Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[CH:3]=1.[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Sn](CCCC)(CCCC)CCCC)[N:42]=2)[CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[N:42]=[C:43]([C:6]3[CH:5]=[C:4]([C:16]4[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:44]=[CH:45][CH:46]=2)[CH:36]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)n1
Reactant: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cc(OS(=O)(=O)C(F)(F)F)n1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Temperature: 25 °C

Procedure:
A stirred mixture of trifluoro-methanesulfonic acid 6-methyl-4-(4-trifluoromethoxyphenyl)-pyridin-2-yl ester (Example A.63) (0.221 g, 0.55 mmol), N-tert-butyl-3-(6-tributylstannanyl-pyridin-2-yl)-benzenesulfonamide (Example F.6) (0.290 g, 0.50 mmol), tetrakis(triphenyl-phosphine)palladium (0.032 g, 5 mol %) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, extracted with ethyl acetate and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the title compound after trituration with diethyl ether as a white solid (100 mg, 34%). MS (ISP) 542.8 [(M+H)+]; mp 148° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][C:11]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[CH2:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(OCC)(=O)C.[CH3:32][N:33](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:20]1[CH:19]=[C:18]([C:11]2([C:14]([F:17])([F:16])[F:15])[CH2:10][C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH:3]=3)[C:32]#[N:33])=[N:13][CH2:12]2)[CH:23]=[C:22]([Cl:24])[CH:21]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Temperature: 90 °C
Reaction time: 4 h
Yield: 32 %

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrole (0.88 g) was dissolved in DMF (10 ml), and the solution was deaerated and then left to stand in an argon atmosphere. To the reaction mixture, Zn(CN)2 (0.45 g) and Pd(PPh3)4 (0.67 g) were added. The mixture was stirred for 4 hours at 90° C. The reaction mixture was returned to room temperature, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, and then dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-fluorobenzonitrile (0.25 g) at a yield of 32%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[O:29]=[C:30]1[NH:34][CH:33]([C:35](O)=[O:36])[CH2:32][CH2:31]1>C1COCC1.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:35]([CH:33]4[CH2:32][CH2:31][C:30](=[O:29])[NH:34]4)=[O:36])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: O=C1CCC(C(=O)O)N1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)C1CCC(=O)N1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
A round bottom flask was charged with (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.08 g, 0.2 mmol), 5-oxopyrrolidine-2-carboxylic acid loaded TFP resin (1.4 mmol/g loading, 0.2 mmol), and a THF-DCM solution (3 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.013 g, 10%). 1H NMR (400 MHz, CD3OD) δ 7.41-7.32 (m, 2H), 7.21-7.13 (m, 1H), 7.05-6.97 (m, 2H), 6.05 (s, 1H), 5.21-5.02 (m, 1H), 4.34-4.19 (m, 3H), 2.44-2.28 (m, 3H), 2.11-1.98 (m, 1H), 1.88-1.81 (m, 1H), 1.51 (d, J=5.2 Hz, 3H), 0.99-0.86 (m, 2H), 0.69-0.61 (m, 2H). MS: Calcd.: 495. Found: [M+H]+ 496.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH2:19])[CH2:8][C@@H:7]1[CH3:20])=[O:5])[CH3:2].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH:26]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH:19][CH2:26][C:25]2[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=[C:23]([C:22]([F:21])([F:35])[F:36])[CH:24]=2)[CH2:8][C@@H:7]1[CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(O)cc2[C@H](N)C[C@@H]1C
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)N1c2cc(OC)c(O)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a stirred suspension of cis-4-amino-6-hydroxy-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (387 mg, 1.38 mmol) in dichloromethane (9 mL) was added 3,5-bis(trifluoromethyl)benzaldehyde (225 μL, 1.38 mmol), followed by acetic acid (80 μL, 1.4 mmol). The reaction was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (440 mg, 2.08 mmol) was added. The reaction was stirred at room temperature for 5 h. Water (5 mL) was added, and the mixture was slowly basified to pH 10 with solid potassium carbonate. The mixture was then extracted with ethyl acetate (3×10 mL), the combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 680 mg crude product. Purification by silica gel chromatography using 0-25% ethyl acetate/hexanes as eluent afforded 458 mg of the title compound (65%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:22][C@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1>>[N:25]12[CH2:24][C@@H:23]([NH:22][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:10]4[O:9][C:8]([NH:7][C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:12][C:11]=34)=[O:19])[CH:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2
Reactant: O=C(O)c1cccc2oc(Nc3ccccc3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(Nc3ccccc3)nc12

