Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[CH3:49]>C(#N)C>[CH3:42][C:43]1[CH:44]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:46]=[CH:47][C:48]=1[CH3:49]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1C
Yield: 36.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3,4-dimethylbenzenesulfonyl chloride (0.0400 g, 0.195 mmol) to obtain 4-(3,4-dimethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0149 g. yield 36%).
Reaction SMILES: [OH:1][C@H:2]([CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:10]([CH2:18][CH2:19][N:20]=3)[C:11]([NH2:17])=[N:12][C:13]=2[C:14]=1[O:15][CH3:16].[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[OH:1][C@H:2]([CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:10]([CH2:18][CH2:19][N:20]=3)[C:11]([NH:17][C:28]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[O:35])=[N:12][C:13]=2[C:14]=1[O:15][CH3:16]
Reactant: COc1c(OC[C@H](O)CN2CCCCC2)ccc2c1N=C(N)N1CCN=C21
Reactant: O=C(O)c1cccnc1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OC[C@H](O)CN2CCCCC2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Yield: 67.6 %

Procedure:
To a slurry of N-(8-{[(2R)-2-hydroxy-3-(piperidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)amine (0.125 g, 0.34 mmol) and nicotinic acid (0.052 g, 0.42 mmol, 1.3 equiv.) in DMF 3.6 mL) was added PyBOP (0.218 g, 0.42 mmol, 1.3 equiv.) followed by diisopropylethylamine (0.23 mL, 1.34 mmol, 4.0 equiv.). The resulting mixture was stirred at room temperature. After a few hours the mixture turned to a clear solution. The resulting solids were removed by filtration, washed sequentially with DMF, water, then MeOH, and dried at 50° C. under reduced pressure to afford N-(8-{[(2R)-2-hydroxy-3-(piperidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide (0.11 g, 66%): HPLC ret. time 1.00 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.30, 1.44 m, 1H), 1.58-1.71 (m, 2H), 1.72-1.85 (m, 3H), 2.89-3.56 (m, 2H), 3.18 (dd, J=10.1, 13.1 Hz, 1H), 3.25-3.31 (m, 1H), 3.45-3.52 (m, 2H), 4.03 (s, 3H), 4.20-4.29 (m, 4H), 4.38-4.49 (m, 1H), 4.53-4.60 (m, 2H), 7.48 (d, J=9.4 Hz, 1H), 7.85 (dd, J=5.3, 7.9 Hz, 1H), 8.04 (d, J=9.1 Hz, 1H), 8.82 (br d, J=8.1 Hz, 1H), 8.93 (dd, J=1.5, 5.3 Hz, 1H), 9.47 (d, J=1.5 Hz, 1H); mass spectrum m/z 479 ((M+1)+, 0.4%).
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](O)=[C:12](F)[C:11]=2F)=[C:6](F)[C:5]=1F)C.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C.O>C1(C)C=CC=CC=1>[C:7]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1
Reactant: CCOc1ccc(-c2ccc(O)c(F)c2F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 80 °C

Procedure:
In a reactor under nitrogen atmosphere, 4.4 g of compound (a4) and 3.2 g of sodium carbonate were added into 20 ml of DMF, followed by stirring at 80° C. 3.8 g of compound (a9) was added thereto, followed by stirring at 80° C. for an hour. The resulting reaction mixture was cooled to 30° C., to which 30 ml of water and 30 ml of toluene were added. The mixture was separated into organic layer and aqueous layer and the organic layer was extracted. The resulting organic layer was separated and washed with salt water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide the residue. The resulting residue was purified by column chromatography (volume ratio heptane: toluene=4:1), further by recrystallization from the solvent mixture of Solmix A-11 and heptane (volume ratio Solmix A-11: heptane=1:2), dried to provide 1.8 g of 4′-ethoxy-2,3,2′,3′-tetrafluoro-4-(trans-4-vinylcyclohexylmethoxy)-biphenylmethoxy)-biphenyl (a10).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH2:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.BrC1C=CC=CC=1.[Li]>CCOCC>[C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH2:2][CH2:3]2)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1cccc2c1NCC2
Reactant: [Li]c1ccccc1
Agent: [Li]
Solvent: Brc1ccccc1
Solvent: CCOCC
Product: O=C(c1ccccc1)c1cccc2c1NCC2
Temperature: 25 °C

