Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][CH2:14][NH2:15].C(OC1C=CC=CC=1)(=O)C.[Na].CC(O)C>O>[C:2]1([CH2:1][C:16]([OH:18])=[O:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: O=C(O)c1ccccc1
Agent: NCCC[C@H](N)C(=O)O
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)Oc1ccccc1
Product: O=C(O)Cc1ccccc1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
7.6 g (0.03 moles) of the L-ornithine benzoate was dissolved in 38 mL H2O and about 4.4 g of sodium phenyl acetate was dissolved 22 mL H2O. Subsequently, the sodium phenyl acetate solution was added to the L-ornithine benzoate solution and left to stir for about 10 minutes About 240 mL of IPA (8:2 IPA:H2O) was added and the solution stirred for 30 minutes before cooling to 4° C. A crystalline solid precipitated after about 3 hrs at 4° C. (L-ornithine phenyl acetate). The precipitate was isolated by vacuum filtration and washed with 48-144 mL of IPA. Yield: 57%
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][CH:6]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[C:5]1=[O:32])#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O>[C:15]1([C:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:4]([CH2:3][C:1]3[NH:35][N:34]=[N:33][N:2]=3)[C:5](=[O:32])[CH:6]([N:21]3[C:22](=[O:31])[C:23]4=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]4[C:25]3=[O:26])[N:7]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCN1C(=O)C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1Cc1nnn[nH]1
Temperature: 145 °C
Yield: 91.1 %

Procedure:
To a solution of (3RS)-1-cyanomethyl-1,3-dihydro-5phenyl-3-phthalimido-2H-1,4-benzodiazepin-2 -one (100.0 g) and sodium azide (46.4 g) in 1-methyl-2-pyrrolidone (1.74 l) was added triethylamine hydrochloride (49.1 g) under stirring. The mixture was heated on an oil-bath at 145° C. and stirred for 4 hours. The reaction mixture was poured into 5% hydrochloric acid (4.8 l) under cooling and stirring. The resultant precipitate was collected by filtration, washed with water several times and dried in vacuo at 50° C. for 5 hours to afford (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4 -benzodiazepin-2-one (100.39 g).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Br:9]Br>ClCCCC>[Br:9][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: BrBr
Solvent: CCCCCl
Product: COC(=O)CC(=O)CBr
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
In 2613 g of 1-chlorobutane was dissolved 523 g of methyl acetoacetate and cooled to 0° C. To this mixture was dropwise added 719 g of bromine at 5±5° C. over a period of one hour, and the mixture was thereafter kept at that temperature for four hours. The reaction mixture was washed with 1161 g of a 10% saline solution. After separating the mixture into an aqueous and organic layers, concentration of the organic layer in vacuous at a temperature of 40° C. or less gave 782.9 g of crude methyl 4-bromoacetoacetate. The gas chromatography analysis indicated that the content of methyl 4-bromoacetoacetate in the crude product was 72% (564 g, 64% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]=[CH:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.Br[CH2:29][CH2:30]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:30][CH2:29][N:12]([S:13]([C:16]3[C:17]4[CH:18]=[CH:19][N:20]=[CH:21][C:22]=4[CH:23]=[CH:24][CH:25]=3)(=[O:14])=[O:15])[CH2:11][CH2:10]2)=[CH:26][CH:27]=1
Reactant: BrCCBr
Reactant: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc2cnccc12)N1CCN(CC=Cc2ccc(Cl)cc2)CC1
Reaction time: 24 h

