Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][C:11](=O)[NH:12][N:13]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:11]1[N:12]=[N:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:10]=1
Reactant: O=c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2cc(Cl)nnc2-c2ccccc2Cl)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A suspension of 6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3(2H)-one (4.1 g, 12.9 mmol) in phosphorus oxychloride (15 mL) was stirred at 95° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The separated aqueous layer was extracted with EtOAc (40 mL×2). The combined organic was washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried Na2SO4) and concentrated under reduced pressure to afford 4.2 g (97%) of the title compound as a pink foam. HPLC/MS (method A): retention time=3.50 min, (M+H)+=335.0.
Reaction SMILES: [I:1]Cl.[CH3:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].C(=O)(O)[O-].[Na+]>ClCCl.CO.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[I:1][C:9]1[CH:10]=[C:4]([CH3:3])[C:5]([C:11]([F:12])([F:13])[F:14])=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1ccc(N)cc1C(F)(F)F
Reactant: ClI
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(I)c(N)cc1C(F)(F)F
Reaction time: 3 h
Yield: 103.1 %

Procedure:
Add a solution of iodine monochloride (27.8 g, 171 mmol) in dichloromethane (180 mL) to a solution of 4-methyl-3-trifluoromethylaniline (25.0 g, 143 mmol) and sodium bicarbonate (14.4 g, 171 mmol) in methanol (180 mL) and dichloromethane (730 mL) at room temperature under nitrogen. Stir the mixture for 3 h and dilute the cooled mixture with aqueous sodium metabisulfite (500 mL). Collect the organic phase, and extract the aqueous phase with methylene chloride (200 mL). Wash the combined organic extracts with brine (250 mL), dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure to provide a brown oil, which crystallizes upon standing to afford the title compound as brown needles (44.4 g, >99%), which is used in the next step without purification. APCI MS m/z 302 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:29](O)(=O)[C:30]([CH3:33])([CH3:32])[CH3:31].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[C:30]([C:33]1[O:24][C:23]([C:22]2[CH:21]=[CH:20][C:19]([O:18][C@H:15]3[CH2:16][CH2:17][C@H:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])[CH2:13][CH2:14]3)=[CH:28][CH:27]=2)=[N:25][N:26]=1)([CH3:32])([CH3:31])[CH3:29]
Reactant: CC(C)(C)C(=O)O
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NN)cc3)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(-c4nnc(C(C)(C)C)o4)cc3)CC2)CC1