Procedure:
A stirred mixture of 0.165 mole (25 g.) of indoline-7-carboxylic acid and 800 ml. of dry ether was treated dropwise with 0.435 mole of phenyllithium which was prepared from 157 g. (0.435 mole) of bromobenzene, 6.94 g. (0.87 mole) of lithium wire and 500 ml. of dry ether. After addition of the phenyllithium, the reaction mixture was refluxed for three hours and then poured onto ice. After warming to room temperature, the mixture was filtered and the ether layer was separated from the aqueous layer. After washing the ether extract with 1N hydrochloric acid, the product was extracted into 12 N hydrochloric acid. Neutralization of the acidic extract caused precipitation of crude product. The product melted at 119°-122°C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17](O)[CH3:18].C(C1C=CC(C(O)=O)=CC=1)CC>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:14][CH2:17][CH3:18])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCO
Agent: CCCc1ccc(C(=O)O)cc1
Solvent: CO
Product: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
The reaction was conducted in the same manner as in the step (i) of the Example 33, except for using 4-(4-hydroxyphenyl)benzoic acid and ethanol in lieu of 4-n-propylbenzoic acid and methanol, respectively, and the resultant was recrystallized from toluene to give ethyl 4-(4-hydroxyphenyl)benzoate.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:29]([NH2:32])[CH2:30][CH3:31]>C(#N)C>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:32][CH2:29][CH2:30][CH3:31])=[O:16])[CH2:3]1
Reactant: CCCN
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CCCNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of 10.96 g (50 mmole) of 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 9.73 g (60 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60° C. for one hour, cooled to room temperature and treated with 4.13 g (70 mmole) of n-propylamine. After stirring for two hours, the solvent was removed in vacuo and the residue partitioned between ether and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated invacuo to give 12.0 g of 5-oxo-1-(phenyl-methyl)-N-propyl-3-pyrrolidinecarboxamide, mp 86°-87° C.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]S[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:25]([O-:29])([O-])(=[O:27])=S.[Na+].[Na+].C(OC([O-])=O)(OC(OC(C)(C)C)=O)=O>ClCCl>[O:27]=[S:25]1(=[O:29])[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:2][CH2:3]1
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCSCC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(=O)[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC1
Yield: 91.6 %

Procedure:
tert-Butyl thiomorpholine-4-carboxylate (1.91 g, 9.42 mol) was dissolved in dichloromethane (50 ml); m-chloroperbenzoic acid (5.0 g, 19 mmol) was gradually added while cooled with ice bath, stirred, and under nitrogen atmosphere; and the reaction mixture was stirred at room temperature for 12 hours. After addition of a saturated aqueous solution of sodium thiosulfate, the reaction mixture was kept stirred for a while; and this was subjected to extraction with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Triethylamine (8.1 ml, 58 ml) were added to the obtained crystals; and the reaction mixture was stirred at room temperature. tert-Butoxycarbonyl dicarbonate (13.3 ml, 58 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure; and the obtained crystals were suspended with a solvent mixture of diethyl ether:ethanol=10:1, filtered off, washed with diethyl ether and dried under aeration to yield the title compound as colorless crystals (2.03 g, 8.63 mmol, 91.6%).
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[C:11]([OH:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1.[Cl:20][C:21]1[CH:37]=[CH:36][C:24]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33](O)[CH3:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:11]([O:19][CH2:34][CH2:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:37][CH:36]=2)=[CH:32][CH:31]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(O)c1ccc(OCc2ccc(Cl)cc2)cc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(OCCc1ccc(OCc2ccc(Cl)cc2)cc1)c1cccnc1
Temperature: 0 °C
Yield: 84.3 %

