Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]1C2[C:6](=[C:7]([OH:12])C=CC=2)[C:5](=[O:13])[CH2:4][CH:3]1CC#N.CN1C2C(=C([OH:28])C=CC=2)C(=O)CC1CC=O.C1(C2SC(=O)CN=2)C=CC=CC=1.[C:45]1([C:51]2[S:52][C:53](=[O:71])[C:54](=[CH:56][CH2:57][CH:58]3[CH2:67][C:66](=[O:68])[C:65]4[C:60](=[CH:61][CH:62]=[CH:63][C:64]=4[OH:69])[N:59]3[CH3:70])[N:55]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>[Ni].N1C=CC=CC=1>[C:51]([NH:55][CH:54]1[CH:56]2[CH:6]([CH:7]([OH:12])[CH:67]3[CH:58]([CH2:57]2)[N:59]([CH3:70])[C:60]2[C:65](=[C:64]([OH:69])[CH:63]=[CH:62][CH:61]=2)[C:66]3=[O:68])[C:5](=[O:13])[C:4]([C:3]([NH2:2])=[O:28])=[C:53]1[OH:71])(=[S:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CN1c2cccc(O)c2C(=O)CC1CC=C1N=C(c2ccccc2)SC1=O
Reactant: CN1c2cccc(O)c2C(=O)CC1CC=O
Reactant: CN1c2cccc(O)c2C(=O)CC1CC#N
Agent: [Ni]
Agent: O=C1CN=C(c2ccccc2)S1
Solvent: c1ccncc1
Product: CN1c2cccc(O)c2C(=O)C2C(O)C3C(=O)C(C(N)=O)=C(O)C(NC(=S)c4ccccc4)C3CC21

Procedure:
The starting material can be obtained by condensation of 3-amino-4-chloroanisole with acetonedicarboxylic acid dimethyl ester to give 4-oxo-5-methoxy-8-chloro-1,4-dihydro-quinoline-2-acetic acid methyl ester, hydrogenation on 5% Pd-on-charcoal in dioxan at 6 atmospheres and 60° to give 4-oxo-5-methoxy-1,4-dihydroquinoline-2-acetic acid methyl ester, reaction with dimethyl sulphate in sodium hydroxide solution to give 1-methyl-4-oxo-5-methoxy-1,4-dihydroquinoline-2-acetic acid, hydrogenation on PtO2 in methanol at 20° and normal pressure to give 1-methyl-4-oxo-5-methoxy-1,2,3,4-tetrahydroquinoline-2-acetic acid, reaction, via the chloride and the amide, to give the nitrile, ether splitting by means of BBr3 to give 1-methyl-4-oxo-5-hydroxy-1,2,3,4-tetrahydroquinoline-2-acetonitrile, reaction with Raney nickel to give 1-methyl-4-oxo-5-hydroxy-1,2,3,4-tetrahydroquinoline-2-acetaldehyde, condensation with 2-phenyl-2-thiazolin-5-one to give 2-phenyl-4-[2-(1-methyl-4-oxo-5-hydroxy-1,2,3,4-tetrahydro-2-quinolyl)-ethylidene]-2-thiazolin-5-one, condensation with acetone dicarboxylic acid monomethyl ester-monoamide to give 4-thiobenzamido-1,4,4a,5,5a,6,11,12-octahydro-3,10,12-trihydroxy-6-methyl-1,11-dioxo-6-aza-naphthacene-2-carboxamide (mixture of stereoisomers), epimerization with pyridine to give 4-de-dimethylamino-4-thiobenzamido-6-methyl-12a-dehydroxy-6-aza-tetracycline and hydroxylation.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)CCC.[N-:15]=[N+:16]=[N-:17].[Na+].C(O)(=O)C>C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:17][N:16]=[N:15][N:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1F
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(=O)O
Solvent: CCOCC
Product: Fc1ccccc1-c1nnn[nH]1
Temperature: 25 °C

