Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[F:21][C:22]([C:28]([F:52])([F:51])[C:29]([F:50])([F:49])[C:30]([F:48])([F:47])[C:31]([F:46])([F:45])[C:32]([F:44])([F:43])[C:33]([F:42])([F:41])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])(O)[C:23]([F:26])([F:25])[F:24].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([O:20][C:22]([F:21])([C:28]([F:51])([F:52])[C:29]([F:49])([F:50])[C:30]([F:47])([F:48])[C:31]([F:45])([F:46])[C:32]([F:43])([F:44])[C:33]([F:42])([F:41])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])[C:23]([F:26])([F:25])[F:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OC(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 92.9 %

Procedure:
With 57 g of oleic acid were mixed 93 g of perfluorooctylethanol and 340 ml of toluene, and 3 g of p-toluenesulfonic acid was slowly added with stirring. The resulting mixture was vigorously refluxed for about 1 hour and 30 minutes to carry out the reaction until water was removed azeotropically. After completion of the reaction, the reaction mixture was cooled and then concentrated under reduced pressure to remove the toluene, and the residue was dissolved in 300 ml of n-hexane. The resulting solution was purified by a column chromatography to obtain 129 g (yield: 88%) of perfluorooctylethyl oleate.
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[C:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=2)[CH:11]=1)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CO>ClCCl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=2[O:16][CH2:17][CH2:18][OH:19])[CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[CH:26][CH:25]=1)[CH3:28]
Reactant: CCOP(=O)(Cc1ccc(OCCO)c(Cc2ccc(CC)cc2)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc(Cc2cc(CP(=O)(O)O)ccc2OCCO)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.5 %

Procedure:
To a solution of [3-(4-ethylbenzyl)-4-(2-hydroxyethoxy)benzyl]phosphonic acid diethylester (0.70 g) in dichloromethane (11.0 mL) was added bromotrimethylsilane (1.1 mL) at 0° C., and the reaction mixture was stirred for 14 hr at room temperature. Methanol (6.0 mL) was added to the reaction mixture, and the mixture was stirred for 10 min at room temperature. Evaporation of the solvent gave the title compound (0.51 g) as a light gray oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:21]=[CH:20][C:8]([O:9][CH2:10][C:11]2[O:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]>CO.[Rh]>[CH2:1]([C:5]1[CH:21]=[CH:20][C:8]([O:9][CH2:10][CH:11]2[O:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: COC(=O)c1ccc(COc2ccc(CC(C)=O)cc2)o1
Agent: [Rh]
Solvent: CO
Product: COC(=O)C1CCC(COc2ccc(CC(C)=O)cc2)O1

Procedure:
Methyl 5-[4-acetonylphenoxymethyl]furan-2-carboxylate, ethylene ketal (12.5 g) was hydrogenated at ambient temperature and pressure, in methanol, in the presence of 5% rhodium on alumina. The reaction mixture was filtered and evaporated to an oil which was purified by column chromatography on silica gel. Elution with chloroform gave methyl 5-[4-acetonylphenoxymethyl]tetrahydrofuran-2-carboxylate, ethylene ketal.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[C:15]([C:20]2[C:21]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[C:17]([NH2:19])[CH:18]=1)=[O:12])[CH3:9]>N1C=CC=CC=1.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[C:15]([C:20]2[C:21]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[C:17]([NH:19][C:1](=[O:3])[CH3:2])[CH:18]=1)=[O:12])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(N)cc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NC(C)=O)cc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
Acetic anhydride (53 mg, 0.5 mmol) was added to a solution of 5″-amino-2-benzyloxy-5-chloro-[1,1′;2′,1″]terphenyl-3″-carboxylic acid ethyl ester (96 mg, 0.21 mmol) in pyridine (2 ml) and the mixture left at room temperature for 1 hour. The resulting solution was diluted with diethyl ether, washed with 1M hydrochloric acid and saturated sodium bicarbonate solution, dried (MgSO4) and evaporated to dryness to yield the title compound as a colourless gum. (102 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:20])[C:8]=1[CH:9]([C:18]#[N:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[NH2:5].[N:21]([O-])=O.[Na+]>C(O)(=O)C.O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:21])[CH:6]=[C:7]([Cl:20])[C:8]=1[CH:9]([C:18]#[N:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1
Reactant: O=N[O-]
Reactant: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc(N)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc(NN)cc1Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 96 %

