Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:21]1CCO[CH2:23][CH2:22]1.ClC(OCC(C)C)=O.C(N)C>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:21][CH2:22][CH3:23])=[O:12])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Cl)cc1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: C1CCOC1
Product: CCNC(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: -25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
To 1.1 g (3.85 mM) of [(tert-butoxycarbonyl)amino](4-chlorophenyl)acetic acid in 10 ml of tetrahydrofurane were added, under stirring at −25° C., 0.5 ml (4.6 mM) of 4-methyl morpholine and 0.52 ml (4.0 mM) of isobutyl chloroformate. After 10 mn were then added, at −25° C. under stirring, 1.9 ml (3.85 mM) of ethylamine 2M in tetrahydrofurane. The reaction mixture was stirred at −25° C. for 1 h, and at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give an oil, which was further purified by silica gel column chromatography, using dichloromethane/cyclohexane (75/25) as eluant, to give 520 mg of tert-butyl 1-(4-chlorophenyl)-2-(ethylamino)-2-oxoethylcarbamate as a white solid.
Reaction SMILES: C(=O)([O-])OC[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Br:13])=[CH:6][C:5]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-:22].[K+].Cl>CO>[Br:13][C:7]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]([OH:22])=[C:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=1
Reactant: [OH-]
Reactant: O=C([O-])OCc1cc([N+](=O)[O-])c(Br)cc1C1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1cc(O)c(C2CCCCC2)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a solution of (4-bromo-2-cyclohexyl-5-nitro-phenyl)methyl carbonate (1.5 g, 4.2 mmol) in methanol (15 mL) was added KOH (353 mg, 6.3 mmol) portionwise at 0° C. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was acidified with 1N HCl. The solvent was evaporated and water was added. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to give 4-bromo-2-cyclohexyl-5-nitrophenol (1.2 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.39 (s, 1H), 5.10 (s, 1H), 2.90-2.83 (m, 1H), 1.91-1.89 (m, 4H), 1.83-1.80 (m, 1H), 1.51-1.24 (m, 5H)
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([CH:12]2[N:17]3[C:18](=[O:31])[CH:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]2([Cl:33])[CH3:32])=[O:11])=CC=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[O:23]([CH2:22][C:21]([NH:20][CH:19]1[C:18](=[O:31])[N:17]2[CH:12]([C:10]([OH:11])=[O:9])[C:13]([Cl:33])([CH3:32])[CH2:14][S:15][C@H:16]12)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: CC1(Cl)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(Cl)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Yield: 51.5 %

Procedure:
In 30 ml of ethyl acetate was dissolved 470 mg of 7-phenoxyacetoamido-3-chloro-3-methyl-cepham-4-carboxylic acid p-nitrobenzylester. To the solution was added 470 mg of 5% palladium-charcoal and the solution was stirred for 19 hours in a stream of hydrogen. After the catalyst was filtered off from the reaction mixture, the filtrate was extracted with 50 ml of 2% aquous sodium hydrogencarbonate solution. After the aqueous layer was separated and adjusted to pH 2 by adding diluted hydrochloric acid, the aqueous layer was extracted again with ethyl acetate. The ethyl acetate layer was washed with water, dried and distilled under reduced pressure. There was obtained 179 mg of 7-phenoxyacetoamido-3-chloro-3-methyl-cepham-4-carboxylic acid as a colourless powder (yield, 15%). The following NMR spectra agreed with those expected from the anticipated structure:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(=O)=O.[Br-:14].[Li+]>CC(C)=O>[Br:14][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: [Br-]
Reactant: CS(=O)(=O)OCCC1CCOCC1
Agent: [Li+]
Solvent: CC(C)=O
Product: BrCCC1CCOCC1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
To 2-(tetrahydro-2H-pyran-4-yl)ethyl methanesulfonate (5.4 g) in dry acetone at room temperature was added lithium bromide (9 g) in one go. The reaction was heated to reflux for 4 hours, under nitrogen. The reaction was cooled to room temperature and concentrated in vacuo. The residue was taken up in dichloromethane (100 ml) and washed with water (50 ml). The organic layer was dried by passing through a hydrophobic frit, and concentrated in vacuo. The product was purified by silica chromatography (40 g) (ISCO) using a gradient elution of 0-50% cyclohexane:ethyl acetate to afford the title compound as a colourless oil (3.5 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]3=[O:18])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19].[F:20][C:21]([F:30])([F:29])[C:22]1[S:26][CH:25]=[C:24]([CH2:27]O)[CH:23]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:27][C:24]4[CH:23]=[C:22]([C:21]([F:30])([F:29])[F:20])[S:26][CH:25]=4)=[CH:13][C:12]3=[O:18])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19]
Reactant: Cc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1csc(C(F)(F)F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)c4)cc3=O)cc2n1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a suspension of 1-(1,2-dimethyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg) in THF (5 ml) were added (5-(trifluoromethyl)thiophen-3-yl)methanol (78 mg), 1,1′-(azodicarbonyl)dipiperidine (128 mg) and tributylphosphine (0.13 ml) at room temperature, and the mixture was stirred at 50° C. overnight. After cooling, the mixture was purified by NH silica gel column chromatography (EtOAc/MeOH). The same reaction was conducted, and the combined products were purified by preparative HPLC (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (129 mg) as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH2:29][CH:30]=[O:31])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1)[CH3:18].[NH4+].[Cl-]>C(OCC)C>[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH2:29][CH:30]([OH:31])[CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:9]=3)[CH2:27][CH2:28]2)=[CH:22][CH:21]=1)[CH3:18]
Reactant: CCOc1ccc(C2(CC=O)CC2)cc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOc1ccc(C2(CC(O)Cc3cccc(Oc4ccccc4)c3)CC2)cc1
Temperature: -78 °C

