Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.Br[CH:14]([CH2:19][CH3:20])[C:15]([O:17][CH3:18])=[O:16].Cl>C1COCC1.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9]([C:8]([CH:14]([CH2:19][CH3:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CCC(Br)C(=O)OC
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(C(=O)OC)C1=CCc2cc(OC)ccc21
Temperature: 60 °C
Yield: 104.4 %

Procedure:
An oven dried 5-L four-necked round-bottomed flask was fitted with a thermometer, a condenser, an addition funnel, and a mechanical stirrer. Under an argon atmosphere, a suspension of 5-methoxy-1-indanone (80.0 g, 494 mmol), Zn powder (Lancaster, 56.2 g, 865 mmol) in THF (2 L, anhydrous) was stirred at 60° C. (internal temperature), while a solution of methyl bromobutyrate (134.1 g, 741 mmol) in THF (400 mL, anhydrous) was added slowly using an addition funnel. After completion of the addition, the reaction mixture was stirred at 60° C. (internal temperature) for 1 h. The reaction was followed by TLC analysis of aliquots following 1 N aqueous HCl workup. After the reaction was completed, it was cooled in an ice-water bath followed by slow addition HCl (3 L, 1 N aqueous solution). The internal temperature was kept below 20° C. The mixture was then extracted with EtOAc (1 L). The organic layer was washed with water until pH 6.0-7.0, then with brine, dried over Na2SO4, and then filtered. The product (127 g, >99%), a yellow oil, was obtained after solvent removal and drying under vacuum. 1H NMR (300 MHz), (DMSO-d6) δ 7.28 (d, 1H), 7.05 (d, 1H), 6.82 (dd, 1H), 6.22 (s, 1H), 3.72 (s, 3H), 3.60 (m, 1H), 3.58 (s, 3H), 3.28 (s, 2H), 1.95 (m, 1H), 1.80 (m, 1H), 0.88 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([CH3:26])=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]([OH:41])=[O:40])[CH2:35][CH2:34]1.C(CN)O>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:38][CH2:37][CH:36]([C:39]([OH:41])=[O:40])[CH2:35][CH2:34]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([CH3:26])=[N:8]2)=[C:4]([C:29]([F:32])([F:30])[F:31])[CH:3]=1
Reactant: O=C(O)C1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C)nn3Cc2ccc(Cl)cc2C(F)(F)F)S1
Solvent: NCCO
Product: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=C3SC(N4CCC(C(=O)O)CC4)=NC3=O)cc12

Procedure:
1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4-carboxylic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Piperidine-4-carboxylic acid following General Procedure C. The compound was then prepared as an ethanolamine salt.
Reaction SMILES: [CH:1]1([O:6][C:7]([NH:9][C@H:10]2[CH2:15][N:14](C(OCC3C=CC=CC=3)=O)[C@@H:13]([CH3:26])[CH2:12][CH2:11]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([O:6][C:7](=[O:8])[NH:9][C@H:10]2[CH2:11][CH2:12][C@@H:13]([CH3:26])[NH:14][CH2:15]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H]1CC[C@@H](NC(=O)OC2CCCC2)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CC[C@H](NC(=O)OC2CCCC2)CN1
Reaction time: 4 h
Yield: 106.5 %

Procedure:
cis-phenylmethyl 5-{[(cyclopentyloxy)carbonyl]amino}-2-methyl-1-piperidinecarboxylate (160 mg, 0.444 mmol) was dissolved in ethanol (3 mL) into a 25 mL RB flask. Pd/C (94 mg, 0.044 mmol) degussa type was added, and the resulting mixture was degassed with vacuum and charged with H2 in balloon. The reaction was stirred for 4 hours, and then filter through syringe filter. The filtrate was concentrated to afford the crude title compound (107 mg) as a clear oil. LC-MS (ES) m/z=227 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]([CH2:20][C:21]([O:23]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:35]1[C@@H:43]2[C@@H:38]([CH2:39][CH:40]=[CH:41][CH2:42]2)[CH2:37][NH:36]1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([CH2:20][C:21]([N:36]2[CH2:37][C@H:38]3[C@H:43]([CH2:42][CH:41]=[CH:40][CH2:39]3)[CH2:35]2)=[O:23])[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:9])=[CH:33][CH:34]=1
Reactant: Cc1ccc(CC(CC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: C1=CC[C@H]2CNC[C@H]2C1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(CC(CC(=O)N2C[C@H]3CC=CC[C@H]3C2)C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Yield: 75.3 %

