Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][C:5]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:16](Cl)(=[O:18])[CH3:17]>C1COCC1.CN(C)C1C=CN=CC=1.[Cl-].[Na+].O>[CH2:10]([O:9][C:7]([C:6]1[C:5]2[CH2:12][CH2:13][CH2:14][CH2:15][C:4]=2[S:3][C:2]=1[NH:1][C:16](=[O:18])[CH3:17])=[O:8])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 2-amino-4, 5, 6, 7-tetrahydrobenzothiophene-3-carboxylate (16 g, 71.1 mmol) in THF (100 mL) was added 4-(dimethylamino)pyridine (434 mg, 3.55 mmol) and acetyl chloride (6.1 mL, 85.3 mmol). After stirring for 2 h at room temperature, the solution was diluted with brine solution (500 mL) and extracted with ethyl acetate (500 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated to provide the title compound (18.3 g, 96%) as a light yellow solid: MS (ES) m/z 268 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17]C(NC(N)=O)(C)C)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=C2CC(C)(C)C)[CH2:3][CH2:2]1.CO>[C].[Pd].O1CCCC1>[NH2:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=[CH:10][C:9]=1[NH:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC(C)(C)NC(N)=O)ccc2n1CC1CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(NCC2CC2)c(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.4 %

Procedure:
A mixture of N-(cyclopropylmethyl)-4-(methylsulfonyl)-2-nitroaniline (Step A, 9.32 g, 34.2 mmol), 10% palladium carbon (950 mg), methanol (250 mL) and tetrahydrofuran (250 mL) was stirred at room temperature for 3 h under hydrogen atmosphere. The resulting mixture was filtered through a pad of celite. The filtrate was concentrated to afford the crude product (9.16 g) as brown viscous oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[CH:20]=[C:19]([NH:21][C:22]2[C:27]3=[CH:28][N:29]([C:31]4[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=4[Cl:38])[N:30]=[C:26]3[C:25]([CH3:39])=[CH:24][N:23]=2)[N:18]=[CH:17][N:16]=1)(C)(C)C>C(Cl)Cl>[Cl:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[N:29]1[CH:28]=[C:27]2[C:22]([NH:21][C:19]3[CH:20]=[C:15]([NH2:14])[N:16]=[CH:17][N:18]=3)=[N:23][CH:24]=[C:25]([CH3:39])[C:26]2=[N:30]1
Reactant: Cc1cnc(Nc2cc(NC(=O)OC(C)(C)C)ncn2)c2cn(-c3c(Cl)cccc3Cl)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2cc(N)ncn2)c2cn(-c3c(Cl)cccc3Cl)nc12
Temperature: 25 °C

Procedure:
TFA (1.5 mL) was slowly added to the crude mixture of {6-[2-(2,6-dichlorophenyl)-7-methyl-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-bis-carbamic acid tert-butyl ester and {6-[2-(2,6-dichlorophenyl)-7-methyl-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-carbamic acid tert-butyl ester in DCM (1.5 mL) at 0° C., under an atmosphere of nitrogen. The reaction mixture was stirred with warming to room temperature over 2 hours. The resultant mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether. The pale yellow solid formed was filtered and washed with diethyl ether to afford the crude title compound (30 mg). The filtrate was concentrated under reduced pressure to afford impure title compound as an yellow oil (220 mg). The two batches were separately dissolved in ethyl acetate, then combined and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to afford the crude residue. This was purified by silica gel flash chromatography (0-10% methanol in DCM), then further purified by HPLC (gradient: 5 to 98% acetonitrile (0.1% ammonium hydroxide) in water (0.1% ammonium hydroxide)], to afford the title compound as a white powder (14 mg, 14% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.51 (d, J=0.9 Hz, 1H), 7.89-7.85 (m, 2H), 7.81-7.74 (m, 2H), 6.51 (br s, 1H), 2.45 (d, J=1.3 Hz, 3H). LCMS (Method B): RT=3.05 min, m/z: 386 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:15](O)=O>C=O>[CH3:15][N:10]([CH2:11][C:12]([OH:14])=[O:13])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C(O)CNc1ccc([N+](=O)[O-])cc1
Reactant: O=CO
Agent: C=O
Product: CN(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Yield: 86 %

