Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10]2=[N:23][C:24]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:25][C:26](=[O:27])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:34]=O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH3:34])[C:10]2=[N:23][C:24]([C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[CH:25][C:26](=[O:27])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=O
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(NCc2ccc(OC)cc2)C1
Product: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(N(C)Cc2ccc(OC)cc2)C1

Procedure:
By analogy with the method described in example 12 using 9-(4-methoxy-benzylamino)-4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester (example 9) in place of 9-amino-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester and formaldehyde (37%) in place of benzaldehyde, the compound was obtained as a solid oil. The compound was used as such in the next step.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(NC2CCNCC2)nc1
Reaction time: 15 h
Yield: 58.3 %

Procedure:
A mixture of methyl 6-[(1-benzyl-4-piperidyl)amino]nicotinate (4.2 g) in MeOH (50 ml) was hydrogenated over 10% palladium-carbon (1.5 g) under an atmospheric pressure of hydrogen at ambient temperature under stirring for 15 hours. After removal of the catalyst and solvent was evaporated in vacuo and the residue was triturated with AcOEt and IPE. The precipitate was collected by filtration to give methyl 6-(4-piperidylamino)nicotinate (1.77 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][NH:18]C(OC(C)(C)C)=O)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C1(C)C=CC=CC=1>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH2:18][CH2:17][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(CN)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate (4.3 g) in toluene (20 ml) was treated dropwise with trifluoroacetic acid (20 ml) and stirred at room temperature for 1 hour, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain methyl 3-amino-2-[[(benzyloxy)carbonyl)amino]propanoate trifluoroacetate (4.4 g).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.C(O)C>[ClH:39].[F:1][C:2]1[C:3]([CH2:23][NH:24][CH3:25])=[CH:4][N:5]([S:14]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2nccn2C)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2nccn2C)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(1-methyl-1H-imidazol-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (229 mg) was dissolved in ethyl acetate (1 mL) and ethanol (1 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol=1:10 to give the title compound as colorless crystals (yield 174 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17](O)=[O:18])[C:6]=2[CH:20]=1.C1C=CC2N(O)N=[N:32][C:30]=2C=1.CCN=C=NCCCN(C)C.CN>CN(C=O)C.CCN(CC)CC>[Br:1][C:2]1[C:3]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([NH:32][CH3:30])=[O:18])[C:6]=2[CH:20]=1
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (33 g, 77 mmol), HOBT (15.6 g, 115.5 mmol) and EDCI (22.2 g, 115.5 mmol) in DMF (250 mL) was stirred at room temperature. After 2 hours, Et3N (50 mL) and CH3NH2 (HCl salt, 17.7 g, 231 mmol) was added to the mixture, and the mixture was stirred overnight. After the solvent was removed, H2O was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with H2O, brine and concentrated in vacuo. The resulting residue was washed with EtOAc to provide the product of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (32 g, yield: 94%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.55 (br s, 1H), 8.46˜8.48 (m, 1H), 8.12˜8.17 (m, 2H), 7.96 (s, 1H), 7.87 (s, 1H), 7.45˜7.50 (m, 2H), 3.16 (s, 3H), 2.93 (d, J=8.4 Hz, 3H). MS (M+H)+: 441/443.
Reaction SMILES: [N+](C1C=CC([O:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=O)=CC=1)([O-])=O.O.[NH2:20][NH2:21]>CO>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[NH:11][C:9](=[O:8])[NH:20][NH2:21]
Reactant: NN
Reactant: O=C(Nc1nccs1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: O
Product: NNC(=O)Nc1nccs1

