Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:21])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:24]=1[NH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:24]=1[N:25]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:11](=[O:21])[C:2]([CH3:1])=[C:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C(=O)CC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: Cc1c(-c2ccccc2)n(-c2cc([N+](=O)[O-])ccc2Cl)c(-c2ccccc2)cc1=O

Procedure:
To 170ml of chlorobenzene were added 3.4 g (0.012 mole) of 2-methyl-1,5-diphenyl-1,3,5-pentanetrione, 10.4 g (0.060 mole) of 2-chloro-5-nitroaniline, 4.1 g (0.022 mole) of para-toluenesulfonic acid and 35.0 g of Molecular Sieves 5A, followed by refluxing for 2 hours. After cooling the reaction mixture, solid matter was removed from the reaction mixture, followed by addition of 200 ml of chloroform. The resultant mixture was washed first with 100 ml of 10% hydrochloric acid and then with 100 ml of a 10% aqueous solution of sodium hydroxide. The mixture was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: ethyl acetate). Upon recrystallization of the resultant crystals from a 2:1 mixed solvent of acetone and hexane, 1.9 g of 1-(2-chloro-5-nitrophenyl)-3-methyl-2,6 -diphenyl-4(1H)-pyridinone having a melting point of 277°-279° C. was obtained.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([CH3:16])[CH:14]=[O:15])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]=[C:13]([CH3:16])[CH2:14][OH:15])=[CH:10][CH:11]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(C)(C)c1ccc(C=C(C)C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(C)(C)c1ccc(C=C(C)CO)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
432.62 g of 3-(p-tert.amyl -phenyl)-2-methyl-acrolein are dissolved in 2500 ml of methanol and treated portionwise while cooling with ice with 38 g of sodium borohydride. Subsequently, the mixture is stirred at room temperature for 2.5 hours, poured into 2500 ml of ice-cold 2-N hydrochloric acid and exhaustively extracted with hexane. The combined hexane extracts are washed neutral with water, dried over sodium sulphate and evaporated. Vacuum distillation yields pure 3-(p-tert.amyl-phenyl)-2-methyl-allyl alcohol of boiling point 128°-133° C./0.04 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[O:4][NH2:5].[CH2:11]([N:14]=[C:15]=[O:16])[CH:12]=[CH2:13]>C1(C)C=CC=CC=1>[CH2:11]([NH:14][C:15]([NH:5][O:4][C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[Cl:1])=[O:16])[CH:12]=[CH2:13]
Reactant: NOc1cc(Cl)ccc1Cl
Reactant: C=CCN=C=O
Solvent: Cc1ccccc1
Product: C=CCNC(=O)NOc1cc(Cl)ccc1Cl
Reaction time: 12 h
Yield: 50.6 %

Procedure:
5.34 g (30.0 mmoles) of 2,5-dichlorophenoxyamine was dissolved in 50 ml of toluene, and then 2.74 g (33.0 mmoles) of allyl isocyanate was added. The mixture was stirred at a temperature of from 25° to 30° C. for 12 hours. The crystals precipitated in the reaction solution were collected by filtration and washed with hexane, whereby, 3.96 g of the desired product was obtained as light yellow crystals (yield: 51%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([Cl:20])=[N:9][S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1)(=O)=O.[F:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[C:26]([F:29])[C:27]=1O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:20][C:8]1[C:7]([CH2:6][O:5][C:27]2[C:26]([F:29])=[CH:25][C:24]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][C:22]=2[F:21])=[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[S:10][N:9]=1
Reactant: CCc1ccc(-c2snc(Cl)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(CC)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-chloro-5-(4-ethylphenyl)-1,2-thiazol-4-yl]methyl methanesulfonate (20 mg, 0.05 mmol, 1.00 equiv), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (16 mg, 0.07 mmol, 1.20 equiv), potassium carbonate (25 mg, 0.18 mmol, 3.00 equiv), N,N-dimethylformamide (2 mL). The resulting solution was stirred overnight at 25° C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3×5 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×10 mL of brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto the TLC with ethyl acetate/petroleum ether (1:15). This resulted in 20 mg (71%) of ethyl 3-(4-[[3-chloro-5-(4-ethylphenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].Br[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[CH2:13]([N:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]1=[O:9])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CBr
Reactant: COc1cc[nH]c(=O)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccn(CC(C)C)c(=O)c1C#N
Temperature: 50 °C
Reaction time: 24 h
Yield: 63.1 %

