Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([O:15]C(C2C=CC=CC=2)=O)=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7]([C:24]#[C:25][CH2:26][OH:27])[N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.O>[OH:15][C:14]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([C:24]#[C:25][CH2:26][OH:27])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: COC(=O)c1nc(C#CCO)c2cccnc2c1OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(C#CCO)c2cccnc2c1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(3-hydroxy-prop-1-ynyl)-8-(1-phenyl-methanoyloxy)-[1,6]naphthyridine-7-carboxylic acid methyl ester (1.00 g, 2.76 mmol) in THF (14 mL) and water (14 mL) was added 1N NaOH (13.8 mL, 13.8 mmol) and the solution was stirred at 50° C. overnight. The THF was removed under reduced pressure and the remaining solution was acidified with 6N HCl to a pH=3. Injected the solution directly onto the Gilson auto-prep running a 95-50% H2O (0.1% TFA)/CH3CN (0.09% TFA) gradient over 35 minutes to obtain the desired compound as a bright yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](Cl)([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:7])C.O=S(Cl)Cl.S(O)(O)(=O)=O.[NH2:32][NH2:33].CC[O-].[Na+]>C(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3([CH3:7])[CH2:5][C:4](=[O:3])[NH:33][NH:32]3)=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: CCOC(=O)CC(C)(Cl)c1ccc(-c2ccc(F)cc2)cc1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A solution of 32.1 g of 3-chloro-3-(4'-fluoro-4-biphenylyl)-butyric acid ethyl ester (obtainable from the hydroxy ester and SOCl2), 15 g of hydrazine sulfate and 20.5 g of sodium ethylate in 500 ml of absolute ethanol is boiled for 2 hours and the solvent is evaporated. Working up gives 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:27][C:19]3[C:20]4[CH:21]=[N:22][NH:23][C:24]=4[CH:25]=[CH:26][C:18]=3[CH2:17][C@@H:16]([NH:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[C:15]2=[O:39])[CH2:10][CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.[CH3:48][S:49]([OH:52])(=[O:51])=[O:50]>ClCCl.C(OCC)C>[CH3:48][S:49]([OH:52])(=[O:51])=[O:50].[O:39]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:27][C:19]2[C:20]3[CH:21]=[N:22][NH:23][C:24]=3[CH:25]=[CH:26][C:18]=2[CH2:17][C@H:16]1[NH:28][C:29](=[O:30])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)OCc3ccccc3)C2=O)CC1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: CCOCC
Product: O=C(N[C@@H]1Cc2ccc3[nH]ncc3c2CN(C2CCNCC2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(7-(R)-Benzyloxycarbonylamino-8-oxo-6,7,8,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL). Anisole (100 μL, 0.92 mmol) was added to the mixture followed by methanesulfonic acid (200 μL). Reaction stirred at room temperature for 30 minutes. Mixture was diluted with diethyl ether, and the mixture stirred at room temperature for 30 minutes. Solvents were decanted off. Residue was dried in vacuo. Title compound was obtained as dark oil in quantitative yield. MS m/e (M+H)+=434.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.C([O-])(=O)C.[Na+].Cl[CH2:16][C:17](=O)[CH3:18]>O>[CH3:18][C:17]1[NH:1][C:2]2[N:7]=[C:6]([OH:8])[N:5]=[C:4]([OH:9])[C:3]=2[CH:16]=1
Reactant: CC(=O)CCl
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc2c(O)nc(O)nc2[nH]1

Procedure:
A mixture of 6-aminouracil) 1.00 g, 7.87 mmol), sodium acetate (1.00 g, 12.2 mmol) and chloroacetone (95%, 1.00 mL, 11.9 mmol) in H2O (40 mL) was heated at reflux for 72 h. The solids were collected, and dried on vacuum to give 6-methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (495 mg).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[Cu](C#N)[C:13]#[N:14]>>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:13]#[N:14])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: N#C[Cu]C#N
Product: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 58.9 %