Procedure:
The 5-(2-fluorophenyl)-1H-tetrazole starting material was prepared as follows. A 3-necked 500 ml round-bottom flask was charged with 2-fluorobenzonitrile (48.4 g, 0.4 mol), n-butanol (160 ml), NaN3 (34.3 g, 0.528 mol) and glacial acetic acid (31.7 g, 0.528 mol). The mixture was warmed to a mild reflux for 24 h under nitrogen behind a safety shield. After the mixture had cooled to room temperature, it was again charged with NaN3 (34.3 g, 0.528 mol) and glacial acetic acid (31.7 g, 0.528 mol). The mixture was warmed to a mild reflux for an additional 24 h under nitrogen, cooled and then diluted with diethyl ether (320 ml). This organic mixture was extracted with 2N NaOH (4×100 ml) and the combined ice-cold basic extracts were carefully acidified to pH 1 with concentrated hydrochloric acid. The product was isolated as a light gray solid (45.2 g, 68.9%) after drying under vacuum at 60° C., mp 160.5°-162° C. [lit. mp 160°-162° C.; George, E. F. and Riddell, W. D., U.S. Pat. No. 3,865,570 (Feb. 13, 1973)]. There was obtained a second crop of product (1.0 g, 1.5%). A 1.0 g sample of this material was crystallized from water to produce a white solid, mp 162.5°-163.5° C.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[CH2:4][C:3](=[O:8])[CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[NH2:19][C:20]1[N:24]([CH3:25])[N:23]([CH3:26])[C:22](=[O:27])[CH:21]=1>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:21]3[C:22](=[O:27])[N:23]([CH3:26])[N:24]([CH3:25])[C:20]=3[NH:19][C:5]3[CH2:6][O:1][CH2:2][C:3](=[O:8])[C:4]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: Cn1c(N)cc(=O)n1C
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: O=C1COCC(=O)C1
Solvent: CCO
Product: Cn1c2c(c(=O)n1C)C(c1ccc(F)c(Br)c1)C1=C(COCC1=O)N2
Temperature: 25 °C
Yield: 38.5 %

Procedure:
2H-Pyran-3,5-(4H,6H)-dione (0.08 g, 0.7 mmol), 3-bromo-4-fluorobenzaldehyde (0.14 g, 0.7 mmol), and 5-amino-1,2-dimethyl-1,2-dihydro-3H-pyrazol-3-one (0.09 g, 0.7 mmol) in ethyl alcohol (2 mL) were heated at 80° C. for 24 hours in a sealed tube. The reaction mixture was allowed to cool to ambient temperature and then filtered to provide the title compound (0.11 g). 1H NMR (300 MHz, DMSO-d6) δ 3.0 (s,3H), 3.12 (s, 3H), 4.12 (s, 1H), 4.52 (q, 2H), 4.78 (s, 1H), 7.23 (m, 2H), 7.48 (dd, 1H), 10.18 (s, 1H); MS (ESI−) m/z 408 (M−H)−.
Reaction SMILES: C([NH:4][C:5]([C@@H:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21]C(C)(C)C(C)(C)[O:18]1)[C:6](NC(C)(C)C)=[O:7])(=O)C.[ClH:39].[OH2:40]>>[ClH:39].[ClH:39].[NH2:4][C:5]([C@@H:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]([OH:21])[OH:18])[C:6]([OH:7])=[O:40]
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)[C@@H]1CCN(Cc2ccc(F)cc2)C1
Reactant: O
Agent: Cl
Product: NC(CCCCB(O)O)(C(=O)O)[C@@H]1CCN(Cc2ccc(F)cc2)C1
Temperature: 25 °C

