Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]([OH:13])[C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:11]2[O:12][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:13][C:10]=2[C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)c(O)c(O)c1Cl
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Product: COC(=O)c1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
Methyl 2,5-dichloro-3,4-dihydroxybenzoate (1.1 g) (about 4.6 mmol) and 2.0 g (8.4 mmol) of dichlorodiphenylmethane are heated together to 150° C. After stirring for 1.5 hours the melt is cooled and the product is crystallized from diethyl ether. There are obtained 1.3 g of methyl 4,7-dichloro-2,2-diphenyl-1,3-benzodioxol-5-carboxylate as white crystals of m.p. 112° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH3:25])=[CH:17][CH:16]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([F:14])=[CH:16][CH:17]=4)[CH:22]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(F)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1c2cc(F)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
A solution of 80 mg (0.33 mmol) of 6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid, 66 mg (0.40 mmol) of 7-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline, 63 mg (0.33 mmol) of EDC and 50 mg (0.12 mmol) of HOBt in 2 mL of DMF is stirred at room temperature for 24 h. The mixture is concentrated in vacuo and the solid residue is partitioned between methylene chloride (3 mL) and saturated aqueous sodium hydrocarbonate solution (3 mL). The organic layer is separated, washed with 0.5 N HCl, water and brine and concentrated in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:5]=[CH:6][CH:7]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To the suspension of 4-(3-bromo-phenyl)-1H-indole (1.48 g, 5.44 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (66 mL) was added pyridinium tribromide (90% purity from Aldrich, 5.80 g, 16.3 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (26 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (1.02 g, 65%) as a tan solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:20]2[CH:25]=[CH:24][NH:23][C:22](=[O:26])[C@@H:21]2[CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])(=[O:19])=[O:18])=[C:12]([CH3:35])[CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:20]2[CH:25]=[CH:24][NH:23][C:22](=[O:26])[C@@H:21]2[CH2:27][C:28]([OH:30])=[O:29])(=[O:19])=[O:18])=[C:12]([CH3:35])[CH:11]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2C=CNC(=O)[C@@H]2CC(=O)OC(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N2C=CNC(=O)[C@@H]2CC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (1.5 ml) was added to a cooled (0° C.) solution of (S)-tert-butyl 2-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydropyrazin-2-yl)acetate (210 mg, 1 eq) in DCM (6 ml) and the mixture was stirred for 2 h at room temperature. The solvent was removed under vacuum and the residue used in the subsequent stage.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4](O)[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=1
Reactant: Cc1nc(O)nc(C)c1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)nc(C)c1[N+](=O)[O-]
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A mixture of Compound 1 (500 mg) and phosphorus oxychloride (3.89 g) was stirred for 3 hours under reflux. After the reaction was completed, the mixture was concentrated under reduced pressure. To the resulting residue, chloroform and water were added and the mixture was cooled and neutralized with a 2N aqueous sodium hydroxide solution to a pH of 5 to 7. The mixture was then extracted with chloroform and the organic layer was concentrated under reduced pressure to obtain 411 mg of the desired product. When necessary, some of the product was purified by silica gel column chromatography (ethyl acetate: hexane=1:1) to give a purified product.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:15]1([CH2:20][CH2:21][C:22](O)=[O:23])[CH:19]=[CH:18][N:17]=[CH:16]1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[N:15]1([CH2:20][CH2:21][C:22]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:23])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C(O)CCn1ccnc1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(CCn1ccnc1)N1c2ccccc2Sc2ccccc21
