Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16](=[S:18])[NH2:17])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].Br[CH2:25][C:26]([C:28]1[N:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=[CH:30][CH:29]=1)=O.O>C(O)C>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2[S:18][CH:25]=[C:26]([C:28]3[N:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=[CH:30][CH:29]=3)[N:17]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cccc(C(=O)CBr)n1
Reactant: COc1ccc(C(N)=S)c2c1oc1ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cccc(-c2csc(-c3ccc(OC)c4oc5ccccc5c34)n2)n1
Reaction time: 20 h
Yield: 28 %

Procedure:
To a stirred solution of 4-methoxydibenzo[b,d]furan-1-carbothioamide (140 mg, 0.544 mmol) in ethanol (5 mL) was added sodium bicarbonate (60 mg, 0.714 mmol) and ethyl 6-(2-bromoacetyl)picolinate (150 mg, 0.551 mmol). The stirring was continued at room temperature for 20 hours. The reaction mixture was poured into the water (25 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated at reduced pressure to give the product, which was purified by column chromatography by using a gradient of ethyl acetate in hexane (0-6%). Yield—28%; Rf 0.5 (Ethyl acetate:Hexane (3:7); HPLC (purity): 98.1%; 1H-NMR (CDCl3) δ: 1.48-1.57 (m, 3H), 4.14 (s, 3H), 4.50-4.55 (m, 2H), 7.07 (d, 1H), 7.49-7.53 (m, 1H), 7.65-7.69 (m, 2H), 7.94-7.98 (m, 1H), 8.09 (d, 1H), 8.42 (s, 1H), 8.47 (d, 1H), 8.73 (d, 1H); MS m/z: 431.1 (M+1).
Reaction SMILES: COC1C=CC(NC2N=NC(C(NC(C3OC=CC=3)=O)C)=CN=2)=CC=1.[NH2:26][CH:27]([C:29]1[N:34]=[N:33][C:32]([NH:35][C:36]2[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=2)=[N:31][CH:30]=1)[CH3:28].C(N(CC)CC)C.[CH:55]1([C:61](Cl)=[O:62])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1>>[CH3:43][O:42][C:40]1[CH:41]=[C:36]([NH:35][C:32]2[N:33]=[N:34][C:29]([CH:27]([NH:26][C:61]([CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[O:62])[CH3:28])=[CH:30][N:31]=2)[CH:37]=[C:38]([O:46][CH3:47])[C:39]=1[O:44][CH3:45]
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccco3)nn2)cc1
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncc(C(C)NC(=O)C3CCCCC3)nn2)cc(OC)c1OC
Yield: 60.2 %

Procedure:
In a similar manner as described for Intermediate 59, using 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (170 mg, 0.56 mmol), triethylamine (0.120 mL, 0.84 mmol) and cyclohexanecarbonyl chloride (0.082 mL, 0.61 mmol) to afford N-[1-(3-{[3,4,5-tris(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]cyclohexanecarboxamide (140 mg) as a yellow solid. MS m/z 416 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[O:10][C:11]([CH2:14][CH3:15])=[CH:12][N:13]=2)=[CH:5][N:6]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([C:11]1[O:10][C:9]([CH2:8][S:7][C:4]2[S:3][C:2]([NH:1][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:6][CH:5]=2)=[N:13][CH:12]=1)[CH3:15]
Reactant: CCc1cnc(CSc2cnc(N)s2)o1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cnc(CSc2cnc(NC(=O)c3ccccc3)s2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
A mixture of 2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole (48.2 mg, 0.2 mmol), benzoyl chloride (24.4 mg, 0.21 mmol) and triethylamine (35 mg, 0.35 mmol) in methylene chloride (0.5 mL) was stirred at rt for 10 min. The organic solution was washed with water and concentrated. The residue was purified by a flash column (SiO2 ; hexanes: ethyl acetate/2:1) to afford N-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]benzamide (41 mg, 59%) as a solid, mp 122-123° C. 1H NMR (CDCl3) δ12.65 (s, 1 H), 7.96 (m, 2 H), 7.61 (m,, 1 H), 7.49 (m, 2 H), 6.88 (s, 1 H), 6.56 (s, 1 H), 3.93 (s, 2 H), 2.61 (q, J=7.6 Hz, 2 H), 1.20 (t, J=7.6 Hz, 3 H); MS m/e 346 (M+H)+ ;
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[C@H:21]([CH3:22])[CH2:20][O:19][C@H:18]([CH2:23][OH:24])[CH2:17]3)[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:28][NH2:29]>CCO>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([C:10]3[N:11]=[C:12]([NH:25][CH3:26])[N:13]=[C:14]([N:16]4[C@H:21]([CH3:22])[CH2:20][O:19][C@H:18]([CH2:23][OH:24])[CH2:17]4)[CH:15]=3)=[CH:7][CH:6]=2)[NH:29][N:28]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 42 h
Yield: 72.8 %

