Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>ClCCl.C(OCC)(=O)C>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[CH:13][NH:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccccc1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(=CNc1cccccc1=O)C(=O)OCC

Procedure:
A mixture of 2-amino-2,4,6-cycloheptatrien-1-one (2 g), described by W. Von E. Doering and L. H. Knox, J. Amer. Chem. Soc., 73, 828 (1951), and diethyl ethoxymethylenemalonate (20 ml) was heated at 140° C. for 2 hr. The reaction was cooled and subjected to chromatography on silica gel using dichloromethane-ethyl acetate (4:1) as the eluant. The pure fractions were pooled to give 4.13 g of 2-[(7-oxo-1,3,5-cycloheptatrien-1-yl)aminomethylene]-propanedioic acid diethyl ester; mp 66°-68° C.; nmr (CDCl3) δ1.35 (m, 6H), 4.35 (m, 2H), 7.35 (m, 5H), 8.4 (d, 1H), 11.4 (broad, 1H); ir (CHCl3) 3230, 1700, 1665, 1580 cm-1 ; uv λ max (MeOH) 356 nm (ε13,770), 292 (9,880), 277 (10,680), 213 (17,020) with shoulders at 338 and 236 nm.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](OC)([O:9]C)[CH3:8])=[N:4][CH:3]=1.Cl>CC(C)=O.O>[Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[N:4][CH:3]=1
Reactant: COC(C)(OC)c1ncc(Br)s1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.4 %

Procedure:
A solution of 5-bromo-2-(1,1-dimethoxyethyl)-1,3-thiazole (35 g) was dissolved in acetone (200 ml) and water (200 ml), was added con. HCl (40 ml). The mixture was stirred for 5 h at room temperature. After concentration to remove acetone, the residue was adjusted to pH=7 by the addition of NaHCO3 and extracted with ether (30 ml×3). The organic layers were washed with brine, dried over Na2SO4 and concentrated to afford 25 g of 1-(5-bromo-1,3-thiazol-2-yl)ethanone as solid (87.4%). 1H-NMR (CDCl3 400 MHz) δ 7.87 (s, 1H, Ar—H), 2.66 (s, 3H, —CH3)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([I:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH3:20]>C(O)C.C(OCC)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([I:12])=[C:9]([O:11][CH2:19][CH3:20])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(I)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: CCOc1cc(C(C)(C)C)ccc1I
Temperature: 25 °C
Yield: 99 %

Procedure:
The mixture of 5-tert-butyl-2-iodo-phenol (132.7 g, 480.6 mmol), potassium carbonate (265.7 g, 1923 mmol) and ethyl iodide (76.9 mL, 961.3 mmol) in ethanol (1.125 mL) was heated at reflux overnight. Upon cooling to room temperature, the reaction mixture was diluted with diethyl ether. The white solids were filtered off, and the filtrate was concentrated in vacuo to give 4-tert-butyl-2-ethoxy-1-iodo-benzene (144.7 g) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Br:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[S:17][C:18]=1[Cl:19]>>[Br:13][C:14]1[CH:15]=[C:16]([S:20]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[N:8]=2)(=[O:22])=[O:21])[S:17][C:18]=1[Cl:19]
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Reactant: Nc1nc(-c2sccc2Cl)cs1
Product: O=S(=O)(Nc1nc(-c2sccc2Cl)cs1)c1cc(Br)c(Cl)s1

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine (59 mg) and 4-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic METHOD B to give a white solid (34.2 mg) with purity >90%: MS (pos) m/z 457.1, 477.1, 479.1.
Reaction SMILES: O(P(O[C:18]1[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21][O:20][CH:19]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:35]>>[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:18]2[N:24]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:23][CH2:22][CH2:21][O:20][CH:19]=2)=[CH:38][CH:37]=1)=[O:35]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: COC(=O)c1ccc(C2=COCCCN2C(=O)OC(C)(C)C)cc1
Yield: 41 %