Procedure:
Following general procedure GP-C1, A mixture of 2-(phenylamino)benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-(phenylamino) benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]=2)[C:5]([NH:16][C:17]([C:19]2[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=[C:22]([C:24]#[N:25])[N:23]=2)=[O:18])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:39]([O:41][CH2:42][CH3:43])=[CH2:40])CCC.CN(C=O)C>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:11]1([CH3:15])[CH2:12][CH2:13][C:8]([C:6]2[C:5]([NH:16][C:17]([C:19]3[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=[C:22]([C:24]#[N:25])[N:23]=3)=[O:18])=[CH:4][CH:3]=[C:2]([C:39]([O:41][CH2:42][CH3:43])=[CH2:40])[N:7]=2)=[CH:9][CH2:10]1
Reactant: CC1(C)CC=C(c2nc(Br)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(OCC)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a round bottom flask containing 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [6-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-yl]-amide (as prepared in the previous step, 32 mg, 0.060 mmol), Pd(PPh3)4 (7 mg, 0.006 mmol), and tributyl-(1-ethoxy-vinyl)-stannane (30 mg, 0.080 mmol) was added DMF (0.7 mL) and the resultant solution was allowed to stir at 100° C. overnight. The reaction was diluted with EtOAc (25 mL), washed with water (2×25 mL), dried (Na2SO4) and concentrated in vacuo. Purification of the residue by preparative TLC (20% EtOAc-hexanes) afforded 12 mg (43%) of the title compound as an oil. Mass spectrum (ESI, m/z): Calcd. for C28H39N5O3Si, 522.2 (M+H), found 522.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:31][C@@H:32]1[O:34][CH2:33]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:34]1[CH2:33][C@@H:32]1[CH2:31][N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2[nH]ncc2c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@H]2CO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A mixture of 1-(1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (750 mg, 2.11 mmol), (R)-(−)-glycidyl nosylate (657 mg, 2.53 mmol) and cesium carbonate (1.03 g, 3.17 mmol) in methyl sulfoxide (6 mL) was stirred at ambient temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by column chromatography (silica gel, ethyl acetate) gave the title compound (480 mg, 55%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=0.9 Hz, 1H), 7.76-7.72 (m, 5H), 7.65 (d, J=9.0 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.47 (dd, J=9.0, 2.1 Hz, 1H), 6.92 (d, J=1.8 Hz, 1H), 6.53 (dd, J=6.9, 1.8 Hz, 1H), 4.79 (dd, J=15, 3.0 Hz, 1H), 4.48 (dd, J=15.3, 5.7 hz, 1H), 3.41-3.37 (m, 1H), 2.88 (app t, J=4.5 Hz, 1H), 2.60 (dd, J=4.5, 2.4 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39]C)=[O:37]>C1COCC1>[C:36](=[O:37])([O:38][CH3:39])[O:15][C:14](=[O:16])[CH2:13][C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)O)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)OC(=O)C[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2 g (5.26 mmol) of (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl) amino]hexanoic acid and 0.56 g (5.73 mmol) of triethylamine are dissolved in 30 ml of THF under argon and cooled to 0° C. 0.59 g (5.73 mmol) of ethyl chloroformate are added, and the mixture is stirred at 0° C. for 3 hours. The reaction mixture is filtered through kieselguhr, and the filtrate is reacted directly.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[O-:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+].IC1C=CC(OC)=C(C=1)C(OC)=O>[Cu-]=O.CC(N(C)C)=O>[CH3:14][O:13][C:5]1[CH:4]=[CH:3][C:2]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [O-]c1ccccc1
Reactant: CCOC(=O)c1cc(I)ccc1OC
Agent: O=[Cu-]
Agent: COC(=O)c1cc(I)ccc1OC
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(Oc2ccccc2)ccc1OC
Temperature: 180 °C
Yield: 54.5 %

