Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][CH2:16][S:17][C:18]4[S:22][C:21]([CH3:23])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.BrBr.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17][C:18]4[S:22][C:21]([CH3:23])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc2c(s1)SCCC1CC(=O)N(c3ccc(Cl)cc3)N=C21
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Reaction time: 0.33 h
Yield: 61.5 %

Procedure:
To a solution of 3.6 g of 2-(4-chlorophenyl)-9-methyl-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one in 50 ml of acetic acid is added dropwise a solution of 1.7 g of bromine in 15 ml of acetic acid stirring for 15 minutes at 40°-45° C. The mixture is stirred for 20 minutes at the same temperature and then poured into 200 ml of water. The precipitated crystals are collected by filtration and washed with water. The resulting crystals are subjected to column chromatography on silica gel and eluted with chloroform. The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 2.2 g of 2-(4-chlorophenyl)-9-methyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as pale brown crystals, melting at 150°-151° C.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]([NH2:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:18][CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH3:8][C:9]([NH:17][C:20](=[O:21])[CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[Cl:18])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)(C)C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(NC(=O)C(Cl)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Into a 200 ml four-necked flask, there were charged toluene (100 ml), α,α-dimethylbenzylamine (9 g) and pyridine (5.8 g), and α-chloro-tert-butylacetyl chloride (11.3 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. The reaction mixture was washed with water to remove pyridine hydrochloride. After the toluene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 15.8 g of N-(α,α-dimethylbenzyl)-α-chloro-tert-butylacetamide. M.P., 159°-160° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C)c4)c3O2)cc1
Yield: 137.3 %

Procedure:
Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 3-methylbenzeneboronic (0.68 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.899 g (69%) of (±)-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.44 (silica, ethyl acetate:hexanes 1:3); mp 81-82° C.; Anal. calcd. for C23H22O4S.0.2H2O: C, 69.39; H, 5.67. Found: C, 69.42; H, 5.49.
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.C(O)(C)(C)C.[OH2:36].[OH2:37].C[N+]([O-])(C)C.S([O-])(O)=O.[Na+]>[Os](=O)(=O)(=O)=O.N1C=CC=CC=1.O>[OH:36][CH2:1][C:2]1([OH:37])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+](C)(C)[O-]
Agent: O=S([O-])O
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)(CO)c3ccccc32)cc1
Reaction time: 2.5 h

Procedure:
To 5-methylidene-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.60 g) are added successively t-butyl alcohol (6.0 ml), water (1.2 ml), pyridine (0.3 ml), osmium tetroxide (1.2 mg) and trimethylamine N-oxide dihydrate (0.22 9), and the mixture is refluxed with stirring for 2.5 hours. After cooling, to the reaction solution is added 20% aqueous sodium hydrogen-sulfite solution (10 ml), and the mixture is stirred at room temperature for 1.5 hour. The reaction solution is extracted with a mixture of ethyl acetate/tetrahydrofuran (1:1). The extract is washed successively with diluted hydrochloric acid and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-hydroxymethyl-5-hydroxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) as white powder, m.p. 136-140° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([CH2:33][C@H:34]3[CH2:38][CH2:37][N:36]([C:39](=[O:42])[NH:40][CH3:41])[CH2:35]3)[C:14]([NH:16][C:17]3[CH:32]=[CH:31][C:20]([C:21]([O:23]CC4C=CC=CC=4)=[O:22])=[CH:19][N:18]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1>C(OCC)(=O)C.[C].[Pd]>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([C@@H:13]([CH2:33][C@H:34]3[CH2:38][CH2:37][N:36]([C:39](=[O:42])[NH:40][CH3:41])[CH2:35]3)[C:14]([NH:16][C:17]3[CH:32]=[CH:31][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=3)=[O:15])=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CNC(=O)N1CC[C@H](C[C@@H](C(=O)Nc2ccc(C(=O)OCc3ccccc3)cn2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNC(=O)N1CC[C@H](C[C@@H](C(=O)Nc2ccc(C(=O)O)cn2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Reaction time: 15 h
Yield: 68 %