Procedure:
A solution of 2-(4-nitrophenoxycarbonyl)aminothiazole, 3.5 g (13 mMole) and 85% hydrazine hydrate, 4.0 ml (69 mMole) in 40 ml of methanol was stirred under nitrogen at 22° C. for 10 days. The mixture was cooled in ice. The insolubles were filtered, washed with cold methanol, dried and recrystallized from ethanol furnishing 780 mg of (thiazol-2-yl)semicarbazide, m.p. 166°-167° C., which was characterized by nuclear magnetic resonance, mass spectra, infrared spectra and elemental analyses.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:34])([F:33])[C:17]1[CH:32]=[CH:31][C:20]2[C:21](=O)[NH:22][C:23]3[CH2:29][CH2:28][CH:27]=[CH:26][C:24]=3[S:25][C:19]=2[CH:18]=1.O>N1C=CC=CC=1>[F:15][C:16]([F:34])([F:33])[C:17]1[CH:32]=[CH:31][C:20]2[C:21](=[S:2])[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[S:25][C:19]=2[CH:18]=1
Reactant: O=C1NC2=C(C=CCC2)Sc2cc(C(F)(F)F)ccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)Sc1ccccc1NC2=S
Yield: 106.6 %

Procedure:
Phosphorus pentasulphide (2.25 g) was added to a solution of 3-trifluoromethyl-9,10-dihydrodibenzo [b,f][1,4]thiazepin-11-one (2 g, 6.8 mmol) in pyridine (30 ml) and the mixture heated under reflux for 6.5 hr. The mixture was allowed to cool and then poured into warm water (100 ml) with stirring. Filtration of the cooled mixture and recrystallisation from ethanol gave the title compound as yellow needles (1.68 g, m.p. 236°-239° C., Rf 0.58, hexane/EtOAc 2:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[C:14]([Cl:21])[C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[C:14]([Cl:21])[C:10]=1[C:11]([O:13][CH3:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(Cl)cc(NC(=O)OC(C)(C)C)c(C(=O)O)c1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(NC(=O)OC(C)(C)C)cc(Cl)c(OC)c1Cl
Yield: 96 %

Procedure:
To a cold (ice bath) stirred solution of 2-(tert-butoxycarbonylamino)-4,6-dichloro-5-methoxybenzoic acid (2.0 g, 5.9 mM) in 20 mL of dry dimethylformamide under a nitrogen atmosphere was added sodium hydride (0.24 g, 5.9 mM); a precipitate formed which slowly redissolved on stirring. To the resulting stirred solution was added iodomethane (8.4 g, 59 mM). After stirring at room temperature for 1.5 hr, the reaction mixture was poured into water and the resulting mixture extracted with ether. The combined ether extracts were washed with brine, dried (MgSO4), filtered and concentrated to leave the title compound as a yellow oil (2.0 g, 96%); MS(CI): 350 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:28])[F:29])=[CH:24][CH:23]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
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: COCCOC
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 35.9 %

Procedure:
A reaction mixture comprising 6.7 g of 4-benzyloxybromobenzene, 5.0 g of 4-(trifluoromethoxy)benzeneboronic acid, 0.3 g of tetrakis(triphenylphosphine)palladium(0), 5.1 g of sodium carbonate, 100 ml of ethylene glycol dimethyl ether and 20 ml of pure water was refluxed for 5 hours. The reaction mixture was extracted with toluene, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the resulting residue was purified through silica gel chromatography (elution solvent: heptane/toluene=7/3) and recrystallized from heptane, and 3.0 g of 4-benzyloxy-4′-(trifluoromethoxy)biphenyl was obtained. m.p.: 136-137.2° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[S:12][CH:11]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[S:12][CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1csc2cc(F)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)c1csc2cc(F)ccc12

Procedure:
A solution of 3.50 g of ethyl α-methoxyimino-α-(6-fluoro-3-benzothienyl)acetate in 75 ml of ethanol containing 40 ml of 0.5N sodium hydroxide was stirred at 24° C. for nineteen hours. The solution was then concentrated to a volume of about 50 ml, and 50 ml of water were added. The aqueous solution was washed with dichloromethane, filtered, and then acidified to pH 2 by addition of 6N hydrochloric acid. The precipitate that formed was collected by filtration and identified as 3.02 g (95%) of α-methoxyimino-α-(6-fluoro-3-benzothienyl)acetic acid. m.p. 150°-151° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[CH:23]=[CH:24][N:25]=[C:11]2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:34])C(=O)C1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([Br:34])=[CH:24][N:25]=[C:11]2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NCc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cc2ncc(Br)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
A solution of [6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-ylmethyl]-carbamic acid tert-butyl ester (543 mg, 1.38 mmol) in DMF (5 mL) was cooled to 0° C., treated with NBS (222 mg, 1.25 mmol), and stirred at 0° C. for 1 h. The reaction mixture was diluted in AcOEt and washed with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→6:4) to yield the title compound (435 mg, 0.92 mmol, 67%) as a beige foam. MS: 472 [M+1]+; HPLC: AtRet=1.93; TLC: RF 0.50 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14](F)=[O:15])=[N:9]1.C([O-])([O-])=O.[K+].[K+].[C:34]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]([NH:43][S:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:42])=[O:41])=[O:15])=[N:9]1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COc1ccc(COc2ccc(Cl)cc2Cn2nc(C(=O)F)cc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ccc(Cl)cc2Cn2nc(C(=O)NS(=O)(=O)c3ccccc3)cc2C)cc1
Reaction time: 16 h