Procedure:
1.31 g of t product of Example 172 was dissolved in 3 ml of dimethylformamide, to the solution were added 644 mg of 1,2-dibromoethane and 1.13 g of anhydrous potassium carbonate at a room temperature, and the mixture was stirred for 24 hours. After adding 100 ml of ethyl acetate, the ethyl acetate layer was sequentially washed with water and a saturated sodium chloride aqueous solution twice in each case, and dried over magnesium sulfate. The solution was filtered and evaporated under a reduced pressure, and resulting residue was purified on a silica gel column (silica gel 50 g, eluant: 5% methanol in chloroform), to obtain 356 mg of the title compound in a colorless amorphous form, while recovering the residual starting material.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[O:16][CH3:17].[N:18]([O-:20])=[O:19].[Na+].C(O)(=O)C.[N+]([O-])(O)=O>O>[CH3:17][O:16][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:9]([CH:8]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(OCCCBr)c(OC)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(OC)c(OCCCBr)cc1[N+](=O)[O-]
Temperature: 40 °C
Yield: 931.3 %

Procedure:
In a 100 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 10.2 g (33.0 mmol) of methyl 4-(3-bromopropoxy)-3-methoxybenzoate (purity: 980%) obtained in Reference Example III-5, 0.23 g (3.30 mmol) of sodium nitrite, and 12.5 mL of acetic acid. The resulting mixture was heated to 40° C. under stirring. To the reaction mixture was dropwise added slowly 13.8 g (132.0 mmol) of nitric acid (60 wt. %), and the mixture was heated at the same temperature for 5 hours. After the reaction was complete, 20 mL of water was added to the reaction mixture, and the aqueous mixture was cooled to 20° C., precipitating a crystalline product. The crystalline product was collected by filtration, washed successively with 30 mL of water and 30 mL of n-heptane, and dried under reduced pressure, to give 10.7 g (isolated yield: 92.0%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of methyl 5-methoxy-4-(3-bromopropoxy)-2-nitrobenzoate as a white crystalline product.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[CH2:12][CH2:11][N:10]2[CH3:18])=[CH:6][CH:5]=1.[OH-].[Na+].N1(O)CCC[CH2:25][CH2:24]1.N1CCCCC1=O.C([Li])C>CCOCC.CC(C)=O.O>[ClH:1].[CH2:24]([C:13]1([OH:17])[CH2:12][CH2:11][N:10]([CH3:18])[CH:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:20][CH:19]=2)[C:14]1([CH3:16])[CH3:15])[CH3:25]
Reactant: COc1ccc(CC2N(C)CCC(=O)C2(C)C)cc1
Reactant: ON1CCCCC1
Agent: Cl
Agent: O=C1CCCCN1
Agent: [Li]CC
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: CCC1(O)CCN(C)C(Cc2ccc(OC)cc2)C1(C)C
Yield: 45 %

Procedure:
The hydrochloride (18 g) of 2-(p-methoxybenzyl)-1,3,3-trimethyl-4-piperidone is converted to the free base by shaking with ether and aqueous sodium hydroxide, followed by evaporation of the ethereal solution. The oily base is dissolved in 30 ml of absolute ether and subsequently reacted with ethyl lithium (3.6 g in 300 ml of benzene) under conditions as described in example 39. According to gaschromatographic examination, conversion to the piperidinol occurs to the extent of only 25 percent. After the addition of water the reaction mixture is worked up as described in example 39 and the crude mixture of piperidone and piperidonal so obtained is treated again with ethyl lithium (2.7 g in 250 ml of benzene). This procedure is repeated once more whereafter still 20 percent of the piperidone appears to be present. Processing as usually furnishes 19 g of an oily base, which is converted to the hydrochloride with the aid of ethanolic hydrogen chloride. After the addition of acetone and ether, 9 g of the above crystalline product separates. Yield 45%. Melting point 232 -234° C with decomposition.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([Cl:17])=[CH:6][CH:5]=2.[H-].[Na+].Cl[CH2:21][C:22]([NH2:24])=[O:23]>O.CN(C)C=O.C1(C)C=CC=CC=1>[C:22]([CH2:21][N:3]1[C:4]2[C:9](=[CH:8][C:7]([Cl:17])=[CH:6][CH:5]=2)[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:2]1[CH3:1])(=[O:23])[NH2:24]
Reactant: Cc1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Reactant: NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)c2cc(Cl)ccc2n1CC(N)=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 3 g. of 2-methyl-3-phenyl-5-chloro-indole in a solvent mixture 7 ml. of toluene and 5 ml. of dimethylformamide is added to a suspension of 0.6 g. of 50% sodium hydride (in paraffin) in 5 ml. of toluene at 20° C. After the reaction mixture is stirred at 20° C. for one hour, a solution of 1.1 g. of chloroacetamide in 20 ml. of dimethylformamide is added thereto at 20° C., and the reaction mixture is stirred under reflux for 5 hours. The resultant mixture is diluted with water and is extracted with benzene. The organic layer is washed with water and dried over sodium sulfate. The solvent is removed to a residue, which is recrystallized from ethanol to give 1-carbamoylmethyl-2-methyl-3-phenyl-5-chloroindole, m.p. 223°-224° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].CCN(CC)CC.[BH4-].[Na+]>CO>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([CH2:18][NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCC(=O)O
Reactant: O=Cc1ccc2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)CCNCc1ccc2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 50 °C
Yield: 43.9 %

