Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]=[O:11])=[N:8][N:7]([CH3:12])[N:6]=1)=[O:4].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH2:10][OH:11])=[N:8][N:7]([CH3:12])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nn(C)nc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nn(C)nc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
2.6 g (13.3 mmol) of 5-formyl-2-methyl-2H-1,2,3-triazole-4-carboxylic acid methyl ester (see Example 2a) in methanol (100 ml) was treated with NaBH4 (601 mg) under stirring for 1 hour at ambient temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried with Na2SO4 and evaporated to give the crude as an oil. Purification on silica gel in ethyl acetate:hexane (2:1) yielded 1.85 g (81%) of the crystalline product, m.p. 112-113° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[O:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][C:16]([OH:21])=[O:15])=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 37 %

Procedure:
To a solution of 4-nitro-3-(trifluoromethyl)aniline (2.0 g, 9.7 mmol) in toluene (30 mL) was added tetrahydrofuran-2,5-dione (1.2 g, 11.6 mmol) and the mixture refluxed for 1.5 h. The reaction mixture was cooled, filtered, and the solid washed with ether to provide 4-(4-nitro-3-(trifluoromethyl)phenylamino)-4-oxobutanoic acid (1.1 g, 39% yield). M+H m/z 307.3.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C:3]([CH3:6])([CH3:5])[CH3:4].[NH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].Cl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:9])[C:3]([CH3:4])([CH3:5])[CH3:6]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
Boc-t-Leu-OH (9.26 g, 40.0 mmol) and Gly-OBzl•HCl (8.06 g, 40.0 mmol) were dissolved in methylene chloride (60 ml), and the solution was maintained at 0° C. Triethylamine (5.60 ml, 40.0 mmol), HOBt (1-hydroxybenzotriazole, 6.75 g, 44.0 mmol), and WSC•HCl (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 8.47 g, 44.0 mmol) were added to the solution, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (50 ml), 5% citric acid aqueous solution (50 ml, twice), saturated brine (50 ml), 5% sodium hydrogencarbonate aqueous solution (50 ml, twice), and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, then the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to obtain a viscous oily material of Boc-t-Leu-Gly-OBzl (15.20 g, 40.1 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[F:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:23]2[CH:24]=[CH:25][C:26]([F:27])=[C:21]([F:20])[CH:22]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(F)c(F)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 3,4-difluorobenzene-1-sulfonyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[NH:8]1[CH2:11][CH:10]([C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:21])[CH2:9]1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]
Reactant: COc1ccc(C(=O)C2CN(C(=O)OC(C)(C)C)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)C2CNC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 714 mg (2.45 mmol) 3-(4-methoxy-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester in 10 mL DCM was added 10 mL TFA and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to give the desired product as a TFA salt, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH2:15][CH3:16])([F:14])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34]>Cl.C(O)(C)C>[CH:17]1([N:7]2[CH2:8][C:9]([CH2:15][CH3:16])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CCC1(F)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cl
Solvent: CC(C)O
Product: CCC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Temperature: 100 °C
Reaction time: 20 h
Yield: 82.7 %