Procedure:
A mixture of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (15.00 g), 1-bromo-2-methylpropane (21.4 g), cesium carbonate (65.2 g) and dimethyl sulfoxide (150 mL) was stirred at 50° C. for 24 hr. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ether to give the title compound (13.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[C:23]([NH:35][CH3:36])=[N:24][C:25]2[CH:26]=[C:27]3[O:34][CH2:33][O:32][C:28]3=[CH:29][C:30]=2[CH:31]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[C:23]([NH:35][CH3:36])=[N:24][C:25]2[CH:26]=[C:27]3[O:34][CH2:33][O:32][C:28]3=[CH:29][C:30]=2[CH:31]=1
Reactant: CNc1nc2cc3c(cc2cc1CCl)OCO3
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNc1nc2cc3c(cc2cc1Cc1c(O)nc(C)c2cc(OC)c(OC)cc12)OCO3
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (147 mg, 670 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.70 mL, 1.40 mmol) at RT followed by 7-(chloromethyl)-N-methyl-[1,3]dioxolo[4,5-g]quinolin-6-amine hydrochloride CCH 34158B (200 mg, 697 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (80 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:7 N NH3 solution in MeOH=100:0 to 95:5) gave 6,7-dimethoxy-1-methyl-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.19 M HCl solution in MeOH (1 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)isoquinolin-3-ol dihydrochloride 60 as a brown solid (30 mg, 6% yield).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C@@H:20]([OH:42])[C@H:21]([OH:41])[C@@H:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:43][S:44](Cl)(=[O:46])=[O:45].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([NH:11][C@H:12]([C@@H:20]([O:42][S:44]([CH3:43])(=[O:46])=[O:45])[C@H:21]([O:41][S:44]([CH3:43])(=[O:46])=[O:45])[C@@H:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]([C@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 90 %

Procedure:
A slurry of 1.50 g (2.64 mmol) of (2S,3R,4R,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexane in 50 ml of anhydrous dichloromethane was cooled to 0° C. and treated sequentially with 0.43 ml of methanesulfonyl chloride, 64 mg of 4-dimethylaminopyridine and 1.1 ml of triethylamine. The resulting mixture was stirred for 15 h with the temperature being allowed to slowly climb to ambient temperature. After treatment with aqueous NH4Cl, the separated organic layer was washed with aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo to provide 1.70 g (90%) of the desired compound, m.p. 153°-155° C. 1H NMR (CDCl3) δ2.73 (m, 2H), 2.92 (m, 2H), 3.09 (s, 6H), 4.61 (m, 2H), 4.83-5.06 (m, 8H), 7.12-7.37 (m, 20H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:13]#[N:14])[C:11]#[N:12])=[CH:5][CH:4]=1)[CH3:2].O.[NH2:16][NH2:17]>C(O)C>[NH2:12][C:11]1[C:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)=[C:13]([NH2:14])[NH:17][N:16]=1
Reactant: CCc1ccc(CC(C#N)C#N)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCc1ccc(Cc2c(N)n[nH]c2N)cc1
Temperature: 25 °C

