Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH2:5][N:6]1[C:13]2[N:9]([N:10]=[CH:11][CH:12]=2)[CH2:8][CH2:7]1)=O.[NH4+:14]>C(O)C>[C:3]([CH2:5][N:6]1[C:13]2[N:9]([N:10]=[CH:11][CH:12]=2)[CH2:8][CH2:7]1)(=[O:2])[NH2:14]
Reactant: COC(=O)CN1CCn2nccc21
Reactant: [NH4+]
Solvent: CCO
Product: NC(=O)CN1CCn2nccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methoxycarbonylmethyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (27 g) in ethanol (135 ml) was added 28% ammonium solution (100 ml). The mixture was stirred overnight at room temperature. The insoluble material was filtered off and the filtrate was evaporated to precipitate the crystals. The crystals were collected by filtration to give 1-carbamoylmethyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (6 g).
Reaction SMILES: [NH2:1][C:2]1[C:12]([Br:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:3]2[C:2]=1[NH:1][C:15](=[O:17])[N:6]([CH2:7][CH3:8])[C:4]2=[O:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCNC(=O)c1cccc(Br)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1c(=O)[nH]c2c(Br)cccc2c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
A mixture of 2-amino-3-bromo-N-ethylbenzamide (2.0 g, 8.23 mmol, 481a), triphosgene (0.830 g, 2.80 mmol, Sigma Aldrich,), DCM (28.0 mL), and DIPEA (1.6 mL, 8.95 mmol) was set stirring at 60° C. with a condenser for 4 h. The mixture was concentrated under reduced pressure to a yellow residue. It was adsorbed onto silica and purified on 24 g SiO2 (eluent: 0-100% EtOAc/hexanes over 25 min, RediSep Gold). The product fractions were combined and concentrated under reduced pressure to give the product as a white solid (736 mg, 98%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (1H, s) 7.95 (1H, dd, J=7.82, 1.37 Hz) 7.98 (1H, dd, J=7.82, 1.37 Hz) 7.15 (1H, t, J=7.82 Hz) 3.93 (2H, q, J=7.04 Hz) 1.15 (3H, t, J=7.04 Hz). m/z (ESI, +ve) 268.9 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])C.[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]3[CH:19]3[CH2:20][CH2:21]3)=[CH:13][C:12]=1[F:17])[CH2:28]2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: OCc1cccc2c1CNC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2nc(N3Cc4cccc(CO)c4C3)c(F)cc2c1=O
Yield: 19 %

Procedure:
310 mg of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 298 mg of 4-hydroxymethylisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in a similar manner as in Example 107 to produce 75 mg of 7-(4- hydroxymethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=2)=[CH:14][CH:13]=1>>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:9])[NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=3)=[CH:16][CH:17]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)Nc2ccc(-c3c[nH]c(=O)cn3)cc2)cc1

Procedure:
Using a procedure similar to that of Example 17 p-tolyl isocyanate is reacted with 5-(4-aminophenyl)-2(1H)-pyrazinone (or its hydrobromide salt) to give 5-[4-(3-p-tolylureido)phenyl]-2(1H)-pyrazinone.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9](Cl)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12].C(OCC)C>C(N(CC)CC)C>[C:9]([C:5]1[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12]
Reactant: O=C(Cl)c1ccccc1O
Reactant: NC(=O)c1nc[nH]n1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: NC(=O)c1n[nH]c(C(=O)c2ccccc2O)n1
Reaction time: 2 h

Procedure:
To a cooled, stirred mixture of 2 g. of 1,2,4-triazole-3-carboxamide and 5.4 g. salicyloyl chloride in 125 ml. of anhydrous diethyl ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 22 hours. The mixture is filtered and the solid is collected and washed successively with diethyl ether, cold water, diethyl ether and dried in vacuo for 4 hours. The solid is extracted with hot, dry acetonitrile. The filtrate is reduced to about half volume by evaporation in vacuo over a warm water bath and filtered to separate a small amount of solid which separates for 2 hours. Further evaporation of the resulting filtrate to a very small volume results in the separation of a solid which is collected, washed with acetonitrile and dried yielding 210 m.p. 125°-135° C. (dec.).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:30]2[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=2[F:37])[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][C@H:14]1[CH2:28][OH:29]>ClCCl>[CH2:21]([O:20][CH2:19][C@@H:16]1[O:17][CH2:18][C@@:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])([C:30]2[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=2[F:37])[C@H:14]([CH2:28][OH:29])[CH2:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.8 %

