Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.P(Br)(Br)[Br:27]>COCCOC>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][Br:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1
Solvent: COCCOC
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (2′-hydroxymethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (1.66 g, 4.68 mmol) in DME (17 mL) was added phosphorus tribromide (0.66 mL, 7.03 mmol), and the reaction was stirred at room temperature for 3 hours. The mixture was cooled to 0° C. and quenched with aqueous NaHCO3 and CH2Cl2. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][C:2]=1O.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[C:9]([OH:11])[CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: Oc1ccc2cccc(O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Oc1cccc2ccc(Cl)nc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a stirred mixture of quinoline-2,8-diol (1 g, 6.21 mmol) was added POCl3 (10 mL) and the mixture stirred at 100° C. for 1 hour before cooling. The mixture was then poured into ice-water (100 mL) slowly and filtered. The collected solid was dried and used in next step without further purification. (780 mg, Yield 70%). 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.17 (dd, J1=8.8 Hz, J1=1.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([N:14]2[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15]2)[N:3]=1.[C:20](Cl)(Cl)=[O:21].[OH-].[Na+].S(=O)(=O)(O)[O-].[K+]>C(Cl)Cl.C1(C)C=CC=CC=1.C(N(CC)CC)C>[N:14]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[N:7]3[O:8][C:20](=[O:21])[N:1]=[C:2]3[N:3]=2)[CH2:15][CH:16]=[CH:17][CH2:18][CH2:19]1
Reactant: COC(=O)Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Reactant: O=C(Cl)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc(N2CC=CCC2)nc2nc(=O)on12
Reaction time: 0.17 h

Procedure:
35 ml of triethylamine are added to a suspension of 13.3 g (0.05 mol) of methyl 2-amino-6-[(3,6-dihydro-1(2H)-pyridyl)]-4-pyrimidinecarbamate-3-oxide in 600 ml of methylene chloride. After cooling to -20°, 32.5 ml (0.06 mol) of a 20% solution of phosgene in toluene are added dropwise within 2 minutes. After 10 minutes, the mixture is treated with 100 ml of 1N sodium hydroxide. The organic phase is separated and extracted with 1N sodium hydroxide. The aqueous extracts are acidified with 25% hydrochloric acid and the milky suspension is extracted with methylene chloride/methanol (95:5). The organic extracts are dried over sodium sulfate and evaporated under reduced pressure. 90 ml of acetonitrile are added to the residue. 5.6 g of dicyclohexylamine are added at 45° to the suspension obtained and the mixture is stirred at this temperature for a further 4 hours. The crystalline precipitate is filtered off under suction, washed with acetonitrile, carefully sucked dry and added to 180 ml of water. The suspension obtained is acidified to pH 3 with a solution of potassium bisulfate and stirred for a further 0.75 hour. After cooling to 0°, the precipitate is filtered off under suction, washed with water and dried at 60° under reduced pressure. After recrystallization from a mixture of methylene chloride/methanol/ether, there is obtained methyl 5-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo-[2,3-a]pyrimidine-7-carbamate of melting point 216°-218°.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[CH:9]=[C:10]([C:12](=[O:14])[CH3:13])[CH:11]=1.[Cu][C:20]#[N:21].[C-]#N.[K+]>O.Cl.C(Cl)Cl>[C:20]([C:6]1[C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[CH:9]=[C:10]([C:12](=[O:14])[CH3:13])[CH:11]=1)#[N:21]
Reactant: COc1cc(C(C)=O)cc(N)c1OC
Reactant: N#C[Cu]
Agent: Cl
Agent: O=N[O-]
Agent: [C-]#N
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(C)=O)cc(C#N)c1OC
Reaction time: 3 h

Procedure:
