Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.[C:45]1([CH:51]2[CH:55](O)[CH2:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1.CCCCCC>[C:45]1([C@H:51]2[CH2:55][CH2:54][CH2:53][C@H:52]2[N:38]2[C:34](=[O:44])[C:35]3[C:36](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:37]2=[O:39])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: OC1CCCC1c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CCC[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
Scheme IB, step B: A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser, addition funnel and a nitrogen blanket is charged with triphenylphosphine (16.19 g, 61.73 mmol) and THF (200 mL). To the solution at 0° C. was added dropwise, a solution of diisopropyl azodicarboxylate (12.15 mL, 61.73 mmol) dissolved in THF (30 mL) over a period of 10 minutes. A massive precipitate formed immediately after addition. To the slurry was then added solid phthalimide (9.08 g, 61.73 mmol), followed by a solution of 5-phenylcyclopentane-1-ol (10.0 g, 61.73 mmol) dissolved in THF (30 mL) over a period of 20 minutes maintaining temperature at 0° C. to 5° C. (reaction mixture went into solution by the end of alcoholic substrate addition). Reaction was then stirred at 0° C. for 4.0 hours and brought to room temperature overnight for convenience. Quenched reaction with water (200 mL) and extracted organics with chloroform (200 mL). Washed the organic with water (100 mL) and dried with anhydrous magnesium sulfate. Subsequent filtration and concentration under reduced pressure afforded an oil which solidified on equilibrating to room temperature. To the precipitate was then added hexane (250.0 mL) with vigorous stirring. Filtered off triphenylphosphine oxide precipitate and concentrated filtrate to an oil. Silica gel plug filtration of the oil with 1:1 ethyl acetate:hexanes and subsequent concentration of product fractions afforded an off white precipitate of (+,−) Cis-2-(2-phenyl-cyclopentyl)-isoindole-1,3-dione (mass=12.5 g, 69.6%); 1H nmr (CDCl3) 6 1.6-1.8 (m, 1H), 2.0-2.1 (m, 1H), 2.2-2.35 (m, 2H), 2.4-2.68 (m, 2H), 3.39-3.5 (m, 1H), 5.0-5.1 (m, 1H), 6.9-7.15 (aromatic, 5H), 7.52-7.64 (aromatic, 4H); 13C (CDCl3) 6 25.4, 28.89, 30.56, 50.34, 54.60, 122.89, 126.44, 128.01, 128.41, 131.67, 139.68, 168.86).
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:11][C:12]1[CH:13]=[C:14]([N:19]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=[CH2:33])=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]>C1(C)C=CC=CC=1>[CH3:27][C:22]1[CH:21]=[C:20]([N:19]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][CH2:33][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:34][CH:35]=2)[C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=2)[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: C=Cc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1
Reactant: CCO[SiH](OCC)OCC
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1)(OCC)OCC
Temperature: 25 °C
Yield: 94.2 %

Procedure:
40 mL of toluene, 6.0 g (37 mmol) of triethoxysilane, and 0.34 mmol of dichloro-(n-cycloocta-1,5-diene) platinum were loaded into a three-neck flask. While being stirred at room temperature, 20 mL of a toluene solution of 9.9 g of 4-[N,N-bis-(3,4-dimethylphenyl) amino] styrene was dropped into the flask. Upon completion of the addition of the drops, the mixture was stirred for 3 hours at 70° C. The solvent was removed under reduced pressure, and a lemon-yellow oily substance of 4-[N,N-bis-(3,4-dimethylphenyl) amino]-[2-(triethoxysilyl) ethyl] benzene was obtained. The amount obtained was 14.0 g (yield was 94.2%).
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=O.[Cl:16][CH:17]([Cl:21])[C:18](Cl)=[O:19]>O>[C:1]1([CH:7]2[N:11]([C:18](=[O:19])[CH:17]([Cl:21])[Cl:16])[CH2:10][CH2:9][S:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2NCCS2)cc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(C(Cl)Cl)N1CCSC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Five (5) grams of 2-phenyl thiazolidine was dissolved in 50 ml. of acetone, 3.1 g. of thiethylamine was added and the mixture stirred in a room temperature water bath, while 4.4 g. of dichloroacetyl chloride was added dropwise. The mixture was allowed to stand for about 30 minutes and then poured into water, extracted with methylene chloride, separated, dried over magnesium sulfate, and the solvent stripped under vacuum. There was obtained a yield of 7.3 g. of an oil, the title compound, ND30 =1.5836.
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:11][CH:10]=[C:9]([CH2:30][OH:31])[N:8]=1)([OH:3])=[O:2]>CO.C(Cl)Cl>[C:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[CH:11][CH:10]=[C:9]([CH2:30][OH:31])[N:8]=1)([OH:3])=[O:2]
Reactant: COc1ccc(CCCCCCCCOc2ccc(CO)nc2/C=C/CC(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CCCCCCCCOc2ccc(CO)nc2CCCC(=O)O)cc1
Reaction time: 5 h