Procedure:
In 40 ml of acetic acid was dissolved 3.0 g of 3,5-dichloro-4-(3,4-dichloro-α-cyanobenzyl)aniline. To the solution was then added 3 ml of 35% hydrochloric acid. To the mixture was added dropwise, while cooling at temperatures ranging from 10 to 12° C., a solution of 0.8 g of 98.5% sodium nitrite in 3 ml of water. The reaction mixture was stirred for 40 minutes under the same conditions, to which was then added 7.0 g of stannous chloride dissolved in 10 ml of 35% hydrochloric acid. The reaction mixture was poured into ice-water, which was then made into alkaline, followed by extraction with 200 ml of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated to afford the titled compound in a yield of 96%, m.p.183-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.C(Cl)(=O)C([Cl:32])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:27])([F:26])[F:28])[CH:19]=2)(=[O:16])=[O:17])[CH2:12][O:13][CH3:14])[C:5]([C:8]([Cl:32])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCN(c1cc(Cl)cnc1C(=O)Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (450 mg, 1.0 mmol) in 3.0 mL CH2Cl2 and DMF (0.02 mL) was added oxalyl chloride (0.110 mL). The mixture was stirred for 2 h and concentrated to dryness provide 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[C:9]=1[N+:15]([O-:17])=[O:16].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[NH2:14][C:10]1[C:9]([N+:15]([O-:17])=[O:16])=[C:8]([O:7][C:6]2[C:5]([Cl:19])=[CH:4][C:3]([Cl:20])=[C:2]([NH:1][C:30]([NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=3)=[O:31])[CH:18]=2)[CH:13]=[CH:12][N:11]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1cc(Oc2ccnc(N)c2[N+](=O)[O-])c(Cl)cc1Cl
Product: Nc1nccc(Oc2cc(NC(=O)Nc3cccc(C(F)(F)F)c3)c(Cl)cc2Cl)c1[N+](=O)[O-]
Yield: 58 %

Procedure:
Method G was used with 4-(5-amino-2,4-dichlorophenoxy)-2-amino-3-nitropyridine and 3-trifluoromethylphenyl isocyanate to afford the title compound as a yellow solid (92 mg, 58%). 1H-NMR (δ, ppm, DMSO-d6): 6.01 (d, 1H, HPy,5, J=5.6 Hz), 7.26 (s, 2H, NH2,Py), 7.35-7.37 (m, 1H, Harom), 7.53-7.55 (m, 2H, Harom), 7.90 (s, 1H, Harom), 7.98 (s, 1H, Harom), 8.03 (d, 1H, HPy,6, J=5.6 Hz), 8.24 (s, 1H, Harom), 8.62 (s, 1H, NHurea), 9.86 (s, 1H, NHurea). 13C-NMR (δ, ppm, DMSO-d6): 99.6 (C-4); 113.9 (C-11); 114.1 (C-14); 118.4 (C-2); 118.7 (C-16); 119.4 (C-7); 121.0 (C-18); 121.9 (C-9); 125.1 (C-15); 129.5 (C-19); 130.0 (C-17); 130.4 (C-8); 136.3 (C-10); 139.7 (C-13); 147.3 (C-6); 151.7 (C-12); 153.4 (C-5); 153.8 (C-1); 157.6 (C-3). LC-MS (m/z): 501 (M+H, 100).
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13]([CH3:32])=[C:14]([C:28]([O:30]C)=[O:29])[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:10][C:11]1[NH:12][C:13]2[CH2:32][O:30][C:28](=[O:29])[C:14]=2[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(Br)c1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a similar manner, 2.02 grams (2.52 grams of 80 percent; 6.31 millimoles) of pyridinium bromide perbromide was added in a single portion to a solution of 2 grams (5.26 millimoles) of dimethyl 2,6-dimethyl-4-(3-bromophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.79 gram (10.0 millimoles) of pyridine in 40 milliliters of chloroform (distilled from P2O5) which had been cooled to 0° C. The resulting mixture was stirred at this temperature for 30 minutes and then heated at reflux temperature for 1.5 hours. Thereafter, the mixture was allowed to cool to room temperature and diluted with chloroform; the diluted solution washed with 2N hydrochloric acid and brine, dried, and the solvent evaporated to obtain methyl 2-methyl-4-(3-bromophenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate product as a yellow foamy material. The latter was chromatographed on silica gel employing 60 percent ethyl acetate--40 percent hexane as eluant to obtain 790 milligrams (41 percent yield) of purified methyl 2-methyl-4-(3-bromophenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate product as a white crystalline solid. An analytical sample of m.p. 229°-231° C. was prepared by recrystallizing from ethyl acetate-hexane. Elemental analyses were as follows:
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH2:6].CO[CH:9]1[CH2:13][CH2:12][CH:11](OC)O1.[OH-].[Na+]>C(O)(=O)C>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:9]=[CH:13][CH:12]=[CH:11]1
Reactant: CSCCCN
Reactant: COC1CCC(OC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CSCCCn1cccc1