Procedure:
Benzyl 6-((R)-2-(4-(cyclopropylsulfonyl)phenyl)3-((S)-1-(methylcarbamoyl)pyrrolidin-3-yl)-propanamido)nicotinate (50.0 mg, 84.6 μmol) was dissolved in ethyl acetate (2 mL), and thereafter, 10% palladium carbon (catalytic amount) was added to the obtained solution. The obtained mixture was stirred under a hydrogen atmosphere for 15 hours. Thereafter, the reaction solution was filtered through a pad of celite, and was then concentrated in vacuo, so as to obtain the captioned compound (28.8 mg, 68%) in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7](=O)[CH2:8][N:9]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH2:10][CH2:11][C:5]=2[CH:4]=1.C(O)(=O)C.Cl.CCO>[C].[Pd].O1CCOCC1>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[CH2:7][CH2:8][N:9]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)(=[O:13])=[O:14])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(S(=O)(=O)c1ccc(C)cc1)CC2=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(S(=O)(=O)c1ccc(C)cc1)CC2
Reaction time: 8 h

Procedure:
7-Methoxy-3-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-benzo[d]azepin-1-one (6.91 g, 20 mmol) (prepared essentially as described by Kanao et al. (1982) Chem. Pharm. Bull. 30:180-88) is added to a mixture of acetic acid (20 ml), 37% hydrochloric acid (8 ml), EtOH (8 ml) and dioxane (80 ml). 1.0 g of 10% palladium-carbon is added to the mixture, and the resulting mixture is hydrogenated under 30-55 psi at rt overnight. The palladium-carbon is removed by filtration, and the filtering cake is washed with MeOH (30 ml×3). The combined organic phase is evaporated to dryness under reduced pressure to give the title compound as a white solid. MS (+VE) m/z 332.1 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:17])[C:9]2[CH:10]=[N:11][C:12]([O:15]C)=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>C(#N)C>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:11]2[CH:10]=[C:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:17])[CH:14]=[CH:13][C:12]2=[O:15])=[CH:21][CH:20]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1ccc(N(C)c2ccc(F)cc2)cn1
Solvent: CC#N
Product: CN(c1ccc(F)cc1)c1ccc(=O)n(Cc2ccc(Cl)cc2)c1
Yield: 33.7 %

Procedure:
According to Scheme 22 Step 2: The title compound was prepared from N-(4-fluorophenyl)-6-methoxy-N-methylpyridin-3-amine (1 eq, 86 μmol, 20 mg) and 4-chloro-benzylbromide (1.7 eq, 0.15 mmol, 30 mg) according to the procedure described for Example 6 Step 2. Reaction conditions: 12 hours at 80° C. in acetonitrile. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 10 g SiO2) using CH2Cl2/AcOEt 50/50 as eluent to afford 1-(4-chlorobenzyl)-5-((4-fluorophenyl)(methyl)amino)pyridin-2(1H)-one (29 μmol, 10 mg, 34%) as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=O.C(N=C=NC(C)C)(C)C>O1CCOCC1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH:16]2[CH2:15][CH2:14][N:13]([C:10]3[CH:9]=[CH:8][C:7]([C:5]4[O:1][CH2:2][CH2:3][N:4]=4)=[CH:12][CH:11]=3)[CH2:18][CH2:17]2)[CH2:20][CH2:21]1)=[O:26])([CH3:29])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(C(=O)NCCO)cc3)CC2)CC1
Agent: [Cu+2]
Agent: CC(C)N=C=NC(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(C4=NCCO4)cc3)CC2)CC1

Procedure:
A solution of tert-butyl 1′-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-4,4′-bipiperidine-1-carboxylate (234 mg; 0.542 mmol) in dioxane (5 mL) was treated with N,N′-diisopropylcarbodiimide (68 mg; 0.084 mmol) and Cu(OTf)2 (10 mg; 0.027 mmol). The mixture was refluxed for 5 hr. The reaction was evaporated and chromatographed (PTLC; 40:1 CH2Cl2/MeOH), giving the title compound.
Reaction SMILES: I[C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1I.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([O:16][CH:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][N:11]3[C:5]2=[N:4][C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:8]=2)=[C:2]3[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:19]1
Reactant: CN1CCC(OC2c3ccccc3CCn3c2nc(I)c3I)CC1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccccc2)c3-c2ccccc2)CC1
Temperature: 105 °C