Procedure:
A mixture of 60 mg (0.15 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid hydrazide, 0.02 ml (0.2 mmol) of pivalic acid and 2 ml of phosphorus oxychloride was refluxed for 2 hr. To the mixture, 1N NaOH solution was added. The mixture was extracted with AcOEt, washed with saturated NaHCO3 solution, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane and methanol=from 98:2 to 19:1. The combined product fractions were evaporated to dryness to yield 25 mg (36%) of the title compound. MS (m/e): 455.4 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([NH2:31])[CH3:30].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>>[CH2:29]([NH:31][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:30]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCN
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide (17 mg) was prepared by following General Procedure N starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), ethylamine (2 M in THF, 123 uL), DPPA (53 uL), and DIEA (43 uL). LC/MS: 436.9 m/z (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 8.43 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.79-7.65 (m, 2H), 7.46 (d, 1H), 7.35 (s, 1H), 3.62 (bs, 3H), 3.30-3.23 (m, 2H), 1.13 (t, 3H), —NH proton signal was not observed.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg+].[C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH2:19]C([O-])=O>O1CCCC1>[O:16]=[C:14]([C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][N:12]=1)[CH2:19][C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cn1
Agent: [Mg+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc(Oc2ccccc2)cn1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 5-phenoxypyridine-2-carboxylic acid (10 g, 46.5 mmol) in tetrahydrofuran (150 ml) was added N,N′-carbonyldiimidazole (8.29. g, 51.1 mmol), and the mixture was heated under reflux for 1 hr. After cooling the reaction solution to room temperature, monobenzyl malonate magnesium salt (10.5 g, 25.6 mmol) was added, and the mixture was heated under reflux for 2 hrs. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the objective substance (11.2 g, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[F:17].CN.C(O)(=O)C.[BH3-][C:25]#[N:26].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:26][CH3:25])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[F:17]
Reactant: [BH3-]C#N
Reactant: O=C(CN1CCOCC1)c1ccc(Br)c(F)c1
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(CN1CCOCC1)c1ccc(Br)c(F)c1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To an ambient temperature solution containing 1.52 g of 1-(4-bromo-3-fluorophenyl)-2-(4-morpholinyl)ethanone (5.04 mmols) in 25 mL of THF was added 10.1 mL of MeNH2 (20.2 mmols, 2M solution in THF). After stirring for 15 min. 0.66 mL of acetic acid and 1.27 g of NaCNBH3 (20.2 mmols) were added to the reaction mixture. The reaction mixture was then warmed to 40° C. and stirred for 24 h. The reaction mixture was quenched with 10% aqueous Na2CO3 (10 mL). The reaction was diluted with 100 mL of EtOAc, and the layers were separated. The organic layer was washed with 10% aqueous Na2CO3 (1×10 mL) and saturated aqueous brine solution (1×10 mL). The organics were then dried over MgSO4, filtered through a frit, and concentrated. The crude title product was isolated as a brown solid (1.6 g, ˜100%) and used without further purification. MS (ES) m/e 317 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH:9]1[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:16]>CN(C=O)C>[C:1]([O:5][C:6](=[O:12])[N:7]([CH2:8][CH:9]1[CH2:10][CH2:11]1)[CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC1CC1)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
A solution of tert-butyl(cyclopropylmethyl)carbamate (4 g, 23.4 mmol) in DMF (35 mL) was added to a suspension of NaH (60% suspension in mineral oil) (0.58 g, 25.7 mmol) in DMF (5 mL) at 0-5° C., to it was added Iodomethane (2.5 mL, 40 mmol) and stirring was continued at 25° C. for 16 h. Reaction mixture was quenched with cold water, extracted with ethyl acetate (3×50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by flash chromatography (Biotage, Column: silica gel 12 g pack size, solid load, Mobile Phase: EtOAc in n-Hexane: 0 to 5% as eluent) to afford tert-butyl(cyclopropylmethyl)(methyl)carbamate (Int-37) as pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.0-2.9 (2H, d), 2.85 (3H, s), 1.4 (9H, s), 0.9-0.7 (1H, bs), 0.5-0.3 (2H, m), 0.2-0.05 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@@H:25]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)[CH3:26])[CH:24]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@@H:25]([C:27]3[CH:34]=[CH:33][C:30]([CH2:31][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:29][CH:28]=3)[CH3:26])[CH:24]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@H](c1ccc(C=O)cc1)n1cc(C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)nn1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: C[C@H](c1ccc(CN2CCCCC2)cc1)n1cc(C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)nn1
Reaction time: 18 h

