Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]>>[F:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40]([NH2:7])=[O:41])=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(F)c(F)c3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)c(F)c3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 221-223° C.; 1H NMR (300 MHz, DMSO-d5) δ 7.47-7.37 (m, 4H), 7.20-7.15 (m, 1H), 4.43 (s, 2H), 4.03-3.98 (m, 2H), 3.50-3.45 (m, 2H), 2.46 (s, 3H); MS (ES+) m/z 352.7 (M+1).
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(OO)(=[O:21])C.O>C(Cl)Cl>[CH2:1]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]2[CH:15]([O:21]2)[CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)OO
Reactant: CCCCCCCCCCOCC1C=CCCC1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCOCC1CCC2OC2C1

Procedure:
A 500 mL round bottom flask equipped with a stirring bar was charged with 16.4g (0.065 mol) 3-decyloxymethylcyclohexene, and 100 mL of methylene chloride. Peracetic acid (15.5 g, 35 wt. % in acetic acid; 0.065 mol) in methylene chloride (80 mL) was added dropwise to above mixture over 30 min. in an ice bath. After the above mixture was reacted at room temperature overnight, 250 mL of water was added to above reaction mixture, the water layer was extracted with methylene chloride (2×150 mL), the organic layer was combined, and washed with saturated sodium carbonate solution (2×150 mL), then with water (2×150 mL) and dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH2:17]1[O:21][C:20]2[CH:22]=[C:23]([Cl:28])[C:24]([CH:26]=O)=[CH:25][C:19]=2[O:18]1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:26]([C:24]2[CH:25]=[C:19]3[O:18][CH2:17][O:21][C:20]3=[CH:22][C:23]=2[Cl:28])[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1cc2c(cc1Cl)OCO2
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Product: CC(C)N1C(=O)NC(c2cc3c(cc2Cl)OCO3)c2cc3c(cc21)OCO3
Yield: 65 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (410 mg) and 6-chloropiperonal (350 mg) by the procedure described in example 10 in 65% yield. 1H NMR (CDCl3): 6.86 (s, 1H), 6.77 (s, 1H), 6.48 (s, 1H), 6.40 (s, 1H), 5.95 (s, 4H), 5.66 (d, J=2.5, 1H), 5.21 (s, 1H), 4.48 (m, 1H), 1.53 (d, J=6.5, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:29])=[C:18]([NH:22]C(=O)OCC=C)[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.CC(O)=O.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.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>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:29])=[C:18]([CH:19]=[CH:20][CH:21]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a solution of 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (15 g, 34.7 mmol) in DCM (500 mL), HOAc (5 g, 83.3 mmol), Pd(PPh3)2Cl2 (0.5 g, 0.69 mmol) were added. Then tri-n-butyl tin hydride (15 g, 52 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by adding saturated NaHCO3 (200 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (1 L×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (200 mL) to afford the title compound. (10.5 g, 87.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.58 (d, J=5.2 Hz, 1H), 7.01-6.96 (m, 2H), 6.89-6.85 (m, 1H), 6.63-6.59 (m, 1H), 5.29 (br. s., 2H), 3.38-3.30 (m, 1H), 1.37 (d, J=6.8 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-(1,2,3]triazol-1-yl-ethyl)amide as a yellow solid (74.1 mg, 65%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:42])[CH2:6][C:7]1[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:40][CH3:41])([C:25]3[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([CH2:37][CH3:38])([OH:36])[CH2:34][CH3:35])=[C:27]([CH3:39])[CH:26]=3)[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:10]([OH:15])=[C:11]([O:13][CH3:14])[CH:12]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:23]([C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:9]2[C:10]([OH:15])=[C:11]([O:13][CH3:14])[CH:12]=[C:7]([CH2:6][C:5]([OH:42])=[O:4])[CH:8]=2)=[CH:21][CH:20]=1)([C:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([CH2:34][CH3:35])([OH:36])[CH2:37][CH3:38])=[C:27]([CH3:39])[CH:26]=1)[CH2:40][CH3:41])[CH3:24]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(CC(=O)OC)cc(OC)c3O)cc2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(CC(=O)O)cc(OC)c3O)cc2)cc1C)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.203 mL, 0.203 mmol) was added to a solution of (4′-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-6-hydroxy-5-methoxy-biphenyl-3-yl)-acetic acid methyl ester (Example 178-(3); 22.1 mg, 0.041 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (1.3 mg, 6%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:22])[CH:3]=1.[H-].[Na+].CO.[CH3:27][N:28](C)[CH2:29]CN>>[CH3:22][C:4]1[CH:3]=[C:2]([N:28]([CH3:29])[CH3:27])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:5]=1
