Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][N:11]([C:21](=[O:24])[CH2:22]Cl)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:39])[CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9](=[O:25])[CH2:10][N:11]([C:21](=[O:24])[CH2:22][N:31]([CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: O=C(CN(C(=O)CCl)C1Cc2ccccc2C1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CN(CC(=O)N(CC(=O)OCc1ccccc1)C1Cc2ccccc2C1)Cc1ccccc1
Yield: 69.5 %

Procedure:
N-Chloroacetyl-N-(indan-2-yl)glycine benzyl ester (3 g) and 2 g of N-benzylglycine ethyl ester are dissolved in 50 ml of methyl ether ketone, 10 g of potassium carbonate is added, and the mixture is refluxed for 24 hours with stirring. After cooling, the insoluble matter is filtered off, and the filtrate is distilled under reduced pressure to give an oil. This is purified by silica gel column chromatography to give 3 g of N-ethoxycarbonylmethyl-N-benzylglycyl-N-(indan-2-yl)glycine benzyl ester as an oil.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2.[ClH:16]>C(O)(=O)C>[Cl:16][CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2
Reactant: Cc1cc(OCC2CO2)c2cn[nH]c2c1
Reactant: Cl
Solvent: CC(=O)O
Product: Cc1cc(OCC(O)CCl)c2cn[nH]c2c1
Reaction time: 1 h

Procedure:
A solution of 2.7 g. 4-(2,3-epoxypropoxy)-6-methylindazole in 10 ml. glacial acetic acid is introduced, while stirring, into 10 ml. glacial acetic acid which has been saturated with hydrogen chloride at ambient temperature. After 1 hour at ambient temperature, the reaction mixture is poured into 300 ml. water and neutralised with sodium bicarbonate, a viscous oil thereby separating out, which solidifies after stirring for a comparatively long time or upon triturating with toluene. When recrystallized from toluene, with the use of fullers' earth, there is obtained 4-(3-chloro-2-hydroxypropoxy)-6-methyl-indazole in the form of colorless needles; m.p. 171°-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])=[CH:29][CH:30]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)cc3)c2cc1OC
Yield: 88 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) was dissolved in toluene (3 ml) with heat, 4-trifluoromethylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 10 minutes. The separated crystals were filtered and washed with toluene to obtain 77 mg of the title compound (yield: 88%).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.[OH-].[Na+:34]>CO>[Na+:34].[S:29]1[CH:30]=[CH:31][C:27]([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@@H:8]4[CH2:9][CH2:10][CH2:11][N:7]4[CH2:6][CH2:5][CH2:4][C:3]([O-:32])=[O:2])=[CH:15][CH:16]=3)=[CH:26][CH:25]=2)=[CH:28]1
Reactant: COC(=O)CCCN1CCC[C@H]1COc1ccc(Cc2ccc(-c3ccsc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])CCCN1CCC[C@H]1COc1ccc(Cc2ccc(-c3ccsc3)cc2)cc1
Temperature: 58 °C
Reaction time: 5.5 h
Yield: 68 %

Procedure:
To the product from step 1 (128 mg, 0.29 mmol) in methanol (5 mL) was added 1N NaOH (0.30 mL). The resulting solution was stirred at 58° C. for 5.5 h. The reaction mixture was concentrated in vacuo. The subsequent powder was washed with ether to afford the title compound (85 mg, 68%); LCMS; m/z: 436.9 (M+1); +H NMR (400 MHz, DMSO-d6); δ 1.54-1.68 (m, 5H), 1.82-1.90 (m, 3H), 2.15-2.26 (m, 2H), 2.70-2.74 (m, 2H), 3.00-3.02 (m, 1H), 3.63-3.67 (m, 1H), 3.87-3.90 (m, 3H), 6.84 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.51 (dd, J1=5.2 Hz, J2=1.2 Hz, 1H), 7.60-7.62 (m, 3H), 7.78-7.79 (m, 1H):
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]([C:21]3[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[C:19]([CH3:31])[C:18]3[C:13](=[CH:14][C:15]([O:32]COCC[Si](C)(C)C)=[CH:16][CH:17]=3)[O:12]2)=[CH:7][CH:6]=1.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH3:28][O:27][C:24]1[N:23]=[C:22]([O:29][CH3:30])[C:21]([C:20]2[CH:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[CH:6][CH:7]=3)[O:12][C:13]3[C:18]([C:19]=2[CH3:31])=[CH:17][CH:16]=[C:15]([OH:32])[CH:14]=3)=[CH:26][N:25]=1
Reactant: C1CCNCC1
Reactant: COc1ncc(C2=C(C)c3ccc(OCOCC[Si](C)(C)C)cc3OC2c2ccc(OCCCl)cc2)c(OC)n1
Product: COc1ncc(C2=C(C)c3ccc(O)cc3OC2c2ccc(OCCN3CCCCC3)cc2)c(OC)n1

