Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH2:18][C@@H:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])[CH:14]=[CH:15][C:16]=1[OH:17].Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[C:13]([CH2:18][C@@H:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)[C@H](O)Cc1ccc(O)c(Br)c1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](O)Cc1ccc(OCOCC[Si](C)(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.7 mL (39.1 mmol) ethyldiisopropylamine were added to a solution of 10.2 g (34.6 mmol) methyl (R)-3-(3-bromo-4-hydroxy-phenyl)-2-hydroxy-propionate in 100 mL DCM and the reaction mixture was cooled in the ice bath. Then a solution of 7.9 mL (44.6 mmol) (2-chloromethoxy-ethyl)-trimethyl-silane in 20 mL DCM was added. The reaction mixture was stirred for 3 h at RT and then combined with another 0.67 mL ethyldiisopropylamine and 0.8 mL (4.5 mmol) (2-chloromethoxy-ethyl)-trimethyl-silane to complete the reaction and stirred for 1.5 h at RT. The reaction mixture was washed with 5% Na2CO3 solution and saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, Cyc/EtOAc 75:25).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([CH:44]=[C:45]([CH:47]=O)[CH:46]=1)[C:40]([O:42][CH3:43])=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([CH:44]=[C:45]([CH:47]=[CH:2][O:3][CH3:4])[CH:46]=1)[C:40]([O:42][CH3:43])=[O:41])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)c1cc(C=O)cc(OCc2ccccc2)c1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=Cc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (methoxymethyl)(triphenyl)phosphonium chloride (1.5 eq.) in THF (0.1 M) at −78° C. was added n-BuLi (1.5 eq.) dropwise. The reaction was stirred at −78° C. for 30 min and then added a solution of methyl 3-(benzyloxy)-5-formylbenzoate (1 eq.) from the previous step in THF. After stirring at rt for 40 min, the reaction was quenched with saturated aqueous NH4Cl solution. The aqueous layer was extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 15% EtOAc in Hex) to afford a mixture of E- and Z-methyl 3-(benzyloxy)-5-[2-methoxyvinyl]benzoate.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[C:19]([C:42]5[CH:51]=[CH:50][C:45]([C:46](OC)=[O:47])=[CH:44][CH:43]=5)=[N:20][N:21]([C:23]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:22]=4)[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:5][CH:4]=1.CSC1SC(C2C3C(=CC=C(C4C(C5C=CC(C(OCC)=O)=CC=5)=NN(C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)C=4)C=3)N=CN=2)=CC=1>>[CH3:1][S:2][C:3]1[S:7][C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[C:19]([C:42]5[CH:43]=[CH:44][C:45]([CH2:46][OH:47])=[CH:50][CH:51]=5)=[N:20][N:21]([C:23]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:22]=4)[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncnc(-c4ccc(SC)s4)c3c2)cc1
Agent: CCOC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncnc(-c4ccc(SC)s4)c3c2)cc1
Product: CSc1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(CO)cc4)cc23)s1

