Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([N:16]2C(=O)[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]4)=[CH:31][CH:30]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15].C1(C)C=CC=CC=1>O1CCCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([C:22]2[C:23]([NH:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][N:36]4[CH2:37][CH2:38][S:39](=[O:42])(=[O:43])[CH2:40][CH2:41]4)=[CH:33][CH:34]=3)=[N:24][O:25][N:26]=2)=[N:18][OH:19])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)c1ccc(CN2CCS(=O)(=O)CC2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=S1(=O)CCN(Cc2ccc(CNc3nonc3C(=NO)Nc3ccc(F)c(Br)c3)cc2)CC1
Temperature: 130 °C
Yield: 5.4 %

Procedure:
A solution of N-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-benzamide trifluoroacetate (20 mg, 28 μmol) in tetrahydrofuran (0.83 mL) was treated with 2.0 M of borane-dimethyl sulfide complex in toluene (42 μL, 85 μmol) was heated in the microwave at 130° C. for 5 min. The reaction mixture was treated with additional 2.0 M of borane-dimethyl sulfide complex in toluene (40 μL, 80 μmol) and heated in the microwave at 130° C. for 10 min. The reaction mixture was quenched with acetic acid, concentrated and purified by preparative LCMS to give the desired product (1 mg, 5%). LCMS for C21H23BrFN6O4S (M+H)+: m/z=553.0, 554.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@@H:10]([CH3:14])[C:11]([NH2:13])=[S:12].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)=O>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@H:10]([C:11]1[S:12][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[N:13]=1)[CH3:14]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: C[C@@H](C(N)=S)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Solvent: CCO
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A mixture of (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylthiobutyramide (26.7 g, 85.4 mmol) and a-bromo-4′-cyano-acetophenone (24.0 g, 0.107 mol) in EtOH (500 ml) was refluxed for 1 hr. The reaction mixture was cooled down to r.t. And the solvent was removed under reduced pressure down to 150 ml. The residue was poured into in to cold (0° C.) saturated NaHCO3 aq. (400 ml). The resulting mixture was extracted with EtOAc (300 ml+150 ml×2). The combined organic layer was washed with brine (200 ml), dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (Wako-gel C-300, Hexane:EtOAc=1:2) to give 4-{2-[(1R,2R)-2-(2,5-Difluoro-phenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]-thiazol-4-yl }-benzonitrile (32.0 g, 86%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]2[S:23][CH:24]=[C:25]([CH:27]3[CH2:30][CH2:29][CH2:28]3)[N:26]=2)[CH:15]=1)=[O:12].[BH4-].[Na+].O1CCCC1.CO>O>[CH:27]1([C:25]2[N:26]=[C:22](/[CH:21]=[CH:20]/[C:16]3[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[CH2:3][OH:2])[CH:19]=[CH:18][CH:17]=3)[S:23][CH:24]=2)[CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)c1ccccc1CC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cc1ccccc1CO)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reaction time: 20 h

