Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCO[N:5]([C:18](=O)[CH3:19])[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][C:7]=1[F:17].[OH-:21].[K+].Cl.ClCCl.[O:27]1[CH2:32][CH2:31][O:30]CC1>O>[C:31]([CH2:32][O:27][CH2:19][CH2:18][NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[F:17])([OH:30])=[O:21]
Reactant: C1COCCO1
Reactant: [OH-]
Reactant: CCOC(=O)c1ccc(N(OCCCl)C(C)=O)c(F)c1
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(O)COCCNc1ccc(C(=O)O)cc1F
Temperature: 70 °C

Procedure:
580 mg (1.91 mmol) ethyl 4-[(2-chloro-ethoxy)-acetyl-amino]-3-fluoro-benzoate in 6 ml dioxane are combined with 3.82 ml (7.64 mmol) 2-molar potassium hydroxide solution and 2 ml of water. Then the mixture is heated to 70° C. for 2 h, then diluted with water and acidified with 6-molar hydrochloric acid. After the addition of dichloromethane the precipitate formed is suction filtered and dried in the drying cupboard at 50° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[CH:13]12[CH2:21][CH:17]([CH2:18][NH:19][CH2:20]1)[CH2:16][N:15]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:14]2.[BH4-].[Na+]>CC#N>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([CH:7]([OH:10])[CH2:8][N:19]2[CH2:20][CH:13]3[CH2:21][CH:17]([CH2:16][N:15]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:14]3)[CH2:18]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)OC(=O)N1CC2CNCC(C2)C1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)OC(=O)N1CC2CC(CN(CC(O)c3ccc(C#N)cc3)C2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
4-Cyanophenacyl bromide (225 mg; 1 mmol) was added to a stirred solution of iso-propyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (iv) above; 212 mg; 1 mmol) in MeCN (2 mL). After stirring for 15 min at 0° C., NaBH4 (40 mg; 1 mmol) was added, and the reaction was allowed to warm to rt over 45 minutes. The reaction mixture was concentrated, dissolved in CH2Cl2 and washed with NaHCO3 (aq.) and brine. The organic layer was separated, dried and concentrated to give an oil which was purified using column chromatography (hexane:EtOAc:IPA; 50:49:1) to give the sub-title compound in 35% yield.
Reaction SMILES: C(OC(=O)[N:7]([C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:17]=2)[CH2:12]1)[CH2:8][CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O.[Cl:43]CCl>>[ClH:43].[F:34][CH:32]([F:33])[O:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([NH:21][C:16]2[CH:15]=[CH:14][C:13]3[CH2:12][C@@H:11]([NH:7][CH2:8][CH2:9][CH3:10])[CH2:20][CH2:19][C:18]=3[CH:17]=2)(=[O:24])=[O:23])=[CH:26][CH:27]=1
Reactant: ClCCl
Reactant: CCCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(NS(=O)(=O)c3ccc(OC(F)F)cc3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Product: CCCN[C@H]1CCc2cc(NS(=O)(=O)c3ccc(OC(F)F)cc3)ccc2C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
[(S)-6-(4-Difluoromethoxy-benzenesulfonylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-propyl-carbamic acid tert-butyl ester (2.08 g, 4.07 mmol) was dissolved in dichloromethane (100 ml). Trifluoroacetic acid (10 ml) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness. Diethyl ether (100 ml) was added and extracted with saturated NaHCO3 solution. To the organic layer was added ethereal hydrochloride solution and the solvent evaporated. To the residue was added diethyl ether (25 ml) and the crystalline product was filtered off to give pure product (1.41 g, 77% yield).
