Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][C@@H:16]([NH:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]([CH3:41])[N:39]=[CH:38][N:37]=2)=[CH:32][CH:31]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25]>C(Cl)Cl.CO>[NH2:6][CH2:15][C@@H:16]([NH:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]([CH3:41])[N:39]=[CH:38][N:37]=2)=[CH:32][CH:31]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25]
Reactant: Cn1ncnc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cn1ncnc1-c1ccc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1

Procedure:
Hydrazine hydrate (0.028 ml, 0.58 mmol) was added to a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,4-triazol-5-yl)benzamide (67.3 mg, 0.116 mmol) in DCM/MeOH (1/0.1 ml).
Reaction SMILES: [CH:1]1([C@@:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:9]2[N:13]=[CH:12][NH:11][N:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][N:11]2[CH:12]=[N:13][C:9]([C@:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)([OH:8])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10]2)[CH2:23][CH2:24]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: O[C@](c1ccccc1)(c1nc[nH]n1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2cnc([C@](O)(c3ccccc3)C3CCCCC3)n2)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
(R)-cyclohexyl(phenyl)1H-1,2,4-triazol-3-ylmethanol (Preparation 2, 3.0 g, 11.7 mmol) was dissolved in acetone (60 mL) and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (3.24 g, 11.7 mmol) added, followed by cesium carbonate (7.60 g, 23.3 mmol). After stirring at 70° C. for 5 hours, the reaction was allowed to cool to room temperature and stirred for a further 16 hours. The solvent was removed in vacuo, and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo. 100 mg of this residue was dissolved in acetonitrile (0.5 ml) and left to evaporate, almost to dryness, at which point the resulting oil began to crystallise. The remainder of the residue was dissolved in acetonitrile (55 ml) and seeded with the crystalline material obtained above. Crystallisation was allowed to occur over 18 hours and the resulting solid collected by filtration to furnish the title compound as a white solid, in 64% yield, 3.4 g.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9])(=[O:5])[CH3:4].Br[CH:17]1[CH2:23][CH2:22][CH2:21][C:20]2[CH:24]=[C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:26]=[CH:27][C:19]=2[C:18]1=[O:36]>CN(C=O)C>[CH3:11][O:10][C:8](=[O:9])[C:7]([NH:6][C:3](=[O:5])[CH3:4])([CH:17]1[CH2:23][CH2:22][CH2:21][C:20]2[CH:24]=[C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:26]=[CH:27][C:19]=2[C:18]1=[O:36])[C:12]([O:14][CH3:15])=[O:13]
Reactant: CCCCCCCCc1ccc2c(c1)CCCC(Br)C2=O
Reactant: COC(=O)C(NC(C)=O)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc2c(c1)CCCC(C(NC(C)=O)(C(=O)OC)C(=O)OC)C2=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 15.2 %

