Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O.S1C=CC=C1C1C=CC=CC=1C(O)=O.[F:31][C:32]([F:48])([F:47])[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([N:39]2[C@@H:46]3[C@@H:41]([CH2:42][CH2:43][NH:44][CH2:45]3)[CH2:40]2)[CH:34]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[C:7]([C:8]([N:44]2[CH2:43][CH2:42][C@@H:41]3[C@@H:46]([N:39]([C:35]4[CH:34]=[C:33]([C:32]([F:48])([F:31])[F:47])[CH:38]=[CH:37][N:36]=4)[CH2:40]3)[CH2:45]2)=[O:10])[CH:11]=1
Reactant: COc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)c1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: COc1ccc(-n2nccn2)c(C(=O)N2CC[C@H]3CN(c4cc(C(F)(F)F)ccn4)[C@H]3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 1 substituting 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid for 2-thiophen-2-yl-benzoic acid and Intermediate 44 for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane. MS (ESI) mass calcd. for C22H21F3N6O2, 458.5; m/z found, 459.2 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[C:17]([Cl:18])=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([CH2:13][OH:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Mn]([O-])(=O)(=O)=[O:20].[K+]>>[C:1]([C:6]1[C:17]([Cl:18])=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([C:13]([OH:20])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc2nc(CO)n(C)c2cc1Cl
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CCCC(=O)c1cc2nc(C(=O)O)n(C)c2cc1Cl

Procedure:
In a manner analogous to that described in Example 12, 2.7 g of 5-butyryl-6-chloro-1-methyl-benzimidazole-2-methanol are oxidised with 2.5 g of potassium permanganate to give 5-butyryl-6-chloro-1-methyl-benzimidazole-2-carboxylic acid with a melting point of 90° (decomposition).
Reaction SMILES: C1(S([CH2:10][C:11](=[CH2:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)=O)C=CC=CC=1.[SnH:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[CH2:27]([Sn:18]([CH2:10][C:11](=[CH2:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29][CH3:30]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C=C(CS(=O)(=O)c1ccccc1)C(=O)OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: C=C(C[Sn](CCCC)(CCCC)CCCC)C(=O)OCC

Procedure:
This compound was prepared from ethyl α-(benzenesulphonylmethyl)acrylate, n-Bu3SnH and AIBN in benzene at 80° C. for 1.5 h according to the procedure described in Journal of the Chemical Society, Chemical Communications, 1986, 1339-1340. 1H NMR (CDCl3) δ 0.85-1.65 (30H, m, 3×CH2CH2CH2CH3, OCH2CH3), 2.00 (2H, s, allylic CH2Sn), 4.15 (2H, q, OCH2CH3, J 7.5 Hz), 5.25 (1H, s, olefinic proton), 5.75 (1H, s, olefinic proton).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].C(#N)C.[C:10]1([CH2:16][CH2:17][C:18](Cl)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:16][CH2:17][C:18]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COC(=O)NN
Solvent: CC#N
Product: COC(=O)NNC(=O)CCc1ccccc1
Reaction time: 15 h
Yield: 80.7 %

Procedure:
To a solution of 18 g. (0.2 moles) of methyl carbazate and 100 ml. of acetonitrile 33.7 g (0.2 moles) of β-phenylpropionyl chloride are added dropwise. The reaction mixture is heated to boiling for 15 hours, clarified and cooled. The crystals are filtered off. Thus 36.85 g of the desired compound are obtained, yield 80.7% m.p.: 118° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([C:34]#[C:35][CH2:36][CH3:37])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28]([C:34]#[C:35][CH2:36][CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCC#C[C@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC#C[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 19 h
Yield: 57.3 %

Procedure:
To a stirred solution of 25.2 (0.050 g, 0.10 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting mixture was stirred for 19 hours. The reaction mixture was then concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted with EtOAc, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 25 (28 mg, 56% yield) as a colorless oil. MS ESI (neg.) m/e: 487.1 (M−H)+.
Reaction SMILES: N1C(C)=CC=CC=1C.[F:9][C:10]([F:23])([F:22])[S:11]([O:14]S(C(F)(F)F)(=O)=O)(=[O:13])=[O:12].[C:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[C@H:25]([CH3:27])O>ClCCl>[F:9][C:10]([F:23])([F:22])[S:11]([O:14][C@@H:25]([CH3:27])[C:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:13])=[O:12]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@H](O)C(=O)OC(C)(C)C
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C[C@H](OS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 90 %