Procedure:
A mixture of 2-chloro-9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (630 mg, 1.93 mmol), 4-amino-3-methoxybenzoic acid (484 mg, 2.9 mmol), isopropanol (20 ml), and concentrated hydrochloric acid (10 drops) was stirred at 100° C. for 20 h. Solid was filtered to give 730 mg product as white solid (83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.3 Hz, 3H) 1.56 (br. s., 3H) 1.67-1.96 (m, 6H) 3.28 (s, 3H) 3.74-3.92 (m, 3H) 3.94 (s, 3H) 4.91 (t, J=7.8 Hz, 1H) 7.21-7.43 (m, 1H) 7.47-7.69 (m, 2H) 8.13 (d, J=8.1 Hz, 1H) 8.24 (s, 1H) 9.32 (br. s., 1H). [M+H] calc'd for C23H28FN5O4, 458. found 458.
Reaction SMILES: O[C:2]1([CH2:8][C@H:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(S(F)(F)[F:29])CC.C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[F:29][C:2]1([CH2:8][C@H:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2(O)CCCCC2)COC1(C)C
Reactant: CCN(CC)S(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CC2(F)CCCCC2)COC1(C)C
Temperature: -78 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
(S)-tert-Butyl 4-((1-hydroxycyclohexyl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (2.70 g, 8.63 mmol) was dissolved in CH2Cl2 and the solution was cooled to −78° C. DAST (2.78 g, 17.2 mmol, 2.0 equiv) was added via syringe and the solution was stirred overnight with concomitant warming to rt. LC-MS showed consumption of the starting alcohol. Satd aq NaHCO3 was added and the mixture was stirred for 1 h. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, and filtered. The resulting solution was treated with m-CPBA (1.5 g, 8.6 mmol) and stirred for 3 h. After this time the olefinic by-products from the fluorination were consumed. The excess m-CPBA was quenched by addition of 10% aq Na2S2O3 (50 mL). The layers were separated and the organic layer was washed with satd aq NaHCO3 and brine, dried over Na2SO4, filtered and evaporated. Flash chromatography on silica, eluting with 0-29% EtOAc in hexanes, afforded (S)-tert-butyl 4-((1-fluorocyclohexyl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (725 mg).
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[Li].O.[OH-].[Li+].[NH2:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:17][C:13]1[CH:12]=[C:11]([NH:10][CH2:2][C:3]([OH:5])=[O:4])[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CCl
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Li+]
Agent: [Li]
Solvent: O
Product: O=C(O)CNc1cccc(O)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
9.2 g of monochloroacetic acid are introduced into 40 ml of water and converted into the lithium salt with 4.1 g of lithium hydroxide monohydrate. 10.4 g of 3-aminophenol are then added and the mixture is stirred at 90° C. for 2 hours. It is then cooled to 20° C. and brought to pH 7 with sodium carbonate.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([C:5]1[N:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]>>[C:3]([C:5]1[N:10]=[CH:9][C:8]([S:11]([NH2:2])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]
Reactant: [NH4+]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cn1
Agent: [OH-]
Product: N#Cc1ccc(S(N)(=O)=O)cn1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To an ice-cold solution of ammonium hydroxide (75 ml, 25% w/v) is added 6-cyanopyridine-3-sulfonyl chloride (12.5 g) portionwise and the mixture is stirred for 30 minutes at 0-5° C. The reaction mixture is then concentrated to ⅕th of its original volume and cooled. The precipitate is filtered and dried under vacuum to afford the title compound as light brown solid (9 g, Yield 80%). 1H NMR (DMSO-d6:400 MHz) δ 9.10 (1H, s), 8.33-8.35 (1H, m), 8.23-8.25 (1H, d); 7.88-8.03 (2H, bs); HPLC (max plot) 98%, Rt 4.67 min; LCMS: (ES+) 183.8.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:13][CH2:14][NH:15][CH2:16][CH:8]1[C:7](=[O:17])[NH:6]2.[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[CH2:21].CO.Cl>C(O)C.C(O)(=O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:20][CH2:21][N:15]1[CH2:14][CH2:13][N:9]2[C:10]3[C:5]([NH:6][C:7](=[O:17])[CH:8]2[CH2:16]1)=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:12][CH:11]=3
Reactant: C=Cc1ccccn1
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2N2CCNCC12
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: CO
Product: O=C1Nc2cc(C(F)(F)F)ccc2N2CCN(CCc3ccccn3)CC12
Yield: 71 %

