Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[S:8][C:4]=2[CH:3]=[N:2]1.OS(O)(=O)=O.[CH3:17]O>>[NH:1]1[C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:17])=[O:10])[S:8][C:4]=2[CH:3]=[N:2]1
Reactant: CO
Reactant: O=C(O)c1cc2[nH]ncc2s1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2[nH]ncc2s1

Procedure:
To a solution of 1H-thieno[3,2-c]pyrazole-5-carboxylic acid (G-1) (3.0 g, 17.9 mmol) in MeOH (50 mL) was added concentrated H2SO4 (0.3 mL). The reaction mixture was stirred at reflux for 60 h. Solvent was removed in vacuo. Ethyl acetate was added to dilute the mixture. The mixture was washed with aqueous NaHCO3 solution, dried over Na2SO4, and concentrated in vacuo to afford the title compound (2.4 g).
Reaction SMILES: C/C(/C=C/C=C(\C)/C=C/C1C(C)=CC(OC(F)(F)F)=C(C)C=1C)=C\C(O)=O.[CH3:28]/[C:29](/[CH:36]=[CH:37]/[CH:38]=[C:39](\[CH3:56])/[CH:40]=[CH:41]/[C:42]1[C:47]([Cl:48])=[CH:46][C:45]([O:49][C:50]([F:53])([F:52])[F:51])=[C:44]([CH3:54])[C:43]=1[Cl:55])=[CH:30]\[C:31]([O:33]CC)=[O:32].[OH-].[K+]>O1CCOCC1>[CH3:28]/[C:29](/[CH:36]=[CH:37]/[CH:38]=[C:39](\[CH3:56])/[CH:40]=[CH:41]/[C:42]1[C:47]([Cl:48])=[CH:46][C:45]([O:49][C:50]([F:52])([F:51])[F:53])=[C:44]([CH3:54])[C:43]=1[Cl:55])=[CH:30]\[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(Cl)cc(OC(F)(F)F)c(C)c1Cl
Agent: CC(/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C)=C\C=C\C(C)=C\C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(/C=C/c1c(Cl)cc(OC(F)(F)F)c(C)c1Cl)=C\C=C\C(C)=C\C(=O)O

Procedure:
In a manner similar to that described in Example 5 for preparing (2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenoic acid, 0.04 mol of ethyl (2E,4E,6E,8E)-3,7-dimethyl-9-[2,6-dichloro-3-methyl-4-(trifluoromethoxy)phenyl]-nonatetraenoate in dioxane solution could be treated with 2N methanolic KOH at reflux for 4 hours. Acidification and extractive workup would produce (2E,4E,6E,8E)- 3,7-dimethyl-9-[2,6-dichloro-3-methyl-4-(trifluoromethyoxy)phenyl]-nonatetraenoic acid.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[C:8]([C:12]([NH2:14])=[O:13])[NH:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CCOC(C)=O.C([O-])(O)=O.[Na+]>ClCCl>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[C:8]([C:12]([NH2:14])=[O:13])[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(S(=O)(=O)N3CCOCC3)c(C(N)=O)[nH]c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1[nH]c2cc(O)ccc2c1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 6-methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 5 (134 mg, 0.395 mmol) in 5 mL of dichloromethane at −78° C. was added boron tribromide solution (1 M in dichloromethane, 1.97 mmol). After 10 minutes the mixture was allowed to warm to room temperature, and stir for an additional 4 hours. The reaction was poured into a mixture of EtOAc and saturated aqueous NaHCO3 solution. The organic phase was washed with water and brine, dried with Na2SO4, filtered, and concentrated in vacuo. Trituration with chloroform gave the titled compound as a brown powder. HRMS (ES) exact mass calculated for C13H16N3O5S (M+H+): 326.0805. Found 326.0794.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4]Cl.[F:12][C:13]1[C:14](=[O:47])[NH:15][C:16](=[O:46])[N:17]([CH:45]=1)[C@@H:18]1[O:44][C@H:22]([CH2:23][O:24]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:20]([OH:21])[CH2:19]1.[OH-].[K+].[I-].[Na+]>O1CCOCC1>[F:12][C:13]1[C:14](=[O:47])[NH:15][C:16](=[O:46])[N:17]([CH:45]=1)[C@@H:18]1[O:44][C@H:22]([CH2:23][OH:24])[C@@H:20]([O:21][CH2:4][C:3]2[C:2]([CH3:1])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=2[CH3:11])[CH2:19]1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CO[C@H]2C[C@H](n3cc(F)c(=O)[nH]c3=O)O[C@@H]2CO)c(C)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A 1.66 g quantity of 2,4,6-trimethylbenzyl chloride was added to a solution of 4.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine, 2.30 g of potassium hydroxide and 1.47 g of sodium iodide in 50 ml of dried dioxane. The mixture was stirred at 60° C. for 3 hours. The solvent was distilled off, and ethyl acetate and water were added to the residue. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off and the residue was dissolved in 50 ml of a 80% solution of acetic acid. The resulting solution was left to stand at 70° C. for 2 hours. The reaction mixture was concentrated and water was added to the concentrate. The mixture was rendered weakly basic with an aqueous solution of sodium hydroxide and washed with ether. The aqueous layer was made weakly acidic with a 6N solution of hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and concentrated. Ether was added to the concentrate to deposit solids and the solids were recrystallized from ethanol, giving 1.69 g of the title compound in a yield of 55%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[CH3:25][NH:26][C:27]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:20])[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([C:27](=[O:28])[NH:26][CH3:25])[CH:30]=3)=[CH:16][CH:17]=2)=[O:10])=[CH:4][C:3]=1[C:21]([F:23])([F:24])[F:22]
Reactant: CNC(=O)c1cccc(N)c1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CNC(=O)c1cccc(NC(=O)c2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
Entry 67: N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-ethoxycarbonylphenyl)urea was synthesized according to Method C1e. N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-ethoxycarbonylphenyl)urea was saponified according to Method D3 to give N-(4-chloro-3-(trifluoromethyl)phenyl-N′-(4-carboxyphenyl)urea. N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-carboxyphenyl)urea was coupled with 3-methylcarbamoylaniline according to Method D1b to give N-(4-chloro-3-(trifluoromethyl)phenyl-N′-(4-(3-methylcarbamoylphenyl)carbamoylphenyl)urea.
Reaction SMILES: C([O:7][CH2:8][C:9]([F:15])([F:14])[S:10]([O-:13])(=[O:12])=[O:11])(=O)C(C)(C)C.[C:16]1([S+:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O-].[Na+].Cl>CO>[F:14][C:9]([F:15])([S:10]([O-:13])(=[O:12])=[O:11])[CH2:8][OH:7].[C:29]1([S+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)C(=O)OCC(F)(F)S(=O)(=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=S(=O)([O-])C(F)(F)CO
Reaction time: 24 h

