Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([OH:15])/[C:8]/2=[CH:11]\[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.CO>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([OH:15])/[C:8]/2=[CH:11]/[C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: NC(=O)/C=C1/c2cc(F)ccc2CC1O
Solvent: ClCCl
Solvent: CO
Product: NC(=O)/C=C1\c2cc(F)ccc2CC1O
Yield: 24.3 %

Procedure:
A solution of (Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide (5.456 g, 0.026 mol) in dichloromethane:methanol/9:1 (1000 ml) was irradiated by an Canrad-Hanovia quartz, mecury-vapor photochemical immersion lamp, 450 wattts (Ace Glass, 7825-35) for 1h. The volitiles were removed by spin evaporation in vacuo to give a light brown solid residue. This residue was chromatographed on Silica Gel 60 using a step gradient going from ethyl acetate:hexanes/1:1 to ethyl acetate:ethanol/1:1. Fractions containing (E)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide were combined and concentrated by spin evaporation in vacuo. The resulting residue was recrystallized from ethanol-hexanes to give 1.31 g (24%) of (E)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide as an off-white crystalline solid, m.p., 159°-163° C., NMR(DMSO-d6): d 8.56 (dd, 1H, JHF =11.0 Hz, JHH =2.9 Hz), 7.67 (br s, 1H), 7.34-7.30 (m, 1H), 7.2-7.13 (m, 1H), 7.06 (br s, 1H),6.18 (s, 1H), 5.69 (d, 1H, J=6.8 Hz), 4.74 (q, 1H, J=12.1 Hz, J=6.0 Hz), 3.21-3.13 (m, 1H) 2.73-2.66(m, 1H); steady state nOe: irradiation at d6.19, observed 5.4% nOe at d4.74, 4.3% at d7.67 and 1.5% at d 5.69.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:5]=1[C:6]#[N:7])([O-])=O.S(=O)(=O)(O)[OH:16].[OH-].[Na+]>O1CCCC1>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:5]=1[C:6]([NH2:7])=[O:16]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1c(N)cccc1N
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5 g (25.373 mmol) 2,6-dinitro-benzonitrile is combined with 20 ml of an aqueous 80% sulphuric acid and stirred for 2 h at 80° C. The reaction mixture is combined with 100 ml of tetrahydrofuran and neutralised with 10% aqueous sodium hydroxide solution. The organic phase is separated off, combined with another 100 ml of tetrahydrofuran and 200 mg palladium on charcoal and stirred for 20 h at 8 bar H2 pressure and 25° C. The solids are filtered off. The filtrate is combined with 300 ml of ethyl acetate and extracted with saturated potassium hydrogen carbonate solution. The organic phase is separated off, dried and the solvent is eliminated in vacuo. The residue is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 7% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution are added.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](O)(=O)[CH3:11]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Nc1cc(Br)cnc1N
Product: Cc1nc2cc(Br)cnc2[nH]1
Yield: 82 %

Procedure:
To 5.06 g of 5-bromo-2,3-diaminopyridine 46 (Ryabukhin et al (2006) Synthesis 21:3715-3726; Oguchi et al (2000) J. Med. Chem. 43(16):3052-3066; Seki et al (1995) J. Hetero. Chem. 32(3):1071-73; Fray et al (1995) J. Med. Chem. 38(18):3524-35) was added 50 mL acetic acid under N2 and the reaction was heated to reflux overnight. Complete reaction was confirmed by LCMS. The solution was concentrated in vacuo and purified by flash chromatography (DCM/MeOH) to give 4.68 g of 6-bromo-2-methyl-3H-imidazo[4,5-b]pyridine 51 (82% yield), which may also be prepared by the methods of Cee et al (2007) J. Med. Chem. 50(4):627-40; Itoh et al (1982) J. Hetero. Chem. 19(3):513-17. 6-Bromo-2-methyl-3H-imidazo[4,5-b]pyridine (4.68 g) in 150 mL THF was added to 0.63 g (1.1 eq) NaH in 10 mL THF under N2 at −78° C. The reaction was stirred at −78° C. for 30 minutes followed by the addition of 3.86 g of SEM-Cl (1.05 eq) and allowed to warm up to room temperature. The reaction was stirred at room temperature 4.5 hours and complete reaction was confirmed by LCMS. The reaction was quenched with water followed by the addition of NaCl (not saturated) and the two products extracted with EtOAc and concentrated in vacuo. The two regioisomers were separated by flash chromatography (EtOAc/Hexanes) to give 2.84 g 6-bromo-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 52 and 1.94 g 6-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine 53 (63% overall yield). 6-Bromo-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 52 (2.08 g) was dissolved in 50 mL toluene followed by the addition of 2.32 g (1.5 eq) of bis(pinacolato)diboron, 0.24 g (0.05 eq) of PdCl2(dppf), and 1.79 g (3.0 eq) of KOAc. The reaction mixture was heated to 95° C. under N2 and let stir overnight. Complete reaction confirmed by LCMS. The mixture was cooled to room temperature, rotovapped and purified by flash chromatography (EtOAc/Hexanes) to give 1.83 g of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 54 (77% yield). MS (Q1) 390.2 (M)+
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([C:23]([O:25]CC)=[O:24])=[CH:17]3)(=[O:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Cl>O1CCOCC1.O>[N:1]1([CH2:7][CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([C:23]([OH:25])=[O:24])=[CH:17]3)(=[O:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc2cc(NS(=O)(=O)CCCN3CCCCC3)ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2cc(NS(=O)(=O)CCCN3CCCCC3)ccc2[nH]1
Reaction time: 24 h

