Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([NH2:15])=[CH:13][C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:11]2)=[CH:6][CH:5]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([NH:15][C:22]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])=[CH:13][C:12]([C:16]([CH3:17])([CH3:19])[CH3:18])=[N:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-benzoic acid methyl ester (5.3 g, 19.4 mmol) in anhydrous THF (200 mL) was slowly added phenyl chloroformate (6.81 mL, 54.3 mmol), followed by sodium carbonate (2.1 g, 19.4 mmol). The mixture was stirred at room temperature overnight. Ethyl acetate (500 mL) was added, followed by saturated sodium carbonate (300 mL). The organic layer was washed with saturated sodium carbonate (3×) and brine (1×), dried over MgSO4, and concentrated at reduced pressure. The residue was washed with ether to give 4.3 g (56%) of the desired product. 1H-NMR (DMSO-d6) δ 10.19 (s, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.73 (d, J=9.0 Hz, 2H), 7.38-7.11 (m, 5H), 6.41 (s, 1H), 3.87 (s, 3H), 1.27 (s, 1H); MS LC-MS [M+H]+=394.1, RT=3.53 min.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)CCC1=O.ClCC(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].CN(C=O)C.ClCC(C1C=C2C(=CC=1)NC(=O)CC2)=O.C(C1CCCNC1)C1C=CC=CC=1.[BH4-].[Na+].[OH-].[Na+]>C(O)C.CO.ClCCl.C(N(CC)CC)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)[OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2cc(C(=O)CN3CCCC(Cc4ccccc4)C3)ccc2N1
Agent: O=C(Cl)CCl
Agent: O=C1CCc2cc(C(=O)CCl)ccc2N1
Agent: O=C1CCc2ccccc2N1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(O)CN3CCCC(Cc4ccccc4)C3)ccc2N1
Reaction time: 2 h

Procedure:
A solution of 36.2 g of 1,2,3,4-tetrahydro-6-(2-(3-benzylpiperidino)-1-oxoethyl)quinolin-2-one ("A"; racemate; obtainable by reaction of 1,2,3,4-tetrahydroquinolin-2-one with chloroacetyl chloride/AlCl3 /DMF to give 6-chloroacetyl-1,2,3,4-tetrahydroquinolin-2-one ("B") and subsequent reaction with (racemic) 3-benzylpiperidine in ethanol in the presence of triethylamine) in 725 ml of methanol is treated with 3.8 g of NaBH4 and then stirred at 10° for 2 hours. Customary working up (sodium hydroxide solution/dichloromethane) gives 6-(2-(3-benzylpiperidino)-1-hydroxyethyl)-1,2,3,4-tetrahydroquinolin-2-one, racemate ("C").
Reaction SMILES: O.[O:2]=[CH:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5]>[Cl-].[Na+]>[OH:2][CH2:3][C:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])=[O:5]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4 %

Procedure:
A water-insoluble tannin preparation [i.e. chinese gallotannin covalently bound to cellulose through the linkage --CH2CH(OH)CH2NH--(CH2)6 --NHCH2CH(OH)CH2 --] is prepared in the same manner as described in Example 1-(2). 25 mg of glucose isomerase (total activity: 690 units) dissolved in 20 ml of an aqueous 0.1 M sodium chloride solution are added to 500 mg (wet form) of the water-insoluble tannin preparation, and the mixture is stirred at 25° C for 20 minutes. Then, the precipitates are collected by filtration and washed with water. 500 mg (wet form) of an immobilized glucose isomerase preparation [i.e. glucose isomerase adsorbed by the water-insoluble tannin preparation] are thereby obtained. It shows an isomerase activity of 326 units. [One unit of glucose isomerase is defined as the enzymatic activity which affords one mg of fructose by reaction with an aqueous 3.6% glucose solution at 70° C for 1 hour in the presence of 0.025 M magnesium sulfate].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])/[CH:5]=[CH:6]/[C:7]#[N:8].[CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][CH:14]=1>>[C:7]([CH:6]1[CH:5]([C:4]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[CH:15]2[CH2:16][CH2:17][CH:18]1[CH:13]=[CH:14]2)#[N:8]
Reactant: N#C/C=C/c1ccc(Cl)c(Cl)c1
Reactant: C1=CCCC=C1
Product: N#CC1C2C=CC(CC2)C1c1ccc(Cl)c(Cl)c1

Procedure:
