Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.C[O-].[Na+].Cl[C:15]1[C:16]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[N:17][C:18]2[C:23]([N:24]=1)=[CH:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=2.CS(C)=O>ClCCl.O>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:16]2[C:15]([N:7]3[CH2:8][CH2:9][CH2:10][CH:5]([CH2:4][O:3][CH3:2])[CH2:6]3)=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=3)[N:17]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: COCC1CCCNC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COCC1CCCN(c2nc3cc(C(=O)OC)ccc3nc2-c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 50-mL sealed tube, was placed a solution of 3-(methoxymethyl)piperidine hydrochloride (170 mg, 1.03 mmol, 2.00 equiv) in dichloromethane (7 mL), and sodium methoxide (128 mg, 2.37 mmol, 5.00 equiv). The resulting solution was stirred for 3 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum and was added into a 8-mL sealed tube with methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol, 1.00 equiv) and DMSO (4 mL). The mixture was stirred overnight at 100° C. Water was added to quench the reaction and the resulting solids were collected by filtration. The residue was purified by silica gel column chromatography with PE/EA (50:1). This resulted in 179.9 mg (88%) of methyl 2-(4-fluorophenyl)-3-(3-(methoxymethyl)piperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [Cl:1]C(N(C)C)=C(C)C.[CH3:9][N:10]1[CH:14]=[C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:12]=[C:11]1[C:23]([OH:25])=O>C(Cl)(Cl)Cl>[CH3:9][N:10]1[CH:14]=[C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:12]=[C:11]1[C:23]([Cl:1])=[O:25]
Reactant: Cn1cc(NC(=O)OC(C)(C)C)nc1C(=O)O
Reactant: CC(C)=C(Cl)N(C)C
Solvent: ClC(Cl)Cl
Product: Cn1cc(NC(=O)OC(C)(C)C)nc1C(=O)Cl

Procedure:
N-(1-chloro-2-methylprop-1-enyl)-N,N-dimethylamine (660 μL, 4.99 mmol) was added to a mixture of 1-methyl-4-(BOC amino)imidazole-2-carboxylic acid (1.00 g, 4.17 mmol) in CHCl3 (8.00 mL). After a few minutes, the 1H-NMR of the reaction mixture showed complete conversion of the acid to the acid chloride. 1H NMR (CDCl3): δ 7.48 (br s, 1H), 3.95 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.Cl.[SH:20][C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([S:20][C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Cc1ccnc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccnc(Sc2nc(-c3ccc(Cl)cc3)c(CCC(=O)O)o2)n1
Yield: 87.8 %

Procedure:
A mixed solution of 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (1.43 g), 2-mercapto-4-methylpyrimidine hydrochloride (1.05 g), potassium carbonate (2.76 g) and N,N-dimethylformamide (20 mL) was stirred at 110° C. under a nitrogen atmosphere for 10 hrs. The reaction mixture was diluted with water, and acidified with 2N aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration and recrystallized from methanol to give 3-[4-(4-chlorophenyl)-2-[(4-methylpyrimidin-2-yl)sulfanyl]-5-oxazolepropionic acid (1.65 g, yield 88%) as colorless prism crystals. melting point: 174–175° C.
Reaction SMILES: [C:1]1([C:7](Cl)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O-:28])(=[O:27])[C:24]([CH3:26])=[CH2:25].[K+]>>[C:23]([O:28][C:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)[O-]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Product: C=C(C)C(=O)OC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1

Procedure:
Diphenyl(p-methoxyphenyl)methyl chloride was reacted with potassium methacrylate using the procedure of Example 1 to produce diphenyl(p-methoxyphenyl)methyl methacrylate (hereinafter abbreviated to MTMA).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1>>[C:17]1([CH3:21])[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH:16]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(NS(=O)(=O)c2ccc(C(=O)O)cc2)c1