A solution of 5.2 g of sodium nitrite in 20 ml of water is added dropwise at 0° within 20 minutes to 14.0 g of 5'-amino-3',4'-dimethoxyacetophenone dissolved in 155 ml of 1N hydrochloric acid. After stirring at -2° for 30 minutes the cold diazonium salt solution is added dropwise within 30 minutes at 5°-10° to a solution of 8.7 g of copper(I) cyanide and 5.45 g of potassium cyanide in 60 ml of water. After completion of the addition 200 ml of methylene chloride are added, and the reaction mixture is stirred at 23° for 3 hours and then filtered. The organic phase is separated, washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride/petroleum ether. There is obtained 5'-cyano-3',4'-dimethoxyacetophenone of m.p. 125°-126°.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:14](=[O:15])[C:5]=2[CH2:4][C:3]2[NH:16][C:17]4[C:22]([C:23](=[O:24])[C:2]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][CH:11]=[CH:10][CH:9]=3.CO.[OH-].[Na+].OO>C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.O>[CH:20]1[CH:21]=[C:22]2[C:23]([C:2]3[C:3]([NH:16][C:17]2=[CH:18][CH:19]=1)=[CH:4][C:5]1[C:14]([C:13]2[C:8]([NH:7][C:6]=1[CH:1]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:15])=[O:24]
Reactant: O=c1c2c([nH]c3ccccc13)Cc1c([nH]c3ccccc3c1=O)C2
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A one liter flask equipped with a thermometer, stirrer and condenser was charged with 40 grams 6,13dihydroquinacridone, 180 ml methanol, 42.5 grams 50% aqueous sodium hydroxide and 14.6 grams of an aqueous presscake containing 1.6 grams naphthalin-1-sulfonic acid methyl quinacridone pigment additive prepared according to Example 2 of Copending U.S. Provisional Patent Application entitled “PIGMENT PARTICLE GROWTH AND/OR CRYSTAL PHASE DIRECTORS”. The mixture was stirred under a slow flow of nitrogen at 50 to 55° C. for one hour. 0.5 grams anthraquinone mono sulfonic acid sodium salt, as catalyst, were added and the reaction mixture was heated to reflux. 67 grams of an aqueous 19.3% hydrogen peroxide solution were added into the reaction mixture with a peristaltic pump at a pumping rate of 0.3 ml/minute, whereby after 15 minutes addition time, 1.2 grams phthalimidomethyl dihydroquinacridone obtained according to Example 2 were added into the reaction mixture followed by another addition of 0.8 grams phthalimidomethyl dihydroquinacridone after 45 minutes while continuously adding the hydrogen peroxide by maintaining reflux and a slow nitrogen flow. The resulting violet suspension was further stirred for 10 minutes at reflux then diluted with 100 ml cold water and filtered. The presscake was washed with hot water, then dried, yielding 38.9 grams violet quinacridone.
Reaction SMILES: N1([BH3-])CCCC1.[Li+].C12OC1CCCC2.C1(O)CCCCC1.[CH2:22]1[O:30][CH:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:23][CH2:22][OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(C2CO2)cc1
Agent: C1CCC2OC2C1
Agent: [BH3-]N1CCCC1
Agent: [Li+]
Solvent: OC1CCCCC1
Product: OCCc1ccccc1

Procedure:
Epoxides are reduced readily with lithium pyrrolidinoborohydride. Thus, cyclohexene oxide is reduced to cyclohexanol, and styrene oxide gives predominantly 2-phenylethanol (see Reaction Sequences 7 and 8). ##STR6##
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1O.C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(=O)=O.CCOC(C)=O>CN(C)P(N(C)C)(N(C)C)=O.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[C:3](=[O:18])[N:4]=[C:5]2[N:6]([C@@H:7]3[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@@H:8]3[O:17]2)[CH:16]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cn2c(nc1=O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Temperature: 150 °C
Yield: 72.2 %

Procedure:
A mixture of 5-methyluridine (16.77 g, 69.2 mmol), diphenyl carbonate (17.8 g, 83.1 mmol) and sodium bicarbonate (100 mg) in hexamethylphosphoramide (175 ml) was heated to 150° C. with stirring until evolution of CO2 ceased (approximately 1 hr). The reaction mixture was cooled and then poured into diethylether (11) while stirring to furnish a brown gum. Repeated washings with diethylether (4×250 ml) furnished a straw colored hygroscopic powder. The solid was purified by short column chromatography on silica gel (400 g). Pooling and concentration of appropriate fractions, which were eluted with CH2Cl2 -MeOH (85:15, v/v) furnished the title compound as a straw colored solid (12 g, 77.3%) which crystallized from EtOH as long needles, m.p. 226°-227° C.