Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][CH2:32]Br>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:32][CH2:31][CH2:30][O:29][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3ccccc32)cc1
Reactant: BrCCCOC1CCCCO1
Product: CC(C)c1ccc(N(CCCOC2CCCCO2)C(=O)C2CCCc3ccccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 6 using N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) and 3-(tetrahydropyran-2-yloxy)propyl bromide (0.52 mL) as starting materials, N-(4-isopropylphenyl)-N-[3-(tetrahydropyran-2-yloxy)propyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.9 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:29](=[O:31])[NH2:30])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:29](=[O:31])[NH2:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cc(C)cc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cn2c3cc(C)cc(OCC(=O)O)c3c3c(C(N)=O)cccc32)c1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A solution of {9-[(3-methylphenyl)methyl)-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (0.12 g, 0.288 mM) and 1.4 mL (2.8 mM) of 2 N NaOH in 14 mL of ethanol was stirred for 30 minutes at 25° C. The reaction was acidified with 1N HCl to pH=2. After stirring 1 hour, the resultant white precipitate was collected by filtration, washed with water, then dried in vacuo to afford 114 mg (95%) {9-[(3-methylphenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid. 1H NMR (DMSO-d6) δ11.1 (bs, 1H), 7.75 (bs, 1H), 7.6 (d, J=8 Hz, 1H), 7.45 (bs, 1H), 7.35 (dd, J=8 and 8 Hz, 1H), 7.2-7.0 (m, 5H), 6.85 (d, J=8 Hz, 1H), 6.45 (s, 1H), 5.6 (s, 2H), 4.8 (s, 2H), 2.4 (s, 3H), 2.2 (s, 3H). MS (ES) m/e 386, 403. Recrystallization from acetone/hexane provided an analytical sample:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=[N:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>CN(C=O)C>[OH:43][CH:44]1[CH2:49][CH2:48][N:47]([C:11](=[O:13])[CH2:10][O:9][C:6]2[C:7](=[O:8])[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH2:46][CH2:45]1
Reactant: Cn1nccc(OCC(=O)O)c1=O
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1nccc(OCC(=O)N2CCC(O)CC2)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
11.1 g (60.2 mmoles) of intermediate 4i are placed in 250 mL of DMF under nitrogen. At 0° C., 21.3 g (66.3 mmoles) of TBTU then 16.8 mL (120 mmoles) of Et3N then 6.1 g (60.2 mmoles) of 4-hydroxypiperidine are added. The reaction medium is agitated for 20 h at ambient temperature then concentrated to dryness. The residue obtained is purified by silica gel flash chromatography (CH2Cl2-MeOH, gradient 100:0 to 90:10 in 40 min). 10.14 g of intermediate 5c are thus obtained in the form of a yellow solid (yield 63%). TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH: 80:20, Rf=0.59.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14](S(C)=O)[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][C@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14]([NH:21][C@H:22]4[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]4)[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)c1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc3ccc(Oc4ccnc(Cl)c4)cc3s2)C1
Temperature: 95 °C
Reaction time: 120 h
Yield: 112 %

Procedure:
To the solution of 6-(2-chloropyridin-4-yloxy)-2-(methylsulfinyl)benzo[d]thiazole (100 mg, 0.31 mmol) in 1.6 ml of NMP was added (S)-tert-butyl 3-aminopiperidine-1-carboxylate (200 mg, 1 mmol) and DIPEA (70 μL, 0.4 mmol). The reaction solution was stirred at 95° C. for 5 days. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give (S)-tert-butyl 3-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (160 mg) as TFA salt. ES/MS m/z 461.1 (MH+).