Procedure:
To a solution of 4-((R)-1-(4-(((R)-1-(3,4-dichlorobenzenesulfonyl)-3-oxo-1,2,3,4-tetra-hydropyrazin-2-yl)methyl)-1H-1,2,3-triazol-1-yl)ethyl)benzaldehyde (0.150 g, 0.288 mmol) and piperidine (0.10 mL, 1.01 mmol) in 1,2-dichloroethane (10 mL) was added NaBH(OAc)3 (0.126 g, 0.594 mmol). After 18 h, the solution was diluted with 60 mL EtOAc and washed with 5% NaHCO3 (60 mL×2), brine (60 mL×2), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on SiO2 (100% CH2Cl2 to 5% 2N methanolic NH3 in CH2Cl2) to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:17][CH2:16][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:18]([C:20]1[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=1)=[CH2:19].[OH-].[K+]>CN1C(=O)CCC1>[C:26]([C:23]1[N:24]=[CH:25][C:20]([CH2:18][CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:17][CH2:16][C:5]2=3)=[CH:21][CH:22]=1)([OH:28])=[O:27]
Reactant: CN1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Reactant: C=Cc1ccc(C(=O)O)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(C(=O)O)ccc3n2CCc2ccc(C(=O)O)nc2)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole-8-carboxylic acid, 5-vinylpyridine-2-carboxylic acid and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([N:41]=[C:42]=[O:43])[CH:37]=[CH:38][C:39]=1[Cl:40]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:42]([NH:41][C:36]3[CH:37]=[CH:38][C:39]([Cl:40])=[C:34]([Cl:33])[CH:35]=3)=[O:43])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)Nc3ccc(Cl)c(Cl)c3)cc2)COC1(C)C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
To a stirred suspension of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (180 mg) in dichloromethane (3 ml) were added sequentially N,N-diisopropylethylamine (0.19 ml) and 3,4-dichlorophenyl isocyanate (137 mg, CAS 102-36-3) and stirring was continued at room temperature for 18 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-(2-{4-[3-(3,4-dichloro-phenyl)-ureido]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (267 mg, 93%) as a colourless amorphous solid. MS (ISP): 529.4 ([{37Cl}M+NH4]+), 527.4 ([{37Cl35Cl}M+NH4]+), 525.4 ([{35Cl}M+NH4]+), 512.2 ([{37Cl}M+H]+), 510.2 ([{37Cl35Cl}M+H]+), 508.2 ([{35Cl}M+H]+), 456.2 ([{37Cl}M+H—C4H8]+), 454.2 ([{37Cl35Cl}M+H—C4H8]+), 452.2 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [H-].[Na+].C([C:5]([CH2:18][CH3:19])(P(O)(O)=O)/[C:6](/[CH3:13])=[C:7](\CC)/[C:8]([O-:10])=[O:9])C.[Cl:20][C:21]1[CH:22]=C([CH:26]=[CH:27][C:28]=1[Cl:29])C=O.[CH2:30]([CH2:33]OC)OC>>[Cl:20][C:21]1[CH:22]=[C:19]([CH:18]=[CH:5][C:6]([CH3:13])=[CH:7][C:8]([O:10][CH2:30][CH3:33])=[O:9])[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: CC/C(C(=O)[O-])=C(/C)C(CC)(CC)P(=O)(O)O
Reactant: COCCOC
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C(C)C=Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of sodium hydride (0.40 g. 10.0 mmol) in anhydrous dimethoxyethane (5 mL) is cooled in a room temperature water bath. While stirring vigorously, triethyl-3-methyl-4-phosphonocrotonate (2.64 g, 10 mmol), is added dropwise over 10 minutes. After gas evolution has stopped, (˜5 minutes) the reaction mixture is treated with a solution of 3,4-dichlorobenzaldehyde (1.75 g, 10 mmol) in anhydrous dimethoxyethane (5 mL). The resulting brown solution is then heated to reflux. After three hours, the mixture is cooled and quenched with saturated aqueous brine. The aqueous layer is extracted several times with EtOAc, and the combined organic layers are dried (sodium sulfate) and concentrated in vacuo. The resulting brown oil is chromatographed on silica gel eluting with 7% EtOAc: 93% hexane to give 1.146 g of a brown oil, which is a 1:1 mixture of alkene isomers at C-2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[NH:20][N:19]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[CH:17]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[CH:21]1([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)[CH:7]=[CH:6][CH:5]=4)[N:14]=3)[NH:20][N:19]=2)[CH2:23][CH2:22]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of N2-(3-aminophenyl)-N4-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine (0.014 g, 0.046 mmol; Shokat Lab: A. Statsyuk) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this 3-(trifluoromethyl)benzoyl chloride (0.007 mL, 0.046 mmol) diluted in CH2Cl2 (5 mL) was added drop wise. The reaction was allowed to warm and was left stirring for 1 hour. The reaction proceeded until completion as judged by TLC and LC-MS. The reaction mixture was concentrated in vacuo, resuspended in 50:50 H20-CH3CN, and purified on a C18 column in CH3CN/H20/0.1% TFA (1-100% gradient) to afford AD76. ESI-MS m/z [M+H]+ found 480.4, calculated 480.2.
Reaction SMILES: [C:1]1(=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>O.C1COCC1.CO>[C:1]1(=[N:15][OH:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: NO
Reactant: O=C1CC2CCCc3cccc1c32
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: ON=C1CC2CCCc3cccc1c32
Temperature: 75 °C
Yield: 101.7 %