Procedure:
In a 500 ml round-bottomed flask, 3.00 g of tert-butyl L-lactate (ee>99%) was dissolved in 165 ml of absolute dichloromethane and cooled to 0° C. under argon. Thereafter, first 3.10 ml of 2.6-lutidine and then slowly 4.15 ml of trifluoromethanesulphonic anhydride were added in succession and the reaction was stirred for 50 min at 0° C. Thereafter, the reaction mixture was diluted with 400 ml of petroleum ether, washed 4 times with 250 ml of a 3:1 mixture of saturated aqueous sodium chloride solution and 1 N hydrochloric acid, dried over MgSO4 and concentrated in vacuo. The residue was applied to a silica gel filter and washed off said filter with a 1:1 mixture of petroleum ether and dichloromethane. After removal of the solvent, the pure tert-butyl (S)-2-trifluoromethanesulphonyloxypropionate (ee>99%) was obtained in a yield of 90%.
Reaction SMILES: CO/N=[C:4](/[C:12]1[O:17][CH2:16][CH2:15]ON=1)\C1C=CC=CC=1O.[C:18]([O:27][CH3:28])(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21].C(=O)([O-])[O-:30].[K+].[K+]>>[CH2:16]([O:17][C:12](=[O:30])[CH2:4][O:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[C:18]([O:27][CH3:28])=[O:26])[CH3:15]
Reactant: CO/N=C(/C1=NOCCO1)c1ccccc1O
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccccc1O
Agent: [K+]
Product: CCOC(=O)COc1ccccc1C(=O)OC

Procedure:
A synthesis of (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) is illustrated in Scheme 2A. According to the synthesis, methyl salicylate reacts with ethyl chloro acetate in the presence of potassium carbonate to give methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6). Hydrolysis of methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6) followed by a consecutive cyclization of 2-(carboxymethoxy)benzoic acid (7) with acetic anhydride in the presence of sodium acetate gives benzofuran-3-yl acetate (8) which is converted to benzofuran-3(2H)-one (9) by methanolysis. Treatment of benzofuran-3(2H)-one (9) with O-methylhydroxylamine and sodium acetate affords benzofuran-3(2H)-one O-methyl oxime (10) which is oxidized with tert-butyl nitrate in hydrochloric acid to yield (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A). In the presence of potassium hydroxide, (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A) opens ethylene oxide resulting (3E)-benzofuran-2,3-dione O2-(2-hydroxyethyl) O3-methyl dioxime (12A) that undergoes potassium hydroxide-catalyzed cyclization to provide (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9])[NH2:5].[C:11](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:11][NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=1
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CNc1cc(Cl)c(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 72 h
Yield: 41.9 %

