Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(OC)=CC=1.C(O)(=O)C.O.[Na+].[Br-].[C:17](O)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>[Ti]>[CH:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)O)cc1
Agent: [Ti]
Agent: [Br-]
Agent: [Na+]
Solvent: COc1ccc(C)cc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C=O)cc1
Temperature: 121.11111111111111 °C
Reaction time: 0.5 h

Procedure:
Two hundred and thirty (230) g. (1.89 moles) p-methylanisole, 399 g. (6.65 moles) acetic acid, 21 g. (1.17 moles) water, 1.73 g. (0.007 moles) Co(OAc)2 0, 1.7 g. (0.007 moles) Mn(OAc)2.4H2 0 and 1.4 g. (0.014 moles) NaBr were combined in a two-liter titanium-clad autoclave. The reactor was heated to 250° F. and pressurized to 150 psi. The air rate was ramped up to reach a value of 0.78 scf/min after 15 minutes. During the oxidation the temperature and pressure were gradually increased to reach final values of 324° F. and 250 psi. The oxidation was complete after 30 minutes. Analysis of the reaction mixture showed p-anisic acid, 85 mole % yield, and p-anisaldehyde, 1.2 mole % yield.
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl.O>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:17][CH:16]=2)=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(CCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(CCc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
4-Phenethylbenzoic acid (30 mg, 0.13 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (103 mg, 0.27 mmol) was dissolved in dichloromethane (20 mL), and then added triethylamine (2 mL) was added. After the mixture were stirred at 25° C. for 0.5 hour, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (20 mg, 0.13 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (15 ml) was added. And the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-phenethylbenzamide (10 mg, 21%). LRMS (M+H+) m/z: calcd 360.18. found 360. HPLC purity (214 nm): 94%. 1H NMR (300 MHz, CD3OD): δ 7.67 (d, J=8.7 Hz, 2H), 7.24-7.12 (m, 7H), 6.10 (s, 1H), 4.48 (s, 2H), 2.95-2.91 (m, 4H), 2.36 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].[CH3:9][C:10]1([CH3:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][CH2:12][CH2:11]1>[N+](C1C=CC=CC=1)([O-])=O>[CH3:9][C:10]1([CH3:20])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:1](=[O:3])[CH3:2])[CH:18]=2)[O:13][CH2:12][CH2:11]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CCOc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
3.4 g of acetyl chloride were dissolved in 30 ml of nitrobenzene and the solution was treated portionwise at 0°-5° C. with 5.7 g of aluminium trichloride. To this mixture was added dropwise at 0°-5° C. a solution of 6.9 g of 4,4-dimethylchromane in 15 ml of nitrobenzene. After stirring for 1 hour, the mixture was poured into ice/water, extracted with ether, the organic phase was washed with 1N sodium hydroxide solution and a saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residual black oil was distilled in a high vacuum. There were obtained 5.1 g of 4,4-dimethyl-6-acetylchromane in the form of a bluish oil of boiling point 110° C./0.02 mmHg.
Reaction SMILES: [N:1]([CH:4]([CH3:21])[CH2:5][N:6]1[C:14]2[C:13]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=3[CH2:11][CH2:10][C:9]=2[CH:8]=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:12]2[CH2:11][CH2:10][C:9]3[CH:8]=[N:7][N:6]([CH2:5][CH:4]([NH2:1])[CH3:21])[C:14]=3[C:13]=2[CH:15]=1
Reactant: COc1ccc2c(c1)-c1c(cnn1CC(C)N=[N+]=[N-])CC2
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Solvent: CCOCC
Product: COc1ccc2c(c1)-c1c(cnn1CC(C)N)CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
1 g (3.5 mmol) of (RS)-1-(2-azido-propyl)-4,5-dihydro-8-methoxy-1H-benz[g]indazole dissolved in 50 ml of anhydrous ethanol was hydrogenated over 100 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 70 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 406 mg (3.5 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 0.98 g (75%) of (RS)-2-(4,5-dihydro-8-methoxy-1H-benz[g]indazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 174°-176° was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:15]=3[O:14][C:13]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:10])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C)C=O.O>[C:44]([O:43][C:41]([CH2:40][O:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([NH:11][C:9]([C@H:6]3[CH2:5][CH2:4][C@H:3]([N:2]([CH3:32])[CH3:1])[CH2:8][CH2:7]3)=[O:10])=[C:13]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=3)=[O:23])[O:14][C:15]=2[CH:20]=1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cc(O)ccc23)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cc(OCC(=O)OC(C)(C)C)ccc23)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-6-hydroxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (90 mg) obtained in Example 151 is dissolved in N,N-dimethylformamide (2 ml), and thereto are added cesium carbonate (110 mg) and t-butyl bromoacetate (35.5 μl). The mixture is stirred at room temperature for 12 hours, and further stirred at 50° C. for 2.5 hours. The reaction solution is allowed to stand for cooling, and diluted with water, and extracted with ethyl acetate. The organic layer is concentrated under reduced pressure, and the resulting residue is purified by NH-silica gel column chromatography (eluent: hexane/ethyl acetate=1/1, then ethyl acetate) to give the title compound (21 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22](O)[CH2:23][CH:24]=[CH:25][CH2:26][CH:27]=[CH:28][CH2:29][CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(#N)C>[Br:20][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: BrBr
Reactant: CCCCCC=CCC=CCC=CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCCCC/C=C\C/C=C\C/C=C\CCBr
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To a 250 mL three-necked round bottom flask was added under nitrogen 9.46 g (36.1 mmol) of triphenylphosphine dissolved in 150 mL of anhydrous acetonitrile. After cooling to 0° C. (ice-salt bath), bromine (5.77 g, 36.1 mmol) was added dropwise with stirring. The mixture was warmed to room temperature and stirred for 30 minutes. 3,6,9-Pentadecatrienol (6.16 g, 27.75 mmol); dissolved in 50 mL of anhydrous acetonitrile, was added dropwise (15 minutes) and stirred for approximately 4 hours. Upon reaction completion acetonitrile was removed in vacuo and the residue was dissolved in 75 mL of ether. Hexanes were utilized to precipitate the triphenylphosphorane side product which was removed by filtration. The crude residue, obtained after concentration of the filtrate in vacuo, was purified over silica gel using ethyl acetate:hexanes (1:9) as eluant. The product 7.0 g (90%) was obtained as a light yellow oil. IR (neat,cm-1) 2958, 2927, 1652, 1267, 723;1H NMR (CDCl3) δ 5.69-5.28 (m, 6H), 3.38 (t, J=7.1 Hz, 2H), 2.89-2.75 (m, 4H), 2.75-2.52 (m, 2H), 2.12-1.93 (m, 2H), 1.49-1.31 (m, 6H), 0.89 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3) δ 131.0, 130.6, 128.9, 127.4 (2C), 126.3, 32.2, 31.5, 30.9, 29.3, 27.3, 25.8, 25.7, 22.6, 14.0; HRMS calculated for C15H25Br (M+) 284.1139, found 284.1101.
Reaction SMILES: I[CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[C@H:5]([F:16])[C@@H:4]1[OH:17].[OH-].[NH4+].[H][H]>C(O)C.[Pd]>[F:16][C@@H:5]1[C@H:4]([OH:17])[C@@H:3]([CH3:2])[O:7][C@H:6]1[N:8]1[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10]
Reactant: [H][H]
Reactant: O=c1ccn([C@@H]2O[C@H](CI)[C@@H](O)[C@H]2F)c(=O)[nH]1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](F)[C@@H]1O
Reaction time: 5 h

