Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][CH:3]=1.[CH:24]1([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:29][C:30]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][N:8]3[CH2:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=3[O:22][CH3:23])=[CH:4][CH:3]=2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1ccc(CN2CCc3ccc(N)cc32)c(OC)c1
Reactant: O=C(O)CC1CCCC1
Product: COC(=O)c1ccc(CN2CCc3ccc(NC(=O)CC4CCCC4)cc32)c(OC)c1
Yield: 26 %

Procedure:
Using a similar procedure to that described in Example 185, but starting from methyl 4-(6-aminoindolin-1-ylmethyl)-3-methoxybenzoate and 2-cyclopentylacetic acid, there was obtained methyl 4-[6-(2-cyclopentylacetamido) indolin-1-ylmethyl]-3-methoxybenzoate in 26% yield as an off-white solid, partial NMR: 2.3 (br s,3H,CHCH2), 3.0 (t,2H,H3 -indoline), 3.4 (t,2H,H2 -indoline).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[C:15]([NH2:19])=[N:14][CH:13]=[CH:12]3)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:48])[C:39]1[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:41](Cl)=[O:42]>ClCCl>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[C:15]([N:19]2[C:41](=[O:42])[C:40]4[C:39](=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:38]2=[O:48])=[N:14][CH:13]=[CH:12]3)=[CH:22][CH:23]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3ccnc(N)c3cn2)cc1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3ccnc(N4C(=O)c5ccccc5C4=O)c3cn2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred mixture of crude 4-5 (10.9 g, <19.3 mmol), triethylamine (8.05 mL, 57.8 mmol), and dichloromethane (75.0 mL) at 0° C. under an atmosphere of nitrogen gas was added phthaloyl dichloride (90%; 3.75 mL, 23.4 mmol). The resulting mixture was stirred at ambient temperature for 15 hours under an atmosphere of nitrogen gas. The reaction mixture was quenched with saturated aqueous NH4Cl (200 mL) and the resulting mixture was extracted with dichloromethane (1000 mL, 500 mL×2). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 200 g, step gradient eluting with 50:1, 40:1, 30:1, 20:1, 10:1, and 5:1 dichloromethane/ethyl acetate) followed by recrystallization from dichloromethane to give 3.94 g (39% in 3 steps) of 4-6 as yellow crystals: 1H NMR (400 MHz, CDCl3) δ 8.94 (1H, br s), 8.33 (1H, d, J=6.0 Hz), 8.02 (2H, m), 7.84 (2H, m), 7.31 (1H, dd, J=6.0, 0.8 Hz), 7.15 (4H, m), 6.85 (4H, m), 6.52 (1H, br s), 4.81 (4H, br s), 3.79 (6H, s); ESI-MS m/z 531 [C32H26N4O4+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[O:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:26][OH:27].O>C(O)(C)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[O:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:26][OH:27])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ncn2c1COC(=O)c1c(Cl)cccc1-2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: NC(=NO)c1ncn2c1COC(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 96 h
Yield: 68.3 %

Procedure:
A mixture of 7-chloro-5,6-dihydro-6-oxo-4H-imidazo [1,5-a][4,1]benzoxazepine-3-carbonitrile (16.86 g, 0.06 mole), potassium carbonate (13.5 g, 0.9 mole) and hydroxylamine hydrochloride (4.6 g, 0.06 mole) in isopropanol (843 ml) containing water (13.5 ml) was stirred at room temperature for 4 days. The reaction mixture was then concentrated to a volume of 256 ml by distillation, cooled to room temperature and water (256 ml) added. The resulting mixture was cooled at 0° C. for 1 hour and the solid collected, washed with water and dried in vacuo at 50° C. to give the product (12 g, 63%), m.p. 252°-254° C.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8]C)=O.[NH2:13][CH:14]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[CH:16]=O>CO>[O:8]=[C:6]1[C:5]([C:4]([O:11][CH3:12])=[O:10])=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=2)=[CH:14][NH:13]1
Reactant: COC(=O)CC(=O)OC
