Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[H][H].[Br:5][C:6]1[CH:7]=[C:8]([SH:12])[CH:9]=[CH:10][CH:11]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(O)(C)(C)C.C1COCC1>[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:12][C:8]2[CH:7]=[C:6]([Br:5])[CH:11]=[CH:10][CH:9]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: [H][H]
Reactant: Sc1cccc(Br)c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Sc2cccc(Br)c2)cc1
Reaction time: 0.17 h
Yield: 118.2 %

Procedure:
A 500 mL round bottomed flask equipped with a magnetic stirbar was charged with sodium hydride (3.78 g of a 60% oil dispersion, 95 mmol), and freshly dried THF (200 mL) under a stream of nitrogen. To the stirred suspension was added t-butanol (8 mL). When hydrogen gas evolution ceased, m-bromobenzenethiol (12.0 g, 63 mmol) was via syringe over 5 rain and the resulting solution was stirred for 10 min. To this solution was added in a single portion p-nitrobromobenzene (10.7 g, 52.9 mmol). The solution was stirred at room temperature for 45 min and sodium hydride (0.5 g of a 60% oil dispersion, 12.5 mmol) was added. After 30 min m-bromobenzenethiol (1.0 mL, 9.7 mmol) was added and the reaction was judged to be complete 30 min later by tlc. The reaction mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x, 100 mL). The combined organic extracts were washed (1x, 15% aqueous sodium hydroxide; 2x, brine), dried (Na2SO4), filtered and concentrated in vacuo to to ~400 mL. Decolorizing carbon was added to the organic extracts and the solution was filtered through a celite pad as and concentrated in vacuo to give the unpurified product as an orange solid (19.4 g). The solid was taken up in ether and treated with decolorizing carbon, filtered through celitc, and the volatiles removed in vacuo. Two recrystallizations from ether/hexanes provided pure 3-(p-nitrobenzenethioxy)bromobenzene.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH:14]([CH2:21][C:22]2([CH3:27])[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:15]3=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C1(C)C=CC=CC=1.OS(O)(=O)=O>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14]([CH2:21][C:22]2([CH3:27])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:15]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(CC2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCC1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1(CC2=Cc3cccc(-c4ccc(C(C)(C)C)cc4)c3C2)CCCC1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
19.5 g of crude 4-(4-tert-butyl-phenyl)-2-[(1-methylcyclopentyl)methyl]-indan-1-one (˜86% purity), 2.06 g (54.5 mmol) of NaBH4 and 52 ml of toluene are charged in a flask equipped with reflux condenser, dropping funnel and magnetic stirring bar. The mixture is warmed to 50° C. and 10 ml of methanol are slowly added with stirring and stirring is continued for 2.5 h to ensure a complete reaction. Excess NaBH4 is carefully hydrolyzed with approx. 30 ml of 2n H2SO4. The organic phase is separated and the water phase is washed with another 26 ml of toluene. The combined organic phases are twice extracted with 2n H2SO4 and dried over anhydrous MgSO4. Most of the solvent is removed in a vacuum and replaced by fresh toluene up to a total volume of 75 ml and 0.22 g of p-toluenesulfonic acid are added. The reaction flask is fitted with a water separator and the reaction mixture is heated to reflux for 1.5 h. The conversion can be monitored by TLC. Once the dehydration is complete, the solution is washed with a saturated NaHCO3 solution and dried over anhydrous MgSO4. The solvent is thoroughly removed in a vacuum and a brown oil is obtained. Purification of the indene is carried out via a column chromatography. Yield: 13.8 g (˜86%) of 7-(4-tert-Butyl-phenyl)-2-[(1-methylcyclopentyl)methyl]-1H-indene.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([O:17][CH3:18])[CH2:15][C:14](=O)[CH2:13][CH:12]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH-:27].[NH4+:28].Cl.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C@:6]3([C@@H:16]([O:17][CH3:18])[CH2:15]/[C:14](=[N:28]/[OH:27])/[CH2:13][C@H:12]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: COC1CC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Reactant: [NH4+]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CO[C@H]1C/C(=N/O)C[C@@H](c2cccc(Cl)c2)[C@]12C(=O)Nc1cc(Br)ccc12
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To the suspension of rac-(1R,2S,6S)-6′-bromo-2-(3-chlorophenyl)-6-methoxyspiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (1.69 g, 3.89 mmol) and NH4OH—HCl (0.27 g, 3.89 mmol) in EtOH (40 mL) was added a queous NaOH solution (1N, 4 mL, 4 mmol). The reaction mixture was heated at reflux for 1 h. TLC analysis indicated the formation of desired product and complete consumption of starting material. The reaction was cooled to room temperature, and water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3, 1:2, then 1:1) to give the less polar product rac-E-(1R,2S,6S)-6′-bromo-2-(3-chlorophenyl)-6-methoxy spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione-4-oxime as a white solid (0.8 g, 46%): HRMS (ES+) m/z Calcd for C22H18BrClN2O3+H [(M+H)+]: 449.0262, Found: 449.0260; rac-Z-(1R,2S,6S)-6′-bromo-2-(3-chlorophenyl)-6-methoxy spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione-4-oxime as a white solid (0.8 g, 46%): HRMS (ES+) m/z Calcd for C22H18BrClN2O3+H [(M+H)+]: 449.0262, Found: 449.0261.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH:16]([NH:19][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[S:21])([CH3:18])[CH3:17]>>[ClH:1].[CH:23]([N:22]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:21][C:20]1=[N:19][CH:16]([CH3:18])[CH3:17])([CH3:25])[CH3:24]
Reactant: Cc1ccc(C(=O)CCl)cc1S(N)(=O)=O
Reactant: CC(C)NC(=S)NC(C)C
Product: Cc1ccc(C2(O)CSC(=NC(C)C)N2C(C)C)cc1S(N)(=O)=O
Product: Cl