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][OH:20])[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:22])([CH3:21])[N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][O:20][S:31]([CH3:30])(=[O:33])=[O:32])[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:22])([CH3:21])[N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CO)no3)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(COS(C)(=O)=O)no3)cc2)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A methylene chloride solution (20 ml) of (4S,5R)-tert-butyl 4-(fluoromethyl)-5-(4-(3-(hydroxymethyl)isoxazol-5-yl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate (876 mg, 2.16 mmol) is cooled to 0° C. and methanesulfonyl chloride (250 mg, 2.16 mmol) is added followed by diisopropylethylamine (278 mg, 2.16 mmol). The reaction is stirred for one hour at 0° C. The reaction is diluted with methylene chloride (20 ml) and washed with water (2×10 ml). The organic phase is dried over sodium sulfate and concentrated to give the title compound (987 mg): m/z (CI) 485 ([M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:8])=[C:5]([F:7])[F:6].[K].[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(Cl)(Cl)Cl>CN(C)C=O.O>[F:8][C:4](=[C:5]([F:7])[F:6])[CH2:3][CH2:2][N:14]1[C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]2[C:10]1=[O:20]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: FC(F)=C(F)CCBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CCC(F)=C(F)F
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 10.0 grams (0.053 mole) of 4-bromo-1,1,2-trifluoro-1-butene in 50 ml of dimethylformamide was added 10.4 grams (0.056) of the commercially available potassium salt of phthalimide. The reaction mixture was warmed to 50° C. where it stirred for four hours. The reaction mixture was allowed to cool and 50 ml of chloroform was added. The mixture was poured into 200 ml of water. The aqueous layer was separated and extracted with two 50 ml portions of chloroform. The combined organic layers were washed with two 50 ml portions of aqueous 5% sodium hydroxide and one 50 ml portion of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 4.8 grams of N-(3,4,4-trifluoro-3-butenyl)phthalimide as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12].[CH2:13](O)[CH3:14]>>[CH:13]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12])=[CH2:14]
Reactant: CCO
Reactant: Cc1c(Br)ccc2c1COC2=O
Product: C=Cc1ccc2c(c1C)COC2=O
Temperature: 140 °C

Procedure:
5-Bromo-4-methyl-2-benzofuran-1(3H)-one (598 mg, 4.47 mmol), potassium vinyl trifluoroborate (507 mg, 2.23 mmol), PdCl2(dppf)-CH2Cl2Adduct (182 mg, 0.223 mmol), and TEA (0.622 mL, 4.47 mmol) were added to 10 mL ethanol in a 20 mL microwave tube. The tube was sealed and degassed, then heated to 140° C. for 20 min. Analysis by LC-MS showed product peak. The reaction mixture was diluted with ethyl acetate, washed with brine twice, dried and evaporated to dryness. The crude product was purified by MPLC chromatography using a 120 g Redi-sep column and 0-80% EtOAc/Hexane solvent system to yield 5-ethenyl-4-methyl-2-benzofuran-1(3H)-one. 1H-NMR (500 MHz, CDCl3): δ ppm 7.76 (d, J=8 Hz, 1H), 7.03 (dd, J=11, 17 Hz, 1H), 5.84 (d, J=17 Hz, 1H), 5.55 (d, J=11 Hz, 1H), 5.29 (s, 2H), 2.34 (s, 3H); LC-MS: M+1=175;
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:5]([CH3:24])=[N:6][C:7]2[N:8]([C:11]([CH3:23])=[N:12][C:13]=2[C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:9]=1O.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:36])=O>>[Cl:36][C:9]1[N:8]2[C:11]([CH3:23])=[N:12][C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[C:7]2[N:6]=[C:5]([CH3:24])[C:4]=1[CH2:3][CH2:2][Cl:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(-c2nc(C)n3c(O)c(CCCl)c(C)nc23)c(C)c1
Solvent: CN(C)c1ccccc1
Product: Cc1cc(C)c(-c2nc(C)n3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of 3-(2-chloroethyl)-8-mesityl-2,6-dimethylimidazo[1,5-a]pyrimidin-4-ol (200 mg, 0.58 mmol) and N,N-dimethylaniline (0.3 mL) in phosphorus oxychloride (3 mL) was heated under reflux for six hours. After evaporating, 3-aminopentane (2 mL) was added to a solution of the residue in acetonitrile (5 mL), followed by stirring at 80° C. for three hours. Water was added, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (10-20% ethyl acetate/hexane), to give the title compound (139 mg) as pale yellow crystals.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].C(=O)=O.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O-:20].[K+]>>[OH:20][C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:1]([OH:2])=[O:4])[CH:15]=2)[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: [O-]c1ccc2ccccc2c1
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc2cc(O)ccc2c1
