Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>ClCCl.C(OCC)C>[Cl:26][CH2:27][C:28]([O:16][CH:11]1[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:13]([CH3:14])([CH3:15])[CH2:12]1)=[O:29]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)CC(OC(=O)CCl)CC(C)(C)N1OC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
A mixture of 45.2 g (0.177 mol) of 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, 17.9 g (0.177 mol) of triethylamine, and 150 ml of dichloromethane is added over a 1 hour interval at 5° C. to a solution of 20.0 g (0.177 mol) of chloroacetyl chloride in 100 ml of dichloromethane. The reaction mixture is stirred at ambient temperature for 1 hour and then diluted with diethyl ether (500 ml). Solids are removed by filtration, and the filtrate is washed with 1N hydrochloric acid (2×100 ml), saturated sodium bicarbonate solution (200 ml), and saturated sodium chloride solution (200 ml), then dried over magnesium sulfate and concentrated to obtain an oil. Purification by flash chromatography on silica gel (5:1 heptane: ethyl acetate) affords 22.6 g (39% yield) of the title compound, a white solid, mp 62°-4° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:6][C:7]=1[CH:8]([OH:10])[CH3:9])[CH3:2].[CH3:21][O:22][C:23](=[O:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][C:27]=1[CH3:33].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:21][O:22][C:23](=[O:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:10][CH:8]([C:7]2[O:6][C:5]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:4][C:3]=2[CH2:1][CH3:2])[CH3:9])=[CH:28][C:27]=1[CH3:33]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)Oc1ccc(CCC(=O)OC)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of 1-[4-ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol (0.114 g, 0.400 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.0789, 0.400 mmole) in toluene (2 mL) at room temperature, is added tributylphosphine (0.200 mL, 0.800 mmole) followed by a solution of 1,1′-(azodicarbonyl)-dipiperidine (0.201 g, 0.800 mmole) in toluene (2 mL). The reaction is stirred overnight, then diluted with hexane (10 mL). The precipitate is removed through filtration and the filtrate is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0–15%) and concentrated to provide the titled compound as a white solid. Mass [EI+] 462 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:16][CH2:17][CH2:18]Br.[H-].[Na+].O>O1CCCC1.CN(C)C=O>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:11]#[N:12])[CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:9]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2ccc(OC(F)(F)F)cc2)CCC1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
A solution of 4-trifluoromethoxyphenylacetonitrile (38.9 g) and 1,3-dibromopropane (39.1 g) in tetrahydrofuran (50 ml) was added under argon to a stirred solution of 50% sodium hydride (19.2 g) in tetrahydrofuran (200 ml) and dimethylformamide (25 ml) at 25°-30° C. over 1 hour. The mixture was stirred at 20° C. for 1.5 hours, then at 30°-40° C. for 1 hour, then cooled and water added. The mixture was filtered and washed with ether. The organic layer was washed with water, dried over magnesium sulphate and the solvent removed by evaporation. The residue was distilled (b.p. 111°-117° C./10 mbar) to give 1-(4-trifluoromethoxyphenyl)cyclobutanecarbonitrile (30.98 g).
Reaction SMILES: [N:1]([CH2:4]/[C:5](=[N:9]\[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[N:15]=1)/[C:6]([OH:8])=[O:7])=[N+:2]=[N-:3].C([N:27](C(C)C)CC)(C)C.[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)#[CH:34]>CC#N.C(O)(C)(C)C.[Cu]I>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([NH:10]/[N:9]=[C:5](\[CH2:4][N:1]3[CH:34]=[C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[N:3]=[N:2]3)/[C:6]([O-:8])=[O:7])[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22].[NH4+:27]
Reactant: CCN(C(C)C)C(C)C
Reactant: C#Cc1ccccn1
Reactant: [N-]=[N+]=NC/C(=N\Nc1nc(-c2ccc(Cl)c(Cl)c2)cs1)C(=O)O
Agent: [Cu]I
Solvent: CC#N
Solvent: CC(C)(C)O
Product: O=C([O-])/C(Cn1cc(-c2ccccn2)nn1)=N/Nc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Product: [NH4+]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
KY-767-batch-A To a solution of (E)-3-azido-2-(2-(4-(3,4-dichlorophenyl)thiazol-2-yl)hydrazono) propanoic acid (E)-KY-757, (100 mg) in CH3CN 1 ml, tert-butanol 0.4 ml was added diisopropylethylamine 96 ul followed by 2-ethynylpyridine (0.4 mmol, 41 ul), CuI (15 mg). The reaction stirred at rt for 3 h. LC-MS assay showed two isomers. The solvent was removed under pressure. The residue was purified on C18 reversed phase flash chromatography column employing a linear gradient of 0-30% A in B (flow rate 40 ml/min), were A is 10% NH4OH in CH3CN and B is water, yielding (14 mg, 18%) of pure (E)-KY-788. MS+(ESI) m/z 373.91, calcd mass 473.85.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH:5]=[O:6].C[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH:9]1[SH:19]>C1(C)C=CC=CC=1>[CH2:3]([O:4][C:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH:9]1[SH:19])=[O:6])[CH3:2]
Reactant: CCOC(=O)C1CCN(C)C(S)C1
Reactant: O=COCCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(C(=O)OCC)C(S)C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
106.3 g (0.88 mol) of chloroethylformate are added dropwise with stirring over a period of 30 minutes to a solution of 100 g (0.48 mol) of 1-methyl-4-ethoxycarbonyl-mercapto-piperidine in 80 ml of toluene which has been heated to 90° C. The solution is then heated for two hours to from 100° to 110° C. After repeated addition of 40 g of chloroethylformate the solution is heated for a further three hours. After leaving it to stand overnight at room temperature it is drawn off by suction using a glass fibre filter. The solution is concentrated on a rotary evaporator and the residue is distilled off. 20 g (94% of the theoretical yield) of 1-ethoxycarbonyl-4-ethoxycarbonyl-mercapto-piperidine are obtained. B.P. 138°-140° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=[O:12])[O:7][CH2:8]2)=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:3]=1[CH2:24][CH:25]=[C:26]([CH3:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30].[C:33]1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)(=O)C>CO>[OH:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=[O:12])[O:7][CH2:8]2)=[C:4]([O:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:3]=1[CH2:24]/[CH:25]=[C:26](\[CH3:32])/[CH2:27][CH2:28][C:29]([O:31][CH3:33])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=CCc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2)CCC(=O)O
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CC/C(C)=C/Cc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2