Procedure:
Benzoyl isothiocyanate (3.40 mL, 25.3 mmol) was added to a solution of [(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(5-bromo-2-fluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C30) (10.84 g, 25.55 mmol) in dichloromethane (255 mL). The reaction mixture was stirred at room temperature for 48 hours and then concentrated under reduced pressure to afford the product as a light yellow solid (9.49 g), which was taken directly to the following step. LCMS m/z 587.0 [M−H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([C:16]1[N:17]=[C:18]([Cl:27])[CH:19]=[C:20]2[C:24]([CH3:25])=[C:23]([CH3:26])[NH:22][C:21]=12)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([O:5][C:6](=[O:28])[N:7]([C:16]1[N:17]=[C:18]([Cl:27])[CH:19]=[C:20]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:21]=12)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2c(N(Cc3ccc(F)cc3)C(=O)OC(C)(C)C)nc(Cl)cc2c1C
Product: Cc1c(C)n(Cc2ccccc2)c2c(N(Cc3ccc(F)cc3)C(=O)OC(C)(C)C)nc(Cl)cc12
Yield: 70 %

Procedure:
In accordance with the same procedures as in Example 657, except for using (5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-(4-fluorobenzyl)-carbamic acid tert-butyl ester prepared in Step 2 and benzyl bromide, the titled compound was obtained as yellow oil. (Yield: 70%)
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=O.Cl.[NH2:12]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)#[N:12]
Reactant: NO
Reactant: O=Cc1ccc(C(=O)O)o1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc(C(=O)O)o1
Temperature: 85 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
A 250-mL, three-neck, round-bottom flask equipped with a mechanical stirrer, a heating mantle, and a condenser was charged with 5-formyl-2-furancarboxylic acid (9.18 g, 65.6 mmol) and pyridine (60 mL). Hydroxylamine hydrochloride (5.01 g, 72.2 mmol) was added and the mixture was heated to 85° C. Acetic anhydride (40 mL) was added and the reaction was stirred at 85° C. for 3 h, after which time the solvent was evaporated at 40° C. under reduced pressure. The residue was dissolved in water, basified with 2.0 N NaOH solution to pH 9, and extracted with 4:1 dichloromethane/2-propanol until the pyridine was completely removed (5×200 mL). The aqueous solution was then acidified with 2.0 N HCl solution to pH 2, saturated with solid NaCl, and extracted with 4:1 dichloromethane/2-propanol (5×200 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to dryness. The residue was crystallized from dichloromethane to give 6.80 g of the title compound as a white solid (76%). Mass spectrum (ESI-neg, m/z) Calcd. for C6H3NO3, 136.0 (M−H), found 136.1. The 1H NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:26])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl.O>[CH:1]1([CH2:7][C@@H:8]([NH:26][C:39]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2nccc3ccccc23)CC1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2nccc3ccccc23)CC1)C1CCCCC1
Reaction time: 8 h

Procedure:
To a mixture of 0.25 g (0.64 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(isoquinolin-1-yl)-piperazin-1-yl]-ethyl}-amine and 0.145 g (1.05 mmol) of anhydrous potassium carbonate in 10 mL of dichloromethane and 1 mL of water at 0° C. was added dropwise 0.10 g (0.70 mmol) of cyclohexanecarboxylic acid chloride. The reaction mixture was allowed to stir under nitrogen overnight, during which time it came up to room temperature. The phases were separated and the aqueous phase was extracted with four additional 10 mL portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with isopropanolic HCl to yield 0.17 g (58%) as a white solid; mp=155-159° C.; MS (+) ESI m/z=463 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[O:4]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>ClCCCl>[C:24]([C:15]1[CH:16]=[CH:17][C:5]2[O:4][CH:3]([C:2]([F:1])([F:18])[F:19])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=2[CH:14]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C1=Cc2ccccc2OC1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)C1=Cc2cc(C(=O)c3ccccc3)ccc2OC1C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 11.9 %

