Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][SH:4].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8]>CO.O1CCCC1>[CH3:3][S:4][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8]
Reactant: CS
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSCC(=O)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To 11.3 g (141 mmole) of 50% aqueous sodium hydroxide dissolved in 50 ml of methanol and cooled to -20° C. was added 7.7 g (160 mmole) of gaseous methyl mercaptan. To this solution was added 30.5 g (130 mmole) of 2-bromo-4'-chloroacetophenone dissolved in 40 g of tetrahydrofuran. After warming to room temperature and stirring for 30 minutes the mixture was concentrated in vacuo, partitioned between hexanes and water, dried over anhydrous magnesium sulfate, filtered, and reconcentrated in vacuo to yield 25.3 g of 2-methylthio-4'-chloroacetophenone, an oil.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([CH2:12][S:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:14])[C:9](O)=[O:10])[CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:44][CH2:45][C:46]#[N:47].CN1CCOCC1>>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([CH2:12][S:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:14])[C:9]([NH:47][CH2:46][C:45]#[N:44])=[O:10])[CH:2]=1
Reactant: N#CCN
Reactant: O=C(O)C(Cc1cccc(-c2ccccc2)c1)CS(=O)(=O)Cc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: N#CCNC(=O)C(Cc1cccc(-c2ccccc2)c1)CS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Biphenyl-3-yl-2-benzylsulfonylmethyl-propionic acid (300 mg, 0.76 mmol), prepared as in Reference 9, was combined with EDC (300 mg, 1.57 mmol), HOBt (300 mg, 1.96 mmol), and aminoacetonitrile hydrochloride (150 mg, 1.6 mmol). Dichloromethyl (4 mL) was added and then 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with magnesium sulfate and evaporated under vacuum. The product, 3-biphenyl-3-yl-N-cyanomethyl-2-benzylsulfonylmethyl-propionamide (273 mg), was crystallized from ethyl acetate/hexane as a white solid; 1H NMR: (DMSO) 8.87 (t, J=5.5 Hz, 1H), 7.68–7.14 (m, 14H), 4.45 (d, J=13.8 Hz, 1H), 4.38 (d, J=13.8 Hz, 1H), 4.13 (m, 2H), 3.49 (dd, J=9.4 Hz, J=14.1 Hz, 1H), 3.28–3.11 (m, 1H), 3.04–2.76 (m, 3H). MS: (M++1) 433.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]([C:7]([CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH2:8])[CH2:5][OH:6].C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:6][CH2:5][CH:4]([C:7]([CH2:9][Si:10]([CH3:13])([CH3:11])[CH3:12])=[CH2:8])[CH2:3][CH:2]([CH3:14])[CH3:1])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C(C[Si](C)(C)C)C(CO)CC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C[Si](C)(C)C)C(COS(=O)(=O)c1ccc(C)cc1)CC(C)C
Temperature: 0 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
4-methyl-2-(3-(trimethylsilyl)prop-1-ene-2-yl)pentan-1-ol (59.1 mg, 0.275 mmol) and triethyl amine (835 mg, 8.25 mmol) were dissolved in anhydrous CH2Cl2 (20 mL), and then the solution was cooled to 0° C. p-toluenesulfonyl chloride (57.7 mg, 0.303 mmol) and DMAP (2.00 mg, 0.0138 mmol) were added thereto and the resulting solution was stirred at 0° C. for 6 hr. Water (30 mL) was added thereto to complete the reaction, extraction was performed by using CH2Cl2 (3×20 mL), an organic layer was washed with a brine solution, anhydrous magnesium sulfate was used to perform drying and distillation under reduced pressure, and then column chromatography was used to obtain 75.1 mg (yield 74%) of the title compound which is colorless and in the oil state.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[H-].[Na+].Br[CH2:11][Cl:12]>CN(C)C=O.O>[Cl:12][CH2:11][S:7][C:4]1[S:3][C:2]([CH3:1])=[N:6][N:5]=1
Reactant: Cc1nnc(S)s1
Reactant: ClCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnc(SCCl)s1
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a solution of 2-methyl-1,3,4-thiadiazole-5-thiol (2.64 g : 20 mMol.) in dimethylformamide (40 ml) is added under ice cooling sodium hydride (880 mg : 60% dispersion in oil: 1.1 equivalents : 22 mMol.) in portions, and the mixture is stirred for 10 minutes. To the resulting solution is added bromochloromethane (40 ml), and the mixture is stirred at the same temperature for another 1 hour and 30 minutes. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and purified by silica gel chromatography (toluene : ethyl acetate=10: 1) to give 5-chloromethylthio-2-methyl-1,3,4-thiadiazole (3.3 g) as colorless oil. Yield: 91%.
Reaction SMILES: [N:1](O)=O.[CH3:4][C:5]([CH3:11])([CH3:10])[C:6](=O)[CH2:7][CH3:8].[NH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[NH2:13]>>[C:5]([C:6]1[CH:7]=[C:8]([NH2:1])[N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:13]=1)([CH3:11])([CH3:10])[CH3:4]
Reactant: NNc1ccccn1
Reactant: CCC(=O)C(C)(C)C
Reactant: O=NO
Product: CC(C)(C)c1cc(N)n(-c2ccccn2)n1
Yield: 99 %