Procedure:
To a solution of di(4-nitrophenyl) 2-(4-methylbenzyl)succinate (2.4 g) in N,N-dimethylformamide (30 ml) was added a solution of cis-3a,4,7,7a-tetrahydroisoindoline (0.62 g) in N,N-dimethylformamide (10 ml) with stirring at 0° C. After stirring at 0° C. for 3 hours, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with three 1N sodium hydroxide solutions, 1N-hydrochloric acid, and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was recrystallized from hexane-ethyl acetate (4:1) to give 1.7 g of 4-nitrophenyl 2-(4-methylbenzyl)-3-(cis-3a,4,7,7a-tetrahydro-2-isoindolinylcarbonyl)propionate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11](=[C:13]1[CH2:18][CH2:17][C@H:16]2[C@H:19]3[C@H:29]([CH2:30][CH2:31][C@:14]12[CH3:15])[C@:27]1([CH3:28])[C:22]([CH2:23][C@@H:24](O)[CH2:25][CH2:26]1)=[CH:21][CH2:20]3)[OH:12].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C@H:24]2[CH2:25][CH2:26][C@@:27]3([CH3:28])[C:22](=[CH:21][CH2:20][C@@H:19]4[C@@H:29]3[CH2:30][CH2:31][C@@:14]3([CH3:15])[C@H:16]4[CH2:17][CH2:18][C:13]3=[N:11][OH:12])[CH2:23]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)c3ccc(N)cc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.4 %

Procedure:
p-Aminobenzoic acid (0.22 g, 1.6 mmol) was added to the stirred solution of 17-oximino-5-androsten-3β-ol (9) (0.5 g, 1.6 mmol) and dicyclohexylcarbodiimide (DCC) (0.34 g, 1.6 mmol) in anhydrous dichloromethane (30.0 ml). The reaction mixture was stirred for 48 hr at room temperature (20-25°) and completion of the reaction was monitored by TLC. The precipitated dicyclohexylurea (DCU) was filtered, solvent removed under vacuum and the residue was crystallized from ethyl acetate:petroleum ether (60:80) to obtain 17-oximino-5-androsten-3β-yl 4-aminobenzoate (14) (0.28 g, 56.0%) mp 165-168° C.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]([NH2:7])=[CH:5][CH:6]=1.[CH3:10][C:11](=[CH2:13])[CH3:12]>>[C:11]([C:5]1[CH:6]=[C:1]([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]=1[NH2:7])([CH3:12])([CH3:10])[CH3:13]
Reactant: C=C(C)C
Reactant: Cc1ccc(N)cc1N
Product: Cc1cc(C(C)(C)C)c(N)cc1N
Temperature: 180 °C

