Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([OH:7])[CH2:5][CH2:4][CH2:3][C@@H:2]1[OH:6].[H-].[Na+].[H][H].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>O1CCOCC1.CO>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][O:6][C@@H:2]1[CH2:3][CH2:4][CH2:5][C@@H:1]1[OH:7]
Reactant: Fc1ccccc1CBr
Reactant: [H][H]
Reactant: O[C@@H]1CCC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O[C@H]1CCC[C@H]1OCc1ccccc1F
Temperature: 70 °C
Yield: 46.1 %

Procedure:
19.4 g (0.19 mol) of cis-1,2-cyclopentanediol were added dropwise to a suspension of 4.8 g (0.2 mol) of sodium hydride (6.0 g of 80% pure sodium hydride in toluene) in 200 ml of dioxan at 5° C. under a nitrogen atmosphere, whilst stirring. After the evolution of hydrogen had ended, the mixture was warmed to 70° C. for 45 minutes and then brought to room temperature and 359 g (0.19 mol) of 2-fluorobenzyl bromide in absolute dioxan were added. After stirring the mixture for 30 minutes, it was heated to the boil for a further 4 hours and cooled and about 10 ml of methanol were added. The mixture was concentrated to dryness on a rotary evaporator, the residue was taken up in water and the mixture was extracted with methylene chloride. The organic phase was dried over sodium sulphate and filtered and the solvent was stripped off from the filtrate on a rotary evaporator. The oily residue was distilled under an oil pump vacuum. 18.4 g (46% of theory) of cis-1-(2-fluorobenzyloxy)-cyclopentan-2-ol of boiling point 95°-100° C./0.1 mm Hg were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:23][S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:31]([C:30]2[CH:29]=[CH:28][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:35][CH:34]=2)=[O:32])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)c1ccc(S(C)(=O)=O)cc1)c1ccc(F)cc1
Temperature: 2.5 °C
Reaction time: 12 h
Yield: 69.3 %

Procedure:
A solution of methyl 2-(4-fluorophenyl)acetate (2.35 g, 14 mmol) in THF (15 mL), at −78° C., was treated dropwise with 1 N lithium bis(trimethylsilyl)amide (14 mL, 14 mmol). After 15 minutes a suspension of 4-(methylsulphonyl)benzoyl chloride (3.3 g, 15 mmol) in THF (25 mL) was added in portions. The reaction mixture was stirred for 60 minutes at −78° C. and at 0 to 5° C. for 12 hours. The mixture was quenched with 10% citric acid, the THF removed in vacuo, and the residue triturated with hexanes to provide the desired product as a solid (yield: 3.4 g; 69%). MS (DCI-NH3) m/z 368 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ3.27 (s, 3H), 3.69 (s, 3H), 6.35 (s, 1H), 7.21 (m, 2H), 7.44 (m, 2H), 8.06 (d, J=9 Hz, 2H), 8.25 (d, J=9 Hz, 2H).
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=1)C(OC)=O.C[OH:16].[CH2:17]([N+:19]([CH2:23]C)(CC)C)C>CN(C)C=O>[CH3:14][O:13][CH2:1][N:19]([CH3:23])[CH:17]=[O:16].[C:1]1([C:2]2[C:11](=[CH:10][CH:9]=[CH:8][CH:3]=2)[CH2:14][O:13]1)=[O:12]
Reactant: CO
Reactant: CC[N+](C)(CC)CC
Reactant: COC(=O)c1ccccc1C(=O)OC
Solvent: CN(C)C=O
Product: COCN(C)C=O
Product: O=C1OCc2ccccc21
Reaction time: 6.9 h
Yield: 64 %
Yield: 82 %