Procedure:
A mixture of 2-fluoro-4-[6-[(2S,5R)-2-(hydroxymethyl)-5-methyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]benzonitrile (151 mg, 0.42 mmol) and hydrazine monohydrate (0.41 mL, 8.44 mmol) in EtOH (4 mL) was stirred at 100° C. in a sealed tube for 42 hours. It was then cooled, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (24 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (113 mg) as a white solid. LC-MS (ES) m/z=370 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.17 (d, J=6.6 Hz, 3H), 2.72-2.93 (m, 4H), 3.37-3.59 (m, 3H), 3.66 (d, J=11.2 Hz, 1H), 3.77 (d, J=11.1 Hz, 1H), 3.94-4.74 (bs, 2H), 4.38 (t, J=5.7 Hz, 1H), 5.38 (s, 2H), 6.54 (m, 2H), 7.59 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.98 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)[CH2:8][CH2:9][CH2:10]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH2:24]>>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)[CH2:8][CH2:9][CH2:10][NH:24][CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N(CCCBr)Cc1ccc2c(c1)OCO2
Product: CNCCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
Benzo[1,3]dioxol-5-ylmethyl-(3-bromo-propyl)-carbamic acid tert-butyl ester (23.0 g, 61.8 mmol) was diluted in methylamine (2.00M in THF, 300 mL, 600 mmol) at rt under an atmosphere of nitrogen and stirred at ambient temperature for 16 h. The solvent was evaporated and saturated sodium carbonate solution was added. The solution was extracted with ethyl acetate (2×150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 18.2 g (91%) of benzo[1,3]dioxol-5-ylmethyl-(3-methylamino-propyl)-carbamic acid tert-butyl ester as a clear oil. [M+H]+ 323.09.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([N:9]([CH3:36])[C:10]([C:12]1[N:16]2[CH2:17][CH2:18][C:19]3[C:24]([C:15]2=[C:14]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[N:13]=1)=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH2:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[O:11])([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C>ClCCl>[C:5]([N:9]([CH3:36])[C:10]([C:12]1[N:16]2[CH2:17][CH2:18][C:19]3[C:24]([C:15]2=[C:14]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[N:13]=1)=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][C:1](=[O:3])[CH3:2])=[C:21]([O:29][CH3:30])[CH:20]=3)=[O:11])([CH3:7])([CH3:8])[CH3:6]
Reactant: COc1cc2c(cc1OCCN)-c1c(-c3cccs3)nc(C(=O)N(C)C(C)(C)C)n1CC2
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(cc1OCCNC(C)=O)-c1c(-c3cccs3)nc(C(=O)N(C)C(C)(C)C)n1CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetyl chloride (10.2 μl) was added dropwise to a mixture of the product of example 31 (50 mg) and DIPEA (55 μl) in dichloromethane (2 ml). After stirring at room temperature for 18 h, the reaction mixture was diluted with dichloromethane and washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (0→100% acetonitrile).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[C:53]([O:59][CH3:60])[C:13]=1[CH:14]=[CH:15][CH:16]([S:26]([CH:29]([CH:39]=[CH:40][C:41]1[C:46]([O:47][CH3:48])=[CH:45][C:44]([O:49][CH3:50])=[CH:43][C:42]=1[O:51][CH3:52])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH2:38])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH2:25])[CH:18]=1>O1CCCC1>[CH3:60][O:59][C:53]1[CH:54]=[C:55]([O:57][CH3:58])[CH:56]=[C:12]([O:11][CH3:10])[C:13]=1/[CH:14]=[CH:15]/[CH:16]([S:26]([CH:29](/[CH:39]=[CH:40]/[C:41]1[C:42]([O:51][CH3:52])=[CH:43][C:44]([O:49][CH3:50])=[CH:45][C:46]=1[O:47][CH3:48])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH:38][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3ccccc3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3ccccc3)c2)c(OC)c1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of