Reaction time: 0.5 h

Procedure:
A mixture of 19.9 g of phenothiazine, 14 g of 3-(imidazol-1-yl)-propionic acid, 20.6 g of dicyclohexylcarbodiimide, and 200 ml of ethyl acetate is stirred for 30 minutes at 0°, and then for 3 hours at 20°. It is worked up in the customary manner to give 10-[3-(imidazol-1-yl)-propionyl]-phenothiazine, melting point 150°-152°.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:35]1([CH3:42])[C:36](Cl)=[CH:37][CH:38]=[CH:39][CH:40]=1>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([O:23][C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:42])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1Cl
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2Oc2ccccc2C)cc1

Procedure:
Following a procedure similar to that described in Example 30A above, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with o-toluyl chloride there is obtained 3-(o-toluyloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3-(o-toluyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol hydrochloride.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=O)=O.[CH3:27][N:28](C=O)C>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N.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>[C:27]([C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2cc(C#N)ccc2C1
Temperature: 80 °C

Procedure:
A mixture of 1,1-dimethylethyl 8-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 31) (0.397 g, 0.999 mmol), zinc cyanide (0.176 g, 1.499 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.115 g, 0.100 mmol) in DMF (4 ml) was stirred and heated at 80° C. for 2 hours then cooled and diluted with EtOAc/water (40 ml of each) and the organic washed with 3×20 ml of water, dried (magnesium sulphate), evaporated and purified by flash chromatography eluting with 1:4 EtOAc/iso-hexane to give the title compound (198 mgs) as a gum which crystallised slowly. MS (ES) C15H18N2O3 requires 274; found 175 [M+H−100]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[C:26]1([O:25][C:23](=[O:24])[N:11]([CH2:10][CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:12]([CH3:14])[CH3:13])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)NCCSc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CCSc1ccc(Cl)cc1)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of 22.8 g (0.1 mole) of N-[2-[(4-chlorophenyl)thio]ethyl]-1-methylethanamine (oil in Preparation 1) and 10.1 g (0.1 mole) of triethylamine in 300 ml of methylene chloride was added dropwise with stirring a solution of 15.7 g (0.1 mole) phenyl chloroformate in 100 ml of methylene chloride. The resulting solution was stirred overnight at room temperature. The methylene chloride layer was extracted with 5% sodium hydroxide solution followed by 1N sulfuric acid. The methylene chloride layer was concentrated to give an oil which crystallized to a white solid. Recrystallization from isopropyl ether gave white crystalline product, m.p. 54°-56° C. in 79.6% yield.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][C:14]=1SC.[C:24]([C:27]1[CH:28]=[CH:29][C:30]([NH:47][CH2:48][CH3:49])=[C:31]([N:33]=[C:34]2[N:38]([CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[C:37](=[O:46])[CH2:36][S:35]2)[CH:32]=1)(=[O:26])[CH3:25]>>[C:24]([C:27]1[CH:28]=[CH:29][C:30]([NH:47][CH2:48][CH3:49])=[C:31]([N:33]=[C:34]2[N:38]([CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[C:37](=[O:46])[C:36](=[C:14]3[N:13]([CH3:12])[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15]3)[S:35]2)[CH:32]=1)(=[O:26])[CH3:25]
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1cccnc1
Reactant: CSc1sc2c([n+]1C)CCCC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2SC3=C(CCCC3)N2C)C(=O)N1Cc1cccnc1

Procedure:
The title compound was prepared in a manner similar to Example 168 by condensing intermediate 3-methyl-2-methylthio-4,5,6,7-tetrahydro-benzothiazol-3-ium p-toluenesulfonate with 2-(5-acetyl-2-ethylaminophenylimino)-3-pyridin-3-ylmethyl-thiazolidin-4-one. MS(ESI): 520 (MH+).