trans-3,4-Dichlorocinnamonitrile (20 g.) and cyclohexadiene (16 g.) were heated at 150°C. for 3 weeks. The solution was evaporated, the resultant oil purified by column chromatography and crystallised from methanol to yield white crystals of 5-cyano-6-(3',4'-dichlorophenyl)bicyclo[2,2,2]oct-2-ene. The latter (14 g.) was hydrogenated as described in Example 1 to yield trans-3-cyano-2-(3',4'-dichlorophenyl)bicyclo[2,2,2]octane as white crystals (14 g.). Similarly the following compounds were prepared:
Reaction SMILES: FC(F)(F)S(OC1C=C(OC)C=CC=1CCC1C=CC(OC)=CC=1)(=O)=O.C(OC1C=CC(B(O)O)=CC=1)C1C=CC=CC=1.C([O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:59]=2[CH2:66][CH2:67][C:68]2[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[CH:70][CH:69]=2)=[CH:54][CH:53]=1)C1C=CC=CC=1>>[CH3:65][O:64][C:62]1[CH:61]=[CH:60][C:59]([CH2:66][CH2:67][C:68]2[CH:69]=[CH:70][C:71]([O:74][CH3:75])=[CH:72][CH:73]=2)=[C:58]([C:55]2[CH:54]=[CH:53][C:52]([OH:51])=[CH:57][CH:56]=2)[CH:63]=1
Reactant: COc1ccc(CCc2ccc(OC)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: COc1ccc(CCc2ccc(OC)cc2OS(=O)(=O)C(F)(F)F)cc1
Agent: OB(O)c1ccc(OCc2ccccc2)cc1
Product: COc1ccc(CCc2ccc(OC)cc2-c2ccc(O)cc2)cc1
Yield: 88.2 %

Procedure:
Synthesized from 5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenyl trifluoromethanesulfonate and 4-benzyloxyphenylboronic acid according to an analogous synthetic method to Example 24, 4′-benzyloxy-5-methoxy-2-[2-(4-methoxyphenyl)ethyl]biphenyl (600 mg) was used according to an analogous synthetic method to Example 22 to provide the title compound (417 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:4][CH:5]([CH3:6])[CH2:8][S:9][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: CCOC(=O)c1sc(-c2ccc(F)c([N+](=O)[O-])c2)nc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(SCC(C)C)c([N+](=O)[O-])c2)nc1C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A reaction mixture solution prepared by suspending 155.2 mg of ethyl 2-[4-fluoro-3-nitrophenyl]-4-methyl-1,3-thiazole-5-carboxylate and 244.4 mg of cesium carbonate in 1.5 mL of N,N-dimethylformamide and adding 49.6 mg of 2-methylpropylthiol was heated under stirring at 80° C. for 5 hours under a nitrogen atmosphere. The reaction mixture solution was cooled to room temperature, 3 mL of water was added and extraction was performed using ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a crude product of ethyl 2-[4-(2-methylpropylthio)-3-nitropheny]-4-methyl-1,3-thiazole-5-carboxylate. (2) The crude product of ethyl 2-[4-(2-methylpropylthio)-3-nitropheny]-4-methyl-1,3-thiazole-5-carboxylate obtained above was reduced using palladium carbon under a hydrogen atmosphere to obtain ethyl 2-[3-amino-4-(2-methylpropylthio)phenyl]-4-methyl-1,3-thiazole-5-carboxylate. (3) A reaction mixture solution prepared by suspending ethyl 2-[3-amino-4-(2-methylpropylthio)phenyl]-4-methyl-1,3-thiazole-5-carboxylate obtained above in 2.0 mL of acetic acid and adding 65 mg of sodium azide and 148 mg of triethyl ortho formate was heated at 70° C. for 5 hours under a nitrogen atmosphere. The reaction mixture solution was cooled to room temperature, water was added and extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduce pressure, followed by purifying by a conventional method to obtain 123 mg of ethyl 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate. (4) A reaction mixture solution prepared by adding 123 mg of ethyl 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate to 2 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 0.5 mL of 2 M sodium hydroxide aqueous solution was stirred at room temperature for 3 hours. After the addition of 0.5 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 3 mL of water was added and extraction was performed using ethyl acetate. The organic phase was concentrated, followed by purifying by a conventional method to obtain 67.9 mg of 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:10][C:11](=[O:33])[CH:12]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:20]C(OC(C)(C)C)=O)=[CH:18][CH:19]=1)[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11](=[O:33])[CH:12]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=1)[CH3:9]