Procedure:
To a solution of 1,2-diiodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 219A) (212 mg, 0.386 mmole) in THF (3 mL) are added benzeneboronic acid (120 mg, 1 mmole), water (3 mL), Ba(OH)2 (460 mg, 2 mmoles) and PdCl2(dppf)2 (40 mg). The flask is evacuated and filled with argon. The reaction mixture is heated at 105° C. for 48 hours. AcOEt is added and the organic phase is washed with water, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) (100:0) to (95:5) to give 4-(1-methylpiperidin-4-yloxy)-1,2-diphenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 90° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C:9](=[O:29])[C@@H:10]([N:18]([CH2:26][CH:27]=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:30])[C:9](=[O:29])[C@@H:10]([N:18]([CH2:26][CH2:27][OH:28])[C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CC=O)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)N(CCO)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
Combine (S)-N-benzyl-N-methyl-2-[N-(t-butoxycarbonyl)-2-oxo-ethylamino]-3-phenyl-propionamide (5.0 mmol) and sodium borohydride (5.0 mmol) in ethanol (20 mL). Stir for 16 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with 0.5M hydrochloric acid solution and water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH2:17][NH:18][CH3:19])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C.[Cl:27][C:28]1[CH:29]=[C:30]([S:35](Cl)(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1[F:34]>C(Cl)Cl>[Br:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]([CH3:19])[S:35]([C:30]2[CH:31]=[CH:32][C:33]([F:34])=[C:28]([Cl:27])[CH:29]=2)(=[O:37])=[O:36])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CNCc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1)S(=O)(=O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
To a solution of t-butyl 2-(2-bromo-4-((methylamino)methyl)phenoxy)acetate (2) (68.8 g, 0.21 mol, 1 eq) in DCM (500 mL) was added triethylamine (42 g, 0.42 mol, 2 eq) and 3-chloro-4-fluorobenzene-1-sulfonyl chloride (47.8 g, 0.21 mol. 1 eq, Aldrich, Milwaukee, Wis., USA). After the mixture was stirred for 2 h at room temperature, DCM was evaporate. Crude product was recrystallized from ethanol to yield tert-butyl 2-(2-bromo-4-((3-chloro-4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (10) (64 g, 59%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH3:13][C:14]1[N:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl.C1COCC1>[NH:4]1[CH2:3][CH:2]([O:1][C:17]2[CH:16]=[CH:15][C:14]([CH3:13])=[N:19][CH:18]=2)[CH2:5]1
Reactant: Cc1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1ccc(OC2CNC2)cn1
Temperature: 55 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
tert-Butyl 3-hydroxyazetidine-1-carboxylate (1.0 g) and 6-methylpyridin-3-ol (570 mg) were mixed with THF (10 ml), and triphenylphosphine (2.3 g) was added thereto. A 1.9 M DIAD/toluene solution (4.5 ml) was added dropwise thereto, followed by stirring at 55° C. overnight. The reaction mixture was concentrated under reduced pressure, and EtOAc and 1M hydrochloric acid were added thereto. The aqueous layer was adjusted to pH of around 10 by the addition of a 4M aqueous NaOH solution, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with DCE (6 ml), and TFA (3 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and then CHCl3 and a 1 M aqueous NaOH solution were added thereto. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure to obtain 5-(azetidin-3-yloxy)-2-methylpyridine (269 mg).
Reaction SMILES: [C:1]1([C@:11]23[CH2:16][C@H:15]2[CH2:14][C:13](=O)[CH2:12]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+].C(OCC)(=O)C.CO.C(N(CC)CC)C>CO>[C:1]1([C@:11]23[CH2:16][C@H:15]2[CH2:14][CH:13]([NH2:24])[CH2:12]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C[C@@H]2C[C@]2(c2cccc3ccccc23)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC1C[C@@H]2C[C@]2(c2cccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 346.7 %