Reactant: NC=C(C=O)c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.5 g. of sodium methoxide in 85 ml. of methanol is added 2.25 g. of dimethyl malonate and 2.93 g. of 3-amino-2-[3-(trifluoromethyl)phenyl]-2-propenal. The mixture is stirred at room temperature for 16 hours with precipitation of a yellow solid. The mixture is heated at reflux temperature for 2 hours, cooled and filtered to obtain a white solid. The solid is washed with ether, suspended in water and acidified with hydrochloric acid to yield 1.75 g. of the product of the Example as a white solid, m.p. 195°-201° C.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14](=[O:18])[N:13]([CH3:19])[C:12]=2[N:20]([C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=C.CC1C=CC=C(C)N=1.[O:44]1CCOCC1>O.O=[Os](=O)(=O)=O>[CH3:19][N:13]1[C:14](=[O:18])[C:15]([CH3:17])=[CH:16][C:11]([NH:10][S:7]([C:4]2([CH2:1][CH:2]=[O:44])[CH2:6][CH2:5]2)(=[O:8])=[O:9])=[C:12]1[N:20]([C:28]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=1[F:35])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25]
Reactant: C1COCCO1
Reactant: C=CCC1(S(=O)(=O)Nc2cc(C)c(=O)n(C)c2N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: Cc1cccc(C)n1
Product: Cc1cc(NS(=O)(=O)C2(CC=O)CC2)c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)n(C)c1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a solution of tert-butyl 3-(1-allylcyclopropanesulfonamido)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-2-yl(2-fluoro-4-iodophenyl)carbamate (2.370 g, 3.838 mmol) in dioxane (38.4 ml) under a nitrogen atmosphere was added H2O (7.7 ml). Then NalO4 (4 eq, 3.284 g, 15.353 mmol) and 2,6-dimethyl pyridin (2 eq, 0.894 ml, 7.676 mmol) were added and the mixture was cooled to 0° C. At this temperature OsO4 (4% in t-butanol, 0.04 eq, 1,925 ml, 0.154 mmol) was added. The mixture was allowed to come to room temperature and then stirred for 18 hours. The mixture was diluted with H2O (4 ml) to form a fine suspension. After stirring for 30 min the precipitate was filtered off and washed with water, which dissolved the precipitate. The filtrate was extracted twice with ethyl acetate, washed once with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography (Biotage system) to afford the title compound (1.92 g, 79%) as a mixture of the aldehyde and a cyclised 1,2-thiazolidin-3-ol 1,1-dioxide form.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4](Cl)[N:3]=1.[CH3:12][SH:13].C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4]([S:13][CH3:12])[N:3]=1
Reactant: CS
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc(N)c(C=O)nc1Cl
Reaction time: 0.5 h

Procedure:
In 3 ml of dimethylformamide there was dissolved 2-amino-5,6-dichloro-3-formylpyrazine (384 mg; 0.002 M), and the solution was cooled in an ice bath. Through the solution there was then bubbled methanethiol gas for 2 minutes. Triethylamine was added, and more methanethiol gas was bubbled through the solution for 3 minutes. The reaction mixture was stirred in the ice bath for 30 minutes and then at room temperature for 30 minutes. The solvent and methanethiol were then removed under nitrogen atmosphere, and the residue was treated with water. The product precipitated, was filtered, and washed with water (333 mg). Elemental Analysis for C6H6N3OSCl.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[NH2:9][CH2:10][CH2:11][OH:12]>CCO>[C:1]([CH2:3][C:4]([NH:9][CH2:10][CH2:11][OH:12])=[O:6])#[N:2]
Reactant: NCCO
Reactant: CCOC(=O)CC#N
Solvent: CCO
Product: N#CCC(=O)NCCO
Yield: 90.6 %

Procedure:
To a solution of ethyl 2-cyanoacetate (10 g, 9.41 mL, 88 mmol) in EtOH (100 mL) was added 2-aminoethanol (5.40 g, 5.34 mL, 88 mmol). The mixture was refluxed for 4 h before concentration in vacuo. The mixture was purified on a 100 g Silica column eluting with 0-10% MeOH/DCM. Desired fractions were collected and concentrated to yield the desired product as a brown oil (10.2 g, 79.7 mmol, 90%). The sample was used directly in the next step without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13]CC2C=CC=CC=2)[CH2:10][C@@H:9]1[C@H:21]1[O:25][C:24]([CH3:27])([CH3:26])[N:23]([C:28](=[O:30])[CH3:29])[C@H:22]1[CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C@H:21]1[O:25][C:24]([CH3:26])([CH3:27])[N:23]([C:28](=[O:30])[CH3:29])[C@H:22]1[CH2:31][C:32]1[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)OC1(C)C
