Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][N:27]=2)=[CH:34][CH:35]=1
Reactant: COc1ccnc(Oc2ccc(I)cc2)n1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(Oc2nccc(OC)n2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 32.1 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (60 mg) was reacted with 2-(4-iodophenoxy)-4-methoxypyrimidine (78 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxypyrimidin-2-yloxy)phenyl]pent-4-enoic acid methyl ester (32 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1→cyclohexane/chloroform=1/1→1/10→0/1) was used for purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[N:12]1.[NH2:22][C:23]1[C:24]([O:41][CH3:42])=[C:25]([CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1)[CH2:26][N:27]([CH3:33])[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31]>>[C:37]([C:35]1[CH:34]=[C:25]([CH2:26][N:27]([CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[CH3:33])[C:24]([O:41][CH3:42])=[C:23]([NH:22][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:13]=[N:12]3)[CH:4]=2)[CH:36]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: COc1c(N)cc(C(C)(C)C)cc1CN(C)CCN(C)C
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2cccnc2)nn1
Product: COc1c(CN(C)CCN(C)C)cc(C(C)(C)C)cc1NC(=O)c1ccc(C)c(-n2cc(-c3cccnc3)nn2)c1

Procedure:
Example 10 was prepared by coupling 4-methyl-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid with N-(3-amino-5-tert-butyl-2-methoxy-benzyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (see U.S. provisional application 60/526,569) in the same manner as Example 1. ESI MS m/z 554 [C32H41N7O2−H]−.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]4=[O:31])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.Cl>C(Cl)Cl.CC(C)=O>[OH:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]4=[O:31])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2noc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)cc1C
Agent: BrB(Br)Br
Agent: Cl
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cc(-c2noc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)ccc1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[3-(6-methoxy-m-tolyl)-1,2-benzisoxazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (5.00 g, 0.0116 mol) in methylene chloride is cooled to -10° C., treated dropwise with 15.1 mL of 1 M boron tribromide in methylene chloride while maintaining the reaction mixture temperature at -15° C. to 0° C., warmed to room temperature, treated dropwise with 5 mL of the boron tribromide solution, stirred at room temperature for one hour, and poured into dilute hydrochloric acid. The resultant aqueous mixture is diluted with acetone, concentrated In vacuo, diluted with water, and filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven at 60° C. to give the title product as a yellow solid which is identified by mass spectral analysis.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[C:13]([NH2:18])(=[O:17])[CH:14]([CH3:16])[CH3:15]>>[C:13]([NH:18][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1)(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C(N)=O
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Product: COC(=O)c1cc(C)nc(NC(=O)C(C)C)n1
Yield: 88 %

Procedure:
The title compound is prepared in 88% yield (1.1 g, a yellow solid) from methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1.0 g, 5.4 mmol) and isobutyramide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13]Cl)[CH:10]([CH2:15]Cl)[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.C(Cl)(Cl)Cl.[O:28]1CCOCC1>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][O:28][CH2:15][CH:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccccc2)=NCC1CCl
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCC1COCCN21

