Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)=[N:9][N:10]3[CH2:15][CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:16]3[CH:17]=[C:18]([NH:22][C:32](=[O:33])[CH2:31][C:28]4[CH:27]=[CH:26][C:25]([C:24]([F:35])([F:23])[F:36])=[CH:30][CH:29]=4)[CH:19]=[CH:20][CH:21]=3)=[N:9][N:10]3[CH2:15][CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(3-pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenylamine (prepared as described in Example 3) (100 mg, 0.324 mmol) in dichloromethane (8 mL), were added in the following order: (4-trifluoromethyl-phenyl)-acetic acid (132 mg, 0.648 mmol), DIPEA (125 mg, 166 uL, 0.972 mmol) and TBTU (312 mg, 0.972 mmol). The reaction mixture was stirred at room temperature for 3 hours. Then it was poured into a solution of saturated NaHCO3, the phases separated, and the organic phase was washed twice with saturated NaHCO3, and twice with water. The organic solvent was evaporated to dryness and the product was purified by flash chromatography over silica gel using dichloromethane-methanol (98:2) as the eluant system. N-[3-(3-pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamide was obtained as a colorless solid (115 mg, 72%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:31])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.Cl[CH:34]([F:36])[F:35]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:31])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[O:30])[C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:23][CH:24]=1)[C:10]([O:17][CH:34]([F:36])[F:35])=[N:11]2
Reactant: FC(F)Cl
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12
Product: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using {8-chloro-3-[4-(2,2-dimethylpropionyl)benzyl]-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy}acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:14][C:13]([F:16])([F:15])[CH2:12][CH2:11][N:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:9]1=[O:28])(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.[F:46][C:47]([F:55])([F:54])[CH2:48][CH2:49][S:50](Cl)(=[O:52])=[O:51]>ClCCl>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[CH2:11][CH2:12][C:13]([F:15])([F:16])[CH2:14][C@@H:8]([NH:7][S:50]([CH2:49][CH2:48][C:47]([F:55])([F:54])[F:46])(=[O:52])=[O:51])[C:9]1=[O:28]
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](NC(=O)OC(C)(C)C)C2=O)c(OC)c1
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN2CCC(F)(F)C[C@@H](NS(=O)(=O)CCC(F)(F)F)C2=O)c(OC)c1

Procedure:
[(R)-1-(2,4-Dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester (0.85 g, 1.85 mmol) was dissolved in 38 ml dichloromethane. 4 M HCl/1,4-dioxan (20 ml) were added dropwise and the mixture was allowed to react for 1 h. The reaction mixture was concentrated under reduced pressure and concentrated once from acetonitrile. To 291 mg of the resultant hydrochloride salt was added CH2Cl2 (20 ml) followed by the dropwise addition of Hünig's base (0.36 ml, 2.1 mmol). A solution of 3,3,3-trifluoropropane-1-sulfonyl chloride (0.19 g, 0.9 mmol) in CH2Cl2 (5 ml) was added and the reaction mixture (pH 8) was stirred for a further 1.5 h. The reaction mixture was purified over silica gel (heptane-ethylacetate, 95:5-0:100): white solid 0.30 g (77%);
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH3:30])=[O:24])[C:5]1=[O:31].C(N(C(C)C)CC)(C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].O>CN(C=O)C>[C:41]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH3:30])=[O:24])[C:5]1=[O:31])(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(C)=O)c1=O
Temperature: 0 °C