Procedure:
2,5-Dibromo-3-nitropyridine (3.80 g, 13.4 mmol) and copper cyanide (2.42 g, 26.8 mmol) were mixed, and stirred under heat at 150° C. for 2 hours. After cooled to room temperature, the contents were filtered, and the residue was washed with acetone. The mother liquid was concentrated, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 3/1) to obtain the intended compound (1.80 g, 59%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[C:13]([CH:17]=2)=[N:14][O:15][N:16]=3)[C:5]([OH:8])=[CH:6][CH:7]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[C:13]([CH:17]=2)=[N:14][O:15][N:16]=3)[C:5]([O:8][CH3:18])=[CH:6][CH:7]=1
Reactant: Oc1ccc(Br)cc1-c1ccc2nonc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)cc1-c1ccc2nonc2c1
Temperature: 18 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 5-(3-bromo-6-hydroxyphenyl)benzofurazan (8.70 g, 30 mmol), potassium carbonate (14.42 g, 90 mmol) and methyl iodide (2.83 mL, 45 mmol) in dimethylformamide (100 mL) is stirred at 18° C. for 16 h. The mixture is then treated with water (600 mL) and extracted with ethyl acetate (3×150 mL). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from t-butylmethyl ether-hexane to give 5-(3-bromo-6-methoxyphenyl)benzofurazan as a beige crystalline solid. m.p. 135-137° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][C:13](OCC)=[O:14])=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[CH2:24]([Mg]Br)[CH3:25]>C(OCC)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][C:13]2([OH:14])[CH2:25][CH2:24]2)=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:3]=1
Reactant: CCOC(=O)CCn1cnc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOCC
Product: OC1(CCn2cnc3c(N4CCOCC4)nc(Cl)nc32)CC1
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of ethyl 3-(2-chloro-6-morpholino-9H-purin-9-yl)propanoate (500 mg, 1.5 mmol) in diethylether (37 mL) was treated with titanium (IV) ethoxide (31 uL, 0.15 mmol) followed by the dropwise addition of 3.0M ethylmagnesium bromide in ether (0.98 mL, 2.9 mmol) at ambient temperature for 90 minutes. Partial conversion prompted the addition of titanium (IV) ethoxide (31 uL, 0.15 mmol) and 3.0M ethylmagnesium bromide in ether (0.98 mL, 2.9 mmol). After 2 hr, the reaction mixture was quenched with an aqueous 1.0M solution of HCl (20 mL) and filtered through a plug of celite, washing with ethyl acetate. The mixture was diluted with water and ethyl acetate and the layers separated. The aqueous phase was extracted into EtOAc (3×), dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford 1-(2-(2-chloro-6-morpholino-9H-purin-9-yl)ethyl)cyclopropanol as a colorless oil (220 mg, 46%). LC/MS (ESI+): m/z 324 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21]([NH:27]C(C1SC(C3N=C(C)SC=3)=CC=1)=O)[CH2:20]2>>[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21]([NH:27][C:15]([C:13]1[S:14][C:10]([CH:9]=[CH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:11][CH:12]=1)=[O:17])[CH2:20]2
Reactant: COC(=O)c1ccc(C=Cc2cccc(Cl)c2)s1
Reactant: Cc1nc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)cs1
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(C=Cc2cccc(Cl)c2)s1
Yield: 19 %

Procedure:
This compound is prepared from methyl 5-[2-(3-chlorophenyl) vinyl]-thiophene-2-carboxylate according to the procedure used to make the compound of Example 31, making non-critical variations. Yield 19%. MS for C20H21ClN2OS (ESI) (M+H)+ m/z 373.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.I([O-])(=O)(=O)=[O:25].[Na+]>CO.O1CCCC1.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:25]
Reactant: COC(=O)CCCCCSc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCCS(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Yield: 80.4 %