Procedure:
A mixture of ethyl 5-iodo-2-methoxybenzoate (4.1 g, 13.4 mmol), sodium phenoxide (1.7-1.8 g, 15 mmol), copper(I) oxide (1.1 g, 7.5 mmol) and dimethylacetamide (approximately 15 mL) was heated 4 hours with stirring at 180° C. The mixture was filtered, diluted with water and extracted with pentane/diethyl ether (7:3, 2× 100 mL). The combined extracts were washed with dilute sodium hydroxide (3×) and water (1×), dried (K2CO3), filtered and concentrated. The residue was dried (P2O5) under vacuum to give crude product (1.17 g) which was combined with crude product (2.4 g) similarly prepared from methyl 5-iodo-2-methoxybenzoate (6 g, 19.6 mmol). The combined crude product was purified by column chromatography eluting with hexane/acetone (96:4) to give ethyl 2-methoxy-5-phenoxybenzoate (2 g, 7.3 mmol), m.p. 52°-52° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([N:7]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8][CH2:9][CH2:10][C:11]1([CH3:16])OCC[O:12]1)[CH3:6])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([N:7]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[CH3:16])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N(CCCC1(C)OCCO1)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N(CCCC(C)=O)C(=O)OC(C)(C)C

Procedure:
To a solution of 4-5 (13.9 g, 0.040 mol) in 100 mL acetone was added p-toluenesulfonic acid (0.05 g). The mixture was heated at reflux for 2 h. After cooling, the mixture was evaporated to one-fifth its initial volume, diluted with EtOAc and then washed with sat. NaHCO3, brine, and dried over Na2SO4. Evaporative removal of the solvent gave 4-6 as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:33])([CH:25]([OH:32])[C:26]1[CH:31]=[CH:30][CH:29]=CN=1)[C:3]([NH:5][NH:6][C:7]([N:9]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12][C:11]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:10]1=2)=[O:8])=[O:4].FC(F)(C(O)C1[S:42]C=CC=1)C(NN)=O.ClC1C=CC2OC3C=CC=CC=3CN(C(Cl)=O)C=2C=1>>[F:1][C:2]([F:33])([CH:25]([OH:32])[C:26]1[S:42][CH:29]=[CH:30][CH:31]=1)[C:3]([NH:5][NH:6][C:7]([N:9]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12][C:11]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:10]1=2)=[O:8])=[O:4]
Reactant: O=C(NNC(=O)C(F)(F)C(O)c1ccccn1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: NNC(=O)C(F)(F)C(O)c1cccs1
Agent: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(NNC(=O)C(F)(F)C(O)c1cccs1)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[2,2-difluoro-3-hydroxyl-1-oxo-3-(2-thienyl)propyl]hydrazide (27) was prepared in the same manner as 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, 2-[2,2-difluoro-3-hydroxy-1-oxo-3-(2-pyridinyl)propyl]hydrazide (11), as described above in Example 11, on a 0.9 mmol scale from α,α-difluoro-β-hydroxy-2-thiophenepropanoic acid, hydrazide (26), prepared as described above in Example 26, and 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carbonyl chloride (2), prepared as described above in Example 2, to yield 0.15 g (39%) of product. Analysis calculated for C21H16N3O4SF2Cl. H2O (M.W. 497.91): C, 50.66; H, 3.64; N, 8.44. Found: C, 50.89; H, 3.33; N, 8.24.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[O:14][CH2:15][C:16](O)=O>Cl>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:16]=1[CH2:15][O:14][C:13]1[CH:19]=[CH:20][CH:21]=[C:11]([O:10][CH3:9])[CH:12]=1
Reactant: Nc1ccccc1N
Reactant: COc1cccc(OCC(=O)O)c1
Agent: Cl
Product: COc1cccc(OCc2nc3ccccc3[nH]2)c1
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A suspension of phenylenediamine (15.12 g, 0.14 mol) and 3-methoxyphenoxyacetic acid (25.5 g, 0.14 mol) in 4M HCl (150 mL) was refluxed overnight under Ar. The reaction mixture was cooled in an ice bath. The solid was collected and washed with cold H2O (200 mL). To the solid was added CH2Cl2 (150 mL) and saturated NaHCO3 (150 mL). After stirring for 1 hr, the organic phase was separated, washed with brine (75 mL), filtered through phase separation filter paper and concentrated in vacuo to give 32.7 g (92%) of 51 as an oil which solidified. The HPLC analysis showed a purity of 98%. 1H NMR (60 MHz, CDCl3): δ 10.0 (br s, 1H), 6.3-7.9 (m, 8H), 5.0 (s, 2H), 3.7 (s, 3H) ppm.
Reaction SMILES: [CH:1]1([CH:7]([O:50][CH3:51])[C:8]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][C:9]=2[CH2:10][N:11]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:12]2[N:13]=[N:14][N:15](CCO[Si](C(C)(C)C)(C)C)[N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C[O:73][CH2:72][CH2:71]1>>[F:37][C:34]([F:35])([F:36])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:39])([F:41])[F:40])[CH:31]=1)[CH2:27][N:11]([CH2:10][C:9]1[CH:42]=[C:43]([C:46]([F:47])([F:48])[F:49])[CH:44]=[CH:45][C:8]=1[CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[O:50][CH3:51])[C:12]1[N:13]=[N:14][N:15]([CH:72]([OH:73])[CH3:71])[N:16]=1
Reactant: C1CCOC1
Reactant: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCO[Si](C)(C)C(C)(C)C)n1)C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C(C)O)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To N-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-(2-(tert-butyldimethylsilyloxy)ethyl)-2H-tetrazol-5-amine (39.3 mg, 0.052 mmol) in THF (0.3 mL) at room temperature was added TBAF in THF (1.0 M, 0.1 mL, 0.1 mmol). The mixture was stirred at room temperature overnight. Solvent was removed and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-50% ethyl acetate in heptane) to afford a colorless oil (29.5 mg, 89%). 1H NMR (400 MHz, CDCl3) δ ppm 0.94-1.13 (m, 5H) 1.17 (d, J=11.20 Hz, 1H) 1.43-1.53 (m, 1H) 1.60 (s, 2H) 1.67-1.74 (m, J=2.90 Hz, 1H) 1.91 (d, J=12.86 Hz, 1H) 2.35-2.42 (m, 1H) 3.06 (s, 3H) 4.08 (d, J=7.05 Hz, 1H) 4.12-4.16 (m, J=5.39 Hz, 2H) 4.62 (t, J=4.98 Hz, 2H) 4.72 (s, 2H) 4.75 (d, J=16.18 Hz, 1H) 4.88 (d, J=16.18 Hz, 1H) 7.36 (s, 1H) 7.49 (d, J=7.88 Hz, 1H) 7.56 (d, J=8.30 Hz, 1H) 7.67 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 639.2, Found: 640.5 (M+1).
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:36][CH2:37][CH3:38])=[C:30]([O:33][CH2:34][CH3:35])[CH:31]=2)[N:26]=[CH:25][N:24]=1>>[CH2:34]([O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:36][CH2:37][CH3:38])[N:26]=[CH:25][N:24]=[C:23]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1)[CH3:35]
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Reactant: CCOc1cc2ncnc(Cl)c2cc1OCC
Agent: Br
Product: CCOc1cc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OCC
Yield: 24 %

