Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]=[CH:6][C:5]1=[O:56])[CH:2]=[CH2:3].C([SnH](CCCC)CCCC)CCC.O>C1(C)C=CC=CC=1.C(O)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH2:7][CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Agent: [Pd]
Agent: CCCC[SnH](CCCC)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 17-Allyl-1-hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone (as prepared in Example 14) (100 mg) in toluene (5 ml) and acetic acid (0.01 ml) was added tetrakis(triphenylphosphine) palladium(0) (0.01 g). After 5 minutes tri n-butyltin hydride (0.04 g) was added and the reaction mixture was stirred at room temperature for 2 hours. Water was added and the reaction mixture was extracted with ether. The ether extracts were dried (magnesium sulphate), filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with ether gave the title compound as a low melting solid (70 mg).
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:18][C:17]=1[F:37])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:37][C:17]1[CH:18]=[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:20]([F:22])=[CH:21][C:16]=1[S:13]([NH:7][C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(=[O:14])=[O:15]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(Oc2cnc(Cl)cc2-c2cccnc2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cscn1)c1cc(F)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cccnc2)cc1F
Reaction time: 0.17 h
Yield: 30.8 %

Procedure:
10 mg (0.03 mmol) of tert-butyl((4-((6′-chloro-[3,4′-bipyridin]-3′-yl)oxy)-2,5-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 3.7 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2 mg (10 mol %) of Pd(PPh3)4, 5.5 mg (0.05 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C@H:2]1[O:4][CH2:3]1.[OH-:13].[K+].[CH3:15]O>>[CH2:6]([O:5][CH2:1][C@@H:2]([OH:4])[CH2:3][O:13][CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: CO
Agent: [K+]
Product: COC[C@H](O)COCc1ccccc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a stirred solution of (S)-benzyl glycidyl ether (S)-2 (4 g, 24.3 mmol) in methanol (40 mL) was added slowly a powdered KOH (4 g; 70 mmol) at 10° C. and the reaction mixture was stirred at 30° C. temperature for 8 h, after which the solvent was evaporated under reduced pressure. The residue was dissolved in ethylacetate (50 mL), washed with water, dried over Na2SO4, and evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether/acetone, 90:10) to afford (S)-1-(benzyloxy)-3-methoxypropan-2-ol (S)-3 as a colorless oil (4.6 g, 98%).
Reaction SMILES: [CH2:1]([C:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H][H]>C1(C)C=CC=CC=1>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: [H][H]
Reactant: CCCCCCCC1=CCC(c2cccc(F)c2)CC1
Solvent: Cc1ccccc1
Product: CCCCCCCC1CCC(c2cccc(F)c2)CC1

Procedure:
The compound (11) was dissolved in a mixed solvent of toluene (150 ml) and Solmix A-11 (150 ml), and 0.86 g of Pd/C(NX type) was added thereto. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed and then the solvent was distilled off. The residue obtained was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder, and further purified by means of recrystallization from Solmix A-11, and dried, giving 44.7 g of 4-heptyl-1-(3-fluorophenyl)-cyclohexane (12). The yield based on the compound (12) was 75.8%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:17]([O:22]C)([O:20][CH3:21])(=[O:19])=[O:18]>C(Cl)Cl>[CH3:21][O:20][S:17]([O-:22])(=[O:19])=[O:18].[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N+:10]=1[O:16][CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc[n+]([O-])c1NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COS(=O)(=O)[O-]
Product: CO[n+]1cccc(C)c1NC(=O)OC(C)(C)C

Procedure:
To a stirred solution of 620 mg (0.29 mmol) of 2-t-butyloxycarbonylamino-3-methylpyridine-N-oxide in 8 mL of CH2Cl2 under Ar was added 262 μL (0.3 mmol) of dimethyl sulfate. The CH2Cl2 was allowed to evaporate under a slow stream of Ar overnight to give the title compound as a light tan solid:
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[CH2:15].C(O)(=O)C>CO>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:14][CH2:15][N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:1]1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: C=Cc1ccccn1
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CCN2CCc3c([nH]c4ccccc34)C2)nc1
Yield: 44 %