benzoyl chloride (10 mmol) in tetrahydrofuran (40 mL) was added dropwise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in tetrahydrofuran. The solution was stirred overnight and the completion of the reaction was monitored by TLC. The solvent was removed and the residue was taken up in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to give (E)-2,4,6-trimethoxystyryl-3-benzamido-4-methoxybenzylsulfone in 76% yield. m.p. 163-166° C. NMR (DMSO-d6) δ 3.82(s, 3H), 3.83(s, 6H), 3.86(s, 3H), 4.2(s, 2H), 6.14(s, 2H), 7.10-7.18(d,1 H vinylic), 7.00-7.86(m, aromatic), 8.90(s,1 H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].Cl.[P:12](Cl)([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13]>ClCCl.C(N(CC)CC)C>[P:12]([O:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5])([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1ccc(O)c(C=O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)Oc1ccc(C)cc1C=O
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-hydroxy-5-methyl benzaldehyde (4A) (1000 mg) in dry dichloromethane (20 mL) and triethylamine (2 mL), diethyl chlorophosphate (1.17 mL) was added in a dropwise manner. The mixture was stirred for overnight and the reaction mixture was acidified using 5% HCl and extracted with ethyl acetate and the extracts were combined, washed with sodium bicarbonate and then concentrated. Flash column chromatography furnished the pure product as colorless oil (1620 mg, 81%): 1H-NMR (500 MHz, CDCl3) δ 10.34 (s, 1H), 7.7 (s, 1H), 7.3-7.4(d, J=8.4 Hz, 1H)7.3 (d, J=8.4 MHz), 4.2-4.3 (m, 4H) 2.3 (s, 3H), 1.3(t, J=6 Hz, 6H) (FIG. 7). 13C-NMR (CDCl3, 50.3 MHz) δ 188.5, 136.1, 135.1, 128.7, 120.8, 664.8, 20.4, 15.9. 31P-NMR (CDCl3, 81 MHz) δ −6.18 (FIG. 8). MS calcd for C12H17O5P 272.23, found 272.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>ClCCl>[CH3:17][CH:16]([CH3:18])[C:15]([C:11]1[CH:12]=[CH:13][C:14]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1)=[O:19]
Reactant: CC(C)C(=O)Cl
Reactant: c1ccc2c(c1)CCCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)C(=O)c1ccc2c(c1)CCCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aluminium chloride (28.0 g, 0.21 mole) was suspended in 200 ml of anhydrous dichloromethane (200 ml) and cooled to 0° C. A solution of 1,2,3,4-tetrahydronaphthalene (26.5 g, 0.2 mole) and isobutyryl chloride (21.3 g, 0.20 mole) in 50 ml of anhydrous dichloromethane was slowly added to this suspension. After the addition was completed, the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was poured onto 300 g of ice water, and the organic layer was separated. The organic layer was successively washed twice with a 5 wt % aqueous hydrochloric acid solution (150 ml) and once with a 2 wt % aqueous sodium bicarbonate solution (150 ml). After drying over anhydrous magnesium sulfate the solution was concentrated under reduced pressure. The yield of 2-methyl-1-(5,6,7,8-tetrahydro-2-naphthalenyl)-1-propanone was 39.7 g or 98%.
Reaction SMILES: [C:1]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[C:2]([CH2:4][C:5]([O:7]CCCC)=O)=[CH2:3].[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][NH2:22])[CH3:19]>>[CH2:14]([O:13][C:1]([CH:2]1[CH2:4][C:5](=[O:7])[N:22]([CH2:21][CH:20]([CH2:18][CH3:19])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3]1)=[O:12])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCC(CC)CN
Reactant: C=C(CC(=O)OCCCC)C(=O)OCCCC
Product: CCCCOC(=O)C1CC(=O)N(CC(CC)CCCC)C1
Temperature: 75 °C

