Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCN2CCCCC2)ccc1Cl

Procedure:
Prepared according to the method described in Example 69 from 2-chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.1 g), piperidine (1 ml),triethylamine (0.5 ml) and tetrahydrofuran (3 ml). Purification by silica gel chromatography eluting with 5% methanol and 1% triethylamine in dichloromethane gave 2-chloro-5-(2-(piperidin-1-yl)ethylamino)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide as a glass. Conversion to the hydrochloride salt upon treatment with excess ethereal hydrochloric acid (2M) gave the title compound as a yellow solid (0.062 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[CH2:7]([C:8]1[O:9][CH:15]=[C:13]([CH2:12][Cl:11])[N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Cc1ccccc1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(Cc2ccccc2)n1
Yield: 33 %

Procedure:
In substantially the same manner as in Reference Example 31, phenylacetamide was allowed to react with 1,3-dichloroacetone to give 2-benzyl-4-chloromethyl oxazole. The yield was 33%. Recrystallization from hexane gave colorless prisms, mp 31-32° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=1.Cl.[CH2:13](O)[CH3:14]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([O:11][CH2:13][CH3:14])=[O:10])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C=Cc1cccnc1

Procedure:
To a stirred suspension of 150 g of β-(3-pyridyl)acrylic acid in 1500 ml of ethanol a slow stream of hydrogen chloride gas is bubbled for 4 to 5 hr, where all solids dissolved. Approximately 500 ml of ethanol are distilled off at atmospheric pressure, the residual solution is cooled and diluted with 1500 ml of ether with stirring. The solids are filtered, washed with ether and resuspended in ethyl acetate. The stirred suspension is neutralized with conc. aq. sodium bicarbonate. The ethyl acetate layer is separated and the aqueous layer is extracted once more with ethyl acetate. The combined organic extracts are washed with brine, dried (MgSO4), evaporated and the residual oil is distilled to give 110 g of ethyl β-(3-pyridyl)acrylate with bp 95°-100° C., 0.1 mm/Hg.
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:18])[C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:20][C:21]1([CH3:28])[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[NH:22]1>O1CCOCC1>[OH:1][CH:2]([CH2:19][N:22]1[C:23]([CH3:27])([CH3:26])[CH2:24][CH2:25][C:21]1([CH3:28])[CH3:20])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:18])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC1(C)CCC(C)(C)N1
Reactant: O=C1c2ccccc2-c2c(OCC3CO3)cccc21
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)N1CC(O)COc1cccc2c1-c1ccccc1C2=O

Procedure:
4 g of 4-(2,3-epoxypropoxy)-9-fluorenone are heated to 150° in an autoclave for 15 hours together with 4 g of 2,2,5,5-tetramethylpyrrolidine in 30 cc of dioxane. After cooling, the reaction mixture is concentrated by evaporation. The residue is taken up in ether and extracted with 2 N hydrochloric acid. The aqueous solution is made alkaline and thoroughly extracted with methylene chloride. The methylene chloride phase is concentrated by evaporation and the residue is crystallized from ethyl acetate/petroleum ether. The title compound has an M.P. of 137°-139°.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:14][OH:15])[CH3:13].C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35].Cl>O1CCCC1>[C:34]([O:15][N:14]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=1[Cl:26])[CH3:13])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)ON=C(C)COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 42.6 %

Procedure:
First, 0.45 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime, 0.12 g of triethylamine, and 10 ml of tetrahydrofuran were placed in a reaction vessel, to which 0.12 g of acetic anhydride was slowly added dropwise with stirring at room temperature. After completion of the addition, the reaction mixture was further stirred at room temperature for 30 minutes, poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with saturated aqueous sodium hydrogencarbonate solution and water in this order, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.21 g (yield, 43%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-acetyloxime, nD25.6 1.5318.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][CH:30]([F:40])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH:30]([F:29])[F:40])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1OC(F)F
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)Oc1ccccc1COc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and (2-difluoromethoxy-phenyl)-methanol. MS (ESI) m/z 535.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1>>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Oc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5cccc(F)c5)nc34)cc21
Temperature: 85 °C
Yield: 17.9 %