Procedure:
This compound was prepared from tert-butyl 3-((diphenoxyphosphoryl)oxy)-6,7-dihydro-1,4-oxazepine-4(5H)-carboxylate and (4-methoxycarbonylphenyl)boronic acid according to the procedure described above in Example 2 (Step 3). The product was isolated as a white solid (41% yield); 1H-NMR (CDCl3) 1.11 (7H, s), 1.61 (2H, s), 2.16-2.18 (2H, m), 3.93-4.22 (7H, m), 6.32 (1H, s), 7.29-7.32 (2H, m), 7.97 (2H, d); MS ES(+) 278.1 (M+-tBu).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)([C:18]([O:20]CC)=[O:19])[C:13]([O:15]CC)=[O:14].[Li+].[OH-]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)([C:13]([OH:15])=[O:14])[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C(Cc1ccc2ccccc2n1)(OC1CCCCO1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc2ccccc2n1)(OC1CCCCO1)C(=O)O
Reaction time: 12 h
Yield: 90.7 %

Procedure:
A solution of ethyl 3-(quinolin-2-yl)-2-(2-tetrahydropyranyloxy)-2-ethoxycarbonyl-propanoate (0.5 g) in 5 ml of methanol is hydrolysed by treatment with a LiOH in MeOH--H2 0 solution. After 12 h at r.t., the solvent is evaporated off under vacuum and the residue is partitioned between AcOEt and an excess of a monobasic potassium phosphate saturated solution. The organic phase is separated, dried, evaporated to dryness to obtain 0.39 g of 3-(quinolin-2-yl)-2-(2-tetrahydropyranyloxy)-2-carboxy-propanoic acid.
Reaction SMILES: [OH:1][C:2]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][O:16][C:17]([NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([CH2:28][OH:29])=[CH:22][C:21]=2[Cl:30])=[O:18])[CH3:13])[CH2:8][CH2:7]1)=[O:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[OH:1][C:2]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)[C:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([N:12]([CH2:14][CH2:15][O:16][C:17]([NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([CH:28]=[O:29])=[CH:22][C:21]=2[Cl:30])=[O:18])[CH3:13])[CH2:10][CH2:11]1)=[O:4]
Reactant: COc1cc(NC(=O)OCCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(NC(=O)OCCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1C=O
Temperature: 25 °C

Procedure:
trans-4-[{2-[({[2-chloro-4-(hydroxymethyl)-5-methoxyphenyl]amino}carbonyl)oxy]ethyl}-(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 62; 200 mg; 0.33 mmol) was dissolved in 8 ml dichloromethane and stirred at room temperature in an inert atmosphere. Dess-Martin reagent (170 mg; 0.40 mmol) was added in 3 portions and the reaction stirred for 30 min. Dichloromethane (15 ml) was added, the solution was washed with 4% aqueous sodium hydrogen carbonate solution and vigorously stirred for 1 hour. The solid was filtered and the organic phase of the filtrate was washed with brine, dried and concentrated to give 197 mg of the title compound enough pure to continue with the next step.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Br:30])[CH:29]=1)[CH2:25]Br>>[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Br:30])[CH:29]=1)[CH2:25][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: BrCc1cc(Br)cc(Br)c1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Br)cc(Br)c2)c1
Yield: 70.6 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dibromobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (380 mg, yield: 70.6%).
Reaction SMILES: CC1C=CC=C(C)N=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18](Br)[C:19]([O:21]C)=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1.[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[CH:28]2>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18]([C:28]3[C:27]4[C:31](=[CH:32][CH:33]=[C:25]([Br:24])[CH:26]=4)[N:30]([CH3:34])[CH:29]=3)[C:19]([OH:21])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: Cn1ccc2cc(Br)ccc21
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2cc(Br)ccc21
Temperature: 80 °C
Yield: 79.4 %