Procedure:
To a solution of 1-[5-chloro-2-(4-methoxy-benzyloxy)-benzyl]-5-methyl-1H-pyrazole-3-carbonyl fluoride, 15, 0.06 g (0.18 mmol) and K2CO3 0.100 g (0.72 mmol) in dry DCM (2 mL), benzenesulfonamide 0.055 g (0.35 mmol) was added. The mixture was stirred under a nitrogen atmosphere for 16 hours before diluting with EtOAc. The organic phase was washed with 2M HCl, followed by brine, dried over MgSO4 and evaporated to dryness. The crude acyl sulphonamide was purified on silica to yield N-{1-[5-chloro-2-(4-methoxy-benzyloxy)-benzyl]-5-methyl-1H-pyrazole-3-carbonyl}-benzenesulfonamide, 16.
Reaction SMILES: [OH:1][C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4](=[O:13])N1C1C=CC=CC=1.Cl.[O:27]1CCOCC1>C(O)(=O)C>[OH:27][C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4](=[O:13])[O:1]1
Reactant: COc1ccc2c(c1)C(O)(c1ccccc1)N(c1ccccc1)C2=O
Reactant: C1COCCO1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(O)(c1ccccc1)OC2=O
Reaction time: 4 h
Yield: 54.9 %

Procedure:
A solution of 109 (3.11 g, 9.39 mmol), 6N hydrochloric acid (150 mL), and dioxane (150 mL) was heated at reflux under Ar for 18 h. Acetic acid (50 mL) was added and refluxing was continued for an additional 4 h. The organic solvents were removed in vacuo and the remaining aqueous was extracted with ethyl acetate (3×), washed with brine and dried with sodium sulfate (anh.). Filtration followed by removal of the solvent in vacuo gave 110 as a white solid (1.32 g, 5.16 mmol, 54.9%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[CH:18]=[CH:17][C:16](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:14]=1)[CH:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2.[C:33]([O:37][CH3:38])(=[O:36])[CH:34]=[CH2:35]>CC#N>[CH3:38][O:37][C:33](=[O:36])[CH:34]=[CH:35][C:16]1[CH:15]=[CH:14][C:13]([CH:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:6][CH2:7][CH:8]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:18][CH:17]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)C2c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2c3ccc(OC)cc3CCC2c2ccccc2)cc1

Procedure:
Prepared by Heck coupling 6c and methyl acrylate in accordance with the general method described in Example IV. Yield (83%); APcI m/z: 440 (M+H+CH3CN+, 100%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN1CCCC1=O.[Cu]I>[C:18]1([N:1]2[C:5](=[O:6])[CH2:4][N:3]3[C:7](=[O:10])[CH2:8][CH2:9][CH:2]23)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CN2C(=O)CCC2N1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C1CCC2N1CC(=O)N2c1ccccc1
Yield: 11.7 %