Procedure:
Prepared according to Example 103, using NaH as a 60% dispersion in mineral oil (47.0 mg, 1.176 mmol, Sigma Aldrich), 3-fluorophenol (108 μl, 1.176 mmol, Sigma Aldrich), and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50 mg, 0.168 mmol) and heating to 85° C. for 17 h. Purification by reverse-phase HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 90%) to provide 2-(2-(3-fluorophenoxy)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (11.2 mg, 11%) as the free base following filtration through a Si-carbonate cartridge (Silicyle) with MeOH. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.10 (1H, m) 7.10 (1H, d, J=1.00 Hz) 6.80-6.87 (1H, m) 6.82 (1H, d, J=1.00 Hz) 6.44-6.49 (1H, m) 6.31-6.38 (1H, m) 6.16-6.24 (1H, m) 6.01-6.07 (1H, m) 5.87-5.99 (2H, m) 5.73 (1H, s) 2.23 (2H, t, J=1.00 Hz) 1.26 (2H, t, J=1.00 Hz). m/z (ESI, +ve) 374.1 (M+H)+.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][CH2:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][C:20]=2[F:31])=[O:18])[C@@H:11]([C:32]([O:34][CH3:35])=[O:33])[CH2:10]1)=O)(C)(C)C.[OH-].[Na+]>C(OCC)(=O)C.CO>[F:31][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:19]=1[C:17](=[O:18])[CH2:16][CH2:15][C@@H:12]1[CH2:13][CH2:14][NH:9][CH2:10][C@@H:11]1[C:32]([O:34][CH3:35])=[O:33])=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
9 cm3 of a 4N solution of hydrochloric acid in ethyl acetate and 10 cm3 of MeOH are added, at a temperature in the region of 20° C., to 4 g (7.23 mmol) of methyl (3R,4R)-1-tert-butyloxycarbonyl-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-oxopropyl]piperidine-3-carboxylate in solution in 20 cm3 of ethyl acetate. After stirring for 4 hours at a temperature in the region of 20° C., the reaction mixture is diluted with 25 cm3 of ethyl acetate and a 5N aqueous sodium hydroxide solution is then added in order to adjust the pH of the aqueous phase to a value of between 8 and 8.5. The organic phase is separated after settling out and the aqueous phase is then extracted with 3 times 40 cm3 of ethyl acetate. The organic phases are pooled, washed with 2 times 50 cm3 of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa) to give 2.33 g of methyl (3R,4R)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-oxopropyl]-piperidine-3-carboxylate in the form of an orange oil.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[CH:28][C:29]#[N:30])[CH:22]=1>>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]2[CH:10]=[C:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH:28]=[C:29]([NH2:30])[N:12]2[N:13]=1
Reactant: N#CC=Cc1cccnc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Product: Nc1cc(-c2cccnc2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, MS m/e (%): 277 (M+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(3-pyridinyl)-2-propenenitrile.
Reaction SMILES: C1N2CCN(CC2)C1.[Cl:9][C:10]1[C:11](Cl)=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([O:17]C)=[O:16].[Cl:21][C:22]1[CH:23]=[C:24]([OH:46])[CH:25]=[CH:26][C:27]=1[CH:28]([CH3:45])[C:29]([OH:44])([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[N:40]=[CH:39][CH:38]=[N:37]2)[C:30]([F:33])([F:32])[F:31].[Li+].[OH-]>CN(C=O)C.C(N(CC)CC)C>[Cl:9][C:10]1[C:11]([O:46][C:24]2[CH:25]=[CH:26][C:27]([CH:28]([CH3:45])[C:29]([OH:44])([C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[N:40]=[CH:39][CH:38]=[N:37]4)[C:30]([F:31])([F:32])[F:33])=[C:22]([Cl:21])[CH:23]=2)=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2nccnc2c1)C(F)(F)F
Agent: C1CN2CCN1CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(c1ccc(Oc2ncc(C(=O)O)cc2Cl)cc1Cl)C(O)(c1ccc2nccnc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DABCO (2 mg) was added to a mixture of methyl 5,6-dichloronicotinate (27 mg, CAS. Reg. No. 56055-54-0), 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinoxalin-6-yl-propyl)-phenol (50 mg), and triethylamine (17 mg) in DMF (5 ml). The mixture was stirred at room temperature overnight. Aqueous LiOH solution (1N, 1 ml) was added and then stirred for 2 hours to hydrolyze the intermediate ester. The mixture was purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (10 mg) as a white foam. MS (m/e)=536.1 [M+H+].
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:2].C1COCC1>C(O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccccc2[N+](=O)[O-])c(OC)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccccc2N)c(OC)c1

