Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:34]=[C:33]([F:35])[C:9]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([O:20]C)[CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:8]([F:36])[CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[CH:34]=[C:33]([F:35])[C:9]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:8]([F:36])[CH:7]=1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1c1nc2ccc(OC)cc2n1Cc1c(F)cc(Br)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1c1nc2ccc(O)cc2n1Cc1c(F)cc(Br)cc1F
Reaction time: 1 h
Yield: 7 %

Procedure:
A solution of BBr3 (5 mL, 1 M in DCM) was added to a mixture of racemic cis-ethyl 2-(1-(4-bromo-2,6-difluorobenzyl)-6-methoxy-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylate (1.5 g, 3.2 mmol) in CH2Cl2 (50 mL) at RT. The reaction mixture was stirred 1 h was and partitioned with H2O (50 mL). The organic layer was separated and concentrated to dryness. The resulting residue was purified by FCC to provide the title compound (110 mg, 87%). MS (ESI): mass calcd. for C23H23BrF2N2O3, 492.09; m/z found, 493.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH2:16]1[C:22]2[CH:23]=[CH:24][C:25]([O:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[CH:26][C:21]=2[CH2:20][CH2:19][NH:18][CH2:17]1>CN(C)C=O>[CH:1]1([C:4]([N:18]2[CH2:19][CH2:20][C:21]3[CH:26]=[C:25]([O:27][CH:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]4)[CH:24]=[CH:23][C:22]=3[CH2:16][CH2:17]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCNCC3)CC1
Reactant: O=C(O)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCN(C(=O)C2CC2)CC3)CC1
Temperature: 25 °C

Procedure:
16 l cyclopropylcarboxylic acid are placed in 3 ml dimethylformamide, then 174 l diisopropylethylamine and 93.1 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) are added. After 15 min 77.5 mg tert-butyl 4-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylate are added. The reaction mixture is stirred at ambient temperature until there is no further reaction and the product is purified directly by preparative HPLC (method B). 70 mg of the product are obtained as a solid. Analytical HPLC-MS (method D): RT=1.37 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.B(O)(O)[C:27]1[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[C:29]([Cl:37])[CH:28]=1>>[CH3:36][O:35][C:33]([C:30]1[CH:31]=[CH:32][C:27]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)=[O:11])=[CH:6][CH:7]=2)=[CH:28][C:29]=1[Cl:37])=[O:34]
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Product: COC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)cc1Cl

Procedure:
In analogy to example 74, step 6, from 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 74, step 5) and (3-chloro-4-methoxycarbonyl)benzeneboronic acid was prepared the title compound as a colorless oil, MS (ESI+): m/z=484.1680 ([M+H]+, 1Cl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13]O)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(Br)(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[C:9]([O:8][C:6]([NH:5][C@@H:4]([CH3:13])[C:3]([O:2][CH3:1])=[O:15])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.1 %

Procedure:
The obtained N-Boc-L-serine methyl ester (6.0 g) and 10.5 g (1.2 eq) of carbon tetrabromide were dissolved in 100 ml of dry THF and a solution prepared by dissolving 8.29 g (1.2 eq) of Ph3P in 50 ml of dry THF was added dropwise under ice cooling, followed by stirring at room temperature for 24 hours. After the reaction, the reaction solution was filtered and purified by silica gel column chromatography to obtain 4.9 g (65%) of methyl(S)-2-tert-butoxycarbonylaminopropanate as a white crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:37]=[CH:36][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:28][C:27]([CH:29]=[CH:30][C:31]([O:33]CC)=[O:32])=[CH:26][CH:25]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:11][C:10]=1[Cl:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.C(O)C>[CH2:1]([O:8][C:9]1[CH:37]=[CH:36][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:28][C:27]([CH:29]=[CH:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:11][C:10]=1[Cl:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)c(Cl)c4)c3c2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)c(Cl)c4)c3c2)o1
Yield: 102.4 %

Procedure:
Prepared according to Procedure H utilizing ethyl 3-(5-{4-[4-(benzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furyl)-2-propenoate (0.65 g) and aqueous sodium hydroxide (2M, 4 mL) in THF (8 mL) and ethanol (4 mL) to afford the title compound (0.63 g). Electrospray MS m/z 498 (MH+).
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9]C)[O:5][CH2:6]C)C.CO[SiH](OC)OC.C1(C)C=CC=CC=1.[NH2:25][CH2:26][CH2:27][CH2:28][Si](OC)(OC)OC>CC1C=CC(C)=CC=1>[CH2:26]([NH2:25])[CH:27]=[CH2:28].[CH3:1][O:3][SiH:4]([O:8][CH3:9])[O:5][CH3:6]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: CCO[SiH](OCC)OCC
Agent: CO[SiH](OC)OC
Solvent: Cc1ccc(C)cc1
Solvent: Cc1ccccc1
Product: C=CCN

