Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]1([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([CH:22]4[CH2:24][CH2:23]4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:4])[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[OH:1][C:2]([C:5]1([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([CH:22]4[CH2:23][CH2:24]4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:4]
Reactant: CC(C)(O)C1(NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(C4CC4)nc23)CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)C1(NC(=O)c2c[nH]c3ncc(C4CC4)nc23)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
In a 10 mL round-bottomed flask, 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-hydroxy-1-methyl-ethyl)-cyclopentyl]-amide (207 mg, 0.45 mmol) was dissolved in CH2Cl2 (5 mL). Trifluoroacetic acid (1.7 mL) was added and the light yellow reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was taken up in toluene (5 mL), concentrated and then dried under high vacuum. The residue was dissolved in CH2Cl2 (2.5 mL) and ethylenediamine (2.5 mL) was added. The reaction mixture was stirred at room temperature for 1 h then H2O and EtOAc were added. The aqueous layer was extracted with EtOAc. The combined organics were washed with H2O and brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography over 12 g of SiO2 using EtOAc/hexanes (gradient: 0-90% EtOAc) to afford 79 mg (53%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-hydroxy-1-methyl-ethyl)-cyclopentyl]-amide as a white solid. MS: (M+H)+=329; mp=232.0-234.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[BrH:12].BrBr>ClC(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Br
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)Cc1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of p-methylphenylacetic acid (0.175 mol, 27.8 g) in tetrachloromethane (250 mL) under a nitrogen atmosphere in a round bottom flask equipped with a reflux condenser and provision for trapping the released HBr was added bromine (0.175 mol, 27.8 g) dissolved in tetrachloromethane. The red/brown mixture was irradiated and brought to reflux with a 250 watt incandescent light source. Over the course of ten minutes, the color was discharged and a crystalline precipitate was formed. The mixture was allowed to cool to room temperature, and the solid was collected by vacuum filtration, and dried in a stream of nitrogen to give (4-bromomethyl-phenyl)-acetic acid as a white solid containing 6.3% by weight p-methylphenylacetic acid as an impurity. (25.1 g, 63%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7]Cl.[CH3:9][NH:10][CH2:11][CH2:12][OH:13]>>[CH3:9][N:10]([CH2:11][CH2:12][OH:13])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: ClCc1ccccn1
Reactant: CNCCO
Product: CN(CCO)Cc1ccccn1

Procedure:
The title compound was prepared from 2-picolyl chloride (3 g) and 2-(methylamino)ethanol (19 ml) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:34])([F:33])[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[NH2:32].Cl>O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]2[C:25]([F:24])([F:33])[F:34])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC2CCCCC2C(F)(F)F)c([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 101.3 %

Procedure:
To a solution of 0.92 g of 4-fluoro-3-nitro-benzoic acid methyl ester in 15 ml of abs. DMF was added 0.84 ml of DIPEA, followed by 0.85 g of 2-(trifluoromethyl)cyclohexylamine. After 16 h at rt, the mixture was poured into water, the pH was adjusted to 4 by the addition of 1 M aqueous hydrochloric acid, and the reaction mixture was extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over sodium sulphate and concentrated to yield 1.62 g (100%) of 3-Nitro-4-(2-trifluoromethyl-cyclohexylamino)-benzoic acid methyl ester.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[O:13]=[C:14]([CH3:17])[CH:15]=O>>[O:13]=[C:14]([CH3:17])/[CH:15]=[N:1]/[CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: CC(=O)C=O
Product: CC(=O)/C=N/C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of tert-butyl 3-aminoazetidine-1-carboxylate (16.8 g, 97.5 mmol) and 2-oxopropanal (10 g, 140 mmol) was stirred for 5 minutes at room temperature. The resulting material was purified via silica gel chromatography (Eluant: 1:1 petroleum ether: ethyl acetate) to give the product as an oil, which was used directly in the next step. Yield: 12.5 g, 55.2 mmol, 57%.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:9][C@H:8]2[C:10](OCC)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[C:1]1([C@H:7]2[CH2:9][C@H:8]2[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@@H]1C[C@@H]1c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: OC[C@@H]1C[C@@H]1c1ccccc1
Reaction time: 2 h
Yield: 102.9 %