Procedure:
A solution of (4-nitro-phenylamino)-acetic acid (1.3 g, 6.6 mmol) in formic acid (5 mL) and formaldehyde (5 mL) was heated at reflux overnight. The mixture was concentrated in vacuo and 1N hydrochloric acid added to the residue giving a pH ˜3. The mixture was extracted with ethyl acetate then the organic phase was washed with water and brine. Concentration in vacuo afforded [methyl-(4-nitro-phenyl)-amino]-acetic acid (1.2 g, 86%) as a yellow solid.
Reaction SMILES: [N+:1]([O-])(O)=O.[Cl:5][C:6]1[C:11]2[CH2:12][C:13]([CH3:16])([CH3:15])[O:14][C:10]=2[C:9]([C:17]([OH:19])=[O:18])=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[NH2:1][C:7]1[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]2[O:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]=2[C:6]=1[Cl:5]
Reactant: CC1(C)Cc2c(Cl)ccc(C(=O)O)c2O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1(C)Cc2c(Cl)c(N)cc(C(=O)O)c2O1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 40 ml of nitric acid and 40 ml of sulfuric acid cooled to 5° C. by means of an external ice bath were added 10 g of 4-chloro-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylic acid over a period of 28 minutes. After stirring at 5° C. for 10 minutes, the mixture was added to ice with stirring. The resulting solid was collected by filtration and washed with water. After air drying, the residue was crystallized twice from ethyl acetate/hexane to provide 3.5 g of the desired subtitle intermediate, m.p. 260°-262° C.
Reaction SMILES: C([NH:9][C:10]1[O:11][C@@H:12]2[C@H:14]([C@@:15]([C:20]3[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=3[F:34])[C:23]([NH:25][C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])=[O:24])([CH:17]([F:19])[F:18])[N:16]=1)[CH2:13]2)(=O)C1C=CC=CC=1.N12CCCN=C1CCCCC2>CO>[NH2:9][C:10]1[O:11][C@@H:12]2[C@H:14]([C@@:15]([C:20]3[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=3[F:34])[C:23]([NH:25][C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])=[O:24])([CH:17]([F:19])[F:18])[N:16]=1)[CH2:13]2
Reactant: COC[C@H](C)NC(=O)c1ccc(F)c([C@]2(C(F)F)N=C(NC(=O)c3ccccc3)O[C@H]3C[C@H]32)c1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COC[C@H](C)NC(=O)c1ccc(F)c([C@]2(C(F)F)N=C(N)O[C@H]3C[C@H]32)c1
Temperature: 65 °C
Yield: 19.1 %