Procedure:
A mixed solution of 4-ethylbenzyl bromide (10.0 g), malononitrile (6.64 g), potassium carbonate (6.94 g) and tetra-n-butylammonium bromide (648 mg) in toluene (100 ml) was agitated at room temperature for 17 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate twice. The extract was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to give 2-(4-ethylphenylmethyl)malononitrile (3.28 g) as a colorless solid. (2) A solution of the above 2-(4-ethylphenylmethyl) malononitrile (1.30 g) and hydrazine hydrate (0.86 ml) in ethanol (35 ml) was heated under reflux for 4 hours. Hydrazine hydrate (0.43 ml) was further added thereto and the mixture was further heated under reflux for 4 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-diethyl ether to give 3,5-diamino-4-(4-ethylphenylmethyl)pyrazole (2.63 g) as pale pink powder. APCI-Mass m/Z 217 (M+H). (3) The above 3,5-diamino-4-(4-ethylphenylmethyl)pyrazole (1.30 g) was added to 50% aqueous phosphoric acid solution (19 ml), and further added thereto was water (10 ml). The mixture was cooled to 0° C., and thereto was added dropwise an aqueous solution (4 ml) of sodium nitrite (912 mg). The mixture was stirred at the same temperature for 30 minutes, and further stirred at room temperature for 4 hours. The reaction mixture was cooled again to 0° C., 10% aqueous sodium hydroxide solution was added thereto to adjust pH of the reaction mixture to 7. The mixture was extracted with ethyl acetate, washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10) to give the desired 4-(4-ethylphenylmethyl)pyrazole (414 mg) as a pale brown semisolid. APCI-Mass m/Z 187 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:17][CH2:18][C:19](OCC)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C>C(OCC)C>[C:7]1([CH2:17][CH2:18][CH2:19][OH:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CCc1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OCCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1.3 grams (0.033 mole) of lithium aluminum hydride in 40 mL of diethyl ether was stirred for one hour. The mixture was then cooled, and a solution of 10.0 grams (0.044 mole) of ethyl 3-(naphth-1-yl)propanoate in 35 mL of diethyl ether was added dropwise at a rate to keep the reaction mixture temperature below 25° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for one hour. The reaction mixture was again cooled, and 50 mL of ethyl acetate was added to destroy excess lithium aluminum hydride. After this time 30 mL of an aqueous 10% sodium hydroxide solution was added dropwise. The reaction mixture was then acidified with aqueous 6N hydrochloric acid, and then it was poured into 300 mL of water. The organic layer was separated, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 8.2 grams of 3-(naphth-1-yl)propanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN
Product: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CNC(=O)Oc1ccccc1

Procedure:
From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl)amide (precursor 5c) and phenyl chloroformate, according to the general working procedure followed by extraction with EA and purification by flash chromatography 55 mg of 2′-(phenoxycarbonylaminomethyl)-biphenyl-2-carboxylic acid (3-methylbutyl)amide were obtained as a resin.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([NH:16][C:17]2[CH:25]=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[N:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:12])=[CH:14][CH:15]=2)[N:5]=[C:4]([NH:16][C:17]2[CH:25]=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[N:3]=1
Reactant: Nc1nc(Nc2ccc3c(c2)OCO3)nn1-c1ccc(C(=O)O)cc1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(Nc2ccc3c(c2)OCO3)nn1-c1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.5 %

Procedure:
A mixture of 4-[5-amino-3-(benzo[1,3]dioxol-5-ylamino)-[1,2,4]triazol-1-yl]-benzoic acid (0.15 g, 0.44 mmol), morpholine (0.05 mL, 0.55 mmol) and HBTU (0.21 g, 0.55 mmol) in THF (5 mL) was stirred at room temperature for 4 h. The reaction was diluted with water, extracted with methanol/dichloromethane, dried (sodium sulfate) and evaporated. Purification by 2 successive semi-preparative HPLC's provided the title compound (0.008 g, 5% yield) as a pale pink lyophilate.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([O:9][C:10]([C:12]1[N:13]=[N:14][N:15]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[C:16]=1O)=[O:11])[CH3:8]>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]([C:12]1[N:13]=[N:14][N:15]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[C:16]=1[Cl:2])=[O:11])[CH3:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine PCl5 (5.73 g, 27.5 mmol) with a solution of 1-(3,5-bis-trifluoromethyl-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (5.30 g, 13.8 mmol) in toluene (150 mL) and heat to 50° C. After 2 h, cool to RT, concentrate solution and dissolve crude material in ether (100 mL). Wash the organic solution with saturated NaHCO3 (2×100 mL) and brine (100 mL), dry, filter, and concentrate. Purify the crude material by passing through a short plug of silica gel using a linear gradient of 50% to 80% EtOAc/hexanes, then recrystallize from 1:1 diethyl ether:petroleum ether (150 mL). MS (ES) 402.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.76 (s, 2H), 5.67 (s, 2H), 4.43 (q, 2H, J=7.0 Hz), 1.40 (t, 3H, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:13]([C:14]2[C:15]3[CH:24]=[CH:23][N:22](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]=3[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)=[CH:12][C:8]2[NH:9][N:10]=[N:11][C:7]=2[CH:6]=1.[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:13]([C:14]2[C:15]3[CH:24]=[CH:23][NH:22][C:16]=3[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)=[CH:12][C:8]2[NH:9][N:10]=[N:11][C:7]=2[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc5[nH]nnc5cc4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2cc3[nH]nnc3cc2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O
Temperature: 20 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
A solution of 4-[5-(2,4-difluorophenoxy)-1H-1,2,3-benzotriazol-6-yl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (67 mg, 0.12 mmol) in ethanol (7.1 mL) was treated with 3.0 M sodium hydroxide in water (408 μL, 1.22 mmol) and stirred at 20° C. overnight. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (21 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.01 (br s, 1H), 7.53-7.41 (m, 1H), 7.36 (s, 1H), 7.33-7.21 (m, 2H), 7.16-6.98 (m, 2H), 6.24 (d, J=2.0 Hz, 1H), 3.56 (s, 3H); LCMS calculated for C20H14F2N5O2 (M+H)+: m/z=394.1. found: 394.1.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([C:8]1[C:13]([O:14][C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].Cl>C(O)C>[F:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[N:17]=[CH:16][C:15]([O:14][C:13]1[C:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:26])=[O:3])=[N:9][CH:10]=[CH:11][CH:12]=1)=[CH:24]2
Reactant: CCOC(=O)C(C)(C)c1ncccc1Oc1cnc2c(F)cccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1ncccc1Oc1cnc2c(F)cccc2c1
Yield: 82.3 %