Procedure:
Bis(butyl) itaconate (400 g; 1.65 Mol) was charged to a 1 L reaction vessel and the material stirred mechanically under nitrogen while heating to 75° C. 2-Ethylhexylamine (1.7 Mol; 219.7 g) was charged to a pressure-equalizing addition funnel and the amine added drop wise to the stirred diester over the course of one hour and stirred at 75° C. for 2 hours after amine addition. The reactor was equipped for distillation and the temperature was increased slowly to 130° C., holding at full vacuum until stripping was complete. Receivers were changed and the pot heated under full vacuum to increase pot temperature to 165 to 185° C. (head temperature 140 to 175° C.). 469.3 g of product 1.58 Mol; 95.6% yield was collected. Sample materials were collected from this preparation and designated 1-(2-ethylhexyl)-5-oxo-3-pyrrolidinecarboxylic acid butyl ester for comparison testing described in the Examples below.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])=[O:17])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOCCOC(=O)CC(C)=O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O

Procedure:
A mixture of 3-nitrobenzaldehyde (4.54 g), 2-ethoxyethyl acetoacetate (5.23 g) and piperidine (85.2 mg) in benzene (15 ml) was refluxed under azeotropic dehydration for 3 hours. The resultant mixture was washed with water, an aqueous solution saturated with sodium chloride and water in turn, dried and concentrated to give an oil of 2-ethoxyethyl 2-(3-nitrobenzylidene)acetoacetate. To this oily product was added ethyl 3-amino-4,4-diethoxycrotonate (6.5 g). The mixture was heated at 110° C. for about 3 hours. The reaction mixture was dissolved in ethyl acetate and washed with water twice and dried. The solvent was removed from the mixture to give an oil (15.58 g). This oil was subjected to column chromatography on silica gel with an eluent (a mixture of 10 parts of benzene and one part of ethyl acetate by volume) to give an oily substance (8.09 g). This oily substance (0.93 g) was treated with a mixture of n-hexane and diethyl ether to give crystals, which were further recrystallized from a mixture of n-hexane and diethyl ether to give yellow granules (565.2 mg) of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 99° to 100° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])OCC[O:44]2)[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14](OC)=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:55][C@@H](CC1C=CC(OCCCC)=CC=1)C(N)=O>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:44])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([OH:25])=[O:24])=[O:20])[C:14](=[O:15])[NH2:55])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc2ccc(OCCCC)cc2)C(=O)OC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)OCCO1
Reactant: CCCCOc1ccc(C[C@H](N)C(N)=O)cc1
Product: CCCCCCCC(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(N)=O)[C@@](O)(CCOC)C(=O)O

Procedure:
An intermediate was synthesized by a method similar to that of No. 5534988, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate, except that (S)-2-amino-3-(4-butoxy-phenyl)-propionamide was used instead of (S)-2-amino-3-(4-butoxy-phenyl)-N-methyl-propionamide, and the title compound was obtained by a synthetic method similar to that of No. 5444958, (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-methoxy-ethyl)-12-oxo-nonadec-4-enoic acid.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[NH2:23][N:24]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][C:27](=O)[N:26]([C:35]2[CH:40]=[C:39]([CH:41]=[N:42][O:43][CH3:44])[C:38]([Cl:45])=[CH:37][C:36]=2[F:46])[C:25]1=[O:47]>C1(C)C=CC=CC=1>[NH2:23][N:24]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][C:27](=[S:10])[N:26]([C:35]2[CH:40]=[C:39]([CH:41]=[N:42][O:43][CH3:44])[C:38]([Cl:45])=[CH:37][C:36]=2[F:46])[C:25]1=[O:47]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: CON=Cc1cc(-n2c(=S)cc(C(F)(F)F)n(N)c2=O)c(F)cc1Cl