Procedure:
2-(E-2-Carboxymethyl-ethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine (300 mg, 0.702 mmol) was dissolved in MeOH (3 mL) and treated with 5% Pd--C catalyst (30 mg). The reaction was stirred under an atmosphere of H2 (balloon pressure) for 5 hours. The reaction was diluted with CH2Cl2, and filtered through Celite, and concentrated. Purification by flash column chromatography (silica, EtOAc:CH2Cl2 :hexane, 25:50:25) gave a pale yellow oil: 1H NMR (250 MHz, CDCl3) δ 7.09 (m, 4H, phenyl, pyridyl), 6.80 (d, J=8.6 Hz, 2H, phenyl), 4.62 (s, 2H, CH2), 3.93 (t, J=6.5 Hz, 2H, OCH2), 3.77 (s, 3H, OCH3), 3.68 (s, 3H, methyl ester), 3.16 (dd, J=7.3, 7.2 Hz, 2H, CH2), 2.77 (dd, J=7.3, 7.2 Hz, 2H, CH2), 2.54 (t, J=7.6 Hz, 2H, benzylic), 1.79 (m, 2H, CH2), 1.57 (m, 2H, CH2), 1.44 (m, 2H, CH2), 1.34 (m, 6H, aliphatic); MS (CI): 430.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1.BrCC(C1C=CC(Cl)=C(Cl)C=1)=O.BrC1C=C(CNC)C=CC=1.[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[OH:49].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[Cl:20][C:15]1[CH:14]=[C:13]([CH:6]2[C:5]3[C:10](=[CH:11][C:2]([N:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]4=[O:49])=[CH:3][CH:4]=3)[CH2:9][N:8]([CH3:12])[CH2:7]2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Oc1ccccn1
Reactant: CN1Cc2cc(Br)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: CNCc1cccc(Br)c1
Solvent: C1COCCO1
Product: CN1Cc2cc(-n3ccccc3=O)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 110 °C
Yield: 7.1 %

Procedure:
To a mixture of 7-bromo-4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.35 mmol) which was prepared following similar method described in Steps A to C of Example 1 starting from 2-bromo-1-(3,4-dichlorophenyl)ethanone and 1-(3-bromophenyl)-N-methylmethanamine, pyridin-2-ol (154 mg, 1.62 mmol), N,N′-dimethylethylene diamine (58 μl, 0.54 mmol), and potassium phosphate (572 mg, 2.69 mmol) in 1,4-dioxane (5 mL) was added copper(1) iodide (51 mg, 0.27 mmol). The mixture was degassed with argon and then heated to 110° C. for 17 hours. The reaction mixture was diluted with water (20 mL) and extracted with methylene chloride (2×25 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was partially purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to give 1-(4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-2(1H)-one (37 mg, 7%): ESI MS m/z 385 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH:17]([O:20][CH3:21])[O:18][CH3:19])[CH:9]=1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1>CC(N(C)C)=O>[CH3:19][O:18][CH:17]([O:20][CH3:21])[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[O:29][C:25]1[CH:24]=[C:23]([NH2:22])[CH:28]=[CH:27][CH:26]=1
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 8 h

Procedure:
K2CO3 (0.34 mol), followed by 4-chloro-2-dimethoxymethyl-1-nitro-benzene (0.2 mol) was added to a solution of 3-amino-phenol (0.3 mol) in DMA (400 mLl) and the reaction mixture was stirred overnight at 130° C. The mixture was cooled to room temperature and the solvent was evaporated. The residue was taken up in H2O and the mixture was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (eluent: CH2Cl2 100%). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C@@H:11]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10].C(N(CC)CC)C.[C:41]1([C:47](Cl)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[C:3]([NH:8][C:9]([C@@H:11]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the crude product of 1-benzyl 4-tert-butyl {(1S)-1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]tetramethylene}biscarbamate and triethylamine (1.01 g) in chloroform (50 ml) was added triphenylmethyl chloride (2.78 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 2% methanol/chloroform to give 1-benzyl 4-tert-butyl ((1S)-1-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamoyl}tetramethylene)biscarbamate (720 mg) as an oil.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[O:19][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: Brc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1Oc1ncccn1
Temperature: 80 °C
Reaction time: 72 h
Yield: 77.4 %

