Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[S:4][C:3]=1[CH3:9].C([Li])CCC.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>C(OCC)C.O1CCCC1>[Br:7][C:6]1[C:2]([CH:21]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=2)[OH:22])=[C:3]([CH3:9])[S:4][C:5]=1[CH3:8]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1sc(C)c(Br)c1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1sc(C)c(C(O)c2ccc(C(F)(F)F)cc2)c1Br
Reaction time: 0.5 h

Procedure:
To a vigorously stirred solution of 3,4-dibromo-2,5-dimethylthiophene (53.2 g, 197 mmol) from Example 11, Step 1, in a mixture of diethyl ether (1 L) and tetrahydrofuran (80 mL) at −74° C. under nitrogen is added n-butyllithium (1.6 M/hexanes, 123 mL, 197 mmol) with a syringe slowly such as to maintain an internal temperature between −70° C. and −74° C. The reaction is stirred for an additional 30 minutes. A solution of p-trifluoromethylbenzaldehyde (27.0 mL, 200 mmol) in 30 mL of diethyl ether is added over 3 minutes. The reaction is stirred for 5 minutes. The cold bath was removed and the solution was stirred for 15 minutes while warming up. It was quenched with 5 mL of methanol then with 300 mL of 1N hydrochloric acid and stirred for 30 minutes. The phases are separated. The organic layer is washed with brine (200 mL), dried over magnesium sulphate and concentrated under reduced pressure to afford the desired compound as a faint yellow oil.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=4)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:36]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH3:36][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[CH:19]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:21]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: N#Cc1ccc(-c2cc(COCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)c2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3′-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (18.3 mg, 0.04 mmol) and formaldehyde (37 wt. % solution in water, 86.4 μL, 3.22 mmol) were combined in acetonitrile (1.0 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (12.6 mg, 0.2 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated to afford 12.1 mg (65%). 1H-NMR (CDCl3, 500 MHz) δ 7.74-7.76 (m, 2H), 7.66 (s, 1H), 7.58-7.60 (m, 2H), 7.44 (s, 1H), 7.41 (s, 1H), 7.36-7.38 (m, 2H), 7.30-7.33 (m, 2H), 7.18-7.21 (m, 1H), 4.45 (s, 2H), 3.48 (s, 2H), 2.58-2.60 (m, 2H), 2.17-2.28 (m, 4H), 2.21 (s, 3H), 1.98-2.08 (m, 2H). Mass spec.: 465.11 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Br[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:33])=[C:29]([CH:32]=1)[C:30]#[N:31].[H-].[Na+]>C1COCC1.CN(C=O)C>[Cl:33][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:17]2[CH2:18][CH2:19][CH:15]([N:12]3[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=4)[CH2:10][CH2:11]3)[C:16]2=[O:20])=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Reactant: N#Cc1cc(CBr)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C3CCN(Cc4ccc(Cl)c(C#N)c4)C3=O)CC2)cc1

Procedure:
To a mixture of 3-(4-(4-methoxybenzoyl)piperidin-1-yl)pyrrolidin-2-one (70 mg, 0.232 mmol) and 5-(bromomethyl)-2-chlorobenzonitrile (80 mg, 0.347 mmol) in THF (1 mL) and DMF (0.1 mL) was added NaH (46.3 mg, 1.16 mmol, 60%). The reaction was concentrated in vacuo then taken up in dichlormethane and MeOH and filtered through a short plug of silica gel. The pooled fractions containing the title material were pooled, concentrated and neutralized with NaHCO3. MeOH was added and the solution was cooled in a freezer. The title compound was obtained by collecting the white solid via filtration (45 mg). HRMS calculated for C25H26ClN3O3 451.1671. found (ESI, [M+H]+) 452.1744.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9](O)=[O:10])[C:6](=[O:12])[C:5]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][C:16](=[O:17])[C:4]1=2)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>CN(C)C=O>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([NH:35][C:36]2[NH:40][N:39]=[N:38][N:37]=2)=[O:10])[C:6](=[O:12])[C:5]2[C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[O:15][C:16](=[O:17])[C:4]1=2)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c3ccccc3oc(=O)c21
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(C(=O)Nc2nnn[nH]2)c(=O)c2c3ccccc3oc(=O)c21
Yield: 56 %