Procedure:
Sodium hydride (720 mg, 18.0 mmol) 60% in mineral oil was suspended in dry DMF (10 mL) and a solution of dimethyl acetamidomalonate (3.00 g, 15 mmol) in dry DMF (10 mL) was added. The solution was stirred at 0° C. for 3 h until the anion had formed. A solution of 4 (2.12 g, 6.0 mmol) in dry DMF (10 mL) was added and the solution warmed to room temperature and stirred overnight. The mixture was poured into distilled water (50 mL), acidified to pH 3 with 1M hydrochloric acid in an ice-bath and extracted into ethyl acetate (3×50 mL). The organic phases were washed with brine (2×30 mL) and dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (Silica gel, 40% EtOAc in hexanes) to give 0.420 g compound 5 (15%). 1H NMR (300 MHz, CDCl3) δ 0.85 (t, 3H, J=6.22 Hz), 1.24 (m, 10H), 1.58 (p, 2H, J=6.95 Hz), 1.97 (s, 3H), 2.45-2.60 (m, 4H), 2.83-3.21 (m, 4H), 3.88 (dd, 1H, J=14.00 Hz, 3.68 Hz), 4.05 (s, 6H), 6.86 (s, 1H), 7.03 (s, 1H), 7.07 (d, 1H, J=8.69 Hz), 7.84 (d, 1H, J=8.36 Hz).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[C:14]([CH:22]([F:24])[F:23])[CH2:15]P(=O)(OC)OC)=[CH:9][CH:8]=1.[CH:32]([CH:34]1[O:39][C:38](C)(C)[O:37][CH:36]([CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:35]1)=O>O1CCCC1>[F:23][CH:22]([F:24])[C:14](=[C:13]([C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=1)[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)[CH:15]=[CH:32][CH:34]1[O:39][CH2:38][O:37][CH:36]([CH2:42][C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:35]1
Reactant: CC(C)(C)OC(=O)CC1CC(C=O)OC(C)(C)O1
Reactant: COP(=O)(CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(F)F)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CC(C=CC(=C(c2ccc(F)cc2)c2ccc(F)cc2)C(F)F)OCO1
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Butyl lithium (1.04 mL of 2.5M solution, 2.6 mmol) was added to a solution of dimethyl [3,3-bis(4-fluorophenyl)-2-difluoromethyl-2-propen-1-yl]phosphonate (1.0 g, 2.6 mmol) in 10 mL of tetrahydrofuran at -78° C. After stirring for 30 minutes, 1,1-dimethylethyl 6-formyl-2,2-dimethyl-1,3-dioxane-4-acetate (0.82 g, 3.2 mmol) was added and the mixture stirred for 64 hrs. at room temperature. The mixture was quenched with saturated ammonium chloride solution and extracted with diethyl ether. The extracts were dried over magnesium sulfate and conentrated in vacuo. The residue was purified by chromatography on silica eluting with 5% ethyl acetate in hexane to give an oil. Crystallization from pentane gave 0.6 g of the title compound; m.p. =124°-125° C.
Reaction SMILES: C([BH3-])#N.[Na+].[O:5]1[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[C:10]([CH2:17][N:18]2[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]2=[O:28])=[CH:9][N:8]3[CH2:7][CH2:6]1.[OH-].[Na+]>CO.C(O)(C(F)(F)F)=O.O>[O:5]1[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH:10]([CH2:17][N:18]2[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]2=[O:28])[CH2:9][N:8]3[CH2:7][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cn2c3c(cccc13)OCC2
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2C(=O)N1CC1CN2CCOc3cccc1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A freshly prepared solution of sodium cyanoborohydride (0.093 g, 1.48 mmol) in CH3OH (0.3 mL) was added dropwise to a 0° C. solution of 2-(2,3-dihydro[1,4]oxazino[2,3,4-hi]indol-6-ylmethyl)-1H-isoindole-1,3(2H)-dione (0.094 g, 0.29 mmol) in TFA (3.0 mL). The mixture was stirred at rt for 1 hour and diluted with H2O (10.0 mL) and made basic by the addition of 15% NaOH. The mixture was then extracted with EtOAc (3×). The combined EtOAc solution was dried over MgSO4 and concentrated in vacuo to dryness. The residue was redissolved in CH2Cl2 and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to preparative TLC (EtOAc/Hex., ½) to give 0.031 g (33%) of light yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.93-7.88 (m, 2 H), 7.80-7.75 (m, 2 H), 6.79-6.77 (m, 1 H), 6.75-6.65 (m, 2 H), 4.46-4.43 (m, 2 H), 4.10-4.05 (m, 1 H), 4.00-3.94 (m, 1 H), 3.77-3.73 (m, 1 H), 3.34-3.33 (m, 1 H), 3.30-3.26 (m, 1 H), 3.17-3.15 (m, 1 H), 3.10-3.08 (m, 1 H); MS (EI) m/z 321 (M++H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:4]=2[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:6](=[O:17])[CH:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:8]=1.[O:32]=[C:33]1[NH:37][C:36]2[CH:38]=[CH:39][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:41][C:35]=2[NH:34]1.[Cl-].[Li+].O.[OH-].[Cs+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O1CCOCC1>[Cl:31][C:29]1[CH:28]=[CH:27][C:4]2[N:5]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:6](=[O:17])[CH:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[N:8]=[C:2]([C:39]3[CH:40]=[CH:41][C:35]4[NH:34][C:33](=[O:32])[NH:37][C:36]=4[CH:38]=3)[C:3]=2[CH:30]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Agent: [Pd]
Agent: [Cl-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3ccc4[nH]c(=O)[nH]c4c3)c3cc(Cl)ccc32)cc1
Temperature: 100 °C