Procedure:
2′,5′-Dideoxy-5′-iodo-2′-fluorouridine (2.9, 8.1 mmoles) was dissolved in 95% ethanol (25 mL). Ammonium hydroxide (1.1 mL, 16.2 mmoles, 2 eq.) was added followed by 10% Pd/C (Aldrich, 0.1 g). Reaction under 50 psi hydrogen was carried out for 5 hours. The mixture was filtered and the pH adjusted to 7 with 1N HCl. The solvents were removed in vacuo and the residue dissolved in water. The product was extracted with ethyl acetate (3×). The ethyl acetate solution was dried with MgSO4, filtered, and the solvent removed in vacuo. The residue was purified by chromatography on 100 g of silica gel eluted with ethyl acetate. The product containing fractions were combined and the solvents removed in vacuo. The yield was 1.1 g, 58%. MS (APCl(−)): m/z (rel. intensity) 229 (100%, M−); 1H NMR (DMSO-d6) δ7.54 (d, 1H, H6, J=8 Hz), 5.76 (d, 1H, H-1′, J=22 Hz), 5.59 (d,1H, H5, J=8 Hz), 5.55 (d, 1H, OH, J=6 Hz), 5.05 (d, 1H, H-2′, J=53 Hz), 3.8 (m, 2H), 1.27 (d, 3H, H-5′, J=6 Hz).
Reaction SMILES: [CH:1]1([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.[CH3:16][C:17]1[S:18][C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:20]([C:22](O)=[O:23])[N:21]=1>>[CH3:16][C:17]1[S:18][C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:20]([C:22]([N:2]2[CH2:3][CH:4]3[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:1]2[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:23])[N:21]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Reactant: CCOC(=O)CC1NCC2CCCCC21
Product: CCOC(=O)CC1C2CCCCC2CN1C(=O)c1nc(C)sc1-c1ccccc1

