Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:12]([NH:22][C:23](=[O:41])[CH2:24][N:25]2[C:33]3[C:32]([F:35])([F:34])[CH2:31][CH2:30][C:29]([F:37])([F:36])[C:28]=3[C:27]([CH:38]([F:40])[F:39])=[N:26]2)[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.Cl.CN.[CH2:45]([N:47](CC)CC)C>ClCCl>[Br:1][C:2]1[C:3]([C@@H:12]([NH:22][C:23](=[O:41])[CH2:24][N:25]2[C:33]3[C:32]([F:35])([F:34])[CH2:31][CH2:30][C:29]([F:37])([F:36])[C:28]=3[C:27]([CH:38]([F:40])[F:39])=[N:26]2)[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[N:4][C:5]([NH:47][CH3:45])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of compound 12C (68 mg, 0.1 mmol) and methylamine hydrochloride (34 mg, 0.5 mmol) in dichloromethane (5 ml) was added triethylamine (697 μL, 0.5 mmol). The reaction mixture was stirring at ambient temperature for 2 hours. The solvent was evaporated and the crude product was purified on reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford the title product. MS (m/z) 627.24 [M+H]+.
Reaction SMILES: C[Mg]Cl.[Br:4][C:5]1[N:10]=[C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=2)=[O:12])[CH:8]=[CH:7][CH:6]=1.[CH2:20](O)C.[Cl-].[NH4+]>C1COCC1>[Br:19][C:15]1[N:14]=[C:13]([C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([Br:4])[N:10]=2)([OH:12])[CH3:20])[CH:18]=[CH:17][CH:16]=1
Reactant: CCO
Reactant: O=C(c1cccc(Br)n1)c1cccc(Br)n1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)(c1cccc(Br)n1)c1cccc(Br)n1
Temperature: 0 °C
Yield: 98.6 %

Procedure:
113 ml (340 mmol) of a 3M methylmagnesium chloride solution in THF were added dropwise with vigorous stirring to a suspension, cooled to −78° C., of 102.6 g (300 mmol) of di(6-bromo-2-pyridyl)ketone in 1000 ml of THF at such a rate that a temperature of −60° C. was not exceeded. When the addition was complete, the mixture was stirred for a further 30 min., then 50 ml of ethanol were added dropwise, the mixture was warmed to 0° C., and 60 ml of semi-saturated ammonium chloride solution were added. The reaction mixture was filtered, the salts were washed twice with 100 ml of THF each time, and the filtrate was evaporated to dryness in a rotary evaporator. The oily residue was taken up in 1000 ml of dichloromethane, and the organic phase was washed three times with 300 ml of water and dried over magnesium sulfate. Stripping off of the dichloromethane left 106.0 g (296 mmol), corresponding to a yield of 98.6%, of the crude product having a purity of about 95% according to 1H-NMR as a yellow-brown oil, which was reacted further without purification.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]=[C:7]1[C:15]2[CH:14]=[CH:13][S:12][C:11]=2[CH2:10][CH2:9][CH2:8]1)(=[NH:3])[NH2:2].[OH-].[Na+]>Cl>[S:4]1[CH2:5][CH2:6][C:7]2([C:15]3[CH:14]=[CH:13][S:12][C:11]=3[CH2:10][CH2:9][CH2:8]2)[N:3]=[C:1]1[NH2:2]
Reactant: N=C(N)SCC=C1CCCc2sccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC1=NC2(CCCc3sccc32)CCS1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
2-(6,7-Dihydrobenzo[b]thiophen-4(5H)-ylidene)ethyl carbamimidothioate (13.8 g, 46 mmol) was suspended in concentrated HCl (150 mL) and stirred at 25° C. until all the solid dissolved. The reaction was monitored by LC/MS until no more starting material remained. The mixture was then neutralised with aqueous 2 M NaOH solution and ice whereupon a solid precipitated out. This was filtered off, washed with water and dried in vacuo to yield the title compound as a white solid (10.35 g, 93%). 1H NMR δ (ppm)(CHCl3-d): 7.05 (1H, d, J=5.25 Hz), 6.88 (1H, d, J=5.24 Hz), 4.79 (2H, s), 3.20-3.01 (2H, m), 2.90-2.74 (2H, m), 2.10-1.98 (2H, m), 1.96-1.77 (4H, m). LCMS (Method f) Rt 2.83 (min) m/z 239 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][N:9]=1>ClCCl>[Cl:7][C:8]1[N:9]=[CH:10][C:11]([CH:14]=[N:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:12][CH:13]=1
Reactant: Nc1nccs1
Reactant: O=Cc1ccc(Cl)nc1
Solvent: ClCCl
Product: Clc1ccc(C=Nc2nccs2)cn1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