Procedure:
A mixture of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.72 g., 0.01 mol), 2-vinylpyridine (1.0 g., 0.01 mol) and 2 ml. of glacial acetic acid were refluxed in 25 ml. of methanol for 24 hours. The solvent was removed in vacuo and the separated solid was suspended in water. The solution was made slightly basic via the addition of solid potassium carbonate and it was extracted with methylene chloride (4×150 ml.). The methylene chloride layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 1.2 g. (44% yield) of 2,3,4,9-tetrahydro-2-[2-(2-pyridinyl)ethyl]-1H-pyrido[3,4-b]indole. This intermediate was dissolved in 50 ml. of dimethylformamide and 0.92 g. (0.04 mol) of sodium hydride was added and stirring was continued for 1 hour. To the stirred solution 0.66 g. (0.004 mol) of benzyl bromide was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the solid residue was suspended in water and extracted with methylene chloride (3×100 ml.). The organic layer was separated, dried and evaporated. The remaining oil was dissolved in ethanol and converted to the dihydrochloride salt; mp 278°-280° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[C:2]1([NH:1][C:15](=[O:16])[C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 39.8 %

Procedure:
Aniline (0.87 mL, 9.57 mmol) was added slowly to a mixture of 4-Bromo-1-benzenecarbonyl chloride (2.0 g, 9.11 mmol) and triethyl amine (1.9 mL, 13.67 mmol) in dichloromethane (95 mL). After 3 hours, solvent was removed under reduced pressure. Ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was re-crystallized from ethyl acetate/heptane to give N1-phenyl-4-bromobenzamide (1.00 g, 40%). 1H NMR (DMSO-d6) δ 7.11 (m, 1H), 7.38 (m, 2H), 7.76 (m, 4H), 7.92 (m, 2H), 10.30 (s, 1H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:29]=[C:30]([S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1)[NH2:27]>>[CH3:38][N:37]([CH3:39])[S:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([N:26]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:27]2)[CH:29]=1)(=[O:36])=[O:35]
Reactant: CN(C)S(=O)(=O)c1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: CN(C)S(=O)(=O)c1cccc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 3-hydrazino-N,N-dimethyl-benzenesulfonamide according to the method described for example 91.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:2]=12.[C:13]([C:20]1[NH:21][CH:22]=[CH:23]N=1)([C:15]1NC=CN=1)=O.N1CCCCC1>ClCCl>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([N:21]3[CH2:20][CH2:13][CH2:15][CH2:23][CH2:22]3)=[O:12])[CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc2nonc2c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C(c1ccc2nonc2c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Benzofurazan-5-carboxylic acid (2.0 g, 12.2 mmol) was suspended in 10 mL dichloromethane. Carbonyl diimidazole (2.0 g, 12.3 mmol) was added, which caused dissolution with gas evolution. The resulting yellow solution was stirred for 40 minutes at room temperature, following which, piperidine (1.2 g, 14.1 mmol) was added. The solution was stirred overnight and then concentrated onto silica. Product was eluted with hexane/ethyl acetate (2:1) and purified by distillation in a kugelrohr at 155-170° C. and 0.5 mmHg. 1-(Benzofurazan-5-ylcarbonyl)piperidine, 2 (2.78 g, 99%), initially a pale yellow oil, crystallized upon cooling. M.p. 88.5-90.5° C. IR: 2938, 2857, 1630, 1519, 1439, 1266, 1223, 996, 881, 816, and 740 cm-1. 1H NMR (500 MHz): δ 7.90 (1H, d, J=9.7 Hz); 7.84 (1H, s); 7.44 (1H, dd, J=9.4 and 1.4 Hz); 3.74 (2H, br s); 3.39 (2H, br s); 1.72 (4H, br s); and 1.57 ppm (2H, br s).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Br[C:12]1[C:13](=[O:25])[N:14]([C:18]([CH:22]([CH3:24])[CH3:23])([CH3:21])[C:19]#[N:20])[C:15](=[O:17])[CH:16]=1.C(O)(C)C.C([O-])(=O)C.[Na+]>CCOCC>[C:19]([C:18]([N:14]1[C:13](=[O:25])[CH:12]=[C:16]([NH:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([OH:10])=[O:9])[C:15]1=[O:17])([CH3:21])[CH:22]([CH3:23])[CH3:24])#[N:20]
Reactant: CC(C)C(C)(C#N)N1C(=O)C=C(Br)C1=O
Reactant: Nc1ccccc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)C(C)(C#N)N1C(=O)C=C(Nc2ccccc2C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.5 %