Procedure:
Ethyl 5-[(3-(piperadin-1-yl)propyl)sulfonamido]indole-2-carboxylate (PREPARATION 83, 1.63 g) is dissolved in 10 ml of dioxane and 5 ml of water. Then 0.59 g of solid potassium hydroxide pellets are added and the reaction is stirred at 20°-25° for 24 hr. Then 8.91 ml of 1N hydrochloric acid is added after diluting the reaction with 100 ml of water. The mixture is extracted with n-butanol (3×50 ml) and the organic layer is separated and evaporated under reduced pressure to provide the title compound, NMR (300 MHz, d6-DMSO) 7.37, 7.27, 7.00, 6.90, 2.91, 2.25, 1.75, 1.31, (peak at 4.3 ppm obscured by DMSO).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:21]N>O>[NH:1]([C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:21]
Reactant: NN
Reactant: CC1(C)C(N)=Nc2ccccc2C1(O)c1ccccc1
Solvent: O
Product: CC1(C)C(NN)=Nc2ccccc2C1(O)c1ccccc1
Yield: 86.3 %

Procedure:
2-Amino-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (10.0 g., 0.0375 mole) was added to anhydrous hydrazine (34g., 1.06 mole) and the solution refluxed for 51/2 hours, cooled, poured on to water, extracted with chloroform, dried and evaporated. Trituration with toluene yielded the title compound as a white solid (9.11g., m.p. 195° - 196° C) [Found: C, 72.5; H, 7.0; N, 14.8% C17H19N3O requires C, 72.6; H, 6.8; N, 14.9%]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9](=[S:25])[NH:8][C:7]=2[N:26]=1.C(=O)([O-])O.[Na+].I[CH2:33][CH3:34].C(#N)C>C(OCC)(=O)C>[CH2:33]([S:25][C:9]1[N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[C:11](=[O:12])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:26][C:7]=2[N:8]=1)[CH3:34]
Reactant: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]c2n1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 7-methoxy-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (383 mg), 1M aqueous sodium hydrogen carbonate solution (1.0 ml), iodoethane (0.4 ml) and acetonitrile (10 ml) was stirred at 100° C. for 1 hr. The reaction mixture was allowed to be cooled, diluted with ethyl acetate (80 ml), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (375 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([CH2:12][OH:13])([CH2:10][OH:11])[CH:8]=[CH2:9])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl-].[NH4+]>ClCCl>[C:1]([O:5][C:6]([C:7]1([CH:8]=[CH2:9])[CH2:12][O:13][C:22](=[O:24])[O:11][CH2:10]1)=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CC(CO)(CO)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC1(C(=O)OC(C)(C)C)COC(=O)OC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 178.8 %

