Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[CH3:3][C:4]1[C:8]([Br:9])=[C:7]([Br:10])[S:6][C:5]=1[Br:11]>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.[Cl-].[Zn+2].[Cl-].C(Cl)Cl>[Br:11][C:5]1[S:6][CH:7]=[C:8]([Br:9])[C:4]=1[CH3:3].[Br:10][C:7]1[S:6][CH:5]=[C:4]([CH3:3])[C:8]=1[Br:9]
Reactant: Cc1c(Br)sc(Br)c1Br
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(Br)csc1Br
Product: Cc1csc(Br)c1Br
Yield: 73.4 %
Yield: 3 %

Procedure:
A catholyte of 300 ml of methanol, 100 ml of methylene chloride, 15 g of zinc chloride, 0.5 g of methyltrioctylammonium chloride and 31 g of 3-methyl-2,4,5-tribromothiophene were electrolysed in electrolysis cell 1 at a current density of 50 mA/cm2 at the start and 25 mA/cm2 at the end of the batch, a voltage of 4 or 3 V, a temperature of 34° to 24° C. and pH of -0.8. The current consumption was 14.8 Ah. After addition of 500 ml of water to the catholyte and working up as described in Example 1, 17.4 g of 2,4-dibromo-3-methylthiophene (yield: 73.4%), 0.71 g of 2,3-dibromo-4-methylthiophene (yield: 3%) and 2.92 g of 4-bromo-3-methylthiophene (yield: 17.8%) were obtained.
Reaction SMILES: C([C@@H]1COC(=O)N1C(=O)[C@H]([CH2:19][S:20]([Cl:23])(=[O:22])=[O:21])C(C)C)C1C=CC=CC=1.[CH3:25][O:26][C:27]([C:29]1(SC(=O)C)[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1C)=[O:28]>>[CH3:25][O:26][C:27]([C:29]1([CH2:19][S:20]([Cl:23])(=[O:22])=[O:21])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:28]
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COC(=O)C1(SC(C)=O)CCCCC1C
Product: COC(=O)C1(CS(=O)(=O)Cl)CCCCC1
Yield: 96 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methyl butyryl)oxazolidin-2-one, from 1-acetylsulfanyl-methylcyclohexanecarboxylic acid methyl ester (20 g), to provide the title compound as a red oil (14 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccc(F)cc1
Yield: 88 %

Procedure:
Prepared according to the procedure described for Example 121 using 4-fluorobenzenesulfonyl chloride (2.14 g, 10 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10.0 mmol) to afford the product (3.522 g); m.p. 209-211° C.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[C:9]([N+]([O-])=O)[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)([O-:4])=[O:3].[CH3:17][OH:18]>>[N+:2]([C:5]1[CH:10]=[C:9]([O:18][CH3:17])[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CO
Agent: [Na]
Product: COc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
Sodium (575 mg, 25 mmol) was dissolved in absolute methanol (100 ml). 1,3,5-Trinitrobenzene (4.26 g, 20 mmol) was then added and the solution was stirred overnight. After evaporation of the solvent, water was added and the precipitate was filtered off, washed with water and dried. The material was used without purification in the next step. Yield: 3.4 g (86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[CH:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[CH:33]=[CH:34][N:30]([C:27]2[CH:26]=[CH:25][C:24]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[CH:29][CH:28]=2)[C:31]1=[O:35])[CH3:12]
Reactant: O=c1[nH]ccn1-c1ccc(-n2cncn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](n1ccn(-c2ccc(-n3cncn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 80 °C
Reaction time: 9.5 h
Yield: 21.6 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.5 g), 1-[4-(1H-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (2.72 g) and cesium carbonate (powder: 9.7 g) were added to N,N-dimethylformamide (150 ml), and the mixture was heated at 80° C. with stirring for 9.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate (400 ml). Ice water (150 ml) was added thereto to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml), 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (50 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:ethyl acetate/acetone=2/1) to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound 9; 1.03 g) as a pale yellow powder.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([OH:3])=[O:2].[Br:15]Br.O.Cl>[N+]([O-])(O)=O>[Br:15][C:12]1[CH:13]=[CH:14][C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: BrBr
Reactant: O=C(O)CCc1ccccc1C(=O)O
Agent: Cl
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=C(O)CCc1ccc(Br)cc1C(=O)O
Temperature: 90 °C