Procedure:
The title product was prepared as a white solid according to the procedure described in Example 34 using 5-[2-[4-(2-Chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-2H-chromen-3-yl]-2,4-dimethoxy-pyrimidine and piperidine as the starting material.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([N:27]4[CH2:32][CH2:31][S:30][CH2:29][CH2:28]4)=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Br)cc2)C1
Reactant: C1CSCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3CCSCC3)cc2)C1
Yield: 31 %

Procedure:
To a solution of 1-(4-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate I, 200 mg, 0.59 mmol) in anhydrous toluene (2 mL) were added Pd2(dba)3 (1.3 mg, 0.002 mmol), BINAP (2.8 mg, 0.004 mmol), sodium tert-butoxide (85 mg, 0.89 mmol) and thiomorpholine (0.07 mL, 0.65 mmol) at r.t. and reaction mixture was refluxed for 17 h. Reaction mixture was then concentrated and the crude product was purified by column chromatography (silica gel, 2:8 EtOAc:Pet. ether) to afford the title compound as viscous liquid (66 mg, 31%).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]([C:17](=[O:19])[CH3:18])[C:12]([O:14]CC)=O)=[CH:5][CH:4]=1.C[Si](Cl)(C)C.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[OH:14][C:12]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([OH:2])[N:8]=2)[N:9]=[CH:10][C:11]=1[C:17](=[O:19])[CH3:18]
Reactant: CCOC(=O)C(=CNc1ccc(OC)nc1)C(C)=O
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: CC#N
Product: CC(=O)c1cnc2ccc(O)nc2c1O
Temperature: 25 °C

Procedure:
To a suspension of ethyl 2-[(6-methoxypyridin-3-ylamino)methylene]-3-oxobutanoate (70 g, 0.32 mol) in acetonitrile (800 ml) was added trimethylsilylchloride (173 g, 1.6 mol) and sodium iodide (140 g, 0.96 mol) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and satd. aq. sodium thiosulfate was added. The mixture was concentrated to remove acetonitrile, diluted with brine and the solids were filtered and dried to provide the intermediate 1-(4,6-dihydroxy-1,5-naphthyridin-3-yl)ethanone. This intermediate was suspended in dichloroethane (350 mL) followed by the addition of phosphorus oxychloride (200 mL) and catalytic N,N-dimethylformamide and the reaction mixture was stirred with heat at 80° C. for 3 h. The reaction mixture was cooled to room temperature and quenched by pouring slowly into ice-cold satd. aq. sodium bicarbonate or 3 N sodium hydroxide. The quenched reaction mixture was concentrated to remove the dichloroethane and the resulting solids were collected by filtration and purified by chromatography (silica, hexanes/ethyl acetate) to provide the desired product (50 g, 74% over 2 steps) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 9.00 (s, 1H), 8.38 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 3.28-3.18 (m, 1H), 1.36 (t, J=7.1 Hz, 3H), ESI MS m/z 241 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[N:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[C:10]=[S:11]>>[Br:1][C:2]1[C:3]([NH:8][C:10]([NH:9][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[S:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1Br
Reactant: COc1ccccc1N=C=S
Product: COc1ccccc1NC(=S)Nc1ncccc1Br

