Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([N:8]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:39][CH:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41]>>[CH:24]1([N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([S:42]([CH:40]([CH3:41])[CH3:39])(=[O:44])=[O:43])[CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Nc1ncc(CN2CCNCC2)s1)N(C1CCCCC1)C1CCCCC1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 44 %

Procedure:
Prepared as described in general procedure (Q) using 1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-urea hydrochloride (36 mg, 0.08 mmol), DIEA (42 μL, 0.24 mmol) and propane-2-sulfonyl chloride (18 μL, 0.16 mmol) to afford 18 mg (44%) of the desired product after purification.
Reaction SMILES: [Mg].I[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[O:13][CH3:14].[F:15][C:16]([F:21])([F:20])[C:17](O)=[O:18].S(=O)(=O)(O)O>C(OCC)C>[F:15][C:16]([F:21])([F:20])[C:17]([C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[O:13][CH3:14])=[O:18]
Reactant: COc1ccc(C(C)(C)C)cc1I
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(C(C)(C)C)cc1C(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
To 0.73 g of magnesium suspended in 5 ml of diethyl ether were added dropwise, under nitrogen, 8.70 g of 2-iodo-4-tert-butylanisole [described in Reference Example 1(a)] dissolved in 15 ml of diethyl ether and heated at reflux for one hour. To this solution were added dropwise 0.74 ml of trifluoroacetic acid dissolved in 3 ml of diethyl ether at room temperature, and heated at reflux for 1.5 hours. The reaction mixture was poured into ice-water, acidified with conc. sulfuric acid and extracted with diethyl ether. The extract was washed with water and saturated brine successively, dried over magnesium sulfate anhydride and concentrated at reduced pressure. The residue was chromatographed on silica gel column using a mixed solvent of methylene chloride and cyclohexane (1:2) as an eluting agent to give 1.83 g of the title compound having the following physical properties as pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([NH2:18])=[CH:13][C:12]=2[CH3:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO[CH:22](OC)[N:23]([CH3:26])[CH2:24][CH3:25].C1CCCCC1.C(OCC)(=O)C>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([N:18]=[CH:22][N:23]([CH2:24][CH3:25])[CH3:26])=[CH:13][C:12]=2[CH3:19])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C)C(OC)OC
Reactant: Cc1cc(-c2ccc(C(C)(C)C)cc2)c(C)cc1N
Solvent: C1CCCCC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(C)C=Nc1cc(C)c(-c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 45 °C
Reaction time: 24 h
Yield: 47.6 %

Procedure:
To a mixture of 2.1 g (6.3 mmol) of 4′-tert-butyl-2,5-dimethylbiphenyl-4-amine in 2.5 ml methanol a solution of 8.8 mmol of N-(dimethoxymethyl)-N-methylethanamine (60% in methanol) was added. The reaction mixture was stirred for 24 hrs at 45° C. The reaction mixture was concentrated in vacuo. Column chromatographic (gradient: cyclohexane->ethyl acetate) yielded 0.96 g (3.0 mmol) 47% of N′-(4′-tert-butyl-2,5-dimethylbiphenyl-4-yl)-N-ethyl-N-methylimidoformamide; log P (pH 2.3)=2.67.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[N:13]3[CH:14]=[C:15](I)[C:16]([C:18]#[N:19])=[CH:17][C:12]3=[N:11][C:10]=2[C:21]([F:24])([F:23])[F:22])[CH2:4][CH2:3]1.[CH3:26][C:27]1(C)C(C)(C)OB(C=C)O1>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>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[N:13]3[CH:14]=[C:15]([CH:26]=[CH2:27])[C:16]([C:18]#[N:19])=[CH:17][C:12]3=[N:11][C:10]=2[C:21]([F:24])([F:23])[F:22])[CH2:4][CH2:3]1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: N#Cc1cc2nc(C(F)(F)F)c(CC3CCC(F)(F)CC3)n2cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: C=Cc1cn2c(CC3CCC(F)(F)CC3)c(C(F)(F)F)nc2cc1C#N
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
3-(4,4-Difluorocyclohexylmethyl)-6-iodo-2-trifluoromethylimidazo[1,2-a]pyridine-7-carbonitrile (20.0 mg, 0.0430 mmol) obtained in step 2 was dissolved in 1,2-dichloromethane (0.60 mL), and the solution was stirred at 60° C. for 1 hour after adding 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (24.0 mg, 0.153 mmol), tetrakis(triphenylphosphine)palladium(0) (4.93 mg, 0.00426 mmol), and water (0.2 mL). The reaction mixture was filtered through Celite (registered trademark), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→50/50) to give 3-(4,4-difluorocyclohexylmethyl)-2-trifluoromethyl-6-vinylimidazo[1,2-a]pyridine-7-carbonitrile (11.0 mg, yield 70%).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[Na].Br[CH2:22][CH2:23][CH:24]=[CH2:25].[OH-].[Na+]>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:25][CH2:24][CH:23]=[CH2:22])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCCBr
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C=CCCn1cnc2c1c(=O)n(CCCC)c(=O)n2CCCC
Temperature: 70 °C
Reaction time: 46 h