Procedure:
A solution of 2-(2-carboxyethyl)benzoic acid (5 g, 25.8 mmol) in 71% nitric acid (20 mL) in an amber vial was treated with bromine (1.3 mL, 25.8 mmol). The vial was capped and heated to about 90° C. for about 20 hours. The reaction was cooled, poured into water and 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (20:1) as eluent to provide the desired product. MS (ESI): m/z 271, 273 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[S:3]([C:6]1[N:7]=[N:8][C:9]([O:12]C)=[CH:10][CH:11]=1)(=[O:5])=[O:4].Cl>O1CCOCC1>[CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][N:7]=1)(=[O:4])=[O:5]
Reactant: COc1ccc(S(=O)(=O)N(C)c2ccccc2)nn1
Agent: Cl
Solvent: C1COCCO1
Product: CN(c1ccccc1)S(=O)(=O)c1ccc(=O)[nH]n1
Yield: 75.3 %

Procedure:
A mixture of 6-methoxy-pyridazine-3-sulfonic acid methyl-phenyl-amide (239 mg), dioxane (4 mL) and concentrated hydrochloric acid (1 mL) was prepared and refluxed for one hour. The mixture was then evaporated to dryness. The resulting solid was triturated with water and the solid was collected to afford the title compound (75%, 171 mg); mp, 157-158° C.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=1)[CH3:6].[CH2:16]([O:18][C:19]([C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[NH2:26])=[O:20])[CH3:17].[BH3-]C#N.[Na+]>C(O)C>[CH2:16]([O:18][C:19]([C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[NH:26][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:5][CH3:6])[N:13]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: CCOc1cccc(C=O)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]ccc1NCc1cccc(OCC)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.5 %

Procedure:
Acetic acid (0.3 mL) was added to 6-ethoxy-pyridine-2-carbaldehyde (0.59 g, 3.9 mmol) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.30 g, 1.9 mmol) in ethanol (10 mL). After 1.5 h, NaCNBH3 (0.24 g, 3.9 mmol) was added, and the resulting mixture was stirred at ambient temperature for 19 h. The solvent was removed in vacuo, ethyl acetate was added to the residue, and insoluble material was removed by filtration. The filtrate was concentrated and the crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 35% ethyl acetate), obtaining 0.25 g (45%) of the title product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH2:19]O)[CH:16]=[CH:17][CH:18]=3)=[N:9]2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:24]>ClCCl>[Br:24][CH2:19][C:15]1[CH:14]=[C:13]([C:10]2[N:11]=[N:12][N:8]([CH2:7][C:6]3[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(Cn2nnc(-c3cccc(CO)c3)n2)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COc1ccc(Cn2nnc(-c3cccc(CBr)c3)n2)cc1
Reaction time: 16 h
Yield: 96.6 %

Procedure:
The alcohol (1 g, 3.37 mmol) of Step (a) was dissolved in dichloromethane (25 mL) and added dropwise at room temperature to a solution of phosphorous tribromide (1 g, 3.7 mmol) in dichloromethane (75 mL). The solution was stirred for 16 hours, then concentrated in vacuo. The residue obtained was triturated with hexane and collected by filtration to yield a white solid (1.17 g, 92%). 1H NMR (CDCl3) δ 8.2 (d, 1H), 7.7 (m, 2H), 7.5 (m, 1H), 7.4 (d, 2H), 6.8 (d, 2H), 5.8 (s, 2H), 4.5 (s, 2H), 3.7 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[Cl:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:26][C:27](=O)[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[Cl:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:26]=[C:27]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:11]=2)=[N:6][CH:7]=1
Reactant: O=C(CBr)CCc1ccccc1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(NC(N)=S)ncc2Br)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)c1
Temperature: 70 °C
Yield: 96.4 %