Procedure:
To a 100 ml three neck round bottom flask was added 3,4,5-trichloroaniline (1.96 g), potassium carbonate (1.66 g), acetonitrile (25 mL) and iodomethane (1.42 g). The reaction mixture was stirred at 40° C. for 3 days under nitrogen in the dark. The reaction mixture was then quenched with ethyl acetate (50 ml) and filtered. The residue was washed with ethyl acetate (3×20 ml). The filtrate and the washings were combined and washed with water (3×30 ml). The organic layer was then filtered through anhydrous MgSO4 and evaporated under reduced pressure. The residue was dissolved in a minimum amount of ethyl acetate/hexane 1:12 and the solution was placed on a wet column of silica gel (80 g) and eluted with ethyl acetate/hexane 300 ml (1:12), 500 ml (1:8) to afford 0.88 g of N-methyl-3,4,5-trichloraniline (42%) as a white solid. The product was used directly for the condensation without characterization. To a 100 ml three neck round bottom flask was added anhydrous DMSO (5 ml), N-methyl-3,4,5-trichloroaniline (0.88 g) crude compound 117 (0.20 g) and anhydrous potassium carbonate (0.56 g). The reaction mixture was stirred at 45° C. for 24 h and then quenched with distilled water (15 ml). The resulting suspension was stirred at room temperature for 4 h and filtered. The residue was extracted with MeOH (100 ml) several times and the extracts which showed a major spot of the product on TLC were pooled and mixed with silica gel (2 g). The mixture was evaporated under reduced pressure and dried in vacuo. The residue was ground into fine powder and poured on top of a dry column of silica gel (40 g). The column was eluted with 3% MeOH in CHCl3. Fractions corresponding to a single spot of the product were pooled and evaporated. The residue was washed with ether and air dried to afford 0.06 g (16% for two steps) of compound 432 as a light yellow solid.
Reaction SMILES: [S:1]1[CH:9]2[C:4]([CH2:5][NH:6][CH2:7][CH2:8]2)=[CH:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[CH:22]([Si:25]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])Cl)([CH3:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[CH:22]([Si:25]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[O:10][C:2]1[S:1][C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1)([CH3:24])[CH3:23].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=C1C=C2CNCCC2S1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](Oc1cc2c(s1)CCNC2)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2.00 g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluenesulfonate, 1.29 g of triisopropylchlorosilane, 0.66 g of triethylamine and 7 ml of methylene chloride was stirred at room temperature for 3 hours. The produced 2-triisopropylsilyloxy-4,5,6,7-tetrahydrothieno-[3,2-c]pyridine-p-toluenesulfonate was not isolated, 0.96 g of 2-chlorobenzyl chloride and 1.21 g of triethylamine were added thereto, and the mixture was allowed to react under further stirring at 40° C. for 10 hours.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[CH:10]=[CH:9][C:8]=1[NH:25][C:26](=[O:28])[CH3:27])[CH2:2]CC.[Br-].[Li+].N12CCCN=C1CCCCC2>C(O)C>[CH2:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[CH:10]=[CH:9][C:8]=1[NH:25][C:26](=[O:28])[CH3:27])[CH3:2]
Reactant: CCCCOC(=O)c1cc(CCc2cc(OC)ccc2OC)ccc1NC(C)=O
Agent: [Br-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc(CCc2cc(OC)ccc2OC)ccc1NC(C)=O

Procedure:
A mixture of 93 mg of 5-[2-(2,5-dimethoxyphenyl)ethyl]-2-acetylamino-benzoic acid butylester, 100 mg of lithium bromide, 55 mg of 1,8-diazabicyclo[5.4.0]undec-7-en and 4 ml of dry ethanol is heated to reflux for 3 hours. After neutralisation with 0.1 N aqueous hydrochloric acid, the mixture is extracted with ethyl acetate. The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. The pure title compound is obtained by silica gel chromatography (hexane/ethyl acetate=6/1) as colourless crystals. mp: 93°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1C.[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:30](=O)([O-])[O-].[K+].[K+].[I-].[K+]>C1(C)C(C)=CC=CC=1>[C:13]1([CH3:30])[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:21]2[CH2:22][CH2:23][C:18]([OH:17])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20]2)=[CH:15][CH:14]=1
Reactant: Cc1ccccc1CCCCCCCCCl
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: Cc1ccc(CCCCCCCCN2CCC(O)(c3ccccc3)CC2)cc1
Yield: 75.1 %

Procedure:
10 g (40 mmol) of 1-chloro-8-tolyloctane, 21.2 g (120 mmol) of 4-hydroxy-4-phenylpiperidine, 5.52 g (40 mmol) of potassium carbonate and 3.3 g (20 mmol) of potassium iodide are heated with 30 ml of xylene at 160° C. for 8 h. The solvent is removed by distillation under reduced pressure. The residue is taken up in dichloromethane/dilute sodium hydroxide solution, and the organic extract is worked up in a conventional manner. The low-boiling compounds are removed by distillation under reduced pressure up to 150° C./0.9 mbar. 11.4 g (94%) of a resin are obtained (see Tab. 1 for physical data).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:10]=[C:11](N)[S:12][CH:13]=1.Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]1([CH3:15])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:10]=[C:11]([C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:24])[S:12][CH:13]=1
Reactant: Cc1cc(C)c(-c2csc(N)n2)c(C)c1
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C)c(-c2csc(C(=O)c3ccncc3)n2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 4-mesitylthiazol-2-amine (7.8 g, 37 mmol)4 in CH2Cl2 (200 mL) was added DMAP (9.0 g, 74 mmol) followed by isonicotinoyl chloride hydrochloride (8.5 g, 48 mmol). Then the mixture was stirred at room temperature for 2 hr. After that, the concentrated mixture was subjected to purification by silica gel chromatography followed by recrystallization from ethanol to give INH41 (10.2 g, 85%) as a white solid; mp 202-203° C. 1H NMR (400 MHz, CDCl3) δ 12.71 (br, 1H), 8.65 (dd, 2H, J=1.6, 4.8 Hz), 7.47 (dd, 2H, J=1.6, 4.8 Hz), 6.79 (s, 1H), 6.54 (s, 2H), 2.15 (s, 3H), 1.87 (s, 6H). 13C NMR (100.5 MHz, CDCl3) δ 164.0, 159.4, 150.2, 148.4, 138.7, 138.0, 136.8, 130.8, 128.5, 121.2, 112.3, 21.1, 20.4. MS (ESI) m/z 324.1 (M+H+), 346.1 (M+Na+). HRMS calculated. for C18H18N3OS (M+H+): 324.1171. found: 324.1167; calculated. for C18H17N3OSNa (M+Na+): 346.0990. found: 346.0984.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O.CC(C)=O>[C:16]1(=[O:25])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=2)[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Oc1cc(Br)cc(Br)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1cc(Br)cc(Br)c1
Yield: 37.3 %

