Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]=O)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10](/[CH:15]=[N:21]/[OH:22])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C=O)ccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(/C=N/O)ccc12
Temperature: 85 °C
Reaction time: 17.5 h
Yield: 52.5 %

Procedure:
Step 1 A mixture of 4-bromo-7-formyl-9H-carbazole-1-carboxamide (prepared according to Step 1 of Example 41-1, 200 mg, 0.631 mmol) and hydroxylamine hydrochloric acid salt (65.7 mg, 0.946 mmol) in ethanol (3 mL) was treated with 2 M aqueous sodium carbonate (0.236 mL, 0.473 mmol) and heated at 80-90° C. After 17.5 h, the mixture was cooled to rt and partitioned between EtOAc and water. The organic phase was dried and concentrated, and the residue was triturated with methanol, and the precipitate was collected by filtration, rinsed with methanol and dried to provide (E)-4-bromo-7-((hydroxyimino)methyl)-9H-carbazole-1-carboxamide as a gray-tan solid (110 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 11.87 (1 H, s), 11.33 (1 H, s), 8.65 (1 H, d, J=8.4 Hz), 8.32 (1 H, s), 8.28 (1 H, br. s.), 8.09 (1 H, s), 7.92 (1 H, d, J=8.1 Hz), 7.64 (1 H, br. s.), 7.58 (1 H, d, J=8.6 Hz), 7.51 (1 H, d, J=8.1 Hz). Mass spectrum m/z 332, 334 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[C:25]1([O:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)=[CH:3][C:2]=1[NH:1][C:32](=[O:33])[O:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl)Oc1ccccc1

Procedure:
To a mixture of 5-(3-amino-4-chlorophenyl)-3-(2-furanyl)-1,2,4-oxadiazole (0.75 and 0.58 g of potassium carbonate in 30 ml of dioxane is added 0.94 g of phenylchloroformate. The resulting mixture is heated at reflux for 2 hours and concentrated to dryness. 50 ml of water is added to the residue and the mixture extracted three times with chloroform. The extracts are dried over magnesium sulfate, filtered and concentrated. The residue is recrystallized from benzene to yield 0.62 g of the title compound, melting point 177°-178°C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][CH:15]=[C:14]([CH3:20])[C:13]=3[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].C(OCC)(OCC)O[CH2:28][CH3:29]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:20])[CH:15]=[N:16][C:17]=3[O:19][CH2:28][CH3:29])[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(C#N)ccc1C1C(C#N)=C(C)Nc2c(C)c[nH]c(=O)c21
Agent: O=S(=O)(O)O
Product: CCOc1ncc(C)c2c1C(c1ccc(C#N)cc1OC)C(C#N)=C(C)N2
Temperature: 140 °C

Procedure:
3620 mg (10.83 mmol) of 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonitrile are suspended in 150 ml (901 mmol) of anhydrous triethyl orthoformate. The reaction mixture is heated to 140° C. Then 10 drops of concentrated sulfuric acid are added each hour. After complete reaction has been detected (analytical HPLC; reaction time about 36 h), the reaction mixture is cooled to room temperature and the precipitated product is filtered off. The precipitate is washed with ethyl acetate and diethyl ether and then purified by flash chromatography (silica gel; mobile phase: initially dichloromethane, then isohexane/ethyl acetate 1:1). The product fractions are combined and concentrated in a rotary evaporator, and the residue is then crystallized from ethyl acetate. Drying under high vacuum results in 1160 mg (30% of theory) of the title compound in the form of yellowish crystals.
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:12][C:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O>C(O)C>[NH2:10][C:3]1[NH:2][C:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[CH:12][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)CC(=N)N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(C(=O)OC)cc2)[nH]c1N
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
Na metal (1.96 g, 85.3 mmol) was added portion wise to ethanol (210 mL) and stirred for 30 minutes to get clear solution. To this was added ethyl 3-amino-3-imino-propanoate hydrochloride (CAS: 57508-48-2, 14.25 g, 85.6 mmol) and stirred at room temperature for additional 30 minutes. Finally, methyl 4-(2-bromoacetyl)benzoate (11 g, 42.8 mmol) was added to the reaction mixture and stirred for 16-20 h at room temperature. After completion of the reaction (as indicated by TLC and LCMS), reaction mixture was filtered through celite and the residue was washed with MeOH (50 mL×2). The combined filtrate was concentrated under reduced pressure and the residue was purified using silica gel column chromatography (40% EtOAc in hexane) to provide XI-7-I (7 g, 56.7% yield). LCMS; m/z: 289.1 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.C(O)(C)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Yield: 49.3 %