Procedure:
A flask was charged with ethyl 3-(5-bromo-2-thioureidopyridin-4-yloxy)-4-chlorobenzoate (0.200 g, 0.464 mmol), 1-bromo-4-phenylbutan-2-one (0.105 g, 0.464 mmol) and triethylamine (0.0470 g, 0.464 mmol). Ethanol (5 mL) was added and the reaction was heated at 70° C. for 6 hours, and then concentrated to provide ethyl the desired product (0.250 g, 95 yield) as white solid. LC/MS (apci) M+2H: 560 (100%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8]([O-:11])(=O)=[O:9])[N:6]=1.[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8]([Cl:14])(=[O:11])=[O:9])[N:6]=1
Reactant: Cc1nc(CS(=O)(=O)[O-])cs1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(CS(=O)(=O)Cl)cs1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium (2-methylthiazol-4-yl)methanesulfonate, 40, (357 mg, 1.66 mmol) is dissolved in phosphorous oxychloride (6 mL) and is treated with phosphorous pentachloride (345 mg, 1.66 mmol). The reaction mixture is stirred at 50° C. for 3 hours, then allowed to cool to room temperature. The solvent is removed under reduced pressure and the residue is re-dissolved in CH2Cl2 (40 mL) and is washed with sat. NaHCO3 and brine. The organic layer is dried over MgSO4, filtered, and the solvent removed in vacuo to afford 0.095 g of the desired product as a brown oil. LC/MS ESI+ 211 (M+1). Intermediates are obtained in sufficient purity to be carried forward according to Scheme IX without the need for further purification.
Reaction SMILES: [N:1]12[CH2:11]CCN=[C:7]1CCCC[CH2:2]2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].ClC(Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl.CNC.C1COCC1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:2](=[O:37])[N:1]([CH3:11])[CH3:7])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(C)C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (1.0 g, 6.8 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol) in acetonitrile (50 mL). The mixture was stirred for 30 minutes, then added slowly to a stirred solution of triphosgen (0.3 g, 1.1 mmol) in acetonitrile (20 mL) over 20 minutes. After stirring for another 10 minutes, a solution of dimethylamine/THF (2.0 M, 1.6 mL, 3.1 mmol) and diidopropylethylamine (0.5 g, 3.7 mmol) was added in one portion. The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved in methylene chloride (80 mL). The methylene chloride solution was washed with 1N HCl (40 mL), water (40 mL), and brine (40 mL), and dried (MgSO4). Solvent was removed and purified by chromatography (silica gel) to give 3-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1,1-dimethyl-urea (0.4 g, 36%) as a white solid: mp 143-145° C.; 1H NMR (DMSO-d6) δ 2.04-2.08 (m, 1H), 2.50-2.63 (m, 2H), 2.84 (s, 6H, 2CH3), 2.84-2.96 (m, m, 1H), 4.68 (d, J=5.6 Hz, 2H, CH2), 5.11-5.18 (dd, J=5.2 and 121.5 Hz, 1H, CH), 6.98 (t, J=5.6 Hz, 1H, NH), 7.69-7.85 (m, 3H, Ar), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.98, 30.93, 35.88, 39.30, 48.82, 121.45, 126.75, 131.38, 132.92, 134.56, 141.44, 148.14, 167.06, 167.63, 169.84, 172.75; Anal. calcd. for C17H18N4O5: C, 56.98; H, 5.06; N, 15.63. Found: C, 56.87; H, 5.16; N, 15.16.
Reaction SMILES: Cl[C:2]1[C:11]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].N1C=CC=CC=1>CC1C=CC(C)=CC=1>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[S:25][C:2]2[C:11]([N:12]=1)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)([O-:22])=[O:21]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)c1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: Cc1ccc(C)cc1
Product: COC(=O)c1cnc2sc(-c3ccccc3[N+](=O)[O-])nc2c1
Temperature: 130 °C
Yield: 57 %

Procedure:
A mixture of methyl 6-chloro-5-(2-nitrobenzamido)nicotinate (1 eq), P2S5 (2.1 eq), and pyridine (7.6 eq) in p-xylene was heated at 130° C. for 2 h. The clear liquid was decanted and allowed to cool to room temperature. The resultant precipitate was collected by filtration and dried to give methyl 2-(2-nitrophenyl)thiazolo[5,4-b]pyridine-6-carboxylate (57% yield).
Reaction SMILES: Cl.CN[O:4][CH3:5].[CH3:6][CH:7]([CH:23]([OH:27])[CH:24]([CH3:26])[CH3:25])[C:8]([N:10]1[C@@H:14](CC2C=CC=CC=2)COC1=[Se])=[O:9]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[OH:27][CH:23]([CH:24]([CH3:25])[CH3:26])[CH:7]([CH3:6])[C:8]([N:10]([O:4][CH3:5])[CH3:14])=[O:9]
Reactant: CC(C)C(O)C(C)C(=O)N1C(=[Se])OC[C@@H]1Cc1ccccc1
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)C(C)C(O)C(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 55.5 %