Procedure:
An aqueous solution of 2-acetamido-N-tert-butyl-2-((R)-1-(4-fluorobenzyl)pyrrolidin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (0.280 g, 0.527 mmol) in 6M hydrogen chloride (10 mL, 60 mmol) was heated under reflux overnight. The reaction was cooled to room temperature, diluted with 20 mL of water, and washed with ethyl acetate (20 mL). The aqueous layer was purified by HPLC (3 injections) using a 5-20% acetonitrile in water. The fractions corresponding to the desired product were concentrated and lyophilized to give 2-amino-6-borono-2-((R)-1-(4-fluorobenzyl)pyrrolidin-3-yl)hexanoic acid dihydrochloride as white powder, which became oily upon exposure to air (hydroscopic). (0.003 g, 2%). 1H NMR (400 MHz, CDCl3, Mixture of diastereoisomers) δ 7.41 (dd, J1=8.1 Hz, J2=6.5 Hz, 2H), 7.12 (t, J=8.1 Hz, 2H), 4.35-4.25 (br, m, 2H), 3.77-3.09 (br. m, 3H), 2.99-2.60 (br. m, 1H), 2.39-1.57 (br. m, 4H), 1.34-1.18 (br. m, 2H), 1.15-1.03 (br. m, 1H), 0.70-0.61 (m, 2H),; ESI MS found for C17H26BFN2O4 m/z 335.3 (M+H-water)+; 351.4 (M−H)−; 333.4 (M−H-water)−.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:39][C@@H:40]([NH2:51])[C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1>O.CN(C=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C@@H:10]([C:14]([NH:51][C@@H:40]([C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=[CH:43][CH:42]=2)[CH3:39])=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H]1CC(=O)N(Cc2ccccc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
A 20 ml DMF solution of 1.16 g of 1-benzyl-5-oxopyrrolidine-3-carboxylic acid was mixed with 2.0 g of WSC hydrochloride and 859 mg of HOBt and stirred at room temperature for 30 minutes. 1.1 g of (1R)-1-naphthylethylamine was added thereto successively and stirred at 60° C. After completion of the reaction, this was mixed with 100 ml of water, extracted with ethyl acetate and washed with 1 M hydrochloric acid. The organic layer was concentrated, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) and then recrystallized from ethyl acetate-hexane to obtain 856 mg and 831 mg of (3R)-1-benzyl-N-[(1R)-1-(1-naphthyl)ethyl]5-oxopyrrolidine-3-carboxamide and (3S)-1-benzyl-N-[(1R)-1-(1-naphthyl)ethyl]5-oxopyrrolidine-3-carboxamide (stereoisomers un-verified). Both of the thus obtained compounds were respectively subjected to reduction in the same manner as in Example 84, made into salt with fumaric acid and recrystallized from ethanol-ethyl acetate to obtain (1R)—N-{[(3S)-1-benzylpyrrolidin-3-yl]methyl}-1-(1-naphthyl)ethanamine fumarate and (1R)—N-{[(3R)-1-benzylpyrrolidin-3-yl]methyl}-1-(1-naphthyl)ethanamine fumarate.
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:6][CH3:7])[O:4][CH3:5].[CH3:16][S:17]([O:20]C)(=[O:19])=[O:18]>C(OCC)(=O)C>[CH3:16][S:17]([O-:20])(=[O:19])=[O:18].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[CH3:16])([O:6][CH3:7])[O:4][CH3:5]
Reactant: CO[Si](CCc1ccccn1)(OC)OC
Reactant: COS(C)(=O)=O
Solvent: CCOC(C)=O
Product: CO[Si](CCc1cccc[n+]1C)(OC)OC
Product: CS(=O)(=O)[O-]

Procedure:
5.0 g of 2-(trimethoxysilylethyl)pyridine and 18 g of ethyl acetate were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 3.6 g of methyl methanesulfonate was dissolved in 24 g of ethyl acetate was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was refluxed over 3 days and therefrom, ethyl acetate was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, 2-(trimethoxysilylethyl)pyridine and methyl methanesulfonate as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in methanol to obtain a 30% methanol solution of trimethoxysilylethylmethylpyridinium methanesulfonate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH2:23]([O:28][C:29]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=1[CH:31]=O)[CH2:24][CH:25]([CH3:27])[CH3:26].[O-]CC.[Na+]>C(O)C>[CH2:23]([O:28][C:29]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=1/[CH:31]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=1)[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OCCC(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCCC(C)C
Yield: 49.3 %

