Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[CH2:8][OH:9].C(N(CC)CC)C>C(Cl)Cl.O>[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[CH2:8][O:9][C:1](=[O:3])[CH3:2]
Reactant: OCc1c(F)cccc1F
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
Acetyl chloride (1.13 mL, 15.8 mmol) was added dropwise to a solution of 2,6-difluorobenzyl alcohol (1.76 g, 12.2 mmol) and triethylamine (3.43 mL, 24.4 mmol) in DCM (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water and extracted with DCM (3×20 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a colourless oil (1.72 g, 76%). 1H NMR 400 MHz δ (CDCl3): 7.37-7.28 (1H, m), 6.96-6.88 (2H, m), 5.20 (2H, s), 2.08 (3H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:15]2[C:10]3=[C:11]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[CH:13][CH:14]=2.C1C(=O)N([Br:30])C(=O)C1.O>C(Cl)Cl.C(#N)C>[Br:30][C:18]1[CH:19]=[CH:20][C:21]2[N:9]3[C:8]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[C:2]([CH3:22])([CH3:1])[C:15]4[C:10]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:16]=2[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2ccccc2-n2c3ccccc3c3cccc1c32
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cccc1c32
Reaction time: 4 h

Procedure:
6.3 g (22.2 mmol) of 8,8-dimethylindolo[3,2,1-de]acridine are initially introduced in 150 ml of CH2Cl2. A solution of 3.9 g (22.3 mmol) of NBS in 100 ml of acetonitrile is subsequently added dropwise at −15° C. with exclusion of light, and the mixture is allowed to come to room temperature and is stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane, and the solid is isolated.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][SH:9].[CH3:10][S:11]SC>[H-].[Na+]>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][S:9][S:11][CH3:10]
Reactant: Cc1ncsc1CCS
Reactant: CSSC
Agent: [H-]
Agent: [Na+]
Product: CSSCCc1scnc1C
Yield: 60.4 %

Procedure:
A mixture of 8.26 g (0.052 mol) of 2-(4-methyl-5-thiazolyl)-ethyl-mercaptan and 33.07 g (0.208 mol) of dimethyldisulphide is treated with 50 mg of sodium hydride (50% dispersion in oil) and the mixture is heated to reflux for 4 hours. The mixture is then left to cool, filtered over 10 g of aluminum oxide (activity I, neutral), which is back-washed with ether, and concentrated in a vacuum. The resulting crude product (9.5 g) is distilled through a Hempel column under a high vacuum, there being obtained 6.45 g of [2-(4-methyl-5-thiazolyl)ethyl]-methyl-disulphide. Boiling point 104°-110°/0.02 mm Hg; nD20 =1.5944; purity: 99%.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([OH:19])[CH2:11][CH2:10]1.CN1CCOCC1.N1C=CN=C1>C(Cl)Cl>[C:1]([Si:5]([O:19][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCOc2ccccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyl-chloro-dimethyl-silane (10.54 g, 70 mmol) was added to a CH2Cl2 (200 mL) solution of 4-chromanol (10.00 g, 66.6 mmol), N-methylmorpholine (10.98 mL, 100 mmol) and imidazole (0.20 g, 3 mmol) at 0° C. The mixture was stirred for 3 days at RT. The reaction was diluted with CH2Cl2 (200 mL), washed with dilute HCl and H2O, dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]1)=[O:11].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl.[CH3:41][O:42][C:43](=[O:48])[CH:44]([CH2:46][OH:47])[NH2:45]>ClCCl>[CH3:41][O:42][C:43](=[O:48])[CH:44]([CH2:46][OH:47])[NH:45][C:18]([CH:15]1[CH2:14][CH2:13][N:12]([C:10](=[O:11])[CH2:9][C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:17][CH2:16]1)=[O:20]
Reactant: Cc1ccc(C)c(CC(=O)N2CCC(C(=O)O)CC2)c1
Reactant: COC(=O)C(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)C(CO)NC(=O)C1CCN(C(=O)Cc2cc(C)ccc2C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-[(2,5-dimethylphenyl)acetyl]-4-piperidinecarboxylic acid (i.e. the product of Example 9, Step B) (1.44 g, 5.23 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.1 g, 5.75 mmol), and N-methylmorpholine (529 mg, 5.23 mmol) in 5 mL of dichloromethane was stirred at room temperature for 15 minutes. DL-Serine methyl ester hydrochloride (814 mg, 5.23 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction was partitioned between 1 N aqueous hydrochloric acid (10 mL) and dichloromethane (10 mL), and the organic layer was washed with 1 N aqueous hydrochloric acid, water and brine, dried over MgSO4 and concentrated under reduced pressure to give 1.61 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](Cl)(=O)C(Cl)=O.CN(C)C=O.CO>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a solution of 3,5-difluorobenzoic acid (10 gm, 63.2 mmol) in dichloromethane (100 mL) was added oxalyl chloride (11.96 gm, 94.9 mmol) at 0° C. followed by addition of dimethylformamide (2 mL). The resulting reaction mixture was stirred for about 3 hours at room temperature. Methanol (100 mL) was added to the reaction mass and stirring was continued further for 20-30 minutes. Solvents were evaporated to obtain an oily mass which was further purified by column chromatography over silica gel (100-200) using ethyl acetate/hexane gradient elution to afford colorless methyl 3,5-difluorobenzoate (10 gm, 91.91%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C(Cl)Cl>[CH3:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[CH:20][N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5]
Reactant: Cc1ccc(N)c(C(=O)NC2CCC(=O)NC2=O)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2ncn(C3CCC(=O)NC3=O)c(=O)c2c1
Yield: 9 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-methyl-benzamide (0.45 g, 1.7 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (80 mg) was heated to 160° C. in a microwave oven for 8 minutes. To the suspension, was added methanol (20 mL), methylene chloride (20 mL), and Celite (5 mL). The solvent was removed in vacuo. The reside was placed in a SIM and was purified with column chromatography (Silca Gel, methanol/methylene chloride 0% gradient 10% in 15 min) to give as 3-(6-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a blue solid (50 mg, 9% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 2.78 min (96.1%); mp: 285-287° C.; 1H NMR (DMSO-d6) δ 2.11-2.18 (m, 1H, CHH), 2.46 (s, 3H, CH), 2.56-2.74 (m, 2H, 2CHH), 2.82-2.93 (m, 1H, CHH), 5.48 (br, 1H, NCH), 7.61 (d, J=8 Hz, 1H, Ar), 7.70 (dd, J=2, 8 Hz 1H, Ar), 7.94 (br, 1H, Ar), 8.33 (s, 1H, CH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.72, 22.51, 30.91, 57.00 (br), 121.09, 125.38, 127.00, 135.89, 137.07, 145.46, 146.45, 159.60, 169.88, 172.44; LCMS: MH=272; Anal Calcd for C14H13N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.78; H, 4.57; N, 15.34.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:16])([F:15])[CH:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][S:2]([O:11][CH2:10][CH2:9][CH:8]([C:7]([F:15])([F:16])[F:6])[CH2:12][CH2:13][O:14][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: OCCC(CCO)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC(CCOS(C)(=O)=O)C(F)(F)F
Temperature: 0 °C