Procedure:
The title compound was prepared from 4,4-dimethyl-3-oxopentane nitrite and 2-hydrazinopyridine, using the same method as that described for preparation 7, as a solid in 99% yield.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@@H:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25][CH2:24][N:23]2[C:33](=[O:42])[C:34]2[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[CH:18][CH:17]=1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@@H:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25][CH2:24][N:23]2[C:33](=[O:42])[C:34]2[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2c(C)cccc2F)[C@H]1c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCCN(C(=O)c2c(C)cccc2F)[C@H]1c1ccc(N)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
Step b) 4 N HCl in 1,4-dioxane (110 mL, 440 mmol) was slowly added to a solution of the above ethyl (2R,3S)-2-[4-(tert-butoxycarbonylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylate (19 g, 39.36 mmol) in dry CH2Cl2 (110 mL) at 0° C. After the addition of HCl, the reaction mixture was allowed to attain rt and stirred for 3 h. The solution was then diluted with ethyl acetate (200 mL), cooled to 0° C., and neutralized with saturated aqueous NaHCO3 to get ethyl (2R,3S)-2-(4-aminophenyl)-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylate (15 g, 100%). MS: (ES) m/z 385 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:19][CH2:20][CH3:21])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])=[CH:8][C:7]([OH:18])=[CH:6][CH:5]=2.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([CH3:28])([O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:19][CH2:20][CH3:21])[C:2]([CH3:1])=[C:10]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(C)c(-c2ccccc2C)c2cc(O)ccc21
Product: CCCn1c(C)c(-c2ccccc2C)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 2-methyl-3-(2-methyl-phenyl)-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)=[N:8][N:7]4[C:2]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CC3)n2)cc1
Product: COc1ccc(-c2nn3c(N4CCOCC4)cccc3c2-c2ccnc(NC3CC3)n2)cc1
Temperature: 140 °C
Yield: 93.2 %

