Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([C:8]1[C:13]2[CH2:14][CH2:15][O:16][C:12]=2[CH:11]=[CH:10][CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:8]2[C:9](=[CH:10][CH:11]=[C:12]3[O:16][CH2:15][CH2:14][C:13]3=2)[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1cccc2c1CCO2
Reactant: O=Cc1ccccc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)NC(c2ccccc2)c2ccc3c(c21)CCO3

Procedure:
A solution of 5.0 g. of 1-isopropyl-1-(2,3-dihydro-4-benzofuranyl)urea, 3.5 ml. of benzaldehyde, 3 drops of methanesulfonic acid and 150 ml. of toluene is stirred and refluxed under a water separator for 20 hours. The resulting solution is cooled and the cooled solution is washed with 150 ml. water, dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an oil of 1-isopropyl-3,4,7,8-tetrahydro-4-phenyl-furo[2,3-h]quinazolin-2(1H)-one.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C(O)(=O)C>O>[O:11]1[C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[C:18]3[S:12][C:13](=[S:14])[NH:15][C:16]3=[O:17])=[CH:5][C:4]=2[O:9][CH2:10]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=C1CSC(=S)N1
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 78.7 %

Procedure:
Twenty grams (133.2 mmol) of piperonal were reacted with 17.74 g (133.2 mmol)of rhodanine in 38.24 g (466.2 mmol) of glacial acetic acid at reflux for about 3 hours. The mixture was then poured into water and stirred overnight. A precipitate formed which was recovered by filtration and then air dried overnight to provide 27.8 g of title product. m.p. 194°-195° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[B:16]([O:25]C(C)C)([O:21]C(C)C)[O:17]C(C)C.C([Li])CCC>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:17][B:16]([OH:25])[OH:21])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OB(O)Oc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
4-Bromochlorobenzene (70.6 g) is added into a four mouth flask connecting with a mechanical stirring apparatus, two constant pressure funnels and a temperature probe. Toluene (588.3 ml) and tetrahydrofuran (THF) (147 ml) are added under stiffing at room temperature under argon, and dissolved to obtain a colorless transparent liquid. Then triisopropyl borate (109.2 ml) and n-butyllithium (176.4 ml, 2.5M in hexane) are respectively added into two constant pressure funnels, and cooled the inner temperature to below −78° C., then n-butyllithium solution is dropped to the flask under controlling a dropping speed to keep the inner temperature below −78° C. After addition, the mixture is kept at the temperature for 1 hour, then triisopropyl borate is dropped into the mixture under the temperature below −78° C., and kept at the temperature for 1 hour after addition, and then the cooling system is removed to naturally warm up to −20° C. HCl solution (360.4 ml, 2.2M) is added to the mixture to warm up to about 10° C., and then placed for layer separation. The aqueous phase is reextracted with toluene (58.8 ml, 2 times). The organic phase is combined together and washed with saturated brine to pH=7 to obtain a colorless transparent liquid, dried with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove most of solvents and the white solid is finally precipitated, filtered to obtain a crystal of 4-chlorophenylboric acid (48 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1.[C:27]([C:29]1[CH:30]=[CH:31][C:32]([F:38])=[C:33](B(O)O)[CH:34]=1)#[N:28]>>[F:38][C:32]1[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[CH:30][C:31]=1[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: CSc1cn(-c2ncc(-c3cc(C#N)ccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Synthesized according to general procedure 1 from (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (1.0 g, 2.309 mmol, 1.0 eq) and (5-cyano-2-fluorophenyl)boronic acid (0.451 g, 2.77 mmol, 1.2 eq). Yield: 0.4 g (36% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[CH3:10])(=[O:20])=[O:19])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Reactant: Nc1cc(Br)cnc1Cl
Solvent: c1ccncc1
Product: Cc1ccc(C)c(S(=O)(=O)Nc2cc(Br)cnc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
3-Amino-5-bromo-2-chloropyridine (510 mg) in dry pyridine (7 ml) was treated with 2,5-dimethylbenzenesulfonyl chloride (962 mg) then stirred at RT overnight. The reaction was purified by prep-HPLC. The combined fractions were concentrated to give a slurry, then filtered, rising with water and dried overnight to give title compound (441 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:17](CC1C=CC=CC=1)[C@@H](C1C=CC=CC=1)C)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([F:16])[CH:8]=1)[CH3:2]>CCO.CC(O)=O.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH:6]([NH2:17])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([F:16])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(c1ccc(OCC)c(F)c1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC(N)c1ccc(OCC)c(F)c1
Reaction time: 12 h