Procedure:
The procedure of Example 1 was followed to produce toluenediamine (5tBTDA) by using 15 grams of powdered montmorillonite clay in place of the silica-alumina catalyst and using 150 g (1.23 moles) of the 2,4-toluenediamine isomer as opposed to the 2,6-isomer. As in Example 1, the reaction contents were purged with nitrogen and then the contents were heated to 180° C. with stirring. Approximately 278 grams or 4.95 moles of isobutylene were then added to the reaction mixture over 20 minutes. The initial reaction pressure increased to 1210 psig and the contents maintained 180° C. for 23 hours. At that time the contents were cooled 150° C. and the reactor vented. The catalyst then was removed by hot filtration.
Reaction SMILES: O1CCCC1.COP([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(OC)=O.[H-].[Na+].[CH:22]([C:26]1[CH2:27][C@@H:28]2[C@H:31]([CH:32]=1)[C:30](=O)[CH2:29]2)([CH2:24][CH3:25])[CH3:23]>O>[CH:22]([C:26]1[CH2:32][C@@H:31]2[C@H:28]([CH:27]=1)[C:29](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:30]2)([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)C1=C[C@@H]2C(=O)C[C@@H]2C1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)C1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A tetrahydrofuran (15 mL) solution of tert-butyl dimethylphosphonoacetate (3.70 g, 16.5 mmol) was added dropwise at 0° C. over 20 minutes to a tetrahydrofuran (15 mL) suspension of sodium hydride (0.68 g, 63%, 18.0 mmol), and the mixture was stirred at 0° C. for 20 minutes. To this solution, a tetrahydrofuran (15 mL) solution of (±)-(1S,5R)-3-sec-butylbicyclo[3.2.0]hept-3-en-6-one (2.48 g, 15.1 mmol) was added dropwise at 0° C. over 15 minutes, and the mixture was stirred at room temperature for 2 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (3.10 g, 78%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:23][C:24](=O)[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Cl:38])[CH:32]=2)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[C:27](Br)[CH:26]=1)C>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:24](=[O:23])[C:25]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Cl:38])[CH:32]=3)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Reactant: NCCCCCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(NCCCCCCCCc1ccccc1)c1ccc(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a flamed dried round bottom flask charged with 8-phenyloctylamine (688 mg, 3.35 mmol, 6.68 μL) in 5 mL THF at −78° C. was added n-BuLi (2.2 mL, 4.4 mmol) as a solution in hexanes. The solution was stirred at −78° C. for 30 min then stirred at room temperature for 15 min. The solution was cooled back down to−40° C. and a cooled (−40° C.) solution of 3-bromo-4-(2-hydroxyethoxy)-5-(3-chloro-4-fluorophenyl)benzoic acid ethyl ester (400 mg, 0.957 mmol) in 10 mL THF via cannula. After the addition was completed, the reaction was warmed up to room temperature, stirred for 10 min, then worked up as in Step 2 of Example 135. The crude yellow oil that was obtained was dissolved in 1:1 EtOAc/Hexanes and filtered through a pad of silica gel with the same solvent system to yield 200 mg, 43% of the amide as a yellow oil. 1H NMR (CDCl3) δ 1.25-1.40 (m, 2H); 1.54-1.65 (m, 2H); 1.80 (bs, 1H); 2.57 (t, J=8.18 Hz, 2H); 3.41 (q, J=6.54 Hz, 2H); 3.90 (t, J=6.13, 2H); 4.12 (t, J=6.13 Hz, 2H); 6.07 (m, 1H); 6.99 (d, J=8.13 Hz, 1H); 7.08-7.18 (m, 3H); 7.20-7.27 (m, 2H); 7.33-7.40 (m, 1H); 7.56 (dd, J=6.54 Hz, 3.27 Hz, 1H); 7.65-7.69 (m, 1H); 7.73 (dd, J=8.13 Hz, 2.58 Hz, 1H).
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.CO[N:12]=[C:13]1[CH2:16][C@H:15]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:14]1[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>O1CCCC1>[CH3:34][C:31]([Si:28]([CH3:30])([CH3:29])[O:27][CH2:26][C@@H:14]1[C@@H:15]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16][C@H:13]1[NH2:12])([CH3:32])[CH3:33]
Reactant: CON=C1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](N)[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 186.3 g (4.9 mol) of sodium borohydride in 4 L of tetrahydrofuran (THF) was added (over a 30 minute period) 376 mL (4.9 mol) of trifluoroacetic acid (TFA), with ice water cooling to maintain temperature below 15° C. [2R,3S]-2,3-bis(((1,1-Dimethylethyl)dimethylsilyl)oxymethyl) cyclobutanone-O-methyl oxime (400 g, 1.03 mol), from Step 1E, in 3 L of THF was added with ice water cooling to maintain the temperature below 20° C. After stirring the reaction mixture at ambient temperature overnight, it was concentrated, diluted with methylene chloride (3 L) and washed portionwise (with cooling) with 400 mL of brine. After filtration, the layers of the filtrate were separated and the aqueous layer was washed with methylene chloride. The combined methylene chloride solution was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give crude title compound which was taken on to the next step without purification.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]([CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[S:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([OH:24])(=[S:23])[CH3:22]>C(OCC)C>[C:21]([S:23][CH:14]([CH2:13][C:11](=[S:12])[C:10]1[CH:19]=[CH:20][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=1)[C:15]([O:17][CH3:18])=[O:16])(=[O:24])[CH3:22]
Reactant: COC(=O)C=CC(=S)c1ccc(-c2ccccc2)cc1
Reactant: CC(O)=S
Solvent: CCOCC
Product: COC(=O)C(CC(=S)c1ccc(-c2ccccc2)cc1)SC(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2.98 g of methyl 3-(4-phenylthiobenzoyl)acrylate in 30 ml of diethyl ether was added 0.8 ml of thioacetic acid, and the resulting mixture was stirred at room temperature for 5 hours. The reaction solution was washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate. The diethyl ether was removed from the solution by evaporation, and the residue was purified by silica gel column chromatography (eluent: hexane-diethyl ether) to give 3.73 g of methyl 2-acetylthio-3-(4-phenylthiobenzoyl)propionate as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9](=[S:18])[NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[H-].[K+].Br[CH:22](Br)[CH3:23].O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]2[C:9]([S:18][CH2:22][CH2:23]2)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CC(Br)Br
Reactant: S=c1[nH]c(-c2ccccn2)c(-c2ccccn2)[nH]1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2nc3n(c2-c2ccccn2)CCS3)nc1
Reaction time: 2 h

