Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[NH:9][CH2:8][CH2:7]2.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>ClCCCl.CO>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=1)[N:9]([C:39]([NH:38][C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1)=[O:40])[CH2:8][CH2:7]2
Reactant: Fc1cccc2c1C(c1ccc(C(F)(F)F)cc1)NCC2
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CO
Product: O=C(Nc1ccc(F)cc1)N1CCc2cccc(F)c2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 8-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.4 g, 1.4 mmol) and diisopropylethylamine (0.5 mL, 2.9 mmol) in anhydrous 1,2-dichloroethane (10 mL) was treated with 4-fluorophenyl isocyanate (0.14 mL, 1.2 mmol) and stirred at RT for 16 h. The solvent was removed under vacuum and the residue was purified by preparative HPLC [gradient 10-90% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give the pure product which was dissolved in methanol (10 mL) and neutralized by passing the solution through a Polymer Lab-HCO3 Macroporous resin cartridge, and the filtrate was concentrated to give 8-fluoro-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 433 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:24]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccccc1Cl
Yield: 36.4 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and 2-chlorobenzoyl chloride (Aldrich, 0.26 g, 1.4 mmol) in 15 mL THF were processed as in Example 132 to afford the title compound (0.13 g, 0.40 mmol, 37% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.28 (s, 3H), 2.32 (s, 3H), 3.31 (s, 3H), 3.76 (t, J=5.3 Hz, 2H), 4.42 (t, J=5.1 Hz, 2H), 7.30-7.46 (m, 3H), 7.77-7.83 (m, 1H); MS (DCI/NH3) m/z 325 (M+H)+; Anal. calculated for C15H17ClN2O2S: C, 55.46; H, 5.28; N, 8.62. Found: C, 55.59; H, 4.81; N, 8.47.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH2:26]([NH2:28])[CH3:27].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:28][CH2:26][CH3:27])=[O:11])[CH:7]=1
Reactant: CCN
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 3 h

Procedure:
To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (500 mg, 1.4 mmol) and ethyl amine (2.1 mg, 4.2 mmol) in DMF (5 ml), added PyBOP (730 mg, 1.4 mmol) then triethyl amine (0.4 ml, 3 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as white powder. MS calcd for (C17H20BN3O5S): 389.12. MS found (ESI negative): (M−H)−=388.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.86 (s, 1H), 9.15 (br, 1H), 7.98 (m, 1H), 7.41 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 7.09 (dd, J=8.4 Hz, 1H), 6.44 (d, J=2 Hz, 1H), 6.33 (dd, J=8.8 Hz, 1H), 4.85 (s, 2H), 3.75 (s, 2H), 3.09 (m, 1H), 1.02 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]2[C:10]=1[C:11]([CH3:21])=[C:12]([CH3:20])[NH:13]2)C1C=CC=CC=1.C1CCCCC=1>[Pd].C(O)C>[CH3:20][C:12]1[NH:13][C:14]2[C:10]([C:11]=1[CH3:21])=[C:9]([OH:8])[CH:17]=[CH:16][C:15]=2[O:18][CH3:19]
Reactant: COc1ccc(OCc2ccccc2)c2c(C)c(C)[nH]c12
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1ccc(O)c2c(C)c(C)[nH]c12

Procedure:
0.14 mole (39.5 g) of 4-benzyloxy-2,3-dimethyl-7-methoxyindole and 4 g of 10% palladium-on-charcoal in 120 ml of 96° ethanol to which has been added 80 ml of cyclohexene is heated under reflux. After 1 hour 30 minutes the catalyst is removed by hot filtration. The desired product is obtained by concentrating the filtrate to dryness. It is purified by dissolving it hot in isopropyl ether, filtering in the presence of charcoal and evaporating the filtrate to dryness. It melts at 164° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:10][C:9]3[CH:12]=[CH:13][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[CH:7][CH:8]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: O=Cc1ccc(-c2cccs2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4cccs4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(2-thienyl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 419.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]=1[O:15]COC)[CH2:10][NH2:11].[CH3:23][S:24][C:25]1[CH:30]=[CH:29][C:28]([N:31](C2C=CC([N+]([O-])=O)=CC=2)[C:32](=O)[O-:33])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:8]=[C:9]([CH2:10][NH:11][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([S:24][CH3:23])=[CH:26][CH:27]=2)=[O:33])[CH:12]=[C:13]([C:19]([CH3:21])([CH3:20])[CH3:22])[C:14]=1[OH:15]
Reactant: COCOc1c(-c2sccc2C)cc(CN)cc1C(C)(C)C
Reactant: CSc1ccc(N(C(=O)[O-])c2ccc([N+](=O)[O-])cc2)cc1
Solvent: Cc1ccccc1
Product: CSc1ccc(NC(=O)NCc2cc(-c3sccc3C)c(O)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61.9 %