Procedure:
A solution of the dibenzylamine 15-4 (30.0 gm, 66.8 mmol) in EtOH/HOAc (340/30 mL) was purged with argon and treated with Pd(OH)2 (6 g) and placed under 1 atm of H2 for 12 h. Additional portions (2.5 g) of Pd(OH)2 were added after 24 h and 48 h. The reaction mixture was purged with argon, filtered through Celite, and the filtrate collected. The filtrate was concentrated to yield the desired amine 15-5.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1)#[CH:2].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[N:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[N+:25]=[N-:26]>C(O)(C)(C)C.O>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([C:1]2[N:26]=[N:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=3)[CH:2]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: C#Cc1cccc(OC)c1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cccc(-c2cn(-c3ccc(C(=O)O)cc3)nn2)c1
Reaction time: 168 h
Yield: 99.3 %

Procedure:
To a solution of 1-ethynyl-3-methoxybenzene (396 mg, 3.00 mmol, Aldrich) in 50% tert-butanol/water (4.0 mL) is added 300 μL (0.30 mmol) of an aqueous solution of sodium ascorbate (594 mg in 3 mL H2O), 100 μL (0.030 mmol) of an aqueous CuSO4.5H2O solution (75 mg in 1 mL H2O), followed by 4-azidobenzoic acid (489 mg, 3 mmol). The resulting mixture is stirred for 7 days, the resulting suspension filtered and washed with H2O (3×30 mL), Et2O (2×15 mL), and hexanes (3×30 mL). The solid is dried overnite in vacuo (70° C., 10 torr) to afford 880 mg (99%) of 4-[4-(3-methoxy-phenyl)-[1,2,3]triazol-1-yl]benzoic acid as a pale yellow powder: m.p. 276-277° C. 1H NMR (300 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.16 (d, J=8.5 Hz, 2H), 8.08 (d, J=8.3 Hz, 2H), 7.52 (m, 2H), 7.40 (t, J=7.8 Hz, 1H), 6.95 (ddd, J=8.3, 2.5, 0.8 Hz, 1H), 3.82 (s, 3H). MS m/z 296.29, calcd for C16H13N3O3 (M+H+) 296.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][N:9](C(OC(C)(C)C)=O)[C:8](=[O:18])[CH2:7][C:6]1=[O:19])[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([CH:5]1[CH2:10][NH:9][C:8](=[O:18])[CH2:7][C:6]1=[O:19])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1CN(C(=O)OC(C)(C)C)C(=O)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC1CNC(=O)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A mixture of rac-tert-butyl 5-isobutyl-2,4-dioxopiperidine-1-carboxylate (300 mg, 1.115 mmol), DCM (1 mL), and TFA (0.1 mL) was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo and chromatographically purified (basic alumina, 40% EtOAc/petroleum ether) to afford rac-5-isobutylpiperidine-2,4-dione (85 mg, 45% yield) as a pale yellow solid: m/z (ESI, +ve) 170 (M+H)+.
Reaction SMILES: C1(OC)C=CC=CC=1.[N+:9]([C:12]1[CH:28]=[CH:27][C:15]2[O:16][C:17]3[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][C:18]=3[O:19][C:14]=2[CH:13]=1)([O-])=O.[H][H]>[Pd].C1COCC1>[NH2:9][C:12]1[CH:28]=[CH:27][C:15]2[O:16][C:17]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][C:18]=3[O:19][C:14]=2[CH:13]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)Oc1cccc([N+](=O)[O-])c1O2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: COc1ccccc1
Product: Nc1ccc2c(c1)Oc1cccc(N)c1O2
Reaction time: 8 h
Yield: 98 %

Procedure:
To a mixture of 1000 ml of anisole and 1000 ml of THF were added 81 g (0.295 mole) of 2,6-dinitrodibenzodioxin and 25 g of 10% palladium/carbon and hydrogen gas was passed through the mixture for 8 hours at room temperature with stirring. The 10% palladium/carbon was filtered and rinsed with THF. The filtrate and the rinsings were mixed, concentrated, and dried under reduced pressure to give 61.9 g (0.289 mole) of 2,6-diaminodibenzodioxin in a 98.0% yield. The product showed a purity of 94.2 area % (HPLC, 254 nm).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][OH:32])=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].[Br:35][C:36]1[CH:37]=[N:38][C:39](Cl)=[N:40][CH:41]=1>C1COCC1.CC(N(C)C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:39]4[N:40]=[CH:41][C:36]([Br:35])=[CH:37][N:38]=4)=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2C)nc1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Br)cn3)nn2C)nc1
Reaction time: 0.08 h
Yield: 24.9 %