Procedure:
5 g of 2-chloro-4'-methyl-3'-sulfamoylacetophenone and 3.2 g of 1,3-diisopropyl thiourea were reacted as prescribed in Example 12 and worked up according to Example 67d). Colorless crystals, melting point: 152° C (decomposition).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>C1COCC1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:15][CH:14]=1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)cc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-chlorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O.O>C(O)(=O)C.C(OCC)(=O)C>[Cl:22][C:10]1[NH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:12]([S:13]([C:16]([F:17])([F:19])[F:18])(=[O:14])=[O:15])[CH:11]=1
Reactant: O=S(=O)(c1cc[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(c1cc(Cl)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(trifluoromethyl)sulfonyl]pyrrole (1.0 g, 0.00323 mol) in acetic acid is treated with thionyl chloride (0.43 g, 0.00323 mol), stirred for 30 minutes, poured into water and decanted to obtain a residue. The residue is dissolved in ethyl acetate and the organic solution is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a dark syrup. Flash chromatography of the syrup using silica gel and a 1:5 ethyl acetate/hexanes solution gives the title product as a yellow solid (0.43 g, mp 109°-112° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [CH3:1][C@H:2]([NH:15][CH2:16][C@@H:17]([C:19]1[CH:20]=[CH:21][C:22]2[N:23](N=N[N:27]=2)[CH:24]=1)[OH:18])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][CH:5]=1.O.O.[Cl:30][Sn]Cl.C(Cl)[Cl:34].[OH-].[Na+]>CO.Cl.CCOCC>[ClH:30].[ClH:34].[NH2:27][C:22]1[N:23]=[CH:24][C:19]([C@H:17]([CH2:16][NH:15][C@@H:2]([CH3:1])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[NH:6][CH:5]=2)[OH:18])=[CH:20][CH:21]=1
Reactant: Cl[Sn]Cl
Reactant: COc1ccc2[nH]cc(C[C@H](C)NC[C@H](O)c3ccc4nnnn4c3)c2c1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: COc1ccc2[nH]cc(C[C@H](C)NC[C@H](O)c3ccc(N)nc3)c2c1
Reaction time: 0.33 h

