Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1]C1C=CC(N)=C([N+]([O-])=O)C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:22]2[CH:23]=[CH:24][C:25](C(F)(F)F)=[CH:26][C:21]=2[N:20]=[C:19]1/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[F:1][C:25]1[CH:24]=[CH:23][C:22]2[N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[C:19](/[CH:31]=[CH:32]/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:20][C:21]=2[CH:26]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Product: Fc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 4-fluoro-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57).
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:18][CH:17]=1
Reactant: Brc1ccc(-c2ccccn2)cc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: OC1(C#Cc2ccc(-c3ccccn3)cc2)CN2CCC1CC2
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (516 mg), 2-(4-bromophenyl)pyridine (400 mg), bis(triphenylphosphine)palladium (II) chloride (100 mg), copper(I) iodide (50 mg) triethylamine (15 ml) and dimethylformamide (10 ml) was stirred at 90° C. under an atmosphere of argon for 2.5 hours. The mixture was allowed to cool to room temperature, alumina (5 g) added and the solvents removed by evaporation. This pre-absorbed material was chromatographed on alumina (30 g) using a mixture of 10% ethanol in ethyl acetate as eluent. There was thus obtained a residue which was crystallised from ethanol/hexane to give 3-[2-(4-[2-pyridyl]phenyl)ethynyl]-3-hydroxyquinuclidine as a solid, m.p. 205°-206° C.; microanalysis, found: C, 77.7; H, 6.4; N, 9.0%; C20H2ON2O.0.25H2O requires: C, 77.8; H, 6.5; N, 9.08%; NMR (DMSO-d6): 1.3(1H, m), 1.6(1H, m), 1.8-2.0(3H, m), 2.7(4H, m), 2.85(1H, d), 3.1(1H, d), 5.6(1H, s), 7.4(1H, m), 7.5(2H, d), 7.85-8.05(2H, m), 8.1(1H, d) and 8.7(1H, d); m/Z 305 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].[Si:18]([O:25][CH2:26][CH2:27][C@@H:28]1[CH2:40][C:39]2[C:38]3[C:37](Cl)=[N:36][CH:35]=[N:34][C:33]=3[S:32][C:31]=2[CH2:30][CH2:29]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C1COCC1>[Si:18]([O:25][CH2:26][CH2:27][C@@H:28]1[CH2:40][C:39]2[C:38]3[C:37]([O:1][CH:2]4[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]4)=[N:36][CH:35]=[N:34][C:33]=3[S:32][C:31]=2[CH2:30][CH2:29]1)([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:19])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(Cl)c3c2C1
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
A solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (181 mg, 0.84 mmol, 1.40 equiv) in 8 mL of distilled THF was added sodium hydride (60% dispersion in mineral oil, 72 mg, 1.80 mmol, 3.00 equiv) at 0° C. and stirred for another 30 min under nitrogen. Then (12S)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraene (230 mg, 0.60 mmol, 1.00 equiv) was added and stirred overnight at room temperature. The reaction was then quenched with saturated aqueous NH4Cl, extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to give 240 mg (71%) of tert-butyl N-(4-[[(12S)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a yellow oil. MS: m/z 562 [M+H]+.