Procedure:
To a solution of N-[4-(1,3-benzodioxol-5-yl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (Example 43) (18 mg) in anhydrous THF (0.5 ml) at 0° C. and under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 3.3 mg) and the mixture was stirred for 5 minutes. To the mixture was added 5-bromo-2-chloropyrimidine (Liquid Crystals, 1993, 14(3), 741) (11.3 mg) in dimethylacetamide (0.1 ml). After stirring for 90 min, the reaction mixture was partitioned between ethyl acetate (3 ml) and saturated ammonium chloride solution (5 ml). The ethyl acetate layer was dried (MgSO4) and blown down under nitrogen to afford a gummy residue. Purification of the residue by column chromatography on silica gel (5 g), eluting in an isocratic fashion with ethyl acetate:hexane (7:4) afforded the title compound as a white solid (6 mg) after freeze drying from t-butanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:18]([O:22][C:23](=[O:39])[NH:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:32]=2[F:38])[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].Cl.C(N=C=NCCCN(C)C)C.ClCCl>CN(C)C1C=CN=CC=1.O>[C:18]([O:22][C:23](=[O:39])[NH:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:33][C:32]=2[F:38])[CH2:27][CH2:26]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COCCOCOc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cc2F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COCCOCOc1ccc(Cl)cc1C(=O)Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
A mixture of 5-chloro-2-(2-methoxyethoxymethoxy)benzoic acid (compound of Reference Example 140; 0.18 g, 0.7 mmol), [1-(4-amino-2-fluorophenyl)piperidin-4-yl]carbamic acid tert-butyl ester (compound of Reference Example 90; 0.28 g, 0.9 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g, 0.9 mmol), 4-dimethylaminopyridine (0.01 g) and dichloromethane (5 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (0.27 g, 70%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7]1[C:12]([S:13](Cl)(=[O:15])=[O:14])=[CH:11][CH:10]=[C:9]([I:17])[CH:8]=1.Cl.S1C(N)=NC=N1>N1C=CC=CC=1>[I:17][C:9]1[CH:8]=[CH:7][C:12]([S:13]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:15])=[O:14])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: Nc1nccs1
Agent: Cl
Agent: Nc1ncns1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 37.9 %

Procedure:
To a stirring solution of 2-aminothiazole (13.2 g, 132.2 mmol) and pyridine (20 mL) under N2, at 0° C., was added pipsyl chloride (20.0 g, 55.1 mmol). The mixture was stirred at ambient temperature for 17 hours. CH2Cl2/MeOH-2/1 (100 mL) was added. The mixture was filtered and the filtrate was purified via silica gel chromatography using 5% MeOH in CH2Cl2. The solid was triturated with CH2Cl2 to obtain the desired sulfonamide as a white solid (8.4 g, 20.9 mmol, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.94-7.90 (m, 2H), 7.57-7.54 (m, 2H), 7.26 (d, J=4.6 Hz, 1H), 6.86 (d, J=4.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]1[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[C:15]([CH3:22])=[N:14]1.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]1[C:17]([CH3:18])=[C:16]([C:19]([N:31]2[CH2:32][CH2:33][CH:28]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:29][CH2:30]2)=[O:21])[C:15]([CH3:22])=[N:14]1
Reactant: COc1ccc(C(F)(F)F)cc1-n1nc(C)c(C(=O)O)c1C
Reactant: C1CCN(C2CCNCC2)C1
Product: COc1ccc(C(F)(F)F)cc1-n1nc(C)c(C(=O)N2CCC(N3CCCC3)CC2)c1C
Yield: 27 %

Procedure:
In analogy to the procedure described in Example 18], 1-(2-methoxy-5-trifluoromethyl-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave, after purification on a flash isolute NH2-column (EtOAc:n-heptane 4:1), the title compound in 27% yield as yellow oil. MS: 451.2 (MH+).
Reaction SMILES: O=[C:2]([C:6]1([C:9]([F:12])([F:11])[F:10])[CH2:8][CH2:7]1)[CH2:3][C:4]#[N:5].[OH-].[Na+].Cl.[C:16]1([CH3:24])[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1>CCO.O>[C:16]1([CH3:24])[CH:21]=[CH:20][C:19]([N:22]2[C:4]([NH2:5])=[CH:3][C:2]([C:6]3([C:9]([F:10])([F:11])[F:12])[CH2:8][CH2:7]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(NN)cc1
Reactant: N#CCC(=O)C1(C(F)(F)F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-n2nc(C3(C(F)(F)F)CC3)cc2N)cc1
Temperature: 80 °C
Yield: 57.4 %