Procedure:
4-(chlorosulfonyl)benzoic acid (500 mg, 2.27 mmol) was treated with m-toluidine (729 mg, 6.8 mmol) using method A to give 4-(N-m-tolylsulfamoyl)benzoic acid as an off white solid. Yield: 463 mg (70%). 1H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.22 (t, J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 3.14 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>>[C:21]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)(=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC(=O)Cl
Reactant: Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Product: CCCC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-chlorobenzoyl)indole (Example 30) and butyryl chloride. m.p.: 157-158° C. 1H-NMR (CDCl3) δ: 9.96 (1H, br s), 8.29 (1H, d, J=8.8 Hz), 8.17 (1H, br s), 7.78 (1H, dd, J=1.5, 1.8 Hz), 7.70-7.59 (2H, m), 7.51 (1H, t, J=7.7 Hz), 7.31 (1H, d, J=1.1 Hz), 7.11 (1H, dd, J=1.8, 8.8 Hz), 2.47 (2H, t, J=7.3 Hz), 1.88-1.75 (2H, m), 1.05 (3H, t, J=7.5 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([F:10])[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:20]1([CH2:26][S:27](Cl)(=[O:29])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:27]([CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:29])=[O:28])=[C:4]([F:10])[CH:3]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NCc1ccc(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(Cc1ccccc1)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a solution of (4-bromo-2-fluoro-phenyl)methanamine (3 g, 14.7 mmol) in dichloromethane (50 mL) was added N,N-diisopropylethylamine (3.3 mL, 19.1 mmol), followed by phenylmethanesulfonyl chloride (3.3 g, 17.6 mmol) and the reaction was stirred at ambient temperature for 3 hours. The reaction was diluted with dichloromethane and washed with water and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (20-100% EtOAc in heptane) to give N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-methanesulfonamide (4.22 g, 80% yield). LCMS (m/z) ES+ 358 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:24])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([C:15]([N:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1)=[O:16])([CH3:14])[CH2:6][CH2:5]2.[O:25]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:25][C:7]([CH3:14])([C:15]([N:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1)=[O:16])[CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:24]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCC(O)CC1)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)N2CCC(O)CC2)=C(C)C1=O
Yield: 90 %

Procedure:
Oxidation as described in protocol B, using 100 mg (0.302 mmol) of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-hydroxypiperidin-1-yl)methanone and 364 mg CAN (0.664 mmol) yielded 95 mg of a yellow syrup.
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[N:6][C:5]1=[O:27].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH:24]([C:21]1[CH:20]=[CH:19][C:18]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]#[CH:17])[CH:9]=3)[N:4]([CH2:3][C:2](=[O:1])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:5](=[O:27])[N:6]=2)=[CH:23][CH:22]=1)([CH3:26])[CH3:25]
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2CC(O)c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 200 mg (0.456 mmol) 1-(2-hydroxy-2-phenyl-ethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one in 2 ml acetone are added 0.17 ml (0.45 mmol) Jones reagent. After stirring for 30 minutes at rt aqueous work up followed by recrystallisation from ethyl acetate yields 4-(4-isopropyl-phenyl)-1-(2-oxo-2-phenyl-ethyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one.
Reaction SMILES: C(OC([N:6]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=2)[C@@:8]2([C@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:12][C:11](=[O:21])[NH:10][C@@H:9]2[C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:7]1=[O:37])=O)C.[OH-].[Na+]>CO>[Cl:36][C:33]1[CH:34]=[C:35]2[NH:6][C:7](=[O:37])[C:8]3([CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=4)[CH2:12][C:11](=[O:21])[NH:10][CH:9]3[C:22]3[C:23]([CH3:29])=[CH:24][CH:25]=[CH:26][C:27]=3[CH3:28])[C:30]2=[CH:31][CH:32]=1
Reactant: CCOC(=O)N1C(=O)[C@]2(c3ccc(Cl)cc31)[C@@H](c1c(C)cccc1C)NC(=O)C[C@H]2c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(C)c1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 70.7 %

Procedure:
In a manner similar to the method described in example 4d, (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,6-dimethylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.41 g, 0.76 mmol) was reacted with NaOH (0.4 g, 10 mmol) in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,6-dimethylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (Yield 0.25 g, 71%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17](O)=[O:18])=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([CH3:32])[CH:31]=1)[NH:28][N:27]=[CH:26]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[CH3:16][C:11]1[NH:12][C:13](=[O:15])[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:8][CH:7]=2)[C:10]=1[C:17]([NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([CH3:32])[CH:31]=1)[NH:28][N:27]=[CH:26]2)=[O:18]
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Reactant: Cc1cc(N)cc2cn[nH]c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2cc(C)c3[nH]ncc3c2)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
The product of Example 5, Step 2 (160 mg, 0.535 mmol, 1.00 equiv), 5-amino-7-methylindazole (79 mg, 0.535 mmol, 1.0 equiv), and EDC (123 mg, 0.642 mmol, 1.20 equiv) were suspended in 1.5 mL DMF. Et3N (0.089 mL, 0.642 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was triturated with EtOAc and CH2Cl2, filtered, and washed with CH2Cl2 to provide 82 mg (36%) of the title compound as an off white solid. MS (ES+) m/e 429 [M+H]+
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=2)[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1>CO>[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=2)[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: COC(=O)c1ccc2c(c1)c(C)nn2-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nn(-c2ccccc2)c2ccc(C(=O)O)cc12
Temperature: 50 °C

