Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[CH3:29][S+](C)(C)=O>C1COCC1.CS(C)=O.C(OCC)(=O)C>[C:1]1([C:7]2([C:9]3[CH:14]=[N:13][C:12]([N:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]4)=[N:11][CH:10]=3)[CH2:29][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(c1ccccc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C3(c4ccccc4)CC3)cn2)CC1
Temperature: 80 °C
Reaction time: 96 h
Yield: 10.5 %

Procedure:
To a solution of tert-butyl 4-(5-(1-phenylvinyl)pyrimidin-2-yl)piperazine-1-carboxylate (366 mg, 1.0 mmol) in THF (20 mL) was added trimethylsulfoxonium iodide (1.1 g 5.0 mmol) in dimethyl sulfoxide (7 mL). The reaction mixture was stirred at 80° C. for 4 days, and diluted with ethyl acetate (200 mL). The organic phase was washed with water (200 mL) and brine (100 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=20:1) to give tert-butyl 4-(5-(1-phenylcyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate (40 mg, 10%) as a yellow solid. MS (ES+) C22H28N4O2 requires: 380, found: 381 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH:21]=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(C)=O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Yield: 66.9 %

Procedure:
30 g of p-nitrobenzaldehyde was reacted with 30 g of p-methoxyacetophenone in 200 ml of acetic acid in the presence of 34 ml of sulfuric acid at room temperature for 1 day, and the reaction mixture was poured into 1 liter of ice-water. After neutralizing the mixture with 48 g of NaOH, crystals formed were collected by filtration, and recrystallized from acetone-acetonitrile (0.2 liter/1.3 liter) to obtain 37.6 g of the desired compound. m.p. 171°-173° C.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:16][CH3:17])[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][N:37]([CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([O:16][CH3:17])[CH2:11][N:10]([C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][N:37]([CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)[C@@H]1C[C@@](OC)(c2ccc(-c3ccccc3)cc2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)OC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
A mixture of (2S,4R)-methyl 4-(biphenyl-4-yl)-4-methoxypyrrolidine-2-carboxylate (100 mg, 0.287 mmol), (S)-2-(tert-butoxycarbonylamino)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoic acid (145 mg, 0.316 mmol), Hunig's Base (0.176 mL, 1.01 mmol) and HATU (131 mg, 0.345 mmol) in DCM (3 mL) was stirred at rt for 18 h. It was then concentrated in vacuo. The residue was dissolved in EtOAc and washed with dilute HCl, followed by sat.aq. NaHCO3 and water. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to yield 250 mg of the crude product as a brown oil. Purification by Biotage eluting with 60% EtOAc/Hexane gave 188 mg (87%) of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoyl)-4-methoxypyrrolidine-2-carboxylate as an off-white foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[C:11]([O:15][C:16](=[O:26])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:16](=[O:26])[O:15][C:11]([CH3:13])([CH3:14])[CH3:12])=[CH:20][CH:21]=2)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)c2cc(Cl)ncn2)cc1

Procedure:
To a cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride in DCM (30 mL), obtained as described above for Intermediate 7, step 1 (1.43 g; 8.10 mmol) was added dropwise, during a period of 15 minutes, a solution of (4-amino-benzyl)-carbamic acid tert-butyl ester (Astatech, 1.50 g; 6.75 mmol) and DIEA (2.33 ml; 13.5 mmol) in DCM (5 mL). At the end of addition the reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. The resulting precipitate was filtered and dried under vacuum. The mother liquors were dried on MgSO4, concentrated under vacuum to give a residue, which was precipitated from cyclohexane. The two solids were combined to give the title compound as a brown solid.
Reaction SMILES: [C:1]([C:3](=[CH:7][CH:8]([CH3:10])[CH3:9])[C:4]([OH:6])=O)#[N:2].[NH:11]1[CH2:14][CH:13]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[N:23][C:24]([NH2:25])=[C:19]3[C:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][C:27]=3[F:39])=[N:17]2)[CH2:12]1.C1CN([P+](ON2N=NC3C=CC=NC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:25][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:16]([CH2:15][CH:13]3[CH2:14][N:11]([C:4]([C:3](=[CH:7][CH:8]([CH3:10])[CH3:9])[C:1]#[N:2])=[O:6])[CH2:12]3)[N:17]=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:28][C:27]=3[F:39])[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2CC1CNC1
Reactant: CC(C)C=C(C#N)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CC(C)C=C(C#N)C(=O)N1CC(Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-cyano-4-methyl-pent-2-enoic acid (48.12 mg, 0.350 mmol), 1-(azetidin-3-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 0.230 mmol) in DCM (2 mL) was added PyAOP (134.9 mg, 0.250 mmol) and TEA (0.1 mL, 0.690 mmol) and the resulting yellow solution stirred at rt for 1 h. LCMS showed that the reaction was completed and the crude mixture was directly loaded onto a silica gel cartridge for purification (0.2 to 3% MeOH: CH2Cl2). Removal of solvent from cleanest fractions afforded afforded 2-[3-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-pent-2-enenitrile (12 mg LCMS. (M+1=512).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3](=[O:18])[C:4]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH3:1][C:2]([CH3:20])([CH3:19])[C:3](=[O:18])[CH:4]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH:5]([C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)[S:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)C(=O)C(=Cc1ccc(F)cc1)n1cncn1
Reactant: Sc1ccccc1
Solvent: CCO
Product: CC(C)(C)C(=O)C(C(Sc1ccccc1)c1ccc(F)cc1)n1cncn1
Reaction time: 1 h
Yield: 90.5 %