Procedure:
To a solution of this tetrazole (391 mg) in 10 ml of methanol, 0.1 ml of concentrated HCl and 473 mg of SnCl2.2H2O were added. The reaction mixture was heated at reflux under nitrogen for 16 hours and then poured into a solution of CH2Cl2 (45 ml) and 1N NaOH solution (64 ml). The mixture was stirred for 20 minutes and the layers then separated. The aqueous phase was further extracted with CH2Cl2. The combined organic extracts were backed washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solution was concentrated and the crude residue (309 mg) was purified by preparative TLC on silica gel (90:10:1 CH2Cl2 :MeOH:NH4OH) to afford pure product which was converted to its hydrochloride salt with ethanolic HCl. The salt was isolated by dilution with ether and filtration, 240 mg; mp 264° C.; [α]D 25°=-8.45 (c= 1.0, MeOH); Analysis: Calculated for C19H24N4O2.2HCl: C, 55.21; H, 6.34; N, 13.56. Found: C, 54.82; H, 6.60; N, 13.08.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([Si:14]1(C2C=CC=CC=2)[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1)[CH2:10][CH2:11][CH:12]=[CH2:13]>>[CH2:9]([Si@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:21])[CH2:18][CH2:19]1)[CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: Oc1ccc(F)cc1
Reactant: C=CCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Product: C=CCCC[Si@H]1CC[C@H](C(=O)Oc2ccc(F)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using (4-fluorophenol and 4-(4-pentenyl)-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[CH:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([S:15](Cl)(=[O:17])=[O:16])[C:9]=2[CH:8]=[CH:7][N:6]=1.CO.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[NH2:1][CH2:2][CH2:3][NH:4][S:15]([C:10]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:14]=2[CH:13]=[CH:12][CH:11]=1)(=[O:16])=[O:17]
Reactant: NCCN
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NCCNS(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 65.7 %

Procedure:
In 200 ml of chloroform was dissolved 12.0 g of 1,2-diaminoethane, and to the solution was added dropwise 100 ml of a chloroform solution containing 4.55 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for two hours, and then the reaction solution was extracted with a 10% aqueous hydrochloric acid solution. The pH of the aqueous layer was adjusted to 10 with a 10% aqueous sodium hydroxide solution, and the aqueous layer was extracted with chloroform. The chloroform layer extracted was washed with water and dried with anhydrous potassium carbonate. Then the chloroform was distilled from the chloroform layer, and the residue obtained was subjected to a column chromatography [silica gel: 200 g; developing solvent: 2% methanol/chloroform (volume ratio)] to give 3.3 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide as an oily substance in a yield of 66%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[Cl:25][C:26]1[N:27]=[N:28][C:29]([Cl:33])=[CH:30][C:31]=1Cl.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[Cl:25][C:26]1[N:27]=[N:28][C:29]([Cl:33])=[CH:30][C:31]=1[N:23]1[CH:24]=[C:20]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([S:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:12])=[O:13])[CH:7]=2)[CH:21]=[N:22]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: Clc1cc(Cl)c(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3cc(Cl)nnc3Cl)c2)c2ccc(F)cc21
Temperature: 85 °C
Reaction time: 24 h
Yield: 38.7 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 200 mg; 0.59 mmol) in MeCN (10 mL) was added 3,4,6-trichloropyridazine (97 mg; 0.529 mmol) and K2CO3 (146 mg; 1.06 mmol) under nitrogen. The mixture was stirred at 85° C. for 24 hours, diluted with EtOAc (100 mL), washed with water (50 mL×3), brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by reversed phase flash chromatography to afford 100 mg (39%) of the title compound a the yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH3:20])[CH2:15]C[O:13][C:12]([CH3:19])([C:16]([NH2:18])=[O:17])[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([N:27]=[C:28]=[O:29])C=CC=CC=1.[C:30]1(C)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:8][CH2:9][C:10]1([CH3:15])[CH2:20][O:13][C:12]([C:16]([N:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:28]([NH2:27])=[O:29])=[O:17])([CH3:19])[O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(COCc2ccccc2)CCOC(C)(C(N)=O)O1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccccc1
Product: CC1(COCc2ccccc2)COC(C)(C(=O)N(C(N)=O)c2ccccc2)O1

Procedure:
4-Benzyloxymethyl-2,4-dimethyl-1,3-dioxane-2-carboxamide (4.5g) and phenyl isocyanate (2.0g) in toluene (50 ml) were heated together under reflux for 20 hours. The toluene was then removed from the mixture under reduced pressure. The residue was triturated with petroleum ether (b.p. 40°-60° C) and recrystallized from ethanol to give the required product m.p. 91°-94° C.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH2:7][C:8]#[N:9].[C:10]([C:18]1C=CC=CC=1)(=O)[C:11]1C=CC=C[CH:12]=1.[CH2:24](Cl)Cl>>[N:9]1[C:8]2[CH:18]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][CH:24]=1
Reactant: ClCCl
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: N#CCN
Agent: O=S(=O)(O)O
Product: c1ccc2[nH]cnc2c1
Reaction time: 18 h
Yield: 82 %