Procedure:
A solution of (E) 6-(1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoic acid (23 g) and p-toluenesulfonic acid (0.8 g) in methanol (150 ml) was stirred for 18 hours then added to water and ethyl acetate. The organc layer was dried and evaporated and the residue was chromatographed on silica gel, eluting with hexane:ethyl acetate: methanol 40:58:2, to afford methyl (E) 6-(1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]([OH:15])=O)[NH:10]2)=[CH:6][CH:5]=1)[CH3:3].[CH3:16][CH:17]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18].C(N=C=NCCCN(C)C)C>>[CH3:18][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:13]([C:9]2[NH:10][C:11]3[CH:12]=[C:4]([N:2]([CH3:1])[CH3:3])[CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:15])[CH2:30][CH2:31]1)[CH3:16]
Reactant: CN(C)c1ccc2cc(C(=O)O)[nH]c2c1
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3ccc(N(C)C)cc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 6-(N,N-dimethylamino)indole-2-carboxylic acid (PREPARATION 89, 0.40 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.43 g) and 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.45 g), the title compound is obtained, mp 153°-154°.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH:17]([C:20]([CH:22]=[CH2:23])=[O:21])([CH3:19])[CH3:18].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:23][CH2:22][C:20](=[O:21])[CH:17]([CH3:19])[CH3:18])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)C(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The thiol of Example 2 (4.76 g, 0.02 mole) was reacted with isopropylvinyl ketone (3.6 g) and triethylamine (3 ml) in methanol (50 ml) by the method of Example 3 to give the title compound, m.p. ca. 50°-53° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[CH3:16][C:17]([CH3:20])([O-])[CH3:18].[Na+].BrCC1CC1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:16][CH:17]3[CH2:20][CH2:18]3)[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Agent: BrCC1CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ncc2c(n1)N1CCOCC1CN2CC1CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.4 %