Reaction SMILES: [N:1]([C@@H:4]([CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[C:5]([N:7]1[CH2:11][CH2:10][S:9][CH2:8]1)=[O:6])=[N+]=[N-].C(NC(C)C)(C)C.[I:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[I:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:14]2[CH2:15][CH2:16][CH:12]([C@H:4]([NH2:1])[C:5](=[O:6])[N:7]3[CH2:11][CH2:10][S:9][CH2:8]3)[CH2:13]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: [N-]=[N+]=N[C@H](C(=O)N1CCSC1)C1CCNC1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: N[C@H](C(=O)N1CCSC1)C1CCN(S(=O)(=O)c2ccc(I)cc2)C1
Reaction time: 18 h
Yield: 83.1 %

Procedure:
To a solution of 28 mg (0.1 mmol) of 3-[(2S)-2-azido-2-pyrrolidin-3-ylethanoyl]-1,3-thiazolidine in methylene chloride (1 mL) was added 0.030 mL of diisopropylamine and 29 mg (0.12 mmol ) of 4-iodobenzenesulfonyl chloride. The mixture was stirred for 18 h and subjected directly to preparative TLC on silica gel (eluent: 60% ethyl acetate in hexanes) to give the desired sulfonamide (40 mg) as an off white solid. This solid was dissolved in wet THF (10%) and 25 mg (0.1 mmol) of triphenyl phosphine was added and stirred at 60° C. for 5 h and concentrated. A mixture of diastereomers were separated by preparative TLC on silca gel (10% methanol in CH2Cl2). Diastereomer I (faster moving isomer) 1H NMR (500 MHz, CDCl3) δ 7.9 (d, 2H, J=8.1 Hz), 7.52 (d, 2H, J=8.1 Hz), 4.65–4.47 (m, 2H), 3.86 (m, 1H), 3.78 9 (dd, 1H, J=6 and 8 Hz), 3.43 (m, 1H), 3.25–3.02 (m, 4H), 2.4 (m, 1H), 1.95 (m, 2H). Diastereomer II (slower moving isomer) 1H NMR (500 MHz, CDCl3) δ 7.91 (d, 2H, J=8.2 Hz), 7.56 (d, 2H, J=8.2 Hz), 4.63–4.41 (m, 2H), 3.86 (m, 1H), 3.79 (m, 0.5H), 3.64 (m, 0.5H), 3.37 (m, 3H), 3.25 (dd, 1H, J=10 and 14 Hz), 3.12 (m, 2H), 3.01 (t, 1H, J=4.4 Hz), 2.4 (m, 1H), 1.94 (m, 1H), 1.61 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH:15]([CH3:17])[CH3:16].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23](Cl)=[O:24]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH:15]([CH3:17])[CH3:16])[C:23](=[O:24])[C:22]1[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:21]=1
Reactant: CC(C)Nc1cnccc1-c1ccccc1Cl
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-isopropyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Yellow solid (19%). MS (ESI): m/z=487.10 [M+H]+.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.CN1CCOCC1.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[C:53]([OH:55])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)[C:53](=[O:55])[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccccn1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(c1ccccn1)N(Cc1ccc(CNCc2ccccn2)cc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 131.1 %

Procedure:
To a stirred solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (209 mg, 0.39 mmol) in dry DMF (1 mL) was added N-methylmorpholine (0.5 mL, 4.45 mmol), picolinic acid (64 mg, 0.52 mmol), 1-hydroxybenzotriazole (57 mg, 0.42 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (85 mg, 0.44 mmol). The reaction mixture was allowed to stir at room temperature for further 18 hours and then concentrated. The residue was diluted with ethylacetate (300 mL) and washed with saturated aqueous NaHCO3, then brine, dried (Na2SO4) and evaporated. Purification of the crude material by column chromatography on silica gel (1.5×20 cm, 50:50 EtOAc/CH2Cl2) gave the desired amide (237 mg, 94%) as a yellow oil.