Reactant: CCOC(=O)C(CSC(C)=O)Cc1ccc(NC(=O)OC(C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CSC(C)=O)Cc1ccc(N)nc1
Reaction time: 1 h
Yield: 141.7 %

Procedure:
TFA (0.5 mL) was added to a solution of 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylaminopyridin-3-yl)-propionic acid ethyl ester (100 mg, 0.26 mmol) in methylene chloride (2 mL) under argon. The solution was stirred for 60 min and concentrated under reduced pressure to give crude 2-acetylsulfanylmethyl-3-(6-amino-pyridin-3-yl)-propionic acid ethyl ester (104 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][N:11]2[N:39]=[C:15]3[CH2:16][C:17](=O)[C:18]4[CH2:19][S:20][N:21]=[C:22]([N:23](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:13]([C:14]=43)=[N:12]2)[C:4]=1[CH3:40].C([O-])(=O)C.[NH4+].C([BH3-])#[N:47].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][N:11]2[N:39]=[C:15]3[CH2:16][CH:17]([NH2:47])[C:18]4[CH2:19][S:20][N:21]=[C:22]([NH2:23])[C:13]([C:14]=43)=[N:12]2)[C:4]=1[CH3:40]
Reactant: [BH3-]C#N
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1c(C)cnc(CN2N=C3CC(N)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
A mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (50 mg), ammonium acetate (68 mg), molecular sieves 4A (50 mg) and methanol (1.5 ml) was stirred at room temperature for four hours. Sodium cyanoborohydride (12 mg) was added to the reaction mixture, followed by stirring at room temperature for three days. The insoluble matter in the reaction mixture was removed by filtration through Celite, followed by washing with methanol (4 ml) twice. The filtrate was concentrated under reduced pressure. Dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml) were added to the resulting residue, and the mixture was stirred at room temperature for four hours. The reaction mixture was concentrated under reduced pressure. Diethyl ether (20 ml) was placed into the resulting residue, and the slurry was washed. Then, the solvent was removed by decantation. The resulting residue was purified by reversed phase liquid chromatography to obtain the title compound (14.1 mg, 43%) as a solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([C:13]2[CH:22]=[C:21]([CH3:23])[C:16]3[NH:17][C:18](=[O:20])[O:19][C:15]=3[CH:14]=2)=[O:12])[CH:5]=1.I[CH3:25]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([C:13]2[CH:22]=[C:21]([CH3:23])[C:16]3[N:17]([CH3:25])[C:18](=[O:20])[O:19][C:15]=3[CH:14]=2)=[O:12])[CH:5]=1
Reactant: CI
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
59 mg (1.4 mmol) sodium hydride (55%, suspension in mineral oil) were added at RT to 0.37 g (1.2 mmol) 6-(6-chloro-2-methyl-pyrimidin-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 5.0 mL. DMF. The reaction mixture was stirred for 30 min at RT. Then 0.10 ml. (1.60 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. Then another 0.10 ml. (1.60 mmol) iodomethane were added and the mixture was stirred overnight at RT. The reaction mixture was diluted with ice water and the precipitate formed was suction filtered. The residue was washed with water and dried i. vac.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:10]([CH3:11])[CH2:9][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[CH:7][CH:6]1[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:4][CH:5]1[CH:10]([CH3:11])[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])[CH2:7][CH:6]1[NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C(C)CC(c2ccncc2[N+](=O)[O-])=CC1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)OC1C(C)CC(c2ccncc2N)CC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 59 %

Procedure:
To a degassed solution of (+/−)-2-(tert-butoxycarbonylamino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enyl acetate (1.0 equiv.) in MeOH and EtOAc (1:1, 0.1 M) was added 10% Pd/C (0.1 equiv.) and the reaction was stirred at room temperature under a hydrogen balloon for 3 days. Upon completion, the solution was filtered through a pad of Celite, the pad was washed with ethyl acetate and the filtrate was concentrated. The crude material contained about 10% of the undesired isomer. The crude was dissolved in ethyl acetate (˜20%) and hexanes and heated until all dissolved. The solution was allowed to sit at room temperature for 2 days. The precipitate was then collected to give (+/−)-4-(3-aminopyridin-4-yl)-2-(tert-butoxycarbonylamino)-6-methylcyclohexyl acetate as the pure product in 59% yield. LC/MS=364.3 (M+H), Rt=0.63 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C1C2C(CCCC2)CCC1.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCC2CCCCC2C1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a mixture of 301 mg (purity: 100%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 827 mg (5.49 mmol) of 2-cyclopropyl-6-methylphenol were added decalin (2.76 g) and 326 mg (5.53 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 348 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 69%) and 1.8 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.Br[CH2:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[OH:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(OCCCNCCO)cc1
Reactant: CCCSCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCCSCCCN(CCO)CCCOc1ccc(C#N)cc1

Procedure:
A mixture of 4-[3-[(2-hydroxyethyl)amino]propoxy]benzonitrile (3 g), 1-bromo-3-(propylthio)propane (2.7 g) and potassium carbonate (3.7 g) in 2-propanol (50 ml) was refluxed for 28 hours. The solvent was evaporated and the residue dissolved in aqueous HCl (2 M) and extracted with diethylether. The aqueous layer was basified with sodium hydroxide (10 M) and extracted with methylene chloride followed by drying over sodium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography. Yield 2.6 g of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1([F:28])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:22]=[C:21]([CH2:23]O)[CH:20]=[CH:19][C:16]=3[C:17]#[N:18])=[CH:14][C:9]=2[N:8]([CH3:25])[S:7]1(=[O:27])=[O:26].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[O:41]1[C:49]2[CH2:48][CH2:47][NH:46][CH2:45][C:44]=2[C:43]([OH:50])=[N:42]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:28][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:22]=[C:21]([CH2:23][N:46]4[CH2:47][CH2:48][C:49]5[O:41][N:42]=[C:43]([OH:50])[C:44]=5[CH2:45]4)[CH:20]=[CH:19][C:16]=3[C:17]#[N:18])=[CH:14][C:9]=2[N:8]([CH3:25])[S:7]1(=[O:27])=[O:26]
Reactant: Oc1noc2c1CNCC2
Reactant: CN1c2cc(-c3cc(CO)ccc3C#N)ccc2N(CC2CC2(F)F)S1(=O)=O
Agent: CS(=O)(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: CN1c2cc(-c3cc(CN4CCc5onc(O)c5C4)ccc3C#N)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
2-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-(hydroxymethyl)benzonitrile (4-3) (30 mg, 0.07 mmol, 1 eq) was dissolved in NMP (1 mL) and triethylamine (0.03 mL, 0.22 mmol, 3 eq) was added followed by mesyl chloride (0.006 mL, 0.08 mmil, 1.1 eq). After 10 minutes, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (23.2 mg, 0.16 mmol, 2 eq) and DIPEA (0.085 mL, 0.49 mmol, 6 eq) were added. The resulting mixture stirred at 80° C. for 1 h. The mixture was cooled and purified by reverse phase chromatography (Waters Sunfire MSC18, 10-100% acetonitrile in water with 0.1% TFA modifier) to afford 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-[(3-hydroxy-6,7-dihydroisoxazolo[4,5-c]pyridin-5(4H)-yl)methyl]benzonitrile (20-1) as a white solid. HRMS m/z (M+H) 528.1521 found, 528.1512 required.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[OH:19][C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:23]3[CH2:22][CH2:21][C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([OH:19])[CH2:25][CH2:24]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: OC1(c2ccccc2)CCNCC1