Procedure:
Prepared by the method described for Ex. 17 from 4-ethyl-1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]pyridine-2-carboxylic acid (2.2 g, 0.0077 mole), 1,1'-carbonyldiimidazole (2.4 g, 0.0148 mole) and 5-aminotetrazole monohydrate (0.76 g, 0.0076 mole) in dimethylformamide (30 ml). Recrystallization from dimethylformamide gives pale yellow crystals (1.5 g, 55%), m.p. above 300.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@@H:12]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][C@@H:15]2[O:29]C(C)(C)[O:31][C@H:14]2[C@@H:13]1[OH:34])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.CO>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[C@@H:13]([OH:34])[C@H:14]([OH:31])[C@@H:15]([OH:29])[CH2:16][N:17]1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:20])=[O:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H]3OC(C)(C)O[C@H]3[C@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.8 %

Procedure:
The above compound (5-2) (100 mg) was dissolved in a solvent mixture of 1,4-dioxane/methanol (5–15 mL) and a cation exchange resin (Muromac, 2.5 g) was added, and then the mixture was stirred at room temperature for 14 hours. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=20:1→10:1) to obtain the titled compound (88 mg).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[C:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1Br)([CH3:9])([CH3:8])[CH3:7].C(I)C>C1COCC1>[C:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[CH2:1][CH3:2])([CH3:9])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1Br
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)ccc1C(C)(C)C
Reaction time: 0.67 h

Procedure:
A solution of n-butyl lithium (1.6M in hexane, 2.67 mL, 4.27 mmol) was added dropwise to a solution of 4-tert-butyl-3-bromobenzoic acid (500 mg, 1.94 mmol) in THF at −78° C. whilst maintaining the temperature below −70° C. After 40 minutes, ethyl iodide (1.55 mL, 19.4 mmol) was added dropwise whilst maintaining the temperature below −65° C. After one hour at −70° C., the mixture was allowed to attain room temperature and stirred overnight The mixture was quenched by the addition of saturated ammonium chloride solution (30 mL) and extracted with ether (30 mL). The organic fraction was dried over magnesium sulphate and evaporated. Purification was achieved by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents, and analysis of the fractions by electrospray mass spectroscopy. This afforded the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][C@@H:21]2[CH3:20])[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCCS2
Reactant: C[C@H]1COCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1SCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (500 mg, 2.26 mmol) and Et3N (457 mg, 4.52 mmol) in DMF (5.0 mL) at 0° C. was added 3-(S)-methylmorpholine (252 mg, 2.49 mmol) dropwise. The reaction was stirred overnight at rt, then the solvent removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was separated, dried and concentrated to give the crude product which was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1) to give 2-chloro-7,8-dihydro-4-((S)-3-methylmorpholino)-6H-thiopyrano[3,2-d]pyrimidine (380 mg, 87%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]([NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:5][CH:6]=[CH:7][CH2:8]OC(=O)C.[CH3:23][O:24][C:25](=[O:34])[CH:26]([NH:30][C:31](=[O:33])[CH3:32])CC=C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[CH3:23][O:24][C:25](=[O:34])[CH:26]([NH:30][C:31](=[O:33])[CH3:32])[CH2:8][CH:7]=[CH:6][CH2:5][CH:4]([NH:13][C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]([O:2][CH3:1])=[O:22]
Reactant: C=CCC(NC(C)=O)C(=O)OC
Reactant: COC(=O)[C@H](CC=CCOC(C)=O)NC(=O)c1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: COC(=O)C(CC=CCC(NC(=O)c1ccccc1)C(=O)OC)NC(C)=O