Procedure:
38.9 g of 1,3-di-n-butyl-xanthine are added at 25° C. to a solution of 3.4 g of sodium in 200 ml of absolute ethanol. 20.5 g of 4-bromobut-1-ene are then added at 50° C. After stirring for 46 hours under a nitrogen atmosphere at 70° C. the reaction mixture is cooled to 20° C., precipitated sodium bromide is filtered off and the filtrate is then evaporated under reduced pressure. The residue obtained is treated with chloroform and 1 N sodium hydroxide solution to remove 1,3-di-n-butyl-xanthine. From the chloroform phase there is obtained a yellow oily residue which after column chromatography on silica gel with methylene chloride/acetone (8:2) as eluent and after distillation under reduced pressure yields 29.7 g (78.8% of theory relative to reacted 1,3-di-n-butyl-xanthine) of the title compound with a melting point of 41° to 42° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)Cc1ccccc1I
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)Cc1ccccc1I
Yield: 90.1 %

Procedure:
To 10 g (0.038 mole) of o-iodophenylacetic acid was added 50 ml of a solution of 5.7 g (0.048 mole) of thionyl chloride in anhydrous benzene, and the mixture was refluxed for 2 hours under agitation. Then, the solvent and unreacted thionyl chloride were removed by distillation under reduced pressure below 40° C. and the residue was subjected to distillation under reduced pressure to obtain 9.6 g of o-iodophenylacetyl chloride as a light yellow oily product having a boiling point of 153° to 156° C. under 8 mmHg in a yield of 90%.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8](=[O:33])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:26][CH2:27][O:28][CH3:29])[CH2:22][CH2:23][O:24][CH3:25])[CH:18]=[CH:17][C:16]=2[N+:30]([O-])=O)[CH:10]=1>CO.[Pd]>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8](=[O:33])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:22][CH2:23][O:24][CH3:25])[CH2:26][CH2:27][O:28][CH3:29])[CH:18]=[CH:17][C:16]=2[NH2:30])[CH:10]=1
Reactant: COCCN(CCOC)c1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: [Pd]
Solvent: CO
Product: COCCN(CCOC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-(bis(2-methoxyethyl)amino)-2-nitrophenyl)-isonicotinamide (270 mg, 0.51 mmol, 1.00 equiv) in methanol (10 mL). The solution was treated with Pd/C (300 mg), and stirred under an atmosphere of hydrogen for 2 h at room temperature in a water bath. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 180 mg (71%) of product as a yellow to green oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][C:9]2[N:13]3[C:14]4[C:19]([NH:20][C:21](=[O:22])[C:12]3=[N:11][C:10]=2[C:27]([O:29]CC)=[O:28])=[CH:18][C:17]([C:23]([F:26])([F:25])[F:24])=[CH:16][CH:15]=4)[C:6]=1[Cl:7]>Br>[C:27]([C:10]1[N:11]=[C:12]2[C:21](=[O:22])[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)[N:13]2[C:9]=1[CH2:8][N:5]1[C:6]([Cl:7])=[C:2]([Cl:1])[N:3]=[CH:4]1)([OH:29])=[O:28]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cn1cnc(Cl)c1Cl
Agent: Br
Product: O=C(O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cn1cnc(Cl)c1Cl

Procedure:
A suspendion of 1-(4,5-dichloro-1-imidazolyl)methyl-2-ethoxycarbonyl-7trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 9) (120 mg, 0.25 mmol) in hydrobromic acid (48% in water) (10 ml) was stirred at 80° C. for 6 h. The mixture was concentrated in vacuo and the residue added acetone. The title compound was isolated by filtration to yield 80 mg (61%) as a hydrobromic salt. M.p. 213°-215° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH3:3].Cl[C:28]1[C:33]([C:34]#[N:35])=[C:32]([CH2:36][CH3:37])[N:31]=[C:30]([S:38][CH3:39])[N:29]=1.CCN(CC)CC>C1COCC1.CCOC(C)=O>[C:34]([C:33]1[C:28]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH3:3])=[N:29][C:30]([S:38][CH3:39])=[N:31][C:32]=1[CH2:36][CH3:37])#[N:35]
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCc1nc(SC)nc(Cl)c1C#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc(SC)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a 20 mL vial were added (S)-tert-butyl 4-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)piperazine-1-carboxylate (63 mg, 0.175 mmol) in THF (5 mL), 4-chloro-6-ethyl-2-(methylthio)pyrimidine-5-carbonitrile (37.5 mg, 0.175 mmol) and Et3N (0.027 mL, 0.193 mmol). The resulting yellow solution was heated to 60° C. and stirred overnight. The next day LCMS indicated the reaction was mostly complete. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO 12 g, 30-100% EtOAc/hexane gradient) to give the title compound as a yellow solid. ESI-MS m/z [M+H]+ calc'd for C27H36N8O2S, 537. found 537.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[Cl:13][C:6]1[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])cc(Cl)c(Cl)c1Cl
Temperature: 100 °C
Yield: 80.1 %