Procedure:
2,6-Dimethylpyridine (0.75 ml) was added to a stirred solution of methyl 2-(1,3-benzodioxol-5-yl)-2-bromoacetate (from Example 61(c), 1.75 g, 6.43 mmol) and 5-bromo-1-methylindole (from step (a), 1.35 g) in anhydrous dimethylformamide (10 ml) at ambient temperature, under a nitrogen atmosphere. The solution was heated to 80° C. for 8 hours. The reaction mixture was partitioned between diethylether and water, separated and the organic layer dried (magnesium sulphate) and evaporated in vacuo. The residue was flash chromatographed (using 50% dichloromethane and 50% hexane as eluant) to give the subtitle compound as a colourless oil (1.98 g).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]1([C:30]([O:32]CC)=[O:31])[NH:15][C:14](=[O:16])[CH:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:12]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]1=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.C(OCC)(=O)C>C(O)C.O>[CH2:3]([C:10]1([C:30]([OH:32])=[O:31])[NH:15][C:14](=[O:16])[CH:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:12]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]1=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)NC(=O)C(CC(C)C)N(OCc2ccccc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)CC1C(=O)NC(Cc2ccccc2)(C(=O)O)C(=O)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
5.3 ml of 1N sodium hydroxide was added to 25 ml of a suspension of 2.32 g of (3RS,6SR)-3-benzyl-1-benzyloxy-3-ethoxycarbonyl-6-isobutylpiperazine-2,5-dione in ethanol. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was adjusted to pH 3 with 1N hydrochloric acid. Thereto were added 80 ml of ethyl acetate and 80 ml of water to conduct distribution. The organic layer was dried with anhydrous magnesium sulfate and then subjected to vacuum distillation to remove the solvent at room temperature to obtain 2.17 g of (3RS,6SR)-3-benzyl-1-benzyloxy-3-carboxy-6-isobutylpiperazine-2,5-dione as a light yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:10][O:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+:11].[OH-]>>[NH2:11][CH2:10][CH:8]([OH:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CC2CO2)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: NCC(O)Cc1ccccc1
Reaction time: 12 h

Procedure:
A solution of 2-(phenylmethyl)oxirane (7.5 g, 56.3 mmol) in NH4OH (100 mL) was stirred at 25° C. in a sealed tube. After 12 h, the solution was concentrated and used directly: LCMS (ES) m/e 152 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C:6]1[NH:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[S:8](=[O:17])(=[O:16])[N:7]=1)C.[OH-].[Na+:20]>CO.O>[Na+:20].[O:17]=[S:8]1(=[O:16])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:15][C:6]([CH2:5][C:4]([O-:18])=[O:3])=[N:7]1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2ncccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])CC1=NS(=O)(=O)c2ncccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
(1,1-Dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-acetic acid ethyl ester (0.25 g, 0.928 mmol) was dissolved in methanol (5 mL) at approximately 60° C. Sodium hydroxide (0.111 g, 2.79 mmol) was dissolved in water (2.5 mL). Upon cooling to 25° C., the solutions were combined. The mixture was stirred at 25° C. for 3 h. The mixture was stored at −40° C. for 16 h. The mixture was concentrated in vacuo to afford the crude product, (1,1-dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-acetic acid sodium salt (˜0.928 mmol), as a yellow film, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH:7]=[CH2:8].[C:10](OC)(=[O:14])[C:11]([CH3:13])=[CH2:12].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:10]([O:9][CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH:7]=[CH2:8])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)OC
Reactant: C=CC/C=C/CCCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC/C=C/CCCOC(=O)C(=C)C
Yield: 87 %