Procedure:
To a mixture of 2a,3,4,5-tetrahydro-2H-acenaphthylen-1-one (12.2 g, 70.9 mmol), hydroxylamine hydrochloride (7.85 g) and water (90 ml) were slowly added sodium acetate (14.5 g), methanol (120 ml), THF (30 ml) and water (60 ml) with stirring while heating at 75° C., and the mixture was stirred for 2 hr and 40 min. After cooling to room temperature, methanol was evaporated under reduced pressure, and the obtained precipitate was collected by filtration, and washed with water to give 2a,3,4,5-tetrahydro-2H-acenaphthylen-1-one oxime (13.5 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.Br[CH2:24][CH2:25][O:26][CH3:27]>>[CH3:27][O:26][CH2:25][CH2:24][N:19]1[CH:20]=[CH:21][C:16]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[N:6]=[C:2]2[CH3:1])=[CH:17][C:18]1=[O:22]
Reactant: Cc1cccc(C#Cc2cn(-c3cc[nH]c(=O)c3)c(C)n2)c1
Reactant: COCCBr
Product: COCCn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O

Procedure:
The title compound, colorless resin, MS: m/e=348.3 (M+H+), was prepared in accordance with the general method of example 3 from 4-(2-Methyl-4-m-tolylethynyl-imidazol-1-yl)-1H-pyridin-2-one and 2-bromoethyl-methylether.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[Cl:10][C:11]([Cl:15])=[C:12]([F:14])[F:13].ClC(F)=C(Cl)F>CC(C)=O>[Cl:10][CH:11]([Cl:15])[C:12]([F:14])([F:13])[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)=C(Cl)Cl
Reactant: Oc1ccccc1
Agent: FC(Cl)=C(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: FC(F)(Oc1ccccc1)C(Cl)Cl
Temperature: 10 °C

Procedure:
In a 500 ml stirred reaction flask equipped with thermometer, air condenser, dropping funnel and ice water bath was placed 94 g (one mole) of phenol and 300 ml of acetone and the mixture was cooled to 10° C. 11.0 Grams of powdered KOH (85 percent) was then added. After the mixture was stirred for one-half hour at 10° C., 2,2-dichloro-1,1-difluoroethene was introduced over a period of one hour while maintaining the temperature at about 10-12° C. At the end of the addition of the dichlorodifluoroethene, a rapid reaction increased the temperature to 50° C. A Dry Ice(R) bath was substituted for the ice bath to cool the reaction mixture to 10° C. rapidly. After stirring overnight, the reaction mixture was poured over two liters of ice, stirred, allowed to settle and the oil layer was separated. The oil layer was washed with bicarbonate of soda solution and with water and the nearly colorless organic layer was separated. After drying over desiccant-grade magnesium sulfate, the organic layer was filtered to give the first-step product.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.B(Br)(Br)Br>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:4]2[CH:5]=[CH:6][C:7]([CH2:9][CH2:10][CH3:11])=[CH:8][C:3]=2[OH:2])=[CH:14][CH:15]=1
Reactant: CCCc1ccc(Oc2ccc(OC)cc2)c(OC)c1
Agent: BrB(Br)Br
Product: CCCc1ccc(Oc2ccc(OC)cc2)c(O)c1
Yield: 32 %