Procedure:
2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 200 mg, 0.882 mmol) was dissolved in DMSO (4.4 mL). Sodium tert-butoxide (102 mg, 1.059 mmol) was then added to give a brown solution. After 5 minutes, (bromomethyl)cyclopropane (86 μL, 0.882 mmol) was added dropwise. The reaction mixture was stirred for 2 hours at room temperature then quenched with aqueous saturated NH4Cl. The reaction mixture was diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was loaded onto an ISCO® silica gel cartridge (12 g) and eluted with an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow oil (100 mg, 40%). ESI-MS m/z [M+H]+ calc'd for C13H17ClN4O, 281.1. found 281.3.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][C:11]([C:21]1[CH:26]=[CH:25][N:24]2[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([C:36](O)([CH3:38])[CH3:37])[N:31]=3)=[CH:28][N:29]=[C:23]2[N:22]=1)([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12].O.C([O-])(O)=O.[Na+]>ClCCCl>[F:7][C:36]([C:32]1[N:31]=[C:30]([C:27]2[N:24]3[CH:25]=[CH:26][C:21]([C:11]([CH3:12])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:10])=[N:22][C:23]3=[N:29][CH:28]=2)[CH:35]=[CH:34][N:33]=1)([CH3:38])[CH3:37]
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(C(C)(C)O)n3)cnc2n1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(C(C)(C)F)n3)cnc2n1
Reaction time: 8 h
Yield: 29.7 %

Procedure:
(Diethylamino)sulphur trifluoride (150 mg, 0.95 mmol) was added to a stirred solution of 2-{4-[7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}propan-2-ol (Example 115, Step 1) (200 mg, 0.47 mmol) in 1,2-dichloroethane (5 ml) at room temperature under N2 and the reaction was stirred overnight. Water (20 ml) was added followed by NaHCO3 solution (20 ml) and then the organics were extracted with CH2Cl2 (3×50 ml) and concentrated under reduced pressure. The residue was purified by column chromatography on silica using 7% EtOH/EtOAc to yield 3-[2-(1-fluoro-1-methylethyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (60 mg, 30%): 1H NMR (400 MHz, CDCl3) δ 10.25 (1H, d, J 7.3), 8.71 (1H, d, J 5.5), 8.48 (1H, s), 7.60 (1H, d, J 7.2), 7.55 (1H, d, J 5.5), 1.87 (6H, d, J 21.6), 0.99 (9H, t, J 8.0), 0.68 (6H, q, J 8.0); m/z (ES+) 430 (M+H+).
Reaction SMILES: [H-].[Na+].N1C=[CH:6][N:5]=[N:4]1.[CH3:8][C:9]([CH3:23])([C:11](=[O:22])[CH:12](Br)[CH:13](Br)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:10].O.[CH3:25][N:26](C)C=O>>[N:5]1([C:12](=[CH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:11](=[O:22])[C:9]([CH3:23])([CH3:10])[CH3:8])[CH:6]=[N:26][CH:25]=[N:4]1
Reactant: CN(C)C=O
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)C(=O)C(Br)C(Br)C(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(=O)C=C(C(=O)C(C)(C)C)n1cncn1

Procedure:
Sodium hydride (100, %%, 0.06 mol) was added to a suspension of triazole (0.06 mol) in dimethyl formamide (100 ml) and the solution stirred at 20° until effervescence ceased. 2,2,7,7-Tetramethyl-4,5,dibromo-octan-3,6-dione (0.03 mol) was added portionwise at 20° to the stirred solution. After refluxing for 2 hours, the solution was cooled and poured into water to give a crystalline solid. Recrystallization from petroleum ether (60°-80°) gave the title compound as a white crystalline solid, m.p. 107°-8°.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:25]([C:27]1[N:31]([CH2:32][CH3:33])[N:30]=[CH:29][C:28]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:26].O>ClCCl>[CH2:32]([N:31]1[C:27]([C:25](=[O:26])[NH:15][C:13]2[CH:12]=[CH:11][N:10]3[CH:16]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[N:14]=2)=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:29]=[N:30]1)[CH3:33]
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: CCOC(=O)c1cnn(CC)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cnn(CC)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Reaction time: 8 h

