Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][Cl:25])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:25][CH2:24][CH2:23][CH2:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([NH:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])=[CH:3][CH:4]=3)=[N:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(CCNc2ncnc3cc(OCCCCl)ccc23)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1ccc(CCNc2ncnc3cc(OCCCCl)ccc23)cc1
Yield: 92.9 %

Procedure:
A solution of [2-(4-amino-phenyl)-ethyl]-[7-(3-chloro-propoxy)-quinazolin-4-yl]-amine (34 mg, 0.095 mmol) and phenyl isocyanate (17.0 mg, 0.143 mmol) in methylene chloride (8 mL) was stirred under nitrogen at room temperature overnight. The solid product formed was filtered to give the title compound as a solid (42 mg, 93%). 1H-NMR (300 MHz, d6-DMSO): δ 8.66 (s, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 8.20 (t, 1H), 8.13 (d, J=9.0 Hz, 1H), 7.42-7.46 (m, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.24-7.29 (m, 2H), 7.08-7.18 (m, 4H), 6.96 (t, 1H), 4.23 (t, 2H), 3.83 (t, 2H), 3.70 (q, 2H), 2.89 (t, 2H), 2.18-2.27 (m, 2H). LC-MS (ESI) m/z: 476.4 (M+1).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.O.[CH3:18][C:19]1[C:20]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:21]([O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:29][CH3:30])=[CH:24][CH:23]=2>C1COCC1>[CH3:18][C:19]1[C:20]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:21]([O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([N:1]3[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]3)=[O:37])=[CH:34][CH:33]=2)[C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:29][CH3:30])=[CH:24][CH:23]=2
Reactant: COc1ccc2c(Oc3ccc(C(=O)Cl)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: O=C(O)C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(Oc3ccc(C(=O)N4CCC(C(=O)O)CC4)cc3)c(-c3ccccc3)c(C)cc2c1
Yield: 69 %

Procedure:
To a suspension of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoic acid (16) (0.149 g, 0.388 mmol) in toluene (3 mL) was added oxalyl chloride (0.06 mL, 0.087 g, 0.687 mmol, 1.8 eq) followed by DMF (1 drop). The reaction mixture was stirred at RT under N2 for 45 min. The reaction mixture was concentrated to give crude 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoyl chloride as a yellow oil. Isonipecotic acid (0.051 g, 0.39 mmol), triethylamine (0.12 mL, 0.087 g, 0.86 mmol) and H2O (2 mL) were combined and the solution was cooled in an ice-water bath under N2. To the cold isonipecotic acid solution was slowly added dropwise a solution of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoyl chloride in THF (2 mL) with stirring under N2. The ice-water bath was removed and the reaction mixture was allowed to stir for 5 d. The pH of the reaction mixture was adjusted to ˜1 (litmus paper) with 1 N HCl and the acidic reaction mixture was partitioned between EtOAc and H2O. The organic phase was separated, washed with H2O (2×), dried over MgSO4, filtered, and the filtrate was concentrated to give the crude title compound. The crude product was purified by flash chromatography over SiO2 with CH2Cl2:MeOH (94:6) to give 0.133 g (69%) of compound 17 as an amorphous solid. 1H NMR (400 MHz; DMSO-d6): δ 1.42 (m, 2H), 1.80 (m, 2H), 2.17 (s, 3H), 2.93 (br s, 2H), 3.87 (s, 3H), 6.59 (d, J=8.6 Hz, 2H), 7.09 (dd, J=2.5 Hz, 9.2 Hz, 1H), 7.15 (m, 4H), 7.25 (m, 3H), 7.35 (d, J=2.4 Hz, 1H), 7.61 (d, J=9.1 Hz, 1H), 7.70 (s, 1H), 12.25 (br s, 1H). AP LRMS m/z 494 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(C1NC=CN=1)(C1NC=CN=1)=O.O.[NH2:28][NH2:29].Cl>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:28][NH2:29])=[O:5]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: NN
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)c1cccc(C(F)(F)F)c1Cl
Reaction time: 0.67 h
Yield: 93.1 %