Procedure:
To a solution of 4.2 g (12.2 mmol) of the compound of Example 3 dissolved in 50 ml of toluene were added 3.70 g (12.2 mmol) of the compound of Example 12. The resulting solution was heated to reflux, stirred at that temperature for 45 minutes and then cooled to room temperature. Any solid particulates which had precipitated upon cooling were removed by filtration and the filtrate was concentrated to dryness to provide a residue. This residue was purified by column chromatography (10-40% ethyl acetate in hexane gradient as eluent) and fractions containing the desired product were combined and concentrated to dryness to provide 3.33 g of title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=3)[C:21]=2[OH:22])=[C:13]([CH3:32])[CH:12]=1)#[N:10].C(O)=O>>[OH:22][C:21]1[N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([N:5]3[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:28])=[CH:25][N:24]=2)[N:19]=[CH:18][C:17]=1[C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][C:13]=1[CH3:32]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCCNCC1
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCCN(C)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using 1-methyl-1,4-diazepane and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (67 mg, 0.145 mmol, 77%) as an off-white solid. MS: 417 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88 (br. s., 2 H) 2.35 (s, 3 H) 2.54 (br. s., 2 H) 2.86 (d, J=17.7 Hz, 3 H) 3.01 (br. s., 1 H) 3.39-3.76 (m, 5 H) 7.45 (d, J=8.1 Hz, 1 H) 7.50 (s, 1 H) 7.78-7.91 (m, 2 H) 8.04 (d, J=7.6 Hz, 1 H) 8.42 (br. s., 2 H) 11.65 (br. s., 1 H)
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:27])[CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31](S(O)(=O)=O)=[CH:30][CH:29]=1>C(O)C1C=CC=CC=1>[CH:1]([CH:14]1[CH2:15][CH2:16][N:17]([C:20](=[O:27])[CH2:21][O:22][CH2:23][C:24]([O:26][CH2:38][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:18][CH2:19]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)COCC(=O)N1CCC(C(c2ccccc2)c2ccccc2)CC1
Solvent: OCc1ccccc1
Product: O=C(COCC(=O)N1CCC(C(c2ccccc2)c2ccccc2)CC1)OCc1ccccc1

Procedure:
In a similar operation, 3.63 grams (10 millimoles) of [2-(4-benzhydrylpiperidino)-2-oxoethoxy]acetic acid, 50 milliliters of benzyl alcohol and 150 milligrams of p-toluenesulfonic acid are mixed together and the resulting mixture heated at reflux temperature for about 6 hours to obtain a product in the reaction mixture. Thereafter, the reaction mixture subjected to reduced pressure to evaporate the alcohol and the residue is dissolved in benzene, the resulting solution washed with bicarbonate solution, dried and the solvent evaporated to obtain a benzyl [2-(4-benzhydrylpiperidino)-2-oxoethoxy]acetate product. The molecular weight of benzyl [2-(4-benzhydrylpiperidino)-2-oxoethoxy]acetate is 453.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1Cl.[CH:15]1([CH2:18][O-:19])[CH2:17][CH2:16]1.[Na+]>CS(C)=O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:19][CH2:18][CH:15]1[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: [O-]CC1CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCC2CC2)c(C(F)(F)F)c1
Temperature: 10 °C
Yield: 42.1 %

