Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([CH2:21][O:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][C:24]=2[O:34][CH3:35])[CH2:10]1)C1C=CC=CC=1>CCO.[Pd]>[C:17]([O:16][C:14]([N:12]1[CH2:13][CH:9]([OH:8])[CH2:10][CH:11]1[CH2:21][O:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][C:24]=1[O:34][CH3:35])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1ccc(OCC2CC(OCc3ccccc3)CN2C(=O)OC(C)(C)C)c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCC2CC(O)CN2C(=O)OC(C)(C)C)c(OC)c1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A stirred mixture of ethyl 4-[4-benzyloxy-1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-methoxybenzoate (1.189 g, 2.449 mmol) and 5% Pd-C (240 mg) in EtOH (10 mL) was hydrogenated overnight at room temp. The mixture was filtered to remove the catalyst and the filtrate was concentrated in vacuo to give ethyl 4-[1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinyl]methoxy-3-methoxybenzoate (735.3 mg, 76%) as a pale yellow oil. To a stirred cold (minus 78° C.) solution of DAST (0.491 mL, 3.718 mmol) in CH2Cl2 (7.4 mL) was added dropwise a solution of this compound in CH2Cl2 (2 mL), and the resulting mixture was stirred overnight. The mixture was quenched with water and extracted with CHCl3. The extract was washed with brine and dried over Na2SO4. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane:EtOAc (3:1, v/v) as eluent to afford 418.7 mg (57%) ethyl 4-[1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinyl]methoxy-3-methoxybenzoate as an oil. 1H-NMR (400 MHz, CDCl3) δ1:39 (t, J=7.3 Hz, 3H), 1.49 (s, 9H), 2.16 (br m, 1H), 2.58 (dd, J=15.6, 19.0 Hz, 1H), 3.60-3.75 (m, 2H), 3.91 (s, 3H), 3.97 (t, J=9.3 Hz, 1H), 4.35 (q, J=7.3 Hz, 2H), 4.33-4.53 (m, 2H), 5.25 (d, J=52.7 Hz, 1H), 7.04 (dd, J=7.8, 56.2 Hz, 1H), 7.55 (s, 1H), 7.65 (br s, 1H); MS (FAB) m/z 398 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([C:10]=1[CH3:11])=[C:8]([CH3:12])[CH:7]=[C:6]([CH3:13])[CH:5]=2.[Li:14]CCCC>CCCCCC>[CH3:1][C:2]1[CH-:3][C:4]2[C:9]([C:10]=1[CH3:11])=[C:8]([CH3:12])[CH:7]=[C:6]([CH3:13])[CH:5]=2.[Li+:14]
Reactant: CC1=C(C)c2c(C)cc(C)cc2C1
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: Cc1cc(C)c2c(C)c(C)[cH-]c2c1
Product: [Li+]
Reaction time: 8 h
Yield: 95.5 %

Procedure:
2,3,4,6-Tetramethylindene (11.12 g, 64.52 mmol) was stirred in hexane (250 mL) as nBuLi (70 mmol, 28 mL of 2.5 M solution in hexane) was added slowly. This mixture was allowed to stir overnight. After the reaction period the desired product was isolated as an off-white solid via filtration and used without further purification or analysis (10.98 g, 95.5 percent yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>CO>[ClH:1].[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([NH:13][C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CO
Product: COC(=O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Product: Cl
Reaction time: 0.25 h
Yield: 74.5 %