Procedure:
A solution of 1-(2-aminoethyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.020 g, 0.047 mmol) and diisopropyl ethylamine (0.041 mL, 0.24 mmol) in DMF (5 mL) under nitrogen was treated with acetic anhydride (0.0044 mL, 0.047 mmol) at ambient temperature. The reaction was warmed slightly to solubilize the reacted at ambient temperature for 10 min. Water was added (2 mL) and the reaction was cooled to 0° C. and concentrated in vacuo. The resulting residue was treated with 1 N NaHSO4 and filtered then triturated with Et2O and dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 1.1 (t, J=6.9 Hz, 3 H), 1.7 (s, 3 H), 3.3 (dd, J=12.5, 5.3 Hz, 2 H), 3.5 (q, J=7.0 Hz, 2 H), 3.5 (s, 4 H), 4.1 (s, 2 H), 4.3 (t, J=6.7 Hz, 2 H), 7.1 (t, J=9.0 Hz, 2 H), 7.4 (dd, J=8.4, 5.5 Hz, 2 H), 8.0 (t, J=5.6 Hz, 1 H), 8.2 (s, 1 H), 8.6 (s, 1 H), 10.4 (s, 1 H), 17.1 (s, 1 H); ES+ MS: 471 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6].[CH3:9][NH:10][CH3:11]>CCOCC>[CH3:8][S:5]([CH2:4][CH2:3][CH2:2][N:10]([CH3:11])[CH3:9])(=[O:7])=[O:6]
Reactant: CS(=O)(=O)CCCBr
Reactant: CNC
Solvent: CCOCC
Product: CN(C)CCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
1-Bromo-3-methanesulfonylpropane (500 mg, 2.5 mmol) was suspended in a dimethylamine solution (2 M in THF; 10 mL, 20 mmol) and stirred at RT, resulting in a crystalline solid. The reaction was left to stand overnight and the reaction mixture was then diluted with Et2O (10 mL) and filtered. The filtrate was concentrated in vacuo resulting in an orange oily solid which was redissolved in Et2O (10 mL), filtered and concentrated in vacuo to give the title compound as an orange oil (420 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl.[NH2:16][C@@H:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29])[CH3:18]>>[CH2:1]([O:8][C:9]([NH:16][C@@H:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29])[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 75.2 %

Procedure:
Benzyloxycarbonyl chloride (0.9 g) was dropwise added to an aqueous solution (10 ml) of (R)-4-(1-aminoethyl)-3-nitrobenzoic acid hydrochloride (1 g) and sodium hydroxide (535 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. Conc. hydrochloric acid was added to the reaction mixture to make the same acidic. The mixture was extracted with chloroform. The extract was washed with water, dried, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 1.05 g of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-nitrobenzoic acid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[NH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([F:17])[C:10]=2[F:16])[CH2:31]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: NC1CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reaction time: 8 h
Yield: 82 %

Procedure:
To 2.0 g (6.64 mmol) of the 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 1.5 g (8.3 mmol) of 3-t-butoxycarbonylaminopyrrolidine and 1.01 g (6.64 mmol) of 1,8-diazabicyclo[5.4.0]undec-7ene. The mixture was stirred overnight and refluxed for two hours. The solids were filtered and washed with ether. They were treated with 5 ml of trifluoroacetic acid and stirred at 25° C. for 1.5 hours. The trifluoroacetic acid was removed and the mixture taken up in water. The pH was adjusted to 7.0 and the solids were filtered and dried to give 2.0 g of the title compound, mp 290°-292° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:8][C:4]1[N:3]=[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cccc(Br)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1

Procedure:
A solution of 4 g (16.88 mmol) of 2,6-dibromopyridine, 3.14 g (16.88 mmol) of tert.butyl piperazine-1-carboxylate and 5.89 ml (33.77 mmol) of N,N-diisopropylethylamine in 30 ml of n-butanol is refluxed for eight hours. The solvent is then distilled off. Purification is by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=2:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[N:14]2[C:18](=[O:19])[C:17]([CH2:27][CH:28]=[CH2:29])([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[NH:16][C:15]2=[S:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37](=[O:40])[CH2:38]Br)=[CH:35][CH:34]=1)#[N:32].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:12]([CH:11]2[N:14]2[C:18](=[O:19])[C:17]([CH2:27][CH:28]=[CH2:29])([CH2:20][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[N:16]=[C:15]2[S:30][CH2:38][C:37]([C:36]2[CH:41]=[CH:42][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)=[O:40])[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: C=CCC1(Cc2ccncc2)NC(=S)N(C2C3CN(C(=O)OC(C)(C)C)CC32)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: C=CCC1(Cc2ccncc2)N=C(SCC(=O)c2ccc(C#N)cc2)N(C2C3CN(C(=O)OC(C)(C)C)CC32)C1=O