Procedure:
(E)-5,7-Dichloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.68 g, 1.44 mmol), 2-oxo-2,3-dihydro-1H-benzoimidazole-5-boronic acid pinacol ester (0.37 g, 1.44 mmol) and lithium chloride (0.183 g, 4.31 mmol) were added to 1,4-dioxane (12 mL). Nitrogen was bubbled into the solution as reagents were added. Tetrakis(triphenylphosphine) palladium(0) (166 mg, 0.144 mmol) was added followed by cesium hydroxide monohydrate (723 mg, 4.31 mmol) and water (1 mL). After bubbling nitrogen through the mixture for 5 minutes it was heated to 100° C. under a nitrogen atmosphere. Following heating for 2 hours, the mixture was cooled to ambient temperature, diluted with ethyl acetate (50 mL), washed with water (2×40 mL), then brine (40 mL), dried with sodium sulfate, decanted, then concentrated in the presence of silica. The resulting silica gel-bound crude product was loaded onto a silica gel column and eluted with a gradient of 0-100% ethyl acetate in hexanes to yield (Z)-7-chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-5-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one as a 2:1 mixture of product:2-oxo-2,3-dihydro-1H-benzoimidazole-5-boronic acid pinacol ester (200 mg, 24%). ESI m/z 571.1, 573.1.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][C:4]=2[CH:3]=[C:2]1[C:9]([O:11][CH3:12])=[O:10].[C:13](O)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[C:13]([N:7]1[CH2:8][C:4]2[CH:3]=[C:2]([C:9]([O:11][CH3:12])=[O:10])[S:1][C:5]=2[CH2:6]1)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1cc2c(s1)CNC2
Reactant: CC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1cc2c(s1)CN(C(=O)C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate (0.023 g, 0.127 mmol) and pivalic acid (0.014 g, 0.14 mmol) in methylene chloride (0.92 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.055 g, 0.146 mmol) and N-methylmorpholine (0.035 mL, 0.32 mmol) respectively. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with additional DCM (2 mL) and washed with saturated aqueous NaHCO3 (2 mL). The aqueous layer was extracted with additional DCM (3 mL), and the combined organic layers were concentrated to afford an oily residue. LCMS (FA) ES+ 268.
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](Cl)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:41][O:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1>ClCCl>[CH3:41][O:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][C:27]([C:24]2[N:16]3[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]4[CH:9]=[CH:8][C:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:31][CH:30]=4)[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17]3)=[CH:26][CH:25]=2)=[O:28])=[CH:45][CH:44]=1
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reactant: COc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(C4CCCCC4)cc2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl chloride prepared in the manner of Example 23 (1.0 g) was added to a stirred mixture of N,N-diisopropylethyl amine (0.31 g) and 4-methoxy aniline (0.35 g) in dichloromethane (25 mL). After stirring overnight at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol® and the eluate evaporated to dryness to provide the desired title compound (1.0 g) as an off-white amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5](=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[OH:6].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:25]([C:16]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=1[O:6][C:5]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=1[C:3]([O:2][CH3:1])=[O:13])([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Methyl-4-methoxysalicylate (12.0 g, 0.066 mol), 4-chloro-3-nitrobenzotrifluoride (9.75 mL, 0.066 mol) and potassium carbonate (18.16 g, 0.131 mol) were mixed in dimethylformamide, under argon, at 150° C. for 16 h. The reaction mixture was filtered and the solvents evaporated. The residue was flash chromatographed (silica gel, ethyl acetate/hexane) to yield the title compound. 1H NMR (250 MHz, CDCl3) δ8.25 (d, 1H), 8.04 (d, 1H), 7.65 (dd, 1H), 6.91 (dd, 1H), 6.81 (d, 1H), 6.70 (d, 1H), 3.88 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](O)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:38]1[C:43](C)=CC=C[C:39]=1C.Cl.CNC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:24])[N:38]([CH3:43])[CH3:39])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: Cc1cccc(C)n1
Agent: CNC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, dimethylamine hydrochloride (96 mg, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-dimethylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-propionamide (10 mg, 20%) as a white solid: ESI-LRMS m/e calcd for C23H31ClN4O4S [M+] 494.2, found 495.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.22 (m, 2H, CH2), 1.43-1.95 (m, 8H, 4×CH2), 2.16-2.31 (m, 1H, CH), 2.79 (t, J=6.6 Hz, 2H, COCH2), 2.92 (s, 3H, NCH3), 2.93 (s, 3H, NCH3), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.6 Hz, 1H, CH), 4.34 (t, J=6.6 Hz, 2H, NCH2), 6.59 (d, J=2.3 Hz, 1H, Ar), 7.36 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.8 Hz. 1H, Ar), 7.59 (d, Jm=1.8 Hz, 1H, Ar), 7.82 (s, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH2:1])=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: Nc1ccccc1B(O)O
Product: Nc1ccccc1-c1ccc(Cn2ccnc2)cn1