Yield: 100 %

Procedure:
Combine (2R,4R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-benzyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.22 mmol), 10% palladium on carbon (12 mg) and methanol (10 mL) and stir overnight under 1 atmosphere of hydrogen. Add filter agent, filter, and concentrate under reduced pressure to provide the desired compound (0.100 g, 98%) as a foam.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[S:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1>C(Cl)(Cl)Cl.CO>[C@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[S:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)S2)c(=O)[nH]1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1ccn([C@@H]2C[C@H](O)[C@@H](CO)S2)c(=O)[nH]1
Yield: 85 %

Procedure:
A solution of 1-(2-deoxy-4-thio-3,5-di-O-toluoyl-β-D-ribofuranosyl)uracil (formula 15) (175 mg, 0.36 mmol) in anhydrous MeOH (30 mL) was stirred at room temperature with a freshly prepared solution of sodium methoxide (39 mg, 0.72 mmol) in MeOH (6.5 mL). A TLC aliquot at 2.5 hours showed complete reaction (CHCl3 -MeOH, 95:5). The solution was rendered neutral with Dowex 50W-X8 (H+) ion-exchange resin, the suspension filtered, and the resin was washed with MeOH. The filtrate was combined and evaporated to dryness, and methyl p-toluate was removed at 50° C./0.01 torr. Crystallization of the residue from absolute EtOH gave pure 2'-deoxy-4'-thiouridine (76 mg, 85%); mp 186°-88° C.; TLC 9:1 CHCl3 -MeOH, Rf 0.30; MS z/e 245 (M+1)+, UV λmax pH 1 266 (9.88), pH 7 266 (9.76), pH 13 266 (8.08); 1H NMR (DMSO-d6, 300 MHz) δ2.10-2.22 (m, 2H, H-2'), 3.20-3.34 (m, 1H, H-4'), 3.52-3.62 (m, 2H, H-5'), 4.36 (s, 1H, H-3'), 5.18 (br s, 1H, OH), 5.30 (br s, 1H, OH), 5.68 (d, 1H, H-5, J=8 Hz), 6.26 (t, 1H, H-1', J=7.0 Hz), 8.0 (d, 1H, H-6, J=8 Hz), 11.34 (br s, 1H, H-3). 13C NMR (DMSO-d6, 300 MHz) δ41.246 (C-2'), 58.981 (C-4'), 60.108 (C-1'), 63.465 (C-5'), 73.438 (C-3'), 102.133 (C-5, J=175.92 Hz), 141.354 (C-6, J=180.75 Hz), 150.615 (C-2), 162.743 (C-4). Anal. Calcd. for C9H12N2O4S: C, 44.25; H, 4.95;N, 11.46; S, 13.12. Found: C, 44.20; H, 4.97; N, 11.42; S, 13.03. 1-(2-deoxy-4-thio-3,5-di-O-toluoyl-α-D-ribofuranosyl)uracil was deprotected in a similar manner as described for 2'-deoxy-4'-thiouridine to provide pure 1-(2-deoxy-4-thio-α-D-ribofuranosyl)uracil (75 mg, 85%), mp 190°-192° C.; TLC 9:1 CHCl3 -MeOH, Rf 0.30; MS z/e 245 (M+1)+, UV λmax pH 1 266 (9.24), pH 7 266 (9.52), pH 13 265 (8.72); 1H NMR (Me2SO-d6, 300 MHz) δ2.0-2.28 (m, 1, H-2'), 2.44-2.54 (m, 1H, H-2'), 3.30-3.38 (m, 1H, H-5'), 3.40-3.48 (m, 1H, H-5'), 3.50-3.56 (m, 1H, H-4'), 4.32 (br dd, 1, H-3', J=2 and 8 Hz), 5.64 (d, 1H, H-6, J=8 Hz), 6.14 (dd, 1, H-1', J=3 and 7.5 Hz), 8.26 (d, 1H, H-5, J=8 Hz); 13C NMR (Me2SO-d6, 300 MHz) δ42.16 (C-2), 60.01 (C-4'), 60.95 (C-1'), 63.57 (C-5'), 74.14 (C-3') 101.16 (C-5, JC,H =175.24 Hz), 142.92 (C-6, JC,H =181.88 Hz), 150.69 (C-2), 162.97 (C-4). Anal. Calcd. for C9H12N2O4S: C, 44.25; H, 4.95; N, 11.46; S, 13.12. Found: C, 44.17; H, 4.97; N, 11.39; S, 13.21.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([B:12]1[O:20][C:17]([CH3:19])([CH3:18])[C:14]([CH3:16])([CH3:15])[O:13]1)[CH:6]=[CH:5]2.CCN([CH2:26][CH3:27])CC>C(Cl)Cl>[O:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([B:12]1[O:20][C:17]([CH3:19])([CH3:18])[C:14]([CH3:15])([CH3:16])[O:13]1)[CH:6]=[CH:5]2)[C:27]1[CH:26]=[CH:10][CH:11]=[CH:2][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC1(C)OB(c2ccc3cc(O)ccc3c2)OC1(C)C
Solvent: ClCCl