Procedure:
2-Acetylamino-7-benzoylamino-oct-4-enedioic acid dimethyl ester 143 was synthesised using standard solution-phase metathesis conditions (refer to Section 7.5.2): 6-Acetoxy-2-benzoylamino-4-hexenoic acid methyl ester 142 (50 mg, 0.16 mmol), dichloromethane (10 mL), second generation Grubbs' catalyst (5 mol %, 7 mg, 8 μmol), methyl-2-acetylamino-4-pentenoate 21a (168 mg, 0.98 mmol), 50° C., 18 h. The desired compound was obtained as a brown oil and purified via column chromatography (SiO2; EtOAc:hexane; 2:1). 1H NMR (500 MHz, CDCl3, mixture of isomers (1:1.2)): δ 1.95, s (major isomer) and 1.97, s (minor isomer), 3H, CH3; 2.42-2.70, m, 4H, H3, 6; 3.62, s (minor isomer), 3.64, s (major isomer), 3.78, s (minor isomer) and 3.79, s (major isomer), 6H, 2×OCH3; 4.63-4.66, m, 1H, H2; 4.85-4.91, m, 1H, H7; 5.35-5.49, m, 2H, H4, 5; 6.20, d, J=7.7 Hz (major isomer) and 6.34, d, J=7.5 Hz, 1H, NH (minor isomer); 6.87, t, J=7.55 Hz, 1H, NH; 7.44, t, J 7.1 Hz, 2H, H4′, 6′; 7.50, t, J 6.9 Hz, 1H, H5′; 7.84, t, J 7.9 Hz, 2H, H3′, 7′. 13C NMR (75 MHz, CDCl3, mixture of isomers (1:1.2)): δ 22.83, CH3; 34.84, 35.05, 35.38 and 35.73, C3, 6; 51.51 and 51.55, C2; 52.35, 52.46, 52.53, 52.60 and 52.66, C7, 2×OCH3; 127.18 and 127.22, C3′, 7′; 128.57 and 128.62, C4′, 6′; 128.88 and 129.00, C4, 5; 131.86 and 131.91, C5′; 133.71, C2′; 167.06, COPh; 170.03 and 170.11, COMe; 172.20, 172.21, 172.24 and 172.43, 2×COOMe. Mass Spectrum (ESI+, CH3OH): m/z 399.2 (M+Na+) C19H24N2O6Na.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH:14]([NH2:16])[CH3:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11]C)C.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:16]([CH:14]([CH2:13][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:1])[CH:5]=2)[CH3:15])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCOc1ccc(CC(C)N)cc1OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC(C)N2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 0.67 h
Yield: 53.2 %

Procedure:
To a stirred solution of 3-(3,4-diethoxyphenyl)-2-aminopropane (1.95 grams, 10.0 mmol) and sodium carbonate (1.06 grams, 10.0 mmol) in 50 milliliters of water was added N-carbethoxyphthalimide (2.19 grams/10.0 mmol). After 10 minutes the reaction mixture was diluted with 40 milliliters of acetonitrile and the mixture stirred for 40 minutes. The reaction solution was partially concentrated in vacuo to remove the acetonitrile. The resulting mixture of an oil and aqueous layer was extracted with methylene chloride (25 milliliters). The organic extract was dried over sodium sulfate and concentrated in vacuo to afford a crude product which was purified by flash chromatography to afford 1.73 grams (53%) of product as a thick oil which slowly solidified to a white wax: 1H NMR (dmso-d6, 250 MHz) δ 7.7 (m, 4 H, Ar), 6.7 (m, 3 H, Ar), 4.63 (m, 1 H, CH), 3.79 (s, 3 H, Ome), 3.73 (s, 3 H, OMe), 3.28 (dd, 1 H, J=13.8, 9.8 Hz) 3.03 (dd, J=13.8, 6.5 Hz, 1 H), 1.54 (d, J=6.9 Hz, 3 H); 13C NMR (dmso-d6) δ 168.4, 148.6, 147.4, 133.7, 131.8, 130.9, 122.9, 120.9, 111.1, 55.7, 55.6, 48.6, 39.3, 18.3 Anal. Calcd for C19H19NO2. Theoretical C, 70.14; H, 5.89; N, 4.30. Found C, 70.08; H, 5.83; N, 4.30.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]#[C:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]3[CH:42]=[CH:41][C:26]([CH2:27][N:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]4)=[CH:25][CH:24]=3)[N:13]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].C(N(CC)CC)C>CN(C=O)C.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:27][N:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:32][CH2:33]3)=[CH:41][CH:42]=2)[N:13]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4cccc(C(N)=O)c4)n3)cc2)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(N)=O)c4)n3)cc2)CC1
Yield: 63 %