Procedure:
126 mg of the title compound was obtained as a yellow solid by the same method as in Example 359 from 238 mg mixture of methyl 4-{4-[4-(5-methylsulfanylthiophen-2-yl)quinazolin-6-yl]-1-trityl-1H-pyrazol-3-yl}benzoate and ethyl 4-{4-[4-(5-methylsulfanylthiophen-2-yl)quinazolin-6-yl]-1-trityl-1H-pyrazol-3-yl}benzoate obtained in the synthesis process in Example 771.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].Cl.[O-:15][C:16]#[N:17].[K+]>O>[F:1][CH:2]([F:13])[O:3][CH2:4][C@@H:5]([NH:6][C:16]([NH2:17])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N[C@H](COC(F)F)c1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)N[C@H](COC(F)F)c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of (S)-2-(difluoromethoxy)-1-phenylethanamine (169 mg, 0.903 mmol) in water (6 ml), was added HCl (3.6 ml, 3.61 mmol) 1N and potassium cyanate (366 mg, 4.51 mmol). The reaction was heated at 80° C. for 2 hrs, then allowed to cool to ambient temperature overnight. The precipitate formed was filtered, washed with water, and dried under high vacuum to provide (S)-1-(2-(difluoromethoxy)-1-phenylethyl)urea MS: [M+H]+ m/z 231. 1H NMR (500 MHz, DMSO-d6) δ 7.42-7.30 (m, 4H), 7.29-7.17 (m, 1H), 6.84-6.45 (m, 2H), 5.61 (s, 2H), 4.97-4.83 (m, 1H), 4.08-3.89 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][C:15]([F:18])([F:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:19])[CH:6]=1.[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]2)[CH2:27][O:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH:36][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=4[Cl:1])=[CH:6][C:7]3=[O:19])[CH2:14][C:15]([F:18])([F:17])[CH3:16])=[N:32]2)[CH2:27][O:26]1
Reactant: CC(F)(F)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(F)(F)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
A solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-pentanoic acid (117 mg, 0.34 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 82 mg, 0.42 mmol) in N,N-dimethylformamide (3 mL) was treated with N,N-diisopropyethylamine (170 μL, 1.02 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (225 mg, 0.51 mmol) and stirred overnight at 25° C. After this time, the mixture was diluted with ethyl acetate (25 mL) and washed with a saturated aqueous solution of ammonium chloride (25 mL), saturated aqueous solution of sodium bicarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL) dried over sodium sulfate and concentrated with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 20% ethyl acetate/hexanes) afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (72 mg, 40%) as a white foam: HR-ES-MS m/z calculated for C24H27N4O5ClF2 [M+Na]+ 547.1530, observed 547.1531.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)/[CH:6]=[C:7](\[CH2:11][CH3:12])/[C:8]([OH:10])=O.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[C:24]([F:27])([F:26])[F:25].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:8](=[O:10])/[C:7](=[CH:6]/[C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([O:2][CH3:1])[CH:4]=2)/[CH2:11][CH3:12])=[CH:19][C:18]=1[C:24]([F:25])([F:26])[F:27]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC/C(=C\c1cccc(OC)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC/C(=C\c1cccc(OC)c1)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
(2E)-2-(3-methoxybenzylidene)butanoic acid (190 mg, 0.92 mmol), 4-chloro-3-(trifluoromethyl)aniline (189 mg, 0.97 mmol) and DMAP (135 mg, 1.11 mmol) were mixed together and stirred in DCM (15 mL). The reaction mixture was cooled to 0° C. and EDCI (118 mg, 1.29 mmol) was added. The reaction was allowed to warm slowly to rt overnight. The mixture was diluted with DCM and washed with 1N HCl, sat. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, 0-15% EtOAc in hexanes) to give the title compound (216 mg). 1H NMR (400 MHz, d6-DMSO): δ 10.44 (s, 1H), 8.29 (d, 1H), 8.05-8.02 (dd, 1H), 7.68 (d, 1H), 7.39-7.35 (m, 1H), 7.22 (s, 1H), 6.99 (d, 1H), 6.95-6.93 (m, 2H), 3.77 (s, 3H), 2.54 (q, 2H), and 1.08 (t, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([CH2:15][C:16]([NH2:18])=[NH:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[C:19]([O:23][C:24]([C:26]1[C:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:30]([OH:40])N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[CH2:33]([O:32][C:31]1[C:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[N:17][C:16]([CH2:15][C:10]2([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=3)[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:18][C:30]=1[OH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: N=C(N)CC1(c2ccc(Cl)c(Cl)c2)CCCC1
Agent: Cl
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Cl)c(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
tert-Butyl 5-(benzyloxy)-2-((1-(3,4-dichlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylate (487) was synthesized as a white solid from 2-(1-(3,4-dichlorophenyl)-cyclopentyl)-acetamidine hydrochloride (486) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (243)
Reaction SMILES: [C:1]([O:5][C:6](=[O:54])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]([C:29]2[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[C:31]([O:37][CH2:38][CH2:39][O:40][Si](C(C)C)(C(C)C)C(C)C)[C:30]=2[F:51])[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[CH:12]=[CH:11][C:10]=1[C:52]#[N:53])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O>[C:1]([O:5][C:6](=[O:54])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]([C:29]2[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[C:31]([O:37][CH2:38][CH2:39][OH:40])[C:30]=2[F:51])[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:24]=[CH:25][CH:26]=[CH:27][N:28]=3)[N:18]=2)[CH:12]=[CH:11][C:10]=1[C:52]#[N:53])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cc(OCCO[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reaction time: 4 h
Yield: 125.9 %