Procedure:
A mixture of 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine (75 mg, 0.19 mmol) and morpholine (2 mL, 23 mmol) was heated in a sealed tube at 140° C. for 4 hours. After cooling to room temperature, the mixture was concentrated. Flash chromatography (1:1 to 1:3 hexanes-ethyl acetate) provided N-cyclopropyl-4-[2-(4-methoxyphenyl)-7-(4-morpholinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (78.4 mg, 92%) as an off-white solid. 1H NMR (CDCl3): δ 8.29 (d, 1 H), 8.08 (d, 1 H), 7.61 (d, 2 H), 7.31 (t, 1 H), 6.98 (d, 2 H), 6.45 (d, 1 H), 6.33 (d, 1 H), 5.40 (broad, 1 H), 4.00 (m, 4 H), 3.89 (d, 3 H), 3.51 (m, 4 H), 2.88 (m, 1 H), 0.89 (m, 2 H), 0.65 (m, 2 H); MS m/z 443 (M+1).
Reaction SMILES: [CH:1]1C=C(Cl)C=C(C(OO)=O)C=1.[C:12]([O:16][C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1SC)([CH3:15])([CH3:14])[CH3:13].[S:29]([O-:32])([O-])=[O:30].[Na+].[Na+]>C(Cl)Cl>[C:12]([O:16][C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[S:29]([CH3:1])(=[O:32])=[O:30])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Reactant: CSc1ccccc1CNC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccccc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
MCPBA (60%, 5.82 g, 20.2 mmol) was added to a solution of (2-methylsulfanyl-benzyl)-carbamic acid tert-butyl ester (2.5 g, 9.87 mmol) in DCM (100 mL) which was pre-cooled to 0 degrees C. After 5 h, 100 ml of a 10% aqueous solution of sodium sulfite (Na2SO3) was added to the reaction and the organic layers were collected, washed with saturated aqueous sodium carbonate (50 mL), dried over MgSO4, filtered and concentrated in-vacuo. Chromatography (silica, 0-15% MeOH in DCM) yielded 1.885 g of (2-methanesulfonyl-benzyl)-carbamic acid tert-butyl ester as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[N:18]=[C:19]4[CH2:24][N:23](C(OCC5C=CC=CC=5)=O)[CH2:22][CH2:21][N:20]4[C:35]=3[CH3:36])[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([SiH](C(C)C)C(C)C)(C)C.CCOCC>Br.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[N:18]=[C:19]4[CH2:24][NH:23][CH2:22][CH2:21][N:20]4[C:35]=3[CH3:36])[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: Cc1c(-c2nc(-c3ccc(OC(C)C)c(Cl)c3)no2)nc2n1CCN(C(=O)OCc1ccccc1)C2
Agent: Br
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1c(-c2nc(-c3ccc(OC(C)C)c(Cl)c3)no2)nc2n1CCNC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A solution of benzyl 2-(3-(3-chloro-4-isopropoxypheny)-1,2,4-oxadiazol-5-yl)-3-methy-5,6-dihydroimidazo[1,2-a] pyrazine-7(8H)-carboxylate (160 mg, 0.315 mmol) in 33% HBr solution in acetic acid (2.00 mL) containing triisopropylsilane (0.065 mL, 0.315 mmol)) was stirred at room temperature under nitrogen for 10 minutes. Ether (20 ml) was added to precipitate the product. The resulting solid was filtered off, treated with saturated bicarbonate solution (10 ml) and extracted with methylene chloride (2×10 ml). The combined organic layers were dried over sodium sulfate, filtered, concentrated to solids and dried under reduced pressure to yield 2-[3-(3-Chloro -4-isopropoxy-phenyl)-[1,2,4] oxadiazol-5-yl]-3-methyl-5,6,7,8-tetrahydro-imidazo [1,2-a] pyrazine (113 mg, 96%) as an off-white solid. LCMS (Table 1, Method a) Rl=3.14 min, m/z 374.24 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, 1H), 7.97 (d,d, 1H), 7.36 (d, 1H), 4.81 (m, 1H), 4.66 (s, 2H), 3.90 (s, 2H), 3.87 (t, 2H), 3.12 (t, 2H), 2.60 (s, 3H), 1.34 (d, 6H).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH3:21])=[C:15]2[C:7]=1[CH:8]1[CH:13]([CH:14]2O)[CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)(Cl)Cl>[CH3:5][C:6]1[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH3:21])=[C:15]2[C:7]=1[CH:8]1[C:13](=[CH:14]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COc1c(C)cc(C)c2c1C(O)C1CCCCC21
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1c(C)cc(C)c2c1C=C1CCCCC12
Reaction time: 2 h
Yield: 88.9 %

Procedure:
5.5 Milliliters of thionyl chloride was added dropwise to a chloroform solution containing 16.1 g of 5,7-dimethyl-8-methoxy-9-hydroxy-1,2,3,4,4a,9a-hexahydrofluorene under ice-cooling. After completion of the addition, reaction was effected at the same temperature for 2 hours. The reaction mixture was washed successively with water twice, saturated aqueous sodium chloride solution and saturated sodium bicarbonate solution and dried with magnesium sulfate. Then, the solvent was distilled off and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:20) to obtain 13.26 g of 5,7-dimethyl-8-methoxy-2,3,4,4a-tetrahydro-1H-fluorene.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.CCOC(C)=O>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([N:23]3[CH2:24][CH2:25][O:20][CH2:21][CH2:22]3)=[CH:32][CH:31]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)S1(=O)=O
Yield: 55.9 %