Procedure:
27.3 g (0.1 mol) of 4,4-dimethyl-1-(4-fluorophenyl)-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one (E,Z isomer mixture) and 11 g (0.1 mol) of thiophenol were stirred with 100 ml of ethanol at room temperature. After 1 hour, the crystals which had separated out were filtered off and dried. 34.7 g (91% of theory) of 4,4-dimethyl-1-(4-fluorophenyl)-1-phenylthio-2-(1,2,4-triazol-1-yl)-pentan-3-one, of melting point 175° C., were obtained.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1)[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][C:4]1[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[O:7][C:3]=1[CH2:1][CH3:2]
Reactant: BrBr
Reactant: CCc1ccc(C(=O)OC)o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCc1oc(C(=O)OC)cc1Br
Temperature: 70 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
To a solution of methyl 5-ethyl-2-furancarboxylate (1.2 g, 7.78 mmol) and aluminum trichloride (1.56 g, 11.68 mmol) in chloroform (15 ml) at 25° C. was added bromine (0.56 ml, 10.90 mmol). The resulting solution stirred at 70° C. in a sealed tube for 2 h and the solution was cooled, concentrated and purified via column chromatography (silica, 5% EtOAc in hexanes) affording methyl 4-bromo-5-ethyl-2-furancarboxylate (1.1 g, 3.26 mmol, 41.8% yield) as a white solid; LCMS (ES) m/z=233, 235 (M, M+2)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH2:35][CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].CS(O[CH2:42][CH2:43][CH2:44][CH2:45][O:46][CH3:47])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O>[CH3:47][O:46][CH2:45][CH2:44][CH2:43][CH2:42][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH2:35][CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:14]1)=[O:11]
Reactant: CCCN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCN(C(=O)c1nc2ccccc2n1CCCCOC)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 15 h
Yield: 94.8 %

Procedure:
tert-Butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(propyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (1.97 g) and 4-methoxybutyl methanesulfonate (754 mg) were dissolved in DMA (50 ml), cesium carbonate (1.93 g) was added and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (0:10-5:5) was concentrated under reduced pressure to give the object product (2.19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([F:11])[CH:4]=1
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-chloro-3-fluoro benzoic acid (450.0 g, 2.586 mol, Fluororochem, Derbyshire, UK) in methanol (4.5 L) was cooled to 0° C. and thionyl chloride (450.0 mL) was added over 30 minutes. The reaction mixture was stirred for 12 hours at ambient temperature. The reaction was monitored by TLC. Upon completion, the solvent was removed under reduced pressure and the residue was quenched with 1.0 M sodium bicarbonate solution (500 mL). The aqueous layer was extracted with dichloromethane (2×5.0 L). The combined organic layer was washed with brine (2.5 L), dried over anhydrous sodium sulfate and concentrated under reduced pressure afforded the title compound as light brown solid. The crude compound was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>>[CH2:21]([N:22]([CH2:25][CH3:26])[CH2:23][CH2:24][N:15]([C@@H:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)[C:16](=[O:18])[CH3:17])[CH3:20]
Reactant: CC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: CCN(CC)CCCl
Product: CCN(CC)CCN(C(C)=O)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
(R)-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was reacted with 2-chloroethyldiethylamine by method F. This resulted in the product with the molecular weight of 348.45 (C18H28N4O3); MS (ESI): 349 (M+H+).
Reaction SMILES: [CH3:1][C:2]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]=[C:18]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:4]1[CH:13]=[CH:12][C:7](C(OC)=O)=[CH:6][CH:5]=1)[CH3:3].[OH-:30].[Na+].[O:32]1[CH2:36]CCC1>CO>[CH3:3][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:12][C:13]=1[C:36]([OH:32])=[O:30])([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]=[C:18]2[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH3:1]
Reactant: C1CCOC1
Reactant: [OH-]
Reactant: COC(=O)c1ccc(C(C)(C)Oc2ccc3c(c2)C(c2ccccc2)=CC3)cc1
Agent: [Na+]
Solvent: CO
Product: CC(C)(Oc1ccc2c(c1)C(c1ccccc1)=CC2)c1ccccc1C(=O)O
Yield: 85 %