Procedure:
A solution of 2,2-bis-hydroxymethyl-but-3-enoic acid tert-butyl ester (202 mg, 1 mmol) and pyridine (0.5 mL, 6 mmol) in dichloromethane (5 mL) was stirred at −78° C. under nitrogen. A solution of triphosgene (150 mg, 0.5 mmol) in dichloromethane (2.5 mL) was added dropwise and the reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was warmed to room temperature and stirred at room temperature for 15 min and saturated ammonium chloride solution was added. The organic layer was separated, washed with hydrochloric acid (1 M), saturated sodium hydrogen carbonate solution and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 4:1 to 3:2 to afford the title compound (204 mg, 89%) as a clear gum. 1H NMR (300 MHz, CDCl3): δ 1.48 (s, 9H), 4.38 (d, J=10.7 Hz, 2H), 4.71 (d, J=10.7 Hz, 2H), 5.39 (d, J=17.4 Hz, 1H), 5.47 (d, J=10.7 Hz, 1H), 5.77 (dd, J=17.4, 10.7 Hz, 1H). LCMS (m/z) 229.1 [M+H], Tr=2.04 min.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[O:6][C:5]=1[CH3:16])(=O)[CH3:2].Cl.[NH2:18][OH:19]>CCO.N1C=CC=CC=1>[CH3:16][C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:8]([CH3:9])[C:4]=1[C:1](=[N:18][OH:19])[CH3:2]
Reactant: CC(=O)c1c(C)oc(-c2ccncc2)c1C
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1c(C)oc(-c2ccncc2)c1C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a stirred solution of 3-acetyl-2,4-dimethyl-5-(4-pyridyl)furan (0.5 g, 2.33 mM) in EtOH (10 mL) and pyridine (2 mL) was added hydroxylamine hydrochloride (0.2 g, 2.79 mM) at room temperature. After stirring overnight, volatiles were removed by evaporation. Ethyl acetate (100 mL) and water (70 mL) were added, and partitioned. The organic layer was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The resulting solid was triturated to give the subtitle compound (0.45 g, 84% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared analogously to intermediate 2 (4-methoxy-3-propoxy-benzaldehyde) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with allylbromide in DMF using K2CO3 as base (see also A. W. White, R. Almassy, A. H. Calvert, N. J. Curtin, R. J. Griffin, Z. Hostomsky, K. Maegley, D. R. Newell, S. Srinivasan, B. T. Golding J. Med. Chem. 2000, 43, 4084-4097).
Reaction SMILES: Cl.[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([NH2:15])=[NH:14])[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:16][O:17][CH:18]([C:23](OC)=[O:24])[C:19](OC)=[O:20].C[O-].[Na+].Cl>CO>[CH2:2]([C@H:7]1[CH2:8][CH2:9][C@H:10]([C:13]2[N:15]=[C:23]([OH:24])[C:18]([O:17][CH3:16])=[C:19]([OH:20])[N:14]=2)[CH2:11][CH2:12]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)C(OC)C(=O)OC
Reactant: CCCCC[C@H]1CC[C@H](C(=N)N)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCC[C@H]1CC[C@H](c2nc(O)c(OC)c(O)n2)CC1
Reaction time: 5 h

Procedure:
This trans-4-pentylcyclohexanecarboxamidine hydrochloride (69 g, 0.30 mol) and dimethyl methoxymalonate (48 g, 0.30 mol) were added to a solution of sodium methylate (56 g, 1.0 mol) dissolved in anhydrous methanol (1 l), followed by heating the mixture under reflux with stirring for 5 hours, thereafter cooling the resulting material, mixing it with 6N-hydrochloric acid (500 ml), agitating the mixed liquid at room temperature for 20 minutes, filtering the liquid under suction through a filter, washing the resulting residue on the filter with water and methanol and drying it under reduced pressure to obtain 2-(trans-4-pentylcyclohexyl)-4,6-dihydroxy-5-methoxypyrimidine (67 g, 0.23 mol).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:21])[NH:5][N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].O.[Na+].Br[CH2:31][CH2:32][S:33]([O-:36])(=[O:35])=[O:34]>CN(C=O)C>[OH2:21].[C:1]([C:3]1[C:4](=[O:21])[N:5]([CH2:31][CH2:32][S:33]([OH:36])(=[O:35])=[O:34])[N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2]
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Reactant: O=S(=O)([O-])CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccccc2)c(-c2ccccc2)nn(CCS(=O)(=O)O)c1=O
Temperature: 110 °C
Yield: 50.1 %