Procedure:
A solution of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.400 g, 1.33 mmol) and 4-morpholinoaniline (0.476 g, 2.67 mmol) in DMF (4 mL) was heated at 140° C. for 15 mins in a microwave reactor. EtOAc was then added, and the resulting mixture was washed with brine and evaporated. The residue was purified by silica gel column chromatography using a 1:1 mixture of petroleum ether and EtOAc as eluant, to give the title compound (0.328 g, 56%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.23-7.18 (m, 1H), 7.15-7.09 (m, 4H), 6.62 (d, 2H), 6.52 (d, 2H), 3.83 (t, 4H), 3.00 (t, 4H), 1.79 (s, 9H); Mass Spectrum: M−H+ 440.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][N:25]([CH2:29][CH2:30]Cl)[CH2:26][CH2:27][Cl:28].Cl.O>CN(C)C=O>[Cl:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][O:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1)[CH3:24]
Reactant: CN(CCCl)CCCl
Reactant: O=c1c2ccccc2sc2c(O)ccc(O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCCl)CCOc1ccc(O)c2sc3ccccc3c(=O)c12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 0.5 g of 1,4-dihydroxythioxanthone in 20 ml of dimethylformamide is stirred for 0.5 h at room temperature with 6 g of potassium carbonate under anhydrous conditions. Mechlorethamine hydrochloride (0.4 g) is then added and the heterogeneous mixture was stirred for 12 h at 50° C. Water is added and the mixture extracted with ethyl acetate. The ethyl acetate solution is washed with water, dried with sodium sulfate, passed through a plug of alumina and concentrated under vacuum to produce 0.4 g (55%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[CH2:7]([Br:10])[CH:8]=[CH2:9]>>[Br-:10].[NH2:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:9][CH:8]=[CH2:7])[N:3]=1
Reactant: C=CCBr
Reactant: Nn1ccnn1
Product: C=CCn1cc[n+](N)n1
Product: [Br-]
Yield: 74 %

Procedure:
In the aforementioned method, 1-amino-1,2,3-triazole (2) 5.00 g (59.5 mmoles) was reacted with allyl bromide 35.00 g (289 mmoles) at 20° C., and upon work-up resulted in a yield of 9.03 g (75%) of 1-amino-3-(2-propenyl)-1,2,3-triazolium bromide (2d), mp 100-101° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[CH2:6][C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2cc(N)c(OC)cc2CC1=O
Product: CCN1CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc2CC1=O
Yield: 36.2 %

Procedure:
Following a procedure similar to 247b, 7-amino-3-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (46 mg, 0.18 mmol) was reacted with N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (60.60 mg, 0.18 mmol), except that the product precipitated from the reaction mixture in the hydrochloride salt form, was collected by filtration, and then free-based by treatment of a solution of the salt in dichloromethane with aqueous saturated NaHCO3. The organic solution was dried (MgSO4), and concentrated to afford N-{(1R,2R)-2-[5-chloro-2-(3-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (35 mg, 36%) as a white solid. MP: 139-150° C.; 1H-NMR (CDCl3) δ 8.00 (s, 1H), 7.95 (s, 1H), 7.33 (s, 1H), 6.65 (s, 1H), 5.25-5.40 (m, 2H), 3.95 (m, 1H), 3.88 (s, 3H), 3.84 (s, 2H), 3.73 (t, J=5.8 Hz, 2H), 3.48 (q, J=7.1 Hz, 2H), 3.25 (m, 1H), 3.12 (t, J=5.6 Hz, 2H), 2.80 (s, 3H), 2.20 (m, 2H), 1.80 (br s, 2H), 1.40 (s, 4H), 1.17 (t, J=7.1 Hz, 3H); LC/MS (ESI+): 537.31 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:7]2[O:8][C:6]2([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:4]=2[O:3]1>C(O)C.[Pd]>[OH:8][C@H:7]1[C@@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:4]=2[O:3][C:2]1([CH3:21])[CH3:1].[OH:8][C@H:7]1[C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:4]=2[O:3][C:2]1([CH3:21])[CH3:1]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2(c3ccccn3)OC12
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](c2ccccn2)[C@@H]1O
Product: CC1(C)Oc2ccc(C#N)cc2[C@H](c2ccccn2)[C@@H]1O
Reaction time: 8 h