Procedure:
A Grignard reagent prepared from 3-phenoxybenzyl bromide (0.98 g), magnesium turnings (0.1 g) in dry diethyl ether (15 ml) under an atmosphere of nitrogen, is cooled with vigorous stirring to -78° C. To this is added a solution of 1-(4-ethoxyphenyl)-1-(2-oxoethyl)-cyclopropane (0.5 g) in diethyl ether (15 ml) over 5 min. The resulting mixture is allowed to warm up to room temperature over 1 h. Saturated NH4Cl solution is added and the mixture extracted with diethyl ether (x3), dried and the solvent evaporated under reduced pressure. The product is purified by t.l.c. on silica eluted with 10% diethyl ether in petroleum ether (b.p. 60°-80° C.). Yield 0.25 g, nD 1.5444.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH2:25][CH3:26])=[CH:23][N:22]([CH3:27])[C:21]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:19])[CH3:16]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:23]2[N:22]([CH3:27])[C:21]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[C:24]=2[CH2:25][CH3:26])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(CC)cn1C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(CC)c(C(=O)c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 13.8 g. (0.0788 mole) of ρ-chlorobenzoyl chloride and 10.5 g. (0.0788 mole) of aluminum chloride in 120 ml. of 1,2-dichloroethane is added to a refluxing soluton of 21.8 (0.0788 mole) of ethyl 3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate. The mixture is heated under reflux for 10 hours and stirred at room temperature for an additional 10 hours. It is then poured into ice-hydrochloric acid. The organic layer is separated and the aqueous layer washed with 1,2-dichloroethane. The combined organics are washed successively with water, N,N-dimethylaminopropylamine, dilute HCl and brine. The colution is then dried over anhydrous magnesium solfate and the solven evaporated in vacuo. The residual red oil residue crystallized on standing. It is recrystallized twice from methanol to give ethyl (5-ρ-chlorobenzoyl)-3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate as a white solid, M.P. 72°-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[CH:9]([OH:10])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C=O)c1cccc(Cl)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)C(C)(C)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a stirred solution of 2-(3-chlorophenyl)-2-methylpropanal (4.6 g, 25.7 mmol) in THF (150 mL) at 0° C. was added MeMgBr (3M in ether, 17.1 mL, 51.3 mmol, 2 eq) dropwise over 2 h. After stirring 1 h at 0° C., the reaction was allowed to warm to room temperature, quenched with 1N HCl and then extracted with EtOAc. The extracts were dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography (silica, Hex/EtOAc=20:1 to 10:1) to give 3-(3-chlorophenyl)-3-methylbutan-2-ol (3.9 g, 78%). 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.28 (m, 2H), 7.18 (m, 1H), 3.85 (q, 1H), 1.32 (d, J=6.4 Hz, 6H), 1.05 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>O=S(Cl)Cl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:23][C:22]1[CH:24]=[CH:25][C:19]([Cl:18])=[CH:20][CH:21]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 6-acetoxy-7-methoxy-quinazolin-4-one (RO0505111-000) (1.0 g, 4.26 mmol) (from Example 15, Step A, supra) in SOCl2 (12.5 mL) (Aldrich) was added a few drops of DMF (0.1 mL). The reaction mixture was then heated with stirring at 100° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (20 mL), then 4-chloroaniline (0.6 g, 4.69 mmol) (Fluka) was added. The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give 6-acetoxy-4-(4-chloro-phenylamino)-7-methoxy-quinazoline as a gray solid. (Yield 1.45 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29](O)[C:28]=4[C:35]=3[CH3:36])[CH2:20][CH2:19]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]>CO>[C:2]1([NH:1][CH:29]2[C:28]3[C:35]([CH3:36])=[C:24]([N:21]4[CH2:20][CH2:19][CH:18]([C:12]5[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][CH3:8])[CH:11]=5)[CH2:23][CH2:22]4)[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]=3[O:31][C:30]2([CH3:33])[CH3:32])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1OC
Solvent: CO
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(Nc3ccccc3)C(C)(C)O4)CC2)cc1OC
Yield: 60 %