Procedure:
7.5 grams (0.027 mole) of the product of Example 1 was caused to react with 3.79 grams of K2CO3 in the least amount of water along with 200 mls of DMF. To this mixture was added 5 drops of 18 crown-6-ether. Into this solution was added 5.79 grams (0.027 mole) of 2-bromoethane sulfonic acid sodium salt and the mixture heated to 110° C. for 3 hours. The solution was filtered and the filtrate was distilled at reduced pressure. The residual solid was dissolved in excess water and poured into conc. hydrochloric acid. The solid that precipitated was filtered and washed with water and then air dried. The recovered solid was recrystallized from acetonitrile to give 2.7 grams of a yellow solid which melted at 138°-140° C.
Reaction SMILES: FC(F)(F)C(O)=[O:4].S(=O)(=O)(O)O.[C:13]([C:15]1[CH:16]=[C:17]([C:22]2[N:26]3[CH:27]=[CH:28][N:29]=[C:30]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=4)[C:25]3=[N:24][CH:23]=2)[CH:18]=[CH:19][C:20]=1[OH:21])#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>>[OH:21][C:20]1[CH:19]=[CH:18][C:17]([C:22]2[N:26]3[CH:27]=[CH:28][N:29]=[C:30]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([S:39](=[O:40])(=[O:41])[NH2:42])=[CH:35][CH:34]=4)[C:25]3=[N:24][CH:23]=2)=[CH:16][C:15]=1[C:13]([NH2:14])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1cc(-c2cnc3c(NCc4ccc(S(N)(=O)=O)cc4)nccn23)ccc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1cc(-c2cnc3c(NCc4ccc(S(N)(=O)=O)cc4)nccn23)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trifluoroacetic acid (1.5 ml) and conc. Sulphuric acid (1.5 ml) were added to 4-{[3-(3-cyano-4-hydroxy-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzenesulfonamide (0.093 g, 0.2 mmol) and the resulting solution was stirred at ambient temperature for 24 hours. The reaction mixture was neutralized with conc. Aqueous sodium carbonate solution and extracted with ethyl acetate (2×50 mL). The organic layers were combined and dried with magnesium sulphate, filtered and concentrated in vaccuo. The crude material was taken up in DMSO and purified by prep HPLC. The product, 2-hydroxy-5-[8-(4-sulfamoyl-benzylamino)-imidazo[1,2-a]pyrazin-3-yl]-benzamide, is obtained as a white solid (4.2 mg, 5%) (LC-MS m/z 439 [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N:15]([C:24](=[O:36])[NH:25][C:26](=O)[C:27]1[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=1[F:34])[NH:16]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N:15]1[C:24](=[O:36])[NH:25][C:26]([C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[N:16]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)NC(=O)c1ccc(I)cc1F)c1cc(CNC(=O)C2CC2)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.2 %

Procedure:
To a solution of tert-butyl 2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-2-((2-fluoro-4-iodobenzoyl)carbamoyl)hydrazinecarboxylate (0.200 g, 0.31 mmol) in DCM (10 mL) was added trifluoro acetic acid (1.0 mL). The reaction mass was stirred at RT for 12 h and refluxed for 15 h. The reaction mass was cooled to RT, basified with NaHCO3 (pH=8), extracted with DCM and concentrated to afford 0.110 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.68 (m, 4H), 1.59 (m, 1H), 4.32 (d, J=5.7 Hz, 2H), 7.38 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.51-7.63 (m, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.88 (d, J=10.2 Hz, 1H), 8.68 (m, 1H), 12.43 (br s, 1H); MS (m/z): 513.01 (M+H)+.
Reaction SMILES: [C:1]([NH:6][CH2:7][C:8]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:9])(=[O:5])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[C:1]([NH:6][CH:7]([C:8]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:9])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)C(=O)NCC(=O)c1ccco1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)C(C)C)C(=O)c1ccco1
Yield: 64.1 %

Procedure:
13.0 g of N-isobutyryl-(2-furylcarbonyl)methylamine, 3.1 g of 61% sodium hydride and 12.2 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 12.0 g of ethyl 3-isobutyrylamino-3-(2-furylcarbonyl)propionate are thereby obtained. Yield: 64.2%
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH:20]1[CH2:24][O:23][CH:22]([OH:25])[CH2:21]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:26]1(C)C=CC(S(O)(=O)=O)=C[CH:27]=1.C(OCC)(OCC)OCC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([CH:20]1[CH2:24][O:23][CH:22]([O:25][CH2:26][CH3:27])[CH2:21]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C4COC(O)C4)cc3c2c1C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc2[nH]c3ccc(C4COC(OCC)C4)cc3c2c1C
Yield: 135.5 %

