Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1.P(Cl)(Cl)[Cl:12].[Cl-].[Cl-].[Cl-].[Al+3].ClCl>P(Cl)(Cl)(Cl)=O>[Cl:12][C:7]1[O:8][C:4]2[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=2[N:6]=1
Reactant: ClP(Cl)Cl
Reactant: Clc1ccc2ncoc2c1
Agent: ClCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc2nc(Cl)oc2c1
Temperature: 100 °C
Yield: 1931.6 %

Procedure:
10 g (0.065 mol) of 6-chlorobenzoxazole, 0.45 g of phosphorus trichloride and 0.09 g of anhydrous aluminum trichloride were initially charged in 30 ml of phosphorus oxychloride (POCl3). With heating and stirring, chlorine gas was introduced at a rate of 0.6 equivalent of chlorine per hour. After an internal temperature of 80° C. had been reached, the stream of chlorine gas was reduced to 0.6 equivalent of chlorine per 6 hours, and the temperature was increased to 100° C. The reaction was monitored by gas chromatography. After all of the starting material had been consumed, most of the POCl3 was distilled off and the residue was subjected to fractional distillation under reduced pressure. This gave a pure fraction of 11.9 g of the 2,6-dichlorobenzoxazole, which solidifies on cooling (GC>99% pure) (>97% of theory).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>[OH-].[Li+].CN(C)C=O>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClC[C@@H]1CO1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and lithium hydroxide (48 mg, 2 mmol) were added to 100 mL N,N-dimethyl formamide. The mixture was stirred at 25° C. for 30 minutes. (S)-epichlorohydrin (18.6 g, 0.2 mol) was then added and the mixture was stirred at 0° C. for 8 hours. The mixture was filtered and the solvent was evaporated to provide 52 g colorless oil with 90% yield. HPLC: 99.0%.
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:3].C([O-])(O)=O.[Na+].[CH3:15][C:16]([CH3:23])([CH3:22])[C:17](=O)[CH2:18][C:19]#[N:20]>CCO>[NH2:20][C:19]1[N:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:3]=[C:17]([C:16]([CH3:23])([CH3:22])[CH3:15])[CH:18]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CCOC(=O)CNN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cn1nc(C(C)(C)C)cc1N
Temperature: 60 °C
Yield: 81.9 %

Procedure:
A mixture of ethyl 2-hydrazinylacetate hydrochloride (0.309 g, 2 mmol), NaHCO3 (0.185 g, 2.2 mmol), and 4,4-dimethyl-3-oxopentanenitrile (0.250 g, 2 mmol) in EtOH (10 mL) was heated at 60° C. overnight. The reaction was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure to afford ethyl 2-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)acetate as solid (0.369 g, 82%). 1H NMR (300 MHz, CDCl3) δ 5.50 (s, 1H), 4.75 (s, 2H), 4.23 (q, 2H), 3.57 (br, 2H), 1.29 (t, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 226 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1)=[O:16].[BH4-].[Na+]>C(O)(C)C>[C:7]1([C:5]2[O:6][C:2]([CH3:1])=[C:3]([CH2:13][CH2:14][CH:15]([C:17]3[CH:30]=[CH:29][C:20]([CH2:21][CH:22]4[S:26][C:25](=[O:27])[NH:24][C:23]4=[O:28])=[CH:19][CH:18]=3)[OH:16])[N:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1oc(-c2ccccc2)nc1CCC(O)c1ccc(CC2SC(=O)NC2=O)cc1
Reaction time: 2 h
Yield: 45.5 %

Procedure:
The title product of Example 9 (0.70 g) was suspended in 50 ml of isopropanol at room temperature. NaBH4 (0.15 g) was added and the mixture stirred for 2 hours, concentrated in vacuo to low volume, diluted with 50 ml of water and extracted 2×200 mL ethyl acetate. The organic layers were combined, washed with brine, dried (MgSO4), stripped in vacuo and the residue chromatographed using 1:1 ethyl acetate:hexane --1% acetic acid to yield 0.32 g of present title product; mp 50°-55° C.; tlc Rf 0.40 (1:1 hexane:ethyl acetate--2.5% acetic acid), 0.28 (2:1 CH2Cl2 :ether).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1>>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Oc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5cccc(Cl)c5)nc34)cc21
Temperature: 85 °C
Reaction time: 17 h
Yield: 19.1 %