Reactant: CN(C)CCN
Reactant: Cc1cc(Cl)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(N(C)C)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 120 °C

Procedure:
A mixture of 800 mg (2.5 mmol) of compound 13 and 101 mg of 60% NaH (2.5 mmol) in 5 ml N,N-dimethyl ethylendiamine was heated in a sealed tube at 120° C. for six hours. To the cooled reaction mixture was carefully added methanol to quench NaH. The resulting mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 10% MeOH/CH2Cl2 with 1% NH40H) to get 100 mg of compound 14.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH:8]([OH:24])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][C:17]2([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=1)=O>CO.O>[NH2:5][CH2:6][CH2:7][CH:8]([C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]2([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:12]=[CH:13][CH:14]=1)[OH:24]
Reactant: O=C(NCCC(O)c1cccc(C#CC2(O)CCCCC2)c1)C(F)(F)F
Solvent: O
Solvent: CO
Product: NCCC(O)c1cccc(C#CC2(O)CCCCC2)c1
Reaction time: 8 h

Procedure:
Deprotection of 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamide was conducted following the method used in Example 18, except that the solvent was 90% MeOH-water and the reaction was stirred overnight. The reaction mixture was concentrated under reduced pressure and partitioned into EtOAc and water. The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The crude material was crystallized from hot EtOAc. After cooling, the product was collected by filtration, washed with EtOAc and hexanes, and dried. Example 99 was isolated as a white solid. Yield (0.210 g, 47%): 1H NMR (400 MHz, DMSO-d6) δ 7.23-7.26 (m, 4H), 5.45 (br s, 1H), 4.68 (t, J=8.4 Hz, 1H), 2.62 (br s, 2H), 1.83-1.88 (m, 2H), 1.48-1.67 (m, 9H), 1.15-1.34 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:18])[C:11]([CH2:16][OH:17])=[CH:12][O:13]2)=[CH:8][CH:7]=1.Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1>CN(C)C=O>[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:15]=[C:14]5[C:9]([C:10](=[O:18])[C:11]([CH2:16][OH:17])=[CH:12][O:13]5)=[CH:8][CH:7]=4)[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: O=c1c(CO)coc2cc(OCCCCl)ccc12
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Solvent: CN(C)C=O
Product: O=c1c(CO)coc2cc(OCCCN3CCC(c4noc5cc(F)ccc45)CC3)ccc12
Yield: 37.4 %

Procedure:
By the procedure described above, starting from 2.0 g (7.5 mmoles) of 7-(3-chloropropoxy)-3-(hydroxymethyl)chromen-4-one and 1.93 g (7.5 mmoles) of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, a solid was obtained by crystallization of the crude product from dimethylformamide to yield 1.27 g of 7-[3-[4-(6-fluoro-1,2-benzisoxazole-3-yl)piperidin-1-yl]propoxy]-3-(hydroxymethyl)-chromen-4-one, mp 200°-202° C.
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-:12])=[O:11])([CH3:9])[CH2:3][CH2:4][C:5](OC)=[O:6].[BH4-].[Na+].O.Cl>C(O)C>[CH3:1][C:2]([N+:10]([O-:12])=[O:11])([CH3:9])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: COC(=O)CCC(C)(C)[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCO)[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Methyl 4-methyl-4-nitropentanoate (17.5 g, 0.1 mol) was dissolved in ethanol (200 ml) and cooled to 5° C., after which sodium borohydride (7.55 g, 0.2 mol) was added. The mixture was stirred at room temperature for 1 h, and at 50° C. for 3 h. Water (100 ml) and hydrochloric acid were added to adjust the pH to 3, and ethanol was evaporated by concentration under reduced pressure. The residue was extracted with ethyl acetate (250 ml) and water (100 ml) and washed with saturated brine. Ethyl acetate was evaporated by concentration under reduced pressure to give the objective compound (14.7 g, yield 91.2%).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O1C2C=CC(O)=CC=2OC1.[CH3:51][C:52]1([CH3:62])[C:56]2[CH:57]=[CH:58][C:59]([OH:61])=[CH:60][C:55]=2[O:54][CH2:53]1>>[C:35]1([CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([OH:33])([C:58]3[C:59]([OH:61])=[CH:60][C:55]4[O:54][CH2:53][C:52]([CH3:62])([CH3:51])[C:56]=4[CH:57]=3)[C:25]2=[O:34])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: CC1(C)COc2cc(O)ccc21