Procedure:
To a solution of 2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene-6-carbaldehyde (23 mg, 0.05 mmol) in 3 mL MeOH, β-alanine (8.7 mg, 0.1 mmol) and catalytic amount Et3N are added. The suspension is heated to 50° C. for 0.5 hours, followed by the addition of 2 mg of NaBH4. After Pre-LC-MS, 10 mg of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophen-6-ylmethyl]-amino}-propionic acid is obtained as a white solid. MS m/z 456[M+1]+. 1H NMR (MeOD-d4): δ 8.22 (d, 1H), 7.93 (m, 2H), 7.86 (d, 1H), 7.81 (s, 1H), 7.40 (m, 1H), 7.34 (d, 1H), 7.28 (m, 3H), 7.24 (m, 2H), 4.26 (s, 2H), 3.15 (t, 2H), 2.52 (t, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]Cl)=[CH:9][CH:8]=1.ClC1C=CC=CC=1>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:9][CH:8]=1
Reactant: ClCCc1ccc(Cl)cc1
Reactant: CC(O)CN
Solvent: Clc1ccccc1
Solvent: O
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
Into a 250-mL round-bottom flask equipped with a magnetic stir bar, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, was charged 1-aminopropan-2-ol (60.0 g, 799 mmol). The mixture was heated to 85° C. and the product from Step A was added while maintaining the reaction temperature below 98° C. Upon completion of the addition the reaction mixture was stirred at 90 to 95° C. for 2.5 h. Chlorobenzene (50 mL) and water (25 mL) were added and the mixture was stirred at 70 to 75° C. for 15 min. The phases were allowed to separate and the lower organic phase was removed. The upper aqueous phase was extracted with chlorobenzene (2×25 mL) at 70 to 75° C. The combined organic phases were washed with water (2×25 mL) at 70 and 75° C. and 87.5 g of solvent was removed by distillation under reduced pressure at 60° C. (bath). The residue was diluted with chlorobenzene (125 mL). The resulting orange solution, which contained 0.032% water by Karl Fischer titration, was stirred overnight at 45° C. (bath).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1.CI.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[CH3:20][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[S:2][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: CSc1ccccc1-c1nc2ccccc2[nH]1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1ccccc1-c1nc2ccccc2n1C

Procedure:
The product of step (a) above (3.25 g), methyl iodide (1.92 g) and potassium carbonate (5.2 g) were stirred together in dry dimethylformamide (50 ml) at room temperature for 24 hours. The reaction mixture was poured into brine and extracted into ethyl acetate, the extract was washed with excess brine, dried over magnesium sulphate and evaporated to dryness in vacuo and the residue was purified by flash chromatography (SiO2 /CH2Cl2 9:1 ethyl acetate) to afford the sub-title compound as yellow solid, MS MW 254 bp 239.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([NH2:14])=[NH:13].O=[C:16]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:17][C:18](OCC)=[O:19]>CN1CCCC1=O.C(O)C>[OH:19][C:18]1[N:14]=[C:12]([NH:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[CH3:1])[N:13]=[C:16]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=1
Reactant: CCOC(=O)CC(=O)c1cccnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Solvent: CCO
Solvent: CN1CCCC1=O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nc(O)cc(-c2cccnc2)n1
Temperature: 150 °C