Procedure:
Example 1 was repeated except that the 41 grams of triethoxy silane was replaced with 30.6 grams of trimethoxy silane (0.25 mole) and toluene was used as a solvent instead of p-xylene, with other conditions remaining the same. After the completion of the reaction, the reaction mixture was subjected to gas chromatography analysis. It was found that gamma-aminopropyl trimethoxy silane was obtained in a yield of 70% on an allylamine basis, while the yield of beta-amminopropyl trimethoxy silane was 0.9% on an a trimethoxy silane basis.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][C@@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([CH2:28][C:29](OC)=[O:30])[CH2:17]2)=[O:14])=[N:5]1)([CH3:3])[CH3:2].[BH4-].[Li+].O>O1CCCC1>[OH:30][CH2:29][CH2:28][C@@H:18]1[CH2:17][C@H:16]([NH:15][C:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)=[O:14])[CH2:20][N:19]1[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: COC(=O)C[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CCO)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.1 %

Procedure:
To a solution of tert-butyl (2S,4S)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (200 mg, 0.45 mmol, step 5 of Example 9) in tetrahydrofuran (5 mL) was added lithium borohydride solution (2 M in tetrahydrofuran, 1.13 mL, 2.25 mmol) at room temperature. The mixture was stirred at room temperature for 20 h. To the resulting mixture water (10 mL) was added. The mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (10 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1:1) to give 182 mg (97%) of the title compound as a white amorphous solid.
Reaction SMILES: [O:1]1[CH2:7][CH:2]1[C:3]([O:5][CH3:6])=[O:4].[I-].[K+].[C:10](=[O:12])=[O:11]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][O:1][C:10](=[O:11])[O:12]1)=[O:4]
Reactant: COC(=O)C1CO1
Reactant: O=C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: COC(C)(C)C
Product: COC(=O)C1COC(=O)O1
Reaction time: 144 h
Yield: 79 %

Procedure:
20 g of methyl epoxypropionate were mixed with 20 g of tert-butyl methyl ether, 1.5 g of tetrabutylammonium bromide and 1.5 g of potassium iodide. The homogeneous mixture was transferred to a 100 ml pressurized reactor and carboxylated for 6 days at 50° C. and a CO2 pressure of 30 bar. After the carboxylation, a two-phase system was obtained; the upper phase consisted of tert-butyl methyl ether, and the lower phase consisted of 4-methoxycarbonyl-2-oxo-1,3-dioxolane (purity 83% (GC), yield 79%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.CO>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[CH:4][CH:3]=1
Reactant: O=CNc1ccc(Br)cc1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a stirred 2M solution of borane methyl sulfide complex in THF (580 mL, 1.16 mol) at 0° C. was slowly added a solution of N-(4-bromo-phenyl)-formamide (Example 1, Step (1), 93 g., 0.465 mol) in 280 mL of THF so that the temperature of the solution did not rise above 5° C. Once the addition of the formanilide was complete, the reaction was brought to reflux and stirred for 3 hours. The reaction was then cooled to 0° C. and 190 mL of methanol was added slowly to control the frothing of the reaction. Then hydrogen chloride gas was bubbled into the solution until the pH was approximately 2. The solvents were removed in vacuo to afford a solid. The solid was dissolved in water and the pH was raised to 10, and the solution was extracted twice with ethyl ether. The combined ether extracts were washed twice with brine and dried over sodium sulfate. Removal of the ether solvent afforded 85.5 grams (98.8%) of (4-bromo-phenyl)-methyl-amine. The spectral properties of the oil were consistent with the desired material. High performance liquid chromatography (“HPLC”) analysis revealed that the oil was greater than 95% of 4-bromophenyl-N-methylaniline. This material was used in the next step without purification. Step (3): 7-Bromo-4-methyl-1,1-dioxo-1,4-dihydro-2H-1l6-benzo[1,2,4]thiadiazin-3-one
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[CH3:8][C:7]1[C:2]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]([F:12])([F:24])[F:25])[CH:16]=2)=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: Cc1cc([N+](=O)[O-])cnc1-c1cccc(OC(F)(F)F)c1
Yield: 91 %