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CC1(C)COc2cc(O)c(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-(diphenylmethyl)-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 3,3-dimethyl-2,3-dihydro-1-benzofuran-6-ol, the title compound was obtained: MS (ES+) m/z 478.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[S:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:46][C:44]2[S:45][C:41]3[C:40]([CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][O:48]4)=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[C:42]=3[N:43]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1ccc(C2CCCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc(C2CCCCO2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-fluorobenzoic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-2-yl)-benzothiazol-2-ylamine in dioxane and DMF. ES-MS m/e (%): 387 (M+H+, 100).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:17]=[CH:16][C:15]([C:18](=[O:24])[NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=O)=O.S(Cl)(Cl)=O>C(OCC)(=O)C>[CH3:22][CH:21]([CH3:23])[CH2:20][NH:19][C:18]([C:15]1[CH:16]=[CH:17][C:7]([C:7]2[C:8]([C:9]([OH:11])=[O:10])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:14]=1)=[O:24]
Reactant: CCOC(=O)c1cc(C(=O)NCC(C)C)ccc1OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)NCC(C)C)ccc1-c1ccccc1C(=O)O
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
4′-((2-methylpropyl)carbamoyl)-2′-ethoxycarbonyl-2-biphenyl carboxylic acid (1.0 g) which was prepared by the same procedure as a series of reaction of Reference Example 4→Reference Example 5, using ethyl 2-trifluoromethylsulfonyloxy-5-((2-methylpropyl)carbamoyl)benzoate, was dissolved into ethyl acetate (20 ml). Thionyl chloride (0.22 ml) was dropped into the above solution. The mixture was stirred for 15 minutes at 50° C. The reaction mixture was cooled to room temperature, and concentrated. A solution of the prepared acyl chloride compound in methylene chloride (10 ml) and triethylamine (0.57 ml) were added to a solution of 4-(N2-t-butoxycarbonyloxyamidino)aniline in methylene chloride (10 ml) at 0° C. The mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate (150 ml), and washed with a saturated aqueous solution of sodium chloride (75 ml, 2 times). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=100:1) to give the present compound (1.56 g) having the following physical data.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([C@@H:13]2[CH2:15][C@@:14]2([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH:28]3[CH2:30][CH2:29]3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:16]([OH:18])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[N:45]1([CH2:50][CH2:51][S:52][C:53]2[S:57][C:56]([NH2:58])=[N:55][CH:54]=2)[CH2:49][CH2:48][CH2:47][CH2:46]1>ClCCl.CN(C)C=O.O>[N:45]1([CH2:50][CH2:51][S:52][C:53]2[S:57][C:56]([NH:58][C:16]([C@:14]3([C:19]4[CH:20]=[CH:21][C:22]([S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[CH:23][CH:24]=4)[CH2:15][C@H:13]3[CH:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:18])=[N:55][CH:54]=2)[CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: O=C(O)[C@]1(c2ccc(S(=O)(=O)C3CC3)cc2)C[C@H]1C1CCCCC1
Reactant: Nc1ncc(SCCN2CCCC2)s1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ncc(SCCN2CCCC2)s1)[C@]1(c2ccc(S(=O)(=O)C3CC3)cc2)C[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Oxalyl chloride (146.89 mL, 1.69 mol) is added over 15 min to a stirred solution of (1R,2S)-2-cyclohexyl-1-(4-cyclopropanesulfonyl-phenyl)-cyclopropanecarboxylic acid (295.00 g, 0.847 mol) in 10 L of anhydrous dichloromethane under an inert atmosphere. Dimethylformamide (654.61 μL, 8.5 mmol) is then added at once, and the resulting solution is stirred overnight. Volatiles are then removed under vacuum at 40° C. to afford an oil, which is dissolved in 3 L of anhydrous dichloromethane. An inert atmosphere is reestablished, and the solution is cooled to <5° C. Triethylamine (177 mL 1.27 mol) is then added dropwise over 20 minutes, leaving a dark solution. Sodium Sulfate (120.25 g, 0.847 mol) is added, followed by 5-(2-pyrrolidin-1-yl-ethylsulfanyl)-thiazol-2-ylamine (213.60 g 0.931 mole). The internal temperature rises to 20° C. The reaction mixture is stirred for 10 min in the cold, and is then allowed to warm to room temperature. After being stirred overnight, the reaction mixture is poured onto 3 L of water. The resulting mixture is stirred for a few minutes, and then the two layers are separated. The aqueous layer is extracted with 1 L dichloromethane, and the dichloromethane solutions are combined, dried over MgSO4, filtered, and concentrated under vacuum at 40° C. The resulting oil (556 g) is applied to silica gel plugs as a dichloromethane solution. Elution of the plugs with 1:12:7 2M ammonia in methanol/methyl t-butyl ether/heptane, followed by 1:19 2M ammonia (in methanol)/ethyl acetate affords a brown foam (351 g). Crystallization of 320 g of this material from methyl t-butyl ether and heptane, affords the title compound (279.4 g) as an off-white solid after drying for 2 days at 45° C. LCMS (m/e): 560 (M+H); [α]D20=−44°.