Procedure:
Prepared according to Example 103, NaH as a 60% dispersion in mineral oil (143 μl, 3.29 mmol, Sigma Aldrich), 3-chlorophenol (334 μl, 3.29 mmol, Sigma Aldrich), and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 140 mg, 0.470 mmol) and stirring at 85° C. for 17 h. Purification by column chromatography (silica gel, 0 to 60% EtOAc/DCM then 5% MeOH/DCM) providing 2-(2-(3-chlorophenoxy)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (35 mg, 19%). 1H NMR (400 MHz, CDCl3) δ ppm 11.28-11.38 (1H, m) 8.23 (1H, d, J=1.00 Hz) 8.04-8.09 (1H, m) 7.61-7.66 (1H, m) 7.48 (2H, q, J=1.00 Hz) 7.36-7.41 (2H, m) 7.19-7.26 (3H, m) 5.84-6.01 (1H, m) 3.58 (2H, t, J=1.00 Hz) 2.55 (2H, t, J=1.00 Hz). m/z (ESI, +ve) 390.0 (M+H)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:1][C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: COCCCCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
Oxalyl chloride (16.0 g, 70 mmol) was added dropwise to a solution of 12-methoxydodecanoic acid (9.8 g, 77 mmol) in 300 mL of anhydrous toluene. After stirring at room temperature for 16 hours the solvent was removed on a rotary evaporator. The residue was taken up in anhydrous toluene and concentrated to give the title compound (17.4 g) as a yellow liquid. The structure was verified by infrared spectroscopy (1796 cm-1) and NMR.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO.O>[CH2:13]([O:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: O=c1cc(CO)occ1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1cc(CO)occ1OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of 17 g (0.12 mole) of kojic acid and 5.1 g (0.13 mole) of sodium hydroxide in 190 ml of 10:1 (by volume) methanol-water was added dropwise 17.5 g (0.14 mole) of benzyl chloride. After 4.5 hours at reflux, the mixture was allowed to cool and was poured into 200 ml of ice-water. The resultant solid was collected, washed with water, and dried, giving 22.4 g of analytically pure title compound, m.p. 128°-130°.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:17][C:18]1([CH3:23])[O:22][CH2:21][CH2:20][O:19]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>>[CH3:1][C:2]([CH3:24])([CH2:17][C:18]1([CH3:23])[O:22][CH2:21][CH2:20][O:19]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-:33])=[CH:8][C:7]=2[N:6]=[CH:5]1
Reactant: CC(C)(Cn1cnc2cnc3ccccc3c21)CC1(C)OCCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(C)(Cn1cnc2c[n+]([O-])c3ccccc3c21)CC1(C)OCCO1

Procedure:
The general method described in Parts I and J of Example 28 was used to aminate 1-[2,2-dimethyl-3-(2-methyl[1,3]dioxolan-2-yl)propyl]-1H-imidazo[4,5-c]quinoline (8.8 g, 27 mmol) by reaction with m-CPBA (11.8 g) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-5-oxido-1H-imidazo[4,5-c]quinoline followed by reaction with p-toluenesulfonyl chloride (9.1 g, 48 mmol) and ammonium hydroxide solution (100 mL) to provide 1-[2,2-dimethyl-3-(2-methyl[1,3]dioxolan-2-yl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine as a light brown solid after chromatography on silica gel (elution with a solution of 7% methanol in dichloromethane that contained about 5 mL of ammonium hydroxide solution per liter of eluent) and recrystallization from aqueous methanol, mp 153-155° C.
Reaction SMILES: C([O:4][C:5]([CH3:26])([CH3:25])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[C:16]=2[CH3:23])=[C:11]([CH3:24])[CH:10]=1)(=O)C.[NH2:27][C:28]1[CH:41]=[CH:40][C:31]([CH2:32][N:33]2[C:37](=[O:38])[NH:36][C:35](=[O:39])[O:34]2)=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+:55]>C(O)(=O)C>[OH:4][C:5]([CH3:26])([CH3:25])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:27][C:28]3[CH:41]=[CH:40][C:31]([CH2:32][N:33]4[C:37](=[O:38])[N-:36][C:35](=[O:39])[O:34]4)=[CH:30][CH:29]=3)[C:16]=2[CH3:23])=[C:11]([CH3:24])[CH:10]=1.[Na+:55]
Reactant: Nc1ccc(Cn2oc(=O)[nH]c2=O)cc1
Reactant: CC(=O)OC(C)(C)CCOc1ccc(-c2cccc(C=O)c2C)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(OCCC(C)(C)O)ccc1-c1cccc(CNc2ccc(Cn3oc(=O)[n-]c3=O)cc2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 56 %