Procedure:
A mixture of 0.865 g of (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester, 0.5 g of sodium borohydride, 75 ml of tetrahydrofuran and 20 ml of methanol was stirred under a positive nitrogen atmosphere for 20 hr. The reaction mixture was condensed in vacuo and the residual materials were mixed with water and extracted with methylene chloride. The combined extracts were washed with water, dried (MgSO4) and condensed in vacuo. The residual materials were further purified by chromatography over florisil using ethyl acetate as the eluant to yield (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzyl alcohol.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([O:4][C:5]([N:7]=[N+]=[N-])=[O:6])[CH3:3].[C:11]1([CH2:17][N:18]2[CH2:23][CH2:22]N[CH2:20][CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.O.CCOCC>[CH3:1][C:2]([CH3:10])([O:4][C:5]([N:7]1[CH2:20][CH2:19][N:18]([CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:23][CH2:22]1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A solution of 3.4 g (0.024 mole) of 1,1-dimethylethoxy carbonylazide in 5 ml of pyridine was rapidly added to a stirred solution of 1-phenylmethylpiperazine (4.2 g, 0.024 mole) in 5 ml of pyridine. An initial exothermic reaction was noted. The mixture was allowed to stir overnight, diluted with water and the product was extracted with two 50 ml portions of ether. The ether extracts were dried (MgSO4), filtered, and evaporated to yield a yellow oil. Column chromatography (2" diameter column, 500 g of silica gel, ether eluent) followed by sublimation at 110°/0.5 mm returned 5.7 g (86%) of white solid, m.p. 64°-73°. The solid was dissolved in 50 ml of ether and cooled to -70°. The resultant white solid was filtered off to yield 4.5 g (68%) of product, m.p. 71-3°. Calc. for C16H24N2O2 (276.38): C, 69.53; H, 8.75; N, 10.14. Found: C, 69.44; H, 8.82; N, 10.15.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[S:4][C:5]([CH3:12])=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.O[CH2:16][CH2:17][NH:18][CH:19]([CH3:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[C:29]([CH2:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH:19]([N:18]2[CH2:17][CH2:16][O:11][CH:8]([C:6]3[N:7]=[C:3]([C:2]([F:14])([F:13])[F:1])[S:4][C:5]=3[CH3:12])[CH2:9]2)[CH3:33])=[CH:22][CH:23]=1)([O:31][CH3:32])=[O:30]
Reactant: Cc1sc(C(F)(F)F)nc1C(=O)CBr
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3nc(C(F)(F)F)sc3C)C2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Prepared by analogy to Example 32 by reaction of 4.2 g (0.0146 mol) of 2-trifluoromethyl-5-methyl-4-bromoacetyl-thiazole with 8 g (0.03 mol) of N-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine in methylene chloride by stirring at room temperature for 20 hours and heating under reflux for 2 hours. The reduction is carried out in 28 ml of trifluoroacetic acid using 2.4 g (0.02 mol) of triethylsilane. The crude product is purified on a silica gel column using toluene/ethyl acetate=7:3 as eluant.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1)[NH2:4].C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[CH3:49][C:37]1[N:36]([CH2:35][C:32]2[CH:33]=[CH:34][C:29]([C:24]3[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:30][CH:31]=2)[C:44]2[C:39]([C:38]=1[CH3:48])=[CH:40][C:41]([C:45](=[O:46])[NH:4][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1)[C:2]([F:14])([F:15])[F:1])=[CH:42][CH:43]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC(C)c1cccc([C@@H](N)C(F)(F)F)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](c3cccc(C(C)C)c3)C(F)(F)F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using (R)-2,2,2-trifluoro-1-(3-isopropylphenyl)ethanamine and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 599 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:20]([O:37][CH2:38][CH2:39][N:40]([CH2:48][CH2:49]O)[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(C=P(CCCC)(CCCC)CCCC)#N.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:20]([O:37][CH2:38][CH2:39][N:40]([CH2:48][CH2:49][CH:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])([C:33]([CH3:34])([CH3:36])[CH3:35])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N(CCO)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 95.2 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (500 mg, 1.65 mmol) obtained in Example 5 and t-butyl N-[2-(t-butyldiphenylsilyloxy)ethyl]-N-(2-hydroxyethyl)carbamate (950 mg, 2.14 mmol) were dissolved in toluene (20 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (600 mg, 2.49 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 9 hours. After the reaction mixture was allowed to cool down, t-butyl N-[2-(t-butyldiphenylsilyloxy)ethyl]-N-(2-hydroxyethyl)carbamate (500 mg, 1.13 mmol) and cyanomethylenetri-n-butylphosphorane (300 mg, 1.24 mmol) were added thereto. Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=15:1 eluate was concentrated under reduced pressure, whereby the title compound (1.14 g, 1.57 mmol, 95%) was obtained as a pale yellowish browh foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12](OC)=[O:13])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[K+].CC(C)=O>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:16])[CH2:10][CH2:11][C:12]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)Nc1cccc(O)c1
Reactant: ClCc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: O=C1CCC(=O)N1c1cccc(OCc2nc3ccccc3s2)c1
Yield: 60.9 %

Procedure:
A mixture of 4-[[3-(hydroxy)phenyl]amino]-4-oxobutanoic acid, methyl ester (1.45 g, 6.5 mmol), 2-chloromethylbenzothiazole (1.20 g, 6.5 mmol), cesium carbonate (1.0 g), sodium carbonate (0.7 g), potassium iodide (5 mg) and acetone (60 ml) is heated at reflux for 2 hours. The reaction is filtered through a pad of Celite and silica gel and the solvent is removed in vacuo. Recrystallization from acetone gives 1.34 g (56% yield) of product, m.p. 175°-176° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][C:16]([NH:27][C:28](=[O:32])[NH:29][CH2:30][CH3:31])=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[C:34]#[CH:35]>CN(C=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:18]2[CH:17]=[C:16]([NH:27][C:28](=[O:32])[NH:29][CH2:30][CH3:31])[N:15]=[CH:14][C:13]=2[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N:1]3[CH:35]=[C:34]([C:33]([O:37][CH2:38][CH3:39])=[O:36])[N:3]=[N:2]3)=[CH:9][CH:8]=2)=[O:12])=[CH:21][CH:22]=1
Reactant: C#CC(=O)OCC
Reactant: CCNC(=O)Nc1cc(Nc2ccc(Cl)cc2)c(C(=O)Nc2ccc(N=[N+]=[N-])cc2)cn1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(Nc2ccc(Cl)cc2)c(C(=O)Nc2ccc(-n3cc(C(=O)OCC)nn3)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
To a solution of Compound 132 (50 mg, 0.11 mmol) in DMF (1.8 mL) was added ethyl prop-2-ynoate (21 mg, 0.2218 mmol), followed by ethyl-diiopropylamine (0.023 mL, 0.13 mmol) and cuprous iodide (3.8 mg, 0.020 mmol) at 0° C. The ice bath was removed and the mixture stirred at RT for 2 hours. Water was added and the mixture extracted with EtOAc (4 times). The organic fractions were combined and concentrated in vacuo to give a residue that was purified by medium pressure chromatography (C18 column), eluting with ACN gradient in water, to give target product. The product was triturated with EtOAc to give Compound 133 (5 mg). 1H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 9.82 (5, 1H), 9.43 (s, 1H), 9.12 (s, 1H), 8.62 (s, 1H), 7.94 (t, J=6.4 Hz, 5H), 7.44 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.26 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.20-3.11 (m, 2H), 1.35 (t, J=7.1 Hz, 3H), 1.07 (t, J=7.2 Hz, 3H), [M+H]+ m/z=549.03.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.N1C=CC=CC=1>ClCCl>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][C:8]([CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CNS(C)(=O)=O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.9 %