Procedure:
8.10 g p-nitro-bromobenzene was added into a 250 ml round-bottom flask containing 50 mL isopropanol, then 7.00 g anhydrous piperazine, 15.00 g anhydrous K3PO4 and 4 ml glycol was added, then 2.00 g CuI was added as catalyster under nitrogen atmosphere (the small-scale reaction was carried out in the absence of nitrogen atmosphere, the results showed mat the yield was low probably because of the oxidation of CuI). The reaction mixture was refluxed for two days under nitrogen atmosphere. The crude product was filtered and concentrated. The concentrate was extracted with chloroform/water. The chloroform extract was dried by anhydrous Na2SO4. Based on higher polarity of product and lower polarity of the starting material, the extract was purified by column-chromatography with gradient elution of petroleum ether:ethyl acetate:ethanol in differ ratio, concentrated the eluate, to produce N-4-nitro-phenyl piperazine as yellow solid (4.10 g, 49.4% yield). Mp: 126-128° C. (lit.: 130-132° C.)
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:28]=[CH:27][C:26]([O:29]CC5C=CC=CC=5)=[CH:25][C:19]=4[S:20][C:21]=3N(C)C)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:38]1[CH:43]=[CH:42][C:41]([O:44][Si](C(C)C)(C(C)C)C(C)C)=[CH:40][CH:39]=1>C1COCC1>[OH:29][C:26]1[CH:27]=[CH:28][C:18]2[C:17]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)=[C:21]([C:38]3[CH:39]=[CH:40][C:41]([O:44][CH2:5][CH2:4][CH2:3][C:2]#[N:1])=[CH:42][CH:43]=3)[S:20][C:19]=2[CH:25]=1
Reactant: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Reactant: CN(C)c1sc2cc(OCc3ccccc3)ccc2c1C(=O)c1ccc(OCCN2CCCC2)cc1
Solvent: C1CCOC1
Product: N#CCCCOc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Yield: 57 %

Procedure:
By essentially following the proceedure described in Example 16, Part C, the title compound was prepared as an oil starting from 6-benzyloxy-2-dimethylaminobenzo[b]thiophene-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part A) and 1-bromo-4-(triisopropylsilyloxy)benzene in 57% yield following MPLC (SiO2; 10% then 15% then 20% THF with 5% TEA in hexanes).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]2([C:32]([F:35])([F:34])[F:33])[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[CH:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:22][CH2:21]4)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([O:40]C(=O)C)C.C(=O)([O-])O.[Na+]>O.C(#N)C.FC(F)(F)C(O)=O.N1C=CC=CC=1C([O-])=O.[Ag+2].N1C=CC=CC=1C([O-])=O>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2([C:32]([F:35])([F:34])[F:33])[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[CH:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:22][CH2:21]4)[CH:14]2[OH:40])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CCC(=O)NC1CCc2cc(N3CCC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)(C(F)(F)F)C3)ccc21
Reactant: CCOC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])O
Agent: O=C([O-])c1ccccn1
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)NC1CCc2cc(N3CCC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)(C(F)(F)F)C3O)ccc21
Yield: 5.8 %