Procedure:
To a stirred solution of 2-aminoacetonitrile bisulfate (2.9 g, 0.013 mmol) in DCM (50 mL) was added benzophenone (3.48 mL, 0.0208 mmol) followed by DEIA (4.53 mL, 0.026 mmol). After stirring 18 h, the DCM solution was washed with water (50 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified on a flash silica gel column (hexanes:EtOAc, 1:1) to give 3 (2.40 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[CH:6][C:3]=1[CH2:4][OH:5].[Cl:14][C:15]([N:17]1[C@H:22]([CH3:23])[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@@H:18]1[CH3:31])=[O:16]>>[ClH:14].[CH3:31][C@H:18]1[CH2:19][NH:20][CH2:21][C@@H:22]([CH3:23])[N:17]1[C:15]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([O:10][CH:11]([F:12])[F:13])[CH:8]=[CH:9][C:2]=1[F:1])=[O:16]
Reactant: OCc1cc(OC(F)F)ccc1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cc(OC(F)F)ccc1F
Product: Cl

Procedure:
2-Fluoro-5-difluoromethoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from 2-fluoro-5-difluoromethoxybenzyl alcohol and cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 52 and 54 to give the product as a white solid (0.1473 g, 84%); νmax (diffuse reflectance)/cm−1 2780, 2314, 1697, 1593, 1501, 1327, 1209, and 1101; δH (400 MHz, DMSO-d6) 9.74 (1H, br), 9.18 (1H, br), 7.35–7.22 (3H, m), 7.20 (1H, t, J 74 Hz), 5.17 (2H, s), 4.31 (2H, m, J 6.4 Hz), 3.16 (2H, d, J 13 Hz), 3.08 (2H, dd, J 5.2 and 13 Hz), and 1.30 (6H, d, J 7.2 Hz).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].[CH:18](=[N:22][OH:23])[C:19]([CH3:21])=O>CC(O)C>[NH2:15][C:14]1[C:13]([C:16]#[N:17])=[N:12][C:19]([CH3:21])=[CH:18][N+:22]=1[O-:23]
Reactant: CC(=O)C=NO
Reactant: N#CC(N)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cc1c[n+]([O-])c(N)c(C#N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.2 %

Procedure:
Aminomalononitrile p-toluenesulfonate salt (20.0 g, 79 mmol) and pyruvaldehyde 1-oxime (6.88 g, 79 mmol) were combined in a flask. iPrOH (140 mL) was added, and the resulting yellow slurry was allowed to stir at room temperature for 18 h, during which time a yellow precipitate accumulated. The mixture was filtered and the precipitate was washed with iPrOH (2×50 mL) and DI H2O (20 mL), then lyophilized to give 2-amino-3-cyano-5-methypyrazine N-oxide (10.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.O>[N:11]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of p-methoxybenzyl chloride (4.26 mL, 31.4 mmol) in DMF (20 mL) was added sodium azide (2.04 g, 31.4 mmol). The reaction mixture was stirred at room temperature for 48 hours, diluted with H2O (200 mL), and then extracted with ether. The combined organic layers were washed w/H2O, dried over Na2SO4, filtered and conc. The clear oil obtained (4.9 g, 96%) was pure enough to use. 1H NMR (CDCl3, 400 MHz) 7.26-7.23 (m, 2H); 6.93-6.89 (m, H); 4.27 (s, 2H); 3.82 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24]([S:26][CH3:27])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:35].[ClH:37].[NH2:7][CH:8]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:18]3[S:25][C:24]([S:26][CH3:27])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: CSc1cc2ncnc(N3CCN(C(=O)C(Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c2s1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CSc1cc2ncnc(N3CCN(C(=O)C(N)Cc4ccc(Cl)cc4)CC3)c2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-[4-(6-methylsulfanyl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed to afford the product 2-Amino-3-(4-chlorophenyl)-1-[4-(6-methylsulfanyl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H]+ 448.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30].[CH2:32]([O:39]C1C=C2C(C(CC(O)=O)=CN2)=CC=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(NC1C(Cl)=CC(CN)=CC=1Cl)(=O)C>>[CH2:32]([O:39][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([CH2:13][C:12]([N:11]=[C:10]([NH2:26])[NH:9][CH2:8][C:6]3[CH:7]=[C:2]([Cl:1])[C:3]([NH:28][C:29](=[O:31])[CH3:30])=[C:4]([Cl:27])[CH:5]=3)=[O:25])=[CH:15][NH:16]2)=[CH:21][CH:20]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Reactant: O=C(O)Cc1c[nH]c2cc(OCc3ccccc3)ccc12
Agent: CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3cc(OCc4ccccc4)ccc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(6-benzyloxy-1H-indol-3-yl)acetic acid in step 15 (A) and 4-acetamido-3,5-dichloro-benzylamine (preparation B) in step 15 (B), the title compound was prepared. MS (ESI) (M+H)+=538.07 1H-NMR(500 MHz, CD3OD) δ 7.34-7.50 (m, 7 H), 7.24-7.34 (m, 1 H), 7.17 (s, 1 H), 7.00 (d, J=2.14 Hz, 1 H), 6.83 (dd, J=8.70, 2.29 Hz, 1 H), 5.10 (s, 2 H), 4.50 (s, 2 H), 3.92 (s, 2 H), 2.19 (s, 3 H).
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1)(=O)=O.[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1
Reactant: C[C@@H]1CCCN1
Reactant: CS(=O)(=O)O[C@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1CCCN1[C@@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Temperature: 25 °C