Procedure:
To a solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1 g, 7.14 mmol; prepared as described in J. Med. Chem. 36, 4214-4220, 1994,) in N-methylpyrrolidone (NMP, 12 cc), CuI (0.2 g, 1.05 mmol), K2CO3 (1 g, 7.14 mmol) and Iodobenzene (5 g, 24.5 mmol) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 45 min. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were gathered and dried over Na2SO4, filtered and concentrated to dryness. The residue was triturated with isopropyl ether. The solid was filtered, triturated with water and filtered to yield 0.18 g of the title compound, mp=185-188° C.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:21]([N:22]2[CH2:27][CH2:26][CH:25]3[NH:28][CH2:29][CH2:30][CH:24]3[CH2:23]2)=[CH:20][C:19]([C:31]#[N:32])=[CH:18][C:17]=1[NH:33][C:34]1[N:39]=[C:38]([N:40]([CH:50]2[CH2:52][CH2:51]2)[CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:37]2=[N:53][CH:54]=[C:55]([C:56]#[N:57])[N:36]2[N:35]=1.C=O.C(O)(=O)C>ClCCl>[Cl:15][C:16]1[C:21]([N:22]2[CH2:27][CH2:26][CH:25]3[N:28]([CH3:1])[CH2:29][CH2:30][CH:24]3[CH2:23]2)=[CH:20][C:19]([C:31]#[N:32])=[CH:18][C:17]=1[NH:33][C:34]1[N:39]=[C:38]([N:40]([CH:50]2[CH2:52][CH2:51]2)[CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)[C:37]2=[N:53][CH:54]=[C:55]([C:56]#[N:57])[N:36]2[N:35]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5NCCC5C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC5C(CCN5C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
Sodium triacetoxyborohydride (20.66 mg, 0.097 mmol) was added to a solution of 2-((2-chloro-5-cyano-3-(hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 442F, 29 mg, 0.049 mmol), paraformaldehyde (14.63 mg, 0.487 mmol) and acetic acid (5.58 μl, 0.097 mmol) in dichloromethane (2 mL) and the reaction mixture was stirred at room temperature for 5 hours. More paraformaldehyde (14.63 mg, 0.487 mmol) and sodium triacetoxyborohydride (20.66 mg, 0.097 mmol) were added and stirring continued overnight. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-30% ethyl acetate/hexanes). 2-((2-chloro-5-cyano-3-(1-methylhexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (27 mg) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Cl:1][C:2]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][C:3]=1[C:17]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([F:14])[CH:16]=1
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(-c2ccc(OC)c(F)c2)c(Cl)c1

Procedure:
Ethyl 5,6-dichloronicotinate (1 g, 4.54 mmol), 3-fluoro-4-methoxyphenylboronic acid (0.965 g, 5.68 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.371 g, 0.454 mmol), cesium carbonate (3.26 g, 10.00 mmol) and THF (30 mL) were refluxed in an 80° C. oil bath under N2 for 2.5 hrs. Volatiles were removed under reduced pressure. The pot residue was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated to afford a dark mixture. The resulting crude mixture was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 40%). Related fractions were pooled and evaporated to afford a white fluffy solid as the titled compound. LCMS calc.=309.06. found=310.01 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccnc(N2CCNCC2)c1
Yield: 42.9 %

Procedure:
A solution of 2-chloro-4-(trifluoromethyl)pyridine (2.0 g, 11 mmol), piperazine (3 g, 30 mmol) and triethylamine (3.1 mL, 22 mmol) in DMF (10 mL) was heated at 100° C. overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc to EtOAc/MeOH/Et3N=9/1/0.5) to give 1.09 g (43%) of pure product. MS calculated for C10H12F3N3: (M+H) 232; found 232.1.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[S:39](Cl)(=[O:41])=[O:40]>N1C=CC=CC=1>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[S:39]([NH:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1)(=[O:41])=[O:40]
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4c(Cl)cccc4Cl)ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 15.7 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 2,6-dichlorobenzenesulfonyl chloride (49, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetat. The crude product was chromatographed on silica gel eluting with 399:1 dichloromethane:methanol to give the title compound (5 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.62 Hz, 6 H) 1.54 (m, 2 H) 1.67 (m, 1 H) 4.46 (m, 2 H) 7.47 (m, 2 H) 7.58 (m, 2 H) 7.68 (m, 3 H) 8.54 (dd, J=7.72, 1.84 Hz, 1 H) 8.88 (dd, J=4.78, 1.84 Hz, 1 H) 11.43 (s, 1 H) 14.02 (s, 1 H). MS (ESI−) m/z 634 (M−H)−.