Procedure:
Ethyl 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 10, Step 1)(1.59 g, 5.8 mmol) was dissolved in 1,2-dichloroethane (3 mL) and added to a 0° C. suspension of aluminum chloride (2.59 g, 19.4 mmol) in 1,2-dichloroethane (3 mL). A solution of benzoyl chloride (1.01 g, 7.2 mmol) in 1,2-dichloroethane (3 mL) was added and the reaction was heated to 80° C. and stirred for 4 hours. The solution was poured onto 3 N HCl and ice and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with 3N HCl, saturated sodium bicarbonate, brine, dried over MgSO4 and concentrated in vacuo. The crude ester was purified by flash chromatography over silica gel (with 1:9 ethyl acetate/hexane as eluant) to afford the ester as a white crystalline solid (0.26 g, 12%): mp 114.7–116.1° C. 1H NMR (CDCl3/300 MHz) 7.82 (dd, 1H, J=8.5 Hz 2.0 Hz), 7.76 (m, 4H), 7.61 (m, 1H), 7.50 (m, 2H), 7.09 (d, 1H, J=8.7 Hz), 5.79 (q, 1H, J=6.8 Hz), 4.34 (m, 2H), 1.36 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:36](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:26][CH2:25]3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:36][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)[CH2:28][CH2:29]3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CN5CCC(N6CCCCC6)CC5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CN5CCC(N6CCCCC6)CC5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 52.6 %

Procedure:
1′-[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl][1,4′]bipiperidyl is prepared as described in Example 179a starting with 0.025 g of 1′-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl][1,4′]bipiperidyl instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.17 cm3 of 5N potassium hydroxide. 0.01 g of 1′-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl][1,4′]bipiperidyl is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][C:4]#[N:5].C1CCN2C(=NCCC2)CC1.[CH3:18][C:19]1[CH:20]=[C:21]([NH:30][C:31]2[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=2)[CH:22]=[C:23]([C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[CH:24]=1>C(#N)C>[CH3:1][C:2]([N:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([NH:30][C:31]3[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=3)[CH:20]=[C:19]([CH3:18])[CH:24]=2)[CH:29]=[N:28]1)([CH3:6])[CH2:3][C:4]#[N:5]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Reactant: CC(C)=CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C(C)(C)CC#N)c2)c1
Temperature: 75 °C

Procedure:
3-Methylbut-2-enenitrile (179 mg, 1.57 mmol) and DBU (143 mg, 0.94 mmol) were added to a stirred solution of N-[3-methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (250 mg, 0.73 mmol) in acetonitrile (3.9 mL). The mixture was heated to 75° C. overnight and concentrated under reduced pressure The residue was purified by column chromatography on silica gel to afford 3-methyl-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]butanenitrile. MS ESI calcd. for C20H20F3N6 [M+H]+ 401. found 401. 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 8.27 (s, 1H), 7.91 (s, 1H), 7.84 (s, 1H), 7.32 (s, 1H), 7.26 (d, J=4.9 Hz, 1H), 7.15 (s, 1H), 3.24 (s, 2H), 2.31 (s, 3H), 1.67 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][O:25][CH3:26])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28].C(=O)([O-])[O-]>O1CCOCC1.O.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>[CH:27]([C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][O:25][CH3:26])(=[O:22])=[O:21])[CH2:18][CH2:19]2)[CH:32]=[CH:31][CH:30]=1)=[O:28]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)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-]
Solvent: O
Solvent: C1COCCO1
Product: COCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Temperature: 160 °C
Yield: 48.4 %

Procedure:
To a solution of 5-bromo-3-(1-{[2-(methyloxy)ethyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (100 mg, 0.22 mmol) in dioxane (3.0 mL) and water (1.0 ml), (3-formylphenyl)boronic acid (186 mg, 1.25 mmol), Pd(PPh3)4 (25.0 mg, 10%) and cessium carbonate (200 mg, 0.45 mmol) were added. The reaction mixture was heated in a Smith synthesizer microwave at 160° C. for 20 min. All solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate/hexane, 1/1) to yield the desired product (50.0 mg, 48%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[NH:3][CH:2]=1.[H-].[Na+].CI.[C:18](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:18][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[N:3]=[CH:2]1
Reactant: O=C([O-])O
Reactant: COC(=O)c1cccc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc2c1ncn2C
Temperature: 0 °C