Procedure:
Benzenesulfonyl chloride (10.6 g, 0.06 mole) is dropped with stirring at 60° C. to a nicotinic acid in 30 ml of pyridine to yield uniform solution. After the solution was stirred at 50°-60° C. for ten minutes, 4-(4-chlorobenzyloxy)phenyl ethanol (13.1 g, 0.05 mole) is added to the solution, and the mixture is stirred for 45 minutes at room temperature. The reaction mixture is poured into 300 ml of ice water to give crystals. The crystals are dissolved into 300 ml of chloroform, the chlorofrom layer is washed with 5% pottassium carbonate solution and water. The chloroform layer is dried over sodium sulfate, and the chloroform is evaporated to give crude crystals. The crude crystals are recrystallized from isopropanol to obtain 15.5 g (84.3%) of a title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH2:15][CH2:16][O:17]S(C)(=O)=O)=[CH:12][C:11]([Cl:22])=[CH:10][C:8]=2[N:9]=1.[CH3:27][O-].[Na+].CO.[Na]>O>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH2:15][CH2:16][O:17][CH3:27])=[CH:12][C:11]([Cl:22])=[CH:10][C:8]=2[N:9]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)OCCCc1cc(Cl)cc2nc(Cc3ccccc3Cl)oc12
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COCCCc1cc(Cl)cc2nc(Cc3ccccc3Cl)oc12

Procedure:
2-(2-Chlorobenzyl)-5-chloro-7-(3-methanesulfonyloxy-1-propyl)-benzoxazole was stirred overnight with a solution of sodium methoxide prepared from methanol (100 ml) and sodium (2.7 g, 0.118 mol). The reaction mixture was diluted with water and extracted with dichloromethane. The dichloromethane solution was washed with water and evaporated to give the crude product (10 g). The crude product was purified over flash chromatography silica gel and eluted with 30% dichloromethane/hexane. The effluent was collected in 200 ml fractions. Fractions 1-7 contained an impurity (7.1 g); fractions 8-11 were collected (1.8 g) and recrystallized three times from hexane to give the title compound (0.4 g), mp 49-51°.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:18]O>>[Br:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=1[C:9]([O:11][CH3:18])=[O:10]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)ccc1Br
Temperature: 25 °C