Procedure:
To a solution of 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (500 mg, 2.8 mmol) (from Example 137A Step 2) in EtOH (10 mL) was added water (7.2 mL) and 1 M NaOH (2.8 mL) followed by p-tolylhydrazine hydrochloride (444 mg, 2.8 mmol) and the solution heated at 80° C. overnight. The solution was cooled to rt, diluted with water and extracted with 2 portions of EtOAc. The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude solid was purified using silica gel chromatography using a gradient of 5-25% EtOAc/hexane to give 1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (452 mg, 57% yield). LC-MS (ESI) m/z 282 (M+H)+
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[B:20](OC)([O:23]C)[O:21]C.Cl>O1CCCC1.C(OCC)C>[F:18][C:13]([F:19])([C:10]1[CH:11]=[CH:12][C:7]([B:20]([OH:23])[OH:21])=[CH:8][CH:9]=1)[C:14]([F:17])([F:16])[F:15]
Reactant: COB(OC)OC
Reactant: FC(F)(F)C(F)(F)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C(F)(F)C(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
A 1.5 M solution of n-butyllithium in tetrahydrofuran (0.57 mL) was added to a solution of 1-bromo-4-pentafluoroethylbenzene (180 mg, 0.65 mmol) in diethyl ether (1.0 mL) at −78° C., and the mixture was stirred for 20 minutes. Thereafter, trimethyl borate (101 mg, 3.28 mmol) was added and the mixture was stirred at −78° C. for 10 minutes and at room temperature for 30 minutes. 6 N aqueous hydrochloric acid (200 μL) was added to the reaction mixture, and the reaction was terminated. The mixture was then purified by silica gel column chromatography to give 4-pentafluoroethylphenylboronic acid as a white solid (111 mg, 71%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([O:20]C)=[O:19].[OH-].[Na+]>O.C(O)(=O)C>[CH3:22][N:2]([CH3:1])[C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)c1c(CC(=O)O)cccc1C(=O)c1ccccc1

Procedure:
A mixture of 500 mg. (1.85 mmole) of methyl 2-dimethylamino-3-benzoylphenylacetate and 15 ml. of 3 N sodium hydroxide was refluxed for 1.5 hr. under nitrogen. The cooled filtered reaction mixture was diluted with an equal volume of water and neutralized with glacial acetic acid. The precipitate which formed could not be recrystallized and was therefore dissolved in benzene and placed on a magnesium silicate column. The column was eluted with benzene-acetone to give 300 mg. of product which melted at 144°-146° C. after recrystallization from benzene-isooctane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:18][O:19][CH2:20][C:21](O)=O>C(OCC)(=O)C>[CH3:16][C:14]([CH3:15])([OH:17])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:21]1[CH2:20][O:19][CH3:18]
Reactant: COCC(=O)O
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Solvent: CCOC(C)=O
Product: COCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Temperature: 170 °C
Yield: 9.9 %