Procedure:
A mixture of 4,5-dichloro-2-nitro-phenylamine (0.500 g, 2.42 mmol), N-chlorosuccinimide (0.403 g, 3.02 mmol), and DMF (5 mL) was heated to 100° C. for 1 h. After cooling to 23° C., the solution was poured into ice water. The yellow precipitate was collected by filtration and dissolved in dichloromethane. The organic phase was washed with water, dried (MgSO4), filtered, and concentrated to yield the titled compound (0.468 g, 81%). 1H NMR (400 MHz, CDCl3): 8.28 (s, 1H), 6.70 (s, 2H). The compound did not yield MS data.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:30][CH3:31])[CH2:24][C:25](OCC)=[O:26])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl.[CH3:36][NH:37][O:38][CH3:39].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1.CO.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:30][CH3:31])[CH2:24][C:25]([N:37]([O:38][CH3:39])[CH3:36])=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC(=O)N(C)OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.1 %

Procedure:
To a solution of ethyl 3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]pentanoate (200 mg, 0.416 mmol) in tetrahydrofuran (10 mL) and methanol (5.0 mL) was added 1N sodium hydroxide (2.0 mL, 2.0 mmol) at room temperature. The mixture was stirred at room temperature for 3 days. To the reaction mixture was added 1N hydrogen chloride (2.0 mL, 2.0 mmol) at room temperature and the mixture was concentrated in vacuo. To the residue was added N,N-dimethylformamide (10 mL) and to the mixture were added N,O-dimethylhydroxylamine hydrochloride (81 mg, 0.83 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (159 mg, 0.83 mmol), 1-hydroxybenzotriazole monohydrate (127 mg, 0.83 mmol) and triethylamine (0.29 mL, 2.08 mmol). The mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-75% ethyl acetate/n-hexane gradient mixture to give the title compound (148.6 mg, 0.30 mmol, 72%) as a pale yellow amorphous.
Reaction SMILES: [BH4-].[Na+].C(O)C.[CH2:6]([N:10]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([C:20](SC)=[O:21])[N:12]=[C:11]1[N:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)[C:7]#[C:8][CH3:9].Cl>C([O-])(=O)C.[Hg+2].C([O-])(=O)C.C(OCC)(=O)C>[CH2:6]([N:10]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][OH:21])[N:12]=[C:11]1[N:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:26][CH2:25]1)[C:7]#[C:8][CH3:9]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=O)SC)c1C(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.5 %

Procedure:
0.187 g of mercury (II) acetate and 0.090 of sodium borohydride were added to 8 ml of an ethanol solution containing 0.265 g of t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4-methylsulfanyl carbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate at 0° C., and the mixture was stirred at room temperature for 4 hours. After 0.187 g of mercury (II) acetate and 0.090 of sodium borohydride had been added to the solution, the mixture was stirred at room temperature for 15 hours. 100 ml of ethyl acetate and 50 ml of 0.5N hydrochloric acid were added to the solution, and the organic layer was washed successively with 50 ml of water and 50 ml of a saturated sodium chloride solution. The mixture was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 0.172 g of the starting material was collected from the fraction eluted with hexane-ethyl acetate (4:1). Then, 0.061 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cnc2[nH]ccc2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2cc(Br)cnc21
Yield: 61.1 %