Procedure:
N,O-Dimethylhydroxyl-amine hydrochloride (380 mg, 3.90 mmol) and 4-dimethylaminopyridine (244 mg, 2.00 mmol) was added to a solution of (4S)-3-(2,4-dimethyl-3-hydroxyl-1-oxopentyl)-4-(phenylmethyl)-2-oxazolidineselone (616 mg, 2.00 mmol) in CH2Cl2 (10 mL). The resulting solution was stirred at room temperature for 4 days. The solvent was removed under reduced pressure. Purification of the residue by silica gel column chromatography (CH2Cl2/ether; 95/5; v/v) afforded 210 mg (55%) of 3-hydroxy-N-methoxy-N,2,4-trimethyl-pentanamide. 1H NMR δ 3.94 (br s, 1H), 3.72 (s, 3H), 3.45 (dd, 1H, J=8.4 Hz, J=2.1 Hz), 3.21 (s, 3H), 3.10 (br m, 1H), 1.73 (m, 1H), 1.16 (d, 3H, J=7.1 Hz), 1.04 (d, 3H, J=6.6 Hz), 0.88 (d, 3H, J=6.8 Hz); 13C NMR δ 178.48, 76.90, 61.48, 35.72, 31.88, 30.20, 19.16, 18.90, 9.90
Reaction SMILES: CO[C:3](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.Cl.[C:20]([NH:24][NH2:25])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>CCO>[N+:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]1[C:14]([C:15]#[N:16])=[C:17]([NH2:18])[N:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:25]=1)([O-:13])=[O:12]
Reactant: COC(Cc1cccc([N+](=O)[O-])c1)=C(C#N)C#N
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)n1nc(Cc2cccc([N+](=O)[O-])c2)c(C#N)c1N

Procedure:
Reagent 2-(1-methoxy-2-(3-nitrophenyl)ethylidene)malononitrile (1.2 g; 4.7 mmol) was combined with tert-butylhydrazine-HCl (0.57 g; 5.2 mmol; Sigma-Aldrich), 1.4 mL triethylamine in 50 mL EtOH for at 2 hours at 80° C. The reaction was concentrated in vacuo, resuspended in brine and extracted with chloroform. The organic layer was dried over MgSO4. Following, the organic suspension was filtered, concentrated in vacuo, and purified on silica gel in 1% MeOH:CHCl3 to yield 3-(3-nitrobenzyl)-1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile (ESI-MS m/z [M−CH3]+ found 285.5, calculated 285.14; 1H NMR (400 MHz, DMSO): δ8.11 (s, 1H), 8.08-8.12 (m, 1H), 7.69 (d, J=8 Hz, 1H), 7.59-7.64 (m, 1H), 3.96 (s, 2H), 3.34 (br, 2H), 1.52 (s, 9H)). This product was combined with formamide as per Cmpd 1 to yield 3-(3-nitrobenzyl)-1-tert-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 327.4, calculated 327.15; 1H NMR (400 MHz, DMSO): δ 8.22 (s, 1H), 8.14 (s, 1H), 8.07 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 7.59 (d, J=8 Hz, 1H), 7.22 (br, 2H), 4.52 (s, 2H), 1.70 (s, 9H)). Reduction of this material was completed as per Cmpd 1 to yield 3-(3-aminobenzyl)-1-tert-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 297.13, calculated 297.17). The reduced precursor was coupled to 3-(trifluoromethyl)phenyl isocyanate and purified as described for Cmpd 1 to yield Cmpd 4 1-(3-((1-tert-butyl-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (ESI-MS m/z [M+H]+ found 484.5, calculated 484.2; 1H NMR (400 MHz, DMSO): δ 9.25 (s, 1H), 8.96 (s, 1H), 8.32 (s, 1H), 8.06 (s, 1H), 7.46-7.55 (m, 2H), 7.40 (s, 1H), 7.29 (d, J=8 Hz, 2H), 7.20 (t, J=8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 4.39 (s, 2H), 1.73 (s, 9H). 13C NMR (400 MHz, DMSO): δ 29.25, 33.40, 60.74, 99.58, 116.43 (d), 116.95, 118.86, 122.13, 122.64, 124.69 (q), 129.29, 129.98 (q), 130.32, 139.60, 140.06, 141.16, 143.31, 149.70, 152.69, 152.92, 154.81, 159.12 (q)).
Reaction SMILES: [CH:1]1([N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH2:7][CH2:6][CH2:5][CH:4]3[CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[Si]([C:32]#[N:33])(C)C.N>C(O)(=O)C>[CH:1]1([N:14]2[CH2:19][CH2:18][C:17]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:32]#[N:33])[CH2:16][CH2:15]2)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH2:7][CH2:6][CH2:5][CH:4]3[CH2:3][CH2:2]1
Reactant: O=C1CCN(C2CCC3CCCc4cccc2c43)CC1
Reactant: Nc1ccccc1
Reactant: C[Si](C)(C)C#N
Agent: N
Solvent: CC(=O)O
Product: N#CC1(Nc2ccccc2)CCN(C2CCC3CCCc4cccc2c43)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
(1RS,3aRS)-1-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-piperidin-4-one (2.62 g, 9.7 mmol) was dissolved in acetic acid (12 ml). Aniline (0.97 ml, 10.6 mmol) and trimethylsilylcyanide (1.2 ml, 9.7 mmol) were added and the mixture was stirred for 3 h at RT. The reaction mixture was poured into cold ammonia solution (40 ml), extracted with methylene chloride (2×200 ml) and brine (150 ml). The combined organic layers were combined, dried with magnesium sulfate and concentrated. Crystallization from diethylether/hexane yielded (1RS,3aRS)-1-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-4-phenylamino-piperidine-4-carbonitrile (3.1 g, 86%) as a pale yellow solid, m.p. 142° C. and MS: m/e=372.4 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([CH3:18])[CH:9]=1)=[O:6].[CH3:19][O:20][C:21]([C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:19][O:20][C:21]([C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[CH:9]=2)=[O:6])[CH2:27][CH2:28]1)=[O:22]
Reactant: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Reactant: COC(=O)C1(c2ccccc2)CCNCC1
Product: COC(=O)C1(c2ccccc2)CCN(CCNC(=O)Nc2cc(C)nc3ccccc23)CC1