Procedure:
131 mg (0.243 mmole) N-(5-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2,3-dihydro-1H-inden-1-yl)propanamide (Ex. No. (II-a-963), known from WO 2010/043315, Table 6, Ex. No. 273) was dissolved in a solution of 0.6 ml water, 6 ml acetonitrile and 1.2 ml trifluoroacetic acid. At 0° C. 86 mg (0.243 mmole) silver-(II)2-pyridinecarboxylate were added in small portions until the solution has been discoloured. Immediately after decolourization ethylacetate and sodium hydrogencarbonate solution were added. The aqueous solution was extracted additionally two times with ethylacetate. The combined extracts were dried and evaporated under reduced pressure. The residue was purified by a reversed phase chromatography with a gradient acetonitrile/water to obtain 9 mg (5.8%) of the title compound as a mixture of isomers. NMR data are given for the main isomer.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][C:15](=[CH2:18])[CH:16]=[O:17].[NH4+].[Cl-]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:16]([OH:17])[C:15]([CH3:18])=[CH2:14])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: C=C(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)C(O)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 1,4-dibromobenzene 1 (42.4 mmol, 10 g) in THF (60 mL) was added butyl lithium(42.4 mmol, 2.5 M in hexane). The mixture was stirred at −78° C. for 1 h. 2-methylpropenal (42.4 mmol, 2.97 g) was added. The mixture was stirred at −78° C. for 1 h. NH4Cl was added. The mixture was extracted with EtOAc. The organic extract was washed with brine, dried and concentrated to an oil. Chromatography (5-15% EtOAc/hexane) gave the desired alcohol.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])C=C.C[Sn](C)(C)[C:25]1[CH:34]=[CH:33][N:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][C:29](=[O:35])[NH:30]2>>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:10]1[N:11]=[C:12]([C:25]2[CH:34]=[CH:33][N:32]=[C:31]3[C:26]=2[CH2:27][CH2:28][C:29](=[O:35])[NH:30]3)[S:13][C:9]=1[C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: C=CCn1ccnc1-c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: C[Sn](C)(C)c1ccnc2c1CCC(=O)N2
Product: O=C1CCc2c(-c3nc(-c4ccc(Cl)cc4Cl)c(-c4ncc[nH]4)s3)ccnc2N1

Procedure:
The title compound was prepared from 5-(1-Allyl-1H-imidazol-2-yl)-2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole and 5-(trimethylstannyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one using procedures analogous to those described in Example 1-C, Steps 8 and 9:LCMS: (FA) ES+ 442, 444. 1H NMR (300 MHz, d6-DMSO) δ: 12.10-11.89 (bs, 1H), 10.64 (s, 1H), 8.25 (d, J=5.28 Hz, 1H), 7.74 (d, J=1.72 Hz, 1H), 7.60-7.46 (m, 2H), 739 (d, J=5.29 Hz, 1H), 7.23-6.94 (m, 2H), 4.11-4.06 (m, 1H), 3.38-3.30 (m, 1H), 3.16 (d, J=5.21 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].S(Cl)([Cl:19])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:19])=[O:7]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1OC
Reactant: O=S(Cl)Cl
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Reaction time: 1 h

Procedure:
9.5 g of 3,4-dimethoxy-5-nitrobenzoic acid are suspended in 95 ml of thionyl chloride. The suspension is stirred at 80° for 1 hour. By two-fold evaporation with the addition of absolute toluene there are obtained 10 g of 3,4-dimethoxy-5-nitrobenzoyl chloride which is dissolved in 100 ml of tetrahydrofuran. This solution is added dropwise to 300 ml of 28 percent aqueous ammonia. The mixture is subsequently stirred at 40° for 2 hours and cooled to 5°. The crystalline precipitate is filtered off. There is obtained 3,4-dimethoxy-5-nitrobenzamide of m.p. 182°-185°.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH2:11][C:10](=[O:14])[N:9]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:31]([CH2:34][C:35]([O:37]CC)=[O:36])=[C:32]=[S:33]>C(Cl)(Cl)Cl>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:32]([NH:31][CH2:34][C:35]([OH:37])=[O:36])=[S:33])[C:10](=[O:14])[N:9]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:8]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CN=C=S
Reactant: O=C1CC(=O)N(C2CCCCC2)C(=O)N1C1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CNC(=S)c1c(O)n(C2CCCCC2)c(=O)n(C2CCCCC2)c1=O
Reaction time: 8 h
Yield: 14.7 %