Procedure:
To a cooled (10° C.) solution containing 22.5 g (0.1 mole) of 3-(trifluoromethyl)-4-chloronitrobenzene in 100 ml of DMSO was added with stirring at ambient temperature a solution containing 0.11 mole of sodium cyclopropylmethoxide (prepared by dissolving 4.9 g of 57% sodium hydride in 7.9 g of cyclopropylmethanol and 50 ml of tetrahydrofuran) in 100 ml of DMSO. The reaction mixture was heated at 50° C. for one hour, poured into ice water and filtered. Recrystallization of the filter cake from hexane gave 11.0 g (42%) of product as a white crystalline solid, m.p. 41°-44° C.
Reaction SMILES: C(OC([N:8]([CH2:34][C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[CH:36]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[C:20]([C:29]([O:31][CH3:32])=[O:30])=[CH:19][C:18]2=[O:33])[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:39]1[C:38]2[CH:43]=[CH:44][C:35]([CH2:34][NH:8][CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=5)[C:20]([C:29]([O:31][CH3:32])=[O:30])=[CH:19][C:18]4=[O:33])[CH2:13][CH2:14]3)=[CH:36][C:37]=2[O:42][CH2:41][CH2:40]1
Reactant: COC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC)ccc12
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Reaction time: 16 h
Yield: 57.5 %

Procedure:
To 2 mL of a chloroform solution containing 0.25 g of methyl 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate, 2 mL of trifluoroacetic acid was added and stirred for 16 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and chloroform were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to give 0.12 g of methyl 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate as a white solid.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.I[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu](I)I>[CH3:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][N:8]=[CH:7][CH:6]=2)[C:1]1=[O:11]
Reactant: O=C1NCCc2ccncc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccncc2C1=O
Yield: 12.4 %

Procedure:
3,4-Dihydro-2,7-naphthyridin-1(2H)-one (I-65f: 80 mg, 0.5399 mmol) was reacted with 3-iodo-4-methylpyridine (177 mg, 0.8099 mmol), copper iodide (8 mg, 10% w/w), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (16 mg, 20% w/w) and potassium phosphate (287 mg, 1.3498 mmol) in 1,4-dioxane (5 mL) to afford the crude product. Purification by column chromatography on silica gel (3% methanol in CHCl3), followed by preparative HPLC afforded 16 mg of the product (12.4% yield).
Reaction SMILES: [CH3:1][C:2]1[O:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O.[CH2:17]([OH:20])[CH:18]=[CH2:19]>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[O:8][C:5]([C:6]([O:20][CH2:17][CH:18]=[CH2:19])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C=O)o1
Reactant: C=CCO
Solvent: ClC(Cl)(Cl)Cl
Product: C=CCOC(=O)c1ccc(CBr)o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-methylfurfural (18 mL, 0.18 mmol) in CCl4 (400 mL) is added pulverized N-bromosuccinimide (71.1 g, 0.40 mmol), and the solution is subjected to sun lamp irradiation. After 15 minutes, the solution begins to reflux vigorously, and then settles down after another 2-3 minutes. After an additional 10 minutes, the dark mixture is cooled to room temperature, and allyl alcohol (200 mL) is added. After 2 hours, the solution is evaporated, and the residue is diluted with Et2O, and washed with saturated NaHCO3 (100 mL), water (100 mL) and brine (100 mL), dried over MgSO4 and evaporated. The residue is chromatographed (silica, 4% EtOAc/hexane) to yield allyl 5-(bromomethyl)-2-furoate, as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH:14]1[CH2:13][CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16]1([N:19]2[C:28]3[C:23](=[CH:24][C:25]([F:30])=[C:26](F)[CH:27]=3)[C:22](=[O:31])[C:21]([C:32]([OH:34])=[O:33])=[CH:20]2)[CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH:14]1[CH2:13][CH2:12][N:11]([C:26]1[CH:27]=[C:28]3[C:23]([C:22](=[O:31])[C:21]([C:32]([OH:34])=[O:33])=[CH:20][N:19]3[CH:16]3[CH2:18][CH2:17]3)=[CH:24][C:25]=1[F:30])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC12CNCCC1C2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: CC(C)(C)OC(=O)NC12CC1CCN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 65 %