Procedure:
A solution of 8.5 g. (0.03 mole) of 2,3,4,4a-tetrahydro-8-trifluoromethyl-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one and 17.5 g. (0.16 mole) of 2-vinylpyridine in 250 ml. of methanol containing 7 ml. acetic acid was heated under reflux for 20 hours. The reaction mixture was cooled, and the solvent was removed under reduced pressure. The residue was precipitated with 1 l. of water. The product was filtered and recrystallized from methanol-water to yield 10.1 g. of free base. 4.5 G. of this free base was dissolved in 150 ml. of absolute ethanol and treated with dry hydrogen chloride saturated ether solution. The product hydrochloride was filtered and recrystallized two times from methanol-ether to give 4 g. (71%) of the title compound as the dihydrochloride salt, m.p. 194°-196° C.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:13]([CH2:14][CH2:15][Cl:16])[N:12]=[CH:11][C:10]=2[C:17]#[N:18])[CH2:5][CH2:4][NH:3]1.C[Al](C)C.Cl.[OH-].[Na+]>C(Cl)Cl.CCCCCCC.CCOC(C)=O>[NH2:18][C:17]1[C:7]2[C:2](=[O:1])[NH:3][CH2:4][CH2:5][C:6]=2[N:8]=[C:9]2[N:13]([CH2:14][CH2:15][Cl:16])[N:12]=[CH:11][C:10]=12
Reactant: N#Cc1cnn(CCCl)c1NC1=CC(=O)NCC1
Agent: C[Al](C)C
Agent: Cl
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1c2c(nc3c1cnn3CCCl)CCNC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a mechanically stirred suspension of 5-[N-(2-oxo-1,2,5,6-tetrahydropyridin-4-yl)]amino-1-(2-chloroethyl)-4-cyanopyrazole (12.31 g.) in dry methylene chloride (100 ml.) under a nitrogen atmosphere at 0° was added slowly trimethylaluminum (68.64 ml. of a 1.35 M solution in heptane). There was a vigorous gas evolution. The resulting yellowish sludge was warmed to room temperature and stirred for one hour. EtOAc was added, the yellow solution was cooled to 0° , and enough 10% v/v aqueous hydrochloric acid was cautiously added to bring the pH to 4 (about 15 ml.). The reaction mixture was stirred overnight (17 hours). 10% w/v Aqueous sodium hydroxide solution (500 ml.) was added and the mixture stirred for three hours, followed by extraction several times into EtOAc/MeOH (9:1 v/v). The extracts were washed with brine, dried over magnesium sulfate, filtered through diatomaceous earth and concentrated to an off-white solid. Chromatography using silica gel with acetone/ methylene chloride (1:1 v/v) as eluant gave 4-amino-1-(2-chloroethyl)-7,8-dihydro-1H-pyrazolo[3,4-b][1,6]-napthyridin -5(6H)-one as a white solid (8.89 g.) (72% yield).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.[Cl-].[Na+].O>[S:30]([O:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)([C:27]1[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (1 g) in dichloromethane (50 mL) was added triethylamine (1.604 mL) and 4-methylbenzene-1-sulfonyl chloride (1.097 g). The mixture was stirred at ambient temperature under nitrogen for 72 hours. The reaction was diluted with methylene chloride (50 mL) and brine (100 mL). The brine layer was extracted with methylene chloride (75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The crude material was purified on a silica gel column eluting with a 15-65% ethyl acetate in hexane gradient to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][C:24]2[S:25][CH:26]=[C:22]([CH3:21])[N:23]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)n1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (200 mg, 0.57 mmol) and 4-methyl-thiazol-2-amine (78 mg, 0.68 mmol). The title compound was obtained as a yellow solid (65 mg, 26% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.01 (2H, m), 7.24 (1H, m), 6.88 (1H, m), 2.23 (3H, m). MS m/z: 446.92, 448.97 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]=[CH:3]1>O1CCCC1.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]=[CH:3]1
Reactant: CCOC(=O)/C=C/c1cn(C)cn1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(C)cn1
Yield: 104 %

Procedure:
A solution of ethyl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate (2.5 g) in tetrahydrofuran (100 ml) was hydrogenated over 10% palladium activated carbon (0.2 g) at room temperature under 2 atmospheric pressure. After removal of catalyst by filtration through Celite pad, the filtrate was concentrated under reduced pressure to give ethyl 3-(1-methyl-1H-imidazol-4-yl)propionate (2.63 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[H-].[Na+].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>CN(C=O)C>[CH2:23]([O:1][CH2:2][CH2:3][N:4]1[C:5](=[O:14])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]1=[O:13])[C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOCc1ccccc1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A solution of 126 (5 g, 26 mmol) in DMF (50 mL) was treated with sodium hydride (1.1 g, 32 mmol, 70% dispersed in mineral oil) for 30 minutes at room temperature, followed by addition of BnBr (6.7 g, 39 mmol). After additional 1 hour, the reaction was quenched by water (200 mL) and extracted with ethyl acetate (4×50 mL). The combined organic layer was washed with brine (3×50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 10%-20% ethyl acetate in petroleum ether to afford 127 as a white solid (4.8 g, 65%). (ES, m/z) [M+H]+ 282.0; 1H NMR (300 MHz, CDCl3) δ 7.85-7.88 (m, 2H), 7.71-7.74 (m, 2H), 7.25-7.31 (m, 5H), 4.55 (s, 2H), 3.95 (t, J=6.0 Hz, 2H), 3.74 (t, J=6.0 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5](Cl)=[O:6].[NH2:15][C:16]([CH3:32])([CH2:19][N:20]1[N:24]=[C:23]2[C:25]([Cl:31])=[CH:26][C:27]([Cl:30])=[C:28]([Cl:29])[C:22]2=[N:21]1)[C:17]#[N:18]>C1COCC1>[C:17]([C:16]([NH:15][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:2]([F:1])[CH:3]=1)([CH3:32])[CH2:19][N:20]1[N:24]=[C:23]2[C:25]([Cl:31])=[CH:26][C:27]([Cl:30])=[C:28]([Cl:29])[C:22]2=[N:21]1)#[N:18]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)c(F)c1
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)(F)F)c(F)c1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 3-fluoro-4-trifluoromethylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (0.075 mmole, described in Example 39) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=494, RT=0.73 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[CH:9]([N:22]1[CH2:25][CH:24]([OH:26])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:9]([N:22]1[CH2:25][CH:24]([O:26][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Clc1ccc(Br)cn1
Product: Brc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)nc1
Yield: 68.5 %