Procedure:
100 mg (0.29 mmol) of 6-(2-hydroxytetrahydrofuran-4-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester is refluxed in 5 ml of toluene with 10 mg of p-toluenesulfonic acid and 52 mg (0.35 mmol) of triethyl orthoformate for 1.5 hours. After concentration, the mixture is chromatographed over silica gel with toluene:glacial acetic acid:water=10:10:1 thus obtaining 29 mg (27% of theory) of 6-(2-ethoxytetrahydrofuran-4-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester as an oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([Br:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([NH:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([Br:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N)c3Cl)cccn2c1Br
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A mixture of 8-(3-amino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine dihydrochloride (100 mg) and acetic anhydride (100 mg) in dry pyridine (2 ml) was stirred at 90° C. for one hour. The cooled mixture was poured into an ice water (10 ml). The precipitated solid was collected, washed with water, and dried under reduced pressure to give 8-(3-acetylamino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine (65 mg) as a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9](Cl)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH3:12]>O1CCCC1>[F:1][C:2]1[C:3]([C:9]([NH2:12])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(Cl)c1ncc(Cl)cc1F
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1ncc(Cl)cc1F
Reaction time: 4 h

Procedure:
4.0 g of 3-fluoro-5chloro-2-pyridinecarbonyl chloride (Example H6) are added in portions to a stirred mixture of 26 ml of 30% aqueous ammonia solution and 4 ml of tetrahydrofuran. The yellowish suspension is subsequently stirred for 4 hours and filtered and the material on the filter is washed with water and n-hexane. After drying in vacuo at 40° C., 1.34 g of the desired compound are obtained as a white solid of melting point 162-164° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=1)#[N:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)[N:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([C:22]3[N:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[CH:31][N:30]=2)=[O:19])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=1)#[N:2]
Reactant: Nc1ccc(-c2cccnn2)cn1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2C#N)ccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(-c4cccnn4)cn3)cc2C#N)ccn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(3-cyano-4-(2-methylpyridin-4-yl)phenyl)acetic acid 111-10 (50 mg, 0.2 mmol), 5-(pyridazin-3-yl)pyridin-2-amine 145-3 (34 mg, 0.2 mmol), 1,3-dicyclohexylcarbodiimide (50 mg, 0.24 mmol) and 4-(dimethylamino)pyridine (4 mg, 0.04 mmol) in DMF (0.9 mL) was stirred at room temperature for 10 hours. The crude product was filtered to remove the insoluble and the filtrate was purified by reverse phase HPLC to give 2-(3-cyano-4-(2-methylpyridin-4-yl)phenyl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 181 as white solid. MS m/z 407.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.13 (s, 1H), 9.22 (dd, 1H), 9.13 (d, 1H), 8.59 (d, 1H), 8.56 (dd, 1H), 8.29 (dd, 1H), 8.23 (d, 1H), 7.98 (d, 1H), 7.83-7.79 (m, 2H), 7.67 (d, 1H), 7.48 9s, 1H), 7.42 (dd, 1H), 3.95 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+:10].[CH2:11]([Si:17]([NH:20][Si:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH3:19])[CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:22]([Si:21]([N-:20][Si:17]([CH3:19])([CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH3:29])[CH3:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[K+:10]
Reactant: CCCCCC[Si](C)(C)N[Si](C)(C)CCCCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCC[Si](C)(C)[N-][Si](C)(C)CCCCCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium bis(n-hexyldimethylsilyl)amide was prepared as follows: Potassium bis(trimethylsilyl)amide (5.07 g, 25.6 mmol) and bis(n-hexyldimethylsilyl)amine (7.66 g, 25.6 mmol) were added to a flask and 50 mL toluene was added. The clear yellow solution was stirred at room temperature for 18 hours and then refluxed for two hours. The toluene and hexamethyldisilazane byproduct were removed from the brown toluene solution under vacuum with heating to 150° C. to yield a brown oil (5.40 g, 63%). Its viscosity was measured to be 271 centipoise at 40° C. It may be flash vaporized from a heated nozzle for CVD applications. Alternatively, it may be dissolved in small amounts of organic solvents to form concentrated solutions that may be flash vaporized.