Procedure:
According to the procedure of example 5 (b) except substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for 2-methoxy-1-(4-methoxyphenoxy)-4-propylbenzene (0.18 mmol; 50 mg) and adding 4 equivalents (0.735 mmol; 735 μl) of boron tribromide, the title compound was prepared in 32% yield (0.06 mmol; 15 mg) after purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—20/80).
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.[NH2:16][OH:17]>>[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[N:16][OH:17])[OH:15]
Reactant: NO
Reactant: O=CCCCCCCCCCCC(=O)O
Product: O=CCCCCCCCCCCC(O)=NO

Procedure:
Vernolia oil undergoes saponification and acification followed by cold temperature (-20° C.) crystallization to yield a methylated product comprised of vernolic, palmitic, oleic, linoleic and stearic acid. The vernolic acid is isolated and further purified through a series of low temperature recrystalizations. The purified vernolic acid, ##STR1## is then hydrogenated to yield 12,13-epoxystearic acid, having the formula: ##STR2## The 12,13-epoxystearic acid is then oxidized to yield 12-oxododecanoic acid, ##STR3## By reacting the 12-oxododecanoic acid with hydroxylamine, 12-oxododecanoic acid oxime ##STR4## is formed. The Nylon-12 monomer, 12-aminododecanoic acid:
Reaction SMILES: Cl[C:2]12[C:11]([O:14][CH3:15])([O:12][CH3:13])[C:6](Cl)([C:7](Cl)=[C:8]1Cl)[CH2:5][N:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:3]2.C(O)(C)(C)C.[Na]>O1CCOCC1>[CH3:15][O:14][C:11]1([O:12][CH3:13])[CH:2]2[CH:8]=[CH:7][CH:6]1[CH2:5][N:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:3]2
Reactant: COc1ccc(CN2CC3(Cl)C(Cl)=C(Cl)C(Cl)(C2)C3(OC)OC)cc1
Agent: [Na]
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: COc1ccc(CN2CC3C=CC(C2)C3(OC)OC)cc1
Temperature: 92 °C
Yield: 9.4 %

Procedure:
1,5,6,7-Tetrachloro-8,8-dimethoxy-3-(4-methoxy-benzyl)-3-aza-bicyclo[3.2.1]oct-6-ene (6.23 g, 146 mmol) and t-butanol (25.13 mL, 263 mmol) were dissolved in dioxane (75 mL) in a flame dried 3N RB equipped with a water condenser and thermometer then heated to a gentle reflux (internal temp 92° C.). Sodium (5.36 g, 233 mmol) was pre-washed sequentially with hexanes/ethanol/THF/hexanes then added portionwise to the above refluxing mixture over 45 min The reaction was heated overnight and judged complete by GCMS. The reaction solution was decanted from the unreacted sodium, then washed with methanol to fully quench residual sodium. Solvent was removed in vacuo, diluted in water (100 mL), cooled in an ice bath, then acidified with 6 N HCl (100 mL). At room temperature, the acidic aqueous layers were washed with ether (2×100 mL) then made alkaline with 1N NaOH. The product was extracted with EtOAc (3×100 mL), washed with saturated aqueous NaCl solution (1×100 mL), dried over Na2SO4, filtered and concentrated to yield the title compound (3.97 g, 94%). (TLC 5% MeOH/CH2Cl2, (NH3) Rf 0.40); 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J=8.3 Hz, 2H), 6.79 (d, J=8.3 Hz, 2H), 5.97 (s, 2H), 3.76 (s, 3H), 3.56 (s, 2H), 3.20 (s, 3H), 3.13 (s, 3H), 2.59 (br s, 2H), 2.53 (d, J=10.6 Hz, 2H), 2.39 (d, J=10.6 Hz, 2H); GCMS m/z 287 (M)+.