Procedure:
A solution of 20 g 7-chloro-1-(β-chloroethyl)2-chloromethyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine in 100 ml dioxane and 250 ml of 6% sodium hydroxide solution is heated under reflux for a period of about 5.5 hours. After heating the solution, the substance is isolated from chloroform under vacuum and subsequently purified chromatographically using aluminum oxide (activity degree II) as absorbent and methylene chloride as eluant. 12.8 g 1,2,4,4a-tetrahydro-9-chloro-7-phenyl-5H[1,4]oxazino-[4,3-a][1,4]benzodiazepine as an oil is obtained. The maleanate having a melting point of 143° to 145° C. is crystallized from isopropanol/ether. The basic compound crystallized from hexane melts at 156°-158° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH3:10][C:11]1[CH:25]=[CH:24][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[OH:16])=[CH:24][CH:25]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(O)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
A Grignard reagent was prepared from magnesium (0.14 g, 5.76 mmol) (Wako Pure Chemical Industries, Ltd.) and p-bromotoluene (0.48 g, 5.45 mmol) (Wako Pure Chemical Industries, Ltd.). 4,4′-dimethylbenzophenone (0.60 g, 2.85 mmol) (Wako Pure Chemical Industries, Ltd.) was dissolved in tetrahydrofuran (5 mL) (KANTO CHEMICAL CO., INC.), and it was added dropwise to the Grignard reagent while cooling with ice, followed by stirring at room temperature for 4 hours. A saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the reaction solution while cooling with ice, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was washed with brine. After that, the organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane (Wako Pure Chemical Industries, Ltd.):ethyl acetate (Wako Pure Chemical Industries, Ltd.)=19:1 as an eluent), to thereby obtain the title compound (0.74 g, 86% yield).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH:14]=O>C(OCC)(=O)C>[F:10][C:11]1[CH:12]=[C:13]([CH:14]=[N:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NN=Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
To a solution of t-butyl carbazate (4.99 g, 37.76 mmol) in ethyl acetate (10 mL) was added with stirring 3,5-difluorobenzaldehyde (5.50 g, 38.7 mmol) followed by hexanes (50 mL). Crystallization occurred and the resulting slurry was stirred at rt for 15 min, then cooled to 0° C. and held at that temperature for 45 min. The solids were filtered, rinsed with cold hexanes and dried in vacuo at 60° C. to afford the title compound as a solid (9.04 g, 93.3%): mp 196.4-196.8° C. (dec); 1H NMR (DMSO-d6) δ 11.16 (br s, 1 H), 7.96 (s, 1 H), 7.28 (m, 2 H), 7.21 (t, 1 H, J=2.2 Hz), 1.45 (s, 9 H); 13C NMR (DMSO-d6) δ 163.3 (dd, J=246.1, 13.5 Hz), 152.9, 141.2, 139.2 (t, J=9.6 Hz), 109.9 (dd, J=20.2, 5.8 Hz), 105.1 (t, J=25.9 Hz), 80.5, 28.7; IR (KBr mull) 3263, 2987, 1709, 1584, 1536 cm−1. A portion was recrystallized (ethyl acetate) for analysis. Anal. Calcd. for C12H14F2N2O2: C, 56.25; H, 5.51; F, 14.83; N, 10.93. Found: C, 56.11; H, 5.49; N, 10.86.
Reaction SMILES: [N:1]1([C:7]([C:9]2[NH:13][N:12]=[C:11]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[S:20](=[O:23])(=[O:22])[CH2:21][C:10]=23)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(#N)C>[CH2:30]([N:12]1[C:11]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[S:20](=[O:22])(=[O:23])[CH2:21][C:10]=2[C:9]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])=[N:13]1)[CH3:31]
Reactant: CCI
Reactant: O=C(c1[nH]nc2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1nc(C(=O)N2CCOCC2)c2c1-c1ccccc1S(=O)(=O)C2
Temperature: 60 °C