Procedure:
With stirring at 0° C., 63 ml of methylsulfonyl chloride in 40 ml of toluene are added dropwise to a solution of 69.3 g of 3-trifluoromethyl-1,5-pentanediol and 140 ml of triethylamine in 150 ml of toluene. After 12 hours' stirring at room temperature, the solid portions are filtered off and the toluene solution is concentrated in vacuo to give in almost quantitative yield 1,5-bismethanesulfonyloxy-3-trifluoromethylpentane; m.p. 40°-45° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][C:26](O)([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[OH-].[Na+].CO>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH:25]=[C:26]([C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:33][CH:34]=4)[CH2:27][CH2:28]3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCCOc1ccc(C2(O)CCN(c3ccc(N4CCN(C(=O)OCc5ccccc5)CC4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COCCCCOc1ccc(C2=CCN(c3ccc(N4CCN(C(=O)OCc5ccccc5)CC4)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 67.5 %

Procedure:
To a solution of 4-[4-[4-hydroxy-4-[4-(4-methoxybutoxy)phenyl]piperidin-1-yl]phenyl]piperazine-1-carboxylic acid benzyl ester (3.41 g) in dichloromethane (50 ml) was added trifluoroacetic acid (8.5 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for further 6 hours. To the reaction mixture was added 1 mol/ml sodium hydroxide solution (170 ml), dichloromethane (136 ml) and methanol (14 ml). The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (50:1 dichloromethane-methanol elution) to give 4-[4-[4-[4-(4-methoxybutoxy)phenyl]-3,6-dihydro-2H-pyridin-1-yl]phenyl]piperazine-1-carboxylic acid benzyl ester (2.23 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([OH:1])[CH:11]=[C:10]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To a solution of methyl 3,5-dihydroxybenzoate (15.0 g, 89.21 mmol) in 350 mL of acetone was added potassium carbonate (13.56 g, 98.13 mmol) followed by benzyl bromide (11.2 mL, 93.6 mmol). And the mixture refluxed for 3 h. After cooling to rt the solids were filtered and the filtrate was evaporated. The residue was chromatographed on silica gel using an EtOAc-hexane gradient to afford 7.08 g (31%) of 3-benzyloxy-5-hydroxybenzoic acid methyl ester. 1H NMR (300 MHz, DMSO-d6) δ 3.81 (s, 3H), 5.10 (s, 2H), 6.64-6.66 (m, 1H), 6.97-7.01 (m, 2H), 7.35-7.45 (m, 5H), 9.89 (br s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][CH:13]=O.[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:13][CH2:12][N:3]4[C:4]5[C:9](=[N:8][CH:7]=[CH:6][CH:5]=5)[CH:10]=[CH:11][C:2]4=[O:1])[CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2ncccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3ncccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of 0.62 g of (2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde in 20 mL of dichloromethane, 1.5 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 0.19 mL of acetic acid were added, and the mixture was stirred at room temperature for 30 minutes, and then 1.0 g of sodium triacetoxyborohydride was added to the reaction mixture, and the mixture was stirred at room temperature for 4 days. Thereto were added water, a saturated aqueous sodium hydrogen carbonate solution and chloroform, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=75:1 to obtain 0.70 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown oily substance.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:16]([NH2:18])=O)=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([CH2:16][NH2:18])=[CH:3][CH:2]=1
Reactant: NC(=O)c1cccc2c1CCCc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc2c1CCCc1ccccc1-2
Yield: 14.9 %