Procedure:
In an electrolytic cell as used in Example 1, 2.56 mol of dimethyl phthalate, 750 g of methanol, 1225 g of dimethylformamide (DMF) and 25 g of triethylmethylammonium methosulfate were subjected to electrolysis at 5 A and 50° C. for 6.9 h. 4.1 mol (current yield: 64%) of N-methoxymethyl-N-methylformamide were formed besides 2.1 mol of phthalide (material yield: 82%).
Reaction SMILES: [CH:1](=[N:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13]([CH:16]=[CH:17][CH2:18]Cl)[CH2:14][S:15][C@H:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:38].[Na+].[C:40]([NH2:48])(=[O:47])[C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1>CC(C)=O.CN(C)C=O>[I-:38].[CH:1](=[N:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13]([CH:16]=[CH:17][CH2:18][N+:44]3[CH:45]=[CH:46][C:41]([C:40](=[O:47])[NH2:48])=[CH:42][CH:43]=3)[CH2:14][S:15][C@H:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C=CCCl)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12
Reactant: NC(=O)c1ccncc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1cc[n+](CC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N=Cc4ccccc4)[C@H]3SC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a chilled mixture of the 3-chloropropenylcephem XVII (Z isomer) (16.4 g) in acetone (5 ml), was added dropwise a solution of sodium iodide (6.3 g, 42 mmole) in acetone (30 ml) over 10 minutes under nitrogen atmosphere, and the mixture was stirred at room temperature. The reaction was monitored by the ratio of uv absorption [E1 cm1% (255 nm)/E1 cm1% (320 nm)]. When the ratio reached below 1.30 (after 45 minutes), the mixture was diluted with carbon tetrachloride (400 ml), and allowed to stand at room temperature. When the ratio came to below 1.10 (after 3 hours), the mixture was concentrated to a half its volume. The concentrate was treated with a small amount of charcoal and diatomaceous earth, and filtered. The filter cake was washed with a 1:1 mixture (100 ml) of methylene chloride and carbon tetrachloride. To the combined solution of the filtrate and washings, was added a solution of isonicotinamide (3.5 g, 28.7 mmole) in dimethylformamide (20 ml) and the mixture was concentrated under reduced pressure. The concentration was allowed to stand at room temperature for 1.5 hours and washed with isopropyl ether (100 ml×3). The residual brown semi-solid was dissolved in methylene chloride (50 ml) and the solution was added dropwise, with stirring, to ethyl acetate (1.5 L). The resulting precipitate was collected by filtration and washed with ethyl acetate (200 ml). After drying over phosphorous pentoxide in vacuo, 17 g of the title compound XXI-H (E isomer) was obtained. Yellow amorphous powder. M.p. 150°-155° C. (dec.). Estimated purity 80% by nmr.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]1=[O:17].Cl[C:19]1[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:21][C:20]=1[F:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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:34][C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][C:19]=1[C:6]1[CH:5]=[CH:4][C:3](=[O:17])[N:2]([CH3:1])[CH:7]=1)[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(F)c1
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: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(CNC(=O)OC(C)(C)C)cc2F)ccc1=O
Temperature: 96 °C
Reaction time: 8 h