Procedure:
3,5-dibromophenol (970 mg, 3.85 mmol) was recrystallized from hexanes. After removal of solvent, N-(4-bromobutyl)phthalimide (1.38 g, 4.89 mmol), K2CO3 (1.88 g, 13.6 mmol), 18-crown-6 (53 mg, 0.20 mmol), and acetone (20 mL) were added. This was refluxed for 1 hour, and then poured into 100 mL of water. The aqueous layer was extracted with dichloromethane (4×30 mL). The organic layers were combined, washed with water, saturated NaHCO3, and brine, then dried over MgSO4 and filtered. Removal of solvent yielded a white solid, which was purified by column chromatography (4:1 hexanes:CH2Cl2) followed by recrystallization in hexanes to yield colorless needles (650 mg, 87%). 1H NMR (CDCl3): 7.860 (m, 2H); 7.733 (m, 2H); 7.220 (t, J=1.6 Hz, 1H); 6.964 (d, J=2.0 Hz, 2H); 3.962 (t, J=6.0 Hz, 2H); 3.770 (t, J=6.6 Hz, 2H); 1.846 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH:7]([CH3:13])[CH2:8]2)[NH:3]1.[CH2:15]1[O:17][CH2:16]1>C(O)CCCCCCC>[OH:17][CH2:16][CH2:15][N:3]1[CH:4]2[CH:9]([CH2:8][CH:7]([CH3:13])[CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:14])[CH3:1]
Reactant: C1CO1
Reactant: CC1CCC2NC(C)(C)CC(C)C2C1
Solvent: CCCCCCCCO
Product: CC1CCC2C(C1)C(C)CC(C)(C)N2CCO
Temperature: 200 °C

Procedure:
1-(2'-hydroxyethyl)-2,2,4,6-tetramethyl decahydroquinoline was prepared. 50 grams of 2,2,4,6-tetramethyl decahydroquinoline and 50 milliliters of 1-octanol were placed into a reactor vessel equipped for heating and agitation and he mix heated to 200° C. Ethylene oxide was then slowly added to the reactor over a period of 7 hours. The reaction mixture was then distilled to yield a liquid product boiling at 106° C. at 0.5 mm Hg. The NMR and infrared spectra were consistent with the desired product. Calculated contents and analyzed contents of the product (formula of C15H29NO) were respectively: 75.26% carbon, 74.36% carbon found; 12.21% hydrogen, 12.24% hydrogen found; and 5.85% nitrogen, 6.04% nitrogen found.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]([OH:29])(=O)[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].[CH3:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].CS(O)(=O)=O>O>[C:25]([O:27][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:1]/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:29]
Reactant: O=C(O)CCCCC(=O)O
Reactant: CCCCCCC
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Agent: CS(=O)(=O)O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)CCCCC(=O)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C