Procedure:
2-Phenylimidazo[1,2-a]pyrimidin-7-amine (example 1, step 1, 648 mg, 3.08 mmol) and triethylamine (519 mg, 715 μA, 5.13 mmol) were combined with dichloromethane (15 ml) to give a light brown solution. Ethyl 5-(chlorocarbonyl)-1-ethyl-1H-pyrazole-4-carboxylate (1.6 g, 2.57 mmol) was diluted in dichloromethan and was added dropwise at 0° C. The reaction was stirred overnight. The reaction mixture was poured into 20 mL water and extracted with dichloromethan (2×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 50% to 100% EtOAc in heptane). The obtained product contained the imide (2 acid chlorides added to amine) as an impurity, but was used in the next step (where the title compound and the impurity give the same product). The title compound was obtained as a light brown solid (510 mg, 49.1%).
Reaction SMILES: [Si:1]([O-])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+].[Na+].[Na+].[Si:10](O)([OH:13])([OH:12])[OH:11].O=[Al-:16]=O.[Na+].[OH-].[Na+]>>[O-:3][Si:1]([O-:4])=[O:2].[O-:12][Si:10]([O-:13])=[O:11].[Na+:6].[Al+3:16]
Reactant: O[Si](O)(O)O
Reactant: [O-][Si]([O-])([O-])[O-]
Reactant: O=[Al-]=O
Agent: [Na+]
Agent: [OH-]
Product: O=[Si]([O-])[O-]
Product: [Al+3]

Procedure:
mixing sodium silicate or active silicic acid gel, sodium aluminate and sodium hydroxide in aqueous solution in the component molar ratios of: Na2O/SiO2 =0.2 to 8; SiO2 /Al2O3 =3 to 20; and H2O/Na2O=20 to 200, to form a gel of sodium aluminosilicate;
Reaction SMILES: [OH:1][CH:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:3].[CH3:17][S:18](Cl)(=[O:20])=[O:19].CCN(CC)CC>>[CH3:17][S:18]([O:1][CH:2]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:8][CH2:9]1)[CH3:3])(=[O:20])=[O:19]
Reactant: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 98.7 %

Procedure:
(±)-1,1-Dimethylethyl 4-{1-[(methylsulfonyl)oxy]ethyl}-1-piperidinecarboxylate (0.74 g, 49%) was prepared as a light brown oil from (±)-1,1-dimethylethyl 4-(1-hydroxyethyl)-1-piperidinecarboxylate (0.56 g, 2.44 mmol), methanesulfonyl chloride (0.23 mL, 2.93 mmol) and Et3N (0.69 mL, 4.88 mmol) in a manner similar to Example 150, Step 1. The crude product was used without further purification. 1H NMR (400 MHz, CDCl3): δ 4.70-4.55 (m, 1H), 4.20-4.10 (m, 2H), 2.99 (s, 3H), 2.70-2.55 (m, 2H), 1.80-1.60 (m, 3H), 1.43 (s, 9H), 1.38 (d, 3H, J=6.4 Hz), 1.35-1.15 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C@@H:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:20][CH2:21][N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:13]=2)=[CH:6][CH:5]=1.[CH2:37]([O:44][C:45]1[CH:50]=[CH:49][C:48]([C@@H:51]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[CH2:52]Br)=[CH:47][C:46]=1[NH:62][S:63]([CH3:66])(=[O:65])=[O:64])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(OCC)(=O)C.O>CS(C)=O>[NH3:1].[CH2:37]([O:44][C:45]1[CH:50]=[CH:49][C:48]([C@@H:51]([O:54][Si:55]([C:58]([CH3:59])([CH3:61])[CH3:60])([CH3:57])[CH3:56])[CH2:52][NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C@@H:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:20][CH2:21][N:22]([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:25])[CH3:24])[CH:13]=3)=[CH:35][CH:36]=2)=[CH:47][C:46]=1[NH:62][S:63]([CH3:66])(=[O:64])=[O:65])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCOc2ccc(CCN)cc2)ccc1O)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Product: N