Reaction SMILES: [CH:1]12[CH2:10][C:5]3([C:11]([O:13]C)=[O:12])[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[N:2]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8]2.C1COCC1.O.[Li+].[OH-]>CO>[C:18]([O:17][C:15]([N:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][C:5]([C:11]([OH:13])=[O:12])([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C12CC3CC(C1)N(C(=O)OC(C)(C)C)C(C3)C2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CC3CC1CC(C(=O)O)(C3)C2
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a 0° C. cooled stirred solution of 2-tert-butyl 5-methyl 2-azatricyclo[3.3.1.13,7]decane-2,5-dicarboxylate, intermediate-9 (0.16 g, 0.5 mmol) dissolved in methanol (3 ml), THF (1 ml) and water (1 ml), LiOH (50 mg, 2 mmol) was added and the resulting reaction mass was stirred at room temperature for 6 hrs. Upon completion of the reaction (reaction monitored by TLC), the solvent present in the reaction mixture was completely removed under vacuum and the crude residue was acidified with saturated citric acid solution and extracted with ethyl acetate (3×15 ml). The organic layer was then washed with brine solution and dried over sodium sulfate and was finally concentrated under vacuum to get intermediate-10 as an oily mass, 0.16 g (95%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1.[CH2:26]([C:30]1[NH:31][CH:32]=[CH:33][N:34]=1)[CH2:27][CH2:28][CH3:29]>O1CCOCC1>[CH2:26]([C:30]1[N:31]([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=3[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=2)[CH:32]=[CH:33][N:34]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCc1ncc[nH]1
Solvent: C1COCCO1
Product: CCCCc1nccn1Cc1cccc(-c2cc(CC(C)C)sc2S(=O)(=O)NC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (70 mg, 0.158 mmol; see Example 1(e)) in dioxane (2.0 mL) was added 2-butylimidazole (58.7 mg, 0.473 mmol) and the reaction mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the sub-title compound in 55% yield as a colourless syrup (42.1 mg, 0.087 mmol).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([NH:18][C@H:19]([CH2:27][OH:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([NH:18][C@H:19]([CH:27]=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
To dimethyl sulfoxide (2.82 mL, 39.8 mmol) dissolved in anhydrous methylene chloride (5 mL) and cooled to -78° C. was added dropwise oxalyl chloride (2.6 mL, 1.5 equiv). After 10 minutes at -78° C., N-Boc-Phenylalaninol (5.00 g, 19.9 mmol) dissolved in anhydrous methylene chloride (75 mL) was cannulated into the reaction mixture. After 15 minutes at -78° C., the reaction was stirred for 2 minutes at 0° C. and then cooled again to -78° C. Triethylamine (11.9 mL, 4.3 equiv) was added dropwise. After 25 minutes, the reaction was quenched with cooled 10% citric acid (15 mL) and then diluted with additional 10% citric acid (75 mL). Ether (300 mL) was added and the solution was washed with water (5×100 mL), brine, water (5×100 mL), and brine, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (4.22 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]N)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.C=O.[C:26]([BH3-])#[N:27].[Na+].[C:30](O)(=O)C>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]([CH3:26])[CH3:30])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: NCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 23, a solution of 8-bromo-1-(aminomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in acetonitrile is treated with formalin, sodium cyanoborohydride and acetic acid to give 8-bromo-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C1(NC2N3N=CC(C=O)=C3N=C([C:16]3[S:20][C:19]([C:21](O)=[O:22])=[CH:18][CH:17]=3)C=2)CC1.CCN=C=NCCCN(C)C.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.[CH3:52][O:53][CH2:54][CH2:55][CH2:56][NH2:57]>CN(C=O)C.C(OCC)(=O)C>[CH3:52][O:53][CH2:54][CH2:55][CH2:56][NH:57][C:21]([C:19]1[S:20][CH:16]=[CH:17][CH:18]=1)=[O:22]
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(C(=O)O)s3)nc12
Reactant: COCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (30 mg, 0.091 mmol), EDCI (19 mg, 0.10 mmol), Et3N (14 μL, 0.10 mmol), and HOBt (14 mg, 0.10 mmol) in 2 mL of DMF pre-stirred for 5 minutes was added 3-methoxypropylamine (10 μL, 0.10 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate, washed with H2O, brine, dried over MgSO4, filtered, and evaporated to dryness to provide 30 mg of 547-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)-N-(3-methoxypropyl)thiophene-2-carboxamide (83%). LCMS (M+1=400)
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:12]([O-:18])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].[C:19](Cl)(=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[CH3:9][C:8]([O:7][C:1](=[O:6])[CH:2]([C:3](=[O:4])[CH3:5])[C:19](=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](=[O:25])[CH:13]([C:14](=[O:15])[CH3:16])[C:12]([O:18][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:17])=[CH:22][CH:21]=1)([CH3:11])[CH3:10]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CC(=O)CC(=O)[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(C(=O)C(C(C)=O)C(=O)OC(C)(C)C)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