Procedure:
According to Scheme 3 Step 1 Method B: 2-Bromopyrimidine (1.26 mmol, 211 mg) was added to a suspension of 2-methoxy-4-nitrophenol (1.15 mmol, 200 mg), Cs2CO3 (1.41 mmol, 460 mg) in DMF (3 mL). The reaction mixture was stirred at 80° C. for 3 days. The reaction mixture was quenched with water. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was washed with a solution of NaOH 3M and dried to obtain 2-(2-methoxy-4-nitrophenoxy)pyrimidine (0.89 mmol, 220 mg, 78%) as a solid. The product was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:15][CH2:16][C:17]3[S:18][CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[N:21]=3)[CH:11]=2)[CH:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]1[N:21]=[C:17]([CH2:16][NH:15][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13]3)[S:18][CH:19]=1
Reactant: COC(=O)c1ccc2cc(NCc3nc(-c4ccccc4Cl)cs3)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2cc(NCc3nc(-c4ccccc4Cl)cs3)ccc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The crude 6-{[4-(2-chloro-phenyl)-thiazol-2-ylmethyl]-amino}-naphthalene-2-carboxylic acid methyl ester from Step A is dissolved in THF (1 mL). A solution of 1 M LiOH in H2O (1 mL) is added and the mixture is stirred for 12 h at rt. The mixture is acidified with 1 M HCl (1 mL) and extracted into EtOAc (20 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound G1 as a white solid: MS calcd. for C21H16ClN2O2S (M+H+) 395.9. found 396.0.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[H-].[Na+].Br[CH2:12][C:13]([CH3:24])=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1.O>CN(C=O)C>[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[C:13]([CH3:24])[CH2:12][O:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=2)=[CH:20][CH:19]=1)([CH3:23])[CH3:22]
Reactant: Cc1ccc(O)cc1
Reactant: CC(=Cc1ccc(C(C)C)cc1)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=Cc1ccc(C(C)C)cc1)COc1ccc(C)cc1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a solution of p-cresol (3.50 g, 32.3 mmol) in DMF (70 mL) was added sodium hydride (a 60% liquid paraffin dispersion, 1.42 g, 35,5 mmol) under nitrogen atmosphere at 0° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added 1-(3-bromo-2-methyl-1-propenyl)-4-isopropyl benzene (9.0 g, 35.5 mmol), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the product was extracted with diisopropyl ether. The extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 8.20 g (yield 91%) of the title compound. Oily matter.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[C:19](O)=[O:20])=[O:13])[CH:9]=[CH:8][C:7]=2[N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)[CH2:3][CH2:2]1.C(N1C=CN=C1)([N:30]1C=CN=C1)=O>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[C:19]([NH2:30])=[O:20])=[O:13])[CH:9]=[CH:8][C:7]=2[N:22]2[CH2:23][C:24]([F:27])([F:26])[CH2:25]2)[CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1CCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Solvent: CN(C)C=O
Product: NC(=O)C1CCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
To an ice-cold solution of 1-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinoyl)pyrrolidine-2-carboxylic acid (8.6 mg, 22.6 μmol) in DMF (2 mL) was added carbonyldiimidazole (10.2 mg, 63.1 μmol). After 5 minutes the reaction mixture was warmed to ambient temperature and stirred for 2 h. NH3 gas was bubbled through the solution for 10 minutes and stirring was continued for 12 h. The reaction mixture was poured onto ice-water (20 mL) and extracted with EtOAc (2×20 mL). The combined extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound (9 mg, quant.) as colorless wax; MS (EI): m/e=381.5 [MH+].
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]([O-:14])=[O:13])=[CH:10][N:11]=[C:5]2[CH:4]=1.[Li+].[OH-].Cl>C1COCC1.CO>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]([OH:14])=[O:13])=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: O=C([O-])c1cnc2cc(C(F)(F)F)ccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc2cc(C(F)(F)F)ccn12
Temperature: 60 °C

Procedure:
To a stirring solution of ethyl 7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (23) (100 mg, 0.387 mmol) in THF:MeOH (4:1, 1.5 mL) was added 2N LiOH (0.25 mL). The reaction was heated at 60° C. for 1 hour. Then, cooled to room temperature and the pH was adjusted between 4-5 with 1N HCl. The solvent was partially concentrated and the resulting aqueous layer was lyophilized to give 7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (24). 1H NMR (400 MHz, d6-DMSO) δ 9.44 (d, J=7.2 Hz, 1H), 8.40 (s, 1H), 8.31-8.30 (m, 1H), 7.48 (dd, J=2.0, 7.6 Hz, 1H). MS m/z 231.2 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[CH:8]1([N:11]2[C:20]3[C:15](=[C:16]([CH3:23])[C:17]([F:22])=[C:18](F)[CH:19]=3)[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH2:10][CH2:9]1>CN1CCCC1=O>[CH:8]1([N:11]2[C:20]3[C:15](=[C:16]([CH3:23])[C:17]([F:22])=[C:18]([N:6]4[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]4)[CH:19]=3)[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH2:9][CH2:10]1
Reactant: CC1CNCCN1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CN1CCCC1=O
Product: Cc1c(F)c(N2CCNC(C)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 90 °C
Yield: 37.4 %

