Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[CH2:21]([N:23]([CH2:33][CH3:34])[C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[CH3:22].P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C=O)C>[CH2:33]([N:23]([CH2:21][CH3:22])[C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:18]2[CH2:19][CH2:20][N:15]([S:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)(=[O:14])=[O:13])[CH2:16][CH2:17]2)=[O:29])=[CH:26][CH:25]=1)[CH3:34]
Reactant: CCN(CC)c1ccc(C(=O)O)cc1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Yield: 27.7 %

Procedure:
To a solution of 1-(2-naphthalenesulfonyl)piperazine hydrochloride (625 mg) and 4-diethylamino benzoic acid (386 mg) in DMF (12 ml) was added diethyl phosphorocyanidate (489 mg) and then triethylamine (606 mg), and the solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and the residue was purified with silica gel column chromatography (dichloromethane:10% ammonia containing methanol=20:1) to give colorless amorphous of the title compound (250 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](O)[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: CSc1nc(O)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nc(Cl)cc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
2-Methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ol (500 mg) and phosphorous oxychloride (2.5 ml) were heated to reflux for four hours. The reaction mixture was concentrated under reduced pressure and the remaining residue dissolved in ethyl acetate (50 ml) and washed with water (2×30 ml). Organics were separated, dried over sodium sulphate and solvent was removed under reduced pressure to yield 4-chloro-2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (478 mg) as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:7]=[CH:6][C:5]=1[OH:18])([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:1][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:7]=[CH:6][C:5]=1[OH:18]
Reactant: CCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCc1ccc(O)c(N)c1
Reaction time: 0.75 h
Yield: 66.6 %

Procedure:
To 95.4 mg(0.38 mmole) of 2-nitro-4-octylphenol in 2 ml of 1:1 glacial acetic acid and water mixture at 85-90° C. was added 0.35 gm of activated iron in three portions over a 15 min period. The reaction was allowed to proceed at the same temperature for 45 min. The reaction mixture was diluted then with 5 ml of water and extracted with 20 ml ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated by rotary evaporation. The crude product was flash chromatographed over silica gel using 30% ethyl acetate in hexane to yield 56 mg of 2-amino-4-octyl phenol, Structure (I-2), in 67% yield.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[C:11]([C:14]1[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:16]([CH3:28])[N:15]=1)([CH3:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:7][C:11]([C:14]1[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:16]([CH3:28])[N:15]=1)([CH3:13])[CH3:12]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)c1c(C(F)(F)F)c(C(C)(C)O)nn1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(C(F)(F)F)c(C(C)(C)F)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
At −10° C., 0.52 ml (3.9 mmol) of diethylaminosulphur trifluoride is added dropwise to a solution of 1.00 g (3.57 mmol) of ethyl 3-(2-hydroxypropan-2-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate in 20 ml of dichloromethane. The mixture is afterstirred for one hour at −10° C., sodium carbonate is added, and the mixture is stirred for 10 minutes at room temperature. After adding saturated sodium carbonate solution, extraction is carried out with dichloromethane, and the combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo on a rotary evaporator. Purification by flash chromatography on silica gel (cyclohexane/ethyl acetate) gives 700 mg of ethyl 3-(2-fluoropropan-2-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (67%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.Cl[CH2:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][CH2:11][N:3]1[C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: OCCCCl
Reactant: Cc1ncc([N+](=O)[O-])[nH]1
Product: Cc1ncc([N+](=O)[O-])n1CCCO