Procedure:
Under a dry nitrogen atmosphere 6,7-dihydro5H-dibenzo[a,c]-cyclohepten-4-carboxamide (0.78 gram, 0.0033 mole) was reacted with lithium aluminum hydride (0.2 gram, 0.0053 mole) in tetrahydrofuran (100 ml) to produce a white solid. The solid was recrystallized from a solution of diethyl ether and petroleum ether to provide 6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-methanamine (0.11 g, mp 200°-210°). The solvent was removed from the mother liquor to yield an additional 0.5 gram of the amine.
Reaction SMILES: O.[NH2:2][NH2:3].C([O:8][CH2:9][CH3:10])(=O)CO.[CH2:11]([N:14]=[C:15]=[S:16])[CH2:12][CH3:13].[OH-].[Na+].Cl>C(O)C>[OH:8][CH2:9][C:10]1[N:14]([CH2:11][CH2:12][CH3:13])[C:15]([SH:16])=[N:3][N:2]=1
Reactant: CCCN=C=S
Reactant: NN
Reactant: CCOC(=O)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1c(S)nnc1CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of hydrazine monohydrate (9.66 g) in ethanol (100 ml), ethyl glycolate (20.09 g) was slowly added dropwise with keeping the reaction temperature under 10° C. at room temperature. The mixture was stirred at room temperature for 4 hours, propyl isothiocyanate (20 ml) was slowly added dropwise thereto with keeping the reaction temperature under 10° C. The mixture was stirred for 64 hours at 40° C., cooled to room temperature, and ice-water (50 ml) was added to the mixture. The mixture was stirred for 15 miuntes, 5N aqueous solution of sodium hydroxide (40 ml) was added to the mixture, and the mixture was stirred for 4 hours at 60°. Concentrated hydrochloric acid was added dropwise to the solution at 0° C. to adjust pH to 6, and the precipitated crystals were removed by filtration. The mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with water, to give 3-hydroxymethyl-5-mercapto-4-propyl-4H-1,2,4-triazole (23.45 g) as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24]>CN(C)C=O.O.C(OCC)(=O)C>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:13][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnccc1NCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
Sodium carbonate (3.20 g, 30.27 mmol) and 4-fluorobenzylamine (2.14 ml, 18.92 mmol) were added to a solution of 4-chloro-3-nitropyridine (3.0 g, 18.92 mmol) prepared in Step 1 of Preparation 1 in 30 ml of anhydrous N,N-dimethylformamide and then the reaction mixture was stirred for 1 hour at 80° C. The reaction mixture was diluted with a mixture of water (10 ml) and ethyl acetate (100 ml) and then washed with water (100 ml) twice. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give the titled compound as a yellow solid (3.01 g, 83.5%).
Reaction SMILES: [C:1]1([S:7][C:8]2[C:9](=[O:20])[C:10]3[C:15]([C:16](=[O:19])[C:17]=2[CH3:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CC=CCC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].CN(C1C=CC=CN=1)C.[O:43]1CC[CH2:45][CH2:44]1>[Pd].N1C=CC=CC=1>[C:1]1([S:7][C:8]2[C:17]([CH3:18])=[C:16]([O:19][C:27](=[O:29])[CH3:28])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[O:20][C:44](=[O:43])[CH3:45])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1=C(Sc2ccccc2)C(=O)c2ccccc2C1=O
Reactant: C1CCOC1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Agent: CN(C)c1ccccn1
Solvent: C1=CCC=CC1
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(Sc2ccccc2)c(OC(C)=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-phenylthio-3-methyl-1,4-naphthoquinone (28.0 g) and 10% palladium on charcoal (56 g) in tetrahydrofuran (1 L) was treated with 1,4-cyclohexadiene (80 mL), stirred overnight at room temperature. The mixture was then treated with a solution of acetic anhydride (40 mL), pyridine (40 mL) and dimethylaminopyridine (2.0 g) in tetrahydrofuran (100 mL), and stirred for 1 hour. Filtration to remove catalyst, followed by aqueous extraction workup as in Example 1, gave 2-phenylthio-3-methyl-1,4-diacetoxynaphthalene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9](O)[CH3:10])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C.C(Cl)Cl>[N:24]([CH:9]([C:5]1[N:6]=[C:7]([CH3:8])[C:2]([F:1])=[CH:3][CH:4]=1)[CH3:10])=[N+:25]=[N-:26]
Reactant: Cc1nc(C(C)O)ccc1F
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(C)N=[N+]=[N-])ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A 250 ml round bottom flask containing 1-(5-fluoro-6-methylpyridin-2-yl)ethanol (Method 14; 550 mg, 3.54 mmol) was charged with triethylamine (0.75 ml, 5.4 mmol) and anhydrous DCM (8.0 ml). The solution was cooled to 0° C., and methanesulfonyl chloride (0.32 ml, 4.1 mmol) was added dropwise. The resulting mixture was allowed to stir at room temperature for 2 hours, and the volatile components were removed using a rotary evaporator. The residue was treated with sodium azide (466 mg, 7.17 mmol) and anhydrous DMF (5.0 ml), and the slurry was allowed to stir at room temperature. After 2 hours, the mixture was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc, and the combined organics were washed with brine, dried, filtered, and concentrated. The crude material was purified by silica gel chromatography (Rf in 90:10 hexanes:EtOAc=0.47) to afford the title compound as a colourless oil (567 mg, 89%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH3:17][O:18][C:19]1[C:20]([CH3:33])=[C:21]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH:22]=[O:23].[Cl-].[NH4+].[O:36]1CCCC1>>[CH3:17][O:18][C:19]1[C:20]([CH3:33])=[C:21]([CH:22]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:1](=[O:36])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[OH:23])[C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: COc1c(C)c(C(O)c2ccc(OC(=O)c3ccccc3)cc2)c(OC)c(OC)c1OC
Reaction time: 2 h
Yield: 92 %