Procedure:
A mixture of 16.57 g (0.065 m) of 4,5-di(2-pyridyl)-1H-imidazole-2-thione in 150 ml of dimethylformamide was stirred at -15° (ice-methanol-dry ice) under nitrogen and 27 ml (6.2 g, 0.15 m) of a 24% suspension of potassium hydride in mineral oil was added gradually. After about 2 hours, a solution of 11.8 g (5.42 ml, 0.0634 m) of dibromoethane in 60 ml of dimethylformamide was added dropwise. The reaction mixture was allowed to attain room temperature overnight. The mixture was poured into 600 ml of water. The aqueous mixture was extracted with 3×200 ml portions of methylenechloride. The combined extracts were washed with 5×100 ml water, brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated under 25 ml of low boiling petroleum ether. The product was separated, dissolved in 50 ml of ethanol. The solution was chilled until crystallization was complete, filtered, and the product was washed with a small portion of cold ethanol and air dried. Yield 9.1 g, m.p. 140°-142°. Crystallization three times from ethanol gave an analytical sample of 5,6-di-(2-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole, m.p. 142°-143°.
Reaction SMILES: CN(C1C=CC=CN=1)C.[C:10]([O:13][C:14](=O)[CH3:15])(=[O:12])[CH3:11].[Cl:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26]C(O)=C[CH:29]=2)[CH:24]=[C:23]1[C:32]([OH:34])=[O:33].C(O)C>C(OCC)(=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:14]([O:13][C:10](=[O:12])[CH3:11])=[CH:15][CH:29]=2)[CH:24]=[C:23]1[C:32]([OH:34])=[O:33]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc2cc(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccccn1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1)cc(C(=O)O)n2Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethylaminopyridine (100 mg) and acetic anhydride (1.12 ml) were added to a solution of N-(3,4-Dichlorobenzyl)-5-hydroxyindole-2-carboxylic acid in ethyl acetate (50 ml) and stirred at ambient temperature for 1 hour. Ethanol (10 ml) was added and the reaction was stirred for 30 min. Solvent partially evaporated and iso-hexane added to give a precipitate, which was filtered off and dried to give the product as a white solid (1.2 g). NMR: δ 2.25 (s, 3H), 5.85 (s, 2H), 6.9 (dd, 1H), 7.3-7.6 (m, 5H); m/z 376, 378 (M−H+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18](Cl)(=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[C:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCCCCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 83 %