Procedure:
This compound was prepared by the method outlined for example 5 step 1. Thus 5-bromo-2-chloropyridine (31.31 g, 0.163 mol) and 1-benzhydryl-azetidin-3-ol (38.92 g, 0.163 mol) were reacted to afford title compound (44.14 g, 64%) as light brown solid.
Reaction SMILES: COC.[N:4]1([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:20]3[C:21]4[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=4[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=3)=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1.[Al+3].[Cl-].[Cl-].[Cl-].CCS>ClC(Cl)C>[N:4]1([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:20]3[C:21]4[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=4[S:23][C:24]=3[C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: COC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: CC(Cl)Cl
Product: O=C(c1ccc(OCCN2CCCC2)cc1)c1c(-c2ccc(O)cc2)sc2ccccc12
Yield: 33 %

Procedure:
By cleaving the methyl ether of 2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone using AlCl3 (about 8 eq) and EtSH (about 10 eq) in dichloroethane at 0° C., the title compound was obtained in 33% yield as an oil following radial chromatography (SiO2; gradient of 2-10% MeOH in CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][CH:12]([CH3:18])[CH2:13][CH2:14][C:15](O)=[O:16].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:15](=[O:16])[CH2:14][CH2:13][CH:12]([CH3:18])[CH3:11])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: CC(C)CCC(=O)O
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CCC(=O)Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of 5-aminoindazole (1.00 g, 7.51 mmol) in N,N-dimethylformamide (15 ml) were added 4-methylvaleric acid (960 mg, 8.26 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (1.72 g, 9.01 mmol), hydroxybenzotriazole (1.12 g, 8.26 mmol) and triethylamine (1.7 ml, 12.0 mmol), and the resulting mixture was stirred overnight at room temperature. Then, the reaction solution was cooled to 0° C. and a 1N-aqueous sodium hydroxide solution was added thereto, followed by extraction with chloroform. The organic layer was washed with water and then a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was dissolved in a mixture of diethyl ether and methanol, followed by adding thereto hexane. The solid precipitated was collected by filtration and dried under reduced pressure to obtain N-(1H-indazol-5-yl)-4-methylpentanamide (1.24 g, 71%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:10]([OH:19])[C:11]([F:18])([F:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:8][C@@H:9]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C@@H:10]([OH:19])[C:11]([F:17])([F:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(F)(F)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C(F)(F)[C@H](O)[C@@H](N)Cc1ccccc1

Procedure:
Ethyl 4(S)-amino-2,2-difluoro-3(R)-hydroxy-5-phenylpentanoate hydrochloride was synthesized in the same manner as in Example 83-(7). That is, ethyl 4(S)-[(tert-butoxycarbonyl)amino]-2,2-difluoro-3(R)-hydroxy-5-phenylpentanoate (an intermediate in Reference Example 6, 908 mg, 2.43 mmol) was treated with a solution of hydrogen chloride in 1,4-dioxane (4N, 6 mL) to give 750 mg (100%) of the target compound as a colorless solid.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:33])([CH3:32])[C:8]12[O:15][C:12]([C:16]([CH3:24])([CH3:23])[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH:13]=[CH:14]1)[CH2:11][C:10]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)=[CH:9]2)([CH3:4])([CH3:3])[CH3:2]>CO.[Rh]>[C:19]([SiH2:18][O:17][C:16]([CH3:24])([CH3:23])[C:12]12[O:15][C:8]([C:7]([CH3:32])([CH3:33])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])([CH2:14][CH2:13]1)[CH2:9][C:10]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)=[CH:11]2)([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C12C=CC(C(C)(C)O[SiH2]C(C)(C)C)(CC(c3ccc(N)cc3)=C1)O2
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)[SiH2]OC(C)(C)C12C=C(c3ccc(N)cc3)CC(C(C)(C)O[SiH2]C(C)(C)C)(CC1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-[1,5-bis-(tert-butyl-dimethyl-silanyloxymethyl)-8-oxa-bicyclo[3.2.1]octa-2,6-dien-3-yl]-phenylamine (as prepared in the previous step, 500 mg, 1.03 mmol) and 5% Rh/Al2O3 (250 mg, 50 wt %) in 20 mL of MeOH was stirred at RT under H2 (balloon pressure) for 2 h. The Rh catalyst was removed by filtration on Celite, and the filtrate was concentrated in vacuo to give 500 mg of the 4-[1,5-bis-(tert-butyl-dimethyl-silanyloxymethyl)-8-oxa-bicyclo[3.2.1]oct-2-en-3-yl]-phenylamine as a light brown oil Mass spectrum (ESI, m/z): Calcd. for C27H47NO3Si2, 490.3 (M+H), found 490.1.