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:33]([O:37][C:38]([CH:40]1[CH:46]([CH:47]=O)[CH2:45][CH2:44][CH2:43][CH2:42][N:41]1[S:49]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)(=[O:51])=[O:50])=[O:39])([CH3:36])([CH3:35])[CH3:34]>C1COCC1.CCCCC>[C:33]([O:37][C:38]([CH:40]1[CH:46]([CH:47]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:45][CH2:44][CH2:43][CH2:42][N:41]1[S:49]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)(=[O:51])=[O:50])=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(C=O)C2C(=O)OC(C)(C)C)cc1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CCCCC(C=Cc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Benzyl triphenylphosphonium bromide (229 mg, 0.528 mmoL) in 2 mL of THF at 0° C. was added 2.0M butyl lithium solution (0.272 mL) in pentane. After five minutes the solution was warmed to ambient temperature, and kept at that temperature for 30 minutes before adding in the 3-Formyl-1-(4-methoxy-benzene sulfonyl)-azepane-2-carboxylic acid tert-butyl ester (200 mg, 0.503 mmoL) dissolved in 1.52 mL of THF. After 20 hours the reaction was quenched by adding water dropwise, the reaction was diluted with ethyl acetate and washed twice with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography (silica: 20% to 25% ethyl acetate in hexanes) to yield 1-(4-Methoxy-benzenesulfonyl)-3-styryl-azepane-2-carboxylic acid tert-butyl ester; MS: (M+H)+ =472, (M+NH4)+ =489.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12](O)[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1.P(Br)(Br)[Br:27]>O1CCOCC1>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([Br:27])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: BrP(Br)Br
Reactant: CCOC(=O)CCC(O)c1cccc(OCc2c(C)cccc2C)c1
Solvent: C1COCCO1
Product: CCOC(=O)CCC(Br)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-hydroxy-butyrate (Step D) in dioxane, add phosphorous tribromide in dioxane dropwise. After stirring at room temperature for 16 hours, quench with water and chloroform. After few minutes, the reaction mixture can be neutralized by mild aqueous base, dry organic layer over Na2SO4, filter, concentrate and purify by flash chromatography on silica gel column (EtOAc:hex).
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].Cl.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH:35]=O.[BH-](O[C:47]([CH3:49])=O)(OC(C)=O)OC(C)=O.[Na+].O>ClCCCl>[CH:17]1[C:16]2[CH:15]([CH2:14][O:13][C:11]([NH:1][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:35][C:31]3[N:30]([CH3:29])[CH:47]=[CH:49][N:32]=3)[CH2:35][C:31]3[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=3)[C:8]([OH:10])=[O:9])=[O:12])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Cn1ccnc1C=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: Cn1ccnc1CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1nccn1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A solution of Fmoc-Lys-OH.HCl (1.822 g, 4.5 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (1.10 g, 10 mmol) in DCE (50 mL) was stirred at 75° C. for 30 min under nitrogen. The reaction mixture was cooled to 0° C., and treated with NaBH(OAc)3 (3.165 g, 15 mmol). The reaction mixture was stirred at room temperature for overnight and decomposed with water. The reaction mixture was extracted with DCM, the organic layer dried and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel to afford (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino)hexanoic acid (2.30 g, 92%). MS (ESI), 557 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:43]1([C:46]2[O:50][N:49]=[CH:48][C:47]=2[C:51](O)=[O:52])[CH2:45][CH2:44]1>CN(C=O)C>[CH:43]1([C:46]2[O:50][N:49]=[CH:48][C:47]=2[C:51]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:2]2)=[O:52])[CH2:45][CH2:44]1
Reactant: O=C(O)c1cnoc1C1CC1
Reactant: c1cncc(C2CCNC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnoc1C1CC1)N1CCC(c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A solution of 3-pyrrolidin-3-yl-pyridine (15 mg, 0.1 mmol), TBTU (48 mg, 0.15 mmol, 1.5 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.1 mmol) in DMF (0.6 mL) was added to 5-cyclopropylisoxazole-4-carboxylic acid (15 mg, 0.1 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (12 mg). MS (ESI, pos. ion) m/z calcd for C16H17N3O2: 283.1321, found 283.1316.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]3[C:18]=2[CH2:19][C:20](O)=[O:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:30][CH2:31][CH2:32][O:33][CH3:34])[CH:24]=1>>[ClH:1].[CH3:34][O:33][CH2:32][CH2:31][N:30]([CH2:29][C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1)[C:20](=[O:21])[CH2:19][C:18]1[N:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]2=[N:10][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: COCCNCc1cccnc1