Procedure:
1-(3-Bromo-pyridin-2-yl)-3-(2-methoxy-phenyl)-thiourea was prepared from 3-bromo-pyridin-2-ylamine (5.0 g, 29.0 mmol) and 1-isothiocyanato-2-methoxy-benzene (4.0 mL, 29.0 mmol) in a manner analogous to Step 19a. The reaction product was isolated as a yellow solid (8.46 g, 86%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 13.62 (br s, 1H), 8.75-8.65 (m, 2H), 8.21 (dd, J=5.1, 1.5 Hz, 1H), 7.91 (dd, J=8.0, 1.6, Hz, 1H), 7.21 (dt, J=7.9, 1.5 Hz, 1H), 7.06-7.00 (m, 1H), 6.98-6.94 (m, 1H), 6.91 (dd, J=7.9, 5.0 Hz, 1H), 3.93 (s, 3H). MS=340 (MH)+. 20b) (8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine was prepared from 1-(3-bromo-pyridin-2-yl)-3-(2-methoxy-phenyl)-thiourea (2.0 g) in a manner analogous to Step 19b. The reaction product was isolated as a white solid (0.47 g, 25%). MP=186-187° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.42 (d, J=6.7 Hz, 1H), 8.31 (dd, J=8.0, 1.1 Hz, 1H), 7.72 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.06-7.01 (m, 1H), 6.95 (ddd, J=8.1, 8.1, 1.1 Hz, 1H), 6.91-6.88 (m, 1H), 6.78-6.73 (m, 1H), 3.90 (s, 3H). MS=319, 321 (MH)+. 20c) (2-Methoxy-phenyl)-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and (4-trifluoromethylphenyl)boronic acid (33.0 mg, 0.174 mmol) with Pd(dppf)Cl2 (0.012 g) as the catalyst in a manner analogous to Step 2e. The reaction product was isolated as a white solid (0.032 g, 53%). MP=184-186° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (dd, J=6.8, 0.9 Hz, 1H), 8.38 (dd, J=8.0, 1.3 Hz, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 7.63-7.58 (m, 2H), 7.08-6.88 (m, 4H), 3.92 (s, 3H). MS=385 (MH)+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH3:7][O:8][CH:9]=[CH:10][CH:11]=[CH:12][CH3:13]>C(=O)([O-])O.[Na+]>[CH3:7][O:8][CH:9]1[CH:10]=[CH:11][CH:12]([CH3:13])[CH:2]([C:1]([O:5][CH3:6])=[O:4])[O:3]1
Reactant: COC(=O)C=O
Reactant: CC=CC=COC
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C1OC(OC)C=CC1C
Temperature: -70 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
In the same manner as in Example 1, a solution of an (R)-binaphthol-dichlorotitanium complex was obtained. This solution was cooled to -70° C. in a dry ice-acetone bath. To this solution were successively added 88 mg (1 mmole) of methyl glyoxylate and 196 mg (2 mmole) of 1-methoxy-1,3-pentadiene. Reaction was then allowed to proceed at -10° C. for 1 hour, and 10 ml of a sodium hydrogencarbonate aqueous solution was added to the reaction mixture to terminate the reaction. This reaction mixture was filtered through Celite and then subjected to extraction once with 20 ml of diethyl ether and twice with 20 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (200 mesh; developing solvent: hexane/ethyl acetate =10/1), thereby obtaining 0.23 g of desired optically active 2-methoxy-6-methoxycarbonyl-5-methyl-5,6-dihydropyran (yield: 63%).
Reaction SMILES: C[O:2][Si:3][O:4]C.[CH:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:12]3[N:44]=[C:43]4[N:45]=[C:36]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=54)[N:35]=[C:33]4[NH:34][C:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=54)=[N:25][C:23]4=[N:24][C:16]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=54)=[N:15][C:14]=2[NH:13]3)[CH:11]=1.O>CS(C)=O>[OH:2][Si:3][OH:4].[CH:7]1[CH:6]=[CH:11][C:10]2[C:9](=[C:14]3[N:15]=[C:16]4[N:24]=[C:23]([C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=54)[N:25]=[C:26]4[NH:34][C:33]([C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=54)=[N:35][C:36]4=[N:45][C:43]([C:42]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=54)=[N:44][C:12]=2[NH:13]3)[CH:8]=1
Reactant: CO[Si]OC
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Solvent: O
Solvent: CS(C)=O
Product: O[Si]O
Temperature: 25 °C