Procedure:
5-bromo-1H-pyrrolo[2,3-b]pyridine (0.3 g, 1.6 mmol) was reacted with (2-chloromethoxy-ethyl)-trimethyl-silane (0.35 g, 2.1 mmol), catalytic amount of benzyl triethyl-ammonium chloride and NaOH (0.2 g, 5.2 mmol) and DCM (20 mL) to afford the crude product. Purification by column chromatography on silica gel (20% ethylacetate in hexane) afforded 0.32 g of the product (64.2% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH2:54]([O:61][NH2:62])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C(Cl)Cl>[CH2:54]([O:61][NH:62][C:14](=[O:16])[C:13]([NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])([CH3:18])[CH3:17])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)NC(C)(C)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NC(C)(C)C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
A solution of 2-(4methoxybenzenesulfonylamino)-2-methylpropionic acid (1.08 grams, 3.95 mmole) in methylene chloride (120 mL) was cooled in an ice bath. Triethylamine (2.2 mL, 15.8 mmole), (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (2.6 grams, 5.88 mmole) and O-benzylhydroxylamine hydrochloride (0.95 grams, 5.95 mmole) were subsequently added. The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was taken up in ethyl acetate. The solution was washed successively with aqueous 1 N hydrochloric acid solution, aqueous saturated sodium bicarbonate solution, water and brine. After drying over sodium sulfate, the solvent was evaporated to afford an oil from which the desired product, N-benzyloxy-2-(4-methoxybenzenesulfonylamino)-2-methyl-propionamide (1.41 grams, 95%), a white solid, was obtained by chromatography on silica gel eluting with 1:2 ethyl acetate/hexanes.
Reaction SMILES: [O:1]1[C:5]2[C:6](=[O:10])[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:18])C(=O)C1.O>CN(C=O)C>[Br:18][C:9]1[C:4]2[CH:3]=[CH:2][O:1][C:5]=2[C:6](=[O:10])[NH:7][CH:8]=1
Reactant: O=c1[nH]ccc2ccoc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cc(Br)c2ccoc12
Temperature: 15 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
A mixture of 6H-furo[2,3-c]pyridin-7-one (1.0 g, 7.4 mmol) in DMF (30 mL) was treated with NBS (1.32 g, 7.4 mmol) in three equal portions at 0° C. After the resulting mixture was stirred at 15° C. for 2 h, it was treated with water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc=3:1) to give the title compound (600 mg, 38%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 11.92 (s, 1H), 8.23 (s, J=2.0 Hz, 1H), 7.47 (s, 1H), 6.88 (m, 1H), 6.88 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[NH:6]2.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[N:6]2[C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=1
Reactant: CON(C)C(=O)c1cc2c(Cl)cccc2[nH]1
Reactant: OB(O)c1cccc(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc2c(Cl)cccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
Activated molecular sieves (4.9 g) 4 Å were placed in an oven dried flask and cooled to room temperature under nitrogen. To the flask was charged with 4-chloro-N-methoxy-N-methyl-1H-indole-2-carboxamide (0.35 g, 1.5 mmol), (3-fluorophenyl)boronic acid (0.62 g, 4.4 mmol) and cupric acetate (0.40 g, 2.2 mmol), methylene chloride (65 mL) and then pyridine (0.47 mL, 5.9 mmol). The reaction mixture was stirred at room temperature overnight, then filtered through a pad of Celite. The filtrate was concentrated and purified on silica gel (eluting with 0-20% EtOAc in hexane) to give the desired product (0.44 g, 90%). LCMS calculated for C17H15ClFN2O2(M+H)+: m/z=333.1. Found: 333.0.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32](O)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=23)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32]([NH:35][C@@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:15]=23)[CH2:3][CH2:2]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c5) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:32]=[CH:31][C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][C:22]=3[CH2:29][CH3:30])=[N:10][CH2:11][C:12]3[N:13]([C:14]([CH:17](Cl)[CH2:18][CH3:19])=[N:15][N:16]=3)[C:7]=2[CH:6]=1)[CH2:2][CH3:3].[CH3:33][NH:34][CH3:35].[I-].[Na+]>>[CH3:33][N:34]([CH3:35])[CH:17]([C:14]1[N:13]2[C:7]3[CH:6]=[C:5]([S:4][CH2:1][CH2:2][CH3:3])[CH:32]=[CH:31][C:8]=3[C:9]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][C:22]=3[CH2:29][CH3:30])=[N:10][CH2:11][C:12]2=[N:16][N:15]=1)[CH2:18][CH3:19]
Reactant: CCCSc1ccc2c(c1)-n1c(nnc1C(Cl)CC)CN=C2c1ccc(CC)cc1CC
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Product: CCCSc1ccc2c(c1)-n1c(nnc1C(CC)N(C)C)CN=C2c1ccc(CC)cc1CC

Procedure:
In the manner given in Example 1, 9-(propylthio)-1-(α-chloropropyl)-6-(2,4-diethylphenyl)-4H-s-triazolo[4,3-a]-[1,4]-benzodiazepine was reacted with dimethylamine in the presence of sodium iodide to give 1-[α-(dimethylamino)propyl]-9-(propylthio)-6-(2,4-diethylphenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.