Procedure:
Sulfuric acid (2 eq) was added to a solution of 2-bromo-5-methoxybenzoic acid (1 eq) in methanol (0.30 M) at 0° C. under N2. The solution was allowed to warm to RT and then refluxed for 5 h. After cooling to RT, the solution was concentrated in vacuo, the residue dissolved in ethyl acetate and washed with 1N NaOH solution (2×). The combined aqueous layers were extracted with ethyl acetate and the combined organics dried over MgSO4. Concentration in vacuo gave methyl 2-bromo-5-methoxybenzoate as a clear oil. EI-MS m/z 245, 247 (M+H)+
Reaction SMILES: [F:1][C:2]([F:29])([C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:3][CH2:4][CH:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:6]([O:8]CC)=[O:7].C(OCC)(=O)CC(OCC)=O.BrCCCCCCC=C.ICCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F.[CH2:66]([C:68]1([C:104]2[CH:109]=[CH:108][C:107]([OH:110])=[CH:106][CH:105]=2)[CH:77]([CH2:78]CCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:76]2[C:71](=[CH:72][C:73]([OH:103])=[CH:74][CH:75]=2)[S:70][CH2:69]1)[CH3:67]>>[CH2:66]([C:68]1([C:104]2[CH:105]=[CH:106][C:107]([OH:110])=[CH:108][CH:109]=2)[CH:77]([CH2:78][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:5]([CH2:4][CH2:3][C:2]([F:29])([F:1])[C:19]([F:27])([F:28])[C:20]([F:25])([F:26])[C:21]([F:24])([F:22])[F:23])[C:6]([OH:8])=[O:7])[C:76]2[C:71](=[CH:72][C:73]([OH:103])=[CH:74][CH:75]=2)[S:70][CH2:69]1)[CH3:67]
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Agent: C=CCCCCCCBr
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Solvent: CCOC(=O)CC(=O)OCC
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate prepared from diethyl malonate, 8-bromo-1-octene and 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane as in Example 5 and the allyl compound prepared in Example 13, the same procedure as shown in Example 13 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[NH:23][Si](C)(C)C.C(N(CC)CC)C>O1CCOCC1.CCOC(C)=O>[CH3:17][N:13]1[C:14]2=[CH:15][NH:23][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]1=[O:18]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(-c3ccccc3)[nH]cc2n(C)c1=O
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 13.4a (Intermediate C) (2.33 g, 6.91 mmol), hexamethyldisilazane (2.90 mL, 13.82 mmol) and triethylamine (2.89 mL, 20.73 mmol) were combined in dioxane (20 mL) and the mixture heated at reflux for 22 hours. Further portions of hexamethyldisilazane (2.90 mL, 13.82 mmol) and triethylamine (2.89 mL, 20.73 mmol) were added to allow the reaction to run to completion. The reaction mixture was cooled to room temperature, diluted with EtOAc (150 mL) and washed with 1M HCl (aq) and brine. The organic phases was dried over sodium sulphate and evaporated under vacuum. The residue was triturated with DCM/diethyl ether/hexane to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][CH:7](C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)C1C=CC(OC)=C(OC)C=1.CC1(C)OC(=O)CC(=O)O1>C(O)C.C(N(CC)CC)C.C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][CH2:7][C:8]([OH:10])=[O:9].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(OC)c1)C(=O)OCC
Agent: CC1(C)OC(=O)CC(=O)O1
Agent: COc1ccc(C=O)cc1OC
Solvent: CCO
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(OC)c(OC)c1
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
By boiling Meldrum's acid (formula III with R9 =R10 =methyl group) with veratraldehyde in an ethanolic medium in the presence of formic acid and triethylamine, monoethyl 3,4-di-(methoxy)-benzylmalonate was obtained. According to our experimental observation, diethyl 3,4-di-(methoxy)-benzylidene malonate could not be hydrogenated to diethyl 3,4-di-(methoxy)-benzylmalonate when using formic acid and triethylamine as reagents. Further on we have observed that by reacting veratraldehyde with Meldrum's acid, formic acid and triethylamine at 100° C. for 2 hours and then by boiling with ethanol for 2 hours 3,4-dimethoxyhydrocinnamic acid and not ethyl 3,4-di-(methoxy)-hydrocinnamate was obtained as final product. Thus, the reaction can be interpreted only in such a way that 5-[3',4'-di-(methoxy)-phenylmethyl]-Meldrum's acid is formed in the manner described above, the dioxane ring of which is opened and one carboxyl group of the 3,4-di-(methoxy)-benzylmalonic acid formed is simultaneously esterified. When the temperature of the reaction mixture is increased after removing the ethanol, the carboxyl group is eliminated and 3,4-di-(methoxy)-hydrocinnamic acid ester is obtained.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][CH3:5].[N+:8]([CH3:11])([O-:10])=[O:9]>>[CH3:5][NH:4][C:3]([S:2][CH3:1])=[CH:11][N+:8]([O-:10])=[O:9]
Reactant: CN=C(SC)SC
Reactant: C[N+](=O)[O-]
Product: CNC(=C[N+](=O)[O-])SC