Procedure:
A mixture of 25 g (0.36 mole) 3-(methylthio)-propylamine and 43 g (0.36 mole) 2,5-dimethoxytetrahydrofuran is placed in a 1-liter 3-neck flask equipped with a stirrer, addition funnel, thermometer and condenser, and 200 ml glacial acetic acid is added dropwise with stirring while maintaining the temperature below 20°C. The reaction mixture is refluxed for 30 minutes and, after cooling, it is made basic (pH 9-10) by the addition of 375 ml 30% aqueous sodium hydroxide and steam-distilled for 3 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][OH:37]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][CH2:35][CH2:36][OH:37])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: OCCCBr
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(OCCCO)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (0.6 g) obtained in Example 2 was suspended in dimethyl sulfoxide (40 ml), and to the suspension was added potassium carbonate (0.8 g), and the mixture was stirred at room temperature for 30 minutes. 3-bromo-1-propanol (0.3 ml) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (500 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, washed with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 3% methanol) to produce the title compound (0.25 g, 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[N:21]=[N:20][C:19]([NH2:22])=[CH:18][CH:17]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:16]3[N:21]=[N:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:8][C:7]=2[CH:14]=1
Reactant: Nc1ccc(Br)nn1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2oc(-c3ccc(N)nn3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
5-methoxybenzofuran boronic acid 1.2 mmol), 6-bromo-3-pyridazinamine (1.0 mmol), Pd(PPh3)2Cl2 (0.024 mmol) and NEt3 (317 μL) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140° C. for 10 min in a microwave reactor. The solvent was removed under vacuum, water was added and the solution was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and the solvent removed under vacuum. The crude substance was purified by preparative HPLC to afford the title compound as a white solid (51 mg). 1H NMR δ ppm 7.77 (d, 1 H) 7.52 (d, 1 H) 7.35 (s, 1H) 7.19 (d, 1 H) 6.79-6.98 (m, 2 H) 6.72 (s, 2 H) 3.80 (s, 3 H); MS m/z 242 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([NH:25][C:26]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=2)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:27])=[CH:21][CH:20]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2ccc(C)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: Cl[CH2:2][CH:3]=O.[NH2:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>C(O)C>[N:5]1[CH:2]=[CH:3][N:14]2[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=12
Reactant: Nc1ncccc1C(=O)O
Reactant: O=CCCl
Solvent: CCO
Product: O=C(O)c1cccn2ccnc12

Procedure:
Chloroacetaldehyde (45% aqueous solution) (6.6 mL, 38 mmol) is added to the stirred solution of 2-aminonicotinic acid (5.0 g, 25 mmol) in ethanol (35 mL) and warmed at reflux for 14 hours. The reaction mixture is concentrated and the crude material is triturated with EtOH-Et2O to afford imidazo[1,2-a]pyridine-8-carboxylic acid. Mp: 296-299° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]2[C:20](=[O:35])[N:21]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH:22]=[CH:23][C:24]=2[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=1.CC1(C)C(C)(C)OB([C:45]2[CH:46]=[N:47][NH:48][CH:49]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH:47]1[CH:46]=[C:45]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:49]=[N:48]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccncc2Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccncc2-c2cn[nH]c2)cc1F
Temperature: 85 °C
Yield: 57 %

Procedure:
In a sealed tube, N-(4-(3-bromopyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.124 g, 0.221 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.064 g, 0.332 mmol), potassium carbonate (0.092 g, 0.664 mmol), and tetrakistriphenylphosphine palladium (0) (0.026 g, 0.022 mmol) were suspended in dioxane (6 mL) and water (1.5 mL). The mixture was degassed with Ar and heated at 85° C. overnight. Additional 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg) and tetrakistriphenylphosphine palladium (0) (0.026 g, 0.022 mmol) were added. The reaction mixture was degassed with Ar and heated at 85° C. for 2 days. The mixture was diluted with EtOAc and extracted with sat. NaHCO3 (aq). The organic extract was washed with brine, dried and evaporated. The crude product was purified by silica gel chromatography (25 g) eluting with CH2Cl2/MeOH to yield N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (69 mg, 56.9% yield). The hydrochloride salt was formed by suspending N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.069 g, 0.126 mmol) in acetonitrile (2 ml) and adding 0.1N HCl (1.51 mL, 0.151 mmol). The mixture was sonicated for 10 min. The solution was diluted with water (2 mL), frozen and lyophilized. The crude lyophilate was dried at 80° C. for 4 h under vacuum to yield N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride (0.069 g, 87% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.32 (s, 1H); 9.15 (s, 1H); 8.49 (d, J=6.5 Hz, 1H); 8.43 (dd, J=12.5, 7.0 Hz, 1H); 8.33 (s, 2H); 7.93 (d, J=7.8 Hz, 1H); 7.69 (dd, J=10.8, 7.3 Hz, 1H); 7.48 (dd, J=8.8, 4.9 Hz, 2H); 7.37 (t, J=8.8 Hz, 2H); 7.25 (d, J=6.5 Hz, 1H); 6.56 (d, J=7.9 Hz, 1H); 4.28 (q, J=7.0 Hz, 2H); 1.34 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 508.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([NH2:12])[CH:3]=1.[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[N:5]=[C:4]([NH:12][C:14](=[O:13])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1cc(Cl)nc(C(F)(F)F)n1
Agent: CN(C)c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc(C(F)(F)F)n1