Procedure:
Using the same procedure as described in Example 2C, the reaction of the title compound of 30A (10.3 mmol) and 4-cyanophenacyl bromide (11.3 mmol) in the presence of potassium bis(trimethylsilyl)amide (11.3 mmol) generated the title compound of 30B, 4.82 g (8.4 mmol, 84% yield).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].C([O-])(O)=O.[Na+].[C-]#N.[K+].[C:22]([Cu])#[N:23]>Cl>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[C:22]#[N:23]
Reactant: Cc1ccc(N)c(F)c1
Reactant: N#C[Cu]
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Product: Cc1ccc(C#N)c(F)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
2-Fluoro-4-methylaniline (15 g, 120 mmol, 1 eq) was dissolved in 600 ml 1M HCl at 0° C. and a 120 ml aqueous solution of sodium nitrite (12.4 g, 180 mmol, 1.5 eq) was added dropwise, maintaining the temperature under 5° C. The solution was neutralized with solid NaHCO3 and poured into a 600 ml aqueous solution of 36 g KCN and 23.8 g CuCN at 60° C. The solution was stirred for 30 min and cooled to RT. The product was extracted 3 times with EtOAc and the combined organic layers were washed with brine and dried with sodium sulfate. The solvent was removed and 16 g (98%) of product was obtained.
Reaction SMILES: C([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@H:11]([O:17][CH3:18])[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:18][O:17][C@@H:11]1[CH2:10][C@H:9]([OH:8])[C@H:14]2[CH2:15][O:16][C@@H:12]1[O:13]2
Reactant: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CO[C@@H]1C[C@H](O)[C@H]2CO[C@@H]1O2

Procedure:
A solution of 1,6-anhydro-4-O-benzyl-3-deoxy-2-O-methyl-β-D-ribo-hexopyranose (see Example 3(1)) (4.5 g) in ethanol (20 ml) was added to a suspension of 10% palladium on carbon (0.2 g) in ethanol (50 ml) and the resulting mixture was stirred in a hydrogen atmosphere until uptake of hydrogen had ceased (5 hours). Celite was added and the mixture was filtered through two layers of glass fibre filter paper. The filtrate was concentrated to give a quantitative yield of the title compound as a colourless syrup which crystallised spontaneously. Filtration with the aid of a little hexane gave 2.52 g (88% yield) of crystalline title compound, m.p. 67°-68° C.; [α]D -87.2°.
Reaction SMILES: N12CCCN=C1CCCCC2.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].[C:34](Cl)(=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CC#N>[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:34](=[O:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCCCCCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 66.3 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 2.22 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, heptanoyl chloride (0.33 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 7:3) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}heptanamide (0.49 g, 66%) as a white solid: mp 130–132° C.; 1H NMR (DMSO-d6) δ d 11.14 (s, 1H), 8.44 (t, J=5.7 Hz, 1H), 7.86–7.78 (m, 2H), 7.71–7.65 (m, 1H), 5.19–5.12 (dd, J=5.2 and 12.4 Hz, 1H), 4.69 (d, J=5.7 Hz, 2H), 2.98–2.83 (m, 1H), 2.64–2.50 (m, 2H), 2.18 (t, J=7.3 Hz, 2H), 2.08–2.04 (m, 1H), 1.53 (t, J=6.0 Hz, 2H), 1.25 (s, 6H), 0.85 (t, J=5.9 Hz, 3H); 13C NMR (DMSO-d6) δ d 172.73, 172.66, 169.79, 167.47, 166.93, 139.54, 134.66, 133.13, 131.50, 127.06, 121.80, 54.86, 48.85, 37.57, 35.23, 30.96, 28.31, 25.16, 21.97, 13.87; Anal. Calcd. For C21H25N3O5+0.3 H2O: C, 62.30; H, 6.37; N, 10.38. Found: C, 62.07; H, 6.29; N, 10.23.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1)(O)(=O)=O>>[CH3:25][N:24]([C:21]1[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=1)[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Reactant: Clc1nc2ccccc2nc1Cl
Product: CN(c1ccc(O)cc1)c1nc2ccccc2nc1Cl