Procedure:
0.33 g of 2-[3-(8-fluoro-quinolin-3-yloxy)-pyridin-2-yl]-2-methylpropionic acid ethyl ester were dissolved in 1 ml of ethanol. 2 ml of 4N aqueous sodium hydroxide solution were added thereto followed by heating to reflux for 48 hours. Subsequently, dilute hydrochloric acid was added thereto followed by extracting with ethyl acetate and distilling off the solvent of the organic layer to obtain 0.25 g of 2-[3-(8-fluoro-quinolin-3-yloxy)-pyridin-2-yl]-2-methylpropionic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([CH3:28])[C:9]=1[C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][N:15]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=[C:14]2[CH:13]=1)=[O:4].O.[OH-].[Li+].Cl>CO.O>[CH3:28][N:8]1[C:9]([C:10](=[O:27])[NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=[C:14]3[CH:13]=2)=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[N:7]1
Reactant: COC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
A white suspension of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid methyl ester (2.37 g, 6.3 mmol) and lithium hydroxide monohydrate (291 mg, 6.93 mmol) in methanol (100 ml) and water (20 ml) is stirred for 5/4 hr at 70° C. giving after 20 min a colorless solution. The methanol is removed in vacuo, the residue is diluted with water and the cooled aqueous solution is neutralized with 2N aqueous hydrochloric acid (3.46 ml, 6.03 mmol). The solid is collected by filtration and dried affording 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (2.21 g, 97%) as a white solid. mp.: >300° C. MS: m/z=361.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH:9]=2)[CH2:4][CH2:3]1.[C:21]([C:23]1[O:27][C:26]([C:28](Cl)=[O:29])=[CH:25][CH:24]=1)#[N:22].CCN(C(C)C)C(C)C>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:28]([C:26]3[O:27][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[O:29])=[C:10]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: Cc1ccsc1-c1cc(N2CCN(C)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccsc1-c1cc(N2CCN(C)CC2)ccc1NC(=O)c1ccc(C#N)o1
Yield: 35.8 %

Procedure:
1-Methyl-4-[3-(3-methyl-thiophen-2-yl)-4-nitro-phenyl]-piperazine (60 mg, 0.18 mmol, as prepared in the previous step) was stirred with 40 mg 5% Pd—C in MeOH (5 mL) under H2 (1 atm) for 2 h. The reaction was filtered through Celite and concentrated in vacuo to afford 40 mg (72%) of 4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine as a brown solid, which was used immediately without further purification. Using a procedure similar to Example 9, step (c), 4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine (40 mg, 0.13 mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (30 mg, 0.19 mmol, as prepared in Example 9, step (c)) in the presence of DIEA (61 μL, 0.34 mmol) to afford 18.9 mg (36%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 2.13 (s, 3H), 2.38 (s, 3H), 2.59-2.62 (m, 4H), 3.24-3.27 (m, 4H), 6.92 (d, 1H, J=2.8 Hz), 7.06 (d, 1H, J=5.1 Hz), 7.15 (d, 1H, J=3.7 Hz), 7.19 (d, 1H, J=3.7 Hz), 7.02 (dd, 1H, J=2.8, 9.0 Hz), 7.42 (d, 1H, J=5.1 Hz), 8.11 (s, 1H), 8.34 (d, 1H, J=9.0 Hz); Mass spectrum (ESI, m/z): Calcd. for C22H22N4O2S, 407.1 (M+H). found 407.1.