Procedure:
3.4 g of Lawesson's reagent were added to a solution of 1-amino-3-(4-chloro-2-fluoro-5-methoxyiminomethylphenyl)-2,4-dioxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine (3.8 g) in 100 ml of toluene. After refluxing for 12 hours, the solvent was removed and the crude product obtained was purified by chromatography. Yield: 2.2 g; m.p.: 172°-174° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([Br:31])[CH:18]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:39]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=N1.C1(N)C(N)=CC=CC=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:39][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[NH:41][C:13](=[O:15])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([Br:31])[CH:18]=1
Reactant: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2Br)S(=O)(=O)N1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
(2S)-2-[(Benzyloxy)-carbonyl]amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid (65.3 mg, 0.128 mmol) in DMF (4 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (67.8 mg, 0.153 mmol). After 5 minutes 1,2-benzenediamine (20.7 mg, 0.192 mmol) and N,N-diisopropylethylamine (111 μL, 0.638 mmol) were added and the solution stirred at rt for 2 h. Purification by preparative LCMS afforded product as a white solid (58 mg, 76%). 1H NMR (400 MHz, CD3OD): δ 7.72 (s, 1H), 7.56–7.23 (m, 10H), 6.91–6.85 (m, 1H), 5.67 (t, J=7.7 Hz, 1H), 5.09 (s, 2H), 4.50–4.47 (m, 1H), 3.46 (dd, J=16.5, 8.8 Hz, 1H), 3.34–3.24 (m, 1H), 3.26–3.08 (m, 2H); LCMS found for C26H26BrN4O6S (M+H)+: m/z=601.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:7][Si:8]([CH3:11])([CH3:10])Cl.N1C=CC=CC=1>C(OCC)C>[C:1]([O:6][Si:8]([CH3:11])([CH3:10])[CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: C/C=C/C(=O)O
Reactant: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: C/C=C/C(=O)O[Si](C)(C)C
Temperature: 38 °C
Reaction time: 0.08 h
Yield: 61.9 %

Procedure:
To a single-neck reaction flask (250 mL) were added of crotonic acid (10.750 g, 0.125 mol), anhydrous ethyl ether (125 mL) and trimethyl chlorosilane (19 mL, 0.150 mol). The mixture was stirred for 5 min. Pyridine (12 mL, 0.150 mol) was dropwise added into the resulting mixture under stirring at the temperature of 35° C. After the addition finished, the mixture was warmed up to the temperature of 38° C. and stirred under relux for 3 hr. The white solid was filtered in vacuo. Ethyl ether was evaporated under atmospheric pressure. The resultant was distilled under reduced pressure to collect the fraction under 10 mmHg at the temperature of 46° C.-48° C. to give (E)-trimethylsilyl 2-butenoate as a colorless liquid (12.242 g). Yield: 62.0%.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CCC>[N+:8]([C:7]1[C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: CCOC(=O)C1CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (1 g, 6.31 mmol), ethyl 4-pyridinecarboxylate (1.19 g, 7.57 mmol) and potassium carbonate (1.31 g, 9.47 mmol) in n-butanol (25 mL) was stirred at reflux for 2 hours, cooled to r.t., poured into water and extracted with diethyl ether. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 2:8) affording the title product (1.38 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N+:14]([O-])=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]3[C@@H:25]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)[O:26][C:27]4([CH2:31][CH2:30][CH2:29][CH2:28]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:42]([O:45]C(=O)C)(=[O:44])[CH3:43]>>[C:42]([O:45][C@@H:16]1[C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]3[C@@H:25]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)[O:26][C:27]4([CH2:31][CH2:30][CH2:29][CH2:28]4)[C:11]=3[C:10]=2[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:18][C:17]1([CH3:20])[CH3:19])(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1c2c(c3c([n+]1[O-])CC(C)(C)C[C@@H]3O[Si](C)(C)C(C)(C)C)C1(CCCC1)O[C@@H]2c1ccc(C(F)(F)F)cc1
Product: CC(=O)O[C@@H]1c2nc(C(C)C)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)CC1(C)C)C1(CCCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Temperature: 130 °C

Procedure:
250 mg (3′R,9′S)-9′-(tert-butyldimethylsilyloxy)-4′-isopropyl-7′,7′-dimethyl-3′-(4-(trifluoromethyl)phenyl)-6′,7′,8′,9′-tetrahydro-3′H-spiro[cyclopentane-1,1′-furo[3,4-c]quinoline]5′-oxide and 3 ml acetic acid anhydride are mixed and heated for 2 hours at 130° C. Excess acetic acid anhydride is removed in vacuo and the residue is diluted with diethylether. After washing with saturated aqueous sodium bicarbonate the organic phase is dried with sodium sulphate. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel (hexane/ethylacetate 95:5).