Procedure:
A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 21-3 (78 mg, 0.33 mmol), tert-butyl 4-chloro-3-fluorobenzylcarbamate 21-5 (94 mg, 0.36 mmol), Pd(PPh3)4 (38 mg, 0.033 mmol) and K3PO4 (140 mg, 0.66 mmol) in dioxane (1.2 mL) and water (0.1 mL) was stirred at 96° C. under argon overnight. After cooling to room temperature, the mixture was filtered through celite and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography to give crude tert-butyl 3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzylcarbamate 21-6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[CH2:34](I)[CH3:35]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:34][CH3:35])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCI
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(c2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3,4-difluorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (200 mg) in DMF (4 mL) was added sodium hydride (60%, 28.4 mg) at room temperature, and the mixture was stirred at 60° C. for 30 min under a nitrogen atmosphere. Ethyl iodide (45.2 μL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with 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. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (37.1 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([N:26]([CH2:42][CH3:43])[C:27]1[CH:28]=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:25]>>[CH2:42]([N:26]([CH2:24][CH3:25])[C:27]1[CH:32]=[C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:30]=[N:29][CH:28]=1)[CH3:43]
Reactant: CCN(CC)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCN(CC)c1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and diethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 95.1.1) to give the title compound as a white solid. (HPLC: tR 2.31 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.13-8.09 (m, 2H), 8.07-8.05 (m, 1H), 7.96-7.91 (m, 2H), 7.60-7.58 (m, 1H), 6.95-6.92 (m, 1H), 3.87 (s, 3H), 3.58 (s, 3H), 3.46-3.39 (m, 4H), 1.97 (s, 3H), 1.13 (t, 6H))
Reaction SMILES: [CH:1]([O:4][C:5]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([C:20]#[C:21][CH3:22])[C:6]=1[NH:7][C:8](=O)[C:9](F)(F)F)([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=C(I)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32].C([O-])([O-])=[O:37].[K+].[K+]>>[CH:1]([O:4][C:5]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:6]=1[NH:7][C:8]([CH3:9])=[C:20]2[C:21](=[O:37])[C:22]1[CH:26]=[C:25]([O:24][CH3:23])[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=1)([CH3:3])[CH3:2]
Reactant: CC#Cc1ccc(OC)c(OC(C)C)c1NC(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Reactant: COc1cc(I)cc(OC)c1OC
Agent: [K+]
Product: COc1cc(C(=O)c2c(C)[nH]c3c(OC(C)C)c(OC)ccc23)cc(OC)c1OC
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of the product of Step C (0.171 g; 0.54 mmol), 3,4,5-trimethoxyphenyl iodide (0.191 g; 0.65 mmol), Cl2Pd(PPh3)2 (0.044 g; 0.063 mmol); dry K2CO3 (0.23 g; 1.62 mmol in anhydrous DMF (5 ml) was degassed under reduced pressure and saturated with CO gas. The resulting mixture was vigorously stirred overnight at room temperature under CO balloon, then diluted to 50 ml with ethyl acetate and washed with water (3×15 ml), brine and dried over anhydrous MgSO4, filtered off and filtrate evaporated to dryness. The residue was purified by flash column chromatography (SiO2 CH2Cl2/ethyl acetate, 9:1) to give the title compound (0.143 g; 64% yield) as a yellow solid. 1H-NMR (CDCl3) 1.27 (d, 6H, J=6.14 Hz); 2.51 (s, 3H); 3.79 (s, 6H); 3.85 (s, 3H); 3.90 (s, 3H); 4.69 (m, 1H, J=6.14 Hz): 6.76 (d, 1H, J=8.75 Hz); 7.04 (s, 2H); 7.11 (d, 1H, J=8.75 Hz); 8.83 (broad m, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.[CH3:34][S:35]([CH2:38][C:39](O)=[O:40])(=[O:37])=[O:36].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:39](=[O:40])[CH2:38][S:35]([CH3:34])(=[O:37])=[O:36])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)CC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.2 %

Procedure:
A mixture of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 2-(methylsulfonyl)acetic acid (79.6 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg), 1-hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=4:1). Crystallization from ethyl acetate-diisopropyl ether gave the title compound (128 mg) as colorless powder crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:12]1[CH:16]=[N:15][C:14]([C:17]([O:19]C)=[O:18])=[N:13]1.ClC1C=C(N2C=NC(C(O)=O)=N2)C=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[N:13]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1nc[nH]n1
Reactant: Cc1ccc(B(O)O)cc1F
Agent: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Product: Cc1ccc(-n2cnc(C(=O)O)n2)cc1F

Procedure:
This intermediate was prepared from 3-fluoro-4-methylphenylboronic acid and methyl 1,2,4-triazole-3-carboxylate in two steps according to the preparation of 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:23])([CH3:22])[N:10](CC3C=CC(OC)=CC=3)[C:11](=[O:12])[C:6]2=[CH:5][CH:4]=1.[N+]([O-])([O-])=O.[NH4+].O.[CH3:30]COC(C)=O>CC#N>[CH2:1]([O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:23])([CH3:22])[NH:10][C:11](=[O:12])[C:6]2=[CH:5][CH:4]=1)[CH3:30]
Reactant: COc1ccc(CN2C(=O)c3ccc(OC)nc3C2(C)C)cc1
Reactant: CCOC(C)=O
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOc1ccc2c(n1)C(C)(C)NC2=O
Yield: 72 %