Procedure:
5N NaOH aqueous solution (6 ml) was added to the solution of methyl 3-methyl-1-phenyl-1H-indazole-5-carboxylate (2.66 g) in methanol 30 ml and stirred at 50° C. for over night. The cooled reaction mixture was quenched with 1N HCl aqueous solution (33 ml) and white precipitate was collected and dried in vacuo at 60° C. to give the title compound as a colorless solid
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH:11]2[C:16](=O)[CH2:15][CH2:14][S:13][CH2:12]2)=O)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:20]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:25]=2)[CH:21]=[CH:22][N:23]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:11]3[CH2:12][S:13][CH2:14][CH2:15][C:16]=3[N:33]=[C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([N:20]4[CH:21]=[CH:22][N:23]=[C:19]4[CH3:18])=[CH:25][CH:26]=3)[N:32]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCSCC1C(=O)Cc1ccc(F)cc1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CSCC3)cc1
Yield: 78 %

Procedure:
4-(4-Fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (103 mg, 78%) was synthesised from 3-(2-(4-fluorophenyl)acetyl)dihydro-2H-thiopyran-4(3H)-one and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for the synthesis of pyrimidines. MS (ES+) m/z 432.2 (M+H)+
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl.[CH3:27]O>>[CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:24])(=[O:25])[NH2:23])[C:14]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]([O:11][CH3:27])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CO
Agent: Cl
Product: CCCCSc1cc(C(=O)OC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid (2.5 g) and methanol (75 ml) is saturated with gaseous hydrogen chloride. The reaction mixture is allowed to warm during saturation. After cooling and standing for 5 hours, the reaction mixture is evaporated in vacuo. The residue is triturated with water and sufficient sodium hydrogen carbonate to neutralize traces of hydrochloric acid. The precipitated methyl 3-n-butylthio-4-phenoxy-5-sulfamylbenzoate is collected and recrystallized from methanol/water to yield the ester with a melting point of 122°-123°C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH3:35]COCC.O>O1CCOCC1>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:11][CH3:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOCC
Solvent: CI
Solvent: O
Solvent: C1COCCO1
Product: COC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
NaNH2 (0.616 g, 15.0 mmol) was added to a flame-dried two-necked 50 ml round bottom flask equipped with a reflux condenser which contained a solution of rac-1-O-benzyl-3-O-tritylglycerol (5.30 g, 12.5 mmol) in anhydrous 1,4 dioxane (30 ml). The reaction mixture was refluxed for one hour under N2. Then CH3I (3.55 g, 25.0 mmol) was added dropwise. The resulting reaction mixture was refluxed overnight. After the mixture had cooled to room temperature, ether and H2O were added. The ether layer was removed and extracted with 1N HCl , H2O, sat. NaHCO3, H2O, and brine. The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give a yellow oil which solidified upon standing. The crude solid was recrystallized with hexanes to yield pure compound 13, rac-1-O-benzyl-2-O-methyl-3-O-tritylglycerol (4.32 g, 78.9%).
Reaction SMILES: C([O:4][C@H:5]1[C@H:12]([O:13]C(=O)C)[C@@H:11]([CH2:17][O:18]C(=O)C)[O:10][C@H:7]([O:8][CH3:9])[C@H:6]1[Cl:22])(=O)C.C[O-].[Na+].C(Cl)(Cl)Cl.CO>CO>[Cl:22][C@H:6]1[C@@H:5]([OH:4])[C@H:12]([OH:13])[C@@H:11]([CH2:17][OH:18])[O:10][C@@H:7]1[O:8][CH3:9]
Reactant: CO[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1Cl
Yield: 90.8 %

Procedure:
A solution of (5) (1 g) in dry methanol (50 ml) was treated with a catalytic amount of sodium methoxide at room temperature for 24 h. T.l.c. (chloroform-methanol, 6:1) showed one product. The solution was deionised by shaking with Amberlyst--15 resin (Trade Mark) and concentrated to give (6) (0.57 g, 90%) as a syrup [α]D +59.9 (c 1.05, water).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][C:17]([OH:30])([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])=[S:10])=[C:6]([O:31][CH3:32])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].C(OCC)(=O)C.CCCCCC>C1COCC1>[CH3:32][O:31][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[S:10][C:9]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][C:17]([OH:30])([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH2:16][CH2:15]3)=[O:13])=[N:8][C:7]=12
Reactant: COc1ccnc(Cl)c1NC(=S)NC(=O)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccnc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Yield: 20 %