Product: CC1(C)OB(c2ccc3cc(Oc4ccccc4)ccc3c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phenylboronic acid (140 mg, 1.1 mmol, 2.0 eq.) was coevaporated with PhMc twice to produce the anhydride. This was treated with crude 6-hydroxynaphthalene-2-boronic acid pinacol ester (150 mg, 0.56 mmol), DCM (5 mL), NEt3 (400 uL, 3 mmol, 5 eq.), and cupric acetate (100 mg, 0.53 mmol, 0.95 eq.) and stirred at ambient temperature during 16 h. The mixture was extracted from 0.1M NaOH into DCM, dried on Na2SO4, concentrated, and chromatographed on silica gel (0→2% EtOAc/hexanes) to give 6-phenoxynaphthalene-2-boronic acid pinacol ester, which was deprotected via Method 5 to provide compound 216 (54 mg, 37%). [M−H]−=263.1 m/z. Activity: A
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:13]([C:12]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[O:14])=[CH:23][CH:22]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)cc1)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
In a 500 mL round bottom flask crude 1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride (47 mmol) was dissolved in 200 mL CH2Cl2 to afford a dark solution. To this solution was added 8.2 g of 4-bromoaniline (47 mmol) and a few pellets of 4-(dimethylamino)pyridine. The resulting slurry was treated with 20 mL of N,N-diisopropylethylamine (115 mmol) to afford a dark solution. After stirring for 2 hours at room temperature the reaction was quenched by the addition of H2O and diluted with additional CH2Cl2. The organic layer was washed with 1N HCl, saturated NaHCO3 solution, dried (Na2SO4), filtered, and concentrated in vacuo to afford crude N-(4-bromophenyl)-1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide as a dark brown syrup. The crude product was purified by silica gel flash chromatography on a 300 g column using gradient elution from 0% to 30% EtOAc/hexane. Most of the product-containing fractions were impure. All product-containing fractions were combined and concentrated in vacuo to afford a sticky orange foam. This material was further purified by silica gel flash chromatography on a 160 g column using gradient elution from 0% to 20% EtOAc/hexane. Appropriate fractions were combined and concentrated in vacuo to afford N-(4-bromophenyl)-1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide as a pale orange foam that was broken up to a powder. The material is not completely pure. Yield: 2.61 g (12% yield); 1H NMR (400 MHz, CDCl3): δ 7.64 (br s, 1H), 7.56-7.55 (impurity), 7.54-7.53 (m, 1H), 7.52-7.51 (m, 1H), 7.50-7.49 (impurity), 7.48-7.44 (m, 3H), 7.43-7.41 (m, 1H), 7.38-7.36 (m, 1H), 7.36-7.34 (m, 1H), 7.11 (s, 1H); GC/MS (EI, 70 eV) 445, 443.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[OH:15][CH2:16][C@@H:17]([NH:25][C:26](=[O:30])[C:27](O)=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]([NH:25][C@@H:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][OH:15])=[O:30]
Reactant: O=C(O)C(=O)N[C@H](CO)Cc1ccccc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C(=O)N[C@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
The mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.256 g; 1.09 mmol), (S)-2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoacetic acid (0.267 g; 1.19 mmol), HATU (0.413 g: 1.09 mmol) and N,N-diisopropylethylamine (0.474 mL; 2.71 mmol) in DMF (5 mL) was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water and was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) to yield 0.251 g (58%) of (S)-N1-(2-(5-chloro-1H-indol-3-yl)ethyl)-N2-(1-hydroxy-3-phenylpropan-2-yl)oxalamide as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:30]([C:27]4[CH:26]=[N:25][C:24]([C:21]5[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=5)=[CH:29][N:28]=4)=[O:31])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1cnc(-c2ccc(F)cc2)cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3cnc(-c4ccc(F)cc4)cn3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 5-(4-fluorophenyl)-2-pyrazinecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:4][CH:3]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1>CN(C)C=O>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]3[CH:12]=[CH:13][C:14]4[N:18]=[C:17]([CH2:19][O:20][C:21]5[CH:34]=[CH:33][C:24]([CH2:25][CH:26]6[S:30][C:29](=[O:31])[NH:28][C:27]6=[O:32])=[CH:23][CH:22]=5)[N:16]([CH3:35])[C:15]=4[CH:36]=3)=[CH:4][CH:3]=2)=[O:46])=[CH:40][CH:39]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(N)cc3)cc21