Procedure:
A mixture of 3-[(3′-formyl-2,2′-dimethylbiphenyl-4-yl)oxy]-1,1-dimethylpropyl acetate (479 mg), 2-(4-aminobenzyl)-1,2,4-oxadiazolidine-3,5-dione (340 mg) and acetic acid (6 ml) was stirred at room temperature for 20 hours. Sodium triacetoxyborohydride (573 mg) was added to the reaction solution, followed by stirring at room temperature for 2 hours. After evaporation of the solvent under a reduced pressure, water was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate), and a mixture of the resulting pale yellow foamy substance (719 mg), THF (5 ml), methanol (5 ml) and a 1 M sodium hydroxide aqueous solution (4 ml) was stirred at 50° C. for 4 hours. The pH was made to 4 to 5 by adding 1 M hydrochloric acid, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate), and a 1 M sodium hydroxide aqueous solution (0.89 ml) was added to a mixture of the resulting pale yellow oil (448 mg), THF (3 ml) and methanol (3 ml), followed by stirring for 10 minutes. After evaporation of the solvent under a reduced pressure, the resulting residue was washed with diethyl ether to obtain sodium 2-[4-({[4′-(3-hydroxy-3-methylbutoxy)-2,2′-dimethylbiphenyl-3-yl]methyl}amino)benzyl]-3,5-dioxo-1,2,4-oxadiazolidin-4-ide (398 mg) as a white solid.
Reaction SMILES: C(S[CH:6]1[N:9]([CH:10]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:30])[CH2:7]1)(C)(C)C.[Cl:31]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:31][CH:6]1[N:9]([CH:10]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:30])[CH2:7]1
Reactant: CC(C)(C)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Temperature: -50 °C
Yield: 90.9 %

Procedure:
A solution of 439 mg (1.0 mmol) of p-nitrobenzyl 2-(4-tert-butylthio-2-oxo-1-azetidinyl)-4,4-dimethyl-3-oxopentanoate in 20 ml of dry methylene chloride is cooled to -50° C. and a solution of 166 mg of chlorine in 1.6 ml of carbon tetrachloride is added. After stirring the mixture for thirty minutes at -50° C., the solvent is evaporated in vacuo and the residue is recrystallized from methylene chloride/hexane, the product (348 mg) being obtained as a crystalline solid as a 6:4 mixture of the diastereomeric title compounds.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[NH:4][N:3]=1.C(SCCSCCSC1N=C2N(N=1)[C:38]([OH:41])=[CH:37][C:36]([CH3:42])=N2)CCCCC>>[CH2:11]([S:10][CH2:9][CH2:8][S:7][C:5]1[N:6]=[C:2]2[N:3]([N:4]=1)[C:38]([OH:41])=[CH:37][C:36]([CH3:42])=[N:1]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCSCCSCCSc1nc2nc(C)cc(O)n2n1
Reactant: CCCCCCCCSCCSc1nc(N)n[nH]1
Product: CCCCCCCCSCCSc1nc2nc(C)cc(O)n2n1

Procedure:
Compound 14 was prepared from Compound 7 using a procedure analogous to that described previously for Compound 20. Recrystallization of the crude product from ethyl acetate gave a 59% yield of a white solid, m.p. 125.5°-127° C. Analysis: Calculated for C16H26N4OS2 : C,54.21; H, 7.39; N, 15.80. Found: C, 53.51; H, 7.21; N, 15.72.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[O-]CC.[Na+]>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: NCCCN
Reactant: Clc1cnccn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCCNc1cnccn1

Procedure:
Reacting 2-chloropyrazine with 1,3-diaminopropane in ethanol containing sodium ethoxide by the procedure of Example 89 gives 2-(3-aminopropylamino)pyrazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1ccc2c(cnn2-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.1 %