Procedure:
Methanesulfonyl chloride (2.32 mL, 3.44 g, 33 mmol) was added dropwise to a stirred, cooled (0° C.) solution of crude 4-aminomethyl-1-t-butoxycarbonyl-4-phenylpiperidine (7.96 g) and pyridine (3.64 mL, 3.56 g, 45 mmol) in dichloromethane (100 mL) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure, aqueous sodium hydrogen carbonate (saturated, 100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×100 mL), aqueous sodium hydrogen carbonate (saturated, 100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (30:70 increasing to 80:20) to give the title compound as a colorless solid (5.65 g, 61% from 4-cyano-4-phenylpiperidine hydrochloride), δH (250 MHz, CDCl3) 7.46-7.26 (5H, m), 3.88 (1H, br t, J 6.7 Hz), 3.72 (2H, m), 3.23 (2H, br d, J 6.7 Hz), 3.13 (2H, m), 2.71 (3H, s), 2.21 (2H, m), 1.78 (2H, m), and 1.44 (9H, s).
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([CH:8]([CH2:9][OH:10])[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC(CO)Cc1ccccc1

Procedure:
Accordingly, diethyl benzylmalonate (1) is reduced with lithium aluminum hydride to afford 2-benzyl-1,3-propanediol (2) which is treated with an equimolar amount of tert-butyldimethylsilyl chloride to give the monoprotected alcohol 3. Swern (dimethylsulfoxide/oxalyl chloride) oxidation of 3 provides the aldehyde 4 which is condensed with the Wittig reagent methyl (triphenylphosphonylidene) acetate to give 6. Conversion of the alcohol 6 to the mesylate 7 followed by azide displacement affords 8 which is sequentially reduced and Boc protected to give 9. Jones oxidation of the tert-butyldimethylsilyl ether 9 provides the Boc protected substituted ω-aminoalkenoic acid 10.
Reaction SMILES: [C:1]([N:8]1[CH2:15][S:14][CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[C:4]([O:3][C:1]([N:8]1[C@H:9]([CH2:10][OH:11])[CH2:13][S:14][CH2:15]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CSC[C@H]1CO
Temperature: 0 °C
Reaction time: 24 h
Yield: 53.1 %

Procedure:
A solution of 4.66 g (20 mmol) of N-Boc-thioproline and 3.84 mL (22 mmol) DIEA dissolved in 10 mL THF was cooled to 0_C and treated with 2.1 mL (22 mmol) of ethyl chloroformate. After 30 min at RT the white precipitate is filtered off, the solution cooled to 0° C. and a solution of 8.32 g (220 mmol) sodium borohydride in 30 mL H2O is added dropwise. The reaction was stirred for 24 h, then cooled to 0° C. and quenched by dropwise addition of acetic acid. The product was then extracted with EtOAc, the combined organics were washed successively with sodium bicarbonate and citric acid, dried with magnesium sulfate, filtered and solvents removed in vacuo to provide 2.33 g of the title compound: MS (ES+) m/e 242 (M+23), 120 (M-Boc+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.COCCOC>[C:13]1([C:2]2[CH:11]=[C:10]([CH3:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Cl)nc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1cc(-c2ccccc2)nc2ccccc12
Yield: 60.8 %