Reaction SMILES: [C:1]1([Si:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:29]([CH3:32])([CH3:31])[CH3:30])[O:8][C:9]2[CH:10]=[C:11]([CH:15]([OH:28])[CH2:16][CH2:17][C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCOCC>C(Cl)Cl>[C:33]1([Si:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:29]([CH3:30])([CH3:31])[CH3:32])[O:8][C:9]2[CH:10]=[C:11]([C:15](=[O:28])[CH2:16][CH2:17][C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])[CH:12]=[CH:13][CH:14]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)c1ccccc1CCC(O)c1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1ccccc1CCC(=O)c1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 20 °C

Procedure:
The alcohol of Step 1 (93 g, 0.179 mol), dissolved in CH2Cl2 (300 mL) was added to a mixture of 4A molecular sieve (94 g, milled) and PCC, (pyridinium chlorochromate, 69 g, 0.321 mol) in CH2Cl2 (1 L) at 10° C. The mixture was then allowed to warm to 20° C. for 2 h and ether (1 L) was introduced. The mixture was filtered through silica and was washed with ether (2 L) and EtOAc:hexane 1:1 (1 L). Evaporation of the filtrate and flash chromatography (10% EtOAc:hexane) of the crude mixture on silica gave the title product. Yield: 81 g, 87%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:10]([CH3:12])([CH3:11])[C:9]([CH3:13])=[N:8][C:5]2=[N:6][CH:7]=1.[Br:14]C1C=CC(Br)=CN=1>>[Br:14][C:2]1[CH:3]=[C:4]2[C:10]([CH3:12])([CH3:11])[C:9]([CH3:13])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC1=Nc2ncc(Cl)cc2C1(C)C
Product: CC1=Nc2ncc(Br)cc2C1(C)C

Procedure:
Compound 3 was prepared analogously to compound 1 (Example 1), except that 2,5-dibromopyridine was used as a starting material.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:36][C:37]([O:39]C)=O)=[CH:7][N:8]2[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][C:18]3[CH2:35][C@:25]4([C:33]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:27][C:26]4=O)[CH2:24][C:19]=3[CH:20]=2)[N:15]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>O.CCO>[O:39]=[C:37]1[CH2:36][C:6]2=[CH:7][N:8]([CH2:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][C:18]5[CH2:35][C@:25]6([C:33]7[C:28](=[N:29][CH:30]=[CH:31][CH:32]=7)[N:27]=[CH:26]6)[CH2:24][C:19]=5[CH:20]=4)[N:15]=3)[C:9]3[C:5]2=[C:4]([CH:12]=[CH:11][CH:10]=3)[NH:1]1
Reactant: COC(=O)Cc1cn(Cc2ccc3cc4c(cc3n2)C[C@]2(C4)C(=O)Nc3ncccc32)c2cccc([N+](=O)[O-])c12
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1Cc2cn(Cc3ccc4cc5c(cc4n3)C[C@@]3(C=Nc4ncccc43)C5)c3cccc(c23)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl (4-nitro-1-{[(7S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2-yl]methyl}-1H-indol-3-yl)acetate from Step A (22 mg, 0.041 mmol) in H2O (0.5 mL) and EtOH (0.5 mL) was added sodium hydrosulfite (ca. 85%; 108 mg, 0.53 mmol). The reaction mixture was stirred at ambient temperature for 1 h, then at 50° C. for 90 min. The reaction mixture was allowed to cool, more sodium hydrosulfite (ca. 85%; 55 mg, 0.27 mmol) was added, and the resulting mixture was heated to 70° C. for 4 h. 3 N hydrochloric acid (0.55 mL, 1.65 mmol) was added and the solution was heated to 70° C. for 18 h. EtOH (1 mL) was added and heating was continued at 100° C. for 24 h, then the cooled mixture was concentrated in vacuo. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=472 (M+1). HRMS: m/z=472.1764; calculated m/z=472.1768 for C29H22N5O2.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.[O:32]=[C:33]1[NH:37][CH:36]([CH2:38][CH2:39][C:40](O)=[O:41])[CH2:35][CH2:34]1>ClCCl.CN(C)C1C=CN=CC=1>[O:41]=[C:40]([NH:7][C@H:6]([C:5]([O:4][CH2:2][CH3:3])=[O:9])[CH3:8])[CH2:39][CH2:38][CH:36]1[CH2:35][CH2:34][C:33](=[O:32])[NH:37]1
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)CCC1CCC(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NC(=O)CCC1CCC(=O)N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5.0 g (0.033 mol) L-alanine ethyl ester hydrochloride is dissolved in 30 ml of dichloromethane. The solution is cooled to 0° C. and 5.42 ml (0.039 mol) of triethylamine is added dropwise over a ten minute period. The mixture is stirred 15 minutes, filtered, concentrated, and diluted with 60 ml of dichloromethane. A mixture of the following is added in a single addition: 4.84 g (0.025 mol) of dicyclohexylcarbodiimide; 200 mg (0.0016 mol) of 4-dimethylaminopyridine; 3.08 g (0.02 mol) of 5-oxo-2-pyrrolidinepropanoic acid. The reaction is allowed to warm to room temperature and stirred for 24 hours. The solids are removed by filtration and are washed with 15 ml of 0° C. dichloromethane. The filtrate is concentrated at reduced pressure to an oil. The oil is chromatographed over silica gel using 19:1 dichloromethane-methanol for elution. Concentration at reduced pressure followed by heating at 0.1 mm pressure and 60° C. yields crystalline analytically pure N-[1-oxo-3-(5-oxo-2-pyrrolidinyl)propyl]-L-alanine, ethyl ester with a melting point of 88°-90° C.
