Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CO[CH:18](OC)[CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C.CN(C)C=[O:41]>O>[NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:18][C:19]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[O:41])[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN(C)C=O
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: COC(CNc1ccccn1)OC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CN1CCN(c2cccc3[nH]ccc23)CC1)Nc1ccccn1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 1.4 g of 1-(4-indolyl)piperazine, 1.26 g of 2-chloro-N-(2-pyridyl)acetamide (prepared as described in Beilstein E III/IV, 22, 3881), 1.3 ml of diisopropylethylamine, and 14 ml of N,N-dimethylformamide was stirred at 60° C. under nitrogen stream for 4 h. Afterwards, the mixture was diluted with 200 ml of water and extracted with ethyl acetate (4×50 ml). The organic layers were washed with water, dried (sodium sulfate) and evaporated to dryness in vacuo affording 2.37 g of the title compound as a crude base, which was crystallized from MeOH affording 1.6 g melting at 198-201° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH:14]([N:17](CC)C(C)C)(C)C.CN.O1CCCC1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:17][CH3:14])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A solution of 5-fluoro-2-nitrobenzoic acid (0.5 g, 2.7 mmol) in dichloromethane (10 mL) was cooled with an ice water bath before the addition of N,N-diisopropylethylamine (1.13 g, 8.1 mmol). To this solution 2M methylamine in tetrahydrofuran (1.6 g, 3.24 mmol) was added dropwise over 5 minutes. 1-Propanephosphonic acid cyclic anhydride as a 50% wt solution in ethyl acetate (2.56 mL, 4.05 mmol) was added dropwise. The ice bath was then removed and stirring continued overnight. The mixture was purified on a 2 g ABW column to afford 5-fluoro-N-methyl-2-nitrobenzamide (0.26 g, 1.31 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([OH:8])=[C:4]2[O:9][C:10]([Cl:12])=[CH:11][C:3]=12.[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]2[CH:11]=[C:10]([Cl:12])[O:9][C:4]=2[C:5](=[O:8])[N:6]([CH3:13])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ncc(Br)c2cc(Cl)oc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Br)c2cc(Cl)oc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A 0.2 M solution of 4-bromo-2-chlorofuro[2,3-c]pyridin-7-ol (143 mg, 0.6 mmol) and K2CO3 (200 mg, 1.45 mmol) in DMF stirred at 0° C. under an atmosphere of nitrogen was treated with MeI (99 mg, 0.7 mmol). The ice bath was removed; the mixture was stirred at rt overnight. The reaction mixture was treated water (15 mL) and was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (15 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of EtOAc (10 to 100%) in hexanes to afford the title compound (113 mg, 85%) as a white solid. LCMS (M+H)+=263.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]SC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:22])[C@H:9]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSC
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](c1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To (R)-methyl 2-(tert-butoxycarbonylamino)-2-phenylacetate (E4) in DMF at −40° C. was added NaH and the solution was warmed to 0° C. for 20 minutes. DMS was added and solution was stirred at room temperature for 3 hours. The mixture was poured into NH4Cl(sat)/HCl (1N) 3:1 and extracted with EtOAc. The organics were dried (Na2SO4), filtered and evaporated to give crude E5. Column chromatography Hexanes/EtOAc gave pure (R)-methyl 2-(tert-butoxycarbonyl(methyl)amino)-2-phenylacetate (E5).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-])=O)[CH:6]=[C:5]1[C:16]1[S:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=1.O1CCCC1.O.NN>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.C(O)C>[NH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[N:4]([CH2:3][O:2][CH3:1])[C:5]([C:16]1[S:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=1)=[CH:6]2
Reactant: CCOC(=O)c1cnc(-c2cc3cccc([N+](=O)[O-])c3n2COC)s1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc(-c2cc3cccc(N)c3n2COC)s1
Yield: 97.4 %

Procedure:
A mixture of ethyl 2-[1-(methoxymethyl)-7-nitro-1H-indol-2-yl]-1,3-thiazole-5-carboxylate (2.44 g), iron(III) chloride hexahydrate (92 mg), activated carbon (1.0 g), tetrahydrofuran (10 mL) and ethanol (5 mL) was heated under reflux for 20 min. To the reaction mixture was added hydrazine monohydrate (2.05 g) over 15 min while heating under reflux. The reaction mixture was heated under reflux for 5 hr, filtrated, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated brine, dried (MgSO4), and concentrated. Isopropyl ether was added to the obtained residue. The resulting crystals were collected by filtration, washed with isopropyl ether, and dried to give the title compound (2.18 g, yield 97%) as yellow crystals. melting point 188-190° C.