2-Aminothiazole (0.75 g, 7.5 mmol) was added to 2-chloropyridine-5-carboxaldehyde (1.0 g, 7.1 mmol) in dichloromethane (25 mL) at room temperature. The suspension was stirred an additional 10 min and then concentrated to dryness under vacuum. The resulting residue was heated to 90 ° C. on a rotory evaporator with a non-returning bump trap to facilitate water removal. After 30 min the resultant yellow solid was checked by NMR to verify reaction completion (by disappearence of the characteristic aldehyde peak at 10.10 ppm (s, 1H)). The title compound was obtained as a yellow solid (1.55 g) and used in the next step without further purification.
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][O:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][C@@H:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
Sodium borohydride (4 mg, 0.11 mmol), followed by MeOH (0.25 mL), was added to a solution of {(Z)-4-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-but-2-enyloxy}-acetic acid methyl ester (28 mg, 0.073 mmol) in CH2Cl2 (0.75 mL) at 0° C. The mixture was allowed to warm to rt. After 1 h at rt, the reaction was quenched with aqueous HCl (0.5 M) and extracted with EtOAc (3×10 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 22 mg (78%) of the title compound.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[N:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)[CH:21]=[CH:22][CH:23]=1>ClCCl.CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]=[C:26]([N:30]=[C:1]=[S:2])[N:27]=[CH:28][N:29]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cc(-c2cccc(Cl)c2)ncn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: S=C=Nc1cc(-c2cccc(Cl)c2)ncn1
Temperature: 60 °C

Procedure:
To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.486 g, 2.091 mmol) in dichloromethane/N,N-dimethylformamide at room temperature was added 6-(3-chlorophenyl)pyrimidin-4-amine (0.43 g, 2.091 mmol). The orange mixture was heated at 60° C. for 18 hours. The LC/MS showed the desired product peak as a major peak. The deep orange mixture was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-(3-chlorophenyl)-6-isothiocyanatopyrimidine (0.12 g, 0.484 mmol, 23% yield) as an orange oil. LCMS R.T.=2.15; [M]+=248.31.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH2:41])=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH:41][C:2]3[N:22]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nc12

Procedure:
7-[8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.630 g, 1.92 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.605 g, 2.31 mmol) in a manner analogous to Example 311b to give product (0.750 g, 71%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.56 (s, 1H), 8.79 (d, 1H), 7.95 (s, 1H), 7.82 (d, 1H), 7.65 (d, 1H), 7.42 (m, 3H), 7.05 (m, 2H), 3.85 (s, 3H), 3.42 (m, 4H), 2.75 (m, 4H), 1.41 (s, 9H): MS=554 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.CC(OC)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(CC(=O)C(=O)O)cc1Br
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C[C@@H](O)C(=O)O)cc1Br
Temperature: -35 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere a mixture of 2.9 g (11.3 mmol) 3-(3-bromo-4-methyl-phenyl)-2-oxo-propionic acid and 2.0 mL (15.1 mmol) triethylamine in 40 mL THF was cooled to −35° C. Then a solution of 5.44 g (17.0 mmol) (1R)—B-chlorodiisopinocampheylborane in 20 mL THF was added dropwise so that the reaction temperature remained between −35° C. and −25° C.; the reaction mixture was kept for 1 h at this temperature, then the cooling bath was removed and the mixture was stirred overnight at RT. To complete the reaction another 3.0 g (9.4 mmol) (1R)—B-chlorodiisopinocampheylborane were added and the mixture was stirred for a further 5 h. While cooling with ice 30 mL 1 M NaOH and 30 mL TBME were added dropwise and the mixture was stirred for 15 min. The aqueous phase was separated off, the organic phase was extracted with 15 mL 1 M NaOH and 25 mL water. The combined aqueous phases were acidified with 2 M HCl while cooling with ice, extracted three times with 40 mL TBME and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was reacted further without purification.