Procedure:
A flask was charged with 3-((1S,5R,6S)-3-benzamido-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluoro-N—((S)-1-methoxypropan-2-yl)benzamide (0.3780 g, 0.795 mmol), 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.143 ml, 0.954 mmol) and MeOH (7.95 ml). The reaction mixture was heated to 65° C. for 4 hours. The crude product was adsorbed onto a plug of silica gel and purified by flash chromatography, eluting with a gradient of 10% to 100% EtOAc:EtOH (75:25) in hexane, to provide the title compound (0.0563 g, 0.152 mmol, 19.07% yield).
Reaction SMILES: [F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:23][CH2:24][C:25](=O)[CH2:26][F:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CN(C)C=O>ClCCl>[F:23][CH2:24][CH:25]([N:5]1[CH2:6][CH2:7][C:2]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])([F:1])[CH2:3][CH2:4]1)[CH2:26][F:27]
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCNCC2)c([N+](=O)[O-])c1
Reactant: O=C(CF)CF
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(OCC2(F)CCN(C(CF)CF)CC2)c([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
To a suspension of EXAMPLE 341C (0.100 g) and 1,3-difluoropropan-2-one (0.025 g) in dichloromethane (2 mL) was added sodium triacetoxyborohydride (0.071 g). After 15 minutes, N,N-dimethylformamide was added dropwise until an orange solution resulted (−15 drops). After stirring overnight additional 1,3-difluoropropan-2-one and sodium triacetoxyborohydride were added. After 3 hours, the reaction was loaded onto silica gel (Reveleris 40 g) and eluted with a gradient of 0.5-5% methanol/dichloromethane over 30 minutes (flow=40 ml/minutes) to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1)=[O:4].CN(C=O)C>CCOC(C)=O>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C1CC[C@@H](NC(=O)C(F)(F)F)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
(R)-2,2,2-Trifluoro-N-(4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (0.5 g), RuCl[(R,R)-Tsdpen(p-cymene)] and DMF (25 mL) were added to a flask that was purged with argon (catalyst prepared using procedure from Org Syn, Vol 82, pg 10-17, note 5). Triethylamine and HCOOH were added and the reaction mixture was stirred at 50° C. overnight. Further addition of catalyst (0.06 g), TEA (0.4 mL) and HCOOH (0.12 mL) were required to drive the reaction to completion after continued heating at 50° C. for an additional 6-8 hr. The reaction mixture was cooled to room temp, diluted with 150 mL EtOAc, and washed with 20 mL distilled water. The organic phase was dried over MgSO4 and concentrated in vacuo, and purified by column chromatography (eluting with 1% MeOH/DCM), to give 0.417 g (83%) of the titled compound. 1H-NMR (300 MHz, CDCl3) □ 7.5 (d, 1H), 7.3 (m, 2H), 7.2 (d, 1H), 6.4 (broad s, 1H), 5.3 (q, 1H), 4.8 (d, 1H), 2.4 (m, 1H), 2.2 (m 1H), 1.8 (m, 2H) ppm.
Reaction SMILES: [I:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].ClC1C=CC=C(C(OO)=[O:68])C=1.O>C(Cl)Cl>[I:1][CH2:2][C:3]1[CH2:4][S:5](=[O:68])[C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
A mixture of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (VIIa) (1.10 g, 1.19 mmoles) and m-chloroperbenzoic acid (m-CPBA) (322 mg, 1.30 mmoles) in CH2Cl2 (22 ml) was stirred at 0° C. for 15 minutes, poured into H2O (50 ml), and then extracted with CHCl3 (50 ml×3). The combined extracts were washed with saturated aqueous NaHCO3 (50 ml) and NaCl successively, dried and evaporated to afford the title compound (VIIa 1-oxide) (1.12 g, quantitative) as an amorphous powder.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.C(N(CC)CC)C.Cl.[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33]>C(O)C>[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:5]1[N:6]=[CH:1][N:2]=[C:3]2[C:4]=1[N:8]=[CH:9][N:10]2[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCc1cccc(I)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCc4cccc(I)c4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 85 °C
Yield: 87.5 %

Procedure:
A mixture of 6-chloropurine riboside (Aldrich Chemical Co., 100 mg, 0.35 mmol), triethylamine (0.146 ml, 1.05 mmol), and 3-iodobenzylamine hydrochloride (103 mg, 0.38 mmol) in ethanol (2 ml) was heated for 18 h at 85° C. in a sealed bottle. After the reaction mixture was concentrated to dryness, the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 10:1) to yield N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine (148 mg, 88%) as a colorless solid: m.p. 172° C.; 1H NMR (DMSO-d6) d 3.54 (m, 1H, H-5'a), 3.67 (m, 1H, H-5'b), 3.96 (d, J=3.3 Hz, 1H, H-4'), 4.14 (m, 1H, H-3'), 4.60 (m, 1H, H-2'), 4.66 (br s, 2H, CH2), 5.16 (d, J=4.4 Hz, 1H, exchangeable with D2O, 3'-OH), 5.34 (br s, 1H, exchangeable with D2O, 5'-OH), 5.43 (d, J=6.1 Hz, 1H, exchangeable with D2O, 2'-OH), 5.89 (d, J=6.0 Hz, 1H, H-1'), 7.11 (pseudo t, J=8.0 and 7.8 Hz, 1H, H-5"), 7.36 (d, J=7.6 Hz, 1H, H-4" or -6"), 7.58 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.72 (s, 1H, H-2"), 8.21 (s, 1H, H-2 or 8), 8.40 (s, 1H, H-2 or 8), 8.48 (br s, 1H, exchangeable with D2O, N6H,).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:5][CH2:4]1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][C:11]([Cl:17])=[O:13])[CH2:5][CH2:4]1
Reactant: CN1CCC(CCC(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCC(CCC(=O)Cl)CC1