Temperature: 280 °C
Yield: 76 %

Procedure:
A stainless steel pressure autoclave is charged with 50 parts of kerosene and 38 parts of potassium carbonate and heated to 280° C. It is then pressurized with 10 bar of carbon dioxide. Over the course of 5 hours, a mixture of 50 parts of potassium β-naphtholate and 38 parts of potassium carbonate are metered in as a suspension in kerosene via a metering pump, part of the kerosene being distilled off, condensed and transferred out of the reaction vessel at reduced pressure. After the usual workup, the 2-hydroxynaphthalene-6-carboxylic acid is obtained in a yield of 76% based on potassium naphtholate used. In addition, 14% of unreacted β-naphthol and small amounts of 2-hydroxynaphthalene-3-carboxylic acid and 2-hydroxynaphthalene-3,6-dicarboxylic acid are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:15]O.Cl>C(Cl)Cl>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cccnc1Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
52 was prepared according to the method of Synth. Comm. 26(12), 2257-2272 (1996). To a nitrogen purged flask was charged 2-chloro-nicotinic acid (1000.0 g, 6.0 moles, 1.0 eq) followed by 9 L methylene chloride. To this was added thionyl chloride (1.4 L, 19.7 moles, 3.2 eq.) and the reaction was heated to 40° C. with vigorous stirring under nitrogen overnight. The acid chloride solution was cooled in an ice bath and methanol (3 L, 74 moles, 12 eq.) was slowly added while keeping the temperature at 20° C. The rate limiting parameter is the vigorous evolution of copious quantities of HCl gas. After the addition, HPLC analysis [Tret starting material=7.5 min, Tret 52=11 min] showed the product had formed immediately. The volatiles were removed in vacuo and the residue extracted from 10% Na2CO3 with EtOAc. The combined organics were dried (MgSO4), filtered, and concentrated to a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16](OC)=[O:17])[N:10]=[CH:9]2)#[N:2].[BH4-].[Na+]>CO>[F:24][C:22]1[CH:21]=[CH:20][C:4]([O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]3)=[C:3]([CH:23]=1)[C:1]#[N:2]
Reactant: COC(=O)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of methyl 2-(5-(2-cyano-4-fluorophenoxy)-1H-indazol-1-yl)acetate 77 (prepared as in Example 3) (60.0 g, 184.4 mmol) in MeOH (370 mL) was added NaBH4 (24.42 g) in five 5 gram portions over 90 minutes. The temperature rose from 25° C. to 44.7° C. at the final addition of NaBH4. The mixture was concentrated under vacuum. To the concentrate was added saturated NH4Cl (600 mL) and EtOAc (600 mL) and the mixture was vigorously stirred for 1 hour. The layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were washed with saturated NH4Cl (2×100 mL), water (200 mL), brine (500 mL), dried over MgSO4, filtered thru GF/F paper and concentrated to a bright orange solid. The crude solid was dissolved in CH2Cl2 (1 L) and hexanes (2.25 L) were added with stirring. A light brown solid formed and after stirring for 30 min the solid was collected and dried under high vacuum to yield 45.5 g. The filtrate was concentrated under reduced pressure. This material was redissolved in CH2Cl2 (100 mL) and hexanes were added (200 mL). The resulting solid (6.2 g) was collected via filtration. The two crops were combined to give 51.7 g (94.3%) of 78A. 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.49 (d, 1H), 7.39-7.36 (m, 2H), 7.21-7.16 (m, 2H), 6.90 (dd, 1H), 4.49 (t, 2H), 4.17-4.13 (m, 2H), 2.81 (t, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=1.[OH-].[K+]>[Cu]>[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([O:15][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: Clc1ccc(Br)cc1
Reactant: COc1ccc(O)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
4-Bromochlorobenzene (3.8 g), hydroquinone monomethyl ether (3.1 g) and potassium hydroxide (1.5 g) and copper powder (0.1 g) were mixed and the reaction was carried out at 160° C. to 200° C. for 3 hours. After cooling to room temperature, the reaction mixture was extracted with benzene (100 ml) and washed with 1N sodium hydroxide, water, and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure and the residue was purified by medium pressure column chromatography using silica gel, to obtain 4-(4-chlorophenoxy)phenol methyl ether (2.5 g).