Procedure:
0.65 g of 2-methylpiperazine was added to a solution of 0.48 g of 1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 5 ml of N-methyl-2-pyrrolidone, followed by heating at 90° C. for 20 minutes. After distilling off the solvent under reduced pressure, the residue was added with ethanol. The resulting crystals were filtered and recrystallized from ethyl acetate-ethanol to give 231 mg of 1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([Cl:19])=[C:6]([O:8][C:9]2[C:10]([F:18])=[C:11]([CH2:16][NH2:17])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25](COCC[Si](C)(C)C)[C:26]=1[C:27](O)=[O:28].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>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([Cl:19])=[C:6]([O:8][C:9]2[C:10]([F:18])=[C:11]([CH2:16][NH:17][C:27]([C:26]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:21])=[O:28])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: NCc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F)c1[nH]cnc1Cl
Yield: 51.9 %

Procedure:
({3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (0.069 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.050 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from EtOH, cooled in an ice bath and filtered to give N-({3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (0.048 g, 0.094 mmol, 51.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br. s., 1H), 8.27 (br. s., 1H), 7.78 (s, 1H), 7.63 (dd, J=8.52, 1.79 Hz, 1H), 7.53 (d, J=8.52 Hz, 1H), 7.39 (m, 1H), 6.76 (s, 1H), 4.54 (d, 2H). LC-MS (ES−) m/z 507.94, 509.95, 511.94 [M−1]. LC-MS (ES+) m/z 509.88, 511.87, 513.88 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[CH:13][CH:14]=[C:15]([F:17])[CH:16]=1)[C:6](/[N:8]=[CH:9]/[N:10](C)C)=O.[CH3:19][NH:20]N>C(O)(=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[C:6]1[N:20]([CH3:19])[N:10]=[CH:9][N:8]=1
Reactant: COC(=O)c1cc(F)ccc1C(=O)/N=C/N(C)C
Reactant: CNN
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)ccc1-c1ncnn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[1-dimethylamino-meth-(E)-ylidene]-5-fluoro-phthalamic acid methyl ester plus regioiosmer (2.9 g, 11.50 mmol) in acetic acid (10 mL) is added methyl hydrazine (6.0 mL, 113.95 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with EtOAc (250 mL) and the organic layer is washed with H2O (150 mL×2), dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residue is triturated with 1:1 EtOAc:hexanes (200 mL), and filtered to remove the white solid. The mother liquor is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 7.5% MeOH in CH2Cl2 as the eluent to afford 5-fluoro-2-(2-methyl-2H-1,2,4-triazol-3-yl)-benzoic acid methyl ester plus regioisomer (1.5 g, 55%).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([SH:25])[CH2:23][CH3:24]>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[C:3]([C:12]([F:15])([F:14])[F:13])[C:2]([S:25][CH2:22][CH2:23][CH3:24])=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 90 °C
Yield: 95.2 %

Procedure:
To a mixture of 5-chloro-2-nitro-4-trifluoromethyl-phenylamine (1.50 g, 6.26 mmol), potassium carbonate (1.72 g, 12.5 mmol), and DMF (31 mL) was added 1-propanethiol (0.620 mL, 6.86 mmol). The reaction mixture was heated at 90° C. for 16 h, then allowed to cool to 23° C. and poured into ice/brine (300 mL). The resulting yellow precipitate was collected to yield the titled compound (1.67 g, 95%). MS (ESI/CI): mass calcd. for C10H11F3N2O2S, 280.1; m/z found, 281.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.41 (s, 1H), 6.58 (s, 1H), 6.36 (br s, 2H), 2.97 (t, J=7.3 Hz, 2H), 1.87-1.72 (m, 2H), 1.10 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH:11]=[C:12]([F:28])[C:13]([F:27])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:18][OH:19])=[C:15]3[C:10]([CH:11]=[C:12]([F:28])[C:13]([F:27])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Solvent: C1CCOC1
Product: OCC(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 29.1, [rac]-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 24.7) was reduced using borane-tetrahydrofuran complex in THF to give the title compound as off-white foam. MS: m/e=391.1 [M+H+].