Reaction SMILES: BrCCCCCCCCCCCO.C([O-])CCCCC.[Na+].P(Br)(Br)Br.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].[SH:45][CH2:46][CH2:47][C:48](OC)=[O:49].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C[O-].[Na+].N1C=CC=CC=1>[CH2:39]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][S:45][CH2:46][CH2:47][CH2:48][OH:49])[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCOCCCCCCCCCCCBr
Reactant: COC(=O)CCS
Agent: BrP(Br)Br
Agent: CCCCCC[O-]
Agent: C[O-]
Solvent: c1ccncc1
Product: CCCCCCOCCCCCCCCCCCSCCCO

Procedure:
11-Bromoundecan-1-ol (m.p. 45°-48° C. ) is reacted with sodium hexanolate and the syrupy product obtained is reacted with phosphorus tribromide in the presence of pyridine. The structure of the oil obtained is confirmed by mass spectroscopy as being 11-bromoundecyloxyhexane. This bromo compound is reacted with methyl β-mercaptopropionate in sodium methylate solution and the oil obtained is then reduced with lithium aluminium hydride to give 3-(11-hexyloxyundecylthio)-propanol; m.p. 27°-29° C. Phosphorylation and choline ester formation in a manner analogous to that described in Example 20C gives the desired end product in a yield of 55% of theory in the form of a monohydrate which sinters at 98° C. and decomposes at 226°-229° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[O:20])=[CH:15][C:14]=2[O:29][CH3:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:39])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])(=[O:39])=[O:20])=[CH:15][C:14]=2[O:29][CH3:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(S(=O)c2ccccc2C#N)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: COc1cc(S(=O)(=O)c2ccccc2C#N)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.2 %

Procedure:
To 3-[4-(2-cyano-benzenesulfinyl)-2-methoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.135 mg, 0.3165 mmol) dissolved in DCM (5 mL) was added m-CPBA (0.115 mg, 0.9495 mmol), and the mixture was stirred at room temperature for 6 hours. DCM was added and the resulting mixture was washed with sodium thiosulfate (10% aqueous solution), NaHCO3 (saturated aqueous solution), water, and brine. The organic phase was then dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (hexane/EtOAc, 1/1) to give 0.125 g (89% yield) of 3-[4-(2-cyano-benzenesulfonyl)-2-methoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=2[CH3:22])=[CH:11][C:10]=1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:41]([O:44][CH2:45][CH2:46]Br)(=[O:43])[CH3:42].[Cl-].[NH4+]>CN(C)C=O>[CH2:45]([O:44][C:41](=[O:43])[CH2:42][O:21][C:17]1[CH:18]=[C:19]([CH3:20])[C:14]([CH2:13][C:12]2[CH:23]=[CH:24][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:11]=2)=[C:15]([CH3:22])[CH:16]=1)[CH3:46]
Reactant: Cc1cc(O)cc(C)c1Cc1ccc(OCc2ccccc2)c(S(=O)(=O)c2ccc(F)cc2)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C)c(Cc2ccc(OCc3ccccc3)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
85 mg (0.18 mmol) of 4-{4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]benzyl}-3,5-dimethylphenol (Example X) are dissolved in 2 ml of dimethylformamide. 30 mg (0.21 mmol) of potassium carbonate and 33 mg (0.20 mmol) of bromoethyl acetate are added. The mixture is stirred at room temperature overnight. Saturated ammonium chloride solution is then added, and the mixture is extracted three times with diethyl ether. The combined organic phases are washed three times with water, dried with sodium sulphate and concentrated under reduced pressure. This gives 80 mg (96.5% of theory) of ethyl (4-{4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]benzyl}-3,5-dimethylphenoxy)acetate.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[C:6]1([CH:1]([OH:5])[CH2:2][CH2:3][CH3:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCC(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCC(O)c1ccccc1

Procedure:
To a stirring solution of 890 mg of commercially available butyrophenone in 30 mL of diethyl ether under an argon atmosphere at 0° C. is slowly added 250 mg of lithium aluminum hydride in portions. After 2 hours the grey suspension is slowly treated with 0.25 mL of water followed by 1.10 mL of 1N sodium hydroxide. After 0.5 hours the resulting whim precipitant is filtered through a pad of magnesium sulfate with diethyl ether washings. The filtrate is concentrated under reduced pressure to afford 0.90 g of the title product as a clear, colorless oil. This product may be used directly in the next reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]#[N:24]>>[C:23]([CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:24]
Reactant: N#CCc1ccccc1I
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2ccccc2CC#N)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (74 mg, 0.39 mmol) and 2-(2-iodophenyl)acetonitrile (60 μL, 0.43 mmol) according to the general procedure IC to give 74 mg (62%) of an orange solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:4). Rf=0.08 (EtOAc:PE, 1:4); 1H NMR (CDCl3) δ 7.55-7.46 (m, 4H), 7.37-7.34 (m, 2H), 7.21 (d, J=8.4 Hz, 2H), 3.96 (s, 2H), 3.67 (s, 3H), 2.97 (t, J=7.7 Hz, 2H), 2.64 (t, J=7.5 Hz, 2H); 13C NMR (CDCl3) δ 173.0, 141.6, 132.3, 131.7, 131.6, 128.9, 128.5, 128.1, 122.9, 120.4, 117.4, 95.6, 85.7, 51.7, 35.3, 30.8, 22.7; ESI-MS m/z 326.1 (M+Na+).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl:61][CH2:62][C:63]([C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([Cl:71])[CH:66]=1)=[O:64].[OH-].[Na+]>>[Cl:61][CH2:62][CH:63]([C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([Cl:71])[CH:66]=1)[OH:64]
Reactant: O=C(CCl)c1cccc(Cl)c1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: OC(CCl)c1cccc(Cl)c1
Temperature: 30 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
The culture of the recombinant Escherichia coli HB101 (pNTRGG1) as obtained in Example 9 was subjected to ultrasonic cell disruption using SONIFIRE 250 (product of BRANSON). To 20 ml of this cell disruption fluid, there were added 3 g of glucose, 2 mg of NADP and 2 g of 2-chloro-1-(3′-chlorophenyl)ethanone. This reaction mixture was stirred at 30° C. for 24 hours while adjusting the pH to 6.5 by dropwise addition of 5 M sodium hydroxide. After completion of the reaction, this reaction mixture was extracted with toluene, the solvent was then removed, and the extract was analyzed in the same manner as in Example 10. 2-Chloro-1-(3′-chlorophenyl)ethanol was obtained in 93% yield. The 2-chloro-1-(3′-chlorophenyl)ethanol formed on that occasion was the R form with an optical purity of 99.9% ee.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:13]=[O:14])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][OH:14])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)c(C)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(C)c(CO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a methanol (0.1 M) solution of methyl 3-bromo-5-formyl-4-methylbenzoate (1 eq.) from the previous step was added sodium borohydride (4 eq.) portionwise. The resulting mixture was stirred at RT for 3 h. The reaction was subsequently quenched with cold 10% aq. HCl and extracted with ether. The combined organic extracts were then washed with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([Br:12])=[C:6]([CH3:13])[C:3]=1[C:4]#[N:5].C(N(C(C)C)CC)(C)C.[CH:23]1([C:26](Cl)=[O:27])CC1>C(OCC)(=O)C>[C:26]([O:10][C:9]1[C:8]([F:11])=[C:7]([Br:12])[C:6]([CH3:13])=[C:3]([C:4]#[N:5])[C:2]=1[NH2:1])(=[O:27])[CH3:23]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1c(Br)c(F)c(O)c(N)c1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(N)c(C#N)c(C)c(Br)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