Procedure:
To a solution of 3-(morpholin-4-ylcarbonyl)-2,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (0.400 g, 1.2 mmol) in acetonitrile (10 mL) is added potassium carbonate (0.49 g, 3.6 mmol) followed by ethyl iodide (0.56 g, 3.6 mmol). The reaction mixture is heated at 60° C. overnight. The crude reaction mixture is filtered through a celite pad and the filtrate concentrated under reduced pressure. The residue is purified by preparative HPLC to afford the title compound as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.02 (d, J=7.72 Hz, 1H), 7.94 (d, J=7.84 Hz, 1H), 7.89 (t, J=7.52 Hz, 1H), 7.72 (t, J=7.64 Hz, 1H), 4.79 (s, 2H), 4.57 (q, J=7.12 Hz, 2H), 3.94 (brs, 2H), 3.66-3.63 (m, 6H), 1.46 (t, J=7.16 Hz, 3H). MS (ESI+): 362.0. HPLC (max plot) 95.0%; Rt 2.99 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[N:16]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[N:10]=[C:11]([S:14][CH3:15])[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:24])=[O:5])[CH3:2].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:32])C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[N:16]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[N:10]=[C:11]([S:14]([CH3:15])=[O:32])[N:12]=[CH:13][C:8]=2[C:7]=1[CH3:24])=[O:5])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CCOC(=O)c1c(C)c2cnc(SC)nc2n(C2CCCC2)c1=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C)c2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
8-cyclopentyl-5-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (138 mg, 0.40 mmol) was dissolved in CH2Cl2 (6 mL) and 2-benzenesulfonyl-3-phenyl-oxaziridine (155 mg, 0.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then the solvent was removed under reduced pressure and the remaining residue was purified by prepative TLC (50% ethyl acetate/hexane). The more polar, product-containing, reaction was extracted into CH2Cl2 and the solvent evaporated to provide 8-cyclopentyl-2-methanesulfinyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a white solid (110 mg, 75.7%). M++1: Calc'd. 364.4. Found 364.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].Br[CH2:12][Si:13]1(C2C=CC=CC=2)[CH2:18][CH2:17][CH:16]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][Si@H:13]2[CH2:14][CH2:15][C@H:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(O)cc1
Reactant: C=CCCC[C@H]1CC[C@H](C2CC[Si](CBr)(c3ccccc3)CC2)CC1
Product: C=CCCC[C@H]1CC[C@H]([C@H]2CC[Si@H](COc3ccc(OCC)cc3)CC2)CC1

Procedure:
The general procedure of Example 39 was repeated using 4-ethoxyphenol and trans-4-(4-bromomethyl-4-phenyl-4-silacyclohexyl)-1-(4-pentenyl)cyclohexane, thereby obtaining the intended product.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]1[C:16]2[C:21]([C:22]([O:33][CH3:34])=[C:23]3[C:28]=1[CH:27]=[C:26]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[CH:24]3)=[CH:20][CH:19]=[CH:18][CH:17]=2.O1CCCC1>C(N(CC)CC)C>[CH3:13][O:14][C:15]1[C:16]2[C:21]([C:22]([O:33][CH3:34])=[C:23]3[C:28]=1[CH:27]=[C:26]([S:29]([O:1][N:2]1[C:3](=[O:12])[C:4]4=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]4[C:6]1=[O:7])(=[O:31])=[O:30])[CH:25]=[CH:24]3)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1c2ccccc2c(OC)c2cc(S(=O)(=O)Cl)ccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c2ccccc2c(OC)c2cc(S(=O)(=O)ON3C(=O)c4ccccc4C3=O)ccc12

Procedure:
A mixture of 0.98 g of N-hydroxyphthalimide, 2.02 g of 9,10-dimethoxyanthracene-2-sulfonyl chloride and 40 ml of tetrahydrofuran was stirred on an ice bath, and 0.34 g of triethylamine was added.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][OH:18])[CH2:11][CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:6][NH:7][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][OH:18])[CH2:11][CH2:10]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCO)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H]1CC[C@H](C#CCO)CC1
Reaction time: 0.25 h

Procedure:
A solution of 9.0 g (33.66 mmol) of trans-[4-(3-Hydroxy-prop-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 185 ml CH2Cl2 was treated at 0° C. with 136 ml of TFA (for 30 min). After 15 min at this temperature, the reaction was evaporated, treated with cold (0° C.) 1 N NaOH (saturated with NaCl) and extracted with CH2Cl2/MeOH 9:1 (3×). The organic phase was dried over Na2SO4 and evaporated to yield 5.84 g (quantitative) of trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol, MS: 167 (M).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH2:4][CH:5]([OH:8])[CH2:6][N:7]=1.S(Cl)(Cl)=O.[C:13](O)(=[O:15])[CH3:14]>>[CH3:1][C:2]1[NH:7][CH2:6][CH:5]([O:8][C:13](=[O:15])[CH3:14])[CH2:4][N:3]=1
Reactant: CC1=NCC(O)CN1
Reactant: CC(=O)O
Solvent: O=S(Cl)Cl
Product: CC(=O)OC1CN=C(C)NC1