Procedure:
The title compound was prepared by condensation of Intermediate 15 (350 mg, 1.071 mmol) with 2-isopentyloxy-3-methoxybenzaldehyde (334 mg, 1.501 mmol) in the presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to afford 280 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.93 (d, J=6.3 Hz, 6H), 1.45 (q, J=6.6 Hz, 2H), 1.85-1.91 (m, 1H), 3.77 (s, 3H), 3.86 (t, J=6.6 Hz, 2H), 6.86-6.94 (m, 2H), 7.00-7.06 (m, 2H), 7.46-7.51 (m, 5H), 7.99 (d, J=4.8 Hz, 1H), 8.07 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 531.20 (M+H)+.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=4)=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:31](O)(=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=4)=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(=O)O
Reactant: CCCCCCCCC1Cc2ccc(-c3ncc(-c4ccc(O)cc4)cn3)cc2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCC1Cc2ccc(-c3ncc(-c4ccc(OC(=O)CCCCCC)cc4)cn3)cc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
0.15 g (0.37 mM) of 2-octyl-5-[5-(4-hydroxyphenyl)pyrimidine-2-yl]indan, 0.05 g (0.38 mM) of heptanoic acid, 0.08 g (0.39 mM) of DCC, 0.01 g of 4-dimethylaminopyridine and 3 ml of methylene chloride were mixed and stirred for 5 hours at room temperature. The resultant N,N'-dichlorhexylurea was recovered by filtration, washed with dichloromethane, and added to the filtrate. The resultant dichloromethane solution was subjected to distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) and recrystallized from a mixture solvent (toluene/methanol) to obtain 0.14 g of 2-octyl-5-[5-(4-heptanoyloxyphenyl)pyrimidine-2-yl]indan (Yield: 72.9%). ##STR143##
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[N+:12]([C:15]1[CH:16]=[C:17]([CH:21]([S:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38]C)[CH:33]=2)[CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].Cl[CH2:41]CCl>>[C:25]1([C:23](=[O:24])[CH2:22][CH:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[S:31][C:32]2[CH:37]=[CH:36][C:35]([C:4](=[O:5])[CH2:3][CH2:2][C:1]([O:6][CH3:41])=[O:7])=[C:34]([OH:38])[CH:33]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClCCCl
Reactant: O=C1CCC(=O)O1
Reactant: COc1cccc(SC(CC(=O)c2ccccc2)c2cccc([N+](=O)[O-])c2)c1
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)CCC(=O)c1ccc(SC(CC(=O)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Succinic anhydride (11.45 g, 0.11 mole) was dissolved in 1,2-dichloroethane (300 ml) and AlCl3 (50.76 g, 0.38 mole) was added under N2. The resulting mixture was stirred for 3 hours at room temperature, cooled to 0° C. and the compound from Step A (13 g, 0.03 mole), dissolved in 1,2-dichloroethane, was added slowly. The reaction mixture was kept at 5° C. for 3 days, then poured on ice, stirred for one hour and the two phases separated by decanting. The aqueous phase was extracted several times with CH2Cl2 (600 ml total). The organic phases were combined, washed with water, dried (MgSO4) and evaporated to dryness to yield the title compound as the free acid which then was converted to the methyl ester in conventional manner by treating the acid with methanol and anhydrous HCl. The ester had the following analysis: calculated: C, 63.27; H, 4.70; S, 6.50; observed: C, 63.19; H, 4.81; S, 6.63.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7][C:6]1=[O:16].ClC([O:21][C:22](Cl)(Cl)Cl)=O.C(N(C(C)C)CC)(C)C.[NH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]2[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=3[CH2:49][N:48]3[CH:56]=[CH:57][CH:58]=[C:47]3[CH2:46]2)=[O:44])=[CH:39][C:38]=1[CH3:59]>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]([C:22](=[O:21])[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]([N:45]3[C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=4[CH2:49][N:48]4[CH:56]=[CH:57][CH:58]=[C:47]4[CH2:46]3)=[O:44])=[CH:39][C:38]=2[CH3:59])[CH2:7][C:6]1=[O:16]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1CN
Reactant: COC(=O)CN1C(=O)CNc2c(F)cccc21
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1C(=O)CN(C(=O)NCc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)c2c(F)cccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-fluoro-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl)acetic acid methyl ester from Example 17A (72 mg, 0.30 mmol) in toluene (5.0 ml) were added trichloromethyl chloroformate (36 μl, 0.30 mmol), diisopropylethylamine (54 μl, 0.30 mmol) and a spatula full of activated carbon. The mixture was heated at reflux for 2 h. The mixture was cooled to room temperature, filtered through Celite® and evaporated. The residue was taken up in THF (4.0 ml) and added to a solution of (4-aminomethyl-3-methylphenyl)-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)methanone from Example G (9 9mg, 0.30 mmol) in THF (4.0 ml) and diisopropylethylamine (54 μl, 0.30 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature, stirred for 18 h and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluant EtOAc:pet. ether 75:25) to give a white solid; yield 61 mg, 34%.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:41]1[S:45][C:44]([C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=[O:51])=[CH:48][C:47]=2[CH3:55])=[N:43][C:42]=1[CH3:56].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.O.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>[F:1][C:2]([F:38])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:41]4[S:45][C:44]([C:46]5[CH:54]=[CH:53][C:49]([C:50]([OH:52])=[O:51])=[CH:48][C:47]=5[CH3:55])=[N:43][C:42]=4[CH3:56])=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CSc1ncc(B2OC(C)(C)C(C)(C)O2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncc(-c2sc(-c3ccc(C(=O)O)cc3C)nc2C)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Yield: 93.1 %