Procedure:
A mixture of anthranilic acid, (13.7 g, 0.1 mol), 3-bromo-α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (27 g, 0.1 mol), isopropanol (200 ml) and sodium acetate (8.2 g) is stirred at room temperature 3 days and then is heated at reflux 1 hour. On cooling, and with the addition of ether, a yellow solid 31.6 g, (19.7%) is obtained, mp 262°-266° C. after crystallizing from acetic acid. Anal. calcd. for C17H17N3O4 : C, 62.37; H, 5.24; N, 12.84. Found: C, 62.24; H, 5.19; N, 12.70.
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([N+:21]([O-])=O)=[CH:9][N:8]=1.C(O)(=O)C.[H][H].C(O)C(F)(F)F>CO.[OH-].[Pd+2].[OH-]>[CH3:2][O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]2[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:21][C:10]2=[CH:9][N:8]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)Cc1cc(OCCOC)ncc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [K]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: OCC(F)(F)F
Product: CCOC(=O)c1cc2cc(OCCOC)ncc2[nH]1
Reaction time: 5 h

Procedure:
3.5 g of dried ethyl 3-[2-(2-methoxyethoxy)-5-nitropyridin-4-yl]-2-oxopropionate potassium salt are dissolved in 50 ml of MeOH, and 2 ml of acetic acid are added. After the addition of 500 mg of palladium hydroxide/C 20%, the mixture is stirred under 1 atm of hydrogen. After 5 h, a further 200 mg of catalyst and 0.75 ml of trifluoroethanol are added. After a further 3 h, all volatile components are removed under reduced pressure and 20 ml of sat. sodium bicarbonate solution are added and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by flash chromatography on silica gel (n-heptane/ethyl acetate=1:2). This gives ethyl 5-(2-methoxyethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate as a yellowish solid. C13H16N2O4 (264.28), MS (ESI): 265 (M+H+).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:11][CH2:12][OH:13])[CH2:5][CH2:6]S(O)(=O)=O.C(CNC(CO)(CO)CO)CNC(CO)(CO)CO.OCC(NC[CH2:42][S:43]([OH:46])(=[O:45])=[O:44])(CO)CO.C(NC(CO)(CO)CO)C(O)CS(O)(=O)=O.NC(CO)(CO)CO.N(CCO)(CCO)CCO>>[CH2:5]1[NH+:4]([CH2:3][CH2:2][CH2:42][S:43]([O-:46])(=[O:45])=[O:44])[CH2:11][CH2:12][O:13][CH2:6]1
Reactant: O=S(=O)(O)CCN(CCO)CCO
Reactant: O=S(=O)(O)CCNC(CO)(CO)CO
Agent: NC(CO)(CO)CO
Agent: O=S(=O)(O)CC(O)CNC(CO)(CO)CO
Agent: OCC(CO)(CO)NCCCNC(CO)(CO)CO
Solvent: OCCN(CCO)CCO
Product: O=S(=O)([O-])CCC[NH+]1CCOCC1