Procedure:
A mixture of 2.0 g (10.15 mmol) of 5-bromoindazole, 2.49 g (20.30 mmol) of 3-pyridyl boronic acid, 2.77 g (15.25 mmol) of copper acetate, and 2.4 mL of pyridine were dissolved in dry dichloromethane and stirred at room temperature. Oxygen gas was bubbled into the solution for 3 min and the mix was stirred in a screw top reaction vial in open atmosphere. After stirring overnight at room temperature, the reaction was monitored by LCMS which indicated ˜10-15% conversion. The mixture was then warmed to 70° C. After 24 hours, the mixture was cooled to room temperature, diluted with brine and extracted with EtOAc. The organic was washed with brine, dried over sodium sulfate, and concentrated in vacuo onto silica gel. The crude was then purified by Combiflash chromatography using a 0-70% EtOAc/hexanes gradient (product eluted at 35% EtOAc). The product containing fractions were combined and concentrated in vacuo to afford 0.31 g (11%) of 5-bromo-1-pyridin-3-yl-1H-indazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[N:6][CH:7]=1.F[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)(Cl)Cl>[C:17]([C:16]1[CH:15]=[C:14]([N:11]2[CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[N:9]=[CH:10]2)[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: N#Cc1cccc(F)c1
Reactant: Fc1ccc(-c2c[nH]cn2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc(-n2cnc(-c3ccc(F)cn3)c2)c1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
In a screw-cap vial, added 4-(5-Fluoro-2-pyridyl)imidazole (0.06 g, 0.30 mmol), 3-Fluorobenzonitrile (0.04 ml, 0.36 mmol), potassium carbonate (0.21 g, 1.5 mmol) and dimethylformamide (1 ml). Stirred the resulting reaction mixture at 110° C. overnight. Cooled the reaction mixture to room temperature, diluted with chloroform (50 ml), sequentially washed with water, (50 ml) and brine (50 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was triturated with 10% diethyl ether in hexanes to yield the title compound (45 mg) as a dirty yellow colored solid. 1H—NMR (CDCl3), δ (ppm): 8.43 (d, 1H), 8.04 (dd, 1H), 7.93 (dd, 2H), 7.70 (m, 4H), 7.48 (dt, 1H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([OH:24])=[CH:16][N:15]=1>CCOC(C)=O.C([O-])(O)=O.[Na+]>[OH:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([CH2:13][NH:12][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:15][CH:16]=1
Reactant: NCc1ncc(O)c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(NCc1ncc(O)c2ccccc12)c1ccccc1
Reaction time: 0.25 h

Procedure:
Benzoyl chloride (0.018 ml) is added dropwise to a stirred mixture of the product from step 3 (20 mg) in a mixture of 2 ml EtOAc and 2 ml of saturated aqueous NaHCO3 solution. After 15 minutes stirring, the organic layer is separated, washed with water, dried and concentrated to a solid. The solid is washed with hexane and dried to yield 20 mg of the title compound as a white solid, m.p. 130-131° C.
Reaction SMILES: C[Si](I)(C)C.[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([NH:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[N:12][NH:13]2)=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28]CC2C=CC=CC=2)=[CH:24][CH:23]=1>CO>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([NH:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[N:12][NH:13]2)=[CH:9][C:8]=1[C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1
Reactant: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccc(OCc4ccccc4)cc3)cc12
Agent: C[Si](C)(C)I
Solvent: CO
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccc(O)cc3)cc12
Yield: 24.3 %

Procedure:
20 cm3 of trimethylsilyl iodide are added to 1.1 g of N-[6-chloro-5-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide, prepared in Example 95, and the mixture is refluxed for 18 hours. 30 cm3 of methanol are added and the reaction medium is refluxed for 30 minutes and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 100 cm3 of ethyl acetate and 100 cm3 of water and the organic phase is washed with 2×75 cm3 of 10% sodium thiosulphate solution and then with 70 cm3 of water and 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure to give 1.44 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 20 cm3 of diisopropyl ether, filtered off, washed with 3×10 cm3 of diisopropyl ether and then dried (90 Pa; 45° C.) to give 210 mg of N-[6-chloro-5-(4-hydroxyphenyl)-1H-indazol-3-yl]butanamide in the form of a white powder.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[Cl:10][CH2:11][C:12](O)=[O:13]>>[CH:8]1[C:9]([C:12]([CH2:11][Cl:10])=[O:13])=[C:1]([OH:2])[C:3]([OH:4])=[C:5]([OH:6])[CH:7]=1
Reactant: O=C(O)CCl
Reactant: Oc1cccc(O)c1O
Product: O=C(CCl)c1ccc(O)c(O)c1O