Procedure:
3-Amino-4-(2-hydroxy-2-methylpropylamino)quinoline (7.5 g, 32 mmol) was combined with methoxyacetic acid (7.5 mL, 97 mmol) and heated at about 170° C. for about 3 hours. The resulting solid residue was dissolved in ethyl acetate (150 mL). The ethyl acetate solution was extracted twice with 0.2 N sodium hydroxide, washed with water, dried over magnesium sulfate, treated with activated charcoal and then concentrated to a volume of about 50 mL. Hexane was added to the ethyl acetate and the resulting precipitate was collected and dried to provide 0.9 g of the desired product as a crystalline solid, m.p. 145-148° C. Analysis: Calculated: %C, 67.3; %H, 6.7; %N, 14.7; Found: %C, 67.2; %H, 6.6; %N, 14.6.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12](=[O:13])[C:11]3([CH2:25][C:16]4=[N:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]4[CH2:14]3)[N:10]([CH3:26])[C:9]2=[O:27])=CC=1>C(#N)C.O>[CH3:26][N:10]1[C:11]2([CH2:25][C:16]3=[N:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]3[CH2:14]2)[C:12](=[O:13])[NH:8][C:9]1=[O:27]
Reactant: COC(=O)c1cnc2c(c1)CC1(C2)C(=O)N(Cc2ccc(OC)cc2)C(=O)N1C
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cnc2c(c1)CC1(C2)C(=O)NC(=O)N1C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 1′-(4-methoxybenzyl)-3′-methyl-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxylate (100 mg, 0.25 mmol) in acetonitrile (8.4 mL) at ambient temperature was added ceric ammonium nitrate (4.1 g, 7.6 mmol) as a solution in H2O (5 mL). After 20 min, the reaction mixture was partitioned between H2O (50 mL) and 9:1-CH2Cl2:i-PrOH (50 mL). The aqueous was extracted further with 9:1 CH2Cl2:i-PrOH (5×50 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude solid was washed with MTBE (3×10 mL) then partitioned between saturated aqueous sodium bicarbonate (5 mL) and EtOAc (10 mL). The aqueous layer was extracted further with EtOAc (10 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound in sufficient purity for use in the next step. MS: m/z=276.1 (M+1).
Reaction SMILES: B(Cl)([C@H]1[C@H](C)C2C(C)(C)C(CC2)C1)[C@H]1[C@H](C)C2C(C)(C)C(CC2)C1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:33](=[O:40])[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:30]=[CH:31][CH:32]=1.N(CCO)CCO>C1COCC1>[OH:40][C@H:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=1)[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]
Reactant: COC(=O)CCC(=O)c1cccc(OC)c1
Agent: C[C@@H]1C2CCC(C[C@H]1B(Cl)[C@@H]1CC3CCC([C@H]1C)C3(C)C)C2(C)C
Solvent: OCCNCCO
Solvent: C1CCOC1
Product: COC(=O)CC[C@H](O)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 78 %

Procedure:
A dried, 25 mL round-bottom flask equipped magnetic stirring bar is cooled to room temperature under a stream of nitrogen. To this is added (−)-DIP-Chloride (6.76 mmol, 2.17 g, 1.2 eq) and THF (10 mL), and the mixture is cooled to −25° C., followed by the addition of methyl 4-(3-methoxyphenyl)-4-oxobutanoate (5.63 mmol). The resulting mixture is then stirred at −20° C. to −30° C. for 10 h. Then, diethanolamine (12.39 mmol, 2.2 eq) is added at −20° C., and the mixture is warmed to room temperature and stirred overnight. This mixture is then filtered, evaporated, and the residue is purified on silica gel (0-33% ethyl acetate in hexane) to give (S)-methyl 4-hydroxy-4-(3-methoxyphenyl)butanoate (985 mg, 79%; >95% based on recovered starting material) as a clear colorless oil. 1H NMR (CDCl3) δ 7.33-7.27 (m, 1H), 6.92-6.84 (m, 3H), 5.52-5.46 (m, 1H), 3.82 (s, 1H), 3.48 (s, 1H), 2.71-2.61 (m, 3H), 2.26-2.12 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]1([S:15]([C:18](=[CH:23]OCC)[C:19](OC)=[O:20])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C2C=CC=CC=2)C=CC=CC=1.CCOCC>[OH:20][C:19]1[C:5]2[C:3](=[C:2]([F:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=[CH:23][C:18]=1[S:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: Nc1ccccc1F
Reactant: CCOC=C(C(=O)OC)S(=O)(=O)c1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)c1cnc2c(F)cccc2c1O
Temperature: 260 °C
Reaction time: 6 h
Yield: 3.3 %

Procedure:
2-Fluoroaniline 7(1) (3.82 g, 0.0344 mol) and methyl 2-phenylsulfonyl-3-ethoxy-acrylate 7(2) (9.59 g, 0.0355 mol) were mixed together in biphenyl ether (21.5 ml). The mixture was stirred in an opened flask for 6 h at 250-270° C. Ethanol was distilled during the first 30 min. After the reaction was completed (LCMS control) the mixture was cooled, the formed solid was filtered off, dissolved in ethanol and solution was boiled with charcoal. After filtration from charcoal ethanol was evaporated, the residue was subjected to chromatography on silica, eluent—gradient of solvent system CHCl3:ethyl acetate=from 10:1 to 5:1. The residue after evaporation of fractions, comprising the final product was washed with ether, it gave 345 mg (3.3%) of 4-hydroxy-3-phenylsulfonyl-8-fluoroquinoline 7(3).