Procedure:
N,N-bis [2-Hydroxyethyl]-2-aminoethanesulfonic acid; (1,3-bis[tris(Hydroxymethyl)methylamino]propane); (N,N-bis[2-Hydroxyethyl]-2-aminoethanesulfonic acid; 2-[bis(2-Hydroxyethyl)amino]ethanesulfonic acid); (N-tris[Hydroxymethyl]methyl-2-aminoethane-sulfonic acid; 2-([2-Hydroxy-1,1-bis(hydroxymethyl)ethyl]amino) ethanesulfonic acid; 3-[N,N-bis(2-Hydroxyethyl)methylamino]-2-hydroxypropanesulfonic acid); (3-[N-tris(Hydroxymethyl)methylamino]-2-hydroxypropanesulfonic acid); (tris[Hydroxymethyl]aminomethane), (2-amino-2-(hydroxymethyl)-1,3-propanediol); (N-[2-Hydroxyethyl]piperazine-N'-[2-hydroxypropanesulfonic acid]); (Piperazine-N,N'-bis[2-hydroxypropanesulfonic acid]); (N[2-Hydroxyethyl]piperazine-N'-[3-propane-sulfonic acid]); Triethanolamine, (2,2'2"-Nitrilotriethanol); and mixtures thereof.
Reaction SMILES: C(O)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:15]([NH:23][C:24](=[O:46])[NH:25][C:26]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:27]=1[O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([O-:33])=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>[Pd].C(OCC)(=O)C.C(Cl)(Cl)Cl>[CH2:15]([NH:23][C:24](=[O:46])[NH:25][C:26]1[CH:41]=[C:40]([C:42]([F:44])([F:45])[F:43])[CH:39]=[CH:38][C:27]=1[O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([OH:33])=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCNC(=O)Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)[O-]
Agent: [Pd]
Agent: OC(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCNC(=O)Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)O
Reaction time: 3 h

Procedure:
A mixture of benzhydrol 2-[2[3-(octyl)ureido]-4-trifluoromethylphenoxy)-benzoate (290 mg, 0.00047 mol) and 10% palladium on carbon (100 mg) in ethyl acetate was hydrogenated in a parr bottle, at 55 psi for three hours. The mixture was diluted with chloroform, filtered through Celite and the filtrate evaporated. The residue was flash chromatographed (silica gel, ethyl acetate/hexane/formic acid) to give the title compound. 1H NMR (250 MHz, CD3OD) δ8.52 (d, 1H), 7.95 (dd, 1H), 7.6 (tt, 1H), 7.35 (tt, 1H), 7.14 (dd, 2H),6.7 (d, 1H), 3.15 (t, 1H), 1.3 (s, 14H) 0.85 (t, 3H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[OH:29][CH2:30][C:31]([CH3:41])([CH3:40])[O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:39][C:36]1[CH:35]=[CH:34][C:33]([O:32][C:31]([CH3:41])([CH3:40])[CH2:30][OH:29])=[CH:38][CH:37]=1)[CH3:28]
Reactant: CC(C)(CO)Oc1ccc(O)cc1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2ccc(OC(C)(C)CO)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.52 g), 4-(2-hydroxy-1,1-dimethylethoxy)phenol (0.32 g), 8 M potassium hydroxide solution (0.22 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.36 g, 58%).
Reaction SMILES: C([O:4][CH:5](OC(C)C)[C:6]([CH3:27])([CH3:26])[C:7](=[O:25])[C@H:8]([CH3:24])[C@@H:9]([O:15][C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17])[C@@H:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[O:25]=[C:7]([C@H:8]([CH3:24])[C@@H:9]([O:15][C:16]([O:18][CH2:19][C:20]([Cl:21])([Cl:22])[Cl:23])=[O:17])[C@@H:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])[C:6]([CH3:27])([CH3:26])[CH:5]=[O:4]
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C(OC(C)C)OC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C=O

