mixture was stirred at room temperature overnight and then quenched with water. After 1 h stirring the product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (7α,14β,15β,17α)17-[(acetyloxy)methyl)]-7-methyl-14,15-methyleneestr-4-en-3-one (0.22 g). 1H NMR (CDCl3) δ5.80 (t, 1H, J=2.8 Hz), 4.05 (dd, part A of AB system, 1H, J=11.0 and 6.3 Hz), 3.95 (dd, part B of AB system, 1H, J=11.0 and 7.1 Hz), 2.03 (s, 3H), 1.08 (s, 3H),. 0.62 (d, 3H, J=7.1 Hz), 0.48 (dd, 1H, J=8.3 and 5.1 Hz), 0.27 (dd, 1H, J=5.1 and 3.5 Hz).
Reaction SMILES: [NH3:1].[CH2:2]([N:9]1[CH2:13][CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH2:2]([N:9]1[CH2:13][CH2:12][C@@H:11]([NH2:1])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Reactant: N
Product: N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 88 %

Procedure:
An autoclave was cooled with an acetone/dry ice bath, and an ammonia gas was blown to pool 477 cc of liquid ammonia (corresponding to 25 equivalent of (S)-1-benzyl-3-(methanesulfonyloxy)pyrrolidine). Thereto was added 180 g of (S)-1-benzyl-3-(methanesulfonyloxy)pyrrolidine (672.1 mmol, optical purity: 100% e.e.), which was heated to 100° C. whereby an internal pressure of 55 barr was observed. After allowing the reaction for 5 hrs, the reaction mixture was cooled to room temperature, and ammonia was removed by distillation under reduced pressure. As the residue, 306.7 g of a brown oily material was obtained (reaction yield: 88%, optical purity: 91.2% e.e.).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[CH:13]=[CH:12][C:11]=2[OH:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][N:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31](Cl)=[O:32]>>[C:1]1([S:7]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[CH:13]=[CH:12][C:11]=2[O:28][C:31](=[O:32])[N:30]([CH3:29])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=S(=O)(c1ccccc1)c1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1O
Product: CN(C(=O)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1S(=O)(=O)c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from 2-benzenesulfonyl-4-(3-chloro-5-trifluoromethyl-pyridine-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (68%, white crystals). HPLC-MS m/z=563.1 (M+1), Rt: 5.3 min.
Reaction SMILES: O[CH:2]([CH:34]([CH3:36])[CH3:35])[CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH:20][C:21]([C:23]3[NH:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[O:22])[CH:14]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1.C(OCC)(=O)C>[CH3:35][CH:34]([CH3:36])/[CH:2]=[CH:3]/[S:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH:20][C:21]([C:23]3[NH:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[O:22])[CH:14]=2)=[CH:11][CH:12]=1)(=[O:5])=[O:6]
Reactant: CC(C)C(O)CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)/C=C/S(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a suspension of N-([4′-[(2-hydroxy-3-methylbutyl)sulfonyl]biphenyl-3-yl]methyl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 105 (0.300 g, 0.593 mmol) and triethylamine (0.579 mL, 4.15 mmol) in THF (6 mL) was added dropwise methanesulfonyl chloride (0.083 mL, 1.07 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with 0.1N hydrochloric acid and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate-diethyl ether to give the title compound as a pale-yellow powder (0.220 g, 76%).
Reaction SMILES: C(O)C.Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([SH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:20]([S:27][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: SCc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Ethanol (150 mL) was added to a mixture of 2-chloro-3-nitro-pyridine (5 g, 31.54 mmol) and potassium carbonate (4.8 g, 34.7 mmol). Benzyl mercaptan (4.09 mL, 34.7 mmol) was added followed by water (30 mL). The mixture stirred at 25° C. for 4 h. Water (350 mL) was added and the product precipitated. The solid was collected by vacuum filtration, rinsed with water (100 mL) and dried in vacuo for 4 h to afford the desired product, 2-benzylsulfanyl-3-nitro-pyridine (6.6 g, 26.8 mmol, 85%), as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 4.47 (2H, s), 7.21-7.31 (3H, m), 7.40-7.45 (3H, m), 8.58 (1H, dd, J1=8.6 Hz, J2=1.7 Hz), 8.83 (1H, dd, J1=4.7 Hz, J2=1.7 Hz).