Procedure:
To a solution of 2-chloro-3-(trifluoromethyl)benzoic acid (1.0 g, 4.5 mmol) in THF (7 mL) was added carbonyl diimidazole (939 mg, 5.8 mmol). After 40 minutes, additional carbonyl diimidazole (200 mg, 1.2 mmol) was added and stirring was continued for 30 minutes. This solution was added dropwise to a separate flask containing hydrazine monohydrate (0.44 mL, 8.9 mmol) in THF (8 mL). After 1 h, 1M HCl was added, and the reaction mixture was extracted with 20% IPA/CHCl3 (×3). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to afford the desired product as a white solid (1.0 g, 94%). MS (ESI): mass calcd. for C8H6ClF3N2O, 238.0; m/z found, 239.0 [M+H]+. 1H NMR (500 MHz, MeOD) δ 7.87 (dd, J=7.9, 1.3 Hz, 1H), 7.72-7.63 (m, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.05 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:22][CH2:21][C@@:12]34[C:13]5[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@:7]3([OH:23])[CH2:8][CH2:9][O:10][CH2:11]4)[CH2:3][CH2:2]1.[C:24](Cl)(=[O:26])[CH3:25].N1C=CC=CC=1>C(Cl)Cl>[C:24]([O:20][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][C@H:6]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:22][CH2:21][C@@:12]4([C:13]=2[CH:14]=1)[C@@:7]3([OH:23])[CH2:8][CH2:9][O:10][CH2:11]4)(=[O:26])[CH3:25]
Reactant: Oc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(O)CCOC3
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(O)CCOC3

Procedure:
Equimolar quantities of 17-cyclopropylmethyl-3,14β-dihydroxy-6-oxamorphinan (XVI), acetyl chloride and pyridine are mixed together in dry methylene chloride and the resultant mixture is heated at reflux for several hours to produce the title compound.
Reaction SMILES: N1([CH:7]=[C:8]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[S:12])[C:9]#[N:10])CCOCC1.I[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CCN(C(C)C)C(C)C>C(#N)C>[C:9]([C:8]1[CH:7]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:12][C:11]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)#[N:10]
Reactant: CCOC(=O)CI
Reactant: N#CC(=CN1CCOCC1)C(=S)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1cc(C#N)c(N2CCOCC2)s1
Yield: 86.7 %

Procedure:
A mixture of 3-morpholin-4-yl-2-(morpholin-4-ylcarbonothioyl)acrylonitrile (0.07 g, 0.26 mmol), ethyl iodoacetate (0.034 mL, 0.29 mmol) and DIPEA (0.091 mL, 0.52 mmol) in ACN (0.55 mL) was subjected to microwave irradiation at 120° C. for 10 min. The crystals formed upon cooling were filtered, washed with cold MeOH and diethyl ether to give the title compound (0.06 g, 87%). LCMS: (AA) ES+ 267.1. 1H NMR (400 MHz, CDCl3) δ: 7.62 (s, 1H), 4.30 (q, 2H), 3.85-3.87 (m, 4H), 3.58-3.60 (m, 4H) and 1.34 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([OH:27])=[O:26])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:28](=[O:30])[CH3:29])=[C:20]([C:25]([OH:27])=[O:26])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)c(C(=O)O)c3)cs2)cc1OCC
Reactant: CC(=O)OC(C)=O
Product: CCOc1ccc(-c2nc(-c3ccc(OC(C)=O)c(C(=O)O)c3)cs2)cc1OCC

Procedure:
A solution of 1 g of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxyphenyl)thiazole in 5 ml of acetic anhydride was stirred at 100° C. for 4 hours with heating. The solvent was distilled off. The residue was dissolved in 50 ml of ethyl acetate. To the solution was added 10 ml of a saturated sodium hydrogencarbonate solution, and phase separation was conducted. The ethyl acetate layer was made acidic with 10% hydrochloric acid, washed with 10 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was recrystallized from ethyl acetate to obtain 145 mg of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-acetyloxyphenyl)thiazole.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:26](=O)([O:32]C(C)(C)C)[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>ClCCl>[C:28]([O:27][C:26]([N:12]1[C:13](=[O:16])[CH2:14][CH2:15][C@H:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 78.9 g of (S)-5-oxo-pyrrolidine-2-carboxylic acid benzyl ester in 400 mL of dichloromethane is added 2.20 g of dimethylaminopyridine and 78.54 g of di-tert-butyl carbonate at room temperature. The mixture is stirred for 4 hours at room temperature. The reaction mixture is then washed twice with 400 mL of 0.5 M sulphuric acid. The organic phase is separated and the solvent removed to give (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester as a semi-crystalline solid.
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[N:25]1([C:31](=[S:33])[NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CCO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:32]=[C:31]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[S:33][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1
Reactant: NC(=S)N1CCCCC1
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Solvent: CCO
Product: CC(C)c1nnc2ccc(-c3sc(N4CCCCC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Yield: 39 %

Procedure:
A mixture of 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.250 g, 0.632 mmol; Preparation #A.2) and piperidine-1-carbothioamide (Oakwood Products Inc., 0.082 g, 0.57 mmol) in EtOH (3 mL) was heated to reflux for about 3 h. After cooling to ambient temperature, the crude mixture was partitioned between DCM and water. The organics were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using heptane/EtOAc (linear gradient, 50:50 to 0:100) to give the title compound (0.098 g, 35%): LC/MS (Table 1, Method a) Rt=4.18 min; MS m/z: 441.8 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH:32][CH3:33]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][N:32]([CH3:33])[CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CN(C)C)C2