Procedure:
A mixture of 1,3-dicyclohexyl-2,4,6(1H,3H,5H)-pyrimidinetrione (660 mg, 2.25 mmoles), diisopropylethylamine (780 uL, 4.5 mmoles) and ethyl isothiocyanatoacetate (340 uL, 2.75 mmoles) in chloroform (20 mL) was stirred overnight. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The solid residue was purified by flash chromatography (dichloromethane) and the fractions evaporated, dissolved in ethanol (5 mL, some heating) and treated with 1 molar sodium hydroxide (3 mL). The mixture was stirred for 30 minutes and acidified to give a solid which recrystallized from ethanol-water to give the title compound (135 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (s, 1 H), 12.54 (t, J=4.80 Hz, 1 H), 4.69 (t, J=12.00 Hz, 2 H), 4.35 (d, J=5.05 Hz, 2 H), 2.25 (q, 4 H), 1.79 (d, J=12.38 Hz, 4 H), 1.63 (d, J=12.38 Hz, 6 H), 1.29 (q, 4 H), 1.13 (q, 2 H).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24](=[O:43])[C:25]([NH2:42])([CH3:41])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:43])[C@@:25]([NH:42][C:12](=[O:14])[C@@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])([CH3:41])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)C(C)(N)Cc1ccc(OCc2ccccc2)cc1
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N[C@](C)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 38 %

Procedure:
A solution of the product from Example Z ((2S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.5 g, 1.95 mmol) and the product from Example D (2-amino-2-methyl-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.73 g, 2.15 mmol) were coupled according to the procedure described in Example 3. The two diastereomeric products were separated by chromatography (silica gel, 1:1 heptane/EtOAc) to give a high Rf product as a white solid (0.43 g, 38%), mp=46-49° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C(O)(=O)C.[N+:25]([CH3:28])([O-:27])=[O:26]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]=[CH:28][N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccccc2C=C[N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
4'-Methylbiphenyl-2-carboxaldehyde (13.21 g, 67.3 mmol (1.0 eq), nitromethane (4.74 mL, 87.5 mmol, 1.3 eq), ammonium acetate (2.07 g, 26.0 mmol, 0.4 eq) and glacial acetic acid (30 mL) were mixed and refluxed for 2 days, at which time more nitromethane (4.74 mL) and ammonium acetate (2.07 g) were added and the reaction was refluxed for an additional 5 hours. The reaction mixture was poured into ice water (300 mL) and extracted with ethyl acetate (300 mL). The ethyl acetate layer was washed with water (3×200 mL), the organic layer dried (MgSO4), the solvent removed in vacuo and the residue chromatographed in 1:1 hexane/toluene to yield 11.22 g of a light yellow oil which crystallized. The product was recrystallized from methylcyclohexane to yield 8.47 g of yellow crystals; m.p. 64.0°-65.0°. NMR (200 MHz, CDCl3) δ8.04 (d, 1H, J= 13 Hz); 7.69 (d, 1H, J=9 Hz) 7.59-7.37 (m, 4H); 7.50 (d, 1H, J=13 Hz); 7.27 (d, 2H, J=7 Hz); 7.19 (d, 2H, J=7 Hz); 2.41 (s, 3H). Anal. Calcd. for C15H13NO2 : C, 75.30; H, 5.48; N, 5.85. Found: C, 75.32; H, 5.56; N, 5.58.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH3:14][C:15]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([CH3:18])[CH2:16]O>>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:7]=1[O:8][CH2:14][C:15]([CH3:18])([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:16])[C:1]([O:12][CH3:13])=[O:11]
Reactant: CC(C)(CO)N1CCCC1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Product: COC(=O)c1ccc(OCC(C)(C)N2CCCC2)c(OC)c1
Yield: 17 %