Procedure:
A suspension of tert-butyl 4-(4-((4-((3-carbamoylphenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I145) (105 mg, 0.18 mmol) and Pd/C (75 mg) was stirred in DMF (5 mL) and triethylamine (0.15 mL) at 30° C. under hydrogen for 18 hours. After filtration the volatiles were evaporated under reduced pressure and the residue chromatographed (Biotage Isolera: 4 g silica cartridge, 0-2% methanol/ethyl acetate) to give the title compound (I146) (66.6 mg, 63% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.20 (s, 1H), 8.67 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.74-7.50 (m, 8H), 7.40-7.35 (m, 2H), 7.33 (s, 1H), 7.24 (d, J=8.6 Hz, 2H), 3.43 (s, 2H), 3.17-3.04 (m, 4H), 2.36-2.23 (m, 4H), 1.38 (s, 9H). LCMS Method C: rt 5.05 min; m/z 585.2 [M+H]+; m/z 583.2 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+].[Cl:24][CH:25]=[CH:26][CH2:27]Cl>CN(C=O)C.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:14]([CH2:27][CH:26]=[CH:25][Cl:24])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(C#N)ccc2c1Br
Reactant: ClC=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2cc(C#N)ccc2c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.7 %

Procedure:
A stirred solution of nitrile 141 (5.78 g, 16.6 mmol) in dry DMF (50 mL) was treated at 0° C. with NaH (0.80 g, 20.0 mmol, 60% in oil). The resulting suspension was warmed to room temperature for 30 min, then cooled to 0° C. again and treated with 1,3-dichloropropene (4.8 mL, 52 mmol, mixed isomers). After stirring at room temperature for a further 6 h, the mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were washed with water (×3), dried, and concentrated to dryness under high vacuum at 80° C. The residue was chromatographed on silica gel, eluting with CH2Cl2, to give tert-butyl 1-bromo-6-cyano-2-naphthyl(3-chloro-2-propenyl)carbamate (142) (6.77 g, 96%) as a foam; 1H NMR [(CD3)2SO] (mixture of rotamers and E and Z forms) δ 8.69 (s, 1H), 8.35 (d, J=8.8 Hz, 1H), 8.13, 8.12 (2 d, J=8.6 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 7.69, 7.63 (2d, J=8.7 Hz, 1H), 6.42-6.29 (m, 1H), 6.17-5.99 (m, 1H), 4.55-4.45, 4.40-4.19, 4.15-3.98 (3 m, 2H), 1.48, 1.24 (2 s, 9H). HRMS (FAB) calcd. for C19H1979Br35ClN2O2(m/z 421.0318, found 421.0306.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH:29]1[CH2:44][CH2:45]O)=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(P([N:61]=[N+:62]=[N-:63])(C2C=CC=CC=2)=O)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[N:61]([CH2:45][CH2:44][CH:29]1[CH:28]([NH:27][C:25]([O:24][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:26])[CH2:33][CH2:32][CH2:31][N:30]1[C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])=[N+:62]=[N-:63]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CCN=[N+]=[N-]
Temperature: 0 °C

Procedure:
Triphenylphosphine (202 mg) was added to the compound 14 (146 mg), tetrahydrofuran (1 mL), diphenylphosphoryl azide (0.17 mL) and 2.2 mol/L of a solution (0.35 mL) of diethyl azodicarboxylate in toluene with stirring at 0° C. The reaction solution was stirred at room temperature for 1 hour and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:3) to obtain the title compound (136 mg) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([O:6][C:7]1[C:12]2[N:13](CC3C=CC4C(=CC=CC=4)C=3)[C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:5].BrCC1C=CC2C(=CC=CC=2)C=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:29])[CH:4]([O:6][C:7]1[C:12]2[NH:13][C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2
Agent: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Oc1cccc2c1NC(=O)CO2

Procedure:
Synthesis of 2-(4-Naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yloxy)-propionic acid methyl ester, I-67. A mixture of compound I-66 (350 mg, 1.5 mmol), 2-(bromomethyl) naphthalene (500 mg, 2.25 mmol), KI (374 mg, 2.25 mmol) and K2CO3 (310 mg, 2.25 mmol) in DMF (8 ml) and water (10 drops) was stirred at rt over night and then partitioned between dichloromethane and water. Water layer was extracted with dichloromethane (3×30 ml). The combined organic phase was washed with water (4×30 ml), brine and dried over sodium sulfate. After removal of solvent, the residue was purified by column chromatography on silica gel with EtOAc/hexane as the eluant to give 300 mg of compound I-67. 1H-NMR (500 MHz, CDCl3).
Reaction SMILES: C[C:2]12[CH:8]3[C:9]([O:11][C:12](=O)[CH:7]3[CH:4]([CH:5]=[CH:6]1)C2)=O>CC(OOC(=O)C1C=CC=CC=1)(CCC(C)(OOC(=O)C1C=CC=CC=1)C)C>[O:11]1[C:12]([C:7]2[CH:4]=[CH:5][CH:6]=[CH:2][CH:8]=2)=[CH:9]1
Reactant: CC12C=CC(C1)C1C(=O)OC(=O)C12
Agent: CC(C)(CCC(C)(C)OOC(=O)c1ccccc1)OOC(=O)c1ccccc1
Product: C1=C(c2ccccc2)O1