Procedure:
The compound is prepared from 1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (Example 1A, 2.6 g, 10 mmol)) and 4-phenyl-piperidine-4-carboxylic acid methyl ester (4.38 g, 20 mmol) using the method of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]Cl.[CH3:11][NH:12][CH:13]=[N:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22]>N1C=CC=CC=1>[CH3:11][N:12]([S:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH:13]=[N:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22]
Reactant: CNC=Nc1c(C)cccc1Cl
Reactant: ClSc1cc(Cl)ccc1Cl
Solvent: c1ccncc1
Product: Cc1cccc(Cl)c1N=CN(C)Sc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
32.1 g of 2,5-dichlorophenylsulfenyl chloride is added dropwise at 5°-10° C., with continuous stirring, to a solution of 27.4 g of N-methyl-N'-(2'-chloro-6'-methylphenyl)-formamidine in 70 ml of pyridine. The mixture is stirred for 20 minutes at room temperature; the excess pyridine is then removed at 1 mm Hg pressure and 50° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[CH2:37][C:38]#[N:39])[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH3:41][C:42]([CH3:46])([CH3:45])[CH:43]=O.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[C:37]([C:38]#[N:39])=[CH:41][C:42]([CH3:46])([CH3:45])[CH3:43])[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CC(C)(C)C=O
Reactant: N#CCC(=O)N1CCCC(n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)C=C(C#N)C(=O)N1CCCC(n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Temperature: 30 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
Into a 50-mL round-bottom flask, was placed N-(4-[4-amino-1-[1-(2-cyanoacetyl)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl)-4-(trifluoromethyl)benzamide (130 mg, 0.24 mmol, 1.00 equiv), 2,2-dimethylpropanal (2 mL), piperidine (1 mL), and methanol (30 mL). The resulting solution was stirred for 24 h at 30° C. in an oil bath. The resulting mixture was concentrated under vacuum and residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1 to give 40 mg (27%) of N-[4-(4-amino-1-[1-[2-cyano-2-(2,2-dimethylpropylidene)acetyl]piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-4-(trifluoromethyl)benzamide as a white solid. MS (ESI, pos. ion) m/z: 617 (M+1), 1HNMR (300 MHz, CDCl3, ppm), 8.364 (1H, s), 8.212 (1H, s), 8.086˜8.059 (2H, t), 7.929˜7.901 (2H, d, J=8.4), 7.827˜7.800 (2H, d, J=8.1), 7.742˜7.715 (2H, d, J=8.1), 6.963 (1H, s), 6.3 (2H, s), 5.031˜4.934 (1H, m), 4.8-3.05 (4H, m), 2.738˜2.067 (5H, m), 1.274 (9H, s).