Procedure:
To a solution in diethyl ether (12.0 mL) of the ethyl cis-2-phenylcyclopropanecarboxylate (1.51 g) obtained in step (1) above, a suspension of aluminum lithium hydride (393 mg) in diethyl ether (12.0 mL) was added at 0° C. After being brought to room temperature, the mixture was stirred for 2 hours. After adding sodium sulfate decahydrate at 0° C., the reaction mixture was brought to room temperature and stirred for an hour. After removing the insoluble matter by filtration, the filtrate was concentrated under reduced pressure to give (cis-2-phenylcyclopropyl)methanol as a colorless oil (1.21 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A166) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[F:32][C:33]1[CH:47]=[CH:46][C:36]2[C:37]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[N:38][O:39][C:35]=2[CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:42][CH2:41][CH:40]([C:37]5[C:36]6[CH:46]=[CH:47][C:33]([F:32])=[CH:34][C:35]=6[O:39][N:38]=5)[CH2:45][CH2:44]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine as in General Procedure 10 to give the title compound. LCMS: m/z=649.95 (M+H+); retention time=1.00 minutes.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.FC(F)(F)S(O[Si:21]([CH3:24])([CH3:23])[CH3:22])(=O)=O>C(Cl)Cl>[CH3:22][Si:21]([CH3:24])([CH3:23])[O:14][C:12]([C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:11][CH:10]=1)=[CH2:13]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(-n2cncn2)cc1
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C)c1ccc(-n2cncn2)cc1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a stirred solution of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethanone (4.5 g, 24.0 mmol) in CH2Cl2 at 0° C., were added TEA (3.7 g, 36.1 mmol) and trimethylsilyl trifluoromethanesulfonate (8 g, 36 mmol) and the resultant reaction mixture was stirred for 1 h. The reaction mixture was quenched with a mixture of sat aq sodium bicarbonate solution and ether. The ether layer and was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (5.5 g) which was taken directly to next step.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][C:12]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:31][CH2:30][C@H:29]([O:32][Si](C(C)(C)C)(C)C)[CH2:28][CH2:27]3)[CH:25]=2)=[C:13]2[CH:17]=[C:16](B(O)O)[O:15][C:14]=12)=O)(C)(C)C.Br[C:48]1[C:56]2[S:55][N:54]=[N:53][C:52]=2[CH:51]=[C:50]([C:57]#[N:58])[CH:49]=1>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]3)[CH:25]=2)=[C:13]2[CH:17]=[C:16]([C:48]3[C:56]4[S:55][N:54]=[N:53][C:52]=4[CH:51]=[C:50]([C:57]#[N:58])[CH:49]=3)[O:15][C:14]=12
Reactant: N#Cc1cc(Br)c2snnc2c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2cc(B(O)O)oc12
Product: N#Cc1cc(-c2cc3c(-c4cnn([C@H]5CC[C@H](O)CC5)c4)cnc(N)c3o2)c2snnc2c1

Procedure:
The title compound was prepared from {7-[bis(tert-butoxycarbonyl)amino]-4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-2-yl}boronic acid and 7-bromo-1,2,3-benzothiadiazole-5-carbonitrile by a procedure analogous to Example 368. MS (ESI): 458.14 [M+H]+; HPLC tR=0.79 min (TOF: polar—2 min).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH:30]=[N:31][N:32]([CH2:34][CH2:35][O:36]C7CCCCO7)[CH:33]=6)=[CH:25][N:24]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[ClH:43]>O1CCOCC1>[ClH:43].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:18][N:19]([C:23]5[N:24]=[CH:25][C:26]([C:29]6[CH:30]=[N:31][N:32]([CH2:34][CH2:35][OH:36])[CH:33]=6)=[CH:27][N:28]=5)[CH2:20][CH2:21][O:22]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(CCOC7CCCCO7)c6)cn5)CCO4)c3n2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(CCO)c6)cn5)CCO4)c3n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
(2S)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)morpholine 290 mg (0.51 mmol) was dissolved in MC 20 ml, and 4 M HCl in dioxane 2 ml was added. The mixture was stirred at room temperature overnight, and when the reaction was completed, the reaction mixture was concentrated under reduced pressure. MC and 4 M HCl in dioxane were removed, and ether was added to precipitate a solid, followed by decanting, to give a product 236 mg (89%).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:23]=[CH:22][C:8]([CH2:9][N:10]([CH3:21])[C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH3:21])[C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:22][CH:23]=1)=[O:3]
Reactant: CCOC(OCC)c1ccc(CN(C)C(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(Cc1ccc(C=O)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
The mixture of benzyl 4-(diethoxymethyl)benzyl(methyl)carbamate (1.0 g, 2.8 mmol) in 3N hydrochloric acid (50 ml) was stirring at room temperature for 1 h. Then the mixture was neutralized with Potassium carbonate. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and concentrated to give benzyl 4-formylbenzyl(methyl)carbamate (730 mg, 92%). 1H-NMR (400 MHz, CDCl3) δ: 2.94 (d, 3H), 4.572 (d, 2H), 5.18 (d, 2H), 7.32-7.39 (m, 7H), 7.84 (m, 2H), 10.00 (s, 1H); LC-MS (ESI) m/z: 284 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.C([O-])(=O)C.[Na+].Cl.[NH2:20][OH:21]>C(O)C.O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:20][OH:21])[CH2:8][CH2:7][CH2:6]2
Reactant: NO
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CCCC2=NO