Procedure:
The procedure similar to that described in Example 57 was repeated, except that 354.0 mg (1.00 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-6,7-diethoxyquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 116.8 mg (yield: 24%) of Compound 98 was obtained as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[F:11])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)(=[O:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Reactant: CC(=O)c1ccccc1O
Product: CC(=O)c1ccccc1OC(CCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1F

Procedure:
Prepared by Procedure A and Scheme AN using 1-(2-hydroxyphenyl)ethanone and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 559.0 (M+H)+.
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:2]2[C:7]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:9]=[N:10][C:6]=3[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCCO
Product: FC(F)(F)c1cc(-c2cccc(Cl)c2)c2c(c1)ncn2-c1ccccc1

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (1.0 g, 2.6 mmol), 3-chlorobenzeneboronic acid (0.6 g, 3.87 mmol), 1,3-propanediol (1 ml, 12.9 mmol), potassium carbonate (1.8 g, 12.9 mmol) and bis(triphenylphosphin)palladium dichloride (100 mg, 0.14 mmol) was stirred at reflux for one hour. The cooled mixture was partitioned between water and ethyl acetate. The organic extract was dried and concentrated under reduced pressure. The concentrate was purified by chromatography on silica gel eluting with a mixture of ethyl acetate and ligroin (2:3, v/v). Removal of solvent left the desired product as a white solid (0.9 g, 94%) m/z, 373.1 (M+H)+.