Procedure:
Methyl 4-(1,1-dimethyl-3-phenyl-1H-inden-5-yloxymethyl)benzoate (300 mg, 0.78 mmol) and 3.9 mL of 2N NaOH in 5 mL of tetrahydrofuran and 5 mL of methanol were stirred at room temperature for 16 hours. The mixture was concentrated and acidified with 1N HCl (10 mL), extracted with ethyl acetate (20 mL×3). The combined extracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The residue was crystallized from ether-hexane to give 247 mg (85% yield) of the title compound as white crystals; 1H-NMR (DMSO-d6) δ 1.31 (s, 6H), 5.20 (s, 2H), 6.57 (s, 1H), 6.89 (dd, J=1.1, 8.2 Hz, 1H), 7.02 (d, J=1.1 Hz, 1H), 7.36-7.57 (m, 8H), 7.95 (d, J=8.3 Hz, 2H), 12.94 (bs, 1H); MS m/e 371 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1.Cl.[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[CH:22][C:21](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:20][C:19]=2[CH2:18][CH2:17]1>>[CH3:1][N:2]([CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1)[C:28](=[O:29])[CH:27]=[CH:26][C:21]1[CH:22]=[N:23][C:24]2[NH:25][C:16](=[O:15])[CH2:17][CH2:18][C:19]=2[CH:20]=1
Reactant: CNCc1ccc2ccn(C)c2c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: Cl
Product: CN(Cc1ccc2ccn(C)c2c1)C(=O)C=Cc1cnc2c(c1)CCC(=O)N2
Yield: 65 %

Procedure:
According to the procedure of Example 35g methyl-(1-methyl-1H-indol-6-ylmethyl)-amine (129 mg, 0.74 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride (190 mg, 0.75 mmol), were coupled to give crude product. Purification by column chromatography (silica gel, 5% MeOH/CH2Cl2) gave the title compound (180 mg, 65%) as a pink solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.64-10.62 (m, 1H), 8.36-8.33 (m, 1H), 8.07-8.06 (m, 1H), 7.55-7.47 (m, 2H), 7.39-7.21 (m, 3H), 6.95-6.88 (m, 1H), 6.38-6.37 (m, 1H), 4.89-4.71 (m, 2H), 3.76-3.74 (m, 3H), 3.08-2.85 (m, 5H), 2.54-2.52 (m, 2H); ESI MS m/z 375 [C22H22N4O2+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:3]=1.[CH2:25](Br)[CH:26]=[CH2:27]>>[NH2:1][C:2]1[N:3]=[C:4]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:27][CH:26]=[CH2:25])[CH:18]=2)=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Reactant: C=CCBr
Product: C=CCn1cc(-c2c(-c3ccco3)nc(N)nc2-c2ccco2)ccc1=O