Procedure:
To a mixture of [2-cyano-5-({[5-ethyl-2-fluoro-3-(2-triisopropylsilanyloxyethoxy)phenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl}amino)benzyl]carbamic acid t-butyl ester (56 mg) and THF (4 mL) there was added a 1M THF solution of tetrabutylammonium fluoride (0.147 mL). The mixture was stirred for 4 hours, and then ethyl acetate (50 mL) and water (50 mL) were added. The mixture was sufficiently shaken, and then the organic layer was separated off, washed twice with water (50 mL) and once with saturated aqueous sodium chloride (50 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate and the solvent in the filtrate was distilled off under reduced pressure to obtain the target compound (56 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:7]C)(=O)[CH2:2][C:3]([CH3:5])=O.Cl.[CH:10]1([NH:16][NH2:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+]>>[CH:10]1([N:16]2[C:1](=[O:7])[CH2:2][C:3]([CH3:5])=[N:17]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NNC1CCCCC1
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1=NN(C2CCCCC2)C(=O)C1
Yield: 78.7 %

Procedure:
A mixture solution of 14.5 mL (0.134 mol) of methyl acetoacetate and 20.2 g (0.134 mol) of cyclohexylhydrazine hydrochloride was stirred for 2 hours at 120° C., and the mixture was cooled. Then, the reaction mixture was neutralized with 30 mL of 4M-sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was treated with hexane. The resulting precipitate was collected to give 19.0 g (79%) of the titled compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=O)=O)=CC=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([CH2:12][CH:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1)=[N+:21]=[N-:22]
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN=[N+]=[N-])O1
Temperature: 80 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (5.73 g, 20.00 mmol) in DMF (40 mL) was added sodium azide (2.6 g, 40.00 mmol) and the reaction mixture was stirred at 80° C. for 18 hr. The solvent was evaporated under reduced pressure, diluted with water (100 mL) and extracted 3 times with ethyl acetate (3×75 mL), which was consecutively washed with H2O (100 mL), brine (100 mL) and finally dried over MgSO4. The solvent was removed under vacuum to afford 2.2 g of 13 as brown oil (76% yield). 1H NMR (CDCl3, 400 MHz) δ: 4.21-4.27 (m, 1H), 4.02 (dd, J=6.4, 8.4 Hz, 1H), 3.74 (dd, J=6.0, 8.4 Hz, 1H), 3.36 (dd, J=4.8, 12.8 Hz, 1H), 3.26 (dd, J=5.6, 12.8 Hz, 1H), 1.43 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5](O)[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)C.O.[NH2:18][NH2:19]>>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[CH:6]=[CH:5][C:4](=[O:3])[NH:18][N:19]=1
Reactant: CCOC(=O)C(O)CC(=O)c1ccccn1
Reactant: NN
Solvent: O
Product: O=c1ccc(-c2ccccn2)n[nH]1

Procedure:
A solution of 2-hydroxy-4-oxo-4-pyridin-2-ylbutyric acid ethyl ester (2.910 g, 13.000 mmol) in 20 mL of 1-buanol was treated with 0.65 mL (1:1 ratio) of hydrazine hydrate, and the mixture was refluxed overnight. The solvents were evaporated to dryness to give 2.000 g (11.500 mmol) of 6-pyridin-2-yl-2H-pyridazin-3-one as a dark solid, which was used in the next step without further purification.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C([O-])([O-])=O.[Na+].[Na+]>CO>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:4]=2[S:16][C:15]=1[C:14]([O:18][CH3:19])=[O:17]
Reactant: N#Cc1ccc(C#N)c([N+](=O)[O-])c1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc2cc(C#N)ccc2c1N
Yield: 82 %

Procedure:
Nitroterephthalonitrile (5.0 g, 28.9 mmol), prepared by the method of Gorvin, U.S. Pat. No. 4,250,182, was treated with 1 equivalent methyl thioglycolate and 1 equivalent Na2CO3 in methanol by the prcx:edure described in Example 41A to yield the title compound (5.50 g, 82%). 1H NMR (300 MHz, DMSO) δ 8.50 (s, 1H), 8.32 (d, 1H), 7.80 (dd, 1H), 7.29 (br s, 2H), 3.81 (s, 3H). MS (DCI/NH3) m/e 250 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([NH:30][C:31]([C@@H:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35][N:34]2C(OC(C)(C)C)=O)=[O:32])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CCOC(C)=O>[CH2:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:42][C@@H:33]([C:31]([NH:30][C@H:10]([CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:11]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH2:17][CH2:18]2)=[O:12])=[O:32])[NH:34]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)c(Cl)c2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Yield: 64.4 %