Procedure:
A mixture of (4R,5S,6S)-1,1-diisopropoxy-5-(2,2,2-trichloroethoxycarbonyloxy)-2,2,4,6-tetramethyl-8-nonen-3-one (4.58 g) and p-toluenesulfonic acid monohydrate (0.45 g) in 100 mL of 3:1 THF/water is heated at reflux for 7 hours. The mixture is cooled and poured into sat. aq. NaHCO3, then extracted with ethyl acetate. The extract is dried over Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2 (3% ethyl acetate/hexanes).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:9][C:10]([OH:12])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[CH2:16]([O:15][C:13]([N:7]1[CH2:8][CH2:9][C:10](=[O:12])[C:3]2[CH:4]=[CH:5][O:1][C:2]=2[CH2:6]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)N(CCC(=O)O)Cc1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(=O)c2ccoc2C1
Temperature: 0 °C
Yield: 41.4 %

Procedure:
3-[(Furan-2-ylmethyl)(ethoxycarbonyl)amino]propionic acid (3.6 g) prepared in the step 4 was dissolved in 300 mL of methylene chloride, then 2.66 g of thionyl chloride and 5 drops of DMF were added thereto and the mixture was heated to reflux for 3 hours. The reaction solution was cooled, 20.0 g of aluminum chloride was added thereto and the mixture was heated to reflux again for 30 minutes. The reaction solution was poured over 300 mL of ice water, the organic layer was separated, washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo therefrom. The residue was purified by silica gel column chromatography to give 1.38 g of the objective compound as yellow liquid.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH2:6]([C:13]1([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C(OCC)C.C(Cl)Cl>[CH2:6]([C:13]1([OH:19])[CH2:18][CH2:17][N:16]([CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: ClCC1CO1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: OC(CCl)CN1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
(rac)-Epichlorohydrin (2.5 ml, 31 mmol) dissolved in diethylether (10 ml) was added at room temperature to a suspension of 4-benzyl-4-hydroxy-piperidine (6.0 g, 31 mmol) in diethylether (40 ml) and CH2Cl2 (40 ml). The mixture was stirred overnight at room temperature, water (50 ml) and CH2Cl2 (50 ml) were added and the organic phase was separated. The water phase was extracted with CH2Cl2, the organic phases were pooled, dried with Na2SO4 and the solvents evaporated. The residue was chromatographed over silica gel (ethyl acetate-MeOH, 9:1) to give 4-benzyl-1-(3-chloro-2-hydroxy-propyl)-piperidin-4-ol (1.0 g, 13%) as a colorless solid, m.p. 194°-195° C. and MS: m/e=(M+H+).
Reaction SMILES: [OH:1]CCCNC(=O)[C@H](C(CO)(C)C)O.[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](Cl)=[O:24])=[CH:19][CH:18]=1.N1C=CC=CC=1>C(OC)(=O)C>[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23]([OH:1])=[O:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Reactant: CC(C)(CO)[C@H](O)C(=O)NCCCO
Solvent: COC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1
Yield: 86 %

Procedure:
17.4 g of D-panthenol )0.085 mol) are placed in 300 ml of methyl acetate while gassing with argon in a 750 ml 4-necked sulphonation flask provided with a thermometer, a 100 ml dropping funnel, a magnetic stirrer and a reflux condenser. A solution of 75.5 g of 4-methoxycinnamic acid chloride (0.38 mol) in 150 ml of methyl acetate is then added dropwise within about 20 minutes. A solution of 33.6 g of pyridine (0.425 mol) is added dropwise within about 40 minutes. The reaction mixture is finally heated to reflux temperature for 4 hours. After cooling the precipitate is filtered off under suction. The filtrate is washed with 2× 150 ml of 5% HCl and then with 2× 100 ml of water. After drying over Na2SO4 the organic phase is concentrated on a rotary evaporator. The yellow, viscous residue (74.2 g) is chromatographed (toluene/ethyl acetate, 7:1) on 1 kg of silica gel (0.040-0.063 mm) under 0.5 bar pressure. There are obtained 50.1 g of yellow <R>-panthenol triester of p-methoxycinnamic acid (yield 86%).