Reaction SMILES: FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:4].[CH3:22][C:23]([CH3:58])([CH2:56][CH3:57])[CH2:24][C:25]1[N:26]=[C:27]([CH:36]([OH:55])[C:37]2([C:43]3[CH:48]=[CH:47][C:46]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=4)=[CH:45][CH:44]=3)SCCCS2)[N:28]([S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:29]=1>C(#N)C.O>[CH3:22][C:23]([CH3:58])([CH2:56][CH3:57])[CH2:24][C:25]1[N:26]=[C:27]([CH:36]([OH:55])[C:37](=[O:4])[C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[CH:45][CH:44]=2)[N:28]([S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:29]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)C2(c3ccc(-c4ccccn4)cc3)SCCCS2)n1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)C(=O)c2ccc(-c3ccccn3)cc2)n1
Temperature: 0 °C

Procedure:
[Bis(trifluoroacetoxy)iodo]benzene (184 mg, 0.48 mmol) was added to a 0° C. solution of 4-(2,2-dimethylbutyl)-2-{hydroxy[2-(4-pyridin-2-ylphenyl)-1,3-dithian-2-yl]methyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (110 mg, 0.20 mmol) in acetonitrile/water (3:1) (4 mL). After stirring at 0° C. until no further reaction (LCMS), the reaction mixture was quenched with saturated aqueous sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1) and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford 4-(2,2-dimethylbutyl)-2-[1-hydroxy-2-oxo-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:12])=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[F:22][C:23]([F:29])([F:28])[CH2:24][C:25](Cl)=[O:26]>ClCCl>[F:22][C:23]([F:29])([F:28])[CH2:24][C:25]([NH:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]2[C:8]=1[CH3:12])=[O:26]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: Cc1c(N)nc2ccc(F)cn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)CC(F)(F)F)nc2ccc(F)cn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-fluoro-3-methylimidazo[1,2-a]pyridin-2-amine (0.033 g, 0.00020 mol) was dissolved in dichloromethane (3.0 mL) and N,N-diisopropylethylamine (0.070 mL, 0.00040 mol) was added. The reaction was cooled to 0° C. and 3,3,3-trifluoropropionyl chloride (29 uL, 0.00024 mol) was added. The mixture was warmed to room temperature and was stirred for 1 hour. Solvent removed and residue was chromatographed on silica (70% ethyl acetate/hexanes) to give 3,3,3-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)propanamide Rf 0.43, 70% ethyl acetate/hexanes; MS m/z 276 (M+H). SH-SY5Y_EC50 (μM): 10.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:21]([OH:23])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[N+:32](=[CH2:34])=[N-:33]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:21](=[O:23])[CH:34]=[N+:32]=[N-:33])=[CH:19][CH:18]=1
Reactant: O=C(NC(Cc1ccc(F)cc1)C(=O)O)OCc1ccccc1
Reactant: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Product: [N-]=[N+]=CC(=O)C(Cc1ccc(F)cc1)NC(=O)OCc1ccccc1

Procedure:
In a manner analogous to that described in Example 19(i), 7.70 g of N-(benzyloxycarbonyl)-3-(4-fluorophenyl)-DL-alanine were treated with isobutyl chloroformate followed by reaction with diazomethane to give 7.15 g of benzyl [2-(4-fluorophenyl)-1(RS)-(2-diazoacetyl)ethyl]carbamate as a yellow solid of melting point 97° C.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][N:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][N:15]=[CH:16][CH:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3cnccc23)CC2CCCN2C1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2=CCN3CCCC3C2)c2ccncc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-6-Azaindole (12 mg, 0.055 mmol), 1-naphthalenesulfonyl chloride (20.9 mg, 0.1 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[K+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(COC)OC>[C:20]1([S:26]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CSc1ccc(-c2c[nH]c3ccccc23)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CSc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a solution of 3-(4-methylthiophenyl)indole (7.34 g, 30.7 mmol), prepared as in step 1, in dimethoxyethane (75 mL) was added powdered KOH (85%, 7.01 g, 125 mmol) and benzenesulfonyl chloride (4.25 mL, 33.3 mmol). A white precipitate formed immediately and the reaction mixture became quite warm. The reaction mixture was stirred for 1 hour during which time it cooled to ambient temperature. Water (50 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo. 1-phenylsulfonyl-3-(4-methylthiophenyl)indole (8.89 g, 76% yield) was obtained by chromatography on silica gel (10%, then 20% ethyl acetate/hexanes).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]([CH3:54])[C:47]1[CH:52]=CC(N)=[CH:49][N:48]=1.O1CCN(CCOC2N=CC(N)=CC=2)CC1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:49]=[N:48][C:47]([N:46]([CH3:54])[CH3:45])=[CH:52][CH:30]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CN(C)c1ccc(N)cn1