Procedure:
4,7-Dichloroquinoline (19.8 g, 100 mmol) and methyl 4-aminobenzoate (15.1 g, 100 mmol) are stirred in 150 mL of methanol in a 500 mL Erlenmeyer flask and heated on a hot plate. After~15 minutes, a yellow solid precipitates out of solution. Another 100 mL of methanol are added and the large chunks of material are broken up. After another 15 minutes of heating, the flask is allowed to cool for 5 minutes and the product is filtered and washed with ether. Air drying in the funnel overnight affords 26.01 g (74.5 mmol, 75% yield) of compound as a pale-yellow solid: 1H NMR (Me2SO-d6, 300 MHz) δ8.74 (d, J=9.3 Hz, 1H), 8.63 (d, J=6.9 Hz, 1H), 8.11 (d, J=8.7 Hz, 2H), 8.09 (d, J=2.1 Hz, 1H), 7.9 (d of d, 1 H), 7.62 (d, J=8.4 Hz, 2H), 7.1 (d, 1H), 3.87 (s, 3H).
Reaction SMILES: C[S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=[O:22])[O:13][CH2:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(C1C=CC(CC(O)=O)=CC=1)(=O)(=O)[NH2:24].BrCC(C1C=CC=CC=1)=O>>[S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=[O:22])[O:13][CH2:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:24]
Reactant: NS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: CS(=O)(=O)c1ccc(C2=C(c3ccccc3)COC2=O)cc1
Agent: O=C(CBr)c1ccccc1
Product: NS(=O)(=O)c1ccc(C2=C(c3ccccc3)COC2=O)cc1
Yield: 40 %

Procedure:
The title compound was synthesized in a manner similar to that described for 47b from 4-sulfamoylphenylacetic acid and 2-bromoacetophenone in 40% yield. 1H NMR (DMSO-d6) δ 5.43 (s, 2H), 7.36–7.45 (m, 5), 7.76 (d, J=8.5 Hz, 2H), 7.96 (d, J=8.5 Hz, 2H); HRMS calc'd for M+ 315.0557. found 315.0573. Anal. (C16H13NO4S) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)=[CH:18][CH:17]=3)=[O:11])=[CH:5][CH:4]=1.[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>O1CCOCC1.CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[CH:18][CH:17]=3)=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)Nc2cc3cc(-c4cn[nH]c4)ccc3cn2)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: COc1ccc(CC(=O)Nc2cc3cc(-c4cnn(C)c4)ccc3cn2)cc1
Temperature: 70 °C

Procedure:
To the solution of 2-(4-Methoxy-phenyl)-N-[6-(1H-pyrazol-4-yl)-isoquinolin-3-yl]-acetamide (30.00 mg, 0.08 mmol) in 2 mL of dioxane was added Cs2CO3 (59.80 mg, 0.18 mmol) and CH3I (13.10 mg, 0.09 mmol). The mixture was heated at 70° C. for 72 hrs. Evaporation of the solvent gave the crude product which was re-dissolved in DMSO and purified by HPLC to give the title compound as a crystalline solid product (7.5 mg, 24.0%). 1H NMR (DMSO-d6, 400 MHz): δ 3.68 (2H, s), 3.73 (3H, s), 3.89 (3H, s), 6.89 (2H, d, J=8.5 Hz), 7.30 (2H, d, J=8.5 Hz), 7.75 (1H, dd, J=8.5, 1.5 Hz), 7.97-8.06 (2H, m), 8.08 (1H, s), 8.37 (2H, d, J=16.6 Hz), 9.03 (1H, s), 10.70 (1H, s). 13CNMR (DMSO-d6, 100 MHz): δ 42.19, 55.03, 106.31, 113.77, 120.33, 121.25, 123.88, 124.41, 127.88, 128.18, 128.9, 130.16, 134.93, 136.86, 137.86, 147.56, 150.80, 158.06, 170.78. HRMS: m/z 373.1660, calc. 373.1659. MS m/z, (APCI); 373.1 [(M+1)+100].
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:46][CH2:47][CH2:48][CH3:49]>CN(C)C=O.O>[CH2:46]([O:38][C:35]1[CH:36]=[CH:37][C:32]([CH:2]([OH:1])[CH:3]([NH:18][C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=23)=[O:20])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=2)=[CH:33][CH:34]=1)[CH2:47][CH2:48][CH3:49]
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and 1-iodobutane (417 mg, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (298 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][C:12](=[O:14])[C@@H:11]([CH3:15])[CH2:10][C@@H:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:4][C:3]=1[F:23].Cl[C:25]1C=CC([C@@H]2OC(=O)[C@H](C)C[C@@H]2C2C=CC=C(Cl)C=2)=C[C:26]=1F.[CH3:47][Si]([N-][Si](C)(C)C)(C)C.[Li+].C(=O)=O.C(#N)C>>[CH2:15]([C@@:11]1([CH3:47])[CH2:10][C@H:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:23])[CH:4]=2)[O:13][C:12]1=[O:14])[CH:25]=[CH2:26]
Reactant: C[C@@H]1C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)c(F)c2)OC1=O
Reactant: C[C@H]1C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)c(F)c2)OC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC#N
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)c(F)c2)OC1=O
Temperature: -10 °C