Procedure:
The title compound was prepared in 17% yield from methyl vanillate and 2-methyl-2-(1-pyrrolidinyl)propanol (Example 188, Part A) by a essentially following the procedure outlined in Example 193, Part A.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])(=[O:11])[CH3:10].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34]>C1COCC1>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](=[O:34])[CH2:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])=[O:11]
Reactant: C=CCCCCCCCCOC(C)=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCCCCCCCOC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (79.8 mL of a 2.0 M solution, 0.160 mol) is placed into a 250 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition fimnel. The flask is cooled to −78° C. 9-Decen-1-yl acetate (14.91 g, 0.075 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of 2-naphthoyl chloride (13.80 g, 0.071 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to −20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (47 mL). The mixture is poured into a separatory fimnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:1][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:14][CH:13]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CSc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
To a solution of phenacyl bromide (1 g), 4-chlorothiophenol (1.37 g), and benzyl triethyl ammonium chloride (78 mg) in dichloromethane (20 ml) NaOH (0.61 g) in water (2 ml) was added. The mixture was stirred vigorously at rt for 16 h. After dilution with water (50 ml) the organic layer was separated, washed with brine (20 ml), dried (MgSO4), and evaporated. The crude was purified by column chromatography on silica gel (petrol ether/ethyl acetate 12:1) to provide 2-(4-chlorophenylthio)-1-phenylethanone (0.74 g) as pale yellow solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1CCOCC1.C(OCC)(=O)C=C.C1(N=C=NC2CCCCC2)CCCCC1.[F:40][C:41]1[CH:42]=[C:43]([N:53]2[CH2:57][C@H:56]([CH2:58][NH:59][C:60](=[O:62])[CH3:61])[O:55][C:54]2=[O:63])[CH:44]=[CH:45][C:46]=1[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C)C1C=CN=CC=1.O1CCCC1.ClCCl.C(O)C>[F:40][C:41]1[CH:42]=[C:43]([N:53]2[CH2:57][CH:56]([CH2:58][NH:59][C:60](=[O:62])[CH3:61])[O:55][C:54]2=[O:63])[CH:44]=[CH:45][C:46]=1[N:47]1[CH2:52][CH2:51][N:50]([C:9](=[O:11])[CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH2:49][CH2:48]1
Reactant: O=C(O)CCN1CCOCC1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C=CC(=O)OCC
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NCC1CN(c2ccc(N3CCN(C(=O)CCN4CCOCC4)CC3)c(F)c2)C(=O)O1
Yield: 88.9 %

Procedure:
3-(4-Morpholinyl)propionic acid (0.600 g, 2.11 mmol), prepared by condensation of morpholine with ethyl acrylate (3 equivalents) in refluxing ethanol, followed by distillation, saponification (1N aqueous sodium hydroxide, tetrahydrofuran, reflux), neutralization (1N HCl) and lyophilization, was combined with 1,3-dicyclohexylcarbodiimide (0.434 g, 2.11 mmol), 4-(dimethylamino)pyridine (13 mg, 0.11 mmol), (S)-N-[[3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.354 g, 1.05 mmol), and 1:1 tetrahydrofuran/dichloromethane (50 mL) at room temperature. After 3 days the reaction mixture was filtered to remove the precipitated 1,3-dicyclohexylurea and the filtrate concentrated in vacuo. The crude product was chromatographed over silica gel (20 g), eluting with a gradient of 1-6% methanol/chloroform, to give 0.446 g (95%) of the title compound as a white solid with mp 209°-210° C. ##STR12##
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:21])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[NH:21][S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(N)c1-c1nnnn1Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(NS(=O)(=O)c2ccccc2)c1-c1nnnn1Cc1ccccc1
Reaction time: 8 h
Yield: 63.8 %

Procedure:
2-(1-Benzyl-1H-tetrazol-5-yl)-3-methoxyphenylamine (Intermediate 13, 0.115 g) was dissolved in pyridine (0.16 mL) and DCM (2 mL). Benzenesulfonyl chloride (0.08 g) was added and the mixture was stirred overnight. The reaction mixture was diluted with DCM and washed with 1N hydrochloric acid, dried with magnesium sulfate and filtered. The filtrate was evaporated to dryness and the residue was purified by flash chromatography on silica, eluting with a mixture of DCM and methanol. The fractions containing the desired product were combined and evaporated to give the title compound as a colorless solid (0.11 g).