Procedure:
Method 24 was followed using 6-chloro-2-(trifluoromethyl)pyrimidin-4-amine (1.0 equiv.), BOC2O (1.0 equiv.), and DMAP (cat.) to afford tert-butyl 6-chloro-2-(trifluoromethyl)pyrimidin-4-ylcarbamate in 64%. LCMS (m/z): 298.1 (MH+); LC Rt=4.73 min.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1C=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=[CH:6]1)(C)C.[NH:30]1C=C(B(O)O)C=N1>>[NH:5]1[CH:6]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)[CH:8]=[N:30]1
Reactant: CCOC(=O)c1cn2cc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)ccc2n1
Reactant: OB(O)c1cn[nH]c1
Product: CCOC(=O)c1cn2cc(-c3cn[nH]c3)ccc2n1
Temperature: 90 °C

Procedure:
This product is prepared under conditions similar to those described for the preparation of Intermediate 15 (step 15.1), replacing the 1-(triisopropylsilyl)pyrrole-3-boronic acid with pyrazole-4-boronic acid and heating at 90° C. by microwave for 37 minutes.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:28]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[C:31]([O:41][CH2:42][C@@H:43]([OH:46])[CH2:44][NH2:45])=[CH:30][CH:29]=1>>[CH:28]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[C:31]([O:41][CH2:42][C@@H:43]([OH:46])[CH2:44][NH:45][CH:2]2[CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]4[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=4)(=[O:16])=[O:17])=[CH:10][CH:9]=3)[CH2:6][CH2:7]2)=[CH:30][CH:29]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c3ccccc3c12
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c6ccccc6c45)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (2S)-3-(9H-carbazol-4-yloxy)-2-hydroxy-propylamine (Berridge et al., Int. J. Radial. Appl. Instrum., 1992, 563) according to the procedure of Example 255 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55-1.75 (m, 2H), 2.00-2.15 (m, 2H), 2.06 (s, 3H), 2.50-2.70 (m, 2H), 3.00-3.50 (m, 3H), 3.60-3.70 (m, 2H), 4.10-4.25 (m, 2H), 4.35-4.50 (m, 1H), 5.97 (brs, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 2H), 6.88 (d, J=8.0 Hz, 2H), 7.10-7.50 (m, 5H), 7.59 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H), 8.22 (d, J=7.8 Hz, 1H), 9.71 (s, 1H), 10.40 (s, 1H), 11.32 (s, 1H); MS (ES) m/z: 627.9 (MH+); HRMS Calcd. for C34H38N5O5S(MH+): 628.2594. Found: 628.2593.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:24])[CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].[NH4+].[Cl-]>C(Cl)Cl>[CH3:32][S:33]([O:14][CH:13]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:12][CH2:11][CH:10]([O:24][S:33]([CH3:32])(=[O:35])=[O:34])[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:35])=[O:34]
Reactant: O=[N+]([O-])c1ccc(C(O)CCC(O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of the product from Example 1B (0.80 g, 2.407 mmol) in dry CH2Cl2 (25 ml) at 0° C. was added triethylamine (1.007 ml, 7.22 mmol), followed by dropwise addition of methanesulfonyl chloride (0.469 ml, 6.02 mmol). The resulting mixture was stirred at 0° C. for 30 min, during which time the starting material slowly went into solution. After stirring an additional 1 h at 0° C., a precipitate began to form. Saturated aq NH4Cl (4 ml) was added, and stirring was continued at room temperature for 20 min. The mixture was washed with water (2×10 ml), and the organic layer was treated with hexanes (10 ml) to give an orange solid that was collected by filtration to give the title compound (0.75 gm, 64% yield).