Procedure:
To solution of 2-methoxy-6-(4-methoxy-benzyl)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one (0.33 g, 1.0 mmol) in CH3CN (5 mL) was added eerie ammonium nitrate (1.64 g, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours before water and EtOAc were added into the mixture. The organic layer was separated, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel column chromatography to give the title compound (0.15 g, 72%) as a solid. MS: 207.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:12])=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:13]1(C)C=CC=C[CH:14]=1>C(O)C>[CH2:13]([O:6][C:5](=[O:7])[C:4]1[C:8]([Cl:12])=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[CH:3]=1)[CH3:14]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1cc(O)c(O)cc1Cl
Solvent: CCO
Product: CCOC(=O)c1cc(O)c(O)cc1Cl
Yield: 95 %

Procedure:
A solution of 3,4-dihydroxy-6-chlorobenzoic acid (48 g: 250 mMol.) in a mixture of toluene (180 ml) and ethanol (180 ml) is heated under reflux under Dean Stark apparatus filled with Molecular Sieves for 12 hours. The reaction mixture is cooled and washed with aqueous sodium hydrogen carbonate and water, dried and concentrated under reduced pressure to give 6-chloro-3,4-dihydroxybenzoic acid ethyl ester (52.7 g). Yield: 95%.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].N1C2C(=CC=CC=2)C=CC=1>[Cu-]=O.S1C=CC=C1C([O-])=O.[Cu+2].S1C=CC=C1C([O-])=O.C(O)C.N1C=CC=CC=1>[N+:20]([C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Br
Reactant: Oc1ccc(S)cc1
Agent: O=[Cu-]
Agent: [Cu+2]
Agent: O=C([O-])c1cccs1
Solvent: CCO
Solvent: c1ccncc1
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Sc1ccc(O)cc1
Temperature: 70 °C

Procedure:
A mixture containing 12.6 g (0.10 mole) of 4-mercapto phenol, 7.15 g (0.05 mole) of copper (I) oxide, and 100 ml of absolute ethanol is heated at reflux under an atmosphere of dry nitrogen until conversion to the copper thiophenate is complete, as indicated by discharge of the reddish color of the copper (I) oxide. The resultant yellow mixture is cooled to 25°, 27.0 g (0.10 mole) of 4-bromo-3-nitro-benzotrifluoride, 100 ml of quinoline, and 10 ml of pyridine are added, and the reaction vessel is equipped with a Newman still head. The reaction is now slowly heated with concomitant removal of the ethanol to 90° and maintained at this temperature until the conversion is complete, as indicated by vpc techniques. The dark liquid is cooled to 70° C., cautiously poured into 500 ml of an ice cold molar hydrochloric acid solution, and filtered, whereupon the residue is extracted with several portions of ether. The combined ether extracts are washed with a 3.0 molar hydrochloric acid solution, water until neutral, a saturated sodium chloride solution, dried (magnesium sulfate), and concentrated in vacuo to afford a quantitative yield of crude product as a dark solid. Recrystalization foam ether-hexane provides yellow crystals, mp 131°-134° of 4-(2-nitro-4-trifluoromethylphenylthio)phenol. This phenol is then reacted with 2-bromopropimate by the procedure of Example 3 above to provide the desired ethyl 2-[4-(2-nitro-4-trifluoromethylphenylthio)phenoxy] propionate, m.p. 63°-64° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[C:25]([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30](O)=[O:31])(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=2[Cl:22])=[O:15])=[CH:11][CH:12]=1)=[O:31])(=[O:27])[CH3:26]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: CC(=O)c1cccc(C)c1C(=O)O
Product: CC(=O)c1cccc(C)c1C(=O)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Yield: 38 %