Procedure:
10 g of dimethoxysilicon phthalocyanine synthesized in Synthesis Example 2 was added to 10 g of water and 90 g of dimethyl sulfoxide (90% DMSO aqueous solution) and reacted at 120° C. for 3 hours. The reaction product was thermally filtrated and washed with DMF and acetone in the order named. After the product was stirred in 50 ml of acetone at room temperature, crystals were separated by filtration and dried to obtain 8.4 g of dihydroxysilicon phthalocyanine. When structural analysis was carried out by mass spectral (negative measurement) and IR (KBr method) methods, the same spectrum as that of Example 1 was obtained. Therefore, it was confirmed that the product was dihydroxysilicon phthalocyanine. According to the X-ray spectrum (FIG. 12), the obtained dihydroxysilicon phthalocyanine is a dihydroxysilicon phthalocyanine having the crystal form of the present invention and a main peak at a 2 0 of 9.20 and other peaks at 12.2, 14.0, 15.3, 19.7, 23.4 and 27.1°, respectively.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[Cl:20]N1C(=O)CCC1=O>C1COCC1.CCOC(C)=O>[CH2:16]([O:15][C:13]([C:10]1[CH:11]=[C:12]2[C:7]([C:6]([Cl:20])=[CH:5][N:4]2[CH:1]2[CH2:2][CH2:3]2)=[C:8]([O:18][CH3:19])[CH:9]=1)=[O:14])[CH3:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OC)c2c(Cl)cn(C3CC3)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a stirred solution of 1.29 g of ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate in 13 ml of THF was added 801 mg of N-chlorosuccinimide and the mixture was stirred at 60° C. for 2 hrs. After diluted with EtOAc, the mixture was washed successively with water and saturated brine, dried over Na2SO4, and concentrated. The residue was purified on SiO2 column chromatography to afford 1.03 g of ethyl-3-chloro-1-cyclopropyl-4-(methoxy)-1H-indole-6-carboxylate as a colorless solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])[CH:7]=[N:8][C:9]=1[Cl:10].I[CH3:17]>CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][N:12]([CH3:17])[C:13](=[O:15])[CH3:14])[CH:7]=[N:8][C:9]=1[Cl:10]
Reactant: CI
Reactant: CC(=O)NCc1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N(C)Cc1cnc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
NaH (41 mg, 1.0 mmol, Aldrich, 60% dispersion in mineral oil) was added portionwise to a solution of N-(5,6-dichloro-pyridin-3-ylmethyl)-acetamide (150 mg, 0.68 mmol, Example 155d) and iodomethane (0.063 mL, 1.0 mmol, Aldrich) in DMF (3.0 mL) with stirring at room temperature. The mixture was stirred for 30 min at room temperature, diluted with EtOAc (30 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 80% EtOAc/hexane to give the title compound. MS (ESI, pos. ion) m/z: 233 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:22])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][OH:21])[N:18]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[CH2:23](I)[CH3:24]>O1CCCC1>[Cl:3][C:4]1[C:5]([CH3:22])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][O:21][CH2:23][CH3:24])[N:18]=2)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCI
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCO)cs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCCc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1
Reaction time: 0.25 h