Procedure:
(3S,5R,6R)-6-(4-Chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one and (3R,5R,6R)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (18 g, 51.0 mmol, Example 4, Step D) was added to an oven dried 500 mL round-bottom flask. The solid was dissolved in anhydrous toluene and concentrated to remove adventitious water. 3-Bromoprop-1-ene (11.02 mL, 127 mmol, passed neat through basic alumina prior to addition) in tetrahydrofuran (200 mL) was added and the reaction vessel was evacuated and refilled with argon three times. Lithium bis(trimethylsilyl)amide (1.0 M, 56.1 mL, 56.1 mmol) was added dropwise at −40° C. (dry ice/acetonitrile bath) and stirred under argon. The reaction was allowed to gradually warm to −10° C. and stirred at −10° C. for 3 hours. The reaction was quenched with saturated ammonium chloride (10 mL), concentrated, and the crude product was diluted in water (150 mL) and diethyl ether (200 mL). The layers were separated and the aqueous layer was washed twice more with diethyl ether (200 mL/each). The combined organic layer was washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was purified by flash chromatography (2×330 g silica gel columns, gradient elution of 0% to 30% acetone in hexanes) to provide the title compound as a white solid. The product can alternatively be crystallized from a minimum of hexanes in dichloromethane. Enantiomeric excess was determined to be 87% by chiral SFC (90% CO2, 10% methanol (20 mM ammonia), 5.0 mL/min, 100 bar (10,000 kPa), 40° C., 5 minute method, Phenomenex Lux-2 (Phenomenex, Torrance, Calif.) (100 mm×4.6 mm, 5 μm column), retention times: 1.62 min. (minor) and 2.17 min. (major)). The purity could be upgraded to >98% through recrystallization in hexanes and dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:18]=[O:19])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:4][CH:3]=1.[CH3:20][Mg]Br.CCOCC>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:18]([OH:19])[CH3:20])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-chloro-1-(3-fluorophenyl)-1H-indole-2-carbaldehyde (50 mg, 0.18 mmol) in tetrahydrofuran (5 mL) was added 3.0 M methylmagnesium bromide in ether (0.091 mL, 0.27 mmol). The reaction was stirred at room temperature for 1 hour, quenched with water, and then extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give the desired product (51 mg). The crude product was used directly in next step. LCMS calculated for C16H14ClFNO(M+H)+: m/z=290.1. Found: 289.7.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)=O.[C:11]([O:14][C@:15]1([C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25](=[CH:26][C:27](=[O:38])[C@@H:28]4C[C@@H:29]42)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[C:16](=[O:18])[CH3:17])(=[O:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].[CH:45]([Cl:48])(Cl)Cl>COCOC.C(Cl)Cl>[C:11]([O:14][C@:15]1([C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25](=[CH:26][C:27](=[O:38])[CH2:28][C@@H:29]2[CH2:45][Cl:48])[C:24](=[CH2:1])[CH2:23]3)[CH2:20][CH2:19]1)[C:16](=[O:18])[CH3:17])(=[O:13])[CH3:12]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Reactant: ClC(Cl)Cl
Reactant: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCOC
Solvent: O=P(Cl)(Cl)Cl
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(C)=O)C(C)=O)[C@]2(C)C1=CC(=O)C[C@@H]2CCl

Procedure:
A suspension of 9.0 g of sodium acetate in 270 ml of chloroform, 270 ml of formaldehyde dimethylacetal, and 35 ml of phosphorus oxychloride is stirred with 9.0 g of 17α-acetoxy-1α,2α-methylene-4-pregnene-3,20-dione for 5 hours at a bath temperature of 65° C. The reaction solution is neutralized with a saturated sodium carbonate solution and diluted with methylene chloride. The organic phase is separated and worked up as usual. The crude product is purified on 500 g of silica gel with a hexaneethyl acetate gradient (0-30% ethyl acetate), thus isolating 7.5 g of 17α-acetoxy-1α-chloromethyl-6-methylene-4-pregnene-3,20-dione, mp 190°-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].CO>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8]
Reactant: COC(=O)CN(c1ccc(Cl)cc1C(=O)c1ccccc1F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CN(c1ccc(Cl)cc1C(=O)c1ccccc1F)S(=O)(=O)c1ccc(N)cc1