2-Amino-5-bromo-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-75) (7.86 g, 32.08 mmol) and diisopropylethylamine (19.5 ml, 112.2 mmol) were dissolved in ethyl acetate (300 ml), and at 0° C., cyclopropanecarbonyl chloride (4.4 ml, 48.12 mmol) was dropwise added, followed by stirring at room temperature for 16 hours under nitrogen atmosphere. After the reaction, ethyl acetate was added to the reaction liquid, followed by washing with water and saturated brine. The organic layer was concentrated under reduced pressure, the resulting residue was recrystallized with diisopropyl ether/ethyl acetate to obtain the entitled compound (8.96 g, 89%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11]C)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(O)cc(Br)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 3-bromo-5-nitroanisole, as described above in Step B, (2.4 g, 10.3 mmol) in methylene chloride (50 mL) was cooled to 0° C. and treated with boron tribromide (1M in CH2Cl2, 158 mL, 158 mmol), giving a clear purple solution. The reaction was warmed slowly to room temperature and stirred at room temperature overnight and heated at reflux for 2.5 hours. The reaction was poured into ice/water, the layers were separated and extracted with methylene chloride. The aqueous layer was neutralized with aqueous saturated NaHCO3 and extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo. This material was purified by column chromatography (10:1 to 5:1 hexane:ethyl acetate). The fractions containing the product contaminated with the bromoanisole were pooled, concentrated and purified using radial, thin layer chromatography (hexane to 5:1 hexane:ethyl acetate) to give 3-bromo-5-nitrophenol as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:22][CH2:21][CH:20]([C@H:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[OH:24])[CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:35]([CH3:37])[CH3:36])[CH:12]=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:39]1[CH2:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH2:41][CH2:40]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:22][CH2:21][CH:20]([C@H:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[OH:24])[CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:35]([CH3:37])[CH3:36])[CH:12]=[C:11]([C:42]3[CH2:43][CH2:44][O:39][CH2:40][CH:41]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(I)c2c(n1)CC1(CCC([C@@H](O)c3ccc(C(F)(F)F)cc3)C1)C[C@@H]2O[Si](C)(C)C(C)(C)C
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: CC(C)c1cc(C2=CCOCC2)c2c(n1)CC1(CCC([C@@H](O)c3ccc(C(F)(F)F)cc3)C1)C[C@@H]2O[Si](C)(C)C(C)(C)C

Procedure:
Obtained by starting from (R)—((S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclopentane-1,7′-quinoline]-3-yl)(4-(trifluoromethyl)phenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The crude product is used directly in the next step.
Reaction SMILES: FC1C=C(C(C)(C)CC(O)(C(F)(F)F)C=O)C2OCCC=2C=1.NC1C=CC=C2C=1C=CN=C2C.[F:35][C:36]1[CH:37]=[C:38]([C:45]([CH3:67])([CH3:66])[CH2:46][C:47]([OH:65])([C:61]([F:64])([F:63])[F:62])[CH:48]=[N:49][C:50]2[CH:59]=[CH:58][CH:57]=[C:56]3[C:51]=2[CH:52]=[CH:53][N:54]=[C:55]3[CH3:60])[C:39]2[O:43][CH2:42][CH2:41][C:40]=2[CH:44]=1.[BH4-].[Na+]>>[F:35][C:36]1[CH:37]=[C:38]([C:45]([CH3:67])([CH3:66])[CH2:46][C:47]([OH:65])([C:61]([F:62])([F:64])[F:63])[CH2:48][NH:49][C:50]2[CH:59]=[CH:58][CH:57]=[C:56]3[C:51]=2[CH:52]=[CH:53][N:54]=[C:55]3[CH3:60])[C:39]2[O:43][CH2:42][CH2:41][C:40]=2[CH:44]=1
Reactant: Cc1nccc2c(N=CC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cccc12
Agent: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: Cc1nccc2c(N)cccc12
Agent: [BH4-]
Product: Cc1nccc2c(NCC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cccc12

Procedure:
Analogously to Example 1, 4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is converted with 5-amino-1-methylisoquinoline into 5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]-1-methylisoquinoline, which is reduced with sodium borohydride to the product.