Procedure:
40 g (2-methyl-5-nitrophenyl)guanidine in 160 mL N-methyl pyrrolidone is dissolved. The mixture is heated to 150° C. and ethyl β-oxo-3-pyridine propionate is added portionwise, to 50 g total in a time period of 5 hours, distillating about 15 g of by-products under a nitrogen flow. At the end of the reaction, the mixture is cooled and diluted with ethanol. The precipitate is filtrated, yielding, upon drying, 46.4 g of product with HPLC purity of 99% (A %), identified through LC-MS and 1H-NMR.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][C:12]([CH3:24])=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6].[CH3:32][Si:33]([CH3:38])([CH3:37])[CH2:34][CH2:35][SH:36].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[C:12]([CH3:24])[N:11]=[CH:10][C:9]=2[N:7]([CH3:8])[C:5](=[O:6])[C:4]2[CH:3]=[C:2]([S:36][CH2:35][CH2:34][Si:33]([CH3:38])([CH3:37])[CH3:32])[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=2)=[C:16]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(SCC[Si](C)(C)C)cc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 5.5 h

Procedure:
A solution of 3-bromo-N-(4-(4-fluoro-2-methoxyphenyl)-6-methylpyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.59 g, 1.19 mmol) and 2-(trimethylsilyl)ethanethiol (159 mg, 187 μL, 1.19 mmol) in dioxane (5.9 mL) was stirred under argon for 5 minutes in a sealed tube. To the clear, light yellow solution were added tris(dibenzylideneacetone)dipalladium (0) (27.2 mg, 29.7 μmol, CAS RN 52409-22-0), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (34.3 mg, 59.3 μmol, CAS RN 161265-03-8) and DIPEA (307 mg, 414 μL, 2.37 mmol) and the reaction mixture was stirred at 120° C. for 5.5 hours, followed by stirring at room temperature overnight. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified twice by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Off-white solid (0.483 g; 73%). MS (ESI): m/z=551.18 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:17][C:18]([CH2:20]Br)=[CH2:19].O>CN(C=O)C.C(OCC)(=O)C>[C:3]([CH:11]([CH2:20][C:18]([Br:17])=[CH2:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C(Br)CBr
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Br)CC(C(=O)OCC)C(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
Sodium hydride (0.26 g, 6.0 mmol) was added under ice cooling to a solution (10 ml) of ethyl benzoylacetate (1.0 ml, 5.77 mmol) in DMF, followed by stirring for 30 minutes, and then 2,3-dibromopropene (0.63 ml, 5.77 mmol) was added. The resulting mixture was stirred at room temperature for 1.5 hours, water was added to the reaction mixture, and extraction with ethyl acetate was performed three times. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1). The solvent was distilled off under reduced pressure, to thereby obtain 1.55 g (yield: 86%) of ethyl 2-benzoyl-4-bromo-4-pentenoate as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:8]=[C:9]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH:10]=[CH:11][C:12]=1[CH:13]=O)[CH:4]=[CH2:5].[CH2:23]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[CH2:3]([O:6][C:7]1[CH:8]=[C:9]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH:10]=[CH:11][C:12]=1[CH:13]=[CH2:23])[CH:4]=[CH2:5]
Reactant: C=CCOc1cc(OS(=O)(=O)C(F)(F)F)ccc1C=O
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: CCCCCC
Product: C=CCOc1cc(OS(=O)(=O)C(F)(F)F)ccc1C=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Methyltriphenylphosphonium bromide (1.95 g, 5.45 mmol) was added to a suspension of sodium hydride (60% in oil) (0.25 g, 6.3 mmol) in THF (35 ml) at 0 C and it was stirred for 30 min at room temperature. To the above solution was added solution of trifluoro-methanesulfonic acid 3-allyloxy-4-formyl-phenyl ester (1.3 g, 4.2 mmol) in THF (15 ml), and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with hexane and extracted with water. Organic phase was washed with brine and evaporated. Silica gel column chromatography (EA:Hex, 1:20) afforded trifluoro-methanesulfonic acid 3-allyloxy-4-vinyl-phenyl ester (0.68 g, 53%).
Reaction SMILES: [CH2:1]([O:17][CH:18]1[O:23][CH:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[CH:20]=[CH:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:28]Cl.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:17][CH:18]1[O:23][CH:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[C:20]([Cl:28])=[CH:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC1C=CC(=O)C(C(C)C)O1
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOC1C=C(Cl)C(=O)C(C(C)C)O1
Yield: 99.4 %