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene by 4-ethyl-2-methoxy-1-(2-nitrophenoxy)benzene (0.66 mmol; 180 mg) and THF by ethanol, the title compound was prepared in quantitative yield (181 mg) and used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH2:15][C:16]([NH:18][C:19]1([C:27]([O:29]C)=O)[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]1)=[O:17].CN(C)C(=O)C.CC(C)([O-])C.[K+].[ClH:43]>O>[Cl:43][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:15]1[C:16](=[O:17])[NH:18][C:19]2([CH2:20][CH2:21][C:22]([F:25])([F:26])[CH2:23][CH2:24]2)[C:27]=1[OH:29]
Reactant: Cl
Reactant: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)cc3)ccc2Cl)CCC(F)(F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1NC2(CCC(F)(F)CC2)C(O)=C1c1cc(-c2ccc(Cl)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.20 g (5.74 mmol) of the compound from Example 8A were initially charged in a solution of 14 ml of DMA (N,N-dimethylacetamide), a solution of 9 ml of DMA and 1.69 g (2.5 eq.) of potassium tert-butoxide was added dropwise at 20° C. and the mixture was stirred at room temperature for 4 h. The mixture was poured into 200 ml of water and the reaction was adjusted to pH 2 using concentrated aqueous hydrochloric acid, and the resulting residue was filtered off with suction. Purification by flash column chromatography (silica gel; ethyl acetate/n-hexane 1:1) gave 1.50 g (52% of theory) of the title compound of melting point m.p. 156° C.
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[CH2:29]=[C:30]1[CH2:34][C:33](=[O:35])[O:32][C:31]1=[O:36].Cl>C1COCC1>[C:16]([C@@H:15]([NH:19][C:33](=[O:35])[CH2:34][C:30](=[CH2:29])[C:31]([OH:36])=[O:32])[CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])([OH:18])=[O:17]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: C=C1CC(=O)OC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(CC(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
S-trans, trans-Farnesyl-L-cysteine (500 mg, 1.54 mmol) was dissolved in mixture of THF and a first portion of K2CO3 (3 mmol) and the resulting solution was cooled to 5° C. with vigorous stirring. To this stirred solution was added 3-methylenedihydro-2,5-furandione (302 mg, 3.07 mmol) portionwise while maintaining the pH at 9.0-10.0 with another portion of K2CO3 (3 mmol). The mixture was stirred at room temperature for 3 h. HPLC analysis showed completion of the reaction. The pH of the reaction mixture then adjusted to 2.0 by the addition of 2 N HCl solution. The acidic solution was extracted three times with 15 mL of ethyl acetate. The combined organic extract was washed with water, brine and dried over Na2SO4, the solvent was removed under reduced pressure to afford crude Compound F, which was further purified by preparative HPLC (552 mg, 82%) to yield Compound F. 1H-NMR (500 MHz, CDCl3): δ 1.59 (s, 6H), 1.67 (s, 3H), 1.68 (s, 3H), 2.05 (m, 8H), 2.88 (dd, J=6.5, 14.0, 1H), 2.95 (dd, J=6.5, 14.0, 1H), 3.17-3.15 (m, 2H), 3.36 (d, J=14 Hz, 1H), 4.77 (dd, J=6, 12.5 Hz, 1H), 5.09 (bt, 2H), 5.22 (t, J=7.5 Hz, 1H), 5.93 (s, 1H), 6.46 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.0, 16.2, 17.7, 25.7, 26.7, 29.9, 32.8, 39.6, 39.7, 40.2, 52.0, 119.4, 123.7, 131.3, 132.0, 135.4, 140.3, 170.3, 171.5, 176.0; ES-MS: mass calcd for Chemical Formula: C23H35NO5S 437.6. Found (M+Na) m/z 446.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br:15]Br>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:14])[CH2:13][Br:15])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(C)=O)cc1
Reactant: BrBr
Product: CCCCOc1ccc(C(=O)CBr)cc1
Temperature: 25 °C

Procedure:
reacting p-n butoxyacetophenone in solution with bromine stirred in slowly at room temperature to form p-n-butoxyphenacyl bromide;
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].CO[C:12](=[O:28])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:15][CH:14]=1>>[CH3:27][CH:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:1][CH:2]([CH3:4])[CH3:3])=[O:28])=[CH:18][CH:17]=1)[CH2:21][CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26]
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1
Reactant: CC(C)CNCC(C)C
Product: CC(C)CCCC(C)Oc1ccc(C(=O)N(CC(C)C)CC(C)C)cc1