Procedure:
2-Chloro-4-methylquinoline (5.0 g, 30 mmol) and phenyl boronic acid (4.4 g, 36 mmol) were dissolved into 100 mL of ethylene glycol dimethyl ether. To the stirred reaction was added triphenylphosphine (0.8 g) and palladium(II) acetate, followed by 50 mL of a 2 M solution of potassium carbonate. The reaction was refluxed for 16 hours. After cooling, the aqueous layer was discarded and additional ethyl acetate added. The organics were washed with a saturated solution of sodium chloride and separated. The organic layer was dried over magnesium sulfate, concentrated, and purified on a silica gel column using 20% ethyl acetate and hexanes as the eluants. The pure fractions were combined and concentrated to give 2-phenyl-4-methylquinoline (4.0 g, 61% yield) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][F:30])[CH:24]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.[Br-].[Li+].N1CCNCC1>CN(C)C=O>[Br:10][C:6]1[CH:5]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][F:30])[CH:24]=4)=[CH:22][C:14]2=3)=[O:12])[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccc(CF)c4)cc32)cc1Br
Agent: C1CNCCN1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(-c3cccc(CF)c3)cc21

Procedure:
By the same method as in the step d) of Example 45, (3,5-dibromo-4-methoxy-phenyl)-[7-(3-fluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone (162 mg, 0.31 mmol), lithium bromide (108 mg, 1.24 mmol) and piperazine (40 mg, 0.47 mmol) were dissolved in N,N-dimethyl formamide (3 ml) and reacted at 100□ to obtain the target compound 64, i.e., (3,5-dibromo-4-hydroxy-phenyl)-[7-(3-fluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone, as white solid (69.4 mg, 44%).
Reaction SMILES: ClCl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][S:13][C:14]1SC2C=CC=CC=2N=1.S[CH:24]([OH:26])C>ClC1C=CC=CC=1>[OH:26][CH2:24][CH2:14][S:13][S:12][C:4]1[S:3][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: CC(O)S
Reactant: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1
Agent: ClCl
Solvent: Clc1ccccc1
Product: OCCSSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 7 h
Yield: 167.6 %

Procedure:
Chlorine gas (17.5 g/0.25 mole) was passed at 0 to 50C into a suspension of 2,2'-dithiobisbenzthiazole (83 g/0.25 mole) in chlorobenzene (600 ml). Mercaptoethanol (39 g/0.5 mole) was then added drop-wise to this solution, followed by stirring for 7 hours at room temperature. The precipitated product was filtered off, mixed with methylene chloride (500 ml) and washed with 5% NaHCO3 solution (500 ml). The organic phase was concentrated by evaporation. A yellowish-brown oil (102 g) was obtained, which crystallised after a short time. m.pt.: 65 to 68° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:24]=1.[F:25][C:26]1[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[CH2:22]([C:19]1[CH:18]=[N:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([C:27]5[CH:28]=[CH:29][C:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:31][C:26]=5[F:25])=[CH:24][C:6]=4[N:7]=3)[CH2:11][CH2:12]2)=[N:21][CH:20]=1)[CH3:23]
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
Reactant: CCc1cnc(N2CCC(c3nc4cc(Br)ccc4o3)CC2)nc1
Product: CCc1cnc(N2CCC(c3nc4cc(-c5ccc(S(C)(=O)=O)cc5F)ccc4o3)CC2)nc1
Yield: 29.7 %

Procedure:
Following the General Procedure-1, the titled compound (30 mg) was prepared from Intermediate 6 (80 mg, 0.21 mmol) and Intermediate 3 (80 mg, 0.27 mmol) as an off-white solid. M.P.: 247-250° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.20 (s, 2H), 7.86 (s, 1H), 7.80 (m, 1H), 7.79-7.74 (m, 1H), 7.66 (t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H), 4.75 (d, J 13.4, 2H), 3.35-3.15 (m, 3H), 3.11 (s, 3H), 2.47 (q, J 7.6, 2H), 2.31-2.22 (m, 2H), 2.09-1.94 (m, 2H), 1.20 (t, J 7.6, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])=[O:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>>[CH2:5]([O:4][C:2](=[O:3])[NH:7][C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:21])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])[CH2:18][CH2:19]2)=[CH:10][CH:9]=1)[CH3:6]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 7, making variations only as required to use ethyl chloroformate in place of n-butyl chloroformate to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a light yellow solid (35% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.30, 7.82-7.85, 7.76, 7.67, 7.52, 7.37, 4.15, 3.15-3.85, 1.10. MS (ES+) m/z 424 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:4]=1)=[O:18]
Reactant: CSc1ncc(Cl)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ncc(Cl)cn1
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 2-methylthio-5-chloropyrimidine (13 mmol) in chloroform (85 ml) was cooled to -20° C. and m-chloroperbenzoic acid (17 mmol) added with stirring. The mixture was stirred for 40 min at -20° C. and for 4 h at 0° C. and left at this temperature overnight. The chloroform solution was then washed with 1 M potassium carbonate (3×10 ml) and the dried (MgSO4) solution evaporated. The residual oily material crystallized on standing; yield 80% m.p. 48° C. (n-heptane). 1H NMR (CDCl3): δ2.93 (Me), 8.83 (2H-4,6).