Procedure:
The 5-chloro-2'-fluoro-2-[N-(methoxycarbonylmethyl)-N-(4-nitrophenylsulfonyl)amino]benzophenone prepared in Example 2, step b, is dissolved in 100 ml of ethyl acetate and 5 ml of methanol and hydrogenated at ordinary pressure for 2 hours in the presence of 620 mg of 10% palladium-on-charcoal; the existence of 3 compounds (starting material, intermediate and expected product) is observed in TLC. The catalyst is filtered off, the solvent is evaporated off and the residue is chromatographed on silica gel. The expected compound is eluted with DCM containing 1% of methanol. After recrystallization from DCM/isopropyl ether, m.p.=168°-170° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C.Cl.[NH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:31][CH2:30]1>C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([N:29]1[CH2:30][CH2:31][CH:32]([O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:34]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)COC1CCNCC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)COC1CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC1
Temperature: 2.5 °C
Yield: 95.4 %

Procedure:
47.3 g (250 mmol) of (S)-2-tert.-butoxycarbonylaminopropionic acid (Fluka) were dissolved in 560 ml of ethyl acetate (Fluka) while stirring and under argon, cooled to 0-5° C. and treated with 31.0 ml (250 mmol) of pivaloyl chloride (d=98; Fluka). The light yellowish solution was treated dropwise within 30 minutes with 35.0 ml (250 mmol) of triethylamine (d=0.726; Fluka), with the temperature being held in the range of 0-5° C. A white suspension formed. The white precipitate was filtered off through a pre-cooled, sintered glass filter (G3) and the filter cake was washed with 140 ml of cold ethyl acetate (0 to 5° C.). To the combined filtrates, a light yellow solution, were added 55.9 g (17.HCl; 250 mmol) of ethyl (piperidin-4-yloxy)-acetate hydrochloride and 66.6 g of K3PO4.3H2O (250 mmol; Merck). The white suspension was treated with 500 ml of deionised water at 5 to 10° C. under argon and while stirring vigorously, with the temperature rising to 20° C. The colourless two-phase system was stirred at 20 to 25° C. for two hours. The aqueous phase was separated and the organic phase was washed with 500 ml of a 1M sodium bicarbonate solution. The organic phase was dried over about 50 g of sodium sulphate, filtered and the filter cake was washed with about 100 ml of ethyl acetate. The combined filtrates were evaporated in a rotary evaporator at 50°/20 mbar, giving 85.5 g (95 wt. %) of ethyl (S)-[1-(2-tert.-butoxycarbonylamino-propionyl)-piperidin-4-yloxy]-acetate as a crude product in the form of a clear, yellowish oil (HPLC analysis: 88.9% (area).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[F:12][C:13]([F:22])([F:21])[C:14]1[C:19](O)=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:5][C:17]1[CH:18]=[CH:19][C:14]([C:13]([F:22])([F:21])[F:12])=[CH:15][CH:16]=1
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: Oc1ccccc1C(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(O[C@H](CCCl)c2ccccc2)cc1