Procedure:
According to the procedure of Example 34A, 1-tert-butoxycarbonylamino-3-azabicyclo[4.1.0]heptane (270.0 mg, 1.27 mmol) and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (275.6 mg, 1.03 mmol were reacted to generate the title compound (304.2 mg, 0.666 mmol, 65%).
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:9])=[N:5][S:6][C:7]=1[Cl:8])#[N:2].[F:10][S:11]([O:14][CH3:15])(=[O:13])=[O:12]>>[F:10][S:11]([O-:14])(=[O:13])=[O:12].[C:1]([C:3]1[C:4]([Cl:9])=[N+:5]([CH3:15])[S:6][C:7]=1[Cl:8])#[N:2]
Reactant: COS(=O)(=O)F
Reactant: N#Cc1c(Cl)nsc1Cl
Product: C[n+]1sc(Cl)c(C#N)c1Cl
Product: O=S(=O)([O-])F
Yield: 92 %

Procedure:
4-Cyano-3,5-dichloroisothiazole (5.0 g, 0.028 mol) and 4 ml of methyl fluorosulfonate were heated at 80°-90° for 30 min under a nitrogen atmosphere. The resulting solid was washed with ether and benzene to yield 7.5 g (92%) of 4-cyano-3,5-dichloro-2-methylisothiazolium fluorosulfonate, mp 160-170. Spectral data (NMR and IR) were consistent with the assigned structure. Analysis calculated for C5H3Cl2FN2O3S2 : C, 20.50; H, 1.02; Found: C, 20.27; H, 1.44.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[NH2:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:24]=[N:25][N:26]([CH2:28][C@H:29]([OH:33])[C:30]([NH2:32])=[O:31])[CH:27]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1>O1CCOCC1.O>[F:9][CH:8]([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:15][C:16]2[CH:17]=[C:18]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][C@H:29]([OH:33])[C:30]([NH2:32])=[O:31])[CH:27]=3)[CH:19]=[C:20]([CH3:22])[CH:21]=2)[N:7]=1
Reactant: FC(F)c1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(-c2cnn(C[C@H](O)C(N)=O)c2)c1
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(C[C@H](O)C(N)=O)c2)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
2-Chloro-4-(difluoromethyl)pyrimidine (24.8 mg, 0.12 mmol) and acetic acid (0.0074 mL, 0.130 mmol) were added to an oven-dried flask containing (2S)-3-[4-(3-amino-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanamide (46.2 mg, 0.12 mmol) dissolved in dioxane (0.41 mL). The mixture was stirred for 3 hours at 120° C. The mixture was then cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (2 to 100% EtOAc/hexanes) to afford (2S)-3-[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanamide. MS ESI calcd. for C18H19F2N6O2 [M+H]+ 389. found 389. 1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.68 (d, J=4.9 Hz, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 7.32 (s, 1H), 7.04 (d, J=4.9 Hz, 1H), 7.01 (s, 1H), 6.87 (t, J=54.4 Hz, 1H), 5.86 (d, J=5.9 Hz, 1H), 4.41-4.33 (m, 1H), 4.24-4.18 (m, 1H), 4.17-4.13 (m, 1H), 2.28 (s, 3H).
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[C:14]([CH3:16])[O:13][C:12](=[O:17])[C:11]=2[CH:18]=1)(=O)C.C1(N=C=NC2CCCCC2)CCCCC1>O.CO.C1COCC1>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[C:14]([CH3:16])[O:13][C:12](=[O:17])[C:11]=2[CH:18]=1
Reactant: CC(=O)Oc1ccc2nc(C)oc(=O)c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nc2ccc(O)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.1 %