Procedure:
To a magnetically stirred mixture of 1-(2-Chloro-4-methoxy-pyridin-3-yl)-3-[4-hydroxy-4-(3-trifluoromethylphenyl)-piperidine-1-carbonyl]-thiourea (100 mg, 0.20 mmol) in THF (10 mL) was added sodium hydride (10 mg, 0.25 mmole, 60% dispersion in mineral oil). The reaction is stirred at reflux overnight. TLC (80% ethyl acetate/hexane) indicated complete consumption of starting material. The reaction was poured into water and the aqueous layer was extracted with ethyl acetate. The resulting organic layers were washed with 2N HCl (2×) and saturated sodium chloride solution and then dried over magnesium sulfate. Purification by flash chromatography gave 4-Hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-b]pyridine-2-yl)-amide (20 mg, 0.04 mmole, 22% yield) as a light yellow solid. (LRMS for C20H19F3N4O3S (M+H)+ at m/z=452.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(Oc2ccccn2)c1
Temperature: 130 °C
Reaction time: 30 h
Yield: 30.3 %

Procedure:
A suspension of 2-bromopyridine (commercially available) (2.0 g, 13.6 mmol), 3-bromophenol (CAS591-20-8) (4.4 g, 24.9 mmol), K2CO3 (5.2 g, 40 mmol) in DMF (30 mL) was stirred at 130° C. for 30 h. The mixture was filtered, concentrated, and purified by column chromatography to give titled compound (1.0 g, 30.3%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[O:4][CH2:5][Cl:6]
Reactant: COCCOCCOCCOCCOCCO
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOCCOCCOCCOCCOC(=O)OCCl

Procedure:
In a manner similar to the method described in Example 3, chloromethyl chloroformate (Aldrich) was reacted with pentaethylene glycol monomethyl ether (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give chloromethyl 2,5,8,11,14-pentaoxahexadecan-16-yl carbonate. This material was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), chiral 3-oxo-2,4,7,10,13,16,19-heptaoxaicosyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C44H54Cl2F2N3O12: [(M+H)+]: 924, found: 924.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CS(C)=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Br)ccc1N1CCOCC1
Reaction time: 0.17 h

Procedure:
To a solution of 4-bromo-1-fluoro-2-nitrobenzene (10.088 g, 45.9 mmol) in dimethyl sulfoxide (20.00 mL, 282 mmol) was added morpholine (6.00 mL, 68.8 mmol). A vigorous exotherm developed and the solution turned an intense orange-red. After 10 min LC-MS indicated no starting material remained and the desired product predominated. The reaction was poured into 200 mL satd aq. Sodium bicarbonate solution and the aq. Mixture was extracted with 200 mL Et2O. The ether extract was washed with 100 mL water followed by 100 mL brine then stirred over anhydrous magnesium sulfate, filtered and the filtrate concd under reduced pressure to afford an orange oil. Mass Spectrum (ESI) m/e=287.0 & 289.0 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>ClC1C=CC=CC=1>[CH2:9]([C:8]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[S:6][CH:7]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCC(=O)CSc1cccs1
Solvent: Clc1ccccc1
Product: CCCCCCCCCCc1csc2sccc12
Yield: 56.3 %

Procedure:
A solution of 1-(thiophen-2-ylsulfanyl)-dodecan-2-one (3.40 g, 11.4 mmol) and amberlyst 15 (5.5 g) in chlorobenzene (200 mL) are refluxed over 4 A molecular sieves (Soxhlet) for 16 h. The reaction is cooled, filtered and concentrated under reduced pressure. The resulting residue is dissolved in petrol and filtered though a small plug of silica to remove coloured impurities. The organics are concentrated under reduced pressure and further purified by column chromatography over RP18 silica (eluant:acetonitrile). The first fraction is collected to afford the product as a colourless oil (1.8 g, 56%). M/Z 280 (M+). 1H NMR (300 MHz, CDCl3) δ 7.34 (1H, dd), 7.18 (1H, d), 6.93 (1H, d), 2.75 (2H, t), 1.70 (2H, quint), 1.40-1.20 (14H, m), 0.88 (3H, t). 13C NMR (75 MHz, CDCl3) δ 147.3, 136.9, 135.1, 127.8, 122.4, 119.0, 31.9, 29.8, 29.65, 29.63, 29.50, 29.49 (2C), 29.4, 22.7, 14.2.