Procedure:
4-{3-[4-(2-aminoethyl)phenoxy]propyl}-2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenol (Preparation 8, 134 mg, 0.27 mmol) and N-{2-(benzyloxy)-5-[(1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]phenyl}methanesulfonamide (Prepared according to WO2005/080324, 145 mg, 0.28 mmol) were heated at 90° C. in dimethylsulfoxide (0.5 ml) for 24 hours. Ethyl acetate (20 ml) and water (10 ml) were added and the organics separated. The aqueous was washed with ethyl acetate (20 ml) and the combined organics washed with brine (10 ml), dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (80/20/2.0 by volume) to furnish the title compound as a glass, 101 mg.
Reaction SMILES: COC(C(S(C)(=O)=O)(CCCC(OC(=O)C)CCCCC)CCCCCCC(OC)=O)=O.COC([C:37]([S:63]([CH3:66])(=[O:65])=[O:64])([CH2:48][C:49]#[C:50][CH:51]([O:59][C:60](=[O:62])[CH3:61])[C:52]([CH3:58])([CH3:57])[CH2:53][CH2:54][CH2:55][CH3:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=O>>[CH3:66][S:63]([CH:37]([CH2:48][C:49]#[C:50][CH:51]([O:59][C:60](=[O:62])[CH3:61])[C:52]([CH3:57])([CH3:58])[CH2:53][CH2:54][CH2:55][CH3:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])(=[O:64])=[O:65]
Reactant: CCCCC(C)(C)C(C#CCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: CCCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Product: CCCCC(C)(C)C(C#CCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O

Procedure:
The synthesis of this compound is carried out by the procedure of Example 3, Step D, except that methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxyheptadecanoate is replaced by an equivalent quantity of methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxy-13,13-dimethyl-10-heptadecynoate.
Reaction SMILES: [CH3:1][N:2]1[CH:9]=[CH:8][C:6](=[O:7])[N:5]([CH3:10])[C:3]1=[O:4].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[CH3:1][N:2]1[CH:9]=[C:8]([S:12]([Cl:11])(=[O:14])=[O:13])[C:6](=[O:7])[N:5]([CH3:10])[C:3]1=[O:4]
Reactant: Cn1ccc(=O)n(C)c1=O
Reactant: O=S(=O)(O)Cl
Product: Cn1cc(S(=O)(=O)Cl)c(=O)n(C)c1=O
Temperature: 25 °C
Yield: 79.2 %

Procedure:
1,3-Dimethyluracil (411 g, 2.93M) was added portionwise over 30 minutes to chlorosulfonic acid (5480 g, 47.0M) with stirring at room temperature. The exotherm was allowed to proceed to 50° C. without cooling. Upon completion of addition, the reaction was heated gradually to reflux (~154° C.) for 2 hours. Upon cooling the reaction was cautiously poured onto ice. The resultant solid was filtered off, washed thoroughly with water and dried in vacuo at 40° C. for 16 hours. An off-white solid (554 g, 79.2%), m.p. 225°-230° C. (dec.) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:7]=2[C:6]=1[CH:18]1[CH2:23][CH2:22][N:21](CC2C=CC=CC=2)[CH2:20][CH2:19]1)=[O:4].Cl[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[CH3:35][O:34][C:32]([N:21]1[CH2:22][CH2:23][CH:18]([C:6]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][C:8]=3[S:9][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:19][CH2:20]1)=[O:33]
Reactant: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1C1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1C1CCN(C(=O)OC)CC1
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a solution of 3-(1-benzyl-piperidin-4-yl)-6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid methyl ester (5.9 g, 13.6 mmol) in DCM (50 mL) was added methyl chloroformate (1.26 mL, 16.3 mmol) drop-wise. The resulting solution was stirred overnight when the volatiles were removed in vacuo. The residue was washed with heptane to yield 4.2 g (77%) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:17][CH2:16][CH2:15][CH2:14][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1c(Cl)cccc1-c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 3-(3-chloro[1,1'biphenyl]-2-yl)-1-propanol (30.0 g, 0.12 mole) and pyridine (11.9 g, 0.15 mole) in methylene chloride (300 ml) was cooled to 0°. Methanesulfonyl chloride (13.9 g, 0.12 mole) was added dropwise to the mixture. After complete addition the mixture was allowed to warm to room temperature and stir for approximately 18 hours. The reaction mixture was diluted with ice water (50 grams) and washed successively with dilute hydrochloric acid (200 ml), saturated aqueous sodium chloride (700 ml) and dilute aqueous sodium hydroxide (200 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to yield (3-chloro[1,1'-biphenyl]-2-yl)propanyl methylsulfonate as a brown oil.