Procedure:
Sodium hydroxide (4 g. 0.1 mol) was dissolved in water (4 ml) and methanol (50 ml). The 6-acetoxy-2-methyl (4H)3,1-benzoxazin-4-one (8.2 g, 0.04 mol), prepared above, in methanol (30 ml) was added, and the mixture refluxed for 3 hours. The solvent was removed by evaporation and the resulting sodium salt dissolved in water and acidified with hydrochloric acid. 5-Hydroxy N-acetyl anthranilic acid was collected as a beige solid and dried under vacuum. The dry solid (7.8 g, 0.04 mol) was then dissolved in dry THF (100 ml) and added to dicyclohexylcarbodiimide (8.24 g, 0.04 mol) in dry THF (50 ml). The mixture was stirred at room temperature for 18 hours and the insoluble urea removed by filtration. The filtrate was evaporated to dryness to give 6-hydroxy-2-methyl (4H)3,1-benzoxazin-4-one (2.7 g, 38%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](Cl)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.CN(C)C=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccc(C)cc3)c2c1
Reactant: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCOc1ccc2nc(N3CCCCC3)n(-c3ccc(C)cc3)c2c1
Temperature: 110 °C
Reaction time: 7.5 h

Procedure:
240 mg of 6-[[2-chloro-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was mixed with 0.2 ml of N,N-dimethylformamide and 0.75 ml of piperidine, and the mixture was stirred for 7.5 hours at 110° C. Another 0.75 ml of piperidine was added, and it was heated for another 4 hours at 110° C. It was mixed with water, extracted with ethyl acetate, the organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 16 mg was obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:4]1.[OH:24][C:25]1([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:34][N:33]=2)[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C(C)C>[OH:24][C:25]1([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:39]=[CH:40][CH:41]=[CH:42][N:43]=3)=[CH:34][N:33]=2)[CH2:30][CH2:29][CH:28]([NH:2][C@H:3]2[CH2:7][CH2:6][N:5]([C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[CH2:4]2)[CH2:27][CH2:26]1
Reactant: N[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Reactant: O=C1CCC(O)(c2ccc(-c3ncccn3)cn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)CO
Solvent: CCN(CC)CC
Product: O=C(NCC(=O)N1CC[C@H](NC2CCC(O)(c3ccc(-c4ncccn4)cn3)CC2)C1)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a solution of N-{2-[(3S)-3-aminopyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide hydrochloride (22.10 g, 47.1 mmol) and 4-hydroxy-4-(5-pyrimidin-2-ylpyridin-2-yl)cyclohexanone (12.7 g, 47.1 mmol) in isobutyl alcohol (80.0 mL) was added triethylamine (19.7 mL, 141 mmol). The reaction mixture was cooled in an ice bath and stirred for 30 minutes. To it was added sodium triacetoxyborohydride (11.0 g, 51.8 mmol) in portion. After being stirred at room temperature for 4 hours, the solvent was removed by evaporation under reduced pressure. Saturated aqueous NaHCO3 solution was added and the solution was extracted with ethyl acetate (150×3). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was columned on silica gel, eluting with ethyl acetate (1% NH4OH aqueous solution)/methanol (95/5 to 80/20). The appropriate fractions were combined and concentrated to give the title compound as a white powder (17.77 g). MS (M+H) 569.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N:34]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[O:47][CH3:48])=[C:35]=O.[CH3:49][C:50]1[C:51]2[CH:52]=[C:53]3[CH2:62][NH:61][CH2:60][CH2:59][N:54]3[C:55]=2[CH:56]=[CH:57][CH:58]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:35]([N:61]1[CH2:60][CH2:59][N:54]3[C:55]4[CH:56]=[CH:57][CH:58]=[C:50]([CH3:49])[C:51]=4[CH:52]=[C:53]3[CH2:62]1)[N:34]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[O:47][CH3:48])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: Cc1cccc2c1cc1n2CCNC1
Reactant: COC(=O)/C=C/c1cccc(F)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCn3c(cc4c(C)cccc43)C2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting with 563 mg (1.2 mmol) of the iminophosphorane from Example 12A, 268 mg (1.2 mmol) of 2-isocyanato-1-methoxy-4-(trifluoromethyl)benzene and 230 mg (1.2 mmol) of 9-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole from Example 31A, the general procedure [M] gives 325 mg (42% of theory) of product.