Reaction SMILES: N1C=CC=CC=1.CS(C)=O.Cl[S:12]([C:15]1[N:23]=[C:22]2[N:17]([C:18]([O:25][CH3:26])=[N:19][C:20]([CH3:24])=[CH:21]2)[N:16]=1)(=[O:14])=[O:13].[NH2:27][C:28]1[C:29]([C:36]([F:39])([F:38])[F:37])=[N:30][N:31]([CH2:34][CH3:35])[C:32]=1[CH3:33]>C(#N)C>[CH2:34]([N:31]1[C:32]([CH3:33])=[C:28]([NH:27][S:12]([C:15]2[N:23]=[C:22]3[N:17]([C:18]([O:25][CH3:26])=[N:19][C:20]([CH3:24])=[CH:21]3)[N:16]=2)(=[O:14])=[O:13])[C:29]([C:36]([F:38])([F:37])[F:39])=[N:30]1)[CH3:35]
Reactant: COc1nc(C)cc2nc(S(=O)(=O)Cl)nn12
Reactant: CCn1nc(C(F)(F)F)c(N)c1C
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CS(C)=O
Product: CCn1nc(C(F)(F)F)c(NS(=O)(=O)c2nc3cc(C)nc(OC)n3n2)c1C
Reaction time: 18 h

Procedure:
Pyridine (0.32 g (4.0 mmol)) and dimethyl sulfoxide (0.03 g (0.4 mmol)) were added to a solution of 1.0 g (4.0 mmol) of 2-chlorosulfonyl-5-methoxy-7-methyl[1,2,4]triazolo[1,5-c]pyrimidine and 0.77 g (4.0 mmol) of 4-amino-1-ethyl-5-methyl-3-(trifluoromethyl)pyrazole in 15 mL of acetonitrile at ambient temperature with stirring. After 18 hours, the volatiles were removed by evaporation under reduced pressure and the residue was partitioned between dichloromethane and water, stirring for 10 min before separation. The solids were recovered by filtration and washed with ether. They were then resuspended in water and the mixture stirred for 30 min. The solids were recovered by filtration, washed with ether, and dried under reduced pressure at 40° C. overnight. The resulting 1.3 g (78 percent of theory) of white powder melting at 208°-209° C. was the title compound (Compound 1).
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[S:11]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]12.[OH-].[Na+]>ClCCl.ClC>[CH:4]([C:16]1[N:13]2[C:12]([S:11][CH:15]=[CH:14]2)=[CH:18][N:17]=1)=[O:5]
Reactant: c1cn2cncc2s1
Reactant: CN(C)C=O
Agent: CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ncc2sccn12

Procedure:
To the mixture of 15.48 ml of DMF and 80 ml of dichloromethane was added dropwise a solution of 18.32 ml of phosphorus oxychloride in 80 ml of dichloromethane under ice-cooling. The mixture was reacted at room temperature for 30 minutes, and a solution of imidazo[5,1-b]thiazole in 40 ml of chloromethane was added dropwise. After heating under reflux for 2.5 hours, the reaction mixture was poured onto ice, adjusted to pH 9.8 with a 5 N aqueous sodium hydroxide solution, extracted five times with 200 ml of dichloromethane, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:ethyl acetate=5:1-ethyl acetate alone—dichloromethane:methanol=10:1). As a low polar component, 5-formylimidazo[5,1-b]thiazole was obtained in a yield of 495 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19].N1CCCCC1>COCCO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:17]2[S:13][C:14](=[O:19])[NH:15][C:16]2=[O:18])=[CH:6][CH:5]=1
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: COCCO
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(C=C2SC(=O)NC2=O)cc1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A solution of 4-formyl-benzoic acid methyl ester (1.0 g, 6.7 mmol), thiazolidine-2,4 dione (0.78 g, 6.7 mmol) and piperidine (0.66 ml, 6.7 mmol) in 2-methoxy-ethanol (20 ml) was refluxed for 2 hrs, cooled to the room temperature and evaporated. The residue was triturated with CH2Cl2 to produce a crystalline material which was collected by filtration to afford the title compound (620 mg, 35% yield). LRMS: 263.3 (calcd.), 264.1 [MH]+ (found).