Reaction SMILES: [CH2:1]([Si:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12](=[CH:13][C@H:14]([OH:31])[C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C:19]2=[O:29])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:50]O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:39]([Si:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:12]3([O:50][C@@H:13]3[C@H:14]([OH:31])[C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C:19]2=[O:29])[CH2:11]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: C[C@]12CC[C@H](O[Si](Cc3ccccc3)(Cc3ccccc3)Cc3ccccc3)CC1=C[C@H](O)[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Reactant: CC(C)(C)OO
Solvent: Cc1ccccc1
Product: C[C@]12CC[C@H]3[C@@H]([C@@H](O)[C@H]4O[C@]45C[C@@H](O[Si](Cc4ccccc4)(Cc4ccccc4)Cc4ccccc4)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1C2=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
24 g of 3β-tribenzylsilyloxy-7β-hydroxy-15β,16β-methylene-5-androsten-17-one is dissolved in 50 ml of toluene, combined with 500 mg of vanadium(IV) oxide acetylacetonate, and heated to 80° C. A solution of 75 ml tert.-butyl hydroperoxide (10 ml 80% tert.-butyl hydroperoxide in 100 ml of toluene) is added dropwise to the reaction mixture, and the latter is allowed to stand for 1.5 hours at this temperature. After cooling, the mixture is washed with water and saturated sodium chloride solution, dried, and evaporated under vacuum, thus obtaining 24.5 g of 3β-tribenzylsilyloxy-5,6β-epoxy-7β-hydroxy-15β,16β-methylene-5β-androstan-17-one.
Reaction SMILES: [CH2:1]([CH2:6][NH2:7])[CH2:2][C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([NH:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:19])=[O:15])=[O:11].O>FC(F)(F)C(O)=O>[CH2:1]([CH2:6][NH2:7])[CH2:2][C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([NH:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[O:15])=[O:11]
Reactant: CC(C)(C)OC(=O)CCNC(=O)CNC(=O)CNC(=O)CN
Agent: NCCCC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NCC(=O)NCC(=O)NCCC(=O)O
Yield: 100 %

Procedure:
820 mg (1.7 mmol) of Mal-Gaba-Gly-Gly-Gly-β-Ala-OtBu was disolved in 9.0 mL of 95:5 trifluoroacetic acid: deionized water and magnetically stirred for 3 hours. Solvent was removed by rotary evaporation under vacuum to give 730 mg (100%) of the title compound. 1H NMR (d6-DMSO) 12.1 (bs, 1H), 8.05-8.20 (m, 3H), 7.82 (t, J=6.0 Hz, 1H), 7.00 (s, 2H), 3.71 (t, J=6.0 Hz, 4H), 3.65 (d, J=6.0 Hz, 2H), 3.41 (t, J=7.2 Hz, 2H), 3.26 (q, J=5.6 Hz, 2H), 2.38 (t, J=7.2 Hz, 2H,), 2.14 (q, J=8.0 Hz, 2H), 1.67-1.77 (m, 2H). 13C NMR (d6-DMSO) 172.70, 171.83, 171.01, 169.50, 168.99, 168.51, 134.38, 42.07, 41.84, 36.75, 34.70, 33.69, 32.28, 23.97 HRMS (M+Na+) Calc. 448.1444 found 448.1465
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17]>C(Cl)Cl>[C:1]1([S:7][CH2:17][CH2:16][C:15]([O:19][CH3:20])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)OC
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCSc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thiophenol (440 mg, 4 mmol) and Et3N (70 μl, 0.5 mmol) were dissolved in CH2Cl2 (5 ml). Methyl acrylate (412 mg, 4.8 mmol) was added dropwise. The reaction was exothermic. After stirring at room temperature for 30 minutes, the excess methyl acrylate was removed in vacuo. TLC: silica gel, Et2O-hexane 1:2, UV Rf =0.58. The crude title ester was used without further purification.