Procedure:
Sodium hydride (95% dry, 80 mg, 3.23 mmol) was added to a stirred solution of EXAMPLE 181A (426 mg, 1.28 mmol) in tetrahydrofuran (10 mL) at room temperature. After stirring for 15 min, the mixture was treated with ethyl iodide (400 mg, 2.56 mmol). The reaction mixture was stirred for 2 h at 55° C. and then quenched with aqueous HCl (1 M, 1 mL) and water was added. The product was extracted with DCM and dried (Sodium sulfate). Evaporation of the solvent gave a residue which was purified by flash chromatography on silica gel eluting with 10% acetone in DCM giving an oil (0.25 g, 54%) which solidified on standing: MS (Ionspray, [M+H]+) m/z 360; Anal. Calcd. (found) for C14H17ClN2O3S2: C, 46.6 (46.5)%; H, 4.7 (4.6)%; N, 7.8 (7.8)%.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[C:40]([NH:44][CH3:45])([CH3:43])([CH3:42])[CH3:41]>>[C:40]([N:44]([CH3:45])[CH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:38][CH:39]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: CNC(C)(C)C
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCN(C)C(C)(C)C)cc2)c1
Yield: 31.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and tert-butylmethylamine (14 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (4.8 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:10])([CH3:9])[C:7](=[O:11])[NH:6][C:5]1=[O:12].C(N(CC)C(C)C)(C)C.CN1CCCC1=O.[Br:29][C:30]1[S:34][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37](Cl)[N:36]=2)=[CH:32][CH:31]=1>CO.C1(C)C=CC=CC=1>[Br:29][C:30]1[S:34][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH:1][CH2:2][CH2:3][N:4]3[C:8]([CH3:9])([CH3:10])[C:7](=[O:11])[NH:6][C:5]3=[O:12])[N:36]=2)=[CH:32][CH:31]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: Clc1nccc(-c2ccc(Br)s2)n1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(Br)s2)n1
Temperature: 180 °C

Procedure:
1.22 mL (0.71 mmol) of a 10% (w/v) solution of 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione in MeOH was added to a 10 mL microwave vessel. The MeOH was evaporated with a stream of N2, to leave an oily solid which was dissolved in 0.34 mL (2.0 mmol) of N,N-diisopropylethylamine, 0.5 mL of N-methylpyrrolidinone and 3.5 mL of toluene, to which was added 0.15 g (0.65 mmol) of 4-(5-bromothiophen-2-yl)-2-chloropyrimidine. The reaction solution was heated in a microwave to 180° C. for 20 min then concentrated in vacuo and purified by flash chromatography eluting with a linear gradient of 75% EtOAc in hexane to neat EtOAc to deliver The title compound. MS (M+H)+ 410.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:46])[CH2:7][N:8]([CH2:40][C:41]([O:43]CC)=[O:42])[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([C:35]([O:37]C)=[O:36])[CH:11]=1)C>>[C:41]([CH2:40][N:8]([C:9](=[O:39])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([C:35]([OH:37])=[O:36])[CH:11]=1)[CH2:7][C:6]([OH:46])=[O:5])([OH:43])=[O:42]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)O)cc(C(=O)N(CC(=O)O)CC(=O)O)c1

Procedure:
Sodium hydroxide hydrolysis of N-(2-ethoxy-2-oxoethyl)-N-[3-methoxycarbonyl-5-(octadecyloxy)benzoyl]glycine ethyl ester as in Example 11 gave N-(carboxymethyl)-N-[3-carboxy-5-(octadecyloxy) benzoyl]glycine, mp 108°-112°. The nmr and mass spectra were compatible with the structure.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[C@@H:10]([NH:14][C:15](=[O:27])[C@@H:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:17])[C@H:9]([CH3:28])[N:8]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:7]=2[CH:36]=1)#[N:2].[Br:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH:40]=[CH:41][C:42]([O:50][CH3:51])=[C:43]2[CH2:48]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH:40]=[CH:41][C:42]([O:50][CH3:51])=[C:43]2[CH2:48][N:12]1[C:11](=[O:13])[C@@H:10]([NH:14][C:15](=[O:27])[C@@H:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])[CH3:17])[C@H:9]([CH3:28])[N:8]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:32])=[O:33])[C:7]2[CH:36]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]1=2
Reactant: COc1ccc2c(Br)cccc2c1CCl
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.7 %

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-8-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (29.5 mg, 56.6 μmol) in DMF (141 μl) was added 5-bromo-1-(chloromethyl)-2-methoxynaphthalene (17.8 mg, 62.2 μmol), cesium carbonate (22.1 mg, 67.9 μmol), and sodium iodide (10.2 mg, 67.9 μmol). The reaction was stirred at rt for 2.5 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-1-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-7-cyano-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (33 mg, 76%) as a white solid. MS m/z 792/794 (MNa)+.