Procedure:
The title compound was prepared (0.068 g, 57%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and dimethylamine (0.18 g, 6.76 mmol). mp 220-222° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.O>CN(C)C=O>[N:13]1([C:4]2[N:3]=[C:2]([O:1][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1O
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 79.2 %

Procedure:
To a solution of ethyl 4-hydroxy-2-(2,3-dihydro-1H-indol-1-yl)-5-pyrimidinecarboxylate (7.1 g, 27.6 mmol) in N,N-dimethylformamide (100 ml) were added potassium carbonate (7.8 g, 60 mmol) and 4-fluorobenzylbromide (3.74 ml, 30 mmol) and the mixture was stirred at 80° C. for 18 h. The reaction mixture was allowed to cool to room temperature and water was added. The precipitated crystals were collected by filtration, washed several times with cold water and cold ether and dried to give the title compound (8.6 g, 79%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([N+:17]([O-])=O)=[CH:15][C:14]([OH:20])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1>CC(O)=O.CO.[Pd]>[NH2:17][C:16]1[C:10]2[O:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[CH:12][C:11]=2[CH:13]=[C:14]([OH:20])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Yield: 35.7 %

Procedure:
A solution of 99 (0.070 g, 0.29 mmol) in AcOH/MeOH was stirred under an atmosphere of H2 in the presence of 10% Pd/C. After TLC analysis indicated reaction was over, the reaction was filtered through Celite, concentrated and chromatographed on silica gel (MeOH/CH2Cl2 1:9) to yield 25 mg of the desired product: Mp=251–254° C.; 1H NMR (DMSO-d6) δ 9.76 (br s, 1 H), 8.65 (br s, 1 H), 7.71 (d, 2 H, J=8.5 Hz), 6.86 (s, 1 H), 6.84 (d, 2 H, J=8.7 Hz), 6.09 (d, 1 H, J=1.9 Hz), 6.02 (d, 1 H, J=1.9 Hz), 5.21 (s, 2 H); MS 242 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]1[CH3:11])=[O:4].Br[CH:13](Br)[C:14]([CH:16](Br)Br)=[O:15]>>[CH3:1][O:2][C:3]([N:5]1[C:9]2([CH3:10])[CH:8]=[CH:7][C:6]1([CH3:11])[CH2:13][C:14](=[O:15])[CH2:16]2)=[O:4]
Reactant: COC(=O)n1c(C)ccc1C
Reactant: O=C(C(Br)Br)C(Br)Br
Product: COC(=O)N1C2(C)C=CC1(C)CC(=O)C2

Procedure:
The title compound was prepared from 2,5-dimethyl-pyrrole-1-carboxylic acid methyl ester (U.S. Pat. No. 4,551,540) and 1,1,3,3-tetrabromoacetone utilizing the [4+3] cycloaddition protocol of Kim and Hoffmann (European Journal of Organic Chemistry (2000), (12), 2195-2201). Mass spectrum (ESI, m/z): Calcd. for C11H15NO3, 210.1 (M+H), found 210.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([CH2:25][CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32](Cl)=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[CH:23][CH:22]=1>CS(C)=O.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][CH2:26][NH:27][C:28]([C:29]2[CH:34]=[CH:33][C:32]([O:8][C:7]3[CH:6]=[CH:5][C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:3][C:2]=3[F:1])=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[O:39])=[CH:40][CH:41]=1
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2[N+](=O)[O-])c(F)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 46.4 %