Procedure:
Using aniline and 5-(4-(3,4-dimethoxyphenyl)piperidino)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 19, the title compound was synthesized in the same manner as in Example 58. Yield 60%. mp. 138–140° C. (methanol).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[CH2:14]([O:13][C:11]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Product: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
The amino group of L-aspartic acid was protected as in Example 2 using benzyl chloroformate, to form N-benzyloxycarbonyl-L-aspartic acid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6](O)[CH2:7][CH2:8][CH3:9]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCCCO
Reactant: C=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CC(=O)OCCCC

Procedure:
The following tests were carried out on the residue stream drawn from the base of a continuously-operating still-reactor column within which n-butanol and acrylic acid were being reacted in the presence of para-toluenesulfonic acid catalyst to form butyl acrylate. Acrylic acid and n-butanol were continuously introduced into the base section of the column, where they were mixed into a continuously-circulating stream drawn from the base of the column which then passed through a reboiler and was reintroduced into the column below the first tray. The esterification reaction took place in the base of the column, from which there was a small continuous drawoff of refractory tars.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:3]1[S:4][C:5]([CH:8]=O)=[CH:6][N:7]=1.[NH2:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:3]1[S:4][C:5]([CH2:8][NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[CH:6][N:7]=1
Reactant: CN(c1ncc(C=O)s1)C1CCCCO1
Reactant: Nc1nccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(c1ncc(CNc2nccs2)s1)C1CCCCO1
Yield: 14.6 %

Procedure:
A solution of 2-(methyl(tetrahydro-2H-pyran-2-yl)amino)thiazole-5-carbaldehyde (250 mg, 1.10 mmol) and 2-aminothiazole (110 mg, 1.10 mmol) in toluene (11 mL) and molecular sieves 3 Å were stirred at reflux overnight. The strongly yellow solution of the corresponding imine was then poured over NaBH4 (212 mg, 5.61 mmol) in hot EtOH (80 mL). The colorless solution was filtered, concentrated and purified by column chromatography yielding N-methyl-N-(tetrahydro-2H-pyran-2-yl)-5-((thiazol-2-ylamino)methyl)thiazol-2-amine (50 mg, 17%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Reactant: C1CCNC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(N5CCCC5)nc4)ccc2OCC3)c(F)c1
Temperature: 150 °C
Yield: 5.9 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene, from the procedure for 249, (470 mg, 1.0 mmol), Pyrrolidine (85 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 294 (31.3 mg, yield: 5.9%). 1HNMR (DMSO-d6, 400 MHz): δ8.81 (s, 1H), 8.38 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.98-7.97 (m, 1H), 7.78-7.77 (m, 1H), 7.76-7.78 (m, 2H), 7.46-7.40 (m, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.51 (t, J=8.8 Hz, 1H), 7.48 (t, J=4.4 Hz, 1H), 7.26 (s, 1H), 6.60 (d, J=8.8 Hz, 1H), 4.38 (s, 2H), 3.54 (s, 3H), 3.22 (s, 2H), 2.07 (s, 4H). ESI-MS: m/z=529 [M+H+]
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:10]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:9]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(-c2ccccc2)ns1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To a solution of benzamidine hydrochloride (5.00 g, 31.9 mmol) and perchloromethyl mercaptan (3.43 ml, 39.2 mmol) in dichloromethane (32 ml) was added dropwise a solution of sodium hydroxide (6.38 g, 160 mmol) in water (13 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.90 g (46.2%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:4][CH:3]=1.[CH3:26][N:27](C=O)C>CCOC(C)=O.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.[C-]#N.[Zn+2].[C-]#N>[CH3:24][N:21]1[CH2:22][CH2:23][C:11]2[N:10]([CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([C:26]#[N:27])=[N:7][CH:6]=3)[OH:25])[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]=2[CH2:20]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(Br)nc2)CCN(C)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C#N)nc2)CCN(C)C1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a degassed solution of 1-(6-bromo-pyridin-3-yl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanol (1 g, 2.5 mmol) in DMF (10 mL) were added Pd(PPh3)4 (0.173 g, 0.15 mmol) and zinc cyanide (585 mg, 5.0 mmol) and the reaction mixture was stirred at 150° C. for 2 h. The reaction mixture was cooled to RT, diluted with EtOAc (250 mL) and filtered. The filtrate was washed with water (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 5-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-pyridine-2-carbonitrile (350 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.55 (s, 1H), 7.38 (d, 1H), 7.23 (d, 1H), 6.93 (s, 1H), 6.81 (s 1H), 6.74 (s,1H), 4.96 (m, 1H), 4.11 (dd, 2H), 3.29 (dd, 2H), 2.95 (m, 1H), 2.88 (m 1H), 2.86 (m, 2H), 2.5 (s, 6H). Separation by chiral HPLC provided enantiomers 140a and 140b.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](OC(=O)C)(=O)[CH3:14].[OH-].[Na+]>Cl>[CH3:13][C:14]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cnc2ccccc2c1S
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2cnc3ccccc3c2s1
Reaction time: 1 h