Procedure:
To this inhibited epoxy diester-styrene mixture 5.49 parts of NADIC methyl anhydride and 0.048 part of 2,5-dimethyl-2,5 bis(benzoyl peroxy) hexane catalyst (sold by Wallace & Tiernan Inc. under the trade name of Luperox 118) were added, at 25° C., to provide the solventless epoxy-styrene impregnating varnish. The catalyst used has a catalytic reaction "kick off" temperature of about 115° C., i.e., it will have a definite catalytic effect to initiate a cure reaction at over about 115° C. The viscosity of the epoxy-styrene impregnating varnish was measured to be about 10 cps to 15 cps at 25° C. To this resin system 0.029 part of various metal acetylacetonates were added. One sample, containing no metal acetylacetonate was used as a control. The weight ratio of epoxy mixture: styrene:metal acetylacetonate was 1:1.9:0.0029. This varnish was prepared in 1 gallon laboratory batches and in 250 gallon large scale commercial batches.
Reaction SMILES: CS(O[C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])(=O)=O.CO.[H][H]>[Pd].C(N(CC)CC)C>[C:9]([OH:11])(=[O:10])[CH:8]([C:7]1[CH:6]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:12]
Reactant: [H][H]
Reactant: CC(C(=O)O)c1ccccc1OS(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C(=O)O)c1ccccc1
Yield: 90 %

Procedure:
To a solution of 24.5 g. of 2-methane-sulphonyloxyhydratropic acid in 200 ml. of methanol 28 ml. of triethylamine and 2 g. of a 5% palladium-on-charcoal catalyst are added. The mixture is hydrogenated at 25° C., under atmospheric pressure until a calculated amount of hydrogen is used up. The catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and acidified with a 20% aqueous hydrochloric acid solution. The separated hydratropic acid is extracted with chloroform. The chloroform solution is dried over sodium sulphate, evaporated and the residue is distilled off. 13.5 g. (90%) of hydratropic acid are obtained, boiling at 145° C. (13 mmHg.); nD25 =1.5219.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([F:13])[CH:5]=1.C(Cl)(=O)C([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:18])=[O:9])=[C:6]([F:13])[CH:5]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(C(=O)O)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Cl)c(F)c1

Procedure:
2-Fluoro-terephthalic acid 4-methyl ester (J. Med. Chem., 52(19), 5950-5966; 2009) (500 mg, 2.25 mmol) was suspended in DCM (10 ml). Then oxalyl chloride (5.08 ml, 58.0 mmol) and a drop of DMF were added. The resulting mixture was refluxed for 14 hrs. The solvents were removed in vacuo, and the resulting crude Intermediate 33 was used in the next step without purification.
Reaction SMILES: O[CH2:2][C:3]([CH2:13][OH:14])([CH2:10][CH2:11][CH3:12])[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6].C(=O)(OCC)OCC.[OH-].[K+]>C(O)C>[OH:9][CH:4]([C:3]1([CH2:10][CH2:11][CH3:12])[CH2:2][O:14][CH2:13]1)[C:5]([F:6])([F:7])[F:8]
Reactant: CCCC(CO)(CO)C(O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(=O)OCC
Solvent: CCO
Product: CCCC1(C(O)C(F)(F)F)COC1
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
A mixture of 3,3-Di-(hydroxymethyl)-1,1,1-trifluorohexan-2-ol (2.8 g.), diethyl carbonate (1.6 ml.), potassium hydroxide (0.1 g) and dry ethanol (4.0 mls) was refluxed gently (oil bath 110°), under a current of nitrogen, for 30 minutes. The ethanol was then removed by distillation. Distillation gave 3-(1-hydroxy-2,2,2-trifluoroethyl)-3-n-propyloxetane (1.7 g.), colourless oil (b.p. 112°, 20-25 m.m.).