Procedure:
The method of Example 1 was substantially repeated, except that a shorter vigreux head (15 cm) was used, with trans-4,7-octadien-1-ol (18.53 g, 0.146 mol), methyl methacrylate (58.8 g, 0.59 mol), phenothiazine (0.5 g), and tetraisopropyl titanate (1.0 mL). When the head temperature rose to 96° C. (pot 117° C.), the methyl methacrylate was removed at 70 mm and the product was distilled to give 24.8 g (87% yield) of clear, colorless liquid trans-4,7-octadienyl methacrylate, bp 64°-65° C./0.2 mm. IR (film): ν 2950, 1712, 1629, 1445, 1311, 1287, 1156, 964, 933, 907, 810 cm-1. UV (isooctane): end absorption. 220 MHz 1H NMR: δ 6.06 (1H, bs, methacrylate vinyl), 5.76 (1H, m, --HC=CH2), 5.50 (1H, m, methacrylate vinyl), 5.41 (2H, m, --HC=CH--), 5.02-4.92 (2H, m, --HC=CH2), 4.11 (2H, t, J=6, OCH2 --), 2.72 (2H, m, doubly allylic CH2), 2.10 (2H, m, allylic CH2), 1.95 (3H, m, allylic CH3), and 1.73 (2H, pentet, J=6, OCH2CH2CH2). 22.63 MHz 13C NMR: δ 167.2, 137.1, 136.7, 130.2, 128.9, 124.9, 115.0, 64.1, 36.8, 29.1, 28.6, 18.3.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH2:12])[CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:19][C:20](Br)=[O:21]>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:19][C:20](=[O:21])[NH:12][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CS(=O)(=O)c1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-Methylsulfonyl-2-aminophenol (Intermediate 102) (690 mg, 3.68 mmol) was dissolved in chloroform (30 mL) and saturated sodium bicarbonate (20 mL). The biphasic reaction mixture was cooled to 0° C. and bromoacetyl bromide (889 mg, 4.42 mmol) was added dropwise. The reaction was stirred overnight at room temperature. The layers were separated and the aqueous layer was filtered to yield the desired product as a solid, 280 mg (33%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]([NH2:13])=[O:12]>C(O)C>[NH2:13][C:11]1[O:12][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(N)=O
Solvent: CCO
Product: CCOC(=O)c1coc(N)n1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A mixture of ethyl bromopyruvate (5.00 g), urea (2.31 g) and ethanol (51 mL) was refluxed overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.87 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:8]2.I[CH3:20]>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]2[CH3:20]
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2n1C
Temperature: 0 °C
Reaction time: 0.04 h
Yield: 97.4 %

Procedure:
NaH (60% dispersion in mineral oil, 0.24 g, 6 mmole) was washed with hexanes, then was suspended in anhydrous DMF (16 mL). The mixture was cooled to 0° C., and ethyl 4,6-dichloroindole-2-carboxylate (1.03 g, 4 mmole) was added. After 2-3 min, iodomethane (1.3 mL, 20 mmole) was added, and the mixture was warmed to RT. The mixture became thick, and stirring became difficult for several minutes. After 0.5 hr, the reaction was cooled to 0° C. and quenched with 10% NH4Cl (2 mL). The mixture was concentrated to dryness, and the residue was partitioned between Et2O (50 mL) and H2O (10 mL). The layers were separated and the organic layer was washed with H2O (5 mL), dried (MgSO4), and filtered, and the filter pad was washed with a little CH2Cl2. Concentration afforded the title compound (1.06 g, 97%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1 H), 7.30 (s, 1 H), 7.17 (d, J=1.5 Hz, 1 H), 4.39 (q, J=7.1 Hz, 2 H), 4.05 (s, 3 H), 1.42 (t, J=7.1 Hz, 3 H); MS (ES) m/e 272 and 274 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:13][CH2:12]2)[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)([N:29]1C=CN=C1)=O.N>ClCCl.C1COCC1.ClCCl.CO>[CH3:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:15][CH2:16]2)[C:8]([N+:24]([O-:26])=[O:25])=[CH:7][C:3]=1[C:4]([NH2:29])=[O:6]
Reactant: Cc1cc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])cc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-methyl-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid (6.2 g, 17.4 mmol) in anhydrous dichloromethane (170 mL), 1,1′-carbonyldiimidazole (7.07 g, 43.6 mmol) was added at 0° C. under N2 atmosphere. The reaction mixture was allowed to stir at room temperature for 2 h. Where upon a solution of ammonia in THF (≈4M) was added slowly at 0° C. under N2 atmosphere. The reaction mixture was allowed to stir at room temperature overnight. After the completion of the reaction as monitored by the TLC, solvent was removed in vacuo. Residue obtained was diluted with dichloromethane/methanol (150 mL, 9:1 by volume), and washed with water. Aqueous layer was again extracted in dichloromethane/methanol (3×50 mL). The combined extract was washed with brine solution and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to afford the pure product 2-methyl-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzamide. Yield (6.0 g, 97%; and yellow solid).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:8]([CH3:11])=[N:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:17](=[CH2:28])[C:18]([O:20]CC1C=CC=CC=1)=[O:19])CCC>C1COCC1.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.[Cu]Cl>[CH3:11][C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:17]([CH3:28])[C:18]([OH:20])=[O:19])[C:3]2=[N:10][N:9]=1
Reactant: C=C(C(=O)OCc1ccccc1)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nnc2c(Br)cccn12
Agent: Cl[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nnc2c(C(C)C(=O)O)cccn12
Temperature: 60 °C
Yield: 103.9 %