Procedure:
The reaction mixture of 2-methyl-5-nitroimidazole (127 g, 1.0 mol) and 1-chloro-3-hydroxypropane (500 g, 5.3 mol) will be refluxed for 24 h. Then, the excessive amount of 1-chloro-3-hydroxypropane will be removed via evaporation under a condition of 2660 Pa. To the residue, 200 ml of water will be added. The mixture will be filtered. The filtrate will be collected. The filter residue will be then rinsed with water. The water phases will be combined and alkalified with saturated sodium bicarbonate aqueous solution up to pH 9. The solution will be placed in the cold room overnight for crystallization. The crystals will be filtered, washed with water, and then dried. The crude product will be recrystallized from ethyl acetate to give 1-(3-hydroxypropyl)-2-methyl-5-nitro-1H-imidazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:28])=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: Nc1ccccc1-c1ccc(F)cc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccccc1-c1ccc(F)cc1)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 1-(ii), 4′-fluoro-(1,1′-biphenyl)-2-amine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-[(4′-fluorobiphenyl-2-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])=[CH:4][C:3]=1[S:17](Cl)(=[O:19])=[O:18].[CH3:21][NH2:22].Cl>O>[CH3:21][NH:22][S:17]([C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])(=[O:19])=[O:18]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1NS(=O)(=O)C(F)(F)F
Reactant: CN
Agent: Cl
Solvent: O
Product: CNS(=O)(=O)c1cc(NS(=O)(=O)C(F)(F)F)c(C)cc1C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of 2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g), a 40% aqueous soltution of methylamine (1 g) and water (20 ml) was stirred at room temperature and allowed to stand overnight at the same temperature. The resultant mixture was made acidic with 5% aqueous hydrochloric acid to precipitate an oily substance, which was then extracted with chloroform. The organic layer was washed with a 5% aqueous solution of hydrochloric acid and water in order and dried over anhydrous magnesium sulfate, followed by concentration. The residue was allowed to stand to give crytals, which were recrystallized from toluene to give 1.1 g of N-methyl-2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonamide (Compound No. 29). M.P., 134.5°-135.5° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=5)=[C:36]([O:49][CH2:50][CH3:51])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:61])=[C:36]([O:49][CH2:50][CH3:51])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)ccn4)c(OCC)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(OCC)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[3-ethoxy-4-[hydroxy(4-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.68 g) was dissolved in dichloromethane (25 ml), and to the solution was added 3-chloroperbenzoic acid (0.28 g) under ice-cooling and the mixture was stirred overnight at room temperature. An aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-ethoxy-4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.89 g) as colorless amorphous.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH:5]([C:7]1[C:16]2[N:17]=[CH:18][N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1)[NH2:6]>O.C(O)(=O)C>[CH3:22][CH:21]([CH3:23])[CH2:20][N:19]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]3[N:1]=[N:6][N:5]=[C:7]3[C:16]=2[N:17]=[CH:18]1
Reactant: O=N[O-]
Reactant: CC(C)Cn1cnc2c(NN)nc3ccccc3c21
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Cn1cnc2c1c1ccccc1n1nnnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 375.5 %

Procedure:
A solution of sodium nitrite (2.0 g, 3 mmole) in water (5 mL) was added to a solution of 4-hydrazino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (4.0 g, 15.7 mmole, Example 7) in a mixture of acetic acid (5 mL) and water (50 mL). The reaction mixture was stirred at ambient temperature for 15 minutes. A precipitate was isolated by filtration, washed with water then air dried to provide 4.1 g of crude product. This material was recrystallized from dichloromethane/ethanol to provide 3.0 g of 6-(2-methylpropyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a cream colored crystalline solid, m.p. 208-212° C. Analysis: Calculated for C14H14N6: %C, 63.14; %H, 5.30; %N, 31.56; Found: %C, 62.60; %H, 5.2; %N, 31.5.
Reaction SMILES: [Cl:1]C1C(C(OCC)=O)=NNC=1C.[CH2:13]([N:17]([CH2:34][CH2:35][CH2:36][CH3:37])[C:18]([C:20]1[CH:24]=[C:23]([CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[NH:22][N:21]=1)=[O:19])[CH2:14][CH2:15][CH3:16]>>[CH2:34]([N:17]([CH2:13][CH2:14][CH2:15][CH3:16])[C:18]([C:20]1[C:24]([Cl:1])=[C:23]([CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[NH:22][N:21]=1)=[O:19])[CH2:35][CH2:36][CH3:37]
Reactant: CCOC(=O)c1n[nH]c(C)c1Cl
Reactant: CCCCN(CCCC)C(=O)c1cc(CCOC2CCCCO2)[nH]n1
Product: CCCCN(CCCC)C(=O)c1n[nH]c(CCOC2CCCCO2)c1Cl
Yield: 79 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1A, N,N-dibutyl-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole-3-carboxamide (355 mg, 1.01 mmol) was converted to the title compound (327 mg, 79%). 1H NMR (CD3OD) δ 4.60 (t, J=3.4 Hz, 1H), 3.94 (td, J=9.7, 6.5 Hz, 1H), 3.79-3.61 (m, 2 H), 3.59-3.41 (m, 3H), 3.39-3.25 (m, 2H), 3.04-2.91 (m, 2H), 1.87-1.34 (m, 12H), 1.27-1.09 (m, 2H), 0.99 (t, J=7.3 Hz, 3H), 0.81 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 386.3 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:21](=[O:22])[O:20]/[C:9](=[C:10](/[C:17]([OH:19])=[O:18])\[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)/[C:8]=2O)=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C>>[CH:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:17](=[O:19])[O:18][C:8]3=[C:7]([C:4]4[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=4)[C:21]([O:20][C:9]=23)=[O:22])=[CH:12][CH:13]=1
Reactant: O=C1O/C(=C(/C(=O)O)c2ccccc2)C(O)=C1c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC2=C(c3ccccc3)C(=O)OC2=C1c1ccccc1