Reaction SMILES: [CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][OH:7].[CH2:9]=[C:10]([CH3:12])[CH3:11].S(=O)(=O)(O)O.[OH-].[Na+]>ClCCl>[CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][O:7][C:10]([CH3:12])([CH3:11])[CH3:9]
Reactant: CSC(=S)NCCO
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CSC(=S)NCCOC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In a sealed glass tube is placed a solution of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester (4.3 g), isobutene (30 ml) and concentrated sulfuric acid (0.1 ml) in dichloromethane (20 ml) prepared at -50° C. to -60° C. The mixture is warmed slowly to room temperature and then left to stand for 17 hours. The reaction mixture is poured into aqueous 0.5% sodium hydroxide and extracted with dichloromethane. The extract is washed with water, dried and concentrated to give N-(2-t-butoxyethyl)dithiocarbamic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH3:12][C:13]1[N:14]=[N:15][CH:16]=[CH:17][CH:18]=1.N1C=CC=NC=1.N1C=CN=CC=1.N1C=CC=CN=1.C(OC(=O)C)(=O)C>C(O)=O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[CH:12][C:13]1[N:14]=[N:15][CH:16]=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: Cc1cccnn1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: c1cnccn1
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=[N+]([O-])c1ccccc1C=Cc1cccnn1

Procedure:
Reaction of a nitrobenzaldehyde (III) with a methyldiazine [pyrimidine (IVA), pyrazine (IVB) or pyridazine (IVC)]in a suitable solvent such as acetic anhydride, formic acid or the like to produce a corresponding [2-(nitrophenyl)ethenyl]diazine (VA, VB or VC) pursuant to the following reaction scheme: ##STR7##
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[CH3:18][O:19][C:20](=[O:36])[CH2:21][O:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][N:27]1[C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C@@H:28]1[CH2:34][OH:35].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][O:19][C:20](=[O:36])[CH2:21][O:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][N:27]1[C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C@@H:28]1[CH:34]=[O:35]
Reactant: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
Trifluoroacetic anhydride (0.24 mL, 1.70 mmol) was added to a solution of DMSO (0.14 mL, 1.97 mmol) in CH2Cl2 (2 mL) at −78° C. After 15 min at −78° C., a solution of [(Z)-4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)but-2-enyloxy]-acetic acid methyl ester (from example 1, step 3, 220 mg, 0.81 mmol) in CH2Cl2 (1.5 mL) was added via cannula. After 20 min at −78° C., triethylamine (0.33 mL, 2.37 mmol) was added and the reaction mixture was allowed to warm to rt. After 1 h at rt, the reaction was quenched with saturated aqueous NH4Cl (15 mL) and the mixture was extracted with CH2Cl2 (3×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10%→50% EtOAc/CH2Cl2, gradient) afforded 150 mg (69%) of [(Z)-4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:56])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:55])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:54])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:53])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:52])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:51])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:50])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:49])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:48])=[CH:35]/[CH2:36][CH2:37]/[C:38](/[CH3:47])=[CH:39]/[CH2:40][CH2:41]/[C:42](/[CH3:46])=[CH:43]/[CH2:44][OH:45].[C:57]([O-])(=[O:59])[CH3:58].[Na+]>C(OC(=O)C)(=O)C.O>[C:57]([O:45][CH2:44][CH:43]=[C:42]([CH3:46])[CH2:41][CH2:40][CH:39]=[C:38]([CH3:47])[CH2:37][CH2:36][CH:35]=[C:34]([CH3:48])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:49])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:50])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:51])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:52])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:53])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:54])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:55])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:56])[CH3:1])(=[O:59])[CH3:58]
Reactant: CC(=O)[O-]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3.5 Grams of undecaprenol were dissolved in 15 ml of acetic acid anhydride and the solution was added with 2.0 g of anydrous sodium acetate at room temperature. The mixture was stirred at 100° C. for one hour to complete the reaction. Upon cooling, the reaction product was poured in water to hydrolyze excessive acetic acid anhydride. After extraction with n-hexane, the extract was washed with water and concentrated. The concentrate was purified by chromatography with 50 g of silica gel in n-hexane/benzene solvent mixture as elution solvent to obtain the final product as a white solid (m.p. 36.0°-37.0° C.). Yield 3.5 g