Procedure:
In 200 g of methanol was dissolved 50.9 g (0.1 mole) of triphenylsulfonium 2-pivaloyloxy-1,1-difluoroethane-sulfonate. To this solution under ice cooling, 2.0 g of a 28 wt % methanol solution of sodium methoxide was added. The reaction solution was aged at room temperature for 24 hours, and 1.0 g of 12N hydrochloric acid was added thereto at a temperature below 10° C. to quench the reaction. The methanol was distilled off in vacuum. To the residue was added 250 g of dichloromethane. The inorganic salt was filtered off, the filtrate was concentrated, and 150 g of diisopropyl ether was added to the concentrate for crystallization. The crystals were filtered and dried, obtaining the target compound. 42 g (purity 99%, net yield 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](O)=[CH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[Na+].BrBr.[NH2:24][C:25]([NH2:27])=[S:26].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:24]=[C:25]([NH2:27])[S:26][C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(O)=Cc2ccncn2)c1
Reactant: NC(N)=S
Agent: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(=O)O
Product: Cc1cccc(-c2nc(N)sc2-c2ccncn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution (70 mL) of 1-(3-methylphenyl)-2-(4-pyrimidinyl)ethenol (3.0 g, 14 mmol) and sodium acetate (2.32 g, 28.26 mmol) in acetic acid was added dropwise a solution (70 mL) of bromine (0.72 mL, 14 mmol) in acetic acid at room temperature over 30 min. The mixture was stirred at room temperature for 2 hrs. Acetic acid was evaporated under reduced pressure, and aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with ethyl acetate and the extract was dried and concentrated. The residue was dissolved in N,N-dimethylformamide (15 mL), and thiourea (1.1 g, 16 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 14 hrs. Aqueous sodium hydrogen carbonate solution was added, and the precipitated solids were collected by filtration. The solids were washed with water, dried and subjected to recrystallization from ethyl acetate to give the title compound (3.4 g, yield 89%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH:7]([P:12]([OH:15])(=[O:14])[OH:13])[P:8]([OH:11])(=[O:10])[OH:9].[N+]([O-])([O-])=O.[Ag+:20]>O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH:7]([P:8]([OH:11])(=[O:9])[OH:10])[P:12]([O-:14])(=[O:13])[O-:15].[Ag+:20].[Ag+:20]
Reactant: O=P(O)(O)C(Nc1nccs1)P(=O)(O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=P([O-])([O-])C(Nc1nccs1)P(=O)(O)O