Procedure:
A process according to claim 1 wherein methylcarbonimidodithioic acid dimethyl ester is reacted with nitromethane in the presence of a secondary catalyst containing a rare earth exchanged faujasite to form 1-methylamino-1-methylthio-2-nitroethene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH:13]=[CH:12][N-:11][C:10]2=[S:14])=[CH:4][N:3]=1.[H-].[Na+].[CH3:17]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:13][CH2:12][N:11]=[C:10]2[S:14][CH3:17])=[CH:4][N:3]=1
Reactant: S=C1[N-]C=CC1Cc1ccc(Cl)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC1=NCCC1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.6 g of 3-(2-chloropyrid-5-yl-methyl)-pyrrolide-2-thione are added to a mixture of 0.1 g of sodium hydride (50% in oil) and 10 ml of dimethylformamide. The mixture is stirred for 20 minutes at room temperature and then 0.38 g of methyl iodide is added. The reaction mixture is stirred for a further 30 minutes at room temperature, poured onto ice-water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated to dryness by evaporation in vacuo. The title compound is obtained in the form of an oil (compound 3.2).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[C:28]([C:31]1[N:32]=[C:33]([CH:37]=O)[N:34]([CH3:36])[CH:35]=1)(=[O:30])[CH3:29]>>[C:28]([C:31]1[N:32]=[C:33]([C:37]2[N:2]([CH2:26][C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([Cl:16])[CH:18]=4)[NH:22][CH:21]=3)[N:1]=[C:3]3[C:4]=2[C:5](=[O:15])[N:6]([CH3:14])[C:7](=[O:13])[N:8]3[CH2:9][CH:10]([CH3:11])[CH3:12])[N:34]([CH3:36])[CH:35]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)c1cn(C)c(C=O)n1
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: CC(=O)c1cn(C)c(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n1

Procedure:
This compound was made following the procedure described above, starting 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first 5-chloro-1H-indole-3-carbaldehyde, followed by 4-acetyl-1-methyl-1H-imidazole-2-carbaldehyde. 508 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4](I)[C:3]=1[C:16]([F:19])([F:18])[F:17].[CH:20]#[C:21][CH3:22]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([C:20]#[C:21][CH3:22])[C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1I
Reactant: C#CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC#Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Temperature: 50 °C
Yield: 65.4 %

Procedure:
A triethylamine (300 mL) solution of N-[4-chloro-2-iodo-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (Example 60A) (40 g, 98.6 mmol) was treated with 1-propyne (39.5 g, 988 mmol) followed by copper iodide (0.94 g, 4.9 mmol) and PdCl2(PPh3)2 (6.9 g, 9.8 mmol) in a Parr Bomb at −78° C. The reaction vessel was purged with N2, sealed and heated gradually to 50° C. overnight, then cooled to −78° C. The cooled mixture was diluted with Et2O and filtered through celite. The Et2O solution was washed with water once, brine once, and dried (MgSO4). Filtration and concentration in vacuo followed by radial chromatography (SiO2, 0-10% EtOAc-hexanes gradient) afforded the title compound as a yellow solid (20.5 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.60 (d, J=9.0 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 2.22 (s, 3H), 1.33 (s, 9H); MS (ES) m/z 318 (M+1) and 320 (M+1, isotope).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.[CH3:19][CH:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])C)=[O:27])[C:21]([OH:23])=O.Cl.[CH2:34](N=C=NCCCN(C)C)C.CC1C=CN=C(N)C=1C>C(Cl)Cl>[CH3:19][CH:20]([CH2:24][NH:25][C:26]([O:28][CH:29]([CH3:31])[CH2:32][CH3:34])=[O:27])[C:21]([N:14]([CH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:23]
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: ClCCl
Product: CCC(C)OC(=O)NCC(C)C(=O)N(Cc1cc(Cl)c2c(c1)OCCCO2)CC(C)C

Procedure:
The mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (600 mg), (±)-2-Methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (475 mg) and of dimethyl aminopyridine (284 mg) in DCM (30 ml) was stirred overnight. The reaction mixture was partitioned between ethyl acetate and water (30 mL each). The aqueous layer was extracted with EtOAc (30 mL×2). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (33% ethyl acetate in hexane) to give (±)-2-Methyl-3-(methylpropan-2-yl)oxycarbonylamino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide as a resin: MS (m+1)=455.5.