Procedure:
To a solution of (1S,5S)-1-(1-naphthyl)bicyclo[3.1.0]hexan-3-one (0.7 g, 3.1 mmol) in methanol (87.5 mL) was added ammonium acetate (24.3 g, 310 mmol), stirred for 15 minutes at room temperature and sodium cyanoborohydride (1.58 g, 25 mmol) was added and the mixture was heated to 60° C. for 2 hours. The reaction was monitored by TLC (ethyl acetate/methanol/triethylamine (89:10:1)). The reaction mixture was concentrated under reduced pressure to remove methanol at 30° C., the crude mass was quenched with water (50 mL). The aqueous layer was extracted with ethyl acetate (3×150 mL). The aqueous layer was saturated with sodium chloride and re-extracted with ethyl acetate (3×150 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 2.4 g of crude oil, which was purified by preparative HPLC to 400 mg (57%) of 99% pure product. 1H NMR δ(300 MHz,CD3OD): 1.1-1.15 (1H,m), 1.21-1.24 (1H,m), 1.88-1.93 (2H,m), 2.24-2.31 (1H,m), 2.45-2.57 (1H,m), 2.90-2.92 (1H,m), 4.10-4.2 (1H,m), 7.37-7.57 (4H,m), 7.74-7.76 (1H,d, 6 Hz), 7.85-7.88 (1H,d,9 Hz), 8.20-8.29 (1H,m). 13CNMR (CD3OD): 140.74, 140.30, 135.51, 133.93, 129.81, 128.64, 127.76, 127.12, 127.01, 126.74, 126.59, 125.67 119.93, 54.97, 43.08, 40.42, 36.16, 34.53, 33.91, 25.88, 24.94, 23.70, 15.76. Purity: 98.5% (a/a) by HPLC. MS, M+(224).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][CH2:11]Br.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[S:8]1[CH2:11][CH2:10][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: Nc1ccccc1S
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)NCCS2
Temperature: 100 °C
Yield: 72.7 %

Procedure:
A mixture of 2-aminothiophenol (5 g, 40 mmol), 1,2-dibromoethane (3.75 g, 20 mmol), K2CO3 (13.8 g, 100 mmol) in THF (30 mL) was heated at 100° C. for 16 h. After completion of reaction, water was added and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (using 100-200 mesh silica) and the desired product was eluted at 15% EtOAc in hexane) to obtained 2.2 g of desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([CH:8]([N:11]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:21][CH:22]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[N:33]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([CH:8]([N:11]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:32]5[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[N:33]=5)[CH2:27][CH2:28]4)=[CH:21][CH:22]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)nc(Br)c1
Reactant: CCC(C(=O)c1ccc(Cl)cc1)n1ncn(-c2ccc(N3CCNCC3)nc2)c1=O
Solvent: ClCCl
Product: CCC(C(=O)c1ccc(Cl)cc1)n1ncn(-c2ccc(N3CCN(c4cc(C)cc(C)n4)CC3)nc2)c1=O
Temperature: 140 °C
Yield: 48 %

Procedure:
(±)-2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-(1-piperazinyl)-3-pyridinyl]-3H-1,2,4-triazol-3-one (6.02 g) and 2-bromo-4,6-dimethylpyridine (5.25 g) were stirred and heated under N2 at 140° C. for 2 days. The mixture was dissolved in CH2Cl2 and purified on a glass filter over silica gel (eluent: CH2Cl2 /CH3OH 100/0 to 97/3). The pure fractions were collected and evaporated, yielding 3.6 g (48%) of (±)-2-[1-(4-chlorobenzoyl)propyl]-4-[6-[4-(4,6-dimethyl-2-pyridinyl)-1-piperazinyl]-3-pyridinyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; mp. 113.2° C. (comp. 32).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:40])([F:39])[C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:22]2[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=2[C:20]([F:19])([F:39])[F:40])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)c1ccc(C(O)c2ccccc2C(F)(F)F)cc1
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: CS(=O)(=O)c1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Yield: 44.4 %

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (6.9 mmol) and 2-(trifluoromethyl)-4′-(methylsulfonyl)benzhydrol (169) (13.8 mmol) using the procedure described for compound (3). After basic aqueous workup, the crude product was partially purified by flash column chromatography [SiO2; ethyl acetate-iso-hexane (30:70→80:20)] to afford an off-white foam (1.69 g) which was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1)[C:5]#[N:6].[CH2:18](OC(OCC)OCC)C.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(Cl)Cl>[Br:17][C:13]1[CH:12]=[C:11]([N:10]2[C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[N:1]=[CH:18]2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1ccc(Nc2cccc(Br)c2)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
A mixture of compound D (1 g, 3.47 mmol), triethylorthoformate (660 mg, 4.5 mmol) and PTSA (200 mg, 1.16 mmol) in THF (10 mL) was stirred at 70° C. for 4 h. After cooling to RT, the reaction mixture was diluted with DCM, washed with sat. NaHCO3 solution to remove PTSA, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using 40% ethylacetate in hexane to afford compound 4 (1 g, 96%) as light brown solid, mp:168.5-174.4° C.