Procedure:
Pulvinic acid (19.0 g., 0.0616 mol.) was refluxed in 250 ml. of acetic anhydride for 15 minutes. The cooled solution was stirred into 1200 ml. of ice and water and the oily mass was crystallized by stirring in 500 ml. of ethanol. The yellow solid was removed, washed with ethanol and dried to yield pulvinic acid lactone, m.p. 221.5- 223°.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][OH:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH3:22]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:10][CH2:9][CH2:8][N:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCCC1
Temperature: 25 °C
Yield: 39.9 %

Procedure:
Add NaH (3.2 g, 80 mmol) portionwise to a 0° C. solution of 2-pyrrolidin-1-yl-ethanol (9.4 mL, 80 mmol) in DMF (180 mL). Stir the reaction 15-20 min until gas evolution ceases. Add a solution of 1-chloro-2-methoxy-4-nitro-benzene (15.0 g, 80 mmol) in DMF (100 mL) via cannula. Warm the reaction to 130° C. and stir for approximately 18 h. Cool to RT and dilute with EtOAc (300 mL). Wash with water (2×100 mL). Extract the organic layer with 1 N HCl (3×150 mL). Wash this acidic layer with EtOAc (100 mL) then basify by adding 1 N NaOH (500 mL) until pH=8-9. Extract the now basic aqueous layer with CH2Cl2 (3×150 mL). Dry the organic layer over Na2SO4 and concentrate to provide 8.5 g (40%) of the desired product as an orange solid. MS/ES m/z 267.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[C:38]([N:41]1[CH2:46][CH2:45][N:44]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:43][CH2:42]1)(=[O:40])[CH3:39]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and N-acetylpiperazine according to conditions described in general procedure C. Mp: 102-104° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.61 (m, 6 H), 1.96 (s, 3 H), 3.28-3.30 (m, 4 H), 3.36 (s, 4 H), 3.47-3.51 (m, 4 H), 6.25 (d, J=5.5 Hz, 1 H), 6.94-6.98 (m, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.42 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.54-7.62 (m, 3 H), 7.82-7.84 (m, 1 H), 7.98-8.00 (m, 1 H), 8.28 (d, J=5.5 Hz, 1 H), 10.44 (s, 1 H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][CH:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[C:13]=1[OH:14])[CH3:7].CN(C)C1C=CC=CC=1>>[CH:15]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:6]([CH3:7])[CH3:5])[C:13]=1[O:14][C:1]([Cl:4])=[O:2])([CH3:17])[CH3:16]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Cl
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Phosgene (13 mL, 20% in toluene) was added to propofol (3.6 g, 20 mmol) under a nitrogen atmosphere. The mixture was cooled to 0° C. and N,N-dimethylaniline (3.3 mL, 26 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature slowly and stirred for 14 h. The solvent was removed in vacuo. The crude product was carried to next step without further purification.
Reaction SMILES: C([O:9][C@@H:10]1[C@:14]([C:16]#[CH:17])([OH:15])[C@H:13]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:12]([CH2:27][O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11]1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1>[C:19]([O:18][C@@H:13]1[C@@H:12]([CH2:27][O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C@@H:10]([OH:9])[C@:14]1([C:16]#[CH:17])[OH:15])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#C[C@]1(O)[C@@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#C[C@]1(O)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate (2R,3R,4R,5R)-2,4-dibenzoyloxy-5-benzoyloxymethyl-3-ethynyl-tetrahydro-furan-3-ol (2.048 g, 4.21 mmol, 1.0 equiv.) is dissolved in methanol (10 ml) and THF (10 ml). K2CO3 (176 mg, 1.26 mmol, 0.3 equiv.) is added, The reaction is stirred at ambient temperature for 2 h, filtered on silica gel, concentrated and purified by flash chromatography to give (2R,3R,4R,5R)-4-benzoyloxy-5-benzoyloxymethyl-3-ethynyl-tetrahydrofuran-2,3-diol as a foam. 1H-NMR (400 MHz, CDCl3): δ 8.06-7.96 (m, 4H), 7.54-7.26 (m, 6H), 5.88 (d, 0.26H, J=6.4 Hz), 5.54 (s, 0.72H), 5.53 (d, 0.72H, J=5.2 Hz), 5.41 (s, 0.28H), 5.28 (bs, 1H), 4.67-4.49 (m, 3H), 4.22 (bs, 1H), 2.67 (s, 0.26H), 2.59 (s, 0.71H); 13C-NMR (100 MHz, CDCl3): δ 166.74, 166.61, 165.74, 165.66, 133.79, 133.71, 133.52, 133.33, 133.24, 130.11, 130.05, 130.02, 129.89, 129.81, 129.44, 129.41, 128.86, 128.75, 128.57, 128.41, 128.36, 81.87, 80.07, 79.23, 77.89, 77.21, 76.61, 76.39, 75.77, 75.58, 72.83, 65.29, 64.26.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=1[O:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=4[O:30][CH3:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCN1CCC(c2noc3cc(Cl)ccc23)CC1
Yield: 98.2 %