Procedure:
Synthesized using 2-aminophenylboronic acid (173 g, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 120 mg, 0.48 mmol, 76%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.17 (s, 2H), 6.74-6.79 (m, 2H), 6.93 (t, J=1.3 Hz, 1H), 7.13 (bs, 1H), 7.16-7.19 (m, 1H), 7.49-7.53 (m, 2H), 7.62 (s, 1H), 7.66 (d, J=8.2 Hz, 1H). 8.48 (d, J=1.8 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.2, 117.3, 117.6, 119.1, 121.1, 122.2, 128.7, 129.3, 130.2, 130.3, 135.8, 137.3, 146.6, 146.7, 159.7; MS (ESI): m/z=250.71 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11][OH:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1>O1CCCC1>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11][O:12][C:18]2[N:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCCO)cc1
Reactant: Clc1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OCCOc2ncc(Cl)cn2)cc1

Procedure:
A mixture of 2-(4-acetamidophenoxy)ethanol (25 g), granular sodium hydride (3.1 g) and dry tetrahydrofuran (250 ml) was heated under reflux for a period of 2 hours. 2,5-Dichloropyrimidine* (19 g) was added and the mixture was heated under reflux for a further 8 hours. The solvent was removed by distillation under reduced pressure, water was added and the crystalline product was collected and dried to give 2-[2-(4-acetamidophenoxy)ethoxy]-5-chloropyrimidine (35 g), m.p. 160° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1[S:11][C:12]([C:16]([C:18](=[C:37](SC)SC)[C:19]([C:21]2[CH:22]=[C:23]([S:27]([NH:30][C:31](=[NH:36])[C:32]([OH:35])([CH3:34])[CH3:33])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=2)=[O:20])=[O:17])=[C:13]([CH3:15])[N:14]=1>CCO>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:37]1=[C:18]([C:16]([C:12]1[S:11][C:10]([CH3:9])=[N:14][C:13]=1[CH3:15])=[O:17])[C:19]([C:21]1[CH:22]=[C:23]([S:27]([NH:30][C:31](=[NH:36])[C:32]([OH:35])([CH3:34])[CH3:33])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: CSC(SC)=C(C(=O)c1cccc(S(=O)(=O)NC(=N)C(C)(C)O)c1)C(=O)c1sc(C)nc1C
Reactant: Nc1ccccc1N
Solvent: CCO
Product: Cc1nc(C)c(C(=O)C(C(=O)c2cccc(S(=O)(=O)NC(=N)C(C)(C)O)c2)=C2Nc3ccccc3N2)s1
Yield: 81.9 %

Procedure:
1,2-Phenylenediamine (81 mg) was added to an EtOH (20 mL) solution of N-[(3-{2-[(2,4-dimethyl-1,3-thiazol-5-yl)carbonyl]-3,3-bis(methylthio)acryloyl}phenyl)sulfonyl]-2-hydroxy-2-methylpropanimidamide (370 mg), followed by heating under reflux for 13 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=50/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(2,4-dimethyl-1,3-thiazol-5-yl)-3-oxopropanoyl]phenyl}sulfonyl)-2-hydroxy-2-methylpropanimidamide (310 mg).
Reaction SMILES: B1([O-])OO1.O.O.O.O.[Na+].[K+].[Br-:11].[CH:12]1([N:15]2[C:22](=[O:23])[CH2:21][CH2:20][NH:19][C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[CH2:16]2)[CH2:14][CH2:13]1>C(O)(=O)C.[NH4+].[NH4+].O.O.O.O.[O-][Mo]([O-])(=O)=O>[Br:11][C:26]1[CH:25]=[CH:24][C:18]2[NH:19][CH2:20][CH2:21][C:22](=[O:23])[N:15]([CH:12]3[CH2:14][CH2:13]3)[CH2:16][C:17]=2[CH:27]=1
Reactant: O=C1CCNc2ccccc2CN1C1CC1
Reactant: [Br-]
Agent: O=[Mo](=O)([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCNc2ccc(Br)cc2CN1C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.4 %