Procedure:
To a solution of 6-(4′-chloro-biphenyl-4-ylsulfanyl)-hexanoic acid methyl ester (900 mg, 2.6 mmol) in methanol (30 mL) and tetrahydrofuran (20 mL) was added dropwise at 0° C. a solution of sodium metaperiodate (608 mg, 2.8 mmol) in distilled water (8 mL). The mixture was heated at 60° C. for 2 hours. The solution was concentrated under reduced pressure to give an oil that was dissolved in ethyl acetate (50 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL), distilled water (50 mL), then with brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (1:1 to 8:2 ethyl acetate:40-60° C. petroleum ether). The solid obtained was recrystallised from diethyl ether/40-60° C. petroleum ether to give the title compound (763 mg, 81%) as a solid, mp 64-65° C.
Reaction SMILES: [CH:1]12[NH:10][CH:5]([CH2:6][C:7](=[O:9])[CH2:8]1)[CH2:4][O:3][CH2:2]2.CCN(CC)CC.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:10]2[CH:5]3[CH2:6][C:7](=[O:9])[CH2:8][CH:1]2[CH2:2][O:3][CH2:4]3)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=C1CC2COCC(C1)N2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC2COCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a stirring mixture of 3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one (408 mg, 2.3 mmol) in dichloromethane (8 mL) was added Et3N (1.2 mL, 9.2 mmol) and 4-chlorobenzenesulfonyl chloride (582 mg, 2.76 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (50 mL) and washed with a saturated aqueous NaHCO3 solution (15 mL). The aqueous phase was separated and extracted twice with EtOAc (2×25 mL). The combined organic phases were then dried (Na2SO4), filtered, concentrated under vacuum, and the residue was purified on a silica gel column (eluant hexane/EtOAc, 50/50 to 100) to give 510 mg (70%) of 9-(4-chloro-benzenesulfonyl)-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one as a white solid; Retention time (min)=1.687 min, Method [1], MS(ESI) 316.1 (M+H); 1H-NMR (300 MHz, CDCl3) δ 7.84-7.81 (m, 2H), 7.56-7.51 (m, 2H), 4.28-4.27 (m, 2H), 3.76 (d, J=12.1 Hz, 2H), 3.61 (d, J=11.5 Hz, 2H), 2.65 (dd, J=15.93, 5.49 Hz, 2H), 2.46 (d, J=15.93 Hz, 2H); 13C-NMR (75 MHz, CDCl3) δ 204.3, 140.1, 139.1, 130.1, 128.7, 71.7, 51.7, 44.4 ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[CH2:13]1[CH:14]2[N:10]([CH2:2][CH:3]=[C:4]([C:3]3[C:4]4[C:9](=[N:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:5]2)[CH2:11][CH2:12]1
Reactant: C1CCNC1
Reactant: c1cnc2[nH]ccc2c1
Solvent: CCO
Product: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1

Procedure:
from 7-azaindole (500 mg, 4.2 mmol), 1,2,3,5,6,8,8a-heptahydrohydro-7-oxo-indolizine (589 mg, 4.2 mmol) and pyrrolidine (3.0 g, 42 mmol) in ethanol (4 mL) heating at reflux for 5 hrs.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[F:22][C:23]1[CH:40]=[CH:39][C:26]2[N:27]=[C:28]([S:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[NH:29][C:25]=2[CH:24]=1.Br[CH2:42][C:43]([NH:45][C:46]1[C:47]([O:59][CH2:60][C:61]([F:64])([F:63])[F:62])=[N:48][C:49]([CH3:58])=[CH:50][C:51]=1[O:52][CH2:53][C:54]([F:57])([F:56])[F:55])=[O:44].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:22][C:23]1[CH:40]=[CH:39][C:26]2[N:27]=[C:28]([S:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([CH2:42][C:43]([NH:45][C:46]4[C:47]([O:59][CH2:60][C:61]([F:64])([F:62])[F:63])=[N:48][C:49]([CH3:58])=[CH:50][C:51]=4[O:52][CH2:53][C:54]([F:56])([F:57])[F:55])=[O:44])[CH2:35][CH2:34]3)[NH:29][C:25]=2[CH:24]=1
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CBr)c(OCC(F)(F)F)n1
Reactant: Fc1ccc2nc(SCCN3CCNCC3)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCSc3nc4ccc(F)cc4[nH]3)CC2)c(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.4 %

Procedure:
1-[2-(5-Fluorobenzimidazol-2-ylthio)ethyl]piperazine tris(trifluoroacetic acid) salt (6.92 g, 11.12 mmol) and 2-bromo-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (4.50 g, 10.59 mmol) were suspended in acetonitrile (90 mL), and potassium carbonate (5.85 g, 42.33 mmol) was gradually added to the suspension. The mixture was stirred for five hours at room temperature, and water (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform:methanol=50:1). The thus-obtained crystals were recrystallized from acetone-ether, to thereby yield 2-[4-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (4.72 g, yield 71%) as pale brown prisms.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH3:12][C@@H:13](O)[CH2:14][CH:15]=[CH2:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:11][C@H:15]([CH2:14][CH:13]=[CH2:12])[CH3:16])[CH:3]=1
Reactant: O=Cc1cc(F)c(F)cc1O
Reactant: C=CC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[C@H](C)Oc1cc(F)c(F)cc1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 9 %