Reactant: Cc1ccn2c(CC(=O)O)c(-c3ccc(Cl)c(Cl)c3)nc2c1
Product: COCCN(Cc1cccnc1)C(=O)Cc1c(-c2ccc(Cl)c(Cl)c2)nc2cc(C)ccn12
Product: Cl
Yield: 74.4 %

Procedure:
According to the method of Example 14, 2-(3,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-(3-pyridinylmethyl)-2-methoxyethylamine were used as raw materials for synthesis, to obtain white solid powder, yield 74.4%. m.p. 235-237° C., ESI-MS m/z: 484[M+H]+, 1H NMR(DMSO-d6, 400 MHz)δ: 2.58(s, 3H), 3.20(s, 0.3H), 3.26(s, 2.7H), 3.57(t, 2H, J=4.76 Hz), 3.76(t, 2H, J=4.76 Hz), 4.43(s, 0.2H), 4.62(s, 1.8H), 4.74(s, 1.8H), 4.97(s, 0.2H), 7.47-7.48(d, 1H, J=7.00 Hz), 7.61(dd, 1H, J=8.4 Hz, 2.24 Hz), 7.8(s, 1H), 7.87-7.88(m, 1H), 7.91-7.92(d, 1H, J=2.24 Hz), 7.95-7.97(d, 1H, J=8.40 Hz), 8.27-8.29(m, 1H), 8.66-8.68(d, 1H, J=7.00 Hz), 8.75-8.79(m, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:10]#[C:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H][H].[CH3:22]I>C1COCC1>[CH3:22][O:3][C:4]1([C:10]#[C:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: [H][H]
Reactant: OC1(C#CCOC2CCCCO2)CCOCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(C#CCOC2CCCCO2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a suspension of sodium hydride (1.2 g of an 80% oil dispersion, 50 mmol) in dry THF (45 mL) was added a solution of 4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran(3.71 g, 15.3 mmol), prepared as in step 1. After hydrogen evolution ceased, methyl iodide (3.0 mL, 48.2 mmol) was added neat and the resulting solution was stirred overnight at ambient temperature. The reaction was quenched by addition of crushed ice and saturated aqueous NH4Cl. The resulting two-phase mixture was extracted with ether (3×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (100 g, 10% ethyl acetate: hexanes) provided 4-methoxy-4-[3-(tetrahydropyran-2-yloxy)prop-1-ynyl]tetrahydropyran (3.74 g, 95 %) as a colorless oil.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[NH:14][C:15](=[O:17])[CH3:16].[OH-].[K+].[CH3:20]S(C)=O.CI>O>[CH3:20][N:12]1[C:13]2[CH2:1][CH:2]([NH:14][C:15](=[O:17])[CH3:16])[CH2:3][CH2:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CS(C)=O
Reactant: CC(=O)NC1CCc2c([nH]c3ccccc23)C1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CC(=O)NC1CCc2c(n(C)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.1 mol of N-(1,3,4,9-tetrahydro-2H-carbazol-2-yl)acetamide, 0.15 mol of powdered KOH, and 75 ml of DMSO was stirred under nitrogen for 2 hr at room temperature. Methyl iodide (0.15 moL) was added in one portion, and, after brief cooling to moderate the exothermic reaction, the mixture was stirred at room temperature for 2 hr. The precipitate obtained by pouring the reaction mixture into excess water, was filtered, washed with water, and recrystallized from ethyl acetate to give the title compound, mp 171°-172°.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=1>C(#N)C>[BrH:1].[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CC#N
Product: Br
Product: COc1ccc2nc(-c3ccc(O)cc3)cn2c1

Procedure:
First, 2-bromo-4′-hydroxyacetophenone and 2-amino-5-methoxypyridine are dissolved in an inactive solvent such as acetonitrile, and are allowed to react with each other at a reflux temperature for 2 to 6 hours to produce 2-(4′-hydroxyphenyl)-6-methoxyimidazo[1,2-a]pyridine hydrobromide salt as white precipitates. The inactive solvent used in this instance may be acetonitrile or another solvent that is usually employed in a similar reaction, for example, methanol and acetone. The reaction temperature may be a temperature allowing refluxing, for example, 90° C. when the solvent is acetonitrile. The amount of the solvent to be used may be an amount sufficient to effect the reaction, however, it should be noted that if the solvent is too much, it will become difficult to obtain precipitates of reaction products. For example, when 2-bromo-4′-hydroxyacetophenone in an amount corresponding to 10 mmol is used for the reaction, the amount of a solvent to be used can be about 40 to 50 mL.