Procedure:
2-Methyl-5-hydroxy-1,4,5,6-tetrahydropyrimidine (JOC 1966, 31, 3838; 1.5 g, 13.3 mmol) was dissolved in glacial acetic acid (100 ml) with stirring, and thionyl chloride (1 ml, 13.1 mmol) was added dropwise. The resulting solution was refluxed 19 hours, then evaporated to dryness in vacuo. The residue was taken up in water (5 ml), the pH adjusted to 9 (sat. Na2CO3), extracted with chloroform and the organics discarded. The aqueous layer was then adjusted to pH 12 (sat. NaOH) and extracted with chloroform. The chloroform was dried (MgSO4) and evaporated in vacuo to 575 mg (28%) white crystals, mp 141°-146° C. 400 MHz nmr confirmed the product calculated: C 53.82, H 7.75, N 17.94; found: C 53.9, H 7.73, N 17.77.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:12]1)(=[O:10])=[O:9].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:12]1)(=[O:9])=[O:10]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under an atmosphere of argon, (2S,4R)-1-tert-butyl 2-methyl 4-(2-chlorophenylsulfonyl)pyrrolidine-1,2-dicarboxylate (5.76 g, 14.3 mmol, Eq: 1.00) was combined with dichloromethane (35.0 ml) to give a light yellow solution. At 0° C., 2,2,2-trifluoroacetic acid (24.4 g, 16.5 ml, 214 mmol, Eq: 15.0) was added dropwise. The reaction was warmed up to room temperature and stirred for 3 h. The reaction mixture was evaporated to dryness. The crude material was dissolved in 100 ml dichloromethane, then extracted with 50 ml satd. Na2CO3 solution and 50 ml H2O. The aqueous layers were washed with 40 ml dichloromethane. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The title compound was obtained as a orange viscous oil (4.02 g, 92.8%, MS (m/e)=304.2 [M+H+]).
Reaction SMILES: O.Cl.[C:3]1([CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].O.C(O[CH:16](OCC)[CH2:17][CH:18](OCC)OCC)C>C(O)C>[C:3]1([CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:18]=[CH:17][CH:16]=[N:10]1
Reactant: Cc1ccccc1NN
Reactant: CCOC(CC(OCC)OCC)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccccc1-n1cccn1
Yield: 83 %

Procedure:
Into a 1 liter, 2-neck flask, fitted with a condenser and a magnetic stirrer, is successively added 90.0 g. (0.570 M.) of o-tolyl-hydrazine hydrochloride hydrate, 100 ml. of water, 63 ml. of 100% ethanol and 139.0 g. (0.633 M.) of 1,1,3,3-tetraethoxypropane. The reaction mixture is then heated slowly to between 80° C. and 90° C., and after maintaining the mixture at this temperature range for a period of about 3 hours, the reaction mixture is quenched on ice water and extracted with ethylacetate/ether. After drying the organic solution over anhydrous sodium sulfate, the solvents are evaporated to obtain a very dark liquid. Distillation in an air oven at a temperature between 110°-120° C. and a pressure of 1 mm. of Hg. yielded a light yellow oil (Yield: 83%).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:24])[CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C>[CH2:3]([O:5][C:6](=[O:24])[CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(CCCCOc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CCCCOc1ccccc1)C(=O)O
Reaction time: 24 h
Yield: 84 %

Procedure:
A solution of 16.1 g of potassium hydroxide in 250 ml of ethanol is added dropwise to 87 g of 4-phenoxybutylmalonic acid diethyl ester in 250 ml of ethanol at room temperature. The mixture is stirred for 24 hours and substantially concentrated in vacuo; the residue is taken up in 500 ml of water and the aqueous mixture is extracted with 200 ml of diethyl ether. The aqueous phase is acidified with concentrated hydrochloric acid, while cooling with ice, and extracted 3 times with 200 ml of diethyl ether each time. After drying over sodium sulfate, the organic phase is concentrated. 66.45 g of 4-phenoxybutylmalonic acid ethyl ester of m.p. 69° to 72° C. are obtained.
Reaction SMILES: [CH2:1]([SH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([OH:15])[CH2:10][CH2:11][CH2:12][C:13]#[CH:14].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CCCCCCC>[CH2:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][S:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCS
Reactant: C#CCCCCO
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Product: CCCCCCCSC=CCCCCO
Yield: 29.7 %