Reaction SMILES: [N:1]1([S:6]([CH2:9][C:10](=O)[CH3:11])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=O.[CH3:23][C:24]1[CH:28]=[C:27]([NH2:29])[NH:26][N:25]=1>N1CCCCC1.O1CCOCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]2[N:26]3[N:25]=[C:24]([CH3:23])[CH:28]=[C:27]3[NH:29][C:10]([CH3:11])=[C:9]2[S:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(N)[nH]n1
Reactant: CC(=O)CS(=O)(=O)N1CCCC1
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: CC1=C(S(=O)(=O)N2CCCC2)C(c2ccc(Cl)c(Cl)c2)n2nc(C)cc2N1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 1-(pyrrolidin-1-ylsulfonyl)propan-2-one (191 mg, 1.0 mmol), 3,4-dichlorobenzaldehyde (175 mg, 1.0 mmol), 3-methyl-1H-pyrazol-5-amine (97 mg, 1.0 mmol), piperidine (2 drops) and Ti(OPr-i)4 (2 drops) in 1,4-dioxane (4.0 mL) in a sealed tube was stirred at 80° C. for 24 hrs. Solvent was removed and the residue was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in hexane gradient) to provide 7-(3,4-dichlorophenyl)-2,5-dimethyl-6-(pyrrolidin-1-ylsulfonyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine as a white solid. LC-MS found: (M+1)+=427.10. The two enantiomers were separated with ChiralPAK AS using 20% EtOH-MeOH(1:1) in heptane as mobile phase.
Reaction SMILES: CN(C=O)C.[N:6]1([CH2:10][C@@H:11]2[CH2:14][C@H:13]([N:15]3[C:19]4[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=4[C:17](I)=[CH:16]3)[CH2:12]2)[CH2:9][CH2:8][CH2:7]1.[C:26]1([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:38]=3)[N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[N:6]1([CH2:10][C@@H:11]2[CH2:14][C@H:13]([N:15]3[C:19]4[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=4[C:17]([C:36]4[CH:35]=[C:34]5[C:39]([CH:40]=[CH:41][C:32]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:33]5)=[CH:38][CH:37]=4)=[CH:16]3)[CH2:12]2)[CH2:9][CH2:8][CH2:7]1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](CN2CCC2)C1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@@H](CN2CCC2)C1
Temperature: 80 °C

Procedure:
To the DMF solution from the preparation of cis-7-(3-azetidin-1-ylmethylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine were added 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (40 mg, 0.12 mmol), Na2CO3 (27 mg, 0.25 mmol), Pd(PPh3)4 (7 mg, 0.006 mmol), and water (0.6 mL). The solution was purged with nitrogen for 10 min and heated to 80° C. for 16 h. To the cooled reaction solution was added sat. Na2CO3 solution (10 mL), the mixture was extracted with EtOAc (3×20 mL), the combined organic layers were washed with water (3×15 mL) and brine, dried over MgSO4, filtered, and concentrated to give a brown oil. Purification by HPLC gave the title compound as brown oil. 1H NMR (CDCl3, 400 MHz): δ=2.06-2.26 (m, 5H), 2.56-2.57 (d, 2H, J=6.2), 2.71-2.77 (m, 2H), 3.21-3.24 (m, 4H), 5.17 (brs, 2H), 5.19-5.26 (m, 1H), 7.31 (s, 1H), 7.46-7.56 (m, 3H), 7.69-7.71 (dd, 1H, J=1.6 & 8.4 Hz), 7.90-7.94 (m, 2H), 8.18-8.20 (m, 2H), 8.26-8.29 (m, 2H), 8.35 (s, 1H). MS (ES+): 461.2 [MH+]. HPLC: tR=2.0 min (polar—5 min).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH2:13][CH:14]([NH2:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:5][O:4][C:2](=[O:3])[NH:16][CH:14]([CH3:15])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1
Reactant: CC(N)Cc1cccc(Cl)c1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)NC(C)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