Procedure:
A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2 benzisoxazole (4.6 g, 19 mmol), 1-[4-(2-chloroethoxy)-3- methoxyphenyl]ethanone (4.3 g, 19 mmol), K2CO3 (2.8 g), a few crystals of KI and acetonitrile (120 ml) was refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to yield 8.0 g of yellow solid. The solid was chromatographed on a Waters Prep 500 LC (silica columns, eluting with methylene chloride/methanol, 5%). Concentration of the appropriate fractions yielded 3.2 g of a light yellow solid, which upon recrystallization from ethyl acetate afforded 2.3 g (28%) of 1-[4-[2-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methoxyphenyl]ethanone as a pale yellow solid, m.p. =133°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][C:11]([C:12]#[N:13])([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:30]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(OC)c(OC)c1
Temperature: 10 °C

Procedure:
Combined 3,4-dimethoxy-phenyl-acetonitrile (20.0 g, 113 mmol) and THF (100 mL). Cooled in a dry-ice/acetone bath. Added dropwise, sodium bis(trimethylsilyl)amide (226 mL, 1.0M in THF, 226 mmol, 2 eq.). After the addition was complete, allowed to warm to 10 ° C. Cooled in a dry-ice/acetone bath. Added dropwise, ethyl bromoacetate (37.7 g, 226 mmol). After the addition was complete, the reaction mixture was allowed to warm to ambient temperature and maintained overnight. Filtered the reaction mixture and concentrated in vacuo to obtain a residue. The residue was partitioned between diethyl ether (600 mL) and water (200 mL). The organic layer was extracted with water (200 mL), saturated NH4Cl (2×100 mL), dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. Chromatographed on silica gel eluting with ethyl acetate/hexane (1:2) to obtain the title compound: Rf =0.42 (silica gel, 1:2 ethyl acetate/hexane).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:22]=[C:23]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:32]=4)[C:24]4[S:29][CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:22]=[C:23]([O:30][C:31]4[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=4)[C:24]4[S:29][CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc3ccsc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCNCC4)cc3)nc3ccsc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
The compound (600 mg, 1.05 mmol) obtained in Step 1 was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.62 mL, 21.0 mmol) was added thereto, followed by stirring at room temperature for 1 hour. After the reaction was complete, the reaction mixture was distilled under a reduced pressure to remove solvent, alkalify (pH 8) with sat. NaHCO3 aqueous solution, and extracted with chloroform 2 times. The organic layer was separated, washed with water and sat. brine, dried with anhydrous sodium sulfate, and then filtered and distilled under a reduced pressure. The residue was separated by column chromatography (chloroform:methanol=10:1 (volume ratio)) to obtain the title compound (yield: 316 mg, 72%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.[S].[OH2:10]>>[CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]([S:5][CH2:4][C:3]([OH:2])=[O:10])=[CH:7][CH:8]=1
Reactant: COCc1cccs1
Reactant: O
Agent: [S]
Product: COCc1ccc(SCC(=O)O)s1
Reaction time: 2 h
Yield: 18 %

Procedure:
Using a similar procedure to that described in Example 32, part (i), 2-methoxymethylthiophene (10.09 g) was lithiated and reacted with sulphur at 25°-30° C. After stirring the reaction mixture for 2 hours, the mixture was poured into water (150 ml) and the aqueous layer separated. A solution of potassium carbonate (5.45 g) and chloroacetic acid (7.45 g) in water (25 ml) was added to the aqueous layer, and the mixture allowed to stand for 18 hours. The mixture was acidified to pH 2 with 2 M hydrochloric acid and extracted with ether (2×150 ml). The organic extracts were combined, dried (MgSO4), treated with activated carbon, and evaporated, to give 2-(2-methoxymethylthien-5-ylthio)acetic acid as a viscous brown oil (3.1 g, 18% yield); NMR: 3.26(s,2H), 3.6(s,2H), 4.52(s,2H), 6.95(d,1H), 7.09(d,1H); m/e (chemical ionisation) 236 (M+NH4)+.