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(NC(=O)Nc4ccc(Cl)cc4)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a mixture of 5-[4-[6-[2-(4-aminophenyl)ethoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g) and N,N-dimethylformamide (10 ml) was added 4-chlorophenyl isocyanate (0.15 g) and the mixture was stirred at room temperature for 1 hour and allowed to stand overnight. The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. To the residue was added diethyl ether. The precipitate was isolated by filtration and recrystallized from a mixture of tetrahydrofuran and ethyl acetate to afford the title compound (0.37 g, mp 157-162° C.).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C=O.[CH3:12][O:13][CH:14](OC)[O:15][CH3:16].Cl>O1CCOCC1.C(=O)(O)[O-].[Na+].CO>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:14]([O:15][CH3:16])[O:13][CH3:12]
Reactant: O=CCCCCCCCCBr
Reactant: COC(OC)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(CCCCCCCCBr)OC
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a 100 mL round-bottomed flask was added 9-bromononanal (7.2 g, 32.5 mmol), methanol (30 mL) and trimethylorthoformate (4 mL, 36.5 mmol). A solution of 4 N hydrochloric acid in dioxane (0.2 mL, 0.8 mmol) was added and the resulting mixture was refluxed for 3 h. The reaction mixture was then cooled to room temperature and solid sodium bicarbonate (100 mg, 1.2 mmol) was added. The resulting mixture was concentrated to one-fourth its original volume under reduced pressure and then ethyl acetate (50 mL) was added. The organic layer was washed with water (2×40 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title intermediate (8.44 g, (97% yield)) as a liquid, which as used in the next step without further purification.
Reaction SMILES: [CH3:1][Al](C)C.Br[C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:13]2)=[N:10][CH:11]=1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C@H:14]1[CH2:15][CH2:16][N:12]([C:9]2[N:8]=[CH:7][C:6]([CH3:1])=[CH:11][N:10]=2)[CH2:13]1
Reactant: C[Al](C)C
Reactant: Clc1ccc(CN[C@H]2CCN(c3ncc(Br)cn3)C2)c(Cl)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 65 °C

Procedure:
Add trimethylaluminium (2 N in hexanes, 190 μL, 0.32 mmol) and tetrakis(triphenylphosphine)palladium (0) (26 mg, 0.022 mmol) to (S)-[1-(5-bromopyrimidin-2-yl)-pyrrolidin-3-yl]-(2,4-dichlorobenzyl)-amine in dry THF (1.5 mL) and heat at 65° C. for 2 h, then add extra trimethylaluminium (2 N in hexanes, 190 μL, 0.32 mmol) and tetrakis(triphenylphosphine)palladium (0) (26 mg, 0.022 mmol) and heat at 65° C. for 30 min and 48 h at room temperature. Add water and extract with chloroform. Combine the organic layers and wash with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and dissolve the residue in methanol (2 mL) and deposit onto an SCX-2 cartridge; eluting with methanol, then with 2 N ammonia in methanol. Concentrate the ammonia washing and chromatograph the residue by preparative mass guided chromatography to give the title compound as a residue. Treatment of the residue essentially as described in Example 1 gives the title compound as its hydrochloride. 1H NMR (300 MHz, CDCl3) δ 8.16 (2H, s), 7.37 (2H, dd, J=5.09, 3.01 Hz), 7.21 (1H, dd, J=8.29, 2.07 Hz), 3.90 (2H, d, J=4.90 Hz), 3.68-3.83 (2H, m), 3.58 (1H, m), 3.39-3.51 (2H, m), 2.14-2.25 (1H, m), 2.12 (3H, s), 1.84-1.96 (1H, m), MS (ES): m/z=337 [M+].