Procedure:
A mixture of 17.62 g (0.1 mole) of 3-amino-4-mercapto-quinoline and 70 ml of acetic anhydride is heated slowly to the boiling point and thereafter heated to boiling for one hour and a half. The reaction mixture is cooled and 600 ml of 1% hydrochloric acid are added dropwise under vigorous stirring. The homogenous solution is made alkaline with a sodium hydroxide solution and the precipitated base is extracted three times with 100 ml of benzene each. The united benzene extracts are clarified, dried and evaporated in vacuo. Thus 2-methyl-thiazolo[4,5-c]quinoline is obtained, m.p.: 99°-100° C. (after recrystallization from a mixture of methanol and water).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:28])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(SCc2ccc(F)cc2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(S(=O)Cc2ccc(F)cc2)CC1
Yield: 96.7 %

Procedure:
Using a similar method to that described in Example 107, step 1, 1-(tert-butoxycarbonyl)-4-(4-fluorobenzylthio)piperidine (1.5065 g, 4.63 mmol) was reacted with 57-86% 3-chloroperoxybenzoic acid (1.0190 g) in dichloromethane (100ml) to give 1.5287 g (97%) of the title compound as a white solid. δH (250 MHz, CDCl3) 1.46 (9H, s), 1.64-1.82 (3H, m), 2.02 (1H, m), 2.63 (1H, m), 2.81 (2H, m), 3.88 (1H, d, J=13.2 Hz), 3.98 (1H, d, J=13.2 Hz), 4.21 (2H, m), 7.08 (2H, t, J=8.6 Hz), 7.29 (2H, m); m/e (ES+) 683 (2M+H)+, 342 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C1(C)C=CC=CC=1.[NH2-].[Na+]>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:7]#[N:8]
Reactant: N#CCc1cccs1
Reactant: Clc1ccccn1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(c1ccccn1)c1cccs1
Temperature: 60 °C

Procedure:
To a well-stirred solution containing 61.5 g. of 2-thienylacetonitrile and 56.5 g. of 2-chloropyridine in 400 ml. of toluene, slowly add a stirred suspension of 40 g. of sodamide in 300 ml. of toluene keeping the reaction temperature at 60°-65° C by cooling with an ice bath. After completing the addition maintain the temperature at 60° C for 2 hrs., add 200 ml. of water to the cooled reaction mixture, decant the tarry by-products and separate the aqueous layer. Evaporate in vacuo the resulting solution and dilute the thick black residue with 300 ml. of ether. Filter the separated solid and evaporate the filtrate. The desired product is distilled off at 145°-150° C/1 ml. and is recrystallized from alcohol to yield α-(2-thienyl)-2-pyridylacetonitrile, m.p. 48°-50° C.