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-{[2-(methylsulfanyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-1,3-oxazolidin-2-one (INTERMEDIATE 21, 2.0 g, 3.46 mmol), 4-(5-bromo-4-methylthiazol-2-yl)-3-methylbenzoic acid (INTERMEDIATE 42, 1.190 g, 3.81 mmol), potassium phosphate (2.2 g, 10.39 mmol) in THF (5 mL) and water (5 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.400 g, 0.346 mmol). It was degassed, and refilled with nitrogen. The reaction mixture was heated to reflux for 2 hours to see complete conversion by LCMS. It was distributed between 100 mL of water and 300 mL of ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated. The crude was purified on a silica gel column, eluting with 30% ethyl acetate in hexanes to give the title compound as white solid (2.2 g, 93% yield). LCMS (M+H)+: 683.0
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:28][C:27]1[O:26][C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:24][C:23]=1[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:5]2[CH:4]=[CH:3][C:2]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:7][C:6]=2[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:16][CH:17]=1
Reactant: COC(=O)Cc1cc(Br)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(-c2ccccc2)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Yield: 74.6 %

Procedure:
Methyl 2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (1.20 g), phenylboronic acid (0.30 g), tetrakis(triphenylphosphine)palladium (0.14 g), 2M aqueous sodium carbonate solution (3.7 mL), methanol (5 mL), and toluene (20 mL) were stirred with heating under reflux for 24 hrs under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give crystals (0.89 g, 74%) of methyl 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-phenylphenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 111-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](=O)[CH2:13]Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:20][C:21]([NH2:23])=[S:22].CCOCC>C(O)C>[NH2:23][C:21]1[S:22][CH:13]=[C:12]([C:11]2[CH:16]=[CH:17][C:8]([O:7][CH2:6][C:5]3[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:20]=1
Reactant: NC(N)=S
Reactant: O=C(CCl)c1ccc(OCc2ccc(Cl)cc2)cc1
Solvent: CCO
Solvent: CCOCC
Product: Nc1nc(-c2ccc(OCc3ccc(Cl)cc3)cc2)cs1

Procedure:
A 8.0 g portion of 4-(4-chlorobenzyloxy)phenacyl chloride and 2.3 g of thiourea were stirred in 70 ml of ethanol under reflux for 1 hour. After cooling, 100 ml of ether was added, and the precipitating crystals were recovered by filtration, resulting in 7.8 g (82.1%) of hydrochloride of 2-amino-4-[4-(4-chlorobenzyloxy) phenyl]thiazole. Recrystallized from 80% ethanol m.p., 248°-250° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@H:9]([OH:23])[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:42]([O:44][CH2:45][CH:46]1[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[C:52]2[C:47]1=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43]>C(Cl)Cl>[C:27]([O:26][C:25]([NH:24][C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C@H:9]([OH:23])[CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)[C:42]([O:44][CH2:45][CH:46]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:52]=2[C:53]2[C:58]1=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:43])=[O:31])([CH3:28])([CH3:30])[CH3:29]
Reactant: COc1cc(CNC[C@@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)cc(OC)c1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CN(C[C@@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)OCC2c3ccccc3-c3ccccc32)cc(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a solution of tert-butyl (2S,3R)-1-cyclohexyl-4-(3,5-dimethoxybenzylamino)-3-hydroxybutan-2-ylcarbamate (66.5 mg, 0.153 mmol) in CH2Cl2 (10 mL) at 0° C. was added DIEA (1.5 mL) followed by 9-fluorenylmethyl chloroformate (39.5 mg, 0.153 mmol) and the resulting mixture was stirred at 0° C. for 2 h and at rt for 2 h. The reaction mixture was concentrated and the residue was diluted with EtOAc and water. The organics were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel to provide (2R,3S)-3-(t-butoxycarbonylamino)-4-cyclohexyl-1-(N-(3,5-dimethoxybenzyl)-N-((9H-fluoren-9-yl)methoxycarbonyl)amino)butan-2-ol (78.5 mg, 78%). 1H NMR: 0.79 (m, 1H), 0.95 (m, 1H), 1.06-1.38 (m, 6H), 1.42 (s, 9H), 1.56-1.70 (m, 6H), 1.83 (m, 1H), 3.25-3.50 (m, 2H), 3.70 (m, 1H), 3.73 (s, 6H), 3.85 (m, 1H), 4.22 (m, 1H), 4.29-4.70 (m, 5H), 6.35 (m, 3H), 7.20 (m, 1H), 7.32-7.48 (m, 4H), 7.58 (m, 1H), 7.69 (m, 1H), 7.75 (m, 1H). MS (E/Z): 659 (M+H+).