Procedure:
To a solution of 4,5-difluoro-2-hydroxybenzaldehyde (1.0 g, 6.33 mmol) in THF (14 ml) were added (R)-(−)-pent-4-en-2-ol (1.090 g, 12.65 mmol) and triphenylphosphine (2.157 g, 8.22 mmol). DIAD (1.599 ml, 8.22 mmol) was added dropwise (exotherm) and the mixture was stirred at rt. After 1.5 h, the mixture was diluted with Et2O and washed with 1N NaOH followed by water (3×'s) then brine, dried (Na2SO4), filtered and concentrated. The yellow oil was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV) to give (S)-4,5-difluoro-2-(pent-4-en-2-yloxy)benzaldehyde (0.1295 g, 0.572 mmol, 9.05% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.36 (d, J=3.2 Hz, 1H), 7.76-7.55 (m, 1H), 6.83 (dd, J=11.9, 6.0 Hz, 1H), 6.04-5.67 (m, 1H), 5.23-5.06 (m, 2H), 4.48 (sxt, J=6.0 Hz, 1H), 2.71-2.35 (m, 2H), 1.41 (d, J=6.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]=[C:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22][C:23]1[CH:28]=[C:27]([F:29])[C:26](F)=[CH:25][C:24]=1[F:31].CCN(C(C)C)C(C)C.Cl>CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]=[C:16]2[CH2:21][CH2:20][N:19]([C:26]3[CH:25]=[C:24]([F:31])[C:23]([Br:22])=[CH:28][C:27]=3[F:29])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cc(F)c(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(Br)cc3F)CC2)CC1

Procedure:
Compound 69c (1.0 g, 3.4 mmol) and 1-bromo-2,4,5-trifluorobenzene were heated with iPr2NEt (1.7 mL, 10.2 mmol) in DMSO (5 mL) at 140° C. for 40 min 1M HCl and EtOAc were added and the organic phase dried over MgSO4 and concentrated. The mixture was purified by chromatography on silica gel eluting with EtOAc/Hexane to give 4-[1-(4-Bromo-2,5-difluoro-phenyl)-piperidin-4-ylideneaminooxy]-piperidine-1-carboxylic acid tert-butyl ester 77a (720 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Cu+2].ClCCl>[C:14]1([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:1])([F:12])[F:13])=[C:4]2[C:8]([O:10][CH3:11])=[O:9])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(C(F)(F)F)ccn1-c1ccccc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 59.4 %

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (810 mg, 4.19 mmol, 1.00 equiv), phenylboronic acid (1.54 g, 12.63 mmol, 3.01 equiv), Cu(OAc)2 (1.52 g, 8.37 mmol, 2.00 equiv), pyridine (1.327 g, 16.78 mmol, 4.00 equiv), 4 {acute over (Å)} Molecular Sieves (1.2 g) and dichloromethane (20.0 mL). The resulting solution was stirred for 2 days at 20° C. The reaction progress was monitored by LCMS. The solids were filtered out and the resulting mixture was concentrated under vacuum. The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9) to yield methyl 1-phenyl-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate as a pink solid (0.67 g, 59%)
Reaction SMILES: COC1C=CC(C[N:10]2[C:14]3[C:15](=[O:26])[NH:16][C:17]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=4[C:19](=[O:20])[C:13]=3[C:12]([CH:27]=[O:28])=[N:11]2)=CC=1.COC1C=CC(CN2C(C=O)=C3C(C(=O)NC4C=C(Cl)C=CC=4C3=O)=N2)=CC=1>C(#N)C.O>[Cl:25][C:23]1[CH:22]=[CH:21][C:18]2[C:19](=[O:20])[C:13]3[C:12]([CH:27]=[O:28])=[N:11][NH:10][C:14]=3[C:15](=[O:26])[NH:16][C:17]=2[CH:24]=1
Reactant: COc1ccc(Cn2nc(C=O)c3c(=O)c4ccc(Cl)cc4[nH]c(=O)c32)cc1
Agent: COc1ccc(Cn2nc3c(=O)[nH]c4cc(Cl)ccc4c(=O)c3c2C=O)cc1
Solvent: O
Solvent: CC#N
Product: O=Cc1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 9 %