Procedure:
A stirred solution of (S)-1-(6-(4-cyanophenyl)benzo[d]thiazol-2-yl)pyrrolidin-3-yl methanesulfonate (Reference Example 13c, 32 mg, 0.080 mmol), (R)-2-methylpyrrolidine (27.3 mg, 0.320 mmol), and N,N-diisopropylethylamine (0.17 mL, 0.961 mmol) in acetonitrile (2 mL) was heated to 150° C. under microwave irradiation for 20 minutes. The reaction mixture was cooled to room temperature then purified by silica gel chromatography (98:2:0 to 98:2:1 dichloromethane/methanol/aqueous NH4OH). Fractions containing product were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give to give 4-(2-((2R,3′R)-2-methyl-1,3′-bipyrrolidin-1′-yl)benzo[d]thiazol-6-yl)benzonitrile. 1H NMR (300 MHz, CD3OD) δ ppm 1.17 (d, J=6 Hz, 3H), 1.45-1.57 (m, 1H), 1.73-1.90 (m, 2H), 1.98-2.20 (m, 2H), 2.24-2.35 (m, 1H), 2.62 (q, J=8 Hz, 1H), 2.83-2.96 (m, 1H), 2.99-3.08 (m, 1H), 3.36-3.62 (m, 3H), 3.69-3.78 (m, 1H), 3.86-3.93 (m, 1H), 7.57 (d, J=8 Hz, 1H), 7.65 (dd, J=2, 9 Hz, 1H), 7.80 (q, J=9 Hz, 4H), 8.03 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 389 (M+H)+.
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8](C)=[CH:7][CH:6]=1)(O)(=O)=O.[CH3:12][N:13]([CH3:30])[C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:25][C:26]([NH2:28])=[NH:27])=[CH:20][C:19]=2[CH3:29])=[O:15].C[O-].[Na+]>CO>[CH3:12][N:13]([CH3:30])[C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:25][C:26]1[N:28]=[C:7]([C:8]3[N:27]=[CH:26][N:25]([CH3:21])[C:10]=3[CH3:11])[CH:6]=[CH:5][N:27]=1)=[CH:20][C:19]=2[CH3:29])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(NC(=N)N)cc2cc(C(=O)N(C)C)[nH]c12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2nccc(-c3ncn(C)c3C)n2)cc2cc(C(=O)N(C)C)[nH]c12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 42.5 mg 4.5, 80.0 mg 7.7 and 10.8 mg sodium methylate in 2 ml methanol was stirred at 140° C. for 60 min under microwave irradiation. The resulting mixture was purified by preparative HPLC. The combined product fractions were evaporated. The residue was dissolved in acetonitrile/water 1/1 and lyophilized to obtain the Example 1.