In a 51, 3-necked, RB flask equipped with a mechanical stirrer, nitrogen sparge, 2 addition funnels, and temperature probe was placed aqueous NaOH (67.7 g in 200 mL distilled water). The mixture was cooled to 10° C. and t-butyl acetoacetate (t-BAA) (259.1 g, 1.64 mol) in 500 ml toluene was added dropwise. Additional toluene (ca. 300 mL) was added to help disperse the solid acetoacetate anion and the reaction cooled to 5° C. Terephthaloyl chloride (159.1 g, 0.78 mol) dispersed in 500 ml toluene was added dropwise at such a rate as to keep the reaction temperature below 10° C. After addition of approximately half of the terephthaloyl chloride solution, co-addition of NaOH (64.4 g in 100 ml distilled water) was started--again at such a rate as to keep the temperature below 10° C. The resulting reaction was stirred for 6 additional hours, acidified with HCl to a pH of 5 and allowed to stand overnight. The resulting organic layer was separated from the aqueous phase, extracted with brine, dried over anhydrous MgSO4, concentrated in vacuo and the resulting crystals collected and washed with heptane to yield 176.7 g (50.7% yield) white crystals, mp 94°-96° C. The mother liquor from this crystallization was seeded to produce 84.8 g additional product collected. Over-all yield 261.5 g (75.1%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:11][C:12]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:13]=1[CH:14]=O.C([O:24][C:25](=O)[C:26](=[O:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:13]4[CH:16]=[C:17]([F:21])[CH:18]=[C:19]([F:20])[C:12]=4[F:11])[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[C:26]([OH:34])[C:25]3=[O:24])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Reactant: O=Cc1cc(F)cc(F)c1F
Solvent: CCO
Product: O=C1C(O)=C(c2ccccc2)C(c2cc(F)cc(F)c2F)N1c1ccc2[nH]cnc2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and 2,3,5 Trifluorobenzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-3-phenyl-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].Br[C:18]1[S:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([S:33](=[O:36])(=[O:35])[NH2:34])=[C:29]([CH3:37])[CH:28]=2)[C:19]=1[CH3:38]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[S:22][C:21]([C:23]([O:25][CH2:26][CH3:11])=[O:24])=[C:20]([C:27]3[CH:32]=[CH:31][C:30]([S:33](=[O:36])(=[O:35])[NH2:34])=[C:29]([CH3:37])[CH:28]=3)[C:19]=2[CH3:38])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1sc(Br)c(C)c1-c1ccc(S(N)(=O)=O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)c(C)c1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
(4-chlorophenyl)boronic acid [0.29 g, 1.85 mmol] and potassium carbonate (0.43 g, 3.09 mmol) were added to a solution of methyl 5-bromo-4-methyl-3-(3-methyl-4-sulfamoylphenyl)thiophene-2-carboxylate (41b, 0.62 g, 1.54 mmol) in a mixture of 5 ml of toluene and 20 ml ethanol at 25° C. A nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.09 g, 0.08 mmol) under nitrogen atmosphere and the reaction mixture was heated at a temperature between about 95° C. to 100° C. for 3 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with ethyl acetate (20 ml). The combined filtrate was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound (0.53 g, 76.8%).
Reaction SMILES: [S:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][CH:5]=1)[C:2]#N.[BH4-].[Na+].Br[CH2:13][C:14]([CH3:19])(C)[C:15]([OH:17])=[O:16].[CH:20](N(C(C)C)CC)(C)[CH3:21]>CO.O>[CH2:20]([O:17][C:15](=[O:16])[C:14]([CH3:19])([CH3:13])[CH2:2][S:1][C:4]1[S:8][C:7]([NH2:9])=[N:6][CH:5]=1)[CH3:21]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CSc1cnc(N)s1
Reactant: CC(C)(CBr)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Reaction time: 0.5 h

Procedure:
5-thiocyanato-thiazol-2-ylamine (15.7 g) was dissolved in degassed methanol and sodium borohydride (4.5 g) in MeOH was added in one portion. The reaction was stirred for 30 min and 3-bromo-2,2-dimethyl-propionic acid (27 g) and diisopropylethylamine (17 mL) was added and the reaction stirred overnight at room temperature. The reaction was diluted with water, partially concentrated in vacuo and 5% citric acid was added until pH 4. The brown precipitate was filtered, washed with water and acetonitrile, and dried over night at room temperature. The residue was stirred with ethanol, filtered, washed with ethanol and dried in a vacuum oven at 40° C. to give 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[CH2:12]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[N:18][C:19](SC)=[N:20][CH:21]=2)[N:16]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH:13]=[CH2:14].C(N(CC)C(C)C)(C)C.[NH2:42][C:43]1[CH:44]=[CH:45][C:46]([N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)=[C:47]([CH2:49][OH:50])[CH:48]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:12]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[N:18][C:19]([NH:42][C:43]3[CH:44]=[CH:45][C:46]([N:51]4[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]4)=[C:47]([CH2:49][OH:50])[CH:48]=3)=[N:20][CH:21]=2)[N:16]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH:13]=[CH2:14]