Procedure:
0.954 mg of 1-(thiazole-2-ylamino)methane-1,1-diphosphonic acid (example 1) are dissolved in 10 ml of water. A solution of 1.018 g of silver nitrate in 5 ml of water is added dropwise, while stirring. The mixture is then stirred for another 30 minutes. The precipitate is filtered off and washed successively with methanol and diethyl ether, yielding the disilver 1-(thiazol-2-ylamino)-methane-1,1-diphosphonate, which has a melting point of more than 320°.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([CH:19]([N:26]1[C:34]2[C:29](=[CH:30][C:31](/[C:35](/[CH3:40])=[CH:36]/[C:37](O)=[O:38])=[CH:32][CH:33]=2)[CH:28]=[CH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18]>>[CH2:17]([CH:19]([N:26]1[C:34]2[C:29](=[CH:30][C:31](/[C:35](/[CH3:40])=[CH:36]/[C:37]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:38])=[CH:32][CH:33]=2)[CH:28]=[CH:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:18]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Product: CCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
73 mg of compound 40 was obtained in a similar manner to those described in Examples 1 and 2 using 465 mg of ethyl 4-(2-aminophenoxy)butyrate and 333 mg of 3-[1-(α-ethylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:18][N:19](CC)CC.C(OC(Cl)=O)C(C)C.CN>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](=[O:13])[NH:19][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-t-butoxycarbonyl-iso-nipecotic acid (10 g) and Et3N (5.92 mL) in THF (32 mL) was added drop-wise iso-butylchloroformate (5.66 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min before diluted with THF (120 mL) and added 2M methylamine (80 mL). The reaction mixture was stirred overnight at room temperature. Excess THF was removed under vacuum. The residue was taken into H2O and extracted into EtOAc. The organic extracts were washed with 1N NaOH, followed by brine. After dried over Na2SO4, it was concentrated to give the crude product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12>C(O)(=O)C.[Zn]>[S:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][CH:2]=2)[CH:8]=[CH:9]1
Reactant: Clc1ccnc2ccsc12
Agent: [Zn]
Solvent: CC(=O)O
Product: c1cnc2ccsc2c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A solution of 7-chlorothieno[3,2-b]pyridine (500 mg, 2.95 mmol) and zinc (193 mg, 2.95 mmol) in acetic acid (5 mL) was stirred at room temperature for 3 days, followed by stirring at 50° C. for 5 hours. The solvent was removed in vacuo and the residue was dissolved in DCM (200 mL) and extracted with 1N NaOH (500 mL). The aqueous layer was washed again with DCM (2×200 mL). The organic layers were combined, dried over Na2SO4, and the solvent was removed in vacuo to yield the title compound as a yellow oil, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C7H5NS, 136. found, 136.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](O)=[O:23])[CH:17]=1)[CH2:10][C:9]2([CH3:26])[CH3:25])=[O:5])[CH3:2].CN(C(ON1N=NC2[CH:38]=[CH:39][CH:40]=[N:41]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CC1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:23])[NH:41][CH:40]3[CH2:38][CH2:39]3)[CH:17]=1)[CH2:10][C:9]2([CH3:25])[CH3:26])=[O:5])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)O)c1)N2
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)NC3CC3)c1)N2
Yield: 100.4 %

Procedure:
The mixture solution of 2-(3-carboxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.2 g, 3.3 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (1.52 g, 4.0 mmol), triethylamine (2.0 mL), cyclopropylamine (330.6 mg, 5.8 mmol) in dry dichloromethane (20.0 mL) was stirred at room temperature for 1 hour, LC/MS showed that reaction finished completely. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-cyclopropylcarbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.3 g, quant.) as a light yellow solid which was used for next step without further purification: MS (ESI) M+1=393.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][N:14](C(OCC3C=CC=CC=3)=O)[CH2:15][CH:7]1[C:6](=[O:26])[NH:5]2>[Pd].C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][NH:14][CH2:15][CH:7]1[C:6](=[O:26])[NH:5]2
Reactant: Nc1ccc2c(c1)NC(=O)C1CN(C(=O)OCc3ccccc3)CCN21
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)NC(=O)C1CNCCN21