Procedure:
To a 150 mL round-bottomed flask equipped with stirring was added tert-butyl(3S)-3-(N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)-amino]phenyl)piperidyl)-2-oxoethyl]carbamoyl}-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step b) (0.54 g, 0.74 mmol) followed by a saturated soln of HCl in EtOAc (50 mL). The reaction mixture was stirred at RT for 1 h and concentrated in vacuo to a white solid. Recrystallization from MeOH:Et2O (1:20) provided the title compound (HCl salt) as a white solid (0.3 g). MP 181° C. (decomposed). MS (ESI, pos. ion) m/z: 629 (M+1); MS (ESI, neg. ion) m/z: 627 (M−1). Calc'd for C31H34Cl2N4O4S: 628.17. Anal. Calcd for C31H34Cl2N4O4S.HC].H2O: C, 51.71; H, 5.74; N, 7.78; Cl, 14.77. Found: C, 51.66; H, 5.39; N, 7.49; Cl, 15.07.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].[OH:23]/[N:24]=[C:25](/[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)\[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].[H-].[Na+].Cl>CN(C)C=O.O>[CH3:12][C:11]1[O:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][C:7]=1[CH2:6][O:5][C:4]1[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=1[CH2:2][O:23]/[N:24]=[C:25](/[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)\[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC/C(=N\OCc1ccccc1OCc1nc(-c2ccccc2)oc1C)c1ccccc1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a stirred solution of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.50 g) and methyl E-4-hydroxyimino-4-phenylbutyrate (990 mg) in N,N-dimethylformamide (40 ml) was added sodium hydride (60% in oil, 200 mg) at 0° C. After stirring for 2 hours, the reaction mixture was poured into water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:4, v/v) gave methyl E-4-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (1.65 g, yield 71%) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14](=[O:25])[N:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[O:25]=[C:14]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)[CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([C:5](=[O:26])[C:4]([OH:27])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCc3ccccc3C2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCC(=O)N2CCc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.1 %

Procedure:
4-[2-Oxo-2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.3 g) in methanol (10 mL) was treated with sodium carbonate (0.113 g) in water (3 mL), and the mixture was stirred at room temperature for 20 minutes. After the solvents were removed in vacuo, water (10 mL) was added and the solution acidified with 3N hydrochloric acid, then the aqueous layer was extracted with dichloromethane-tetrahydrofuran (1:1). The organic layer was dried (MgSO4), evaporated and the residual solid was crystallized from acetone-tetrahydrofuran-hexane to yield 0.078 g of 4-[2-oxo-2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethoxy]-alpha-oxobenzeneacetic acid, mp 218°-220° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[N:17]([C:25](=[O:43])[C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:41])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:28][C:27]=3[CH3:42])[CH2:16][CH2:15][CH2:14]2)(=O)=O)=CC=1.[I-].[Na+].[C:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:49])[CH3:48].Cl>CN(C)C=O.C(OCC)C>[ClH:24].[C:47]([N:50]1[CH2:55][CH2:54][N:53]([CH2:11][CH2:12][CH:13]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[N:17]([C:25](=[O:43])[C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:41])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:28][C:27]=3[CH3:42])[CH2:16][CH2:15][CH2:14]2)[CH2:52][CH2:51]1)(=[O:49])[CH3:48]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)N1CCN(CCC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.5 %

Procedure:
To a solution of 5-[2-(p-toluenesulfonyloxy)ethyl]-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g) in dry dimethylformamide (20 ml) are added sodium iodide (0.178 g) and 4-acetylpiperazine (0.152 g), and the mixture is stirred at room temperature for one hour. The mixture is heated at 50° C. for 2 hours, and further at 60° C. for 3 hours. To the reaction solution are added 1N-hydrochloric acid and diethyl ether, and the aqueous layer is collected and neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. The dichloromethane layer is washed with water, dried, and the solvent is distilled off. To the resulting residue is added hydrochloric acid/ethanol to give 5-[2-(4-acetyl-1-piperazinyl)ethyl]-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (150 mg) as colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:34][CH:33]=1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and 4-ethoxycarbonylphenylboronic acid were reacted to provide 4′-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-carboxylic acid ethyl ester, which was hydrolyzed to the acid as described in Example 36, Step 7.