Procedure:
Obtained (1.25 g, yield 91%) following the procedure described in Intermediate 27, starting with 2-bromo-3-methyl-5-nitropyridine (4.61 mmol, 1.0 g), 3-(trifluoromethoxy)phenyl boronic acid (4.61 mmol, 0.95 g).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:5]=1[CH2:6][O:7]C=O)=[O:2]>C(#N)C.C(O)CCC>[OH:7][CH2:6][C:5]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:4]=1[NH:3][CH:1]=[O:2]
Reactant: COc1ccc(NC=O)c(COC=O)c1
Solvent: CC#N
Solvent: CCCCO
Product: COc1ccc(NC=O)c(CO)c1
Temperature: 20 °C
Reaction time: 65 h

Procedure:
1.70 g of Candida antarctica B lipase (CAL-B) were added to a solution of 5.90 g of the product from stage 1 in a mixture of 190 ml of anhydrous acetonitrile and 10.3 ml of n-butanol and stirred for 65 hours at 20° C. The mixture was then filtered and washed with acetonitrile. After concentrating the filtrate by evaporation in vacuo, 5.00 g (98% of theory) of the title compound remained.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([CH:25]=[O:26])=[C:11]([I:27])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:23])[CH3:24])[C:12]([C@H:25]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=3)[OH:26])=[C:11]([I:27])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)F)cn1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 2-bromo-5-(trifluoromethyl)pyridine.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH2:5][C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.OS(O)(=O)=O.[CH3:34]O>>[CH3:34][O:16][C:15](=[O:17])[CH2:14][CH2:13][C@H:12]([C@@H:11]1[C@:19]2([CH3:27])[C@H:8]([C@H:7]3[C@H:22]([CH2:21][CH2:20]2)[C@:23]2([CH3:26])[C@@H:4]([CH2:3][C@H:2]([OH:1])[CH2:25][CH2:24]2)[CH2:5][C:6]3=[O:28])[CH2:9][CH2:10]1)[CH3:18]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid (KLCA) with CH3OH and H2SO4 to form 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester (1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([N:23]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH3:22])=[N:3][C:4]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:9][CH:10]=1
Reactant: CNCCCCO
Reactant: Cc1ccc(-c2ncc(Cl)nc2-c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ncc(N(C)CCCCO)nc2-c2ccc(C)cc2)cc1
Temperature: 100 °C
Reaction time: 26 h
Yield: 75 %

Procedure:
To a solution of 3.00 g of 2-chloro-5,6-di-p-tolylpyrazine and 1.57 g of 4-(methylamino)-1-butanol in 15 ml of N,N-dimethylformamide, 2.26 g of potassium carbonate was added. After heating with stirring at 100° C. for 26 hours, the reaction solution was extracted with diethyl ether after adding ice water. The extract was washed in turn with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the resulting crystal was washed with diisopropyl ether to obtain 2.76 g of the desired compound as a colorless crystal having a melting point of 94 to 96° C.
Reaction SMILES: [NH2:1]/[C:2](=[N:10]\[O:11][C:12]([C@H:14]([CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O)/[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1>C1(C)C(C)=CC=CC=1>[CH:26]1([CH2:25][CH2:24][CH2:23][C@@H:14]([C:12]2[O:11][N:10]=[C:2]([CH2:3][C:4]3[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=3)[N:1]=2)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)Cc1ccncc1
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ccncc2)no1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A solution of tert-butyl (3R)-3-[({[(Z)-1-amino-2-(4-pyridinyl)ethylidene]amino}oxy)carbonyl]-6-cyclohexylhexanoate (Preparation 104) (840 mg, 1.60 mmol) in xylene (15 ml) was heated at 130° C. for 4.5 hours. After cooling to room temperature the reaction mixture was purified by column chromatography on silica gel eluting with a gradient system of 90:10 (pentane:ethyl acetate) gradually changing to 50:50 (pentane:ethyl acetate) to afford the title compound as a yellow oil (420 mg).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[Cl:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[CH:25]1[O:27][CH2:26]1>CO>[CH2:1]([N:8]([CH2:26][CH:25]([OH:27])[C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[Br:22])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=1[Cl:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccccc1C1CO1
Reactant: COc1ccc(CCNCc2ccccc2)c(Cl)c1OC
Solvent: CO
Product: COc1ccc(CCN(Cc2ccccc2)CC(O)c2ccccc2Br)c(Cl)c1OC