Procedure:
To 1.332 gr (10 mmol) of n-heptyl mercaptan and 981 mg (10 mmol) of 5-hexyn-1-ol dissolved in 25 ml of heptane under an argon atmosphere was added a few crystals of dibenzoyl peroxide. The reaction was stirred magnetically and heated to reflux for 18 hours. It was then cooled and poured into 25 ml of 10% sodium bicarbonate and extracted with 3×25 ml of ethyl acetate. The organic phases were combined and dried over sodium sulfate, filtered, and evaporated to yield a yellow oil. The oil was chromatographed on eight silica gel type GF preparative plates, using hexane-ethyl acetate (4:1) as developing solvent. Following removal of the band corresponding to product from the plates, the product was extracted from the silica with methanol, 684 mg (30% yield) of pure 7-thia-tetradecan-5-ene-1-ol was obtained as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].Cl[CH2:15][O:16][CH3:17]>C1COCC1.CN(C)C=O>[CH3:15][O:16][CH2:17][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: COCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCOc1cccnc1
Temperature: -15 °C

Procedure:
Dissolve 3-hydroxypyridine (7 g, 74 mmol) in THF (20.6 mL) and dimethylformamide (34.4 mL) and cool to −15° C. Add potassium tert-butoxide (8.3 g, 74 mmol) and stir at −15° C. for 30 min. Treat the mixture with chloromethylmethyl ether (5.81 mL, 77 mmol) dropwise over 40 min. After the addition is complete, stir the mixture at −15° C. for an additional hour. Remove the ice bath and allow the mixture to warm slowly to 15° C. Pour the mixture into saturated aqueous sodium chloride and stir vigorously for 10 min. Extract the resulting solution with three portions of ethyl acetate. Combine the organic extracts and wash with saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate in vacuo. Use the resulting product without further purification. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=3 Hz, 1H), 8.28 (d, J=5 Hz, 1H), 7.37-7.42 (m, 1H), 7.21-7.27 (m, 1H), 5.20 (s, 2H), 3.49 (s, 3H).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4][SH:5].[OH-].[K+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CO.C(O)C>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:15]([S:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CC(C)=CCC/C(C)=C/CS
Reactant: Clc1ccc(C(Cl)Cn2ccnc2)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CC(C)=CCC/C(C)=C/CSC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 54.6 %

Procedure:
To a stirred solution of (E)-3,7-dimethylocta-2,6-dienylmercaptan (1.00 g=5.9 mmol) in methanol (40 ml) was added potassium hydroxide (0.33 g=5.8 mmol) and 1-chloro-1-(2,4-dichlorophenyl)-2-(1H-imidazole-1-yl)ethane (1.62 g=5.9 mmol) in ethanol at room temperature, and then the reaction mixture was refluxed for 90 minutes. After cooling, the methanol was evaporated, and then the residue was diluted with chloroform. The chloroform layer was washed with water, followed by drying over anhydrous sodium sulfate. Concentration followed by column chromatography on silica gel (ethyl acetate:hexane=2:3) gave 1.32 g of Compound 10 as a colorless oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=1)[C:12]#[N:13].C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C>O1CCCC1>[C:12]([C:11]1[CH:14]=[C:7]([B:20]([OH:21])[OH:19])[CH:8]=[CH:9][C:10]=1[F:15])#[N:13]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cc(B(O)O)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium (5.6 ml, 2.5M in hexanes) was added over a 20 minute period to a solution of 5-bromo-2-fluorobenzonitrile and triisopropylborate (3.46 ml) in tetrahydrofuran (10 ml) at −78° C. The resulting solution was stirred at −78° C. for 30 minutes and then quenched by the addition of a 2M hydrochloric acid (20 ml) and extracted into ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by trituration using diethyl ether: hexane 1:2 to afford the sub-title compound as a solid (1.24 g).