Procedure:
Ethyl 2-(2-(2-methyl-5-phenylthiazole-4-carbonyl)octahydro-1H-isoindol-1-yl)acetate was prepared according to general procedure A using ethyl 2-(octahydro-1H-isoindol-1-yl)acetate and 2-methyl-5-phenylthiazole-4-carboxylic acid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][C:20]=4[O:33][CH3:34])=[C:14]([CH2:35][CH2:36][CH3:37])[N:13]4[N:38]=[CH:39][CH:40]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][C:20]=3[O:33][CH3:34])=[C:14]([CH2:35][CH2:36][CH3:37])[N:13]3[N:38]=[CH:39][CH:40]=[C:12]23)[CH2:9][CH2:10]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2OC)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2OC)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-methoxybiphenyl-2-carbonitrile (1.1 g) in tetrahydrofuran (10 mL) was added 3M hydrochloric acid (10 mL), and the mixture was stirred at 60° C. for 5 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 8M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (10 mL)-tetrahydrofuran (10 mL). Thereto was added sodium borohydride (0.075 g) at 0° C. After stirring for 2 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.93 g, 95%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.Cl.CN(C)CCCN=C=NCC.O.N1(O)C2C=CC=CC=2N=N1.[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1[O:47][CH:48]([CH3:50])[CH3:49])[C:40]([NH:42]O)=[NH:41]>CN(C=O)C.O>[Cl:36][C:37]1[CH:38]=[C:39]([C:40]2[N:42]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[CH:2][NH:1]4)[O:12][N:41]=2)[CH:44]=[CH:45][C:46]=1[O:47][CH:48]([CH3:50])[CH3:49]
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: CC(C)Oc1ccc(C(=N)NO)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(-c2noc(-c3cccc4[nH]ccc34)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
Under an atmosphere of nitrogen a mixture of 1H-indole-4-carboxylic acid (3.88 g, 24.05 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (4.61 g, 24.05 mmol) and benzotriazol-1-ol hydrate (3.68 g, 24.05 mmol) in anhydrous DMF (61.4 ml) was stirred at ambient temperature for about 1 h. To the reaction mixture a solution of 3-chloro-N-hydroxy-4-isopropoxybenzamidine (5.0 g, 21.87 mmol) in DMF (11.51 ml) was added. The mixture was stirred and heated at about 140° C. for about 2 h. The mixture was cooled to ambient temperature and poured into water (IL). The product was partitioned between ethyl acetate and the aqueous phase. The organic layer washed with 1N HCl (4×150 mL), 1N NaOH (2×150 mL) and water (2×300 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the crude product was purified by elution through Florisil with heptane/ethyl acetate (2:1) to give 3-(3-chloro-4-isopropoxyphenyl)-5-(1H-indol-4-yl)-1,2,4-oxadiazole (2.76 g, 35.7%). LCMS (Table 1, Method b) Rt=2.69 min, m/z 354.17 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccc(Cl)c2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A for Example 13i, and 3-chlorobenzenesulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 mL) and 0.28 mL was added to the reaction mixture. MS 585 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C@@H]3C[C@H](C)CC[C@H]3C(C)C)[C:6]3[CH2:21][CH:22]4[NH:26][CH:25]([C:5]=3[C:4]=2[C:3]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:23]4.O.[OH-].[Li+]>O1CCCC1.CO.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:21][CH:22]4[NH:26][CH:25]([C:5]=3[C:4]=2[C:3]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:23]4
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1n1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)c1c(Br)ccc2[nH]c3c(c12)C1CCC(C3)N1
Reaction time: 2.5 h
Yield: 92.1 %

Procedure:
To a solution of the product from step E (8.51 g, 15.23 mmol) in tetrahydrofuran (102 mL) and MeOH (51 mL) was added a solution of lithium hydroxide monohydrate (1.92 g, 45.69 mmol) in water (25 mL) at ambient temperature. The mixture was stirred vigorously for 2.5 h, quenched with aqueous saturated NH4Cl solution (75 mL), and extracted with ethyl acetate (2×200 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate, 70:30) to afford (+)-tert-butyl 2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (5.29 g, 92%) as a white solid: [α]D=+142.4° (c 0.33, MeOH); 1H NMR (CDCl3, 300 MHz) δ 7.93 (s, 1H), 7.61 (d, J=0.9 Hz, 1H), 7.11-7.23 (dd, J=16.8, 8.4 Hz, 2H), 5.14 (s, 1H), 4.65 (s, 1H), 3.28-3.57 (m, 1H), 2.47 (d, J=16.2 Hz, 1H), 2.10-2.38 (m, 2H), 1.88-1.98 (m, 1H), 1.54-1.70 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:20][CH2:19][CH2:18][C@@H:17]3[N:12]2[C:13](=[O:21])[CH2:14][CH:15]=[CH:16]3)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[H][H]>CO.[Pt]=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:20][CH2:19][CH2:18][C@@H:17]3[N:12]2[C:13](=[O:21])[CH2:14][CH2:15][CH2:16]3)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc([C@H]2CCC[C@H]3C=CCC(=O)N32)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: COC(=O)c1ccc([C@H]2CCC[C@H]3CCCC(=O)N32)cc1
Yield: 85.6 %