Procedure:
The title compound was synthesized in a similar manner to Example 66 using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone and allyl bromide.
Reaction SMILES: C([BH3-])#N.[Na+].[I:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:10]=[C:11]3[CH2:18][NH:17][CH2:16][CH2:15][N:12]3[C:13]=2[CH:14]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[I:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH:11]3[CH2:18][NH:17][CH2:16][CH2:15][N:12]3[C:13]=2[CH:14]=1
Reactant: Ic1ccc2cc3n(c2c1)CCNC3
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Ic1ccc2c(c1)N1CCNCC1C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
Sodium cyanoborohydride (95%, 1.6 g, 24 mmol) was added over 3 min to a stirred solution of 7-iodo-1,2,3,4-tetrahydropyrazino[1,2-a]indole (2.2 g, 7.4 mmol) in acetic acid (50 mL) at 10° C. under Ar. After complete addition the reaction was allowed to warm to room temperature and stirred for 18 h. The mixture was cautiously poured into a mixture of saturated aqueous sodium hydrogen carbonate solution (150 mL) and ethyl acetate (100 mL). The mixture was partitioned and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (1×100 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)] to give the product as a yellow oil (1.74 g, 79%) which was used immediately.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[CH3:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:7]3[CH2:8][CH2:9][C:10]4[O:2][CH:3]=[CH:4][C:5]=4[CH2:6]3)=[O:24])=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)c2ccc(C(=O)N3CCc4occc4C3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.308 g (1.2 mmol) of 4-(4-methoxybenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to yield the desired product.
Reaction SMILES: NC1N=[C:5]2[C:6](OC)=CC=C(Cl)[N:4]2N=1.[Cl:14][S:15]([C:18]1[C:27]([O:28][CH3:29])=CC=CC=1C(OC)=O)(=[O:17])=[O:16].N1C=CC=CC=1.CS(C)=O.Cl[CH2:41][Cl:42]>Cl.C(#N)C>[Cl:42][C:41]1[CH:6]=[CH:5][N:4]=[C:27]([O:28][CH3:29])[C:18]=1[S:15]([Cl:14])(=[O:16])=[O:17]
Reactant: ClCCl
Reactant: COc1ccc(Cl)n2nc(N)nc12
Reactant: COC(=O)c1cccc(OC)c1S(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1nccc(Cl)c1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
A mixture of 0.90 g (4.5 mmol) of 2-amino-5-chloro-8-methoxy[1,2,4]triazolo[1,5-a]pyridine and 35 mL of dry acetonitrile was prepared and 2.39 g (9.06 mmol) of methyl 2-chlorosulfonyl-3-methoxybenzoate, 0.72 g (9.1 mmol) of dry pyridine, and 0.071 g (0.91 mmol) of dimethyl sulfoxide were added with stirring at ambient temperature keeping the system dry. After 16 hours another 0.35 g (4.5 mmol) of dry pyridine was added and after an additional 48 hours the volatile components of the mixture were removed by evaporation under reduced pressure. The residue obtained was diluted with 50 mL of dichloromethane and 50 mL of 2N aqueous hydrochloric acid and the mixture was stirred vigorously for 72 hours. The solids present were recovered by filtration and washed with 3×25 mL of water, 3×10 mL of dichloromethane, and 3×10 mL of diethyl ether to obtain the title compound as a white solid. The total filtrate and washes were combined and were diluted with 25 mL of dichloromethane and 25 mL of 2N aqueous hydrochloric acid in a separatory funnel. The phases were separated and the organic phase was washed with 3×50 mL of 2N aqueous hydrochloric acid. It was then dried over sodium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a yellow solid. This was suspended in 5.0 mL of dichloromethane and the solids were recovered by filtration and washed quickly with 2×5.0 mL of dichloro-methane and 2×15 mL of diethyl ether to obtain additional title compound as a white solid. The combined title compound amounted to 1.09 g (56 percent of theory) and melted at 290°-292° C. with decomposition.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].Cl.CN(C)CCCN=C=NCC.Cl.[CH3:28][NH:29][O:30][CH3:31].CN(C)C=O>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:29]([O:30][CH3:31])[CH3:28])=[O:14])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CNOC
Reactant: CCc1n[nH]c2cc(C(=O)O)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCc1n[nH]c2cc(C(=O)N(C)OC)ccc12
Yield: 34.3 %

Procedure:
3-ethyl-1H-indazole-6-carboxylic acid (3.9 g, 0.020 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.3 g, 0.022 mol) and 4-dimethylaminopyridine (3.11 g, 0.0254 mol), N,O-dimethylhydroxylamin hydrochloride (2.8 g, 0.028 mol) were dissolved in methylene chloride (200 mL) and N,N-dimethylformamide (20 mid) and the solution stirred at room temperature for one hour. The resulting mixture was poured in iced water. The aqueous layer was removed, and extracted with ethyl acetate (2×50 mL). The combined organics were washed with 1 N HCl, 2N NaOH, water, and brine, then dried. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel eluting with a gradient of 50% ethyl acetate in hexanes to 100% ethyl acetate over 30 minutes to give 1.6 g (33%) of 3-ethyl-N-methoxy-N-methyl-1H-indazole-6-carboxamide.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:24])=[N:10][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([C:34]5[CH:33]=[CH:32][CH:31]=[C:30]([F:29])[CH:35]=5)=[CH:3][C:4]([C:25]([F:28])([F:26])[F:27])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:24])[CH2:13]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: OB(O)c1cccc(F)c1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cccc(F)c3)c2[nH]1

Procedure:
7-Bromo-2-[(2R)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl]-5-(trifluoromethyl)-1H-benzoimidazole (95 mg, 0.2 mmol, Example 77) and 3-fluoro-phenylboronic acid (35 mg, 0.25 mmol, Aldrich) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 490 (M+1).