Reaction SMILES: [F:1][C:2]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:26]=[CH:25][C:10]([C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)=[O:12])=[CH:9][CH:8]=1.CCCCCC.FC(F)(F)CCCOC1C=CC(C(OC2C=CC(/C=C/C(O[CH2:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][C:65]=3[NH2:71])=O)=CC=2)=O)=CC=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:31])([C:27]([F:28])([F:29])[F:30])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:26]=[CH:25][C:10]([C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH2:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][C:65]=3[NH2:71])=[O:23])=[CH:16][CH:15]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: Nc1ccc(CCOC(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)F)cc3)cc2)c(N)c1
Reactant: O=C([O-])/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)C(F)(F)F)cc2)cc1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: Nc1ccc(CCOC(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)C(F)(F)F)cc3)cc2)c(N)c1

Procedure:
5.35 g (8.38 mmol) of (2E)3-{4-[(4-(4,4,5,5,5-pentafluoropentoxy)benzoyl)oxy]phenyl}acrylate are dissolved in a mixture of 54 ml of N,N-dimethylformamide and 6 ml water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) Zinc powder are added portionwise within 60 min. The mixture is allowed to react for 2 hours. The reaction mixture is then partitioned between ethyl acetate and water and filtered. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate (1:3) as eluant and crystallization form ethylacetate:hexane mixture yielded 3.30 g 2-(2,4-Diaminophenyl)ethyl (2E)3-{4-[(4-(4,4,5,5,5-pentafluoropentoxy)benzoyl)oxy]phenyl}acrylate as yellowish crystals 2-(2,4-Diaminophenyl)ethyl (2E)3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}acrylate is prepared analogous to example 4 using (2E)-3-(4-{[4-(4,4,4-trifluorobutoxy)benzoyl]oxy}phenyl)acrylic acid.
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10](OCC#N)=[O:11]>ClCCl>[C:8]([CH:2]([NH:1][CH:10]=[O:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:9]
Reactant: N#CCOC=O
Reactant: CCOC(=O)C(N)C#N
Solvent: ClCCl
Product: CCOC(=O)C(C#N)NC=O
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To ethyl 2-amino-2-cyanoacetate (800 mg, 6.24 mmol) in dichloromethane (5 mL) was added cyanomethyl formate (531 mg, 6.24 mmol) in dichloromethane (5 mL) dropwise at 0° C. The reaction was warmed up to room temperature for twelve hours. The reaction was concentrated and purified by silica gel chromatography to give an oil of ethyl 2-cyano-2-formamidoacetate (500 mg). NMR spectrum shows a mixture of starting material and desired product in a 1:1 ratio. The product was dissolved in methylene chloride (10 mL). To this solution was added cyanomethyl formate (797 mg, 9.37 mmol) and the reaction was stirred for twelve more hours. The reaction was concentrated and purified with silica gel chromatography to give an oil of ethyl 2-cyano-2-formamidoacetate (460 mg). 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 6.61 (s, 1H), 5.55 (d, 2H), 4.36 (q, 2H), 1.35 (t, 3H).