Procedure:
Dissolve 100 g (0.57 mol) of 6-methoxy-1-tetralone in 2.5 litres of a mixture of ethanol/water: 80/20. There are then added, at ambient temperature, 85 g (1.04 mol) of sodium acetate and 43 g (0.62 mol) of hydroxylamine hydrochloride. Heat the suspension at reflux for 4 hours. Dilute the mixture with 5 litres of water and extract with ethyl ether, wash with water, dry over magnesium sulphate and filter. After evaporating off the solvent, 99 g of a beige solid are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10]Br.[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21]>C(#N)C>[Br:7][CH2:8][CH2:9][CH2:10][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cc1ccccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1ccccc1OCCCBr
Temperature: 20 °C

Procedure:
254.5 g of potassium carbonate and 654 cm3 of 1,3-dibromopropane are added to a solution of 153 g of methyl (2-hydroxyphenyl)acetate in 1400 cm3 of acetonitrile. The suspension obtained is refluxed for 20 hours, cooled to 20° C. and then filtered The filtrate is concentrated to dryness at 50° C. under reduced pressure. The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 8.8 cm, height 43 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (95/5 by volume) and collecting fractions of 300 cm3. Fractions 18 to 53 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 130.6 g of methyl 2-(3-bromopropoxy)phenylacetate are obtained in the form of an orange-coloured oil.
Reaction SMILES: FC(F)(F)S(OC1C=CC=CC=1CC1CCC2C(=CC=C(OC)C=2)C1)(=O)=O.COC1C=CC(CCN)=CC=1.C[O:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[CH2:56][CH:57]2[CH2:66][CH2:65][C:64]3[C:59](=[CH:60][CH:61]=[C:62]([O:67]C)[CH:63]=3)[CH2:58]2)=[CH:43][CH:42]=1.N>Br>[OH:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:47][CH2:48][NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[CH2:56][CH:57]2[CH2:66][CH2:65][C:64]3[CH:63]=[C:62]([OH:67])[CH:61]=[CH:60][C:59]=3[CH2:58]2)=[CH:45][CH:46]=1
Reactant: COc1ccc(CCNc2ccccc2CC2CCc3cc(OC)ccc3C2)cc1
Agent: Br
Agent: COc1ccc(CCN)cc1
Agent: COc1ccc2c(c1)CCC(Cc1ccccc1OS(=O)(=O)C(F)(F)F)C2
Product: Oc1ccc(CCNc2ccccc2CC2CCc3cc(O)ccc3C2)cc1

Procedure:
Synthesized from 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)phenyl trifluoromethanesulfonate (1.6 g) and 2-(4-methoxyphenyl)ethylamine (0.9 g) according to an analogous synthetic method to Example 116,to the total amount of [2-(4-methoxyphenyl)ethyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)phenyl]amine (crude product) was added 48% hydrobromic acid (30 ml), and the solution was refluxed overnight. To the reaction solution was added concentrated aqueous ammonia, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.1 g).
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24]>C(N(CC)CC)C>[CH2:21]([NH:25][C:26]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: CCCCN=C=O
Solvent: CCN(CC)CC
Product: CCCCNC(=O)OCCCCC/C=C(\c1ccccc1)c1cccnc1
Yield: 84.8 %