Procedure:
Sodium perborate tetrahydrate (1.07 g, 6.94 mmol) was added in one portion to a suspension of KBr (0.770 g, 6.47 mmol), 5-cyclopropyl-2,3,5,6-tetrahydrobenzo[b][1,5]diazocin-4(1H)-one (1.00 g, 4.62 mmol) and ammonium molybdate tetrahydrate (0.114 mg, 0.092 mmol) in acetic acid (10 ml). The mixture was stirred at room temperature for 24 hours, then quenched with sodium carbonate (aqueous saturated) and a few drops of NaOH (10% aqueous). The mixture was extracted with ethyl acetate and the combined organic phases were washed with sodium carbonate, dried over sodium sulfate filtered and concentrated. Purification of the crude mixture by silica gel flash chromatography (0-20% methanol in ethyl acetate) gave the desired product as a brown solid (0.619 g, 45%).
Reaction SMILES: C[O:2][C:3](=[O:49])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]2[C:25]3[C:17](=[CH:18][C:19]4[CH2:20][O:21][CH2:22][C:23]=4[C:24]=3[CH3:26])[C@@H:16]([N:27]([CH2:34][C:35]3[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=3)[C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)[CH2:15][CH2:14][CH2:13]2)[CH2:7][CH2:6]1.[OH-].[Na+].Cl>CO.O>[F:48][C:45]([F:46])([F:47])[C:37]1[CH:36]=[C:35]([CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=1)[CH2:34][N:27]([C:28]1[N:29]=[N:30][N:31]([CH3:33])[N:32]=1)[CH:16]1[C:17]2=[CH:18][C:19]3[CH2:20][O:21][CH2:22][C:23]=3[C:24]([CH3:26])=[C:25]2[N:12]([CH2:11][CH:8]2[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:49])=[O:2])[CH2:6][CH2:7]2)[CH2:13][CH2:14][CH2:15]1
Reactant: COC(=O)CC1CCC(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc4c(c(C)c32)COC4)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c2c(cc3c1N(CC1CCC(CC(=O)O)CC1)CCCC3N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)COC2
Temperature: 60 °C

Procedure:
To a solution of (S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-4-methyl-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-cyclohexyl)-acetic acid methyl ester (0.15 mmol) in methanol (5 mL), add 5 N sodium hydroxide (3 mL). Heat the mixture to 60° C. for 2 h, then cool to room temperature and dilute with water (20 mL). Neutralize the reaction with 5M HCl and extract the organics with ethyl acetate (3×10 mL). Dry the combined organics over sodium sulfate, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (10-70%) to obtain the title compound as a colorless foam. MS (ES+): 681 (M+H).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(#N)C.CCOC(C)=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([F:13])[CH:15]=2)[C:3]([OH:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=C(O)C(Br)c1ccc(F)cc1
Reactant: Nc1cccc(F)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)C(Nc1cccc(F)c1)c1ccc(F)cc1
Temperature: 100 °C
Yield: 90.1 %

Procedure:
A mixture of 2-bromo-2-(4-fluorophenyl)acetic acid (500 mg, 2.15 mmol) and 3-fluoroaniline (477 mg, 4.29 mmol) in acetonitrile (8 mL) is heated under microwave irradiation at 100° C. for 50 minutes. Then 3-fluoroaniline (238 mg, 2.15 mmol) is added again and reaction is heated at 120° C. for 45 minutes in a microwave oven (LC-MS monitoring: complete conversion). The organic solution is diluted with EtOAc and washed with 2N HCl and then with brine. The organic phase is dried over Na2SO4, filtered and the solvent is evaporated to give intermediate I131 as a white solid (510 mg, 90% yield).