Procedure:
N-[(2-Acetyl-6-methylphenyl)carbonyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine was prepared in 38% yield from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-acetyl-6-methylbenzoic acid using the general procedure described in example 3. HR MS: Obs. mass, 547.0579. Calcd. mass, 547.0594 (M+Na).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[O:8][CH2:9][C:10]3[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=3[CH:12]([C:13](O)=[O:14])[C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23]>>[CH:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:25]([CH:22]([CH3:24])[CH3:23])[C:26]=1[NH:27][C:13]([CH:12]1[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[CH2:9][O:8][C:7]2[CH:20]=[CH:21][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]1=2)=[O:14])([CH3:34])[CH3:33]
Reactant: O=C(O)C1c2ccccc2COc2ccc([N+](=O)[O-])cc21
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1c2ccccc2COc2ccc([N+](=O)[O-])cc21
Yield: 45.3 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.18 g of 6,11-dihydro-2-nitrodibenz[b,e]oxepin-11-carboxylic acid obtained in Example 62 (Compound AA) in place of Compound A and 0.73 g of 2,6-diisopropylaniline in place of aniline to obtain 0.83 g of Compound 46.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@H:5]([O:7][CH2:8][CH2:9][OH:10])[C@@H:4]([OH:11])[C@H:3]1[OH:12].[Cl:13][C:14]1[C:19]([NH2:20])=[C:18](Cl)[N:17]=[C:16]([S:22][CH2:23][CH2:24][CH3:25])[N:15]=1.[N:26](CCO)(CCO)CCO.N([O-])=O.[Na+]>C(OCC)(=O)C.C(O)(=O)C>[Cl:13][C:14]1[C:19]2[N:20]=[N:26][N:1]([C@@H:2]3[CH2:6][C@H:5]([O:7][CH2:8][CH2:9][OH:10])[C@@H:4]([OH:11])[C@H:3]3[OH:12])[C:18]=2[N:17]=[C:16]([S:22][CH2:23][CH2:24][CH3:25])[N:15]=1
Reactant: N[C@@H]1C[C@H](OCCO)[C@@H](O)[C@H]1O
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Reactant: OCCN(CCO)CCO
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Temperature: 90 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
A mixture of (1S,2S,3R,5S)-3-amino-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (OLA; 0.89 g, 5 mmol), 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (CLINA; 1.19 g, 5 mmol) and triethanolamine (1.49 g, 10 mmol) was stirred neat for 24 h at 90° C. After cooling to ambient temperature, the viscous reaction mixture was dissolved by the addition of acetic acid (3 mL). While maintaining the reaction temperature at 15-20° C. there was added sodium nitrite (0.38 g, 5.5 mmol) and the reaction mixture left stirring for 12 h. The reaction mixture was diluted with ethyl acetate (35 mL), washed with water (2×25 mL) and evaporated under reduced pressure. The crude product was triturated in hexane (20 mL) and filtered to give CLTOL as an off-white powder (1.61 g, 83% yield): 13C NMR (CDCl3, 125 MHz) δ13.4, 22.0, 33.5, 33.7, 61.75, 61.77, 71.1, 74.9, 75.4, 82.0, 131.8, 150.7, 152.9, 171.8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.C(N(CC)CC)C.[Cl:39]/[CH:40]=[CH:41]\[C:42](O)=[O:43].C(Cl)Cl.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[Cl:39]/[CH:40]=[CH:41]\[C:42]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:10]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:20]([Cl:30])=[C:21]([O:28][CH3:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=2[Cl:25])=[O:17])[N:12]=[CH:13][N:14]=1)=[O:43]
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3N)ncn2)c1Cl
Reactant: O=C(O)/C=C\Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3NC(=O)/C=C\Cl)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
The title compound was synthesized following the approach outlined in Procedure 2A (Example 100), modifying step (i) to the following procedure: To a solution of 1-(6-((2-aminophenyl)amino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylurea (20 mg, 0.043 mmol), triethylamine (21.8 g, 0.22 mmol), and (Z)-3-chloroacrylic acid (5.5 g, 0.052 mmol) in DCM (0.86 ml, 13.3 mmol), cooled to 0° C. was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (49 g, 0.78 mmol, 50% solution of EtOAc). The resulting mixture was stirred at room temperature for 2 h and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (15 mg, yield: 63%). 1H NMR (400 MHz, CDCl3) δ X; MS (ESI): 551.0 [M+H]+.