Reaction SMILES: [NH3:1].Cl[C:3]1[CH:4]=[N:5][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:10])[C:8]=1[Cl:9].C1C(O)=CC=C(S(O)(=O)=O)C=1>>[NH2:1][C:3]1[CH:4]=[N:5][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:10])[C:8]=1[Cl:9]
Reactant: N
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Agent: O=S(=O)(O)c1ccc(O)cc1
Product: Nc1cnn(-c2ccccc2)c(=O)c1Cl
Temperature: 130 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
85 parts by volume of 15% (wt %) strength aqueous ammonia, 12.05 parts by weight of 4,5-dichloro-1-phenylpyridaz-6-one and 6.2 parts by weight of a 70% strength aqueous solution of phenol-4-sulfonic acid (parts by volume bearing the same relationship to parts by weight as the liter to the kilogram) are introduced into a jacketed pressure vessel having a capacity of 300 parts by volume. The reaction mixture is heated to 130° C. while stirring and kept for 4 hours at this temperature, while still stirring. The autogenous pressure which is hereupon generated is 6 bars. The reaction mixture is then allowed to cool to room temperature (20° C.) and the mother liquor is completely filtered off. The solid reaction product is washed with water and dried in vacuo at 100° C. There is obtained 9.8 parts by weight (89% of theory) of 4-amino-5-chloro-1-phenylpyridaz-6-one of melting point 205°-206° C. The amount of 5-amino-4-chloro-1-phenylpyridaz-6-one is determined gas-chromatographically and found to be 1%, and the amount of 4-amino derivative 99%.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[NH:11][C:12](=[O:28])[N:13]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:14]=1)#[N:9]>ClCCl>[O:28]=[C:12]1[NH:11][C:10]([C:8]#[N:9])=[CH:14][N:13]1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C#N)[nH]c2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cn(C2CCNCC2)c(=O)[nH]1
Reaction time: 0.33 h

Procedure:
Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl 4-(4-cyano-2-oxo-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate (25 mg, 0.086 mmol) in dichloromethane (6 mL). After 20 min, the reaction was concentrated to give the title compound. MS 193.3 (M+1)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]1([NH2:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(CC)CC>CN1C(=O)CCC1>[N+:8]([C:7]1[C:2]([NH:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 52.6 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (3.49 g, 22.0 mmol), phenylamine (2 mL, 22.0 mmol) and Et3N (3.1 mL, 22.0 mmol) in NMP (7 mL) was stirred at 100° C. for 1.5 h under a nitrogen atmosphere. Additional amounts of Et3N (0.2 mL) and of phenylamine (0.1 mL) were added and the stirring was continued for further 30 min. The mixture was then partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 10-100% DCM in pentane) affording (3-Nitropyridin-2-yl)phenylamine as a red crystalline solid (2.49 g, 58%). LCMS: RT 3.53 min [M+H]+ 216.0.