Procedure:
A solution of 1-(4-methoxyphenylmethyl)-7-chloro-3-formylpyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione or 2-(4-methoxyphenylmethyl)-7-chloro-3-formylpyrazolo[3,4-c][1]benzazepine-4,10(2H,9H)-dione from Example 20(b) above (400 mg, 1.01 mmol) and ceric ammonium nitrate (2.2 g, 4.03 mmol) in a mixture of acetonitrile (12 mL) and water (4 mL) was stirred for 17 hours at room temperature and filtered. The isolated solid was washed with a mixture of acetonitrile (12 mL) and water (4 mL) followed by acetone (10 mL). The acetonitrile-water solutions were extracted with ethyl acetate. The solid material from above was combined with the ethyl acetate extract and solvent was removed by rotary evaporation. The residue was washed with hot methanol (1×20 mL then 1×10 mL) and dried to give the title compound (25 mg, 9%).
Reaction SMILES: ClCCl.Cl[C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][N:6]=1.[CH2:19](N(CC)CC)[CH3:20]>C(O)C>[CH:19]([C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][N:6]=1)=[CH2:20]
Reactant: COC(=O)c1cnc(Cl)c(C(=O)OC)c1
Reactant: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: C=Cc1ncc(C(=O)OC)cc1C(=O)OC

Procedure:
A dichloromethane adduct of (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.359 g) was added to a mixture of dimethyl 2-chloropyridine-3,5-dicarboxylate (1.01 g), potassium vinyl trifluoroborate (1.18 g), triethylamine (1.22 mL), and ethanol (10 mL), and the resultant mixture was stirred at 95° C. for 1 hour in an argon atmosphere. The solvent in the reaction mixture was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (880 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(-c2cccc(F)c2)cn1
Temperature: 100 °C

Procedure:
To a round bottom flask was added methyl 5-bromopicolinate 6-5 (900 mg, 4.2 mmol), 3-fluorophenylboronic acid 6-6 (875 mg, 6.3 mmol), Pd(PPh3)4 (482 mg, 0.42 mmol), saturated Na2CO3 (3 mL), ethanol (3 mL) and toluene (9 mL). The reaction was refluxed at 100° C. for 3 hours. The reaction was cooled down to room temperature, and the precipitate was collected by filtration and briefly washed with ethyl acetate. The sodium salt was acidified with 1N HCl to give 5-(3-fluorophenyl)picolinic acid 6-7 as a white solid. MS m/z 218.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1O)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].P(Br)(Br)([Br:22])=O>C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1[Br:22])=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=P(Br)(Br)Br
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Br
Yield: 51 %

Procedure:
To a stirred solution of 6-chloro-4-hydroxy-2-isopropyl-quinoline-3-carboxylic acid methyl ester (800 mg, 2.86 mmol) in DCM (15 ml) was added POBr3 (1.23 g, 4.3 mmol) at 25° C. and the resulting reaction mixture was refluxed for 6 h. The reaction mixture was diluted with cold water, extracted with DCM, washed with brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (eluting with 5% EtOAc in hexane on 100-200 mesh silica gel column chromatography) to afford pure 4-bromo-6-chloro-2-isopropyl-quinoline-3-carboxylic acid methyl ester (500 mg, 51%) as an off white solid. LC-MS: 343 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][Si](C(C)(C)C)(C)C)=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:16]([O:18][C:19]1[CH:23]=[C:22]([N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33]4[O:34][C:35]([CH3:38])=[N:36][N:37]=4)=[CH:32][C:27]=3[N:26]=[CH:25]2)[S:21][C:20]=1[C:39]([O:41][CH3:42])=[O:40])[CH3:17].ClC1C(O)=CC=CC=1[C@H](OC1C=C(N2C3C=C(C#N)C=CC=3N=C2)SC=1C(OC)=O)C>>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:16]([O:18][C:19]1[CH:23]=[C:22]([N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33]4[O:34][C:35]([CH3:38])=[N:36][N:37]=4)=[CH:32][C:27]=3[N:26]=[CH:25]2)[S:21][C:20]=1[C:39]([O:41][CH3:42])=[O:40])[CH3:17]
Reactant: COC(=O)c1sc(-n2cnc3cc(-c4nnc(C)o4)ccc32)cc1O[C@H](C)c1cccc(O[Si](C)(C)C(C)(C)C)c1Cl
Agent: COC(=O)c1sc(-n2cnc3ccc(C#N)cc32)cc1O[C@H](C)c1cccc(O)c1Cl
Product: COC(=O)c1sc(-n2cnc3cc(-c4nnc(C)o4)ccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Yield: 35.1 %

Procedure:
The title compound was prepared from methyl 3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (82.0 mg, 0.312 mmol) using a procedure analogous to Intermediate 3, Step F to give 55.9 mg of the desired product. MS (ESI): 511 [M+H]+.