Procedure:
The condensation of pyrogallol and chloroacetic acid to form ω-chloro-2,3,4-trihydroxyacetophenone according to the invention is carried out using boron trifluoride as the condensing agent with a two-fold excess of chloroacetic acid. The reagents are mixed in any suitable manner and stirred together with moderate heating. When the reaction is complete the excess chloroacetic acid and boron trifluoride complex is removed by washing with water and filtering and, if desired, the product is recrystallized from water. Advantageously, the pyrogallol and chloroacetic acid are heated at a moderate temperature, say, about 65° C., until fusion is almost complete and the mixture is fluid. The boron trifluoride is then introduced under the surface at a moderate rate while the mixture is stirred and the temperature is maintained at about 65° C., and stirring and heating is continued until the reaction is complete, usually within about 3 hours. Higher or lower temperatures can be used, providing the temperature is high enough to give a fluid mix and not so high as to cause decomposition of the reagents or the product. Ordinarily, it will not be found necessary or advisable to heat above about 75° C. or to heat below about 60° C.
Reaction SMILES: C(O[CH:4]=[N:5][C:6]1[S:15][C:9]2[CH2:10][N:11]([CH3:14])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:16]([O:18]CC)=O)C.[CH2:21]([CH2:23][NH2:24])[OH:22]>C(O)C>[OH:22][CH2:21][CH2:23][N:24]1[C:16](=[O:18])[C:7]2[C:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][C:9]=3[S:15][C:6]=2[N:5]=[CH:4]1
Reactant: NCCO
Reactant: CCOC=Nc1sc2c(c1C(=O)OCC)CCN(C)C2
Solvent: CCO
Product: CN1CCc2c(sc3ncn(CCO)c(=O)c23)C1

Procedure:
86.4 g (292 mmol) of 2-ethoxymethyleneamino-3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in 200 ml of ethanol were mixed with 17.6 ml (292 mmol) of ethanolamine and refluxed for 2 h. The mixture was then concentrated under reduced pressure, and the residue was taken up in 30 ml of ethyl acetate with stirring. The solid which precipitated overnight was filtered off with suction and washed with a little ethyl acetate. After recrystallization from ethanol, 48.0 g (62%) of product with melting point 163-165° C. were isolated.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[CH3:12][NH:13][CH3:14]>C(O)C>[CH3:12][N:13]([CH3:14])[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2
Reactant: O=C1NCc2cc(F)ccc21
Reactant: CNC
Solvent: CCO
Product: CN(C)c1ccc2c(c1)CNC2=O
Temperature: 165 °C
Yield: 81 %

Procedure:
A 500-mL high-pressure bomb reactor was charged with 123b (2.20 g, 14.5 mmol) ethanol (30 mL) and excess dimethylamine (50 mL). The mixture was heated at 165° C. for 36h. After this time, the mixture was concentrated and the resulting residue was purified by flash column chromatography (silica, 98:2 ethyl acetate/triethyl-amine) to afford an 81% yield (2.40 g) of 123c as a yellow solid: mp 122-124° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.44 (d, 1H, J=9.3 Hz), 6.77 (m, 2H), 4.24 (s, 2H), 2.99 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:17][C:18]1([CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH2:21][O:20][CH2:19]1>>[CH3:27][N:25]([CH3:26])[C:23]([CH2:22][C:18]1([NH:17][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])[CH2:19][O:20][CH2:21]1)=[O:24]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Reactant: CN(C)C(=O)CC1(N)COC1
Product: CN(C)C(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(Cl)cn2)COC1

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c) and 2-(3-Amino-oxetan-3-yl)-N,N-dimethyl-acetamide as starting materials and isolated (4 mg, 5%) as colorless oil; MS (ESI, m/z): 396.4 (M+H+).