At 0° C., methyl chloroformate (0.67 g, 7.1 mmol) was added dropwise to a mixture of 2-(3-chloro-phenyl)-1-methyl-ethylamine (1.0 g, 5.9 mmol) and potassium carbonate (1.63 g, 11.8 mmol) in THF (20 mL). After the addition, the mixture was stirred at room temperature overnight. After filtration and evaporation of the volatiles, the crude product was purified by flash column chromatography (silica gel, 12 g, 50% hexane in dichloromethane) to give the title compound as a white solid (1.2 g, 90%). MS: 228.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][C@H:16]1[CH2:18][O:17]1.C(N(CC)CC)C>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:15][C@@H:16]([OH:17])[CH3:18])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[C@H]1CO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H](O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Yield: 92.5 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300 mg, 1.5 mmol)(Aldrich Cat. No. 525057), (S)-(−)-methyloxirane (130 μL, 1.9 mmol) and triethylamine (0.45 mL, 3.2 mmol) in acetonitrile (1.0 mL) in a reaction vial was stirred at 50° C. for 2 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.35 g). LCMS (M+H)+=253.0.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CO[CH2:7][Cl:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([S:17][CH3:18])[CH:11]=1.O>C(=S)=S>[Cl:8][CH2:7][C:15]1[C:10]([F:9])=[CH:11][C:12]([S:17][CH3:18])=[C:13]([CH3:16])[CH:14]=1
Reactant: CSc1cc(F)ccc1C
Reactant: COCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: CSc1cc(F)c(CCl)cc1C
Reaction time: 0.5 h

Procedure:
To a suspension of aluminum chloride (29 g) in carbon disulfide (300 ml) is added chloromethyl methyl ether (17 ml), and the mixture is stirred for 30 minutes. To the mixture is added 4-fluoro-2-methylthiotoluene (17.2 g), and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added water, and the mixture is extracted with diethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-chloromethyl-4-fluoro-2methylthiotoluene (21 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C(O)(=O)C.[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1>C(O)C>[ClH:20].[Cl:20][C:18]1[CH:19]=[C:14]2[C:15](=[CH:16][CH:17]=1)[N:21]1[CH:22]=[CH:23][CH:24]=[C:25]1[C:5]1([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[NH:13]2
Reactant: CN1CCC(=O)CC1
Reactant: Nc1cc(Cl)ccc1-n1cccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCC2(CC1)Nc1cc(Cl)ccc1-n1cccc12
Product: Cl

Procedure:
1.7 g (0.016 mole) of 1-methyl-4-piperidone and 3 ml. of glacial acetic acid are added to a solution of 2.7 g (0.014 mole) of 1-(2-amino-4-chloro-phenyl) pyrrole, Example 13(b), in 50 ml. of absolute ethanol. The solution is refluxed for 36 hours and concentrated, and the residue dissolved in water. The aqueous solution is filtered, and the filtrate is basified. A solid precipitates, is filtered, and dried. The solid is dissolved in ether and ethereal-hydrogen chloride is added. The resulting precipitate is filtered, dried, and recrystallized from methanol to give 7-chloro-4,5-dihydro-1'-methylspiro-[pyrrolo (1,2-a)quinoxaline-4,4'-piperidine] hydrochloride, m.p. 297°-298° C.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26]C)[CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:6][C:5]=1[C:30]([F:33])([F:32])[F:31])([O-:3])=[O:2].B(Br)(Br)Br.CCOC(C)=O.CCCCCC>C(Cl)Cl>[N+:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[S:18][C:19]4[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:15][CH:16]=2)=[O:9])=[CH:6][C:5]=1[C:30]([F:33])([F:32])[F:31])([O-:3])=[O:2]
Reactant: COc1ccc2nc(-c3ccc(NC(=O)c4ccc([N+](=O)[O-])c(C(F)(F)F)c4)cc3)sc2c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nc3ccc(O)cc3s2)cc1)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 72.6 %

Procedure:
Prepared as described in the Demethylation section using 4-nitro-3-trifluoromethyl-N-[4-(6-methoxybenzothiazol-2-yl)-phenyl]-benzamide (0.10 g, 0.21 mmol) in dry DCM (10 ml) and BBr3 (1.0 M solution in DCM, 1.1 ml, 1.1 mmol) to give the title compound (0.07 g, 71%) as a yellow solid after work-up and flash chromatography (3:1 EtOAc/Hexane).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)=[O:13].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].Cl>CS(C)=O.O>[CH3:20][N:17]1[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:15][CH2:16]1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CN1CCN(C(=O)CCc2ccccc2O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccccc1CCC(=O)N1CCN(C)CC1