Product: OC1(c2ccccc2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (Example 3) and 4-hydroxy-4-phenylpiperidine via General Procedure B-3 yielded 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-phenylpiperidin-4-ol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([CH2:16]Br)[C:7]1=2)[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CC#N.O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([CH2:16][N:20]=[N+:21]=[N-:22])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(CBr)c21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(CN=[N+]=[N-])c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a crude (4-bromomethyl-1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester in CH3CN/H2O (10/2 mL) was added sodium azide (3.1 g, 48 mmol). The solution was stirred overnight at r.t. The crude solution was purified by HPLC, yielded 450 mg of the title compound. 1H NMR (300 MHz, CD3CN) δ 7.21 (s, 1H), 6.99 (s, 1H), 5.61 (dd, 1H), 4.31-4.56 (dd, 2H), 4.10 (q, 2H), 3.02-3.14 (dd, 1H), 2.37-2.43 (m, 1H), 1.21 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[NH:6][C:5]2=[NH:13].Cl.Cl.N[CH:17]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:18]([NH:20][C:21]1([C:28]#[N:29])[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=[O:19]>>[C:28]([C:21]1([NH:20][C:18](=[O:19])[CH:17]([NH:13][C:5]2[C:4]3[C:8](=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=3)[C:7](=[O:12])[N:6]=2)[CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)#[N:29]
Reactant: N=C1NC(=O)c2cc(F)c(F)cc21
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Agent: Cl
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NC(=O)c3cc(F)c(F)cc32)CC1

Procedure:
The title compound was prepared from 5,6-difluoro-2,3-dihydro-3-imino-1H-isoindol-1-one and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 15. MS, m/z 458.3=M+1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: O=Cc1cccnc1
Reactant: COC(=O)c1cc(Cl)cn1N
Solvent: CO
Product: COC(=O)c1cc(Cl)cn1N=Cc1cccnc1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester and pyridine-3-carbaldehyde in refluxing methanol for 12 h. 1H NMR (CDCl3, δ in ppm): 8.43 (s, 1H), 8.29-8.13 (m, 2H), 7.51-7.43 (m, 2H), 7.23 (d, 1H, J=1.8 Hz), 6.91 (d, 1H, J=1.8 Hz), 3.84 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:13]=[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.[CH3:24][NH2:25].O>>[CH3:22][N:21]([CH3:23])[CH:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:12]2[C:11]3[C:10]4[CH2:9][CH2:8][CH2:7][C:6]=4[S:5][C:4]=3[N:3]=[C:2]([NH:25][CH3:24])[N:13]=2)[CH2:16][CH2:17]1
Reactant: CN
Reactant: CN(C)C1CCC(Nc2nc(Cl)nc3sc4c(c23)CCC4)CC1
Solvent: O
Product: CNc1nc(NC2CCC(N(C)C)CC2)c2c3c(sc2n1)CCC3
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a 10-mL sealed tube placed 4-N-[10-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (120 mg, 0.34 mmol, 1.00 equiv) and CH3NH2—H2O solution (40%, 3 mL) was stirred overnight at 70° C. in an oil bath. After completion of the reaction, the resulting mixture was concentrated under vacuum and the crude product (140 mg) was purified by Prep-HPLC with the following conditions (Waters): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, mobile phase, water with 0.05% NH4HCO3 and CH3CN (25% CH3CN up to 100% in 15 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the corresponding 12-N-[4-(dimethylamino)cyclohexyl]-10-N-methyl-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene-10,12-diamine (50 mg) as a white solid. MS (ES, m/z): 346 [M+H]+; 1H NMR (300 MHz, CD3OD): δ 4.75-4.70 (1H, m), 4.64 (1H, d), 4.05-3.94 (1H, m), 3.00 (3H, d), 2.89-2.87 (4H, m), 2.54-2.38 (2H, m), 2.32 (6H, s), 2.25-2.21 (3H, m), 1.96 (2H, d), 1.50-1.35 (2H, m), 1.29-1.19 (2H, m).