Procedure:
Dioleyl adipate was synthesized by refluxing 733 grams (2.73 moles) oleyl alcohol, 190 grams (1.30 moles) adipic acid, 340 grams (500 ml.) heptane and 1.9 grams (0.02 mole) methane sulfonic acid under a nitrogen atmosphere for 5 hours, in a 3-liter, 3-necked flask equipped with an air driven stirrer, thermometer, reflux condenser and heating mantle. Approximately 47 ml. of water produced in the reaction was removed in a Dean-Stark trap. The reaction mixture was cooled to 25° C., diluted with 500 ml. of hexane and the resulting solution was washed 3 times with successive 200 ml. portions of 2% aqueous sodium hydroxide and water, followed by a water wash until the solution tested neutral using PH paper. The washed solution was clarified by vacuum filtration through a 1.4 inch bed of celite and dried over molecular sieves. Rotary evaporation removed most of the solvent from the reaction mixture. The remaining solvent was removed from the reaction mixture by high vacuum stripping at a pressure of 0.3 mm. Hg and a temperature of about 250° C. to about 265° C. The dioleyl adipate produced was examined and found to contain 2.1% oleyl alcohol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([NH:27][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:29][CH3:30])=[O:26])=[CH:22][CH:23]=3)[C:18]([CH3:37])=[C:17]2[CH3:38])=[CH:11][CH:10]=1)#[N:2].[Si]([N:43]=[N+:44]=[N-:45])(C)(C)C>C1(C)C=CC=CC=1>[NH:43]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([NH:27][CH:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:29][CH3:30])=[O:26])=[CH:22][CH:23]=4)[C:18]([CH3:37])=[C:17]3[CH3:38])=[CH:13][CH:14]=2)=[N:2][N:45]=[N:44]1
Reactant: CCC(NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C#N)cc1)c1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCC(NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1ccccc1

Procedure:
To a solution of 1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-N-(1-phenylpropyl)-1H-indole-5-carboxamide (27 mg, 0.05 mmol, 1 equiv) in toluene (0.6 mL) in a high-pressure vial were added TMSN3 (14 μL, 0.05 mmol, 2 equiv) and Bu2SnO (2 mg, 0.005 mmol, 0.1 equiv). The vial was sealed and the reaction mixture was heated at reflux for 2 h. After concentration, the residue was purified by preparative HPLC to afford a beige powder. ESI-MS (m/z): 541 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[NH:21][CH:22]2[CH2:31][CH2:30][C:25]3(OCC[O:26]3)[CH2:24][CH2:23]2)=[N:7]1)C.Cl>CO>[CH3:20][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([NH:21][CH:22]3[CH2:31][CH2:30][C:25](=[O:26])[CH2:24][CH2:23]3)[CH:15]=1)[NH:12][C:11]([C:8]1[S:9][CH2:10][C@@H:6]([CH2:5][C:4]([OH:32])=[O:3])[N:7]=1)=[CH:19]2
Reactant: CCOC(=O)C[C@@H]1CSC(c2cc3cc(C)cc(NC4CCC5(CC4)OCCO5)c3[nH]2)=N1
Agent: Cl
Solvent: CO
Product: Cc1cc(NC2CCC(=O)CC2)c2[nH]c(C3=N[C@H](CC(=O)O)CS3)cc2c1
Yield: 4.9 %

Procedure:
{(R)-2-[7-(1,4-dioxa-spiro[4,5]dec-8-yl)amino-5-methyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid ethyl ester (177 mg, 4 mmol) prepared in Step A was dissolved in methanol (10 mL). HCl (conc. 2 mL) was added thereto, and the mixture was reacted for 6 h at 60° C. The solvent was removed under reduced pressure, and water was added to the residue. The reaction mixture was extracted with EtOAc, dried, concentrated, and purified by HPLC to give the title compound (76 mg, Yield 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]#[C:19][CH3:20])[N:13]=[CH:12][N:11]=1)=[O:9].[CH3:21][Li].[Cl-].[NH4+]>O1CCCC1>[CH2:17]([O:16][C:14]1[CH:15]=[C:10]([C:8]([OH:9])([CH3:21])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:11]=[CH:12][N:13]=1)[C:18]#[C:19][CH3:20]
Reactant: [Li]C
Reactant: CC#CCOc1cc(C(=O)c2ccccc2F)ncn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(C(C)(O)c2ccccc2F)ncn1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
In 3.7 ml of tetrahydrofuran was dissolved 0.4 g of 6-(2-butynyloxy)pyrimidin-4-yl 2-fluorophenyl ketone, to which 3.6 ml (1.14 mol/l diethyl ether solution) of methyl lithium was added dropwise at −78° C. After stirring at −78° C. for 3 hours, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.34 g of 4-(2-butynyloxy)-6-(α-hydroxy-α-methyl-2-fluorobenzyl)pyrimidine (the present compound (157)).