Procedure:
A suspension of 3-(1-methylpiperid-4-yl)propionic acid hydrochloride (WO 9620173 A1, Example 1)(0.33 g, 0.00159 mole) in dry dichloromethane (10 ml) was treated with dimethylformamide (1 drop) and oxalyl chloride (0.416 ml, 0.605 g, 0.00477 mole) under an atmosphere of argon. After stirring for 3½ hours the mixture was concentrated in vacuo. The residue was dissolved in dry dichloromethane and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([Cl:20])[CH:22]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CCNC(=O)OC(C)(C)C)N1CCC(=O)CC1
Reactant: NCc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H](CCNC(=O)OC(C)(C)C)N1CCC(NCc2cccc(Cl)c2)CC1
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
Following general procedure A: to a solution of [(R)-3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (0.25 g, 0.94 mmol) in CH2Cl2 (20 ml) was added 3-chloro-benzylamine (0.14 ml, 1.13 mmol) and the mixture was stirred for 5 min. NaBH(OAc)3 (0.30 g, 1.41 mmol) and acetic acid (10 drops) were added and the mixture was stirred at rt under N2 overnight. The crude product was purified by flash chromatography (CH2Cl2, 5% MeOH, 1% NH4OH) to afford {(R)-3-[4-(3-chloro-benzylamino)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester as a yellow oil (305 mg, 82%). 1H NMR (CDCl3) δ 0.92-0.94 (d, 3H, J=6 Hz), 1.27-1.39 (m, 2H), 1.44 (s, 9H), 1.60-1.72 (m, 2H), 1.82-1.97 (m, 2H), 2.02-2.14 (m, 1H), 2.32-2.51 (m, 2H), 2.68-2.87 (m, 3H), 3.05-3.11 (m, 1H), 3.23-3.37 (m, 1H), 3.79 (s, 2H), 4.40 (s, 1H), 6.01 (br s, 1H), 7.16-7.25 (m, 3H), 7.33 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:43]([S:49][CH2:50][CH3:51])=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:43]([S:49][CH2:50][CH3:51])=[N:42][N:41]=5)=[O:61])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nnc(SCC)n4CC(C)C)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nnc(SCC)n4CC(C)C)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(5-ethylthio-4-isobutyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (697 mg) in dichloromethane (15 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.35 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 4:1→9:1 →ethyl acetate→ethanol:ethyl acetate 1:19), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(5-ethylthio-4-isobutyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 147) (574.6 mg) as yellow amorphous.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][OH:16])[CH:8]=1)([O-])=O.[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@@H:29]([CH2:33][CH2:34][CH3:35])[C:30](O)=[O:31])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[OH:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:7]1[CH:8]=[C:4]([NH:1][C:30](=[O:31])[C@@H:29]([NH:28][C:26](=[O:27])[CH2:25][C:20]2[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=2)[CH2:33][CH2:34][CH3:35])[N:5]=[CH:6]1
Reactant: O=[N+]([O-])c1cn(-c2ccccc2CO)cn1
Reactant: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(-c2ccccc2CO)cn1

Procedure:
(2-(4-nitro-1H-imidazol-1-yl)phenyl)methanol was reduced and coupled with (S)-2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 443 m/z (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[N:13]=1.[Br-].[C:22]([C:24]1[CH:29]=[CH:28][C:27]([Zn+])=[CH:26][CH:25]=1)#[N:23]>O1CCCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:27]3[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: N#Cc1ccc([Zn+])cc1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(I)cc2)CO1
Agent: Cl[Pd]Cl
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The compound of Example 2 (6.5 g, 17 mmol) and bis(triphenylphosphine) palladium dichloride (0.15 g, 0.45 mmol) were dissolved in tetrahydrofuran (60 mL). The compound 4-cyanophenylzinc bromide (Rieke Organometallics, Lincoln, Nebr., 0.28 M in tetrahydrofuran, 72 ml) was added over 2 min and the mixture was stirred at 25° C. for 18 h. The reaction mixture was diluted with water (200 mL) and extracted with ether (100 mL). The aqueous layer was extracted with dichloromethane (100 mL) and the combined organic layers were dried over magnesium sulfate and evaporated. The residue was subjected to silica gel chromatography with hexanes/ethyl acetate 5:1 as eluent. The title compound was isolated as a yellow solid (4.5 g): m.p. 136°-138° C. 1H NMR (CDCl3, 300 MHz) δ 7.8-7.0 (11H), 5.6 (1H), 4.9 (1H), 4.3 (1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([O:11][CH2:25][CH3:26])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccc(F)cc2)c(F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(-c2ccc(F)cc2)c(F)c1
Temperature: 0 °C