Procedure:
Beginning with 0.01 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0077 mL (0.048 mMol) hexanoyl chloride, 0.012 gm (84%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[NH2:8][C:9]1[CH:15]=[CH:14][C:12]([OH:13])=[CH:11][C:10]=1[OH:16].Cl[CH2:18][C:19](Cl)=[O:20]>O.C1(C)C=CC=CC=1>[OH:13][C:12]1[CH:14]=[CH:15][C:9]2[NH:8][C:19](=[O:20])[CH2:18][O:16][C:10]=2[CH:11]=1
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1COc2cc(O)ccc2N1
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
K2CO3 (250 g, 1.8 mol, 4 eq) was dissolved in water (1100 mL) in a 3 L round bottomed flask, vacuum degassed 3 times, then cooled to 0 to 5° C. 4-Amino resorcinol HCl (73 g, 0.45 mol, 1 eq) was added though a strong nitrogen purge, and the blue solution was again degassed 3×. Choroacetyl chloride (45 mL, 64 g, 0.57 mol, 1.25 eq) was dissolved in toluene (225 mL), and was added over 1 h maintaining the temperature below 5° C. the ice bath was removed, and the mixture (biphasic with suspended crystalline product) was stirred overnight. The intermediate 2 was then isolated via filtration giving 53 g (71%) after a water wash (550 mL) and drying.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:26]=[CH:27][C:7]=1[CH2:6]2)=[O:4].Cl.[F:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[CH3:1][O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21]([N:39]4[CH2:40][CH2:41][C@@H:37]([F:36])[CH2:38]4)=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:26]=[CH:27][C:7]=1[CH2:6]2)=[O:4]
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: F[C@@H]1CCNC1
Agent: Cl
Product: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CC[C@@H](F)C3)nc1)C2

Procedure:
The title compound was prepared by the method of Example 20 using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid methyl ester and (R)-3-fluoropyrrolidine hydrochloride. LCMS (Method G): 556.2 (M+H)+, Retention time 3.4 minutes.
Reaction SMILES: ClCC([NH:5][C:6]([N:8]([C:10](=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:21][C:20]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)([C:22]([F:25])([F:24])[F:23])[O:19][N:18]=2)=[CH:13][C:12]=1[CH3:34])[CH3:9])=[O:7])=O.C(N(CC)CC)C>CO>[C:6]([N:8]([CH3:9])[C:10](=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:21][C:20]([C:26]3[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=3)([C:22]([F:25])([F:23])[F:24])[O:19][N:18]=2)=[CH:13][C:12]=1[CH3:34])(=[O:7])[NH2:5]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)C(=O)NC(=O)CCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 0.40 g of N-chloroacetyl-N′-[4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylbenzoyl]-N′-methyl urea synthesized in Synthetic Example 27 and 0.04 g of triethylamine in 4 mL of methanol was stirred at room temperature for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 1:4 to 4:1) to obtain 0.31 g of the aimed product as white crystal.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:22]([O:26][C:27](=[O:41])[CH:28]=[CH:29][C:30]1[CH:39]=[C:38]2[C:33]([O:34][CH2:35][C:36](=[O:40])[NH:37]2)=[N:32][CH:31]=1)([CH3:25])([CH3:24])[CH3:23].[NH4+].[Cl-]>C1COCC1>[C:22]([O:26][C:27](=[O:41])[CH2:28][C@H:29]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[C:30]1[CH:39]=[C:38]2[C:33]([O:34][CH2:35][C:36](=[O:40])[NH:37]2)=[N:32][CH:31]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=Cc1cnc2c(c1)NC(=O)CO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)c1cnc2c(c1)NC(=O)CO2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N-benzyl-α-(R)-methylbenzylamine (0.82 g, 3.87 mmol) in THF (25 mL) at 0° C. was treated with n-BuLi (1.6 mL of a 2.5 M soln in hexanes). The resulting solution was stirred at 0° C. for 30 min and then cooled to −78° C. A solution of acrylate 20-5 (0.485 g, 1.76 mmol) in THF (5 mL) was added. After stirring for 15 min at −78° C., satd aq NH4Cl soln (5 mL) was added and the cold bath removed. The mixture was warmed to room temperature, and extracted with Et2O (2×40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (40% ethyl acetate/hexanes) to give the β-aminoester 20-6 as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:12][CH2:11][Br:10]
Reactant: BrCCBr
Reactant: Cc1ccc(O)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(OCCBr)c(Br)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 2-bromo-4-methylphenol (5.0 g, 26 mmol), 1,2-dibromoethane (7.0 g, 37 mmol) in water (20 mL) and NaOH (1.1 g, 28 mmol) was stirred at 100° C. for 24 h. The mixture was extracted with DCM (150 mL), washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1) to give the title compound (1a).