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C:9]1[C:14](=[O:15])[C:13]([O:16][CH3:17])=[CH:12][N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][C:19]=2[O:29][CH3:30])[N:10]=1)=[O:8]>C1COCC1>[C:7]([C:9]1[C:14](=[O:15])[C:13]([O:16][CH3:17])=[CH:12][N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][C:19]=2[O:29][CH3:30])[N:10]=1)(=[O:8])[CH3:1]
Reactant: C[Mg+]
Reactant: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(=O)N(C)OC)n1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(C)=O)n1
Reaction time: 1 h
Yield: 27.4 %

Procedure:
MeMgBr (1 M solution in THF, 50 mL, 50 mmol) was added dropwise at −78° C. to a solution of N,5-dimethoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (6.32 g, 16.4 mmol) in THF (100 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with AcOEt and recrystallized from MeOH to give the title compound (1.53 g, 27% yield) as pale yellow prisms: mp 193-196° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.69 (3H, s), 3.90 (3H, s), 4.00 (3H, s), 6.54 (1H, dd, J=1.9, 2.3 Hz), 7.30 (1H, dd, J=2.3, 8.7 Hz), 7.57 (1H, d, J=8.7 Hz), 7.63 (1H, d, J=2.3 Hz), 7.77-7.78 (2H, m), 8.00 (1H, d, J=2.3 Hz). Anal. Calcd for C17H16N4O4: C, 59.99; H, 4.74; N, 16.46. Found: C, 59.68; H, 5.00; N, 16.26.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17]C)=O)=[C:13]([CH2:19]Br)[NH:12][C:11]3[CH2:21][O:22][CH2:23][C:24](=[O:25])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:26][NH2:27].CO>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[C:15](=[O:17])[N:27]([CH3:26])[CH2:19][C:13]=3[NH:12][C:11]3[CH2:21][O:22][CH2:23][C:24](=[O:25])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1=C(CBr)NC2=C(C(=O)COC2)C1c1ccc(F)c(Br)c1
Reactant: CN
Solvent: CO
Product: CN1CC2=C(C1=O)C(c1ccc(F)c(Br)c1)C1=C(COCC1=O)N2

Procedure:
A solution of the product from Example 25B (0.16 g, 0.34 mmol) and 2M methyl amine in methanol (3.5 mL, 7.0 mmol) was stirred at ambient temperature for 16 hours and concentrated. Purification of the residue on silica gel (5% and then 10% methanol in methylene chloride) provided an oil which was crystallized from ethanol, collected by filtration and dried to yield the title compound (0.016 g) as a white solid.
Reaction SMILES: C(N1C2C(=CC=CC=2)C(C2C(O)=C[C:19]3[O:20]COC=3C=2)C1=O)CCCCC.[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:38]1[C:39]([OH:47])=[CH:40][C:41]3[O:45][CH2:44][CH2:43][C:42]=3[CH:46]=1)[C:31](=[O:37])[NH:32]2.BrCC(OCC)=O.C=O>>[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30]([C:38]1[C:39]([OH:47])=[CH:40][C:41]3[O:45][CH2:44][CH2:43][C:42]=3[CH:46]=1)([CH2:19][OH:20])[C:31](=[O:37])[NH:32]2
Reactant: O=C1Nc2cccc(Br)c2C1c1cc2c(cc1O)OCC2
Reactant: CCCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: C=O
Agent: CCOC(=O)CBr
Product: O=C1Nc2cccc(Br)c2C1(CO)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 31D, and making non-critical variations to replace 1-hexyl-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, and ethyl bromoacetate with para-formaldehyde, the title compound was obtained that was used directly for further reaction.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[C:23]([CH:25]=1)[NH2:24]>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: Nc1cc(Cl)ccc1O
Product: Oc1ccc(Cl)cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol) and 5-chloro-2-hydroxyaniline (25 mg, 0.173 mmol) similar to Example 185 and was isolated as a solid (7 mg, 16% yield). 1H NMR (CDCl3): 9.68 (d, J=0.9 Hz, 1H), 8.84 (t, J=2.4 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H), 7.89 (brs, 1H), 7.41 (s, 1H), 7.07 (m, 2H), 6.91 (d, J=8.7 Hz, 1H).