Procedure:
Platinum oxide (10 mg) was added to a solution of (6R*,9aS*)-6-(4-carbomethoxyphenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (145 mg) in methanol (5 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for three hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 125 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: ClC1N=C(C2C=CC(SN)=CC=2)C=CN=1.[Cl:16][C:17]1[N:22]=[C:21]([S:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH:20]=[CH:19][N:18]=1.[C:31](O)(=[O:34])[CH:32]=[CH2:33]>>[Cl:16][C:17]1[N:22]=[C:21]([S:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])=[CH:28][CH:29]=2)[CH:20]=[CH:19][N:18]=1
Reactant: C=CC(=O)O
Reactant: Nc1ccc(Sc2ccnc(Cl)n2)cc1
Agent: NSc1ccc(-c2ccnc(Cl)n2)cc1
Product: C=CC(=O)Nc1ccc(Sc2ccnc(Cl)n2)cc1
Yield: 55.9 %

Procedure:
In a procedure analogous to Example 15, reaction of 4-(2-chloropyrimidin-4-ylthio)benzenamine 2-chloro-4-(4′-aminothiophenyl)pyrimidine (800 mg, 3.37 mmol) and acrylic acid (463 μL, 6.74 mmol) furnished the product (550 mg, 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].[Br:16]C1CC(=O)NC1=O.C1(=O)NC(=O)CC1>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC=C(C(=O)OC)c1ccccc1C
Reactant: O=C1CC(Br)C(=O)N1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(C(=O)OC)c1ccccc1CBr
Temperature: 90 °C
Yield: 97.3 %

Procedure:
20.6 g of the methyl α-(2-methylphenyl)-β-methoxyacrylate obtained as described in Method A, 17.65 g of bromosuccinimide, 0.2 g of azobisisobutyronitrile and 150 ml of CCl4 are slowly heated to 90° C. and kept at this temperature until all the succinimide floats on the solvent. The mixture is filtered, the filtrate is evaporated down, the remaining oil is dissolved in about 5 ml of acetone and the solution is brought to crystallization with n-hexane. 27.5 g of colorless crystals of melting point 86°-87° C. are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:23]C(=O)OC(C)(C)C)[C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[CH:2]1.[ClH:31]>C(OCC)(=O)C>[ClH:31].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[NH2:23])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)cs1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)cs1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To (1.2 g, 2.85 mmol) of tert-butyl (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1,3-thiazol-2-yl)ethylcarbamate was added ethyl acetate (10 ml) and 20 ml of a 1N HCl solution in ethyl acetate. The solution was stirred for about 2 hours at about 20° C. followed by about 2 hours at about 50° C. The crystals which formed on cooling were collected by filtration and washed with diethyl ether to give 1 g of the title product as an orange powder. Melting point: 170-172° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH2:4][CH2:3]1.I.CS[C:21]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)=[NH:22]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[NH:22])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH2:4][CH2:3]1
Reactant: CN1CCC(n2ccc3cc(N)ccc32)CC1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CN1CCC(n2ccc3cc(NC(=N)c4cccs4)ccc32)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 56.2 %

Procedure:
Compound 81 (100 mg, 0.436 mmol) is charged to a small, argon purged flask fitted with a magnetic stir bar. Anhydrous ethanol (7 mL) and thiophene-2-carboximidothioic acid methyl ester hydroiodide (217.6 mg, 0.763 mmol) are added to the flask and the reaction was stirred under argon at ambient temperature for 23 hours, at which time the solvent was evaporated and the residue was partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95 to 7.5:92.5) to yield a yellow solid, 82 (83 mg, 56.2%). 1H NMR (DMSO-d6) δ 1.85-2.05 (m, 4H), 2.10-2.19 (m, 2H), 2.24 (s, 3H), 2.90 (d, 2H, J=11.4 Hz), 4.20-4.32 (m, 1H), 6.25 (br s, 2H), 6.35 (d, 1H, J=3.0 Hz), 6.69 (dd, 1H, J=9.8, 1.4 Hz), 6.98 (s, 1H), 7.07-7.10 (m, 1H), 7.41 (d, 1H, J=3.1 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.59 (d, 1H, J=5.1 Hz), 7.71 (d, 1H, J=3.1 Hz); ESI-MS (m/z, %): 339 (MH+, 100%); ESI-HRMS calculated for C19H23N4S (MH+): 339.1637, observed: 339.1647.