Procedure:
1.39 g of methyl 3H-benzimidazole-4-carboxylate are dissolved under argon in 20 ml of N,N-dimethylformamide. The solution is cooled to 0° C. in an ice bath and admixed in portions with 0.299 g of sodium hydride (60% dispersion). 0.744 ml of methyl iodide is added and the reaction mixture is heated to 45° C. over 17 hours. The reaction mixture is subsequently poured onto 50 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with 2:1 tetrahydrofuran/tert-butyl methyl ether (2×150 ml). The combined organic phases are washed with 50 ml each of saturated aqueous sodium hydrogencarbonate solution and water, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rt=1.95.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH2:31]([N:33]([CH2:39][CH3:40])[CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH3:32]>>[CH2:31]([N:33]([CH2:39][CH3:40])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29])[CH3:32]
Reactant: CCN(CC)CCCCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: CCN(CC)CCCCNC(=O)Nc1snc(OCc2c(F)cc(C)c(F)c2F)c1C(N)=O

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-diethyl-butane-1,4-diamine by the procedure analogous to Example 1. MS (APCl, m/z): 488 [M+H]+.
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(=O)=O.Cl.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH:25]2[OH:30])[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:32][C:17]([F:16])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:5][CH2:6][C:7]#[C:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:26][CH:25]2[OH:30])[CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)CCC#Cc1ccccc1
Reactant: OC1CNCCC1c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1CN(CCC#Cc2ccccc2)CCC1c1cccc(C(F)(F)F)c1
Yield: 20.5 %

Procedure:
A mixture of 1-mesyl-4-phenylbut-3-yne (352 mg, 1.57 mmol), 4-(3-(trifluoromethyl)phenyl)piperidin-3-ol hydrochloride (530 mg, 1.88 mmol) and K2CO3 (542 mg, 3.93 mmol) in 20 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×20 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as an off white solid (120 mg, 21%): mp 77-79° C.; 1H NMR (CDCl3) 1.71 (m, 2 H), 2.15 (m, 3 H), 2.40 (bs, 1 H), 2.62 (m, 4 H), 2.72 (m, 1 H), 2.83 (m, 2 H), 7.27-7.81 (m, 9 H).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[CH:19]1([Mg]Cl)[CH2:21][CH2:20]1>C1COCC1>[CH:19]1([CH:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:18][CH:17]=2)[CH:7]2[C:8](=[O:16])[O:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]2=[O:13])[CH2:21][CH2:20]1
Reactant: Cl[Mg]C1CC1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(C(c2ccc(O)cc2)C2CC2)C(=O)O1

Procedure:
To a solution of 21.1 (8.00 g, 32 mmol) in THF (100 mL) was added a 2.0 M solution of cyclopropylmagnesium chloride in THF (97 mL, 193 mmol (commercially available from Aldrich)) dropwise at 0° C. over 1 hour. Upon completion of the addition, the mixture was quenched with 1 N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was chromatographed on silica gel (20-30% EtOAc/hexane) to afford 21.2.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37](O)=[O:38])[C:32]2=[O:40])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:37]([C:33]5[C:32](=[O:40])[N:31]([C:28]6[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=6)[CH:36]=[CH:35][CH:34]=5)=[O:38])=[CH:3][CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Yield: 71.1 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.486 mmol), N,N-dimethylacetamide (3.0 mL), 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (170 mg, 0.729 mmol), HATU (277 mg, 0.729 mmol) and N,N-diisopropylethylamine (127 μL, 0.729 mmol) and in the same manner as in Example 10, the title compound (181 mg, 71%) was obtained as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>CO>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCC(F)(F)F)cn1
Reaction time: 2 h

Procedure:
Under an atmosphere of nitrogen a solution of 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester (216 mg, 0.92 mmol) in methanol (1 ml) was treated with a solution of lithium hydroxide monohydrate (78 mg, 1.84 mmol) in methanol (0.1 ml). After stirring for 2 hours the reaction mixture was evaporated at reduced pressure. The residue was treated with hydrochloric acid (1N), the solid material was filtered then washed with water, finally dried at high vacuum. The 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid was obtained as a white solid (125 mg, 61% of theory).