Procedure:
In 50 ml of carbon tetrachloride was dissolved 3.8 g of 6-cetyloxy-2-isopropyl-2H-pyran-3(6H)-one with stirring. Into the solution was gradually introduced chlorine gas (0.71 g) at a temperature below 10° C. and after the subsequent stirring for 30 minutes was added dropwise 0.8 g of pyridine maintaining the temperature below 15° C. A crystal from the reaction mixture was separated by suction filter. The filtrate was washed with 5% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. By the distillation of solvent was obtained 4.12 g of 6-cetyloxy-4-chloro-2-isopropyl-2H-pyran-3(6H)-one [compound 2] in a yellow viscous oily form.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:13][CH2:12]2.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:30]=1>C(OCC)(=O)C.O>[C:36]([NH:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:13][CH2:12]3)=[CH:34][CH:33]=1)(=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(Nc1ccc(CBr)cc1)c1ccccc1
Reactant: Oc1ccc2c(c1)CCC(CCN1CCCCC1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1)c1ccccc1
Reaction time: 1 h
Yield: 22.1 %

Procedure:
Sodium hydride (60% oily, 85 mg) was added to DMF solution of 6-hydroxy-2-(2-piperidinoethyl)tetralin (500 mg) at room temperature, which was stirred for 1 hour. N-[4-(bromomethyl)phenyl]benzamide (670 mg) was added to the reaction mixture at room temperature, which was stirred for 1 hour. Water was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent: THF), and recrystallized (ethyl acetate) to give the titled compound (200 mg).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[K+].Br[CH2:11][C:12]([O:14]CC)=[O:13].[OH-].[Na+].Cl>C(O)C>[SH:7][C:4]1[S:3][C:2]([S:1][CH2:11][C:12]([OH:14])=[O:13])=[N:6][N:5]=1
Reactant: CCOC(=O)CBr
Reactant: Sc1nnc(S)s1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CSc1nnc(S)s1
Yield: 72.1 %

Procedure:
After stirring a mixture of 60 g of 2,5-dimercapto-1,3,4-thiadiazole, 25 g of potassium hydroxide, and 750 ml of ethanol for one hour at 70° C., 68 g of ethyl α-bromoacetate was added to the mixture and then the resultant mixture was refluxed for 2 hours. After cooling the reaction mixture, insoluble matters were filtered off and the filtrate thus formed was concentrated under reduced pressure. To the residue thus formed was added 600 ml of 10% sodium hydroxide. The mixture was stirred for one hour at 80° C. After cooling, the reaction mixture was acidified by the addition of concentrated hydrochloric acid (below pH 1) and crystals thus formed were collected by filtration, washed with water, and recrystallized from acetone to provide 60 g of [(5-mercapto-1,3,4-thiadiazol-2-yl)thio]acetic acid.