Temperature: 80 °C
Reaction time: 3.75 h
Yield: 9.3 %

Procedure:
10% sodium hydroxide aqueous solution (6.70 g) was added to a solution containing 3-(2-hydroxyphenyl)-1-(4-methylpiperazino)-1-propanone (2.07 g) obtained in Example 3(1) in dimethylsulfoxide (21 ml). The mixture was heated up to 80° C. and 1-bromooctadecane (2.78 g) was added thereto. After being stirred for 3.75 hours at 80° C., the reaction mixture, with water added thereto, was neutralized with 1N hydrochloric acid. The deposited solid was corrected by filtration and washed with water. This solid was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=50:1 to 10:1), thereby yielding the entitled compound (0.39 g) as white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:6]1[CH2:9][C:8](=O)[CH2:7]1.C[Si]([C:15]#[N:16])(C)C.[OH-].[Na+]>ClCCl.C(O)(=O)C>[N:1]1([C:8]2([C:15]#[N:16])[CH2:9][O:6][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#N
Reactant: C1CCNC1
Reactant: O=C1COC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#CC1(N2CCCC2)COC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (7.4 g, 104 mmol) was slowly added at 0° C. to acetic acid (33 mL). 3-Oxetanone (1.5 g, 21 mmol) and trimethylsilyl cyanide (5.3 g, 52 mmol) were also added at 0° C. The reaction mixture was stirred at room temperature overnight and diluted with 100 mL dichloromethane. 32% sodium hydroxide solution was pH-9 (˜50 mL). The mixture was extracted twice with dichloromethane. The combined organic phases were dried on sodium sulfate, filtered and carefully evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol 1:0→19:1) yielded 3-pyrrolidin-1-yl-oxetane-3-carbonitrile as a light yellow oil (3.22 g, contains 19% dichloromethane, 92%), MS: m/e=153.1 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O.CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 8.00 g. of p-chlorocinnamic acid and 4.72 ml. of thionyl chloride in 50 ml. ether is added 1.01 ml. of dimethyl formamide. Two liquid phases are then formed and the reaction mixture is stirred overnight at room temperature. The upper phase is decanted and the solvent evaporated from it to yield p-chlorocinnamoyl chloride.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.C1COCC1.CO.Cl>C1COCC1>[CH:1]1([NH:7][S:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:13]([CH2:14][OH:15])[CH:12]=2)(=[O:9])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)NC2CCCCC2)c1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(NC1CCCCC1)c1cccc(CO)c1
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of 3-[(cyclohexylamino)sulfonyl]benzoic acid (2.25 g) in THF (100 ml) under nitrogen at 0° was treated dropwise with 1M borane-THF solution (23.82 ml). The mixture was stirred at 0° for 0.5 h and then at 20° for 72 h. The mixture was cooled to 0° and MeOH (20 ml) was added dropwise. The mixture was stirred for 15 min and then 2N hydrochloric acid (50 ml) was added and the mixture was allowed to warm to 20°. The bulk of the organic solvents were removed by evaporation in vacuo and the residual aqueous phase was extracted with EtOAc (2×40 ml). The combined extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The residue was putted by SPE on alumina (10 g, activated, neutral, Brockmann 1). Elution with MeOH-dichloromethane (1:20) gave the title compound (1.944 g). LCMS RT=2.95 min, ES+ve 270 (MH)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:23][C:22]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc(C(F)(F)F)cc2C1=O
Yield: 11.7 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-4-d: 120 mg, 0.558 mmol) was reacted with 3-iodo-4-methyl-pyridine (134 mg, 0.613 mmol), 1,4-dioxane (5 mL), copper iodide (10.6 mg, 0.0558 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (23.7 mg, 0.167 mmol) and potassium phosphate (354 mg, 1.674 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afforded 20 mg of the product (11.71% yield).