Procedure:
2,3-Dichloroquinoxaline (prepared according to the method of H M Woodburn, J. Org. Chem., 1958, 23, 262) was reacted with 4-(N-methylamino)phenol sulfate, following essentially the same procedure as that described in Example 1 Part (a), to give 4-[N-methyl-N-(3-chloro-2-quinoxalinyl)amino]phenol. Proton magnetic resonance spectrum (d6 -acetone; δ in ppm): 7.5-8.1 (4H, m, quinoxaline protons); 7.1 (4H, m, phenoxy protons); 3.5 (3H, s, N-CH3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH2:18][OH:19])[NH:15][C:12]2=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]=[O:19])[NH:15][C:12]2=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc2cc(OCc3ccccc3)cnc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2cc(OCc3ccccc3)cnc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
The suspension of 0.3 g (1.2 mmol) (5-benzyloxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-methanol and 0.82 g (9.4 mmol) manganese dioxide in 15 ml dichloromethane was stirred 3 h at room temperature. After filtration over dicalite speed plus®(Aldrich) the solvent was evaporated to give 0.22 g (74%) of the desired compound as a light brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[Na+]>CN(C)C=O>[O:27]([CH2:26][CH2:25][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)[CH:5]=[CH:6][CH:7]=1)[Si:28]([C:41]([CH3:43])([CH3:42])[CH3:44])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Oc1cccc(-c2cn3cc(I)ccc3n2)c1
Reactant: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCOc1cccc(-c2cn3cc(I)ccc3n2)c1)(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
300 mg (corresponding to 0.893 mmol) of 2-(3′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine was dissolved in 5.0 mL of dimethylformamide, and 370 mg (corresponding to 2.68 mmol) of potassium carbonate was added thereto. Then, 357 mg (corresponding to 0.982 mmol) of 1-bromo-2-(t-butyldiphenylsiloxy)ethane was added thereto. After the reaction mixture was stirred at 90° C. for 2 hours, a saturated sodium chloride solution was added, and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/1) to obtain 477 mg (corresponding to 0.771 mmol) of 2-[3′-(2″-t-butyldiphenylsiloxyethoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 2-8, Step 4).
Reaction SMILES: NC1SC2C3C(CC=2C=1[C:14]([NH2:16])=[O:15])=CC=CC=3.[NH2:17][C:18]1[S:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[C:19]=1[C:31]([NH2:33])=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=3>>[NH:17]([C:18]1[S:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[C:19]=1[C:31]([NH2:33])=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Reactant: NC(=O)c1c(N)sc2c1CCc1ccccc1-2
Product: NC(=O)Nc1sc2c(c1C(N)=O)CCc1ccccc1-2

Procedure:
The title compound was prepared by the same procedure as Example 2 except 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide was replaced with 2-amino-4,5-dihydro-naphtho[1,2-b]thiophene-3-carboxylic acid amide to give the above title compound as brown solid. ESMS m/z: 288 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:18])(=[O:17])[C:7]=2[CH:19]=1)#N.N1C=CC=CC=1.C(O)(=[O:28])C.[PH2]([O-])=O.[Na+]>[Ni].O>[CH:5]1[C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:18])(=[O:17])[C:7]=2[CH:19]=[C:3]([CH:1]=[O:28])[CH:4]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Mix 267 mg (1 mmole) of 3-cyano-dibenzo[b,f]thiepin-5,5-dioxide, 10 ml pyridine, 5 ml acetic acid, and 5 ml water. Add 0.5 g sodium hypophosphite and approximately 0.1 g Raney nickel. Stir at 25° C. for 24 hours and then at 45°-50° C. for 2 hours. Filter the reaction mixture to remove the catalyst and wash any product from the catalyst using 10 ml ethyl acetate. Add 10 ml 6N hydrochloric acid and separate the organic layer containing the product. Evaporate the organic layer to obtain a solid residue comprising the title product, m.p., 175°-177° C. Swishing with methanol and drying the residue gives product melting at 177°-178° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].C(OC([N:33]1[CH2:38][CH2:37][N:36]([S:39]([C:42]2[S:43][C:44](Br)=[CH:45][CH:46]=2)(=[O:41])=[O:40])[CH2:35][CH2:34]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N:36]1([S:39]([C:42]2[S:43][C:44]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=5)=[N:8][C:7]=34)=[CH:45][CH:46]=2)(=[O:41])=[O:40])[CH2:35][CH2:34][NH:33][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1)N1CCNCC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and 4-(5-bromo-thiophene-2-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (example B.52) (206 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as an orange solid (96 mg, 33%). MS (ISP) 586.1 [(M+H)+]; mp 160° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17][CH:16]=2)O1.Br[C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[C:29]([N+:40]([O-:42])=[O:41])[CH:28]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C.COCCOC>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([C:27]2[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])=[C:29]([N+:40]([O-:42])=[O:41])[CH:28]=2)=[CH:16][N:17]=1
Reactant: CC1(C)OB(c2cncc3ccccc23)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2cncc3ccccc23)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100 %

Procedure:
Water (15 mL), sodium carbonate (4.6 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (5.1 g), and bis(triphenylphosphine)palladium(II) dichloride (0.24 g) were added to an ethylene glycol dimethyl ether (50 mL) solution of tert-butyl 4-bromo-2-nitrobenzoate (5.0 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 85-75% hexane/ethyl acetate] to obtain 5.8 g of tert-butyl 4-(isoquinolin-4-yl)-2-nitrobenzoate as a brown oily substance.