Procedure:
646 mg of 1a,7b-dihydro-2,2-dimethyl-7b-(2-pyridyl)-2H-oxireno[c][1]benzopyran-6-carbonitrile were dissolved in 100 ml of ethanol and 100 mg of 10% palladium-on-charcoal were added. The mixture was shaken under a hydrogen atmosphere overnight and then filtered. The filtrate was evaporated and the resulting oil was chromatographed twice on silica gel, with the elution being carried out initially using ethyl acetate/petroleum ether (1:3) and then 1% to 2% (v/v) methanol/dichloromethane. There were obtained 66 mg of rac-cis-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile of melting point 186°-188° C. (from acetonitrile) and 340 mg of rac-trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile of melting point 175°-176° C. (from t-butyl methyl ether).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:18](=O)[C:17]=2[C:20]2[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(#N)[CH:36]([CH2:38][C:39]#[N:40])O.[NH2:42]CCC(O)=O.C(OC(=O)C)(=O)C>>[C:26]([C:24]1[CH:25]=[C:20]([C:17]2[C:18](=[C:38]([C:36]#[N:42])[C:39]#[N:40])[C:16]=2[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:13])[CH3:15])[CH:8]=2)[CH:21]=[C:22]([C:31]([CH3:34])([CH3:32])[CH3:33])[C:23]=1[OH:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: NCCC(=O)O
Reactant: N#CCC(O)C#N
Reactant: CC(C)(C)c1cc(-c2c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)c2=O)cc(C(C)(C)C)c1O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)c1cc(C2=C(c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2=C(C#N)C#N)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 540.8 %

Procedure:
A mixture of 1.00 g (2.17 mmol) of bis(3,5-di-tert-butyl-4-hydroxyphenyl)cyclopropenone 4, 0.29 g (4.3 mmol) of malonitrile and 0.02 g of β-alanine in 3.0 ml of freshly distilled acetic anhydride was heated to reflux with stirring for 20 min. A white precipitate formed in the reddish brown solution. The mixture was cooled to room temperature, and the precipitate was collected by filtration and recrystallized from benzene to give 0.62 g (56%) of 6a as pale yellow needles; mp 280-281°, (dec); ir (KBr) 3560(m), 2960-2860(m), 2213(m), 2197(m), 1850(w), 1595(m), 1490(s), 1470(m), 1450(w), 1410(s), 1370(s), 1360(s), 1310(s), 1255(s), 1240(m), 1200(w), 1100(m), 1025(w), 925(w), 900(w), 890(sh), 885(w), 780(w), 760(w), 675(2), 655(w), 595 cm-1 (w); nmr (CDCl3) δ1.52(s, 36HO), 5.98(s,2H), 7.91(s,4H); uv-visible λmax (methanol) 233 nm (log 4.40), 242(4.34), 252(4.29), 299(4.62), 313(4.57), 368(4.54), 396(sh) (4.44); only the longest wavelength absorptions will be shown for the uv-visible spectrum in nonpolar solvents, λmax (benzene) 381 nm, 400(sh); mass spectrum m/e 510.32500 (calc. 510.32462); Anal. Calcd. for C34H42N2O2 : C, 79.95; H, 8.29; N, 5.49. Found: C, 80.03; H, 8.32; N, 5.43.
Reaction SMILES: Cl[C:2]1[N:3]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[CH:6]2.[OH-:29].[K+]>CO>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[CH:6]=[C:5]2[C:10]([C:2](=[O:29])[N:3]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: COc1ccccc1-c1ccc2c(Cl)n(-c3ccc(C(F)(F)F)cc3)nc2c1
Agent: [K+]
Solvent: CO
Product: COc1ccccc1-c1ccc2c(=O)n(-c3ccc(C(F)(F)F)cc3)[nH]c2c1
Temperature: 160 °C

Procedure:
The product of Step 1 (100 mg) was dissolved in 1N KOH in MeOH (2 mL) and heated at 160° C. for 2 min via microwave irradiation. The resulting yellow solution was concentrated, diluted with water and acidified with 2N HCl. The precipitate was collected and recrystallised from EtOH/H2O to give 21 mg of product as colourless needles. 1H NMR (500 MHz, DMSO): 3.81 (3H, s), 7.08 (1H, t, J 7.4 Hz), 7.18 (1H, d J 7.4 Hz), 7.31 (1H, dd, J 1.2 and 8.0 Hz), 7.38 (1H, dd, J 1.2 and 8.0 Hz), 7.39-7.42 (1H, m), 7.44 (1H, s), 7.79 (1H, d, J 8.0 Hz). 7.89 (2H, d, J 8.5 Hz), 8.18 (2H, d, J 8.5 Hz), 10.76 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:31](=[O:32])[CH2:30][OH:33])[CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2
Reactant: O=C(O)CO
Reactant: Clc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Product: O=C(CO)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1

Procedure:
{5-Chloro-2-[(R)-4-(2-piperazin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine prepared in Example 160 and glycolic acid were reacted according to the same procedure as Step B of Preparation 101 to give the title compound.