Procedure:
Methyl 2-(3-fluoro-4-hydroxyphenyl)acetate (prepared in Step A; 163 mg, 0.885 mmol) was diluted with DMSO (3 mL) followed by the addition of K2CO3 (122 mg, 0.885 mmol) and N-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (prepared in Step B; 300 mg, 0.885 mmol). The reaction was stirred at 80° C. for 12 hours. The reaction was cooled, diluted with DCM and washed with 10% aq. sodium carbonate, water and brine. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified by silica gel chromatography, eluting with hexane:acetone (2:1) to yield methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-3-fluorophenyl)acetate (200 mg, 46.4% yield).
Reaction SMILES: [C:1]([C-:3]([C:6]#[N:7])[C:4]#[N:5])#[N:2].[K+].S(=O)(=O)(O)O.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]>O.C(OCC)C>[NH2:2][C:1]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:15][CH3:16])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: CCCNCCC
Reactant: N#C[C-](C#N)C#N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCCN(CCC)C(N)=C(C#N)C#N
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
In the manner of Example VI, part C, 25 g of potassium tricyanomethanide in 75 ml of water and 100 ml of diethyl ether were treated with 19 g of concentrated sulfuric acid to give an ether solution of HN=C=C(CN)2. The ether solution was treated with 19.6 g of dipropylamine and the mixture allowed to stand for 1/2 hour. The ether was removed by distillation under reduced pressure and the residue heated to 150°. To the hot residue were added 500 ml of aqueous ethanol and the mixture was boiled vigorously for 15 minutes. The mixture was again concentrated and the residue heated at 150° for about 16 hours. The mixture was dissolved in aqueous ethanol, treated with activated charcoal and chilled for two days at about 5°. The separated solid was collected by filtration and dried to give 31 g of 3-amino-2-cyano-3-(dipropylamino)propenenitrile, m.p. 100°-105° from toluene. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[O:15][C:16]([CH3:19])=[CH:17][N:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]([C:14]2[O:15][C:16]([CH3:19])=[CH:17][N:18]=2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc(Cc2ccc(OCc3ccccc3)cc2)o1
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(c1ccc(OCc2ccccc2)cc1)c1ncc(C)o1
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
To a solution of 2-(4-(benzyloxy)benzyl)-5-methyloxazole (M5.2) (3.23 mmol) in THF (25 mL) at −78° C., was added dropwise LDA (4.5 mmol). The mixture was stirred for 18 minutes, followed by addition of ethyl bromoacetate (4.5 mmol). It was allowed to warm to room temperature for 3 hours, followed by addition of water, which was extracted with EtOAc. The extract was washed with brine and dried over Na2SO4 using standard work up conditions. Column chromatography (1/3 EtOAc/hexane) of the residue afforded compound M5.3. MS ESI (pos.) m/e: 366 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:15](Cl)(=[O:26])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C.O>CCOC(C)=O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:26])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCCCO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
tert-Butyl 5-hydroxypentylcarbamate (950 mg, 4.67 mmol) was dissolved in EtOAc, 4-nitrophenyl carbonochloridate (1.130 g, 5.14 mmol) was added, the mixture cooled on an icebath, triethylamine (0.85 mL, 6.07 mmol) was added with stirring and the mixture gradually allowed to reach rt and stirred overnight. The mixture was transferred to a separatory funnel with EtOAc and H2O, and shaken. The organic phase was extracted with 1N HCl, H2O, NAHCO3 (aq., sat.), H2O (twice), brine, dried over Mg2SO4, filtered and concentrated. The residue was purified by chromatography (mixtures of petroleum ether and EtOAc) to afford compound 1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][CH3:21].C(N(CC)CC)C>O.N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH:21]=[C:20]([C:19]([O:23][CH3:24])=[O:22])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=NO)cc1
Reactant: CCC(=O)OC
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cc2)no1
Reaction time: 0.5 h

Procedure:
Added to 100 ml of chloroform were 10.0 g (74.1 mmol) of 4-methylbenzaldoxime, 9.9 g (74.4 mmol) of N-chlorosuccinimde and 0.4 ml of pyridine. After N-chlorosuccinimide was completely dissolved, the resulting solution was stirred for further 30 minutes. Under ice cooling, 9.3 g (110.7 mmol) of methyl propionate and 9.0 g (89.1 mmol) of triethylamine were added. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was added with water and then extracted with chloroform. The extract was treated by a method known per se in the art. Subsequent purification on a silica gel column (eluent: chloroform) gave 3-(4-methylphenyl)-5-methoxycarbonylisoxazole as crystals. Analytical results of the crystals obtained: Yield: 8.0 g (49.8%). Melting point: 106°-108° C.
Reaction SMILES: CO[C:3](=[S:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[NH2:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+]>CCOCC>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][C:15]([OH:17])=[O:16])=[S:11])=[CH:9][CH:8]=1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: COC(=S)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)C[C@H](NC(=S)c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.6 %

Procedure:
A mixture of methyl-4-chlorothiobenzoate (2.11 g, 11.3 mmol), aspartic acid (2.7 g, 2.02 mmol), aq NaOH (3N, 8.8 ml), and Et2O (8 ml) were vigourously stirred at room temperature for 3 days. The aq. layer was separated, acidified (dil.HCl), and extracted with Et2O (2×25 ml). The combined ether extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to yield N-p-chlorothiobenzoylaspartic acid (0.23 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6](O)=[O:7])#[N:2].C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.C(Cl)Cl>[C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6]([Cl:18])=[O:7])#[N:2]
Reactant: N#Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1c(F)c(F)cc(C(=O)Cl)c1F

Procedure:
111 g of 3-cyano-2,4,5-trifluoro-benzoic acid, 84 g of oxalyl chloride and a few drops of dimethylformamide in 930 ml of dry methylene chloride are stirred at room temperature for 5 hours. The reaction mixture is concentrated by evaporation and the residue is distilled in vacuo.