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].Cl[CH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>CN(C)C=O>[S:32]1[CH:33]=[CH:34][N:35]=[C:31]1[CH2:30][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:15]2[CH:14]=[C:13]([C:12]3[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=3)[O:17][N:16]=2)=[CH:20][CH:21]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: ClCc1nccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4nccs4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (50 mg, 0.18 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (35.4 μL, 0.18 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a suspension of this solid in N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-thiazole (28.4 mg, 0.21 mmol) described in manufacturing Example 88-1-2, which was stirred for 3 hours at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (43.0 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:24]([NH2:31])[C@@H:23]1[OH:32]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:17]([OH:18])[CH2:19][NH:31][C@@H:24]4[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:22][CH:23]4[OH:32])=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Solvent: CN(C)C=O
Solvent: CCO
Product: OC(CN[C@@H]1c2ccccc2CC1O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and (1S, 2R)-(−)-cis-1-amino-2-indanol in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=435.
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH3:23])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2].[BH4-].[Na+].[C:26](O)(=O)[CH2:27][CH3:28]>>[CH2:1]([N:3]([CH2:26][CH2:27][CH3:28])[CH:4]([CH3:23])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2]
Reactant: CCC(=O)O
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3cc(OC)ccc23)C1
Agent: [BH4-]
Agent: [Na+]
Product: CCCN(CC)C(C)CN1CCc2c(c(=O)oc3cc(OC)ccc23)C1

Procedure:
Prepared by the method described for Example 59 from 3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.0 g, 0.009 moles), propionic acid (20 ml), and sodium borohydride (2.0 g, 0.053 moles). The free base is obtained crystalline. Recrystallization from acetonitrile gave the product (2.0 g), mp 100°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH2:15][CH2:16][OH:17])[CH:12]=[C:11]([CH2:18]N(CC)CC)[C:10]=3[OH:24])[N:8]=[C:4]2[CH:3]=1.[Cl:27][C:28]1[CH:46]=[CH:45][C:31]2=[N:32][N:33]([C:35]3[CH:40]=[C:39]([CH2:41][CH2:42][OH:43])[CH:38]=[CH:37][C:36]=3[OH:44])[N:34]=[C:30]2[CH:29]=1.CO.C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:18]([C:37]1[CH:38]=[C:39]([CH2:41][CH2:42][OH:43])[CH:40]=[C:35]([N:33]2[N:32]=[C:31]3[CH:45]=[CH:46][C:28]([Cl:27])=[CH:29][C:30]3=[N:34]2)[C:36]=1[OH:44])[C:11]1[CH:12]=[C:13]([CH2:15][CH2:16][OH:17])[CH:14]=[C:9]([N:7]2[N:6]=[C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]3=[N:8]2)[C:10]=1[OH:24]
Reactant: CCN(CC)Cc1cc(CCO)cc(-n2nc3ccc(Cl)cc3n2)c1O
Reactant: OCCc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: OCCc1cc(Cc2cc(CCO)cc(-n3nc4ccc(Cl)cc4n3)c2O)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Yield: 55 %

Procedure:
In 100 ml of xylene were dissolved 37.0 g (93.9 mmols) of crude 2-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)-6-(N,N-diethylaminomethyl)phenol synthesized in Example 10 and 27.2 g (93.9 mmols) of the purified product of 2-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol synthesized in Example 7. 5 ml of methanol solution of 28% sodium methylate was added, and the mixture was refluxed in a nitrogen stream for 10 hours. The subsequent treatment was carried out in the same manner as in Example 12, giving 30.8 g of 2,2'-methylenebis[6-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol] as pale yellow crystals (yield 55.0%, purity 99.0%).