Procedure:
To a solution of 0.13 g (0.61 mmol) of 8-bromo-3-methyl[1,2,4]triazolo[4,3-a]pyridine from Step B above in 4 mL of anhydrous THF was added a solution of 0.36 g (0.80 mmol) of benzyl 2-(tributylstannyl)acrylate (see Intermediate 62, Step B) in 1 mL of anhydrous THF, 0.11 g (0.09 mmol) of tetrakis(triphenylphosphine)palladium(0) and 0.067 g (0.67 mmol) of copper (I) chloride. The reaction mixture was heated to 60° C. for 6 h, cooled and filtered through a pad of Celite®. The pad was washed with 15 mL of a dichloromethane and the combined filtrates were evaporated to dryness. The crude residue was purified by silica gel chromatography eluting with a 0-6% methanol in ethyl acetate gradient to afford the title compound (0.13 g, 73%). LC-MS: m/z (ES) 294 (MH)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1>ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15](=[O:16])[NH:9][N:8]=2)[CH:7]=1
Reactant: NNc1ccc(I)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=c1[nH]nc2ccc(I)cn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-iodo-2-hydrazinopyridine (470 mg, 2 mmol) in dichloromethane (30 mL) was added a solution of N,N-carbonyldiimidazole (389 mg, 2.4 mmol) in 20 mL of dichloromethane. After stirring at room temperature for 2 h, the mixture was washed sequentially with water, 0.5N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate solution. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure to afford the product. The resultant yellow crystals that precipitated from the aqueous phase upon standing overnight were collected and dried in vacuo to afford additional product. LC/MS 261.8 (M+1).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH3:5])[CH2:2]1.[CH:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>CO>[OH:1][CH:3]([CH2:4][CH3:5])[CH2:2][NH:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCC1CO1
Reactant: NC1CCCCC1
Solvent: CO
Product: CCC(O)CNC1CCCCC1
Yield: 61.3 %

Procedure:
To methanol (200 ml) are added 1,2-epoxybutane (72.2 g) and cyclohexylamine (99.2 g), and the mixture is refluxed for 6 hours. The mixture is concentrated under reduced pressure to remove the solvent to give N-(2-hydroxybutyl)-N-cyclohexylamine (105 g) as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)[C:3]([N:5]1[CH2:10][C@@H:9]([CH3:11])[N:8]([C:12](=[O:24])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:7][C@@H:6]1[CH2:25][CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[NH:30])=[O:4].N[C@@H:44]([C:56](O)=[O:57])CC1C=C2C(C=CC=C2)=CC=1>>[NH:28]([CH2:27][CH2:26][CH2:25][C@H:6]1[CH2:7][N:8]([C:12](=[O:24])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C@H:9]([CH3:11])[CH2:10][N:5]1[C:3](=[O:4])[C@H:2]([NH:1][C:56](=[O:57])[CH3:44])[CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)[C:29]([NH2:31])=[NH:30]
Reactant: N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: C[C@@H]1CN(C(=O)[C@H](N)Cc2ccc3ccccc3c2)[C@@H](CCCNC(=N)N)CN1C(=O)Cc1ccc2ccccc2c1
Product: CC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)N1C[C@@H](C)N(C(=O)Cc2ccc3ccccc3c2)C[C@@H]1CCCNC(=N)N

Procedure:
The following compound was synthesized by the method of Scheme 6. The compound of Example 38 was treated by the method of Example 36 to introduce an acetyl group at the amino group of the D-2-Nal residue. It was tested as described above with the results shown. The mass was analyzed as 607.7 (M+H).