Procedure:
The title compound was prepared by the method of example 55 using [S]-3-chloro-1-phenylpropanol (2.57 g, 15 mmol), α, α, α-trifluorocresol (2.4 g, 15 mmol) in THF (40 ml) at room temperature. Workup provided the optically pure title compound as a thick liquid, bp 180°-200° C./0/5 mm. [α]D +2.3° (c 10, CHCl3 ; 13C NMR (CDCl3): 140.50, 129.39, 128.66, 127.56, 127.38, 127.19, 127.01, 126.34, 116.45, 77.82, 41.69, 41.38. Mass spectrum (EI): 153/155 (45), 91 (100). (CI): 314/316, (1, M+), 153/155 (100). Anal. Calcd. for C16H14ClNO: C, 61.05; H, 4.45; Cl, 11.29; F, 18.12. Found: C, 61.06; H, 4.51; Cl, 11.16; F, 18.22.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[F:22])([CH3:14])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=3)[N:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccccc2F)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(2-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester by the procedure of Example 26. 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H, J=8.60 Hz), 7.12-6.96 (m, 4H), 6.79 (d, 2H, J=8.60 Hz), 4.15 (t, 2H, J=6.65 Hz), 3.26 (d, 1H, J=14.08 Hz), 3.19 (d, 1H, J=14.08 Hz), 2.98-2.80 (m, 2H), 2.32 (s, 3H), 2.02 (d, 2H, J=10.95 Hz), 1.81 (d, 2H, J=12.90 Hz), 1.70 (d, 1H, J=12.90 Hz), 1.85 (q, 2H, J=11.73 Hz), 1.40 (s, 3H), 1.39-1.23 (m, 3H). HRMS (ES+) m/z exact mass calcd for C28H33FNO5 482.2343, found 482.2349.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:4][C@H:5]([CH2:9][NH:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl.CS(C)=O>[CH:2]([C@@H:3]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:4][C@H:5]([CH2:9][NH:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH:6]([CH3:7])[CH3:8])=[O:1]
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@@H](CO)NC(=O)OC(C)(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@@H](C=O)NC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of 2.65 g of tert-butyl (1(S)-hydroxymethyl-3(S)-{[2-(3-methoxypropoxy)-benzoylamino]methyl}-4-methylpentyl)carbamate, 2.44 ml of triethylamine in 20 ml of dichloromethane is cooled to 0° C. The solution of 3.07 g of sulphur trioxide-pyridine complex in 12 ml of dimethyl sulphoxide is added dropwise over 1 hour and then the mixture is stirred for another 1 hour. The reaction mixture is admixed with 20 ml of ice-water and extracted with dichloromethane (3×). The combined organic phases are washed with 10% aqueous sodium hydrogensulphate solution, water, 1M sodium hydrogencarbonate solution and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a slightly yellowish foam. Rf=0.33 (3:1 EtOAc-heptane); Rt=4.65 (gradient I).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]([CH3:15])[C:7](=[O:16])[C:6]=2[CH:17]=1.[I:18]I.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([I:18])=[C:10]3[CH2:9][N:8]([CH3:15])[C:7](=[O:16])[C:6]=2[CH:17]=1
Reactant: II
Reactant: CN1Cc2cncn2-c2ccc(F)cc2C1=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O

Procedure:
2.31 g (10 mmol) of 8-fluoro-4,5-dihydro-5-methyl-6H -imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 95° for 1.5 hours with 8.88 g (35 mmol) of iodine in 25 ml of N,N-dimethylformamide. The reaction mixture was then poured into 300 ml of water, decolorized with sodium thiosulfate solution and extracted four times with methylene chloride. The organic extracts were washed three times with water, dried over magnesium sulfate and evaporated. After recrystallization of the residue from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 187-188°.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:28])([CH3:27])[CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([CH2:17][O:18][Si](C(C)(C)C)(C)C)[CH:14]=[CH:13][C:12]3=[O:26])[C:5]=2[CH:4]=1)#[N:2].Cl.O>CO.O1CCOCC1>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[O:7][C:8]([CH3:27])([CH3:28])[CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:12]3=[O:26])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2cc(CO[Si](C)(C)C(C)(C)C)ccc2=O)c2cc(C#N)ccc2O1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CC1(C)C=C(n2cc(CO)ccc2=O)c2cc(C#N)ccc2O1
Yield: 94.5 %

Procedure:
In 11.5 ml of methanol, is dissolved 1.16 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-5-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 13. Then, 2.87 ml of 4N hydrochloric acid in dioxane is added to the solution at 0° C., and reacted at room temperature for 1.5 hours. After stopping the reaction by adding water, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/20 mixture of methanol/methylene chloride as a developing solvent to obtain 0.80 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-5-hydroxymethyl-1-pyridinyl)-2H-benzo[b]pyran.