Procedure:
Under ice-cooling, into a Grignard reagent (30 ml, a tetrahydrofuran solution) prepared from 4-(benzyloxy)bromobenzene (8.00 g, 0.030 mol) and magnesium (0.81 g, 0.033 mol) was dropped a solution of 3,4,5,6-tetramethoxy-2-methylbenzaldehyde (3.65 g, 0.015 mol) in anhydrous tetrahydrofuran (20 ml) and the mixture was stirred for 2 hours more. The reaction solution was poured into a saturated aqueous solution of ammonium chloride followed by extracting with ether. The extract was washed with a saturated saline and dried. The reaction solution was filtered and the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (5.93 g, 0.014 mol, 92%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([Cl:25])[CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[ClH:25].[Cl:25][C:4]1[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:6][C:7]([F:8])=[C:2]([N:28]2[C@H:27]([CH3:26])[CH2:31][O:30][C:29]2=[O:32])[CH:3]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3cc(F)c(Br)cc3Cl)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cc(F)c(N4C(=O)OC[C@H]4C)cc3Cl)CC2)c(C)c1
Product: Cl
Yield: 40.8 %

Procedure:
By reaction and treatment in the same manner as in Example 79 and using (4-bromo-2-chloro-5-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.5 g) described in Preparation Example 72 and (R)-4-methyloxazolidin-2-one (400 mg) described in Preparation Example 25, the title compound (347 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[O:10][C:9](=[O:25])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCN(CC)CC.CO.CS(C)=O>[C:9]([C:13]1[CH:12]=[C:11]2[C:16]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9](=[O:25])[O:10]2)=[CH:15][CH:14]=1)([O:10][CH3:11])=[O:25]
Reactant: O=c1cc(-c2ccccc2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2o1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(-c3ccccc3)cc(=O)oc2c1

Procedure:
A solution of 4-phenyl-7-trifluoromethanesulfonyloxycoumarin (1.75 g) and tetrakis (triphenylphosphine)palladium (0) (600 mg) in Et3N (1.3 mL), MeOH (15 mL) and DMSO (25 mL) was stirred under an atmosphere of carbon monoxide for 1 hr at 70° C. The mixture was then poured onto sat'd. NH4Cl solution, extracted with EtOAc, dried and evaporated. Chromatography on silica gel (30% EtOAc/hexane) yielded the title compound as a solid, m.p. 133°-135° C.