Procedure:
By the procedure given in Example 47, diisobutylamine is reacted with p-[(1,5-dimethyl-hexyl)-oxy]-benzoic acid methyl ester to produce p-[(1,5-dimethyl-hexyl)-oxy]-N,N-diisobutylbenzamide (nD24 = 1.4968).
Reaction SMILES: [SH:1][C@H:2]1[CH2:6][N:5]([S:7]([CH3:10])(=[O:9])=[O:8])[C@H:4]([CH2:11][OH:12])[CH2:3]1.N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl>[OH:12][CH2:11][C@H:4]1[N:5]([S:7]([CH3:10])(=[O:9])=[O:8])[CH2:6][C@H:2]([S:1][C:19](=[O:21])[CH3:20])[CH2:3]1
Reactant: CS(=O)(=O)N1C[C@H](S)C[C@H]1CO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)S[C@@H]1C[C@@H](CO)N(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.8 %

Procedure:
To a solution of (2S,4R)-(4-mercapto-1-methanesulfonyl-pyrrolidin-2-yl)-methanol (0.28 g) in dichloromethane (10 ml) were added pyridine (0.131 g) and acetic anhydride (0.160 g). The reaction mixture was stirred for 4 h at room temperature, treated with ice/water and extracted with EtOAc. The organic phase was washed with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:2 as eluent to obtain thioacetic acid (3R,5S)-S-(5-hydroxymethyl-1-methanesulfonyl-pyrrolidin-3-yl) ester (0.080 g) as a viscous oil.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[N+:17]([O-:18])=[C:16]3[CH2:19][CH2:20][CH2:21][CH2:22][C:15]3=[N:14]2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:25](I)[CH3:26].O>CN(C)C=O>[F:1][C:2]1[C:12]([N:13]2[N+:17]([O-:18])=[C:16]3[CH2:19][CH2:20][CH2:21][CH2:22][C:15]3=[N:14]2)=[CH:11][C:5]2[N:6]([CH2:25][CH3:26])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc2N1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)COc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc21
Temperature: 40 °C

Procedure:
To a solution of 2-(7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl)-4,5,6,7-tetrahydro-1,2,3-benzotriazole-1-oxide (0.5 g) in dimethylformamide (5 ml), sodium hydride (0.1 g) and then ethyl iodide (0.3 g) were added, followed by heating at 40° C. for 2 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration, dried and recrystallized from a mixture of acetonitrile and isopropanol (1:10) to give Compound No. 2 (0.4 g). m.p., 143°-144° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])([CH3:13])([CH3:12])[CH3:11]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[N:17]\[S:14]([C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:16])=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)S(N)(=O)=O
Reactant: O=Cc1cccc(Br)c1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)(=O)/N=C\c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-bromo-benzaldehyde (1.27 mL, 10.8 mmol) in THF (50 mL) were added titanium(IV) ethoxide (0.786 mL, 21.6 mmol) and tert-butylsulfonamide (1.31 g, 10.8 mmol), and stirring was continued for 16 h at 65° C. After cooling to RT, volatiles were evaporated, and the residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 3:1) to afford the title compound. MS (LC/MS): 289 [M+H]+; tR (HPLC conditions f): 2.35 min.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@H:9]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH2:8][S:7][CH2:6]1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[C:13]1([C@H:11]([NH:10][C@@H:9]2[CH2:8][S:7][CH2:6][C@H:5]2[C:3]([OH:4])=[O:2])[CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H]1CSC[C@H]1N[C@H](C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](N[C@@H]1CSC[C@H]1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of Preparation of (3R,4S)-4-[(R)-1-phenyl-ethylamino]-tetrahydrothiophene-3-carboxylic acid methyl ester (673 mg, 2.54 mmol) in tetrahydrofuran (5 mL) was treated with 1.0 M sodium hydroxide solution (5.0 mL, 5.0 mmol) and the heterogeneous mixture was stirred at room temperature. After 75 min, the now homogeneous solution was treated with 1.0 M hydrochloric acid (5.0 mL, 5.0 mmol) and concentrated in vacuo. The residue was dissolved in water and lyophilized to provide the product, along with sodium chloride, as a fluffy white solid (928 mg, quantitative), used without further purification. 1H NMR (300 mHz, DMSO-d6) δ7.4-7.2 (m, 5H), 3.87 (q, J=6.6 Hz, 1H), 3.27 (dd, J=13.6, 7.0 Hz, 1H), 3.0-2.8 (m, 3H), 2.5 (m, 2H), 1.26 (d, J=6.6, 3H), ESI MS: (M+H)+252.0.