Agent: NC(N)=O
Agent: Nc1ccc(OCCN2CCOCC2)nc1
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(N(C)C)nc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 6-(2-morpholinoethoxy)pyridin-3-amine N2,N2-dimethylpyridine-2,5-diamine as the aniline component. (5%, MS=514.3 (M+H))
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([F:26])=[CH:21][C:20]=3[Cl:27])=[C:16]([C:28](OCC)=[O:29])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([F:26])=[CH:21][C:20]=3[Cl:27])=[C:16]([C:28]([N:43]3[CH2:44][CH2:45][CH:40]([C:37]4[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=4)[CH2:41][CH2:42]3)=[O:29])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(C)c(F)cc1Cl
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: Cc1cc(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(=O)(=O)NC(C)(C)C)cnn23)c(Cl)cc1F
Yield: 24 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-chloro-4-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (2.94 g, 6.07 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (1.18 g, 6.58 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.90 g, 33%) was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[C:23]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][NH:14][C:13]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:11]([O:10][CH3:9])[CH:12]=1
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: COc1ccc(N)cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(NCc2ccccc2-c2ccccc2)cc1OC
Temperature: 80 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
Potassium carbonate (1.38 g, 10 mmol), catalytic amount of potassium iodide, and 3,4-dimethoxyaniline (1.53 g 10 mmol) were added to a solution of 2-(bromomethyl)biphenyl (1.83 mL, 10 mmol) in acetonitrile (200 mL). The reaction mixture was heated and stirred at 80° C. for 18 hours, then was cooled to room temperature. The solid was filtered and the filtrate concentrated to dryness. Purification by silica gel column chromatography using 20% ethyl acetate in hexanes as the eluant afforded the pure product (1.04 g). MH+320: 1H (CDCl3) δ 3.77 (3H, s), 3.78 (3H, s), 4.21 (2H, s), 6.05 (1H, dd, J=8, 3), 6.14 (1H, m) 6.67 (1H, d, J=8), 7.28-7.42 (8H, m), 7.54 (1H, m).
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N:11][N:12]=[C:13]2O)=[CH:8][CH:7]=1)[C:3]([CH3:5])=[O:4].O=P(Cl)(Cl)[Cl:26].C([O-])(O)=O.[Na+]>C(#N)C.O>[NH:2]([C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N:11][N:12]=[C:13]2[Cl:26])=[CH:8][CH:7]=1)[C:3]([CH3:5])=[O:4]
Reactant: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(Cl)c2c1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, a suspension of 2.24 g (7.6 mmol) 7-acetamino-1-hydroxy-4-(4-pyridylmethyl)phthalazine hydrochloride (ml -oxo-4-[pyridyl-(4′)-methyl]-7-acetamino-1,2-dihydrophthalazine hydrochloride: for preparation see German Auslegeschrift no. 1 061 788 [published 23.07.1959]) in 22 ml acetonitrile is spiked with 1.74 ml (19 mmol) phosphoroxychloride and heated for 4 h to 95° C. The mixture is cooled to 10° C., and 7.5 g NaHCO3 in 30 ml water is added. The deep-red suspension is stirred for 15 min, filtered, and washed out with water. Drying under HV yields the title compound: HPLC: tRet(Grads-40)=10.2; FAB MS (M+H)+=313.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:15]([Sn](CCCC)(CCCC)C#CC)[CH2:16][CH2:17]C>C1(C)C=CC=CC=1.CCOC(C)=O.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:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:2]([C:15]#[C:16][CH3:17])=[CH:7][N:6]=1
Reactant: CCC(CC)Nc1nc(Cl)ncc1Br
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC#Cc1cnc(Cl)nc1NC(CC)CC
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a microwave vial is added a solution of (5-bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (0.5 g, 1.80 mmol) in anhydrous toluene (10 mL), tributyl(1-propynyl)-tin (1.1 mL, 3.6 mmol) and Pd(PPh3)4 (41.5 mg, 0.036 mmol). The reaction mixture is heated at 120° C. for 1 h by employing microwave. The reaction mixture is diluted with EtOAc, washed with NaHCO3 aqueous solution and water, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, EtOAC/hexane 1:5) gave 0.32 g of (2-chloro-5-prop-1-ynyl-pyrimidin-4-yl)-(1-ethyl-propyl)-amine