Reactant: CN1CCN(c2ccc(N)cc2CO)CC1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1ccccn1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)c(CO)c3)nc2n1-c1ccccn1
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
796 mg of m-chloroperbenzoic acid (>65%) was added to toluene (20 mL) solution of 898 mg of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3one, and stirred for 30 minutes. 1.60 mL of N,N-diisopropylethylamine, 800 mg of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol and 10 mL of tetrahydrofuran were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with a mixed solution of chloroform/isopropanol (80/20). This was dried with anhydrous magnesium sulfate, the solvent was evaporated away, and the residue was purified through basic silica gel column chromatography (hexane/ethyl acetate=50/50 to 0/100). The resulting crystal was recrystallized from ethanol to obtain 941 mg of the entitled compound as a white crystal.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.Br[CH2:36][C:37]([O:39][CH2:40]C)=[O:38].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:7]2[C:2](=[O:1])[N:3]([CH:29]3[CH2:30][CH2:31][N:32]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:34]3)[C:4]3[N:5]([N:26]=[CH:27][N:28]=3)[C:6]=2[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1)#[N:22]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCNCC2)c2ncnn12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(CC(=O)OC)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (453 mg), ethyl bromoacetate (184 mg), potassium carbonate (276 mg) and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=60/40→35/65 (volume ratio)] to give the title compound as a colorless amorphous compound (418 mg, 80%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C([C:31]2[C:35]3[S:36][CH:37]=[CH:38][C:34]=3O[N:32]=2)C=CC=1.S1C=CC=C1CN.C(=O)([O-])[O-].[K+].[K+]>>[O:14]1[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][CH2:3][CH2:2][NH:32][CH2:31][C:35]2[S:36][CH:37]=[CH:38][CH:34]=2)=[N:13]1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: NCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cc(OCCCNCc2cccs2)cc(-c2noc3ccsc23)c1
Yield: 94 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 2-thiophenemethylamine and potassium carbonate essentially as described above in example 4. Combine the appropriate fractions and concentrate to give the title compound (0.35 g, 94% Yield) as an oil. Purity by LC/MS (APCI)=100% area, [M+H]+=371 m/e.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][O:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].[OH-].[K+].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1(C)C=CC=CC=1>[C:1]([NH:4][C@@H:5]1[C@@:14]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([OH:15])[C@H:13]([O:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:12]([CH2:17][O:18][C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: C=CCOC1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=CCOC1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Yield: 88 %

Procedure:
10 g of (c), 12 g of KOH and 7 ml of benzyl bromide in 340 ml of toluene were heated under reflux for 3 h. The suspension obtained was then hot filtered through Celite and the solid residues were washed with hot toluene. The filtrates were then combined and washed. After washing and evaporating off the solvents, a yellow-white solid was obtained: 12 g (yield: 88%).
Reaction SMILES: Cl.[CH3:2][C@@H:3]([NH2:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[C:16]([NH:24][C:25]([NH:8][C@H:3]([CH3:2])[C:4]([F:7])([F:6])[F:5])=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](N)C(F)(F)F
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=S)NC(=O)c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
Dissolve (R)-1-methyl-2,2,2-trifluoroethylamine hydrochloride (3.73 g, 25 mmol) in chloroform (50 mL) containing triethylamine (3.5 mL, 25 mmol). Cool to 0° C. in an ice bath and dropwise add benzoyl isothiocyanate (3.35 mL, 25 mmol) over 10 min. Warm the mixture to room temperature and stir overnight. Concentrate in vacuo and purify by chromatography on silica gel (200 g) eluting with hexane/EtOAc (19:1 to 4:1 over 40 min; 50 mL/min) to afford the desired intermediate as a light yellow oil (6.2 g, 90%).
Reaction SMILES: [OH:1][C@@H:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:3].[CH3:16][S:17](Cl)(=[O:19])=[O:18].CCN(CC)CC>C(Cl)Cl>[CH3:16][S:17]([O:1][C@@H:2]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)[CH3:3])(=[O:19])=[O:18]
Reactant: CC(C)OC(=O)N1CCC([C@@H](C)O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC([C@@H](C)OS(C)(=O)=O)CC1
Yield: 102.8 %

Procedure:
1-Methylethyl 4-{(1R)-1-[(methylsulfonyl)oxy]ethyl}-1-piperidinecarboxylate (0.7 g, 100%) was prepared as a light yellow oil from 1-methylethyl 4-[(1R)-1-hydroxyethyl]-1-piperidinecarboxylate (0.5 g, 2.32 mmol), methanesulfonyl chloride (0.22 mL, 2.79 mmol), Et3N (0.49 mL, 3.48 mmol) and CH2Cl2 (30 mL) in a manner similar to Example 150, Step 1. The crude material was used without further purification. 1H NMR (400 MHz, CDCl3): δ 4.88 (septet, 1H, J=6.2 Hz), 4.70-4.55 (m, 1H), 4.30-4.10 (m, 2H), 2.99 (s, 3H), 2.75-2.60 (m, 2H), 1.80-1.60 (m, 3H), 1.38 (d, 3H, J=6.3 Hz), 1.35-1.15 (m, 8H).