Procedure:
In the presence of triethylamine, (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (2.0 g, 7.4 mmoles) was reacted with n-butyl isocyanate (0.8 g) in the same manner as Example 9 to give 1-(n-butyl)aminocarbonyloxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (Compound Id-25, 2.3 g) as an oil
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:8]1[C:7]([Cl:12])=[C:3]([C:2]([Cl:1])=[C:10]([Cl:11])[CH:9]=1)[C:4]([OH:6])=[O:5])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1c(Cl)ccc(Cl)c1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(Cl)c(Cl)cc([N+](=O)[O-])c1Cl
Temperature: 43 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
2,3,6-Trichlorobenzoic acid (20.84 g, 92.4 mmol, prepared by the method of M. T. Goebel, U.S. Pat. No. 3,391,185, E.I. DuPont, Jul. 2, 1968) was stirred at 40°-45° C. in 89.1 mL of concentrated sulfuric acid. A solution containing 23.2 g of concentrated sulfuric acid and 23.2 g of fuming nitric acid was added at a rate so to maintain the temperature between 40°-45° C. An additional 20 mL of concentrated sulfuric acid was added. The reaction mixture was stirred at 43° C. for 1.5 hours and then poured over ice water. The resulting crystals were filtered and recrystallized from toluene-hexane to give 23.40 g (94%) of product; mp 149°-151° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][SH:5].CS(O[C@H:15]1[CH2:20][CH2:19][C@H:18]2[C@H:21]3[C@H:31]([C:32](=[O:34])[CH2:33][C@:16]12[CH3:17])[C@:29]1([CH3:30])[C:24](=[CH:25][C:26](=[O:35])[CH:27]=[CH:28]1)[CH2:23][CH2:22]3)(=O)=O>>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][S:5][C@@H:15]1[CH2:20][CH2:19][C@H:18]2[C@H:21]3[C@H:31]([C:32](=[O:34])[CH2:33][C@:16]12[CH3:17])[C@:29]1([CH3:30])[C:24](=[CH:25][C:26](=[O:35])[CH:27]=[CH:28]1)[CH2:23][CH2:22]3
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Reactant: Cc1ccccc1CS
Product: Cc1ccccc1CS[C@@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
In a manner similar to that described in Example 1A, 2-methylbenzylmercaptan is reacted with 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione to obtain the title compound of this example.
Reaction SMILES: Cl.N(CCO)(CCO)CCO.[O-]S([O-])(=O)=O.[Mg+2].[CH3:18][O:19][C:20](=[O:50])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[CH:38][C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][C:43]([Cl:49])=[CH:44][CH:45]=3)[N:40]=2)[CH:32]=1)=[O:30].CC(O)C>C1(C)C=CC=CC=1>[CH3:18][O:19][C:20](=[O:50])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[CH:38][C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][C:43]([Cl:49])=[CH:44][CH:45]=3)[N:40]=2)[CH:32]=1)[OH:30]
Reactant: COC(=O)c1ccccc1CCC(=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)O
Solvent: OCCN(CCO)CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reaction time: 0.17 h

Procedure:
To a jacketed 2-L 3-neck flask under nitrogen with jacket temperature set at 51° C. via an external heat exchanger and equipped with internal thermometer and mechanical stirrer at 250 rpm was added 300 mL 100 mM pH 8.0 triethanolamine-HCl, 0.6 mL 1 M MgSO4, 3.0 g of SEQ ID NO:20 catalyst as prepared in Example 3, 0.1 g NADP-Na2, to give a pale yellow solution. After stirring for 10 minutes, 100 g 2-[3-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-ketopropyl]benzoic acid methyl ester was added portion-wise over ˜5 minutes. To the slurry was added 500 mL (390 g) of IPA and 100 mL (85 g) toluene. The progress of the reaction was monitored by achiral HPLC as described in Example 4 and 6. The procedure as described in Example 9 was used for sampling and sample prep.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@@H:10]([CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@@H:10]([CH2:32][C:33]([OH:35])=[O:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a round-bottomed flask with tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetate (0.057 g, 0.099 mmol; Example 21, Step D) in DCM (1 mL) was added TFA (1.129 g, 9.90 mmol) at 0° C. The ice-bath was removed and the mixture was stirred at rt for 3 h. The solvent was removed. Purification by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 10 to 90% acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) provided the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CN(C)C=O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([CH3:12])[N:3]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(F)(F)F)c(Cl)n1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(C)ccc2C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
2-Chloro-6-methyl-3-(trifluoromethyl)pyridine (200 mg, 1.02 mmol, Eq: 1.00), (4-methoxyphenyl)methylamine (168 mg, 159 μL, 1.23 mmol, Eq: 1.2) and potassium carbonate (212 mg, 1.53 mmol, Eq: 1.5) were combined in dimethylformamide (1.2 mL) to give a light yellow suspension. The mixture was stirred at 120° C. for 2 h. Additional potassium carbonate (141 mg, 1.02 mmol, Eq: 1) and (4-methoxyphenyl)methanamine (140 mg, 133 μL, 1.02 mmol, Eq: 1) were added and the mixture was stirred at 120° C. for 7 h. Saturated aqueous sodium chloride solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to an oil. The product (100 mg, 33%) was obtained as a colorless oil by column chromatography (SiO2, ethyl acetate/n-heptane). MS: m/z=297.3 (M+H+)