Procedure:
2-(2,4'-Difluoro-4-biphenylyl)propionic acid (830 mg.), ethanol (10 ml.) and concentrated sulphuric acid (0.5 ml.) were refluxed for 16 hours. The solution was diluted with ice-water (200 ml.) and extracted with ether. After the usual washing, evaporation of the ether and distillation of the residue gave ethyl 2-(2,4'-difluoro-4-biphenylyl)-propionate, b.p. 145°-146°C./0.8 mm.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=1)([O-])=O>[Pd].C(O)C>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[C:4]([NH2:1])[CH:12]=[CH:11][C:7]1=2
Reactant: O=[N+]([O-])c1ccc2sccc2c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2sccc2c1
Yield: 101.3 %

Procedure:
A mixture of 5-nitrobenzo[b]thiophene (3.09 g, 17.0 mmol) and 10% palladium on carbon (Aldrich, cat. No. 20,569-9) (150 mg) in ethanol (90 mL) was shaken in a Parr flask under a hydrogen atmosphere of 3 bar. After 16 h the catalyst was filtered off over a celite pad and washed with ethanol (2×30 mL). The filtrate was evaporated in vacuo to yield benzo[b]thiophen-5-amine (2.57 g, 100%) as a dark purple amorphous solid. 1H NMR δ (CDCl3, 400 MHz) 3.70 (br. s., 2H), 6.78 (dd, J=8.61, 1.96 Hz, 1H), 7.10 (d, J=2.35 Hz, 1H), 7.14 (d, J=5.09 Hz, 1H), 7.38 (d, J=5.48 Hz, 1H), 7.63 (d, J=8.61 Hz, 1H)
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[N:6]1.[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[O:35][CH2:34][C:33]2=[O:42])[CH2:28][CH2:27]1.C(N(CC)CC)C>CCO>[OH:1][CH:2]([CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)=[N:6]1)[CH2:3][N:26]1[CH2:27][CH2:28][CH:29]([N:32]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[O:35][CH2:34][C:33]2=[O:42])[CH2:30][CH2:31]1
Reactant: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2cnccn2)cc1
Reactant: O=C1COc2ccccc2N1C1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1COc2ccccc2N1C1CCN(CC(O)Cn2cc(-c3cnccn3)c(-c3ccc(C(F)(F)F)cc3)n2)CC1
Temperature: 80 °C
Yield: 21.2 %

Procedure:
To a solution of 2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (76 mg, 0.220 mmol) and 4-piperidin-4-yl-4H-benzo[1,4]oxazin-3-one (61 mg, 0.231 mmol) in EtOH (1.1 mL) was added triethylamine (0.031 mL, 0.220 mmol). The reaction mixture was heated to 80° C. overnight, concentrated, and purified by column chromatography (silica, 5-10% MeOH/CH2Cl2) to afford 4-(1-{2-hydroxy-3-[4-pyrazin-2-yl-3-(4-trifluoromethyl-phenyl)-pyrazol-1-yl]-propyl}-piperidin-4-yl)-4H-benzo[1,4]oxazin-3-one (27 mg, 21%). TLC (silica, 5% MeOH/CH2Cl2): Rf=0.09. MS (electrospray): m/z 579.2 (579.2, calculated for C30H29F3N6O3, M++H). 1H NMR (400 MHz, CDCl3): 8.53 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.16 (d, J=5.4 Hz, 1H), 7.00-7.03 (m, 3H), 4.49 (s, 2H), 4.39 (d, J=10.8 Hz, 1H), 3.13 (d, J=11.9 Hz, 1H), 2.96 (d, J=11.9 Hz, 1H), 2.59-2.80 (m, 2H), 2.40-2.55 (m, 3H), 2.17 (t, J=11.9 Hz, 1H),1.77 (d, J=11.9 Hz, 2H).