Procedure:
Similarly 2.71 g of N-benzyl-2-chloro-3,4-dimethoxyphenethylamine and 2.33 g (0.015 mol) of o-bromostyrene oxide are reacted in methanol to give N-benzyl-N-[2-(2-chloro-3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-bromophenyl)ethylamine. The latter is converted to its hydrochloride, which is dissolved in 90 ml of methanol and hydrogenated over 1 g of 10% palladium-on-carbon in 10 ml of ethyl acetate at room temperature for six hours. The reaction mixture is filtered and evaporated in vacuo to leave N-[2-(2-chloro-3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-bromophenyl)ethylamine hydrochloride.
Reaction SMILES: Cl.N[C@@H](CC(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.[BH4-].[Na+].[CH:24]1(/[CH:30]=[C:31](/[N:38]2[CH:42]=[N:41][CH:40]=[N:39]2)\[C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>ClCCCl.CN(C)C=O>[CH:24]1(/[CH:30]=[C:31](/[N:38]2[CH:42]=[N:41][CH:40]=[N:39]2)\[CH:32]([OH:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CC(C)(C)C(=O)/C(=C\C1CCCCC1)n1cncn1
Agent: CC(C)C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)/C(=C\C1CCCCC1)n1cncn1
Temperature: -20 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
In a nitrogen atmosphere, 0.275 g (0.90 mmole) of (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol hydrochloride was suspended in 5 ml of 1,2-dichloroethane, and after cooling to -20° C., a solution of 0.034 g (0.90 mmole) of sodium borohydride in 0.5 ml of dimethylformamide was added. The temperature of the suspension was then raised from -20° C. to room temperature over 2 hours. Thereafter, a solution of 157 mg (0.60 mmole) of (E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-one in 2 ml of 1,2-dichloroethane was added dropwise to this suspension at room temperature, and stirring was carried out for 24 hours. To this reaction solution was added 6 ml of 2N hydrochloric acid, and after removing liberated (S)-2-amino-1,1-diphenyl-4-methylpentan-1-ol hydrochloride by filtration, the organic layer was washed with water and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 0.158 g of (-)-(E)-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-ol. The conversion was 93.7%, and the composition of the product was: E-form alcohol, 95.7% and Z-form alcohol, 4.3%. The enantiomer ratio of the E-form alcohol was: (+)-isomer, 18.8% and (-)-isomer, 81.2%.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[C:18](=[O:20])[CH3:19])[C:14]1[N:10]([CH:11]=[C:12]([C:21]3[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[C:23]([CH3:29])[N:22]=3)[N:13]=1)[CH2:9][CH2:8][O:7]2>CO>[F:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[CH:18]([OH:20])[CH3:19])[C:14]1[N:10]([CH:11]=[C:12]([C:21]3[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[C:23]([CH3:29])[N:22]=3)[N:13]=1)[CH2:9][CH2:8][O:7]2
Reactant: CC(=O)c1cc2c(cc1F)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2cc(C(C)O)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a stirred suspension of NaBH4 (638 mg, 16.8 mmol) in MeOH (15 mL), was added a solution of 1-{12-fluoro-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethan-1-one (1.55 g, 4.20 mmol) in MeOH (15 mL) at 0° C. under a nitrogen atmosphere. After the addition was completed, the cooling bath was removed and the mixture was stirred at room temperature for 1 h. After removal of the solvent, the residue was purified by silica gel chromatography using 5% dichloromethane in methanol as eluant to give the title compound (1.5 g, 96% yield) as a white solid. LCMS m/z [M+H]+ 372.1
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:33])[CH:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:6]2[C:13]([CH3:32])=[C:14]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:5]=2[O:4]1.[OH-].[Na+]>C(OCC)(=O)C.C1COCC1>[CH3:2][C:3]1([CH3:33])[CH:7]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[C:6]2[C:13]([CH3:32])=[C:14]([N:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:5]=2[O:4]1
Reactant: Cc1c(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 4N hydrogenchloride in ethyl acetate (20 ml) was added to a solution of tert butyl 4-(2,2,4,6,7-pentamethyl-3-pyrrolidinyl-2,3-dihydro-1-benzofuran-5-yl)piperazinecarboxylate (3.55 g, 8 mmol) obtained in Example 132 in THF (20 mL) and ethyl acetate (20 ml) and the mixture was stirred at 60° C. for 3 hours. The resulting mixture was cooled to 0° C. made to weakly alkaline using 1N sodium hydroxide aqueous, and extracted with ethyl acetate. The organic extract was washed using saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate) to obtain 2.72 g (yield 100%) of the title compound as an amorphous powder.