Procedure:
A mixture of 1.5 g. of 8amino-3-carbobenzoxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)-one, 1.5 g. of 10% Palladium on carbon catalyst and 150 ml. of ethanol is hydrogenated for 1/2 hour at 45 p.s.i. The catalyst is filtered and the filtrate concentrated to a volume of 50 ml. Ethanolic hydrochloric acid is added, and the product precipitates as the hydrochloride salt. Weight of product 0.70 g., m.p. 294-295° dec. Recrystallization from ethanol-water gives 0.45 g. of pure product, m.p. 315-317° dec.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[CH2:8](O)[CH2:9][OH:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.CCOCC.CCOC(C)=O>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: OCCO
Reactant: O=Cc1nccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: c1csc(C2OCCO2)n1
Temperature: 25 °C
Yield: 133.7 %

Procedure:
A solution of thiazole-2-carbaldehyde (100 g, 0.88 mol), ethane-1,2-diol (164 g, 2.65 mol), p-toluenesulfonic acid monohydrate (50 g, 0.26 mol) in toluene (1000 mL) was refluxed overnight with azetropic removal of water. The mixture was cooled to rt, diluted with ether (1000 mL), and washed with sat. NaHCO3 solution (200 mL), brine (200 mL), dried (Na2SO4), and concentrated to give a yellow oil. Flash column chromatography (petroleum ether: EtOAc, 100:1 to 50:1) afforded 2-(1,3-dioxolan-2-yl)thiazole (185 g, 66%). 1H NMR (CDCl3, 300 MHz) δ 7.75 (s, 1H), 7.31 (s, 1H), 6.09 (s, 1H), 4.04 (m, 4H).
Reaction SMILES: O.[CH2:2]([O:9][C:10]([CH3:14])([CH:12]=C)[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:16].[Na+]>[Os](=O)(=O)(=O)=O.O1CCOCC1>[CH2:2]([O:9][C:10]([CH3:11])([CH3:14])[CH:12]=[O:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC(C)(C)OCc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A mixture of 100 mL of water, 300 mL of dioxane, 20 g (0.11 mol) of 2-benzyloxy-2-methyl-3-butene and 1 g of osmium tetroxide was stirred at room temperature for 30 minutes then 51 g (0.22 mol) of finely ground sodium periodate was added in portions over 30 minutes. Stirring was continued for 2 hours then the mixture filtered and the filtrate extracted with several portions of ether. The combined extracts were dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. Distillation afforded 7.3 g (0.041 mol,37%) of product, b.p. 85°-88° C. (2 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[CH:14]([O:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[Br:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Br:32][CH2:33][C:34]([N:12]1[CH2:13][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:10]([CH:14]([O:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH3:15])[CH2:11]1)=[O:35]
Reactant: O=C(Cl)CBr
Reactant: CC(Oc1ccc(C#N)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)CBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 703.7 %

Procedure:
To a stirred solution of 6-{(SR)-1-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (XV-B-4) 30 mg (0.083 mmol) in CH2Cl2 (3 mL) at RT, 0.013 ml (0.01 mmol) of Et3N and 0.0083 mL (0.01 mmol) of bromo-acetyl chloride were added. Stirring was continued over night and then concentrated under vacuo. The crude residue was dissolved in EtOAc, washed with H2O. The organic phase was dried over Na2SO4 and the product was purified by flash chromatography (SiO2, EtOAc) to yield the title product 34 mg (85%) as a colorless oil.
Reaction SMILES: C(O[C:6](=[O:26])[CH:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1)=O)(C)(C)C.Cl.Cl.[NH:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>N1C=CC=CC=1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:7]1[C:6](=[O:26])[N:30]2[CH2:31][CH2:32][CH2:33][N:29]2[C:8]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1
Reactant: CSc1nccc(C(=O)C(Cc2ccccc2Cl)C(=O)OC(C)(C)C)n1
Reactant: C1CNNC1
Agent: Cl
Solvent: c1ccncc1
Product: CSc1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1
Reaction time: 17 h
Yield: 22 %

Procedure:
To a solution of 2-(2-chlorobenzyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-3-oxo-propionic acid tert-butyl ester, 6 (2.0 g, 5.7 mmol)) in pyridine (40 mL) is added pyrazolidine-bishydrochloride (1.2 g, 8.1 mmol). After stirring the reaction for 10 min at room temperature, the mixture i stirred at 90° C. for 2.5 hours and then at 60° C. for 17 hours. The solution i concentrated in vacuo and the resulting curd product is purified over silica (EtOAc followed by 20% MeOH/EtOAc) to afford 460 mg (22%) of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.58 (d, J=5.1 Hz, 1H), 7.42-7.2 (m, 4H), 6.96 (d, J=5.1 Hz, 1H), 4.42-4.3 (m, 4H), 4.10 (s, 2H), 2.95-2.75 (m, 2H), 2.58 (s, 3H); ESI+ MS: m/z (rel intensity) 373.0 (100, M++H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)[C:10]([C:25](=[O:31])[C:26]([O:28]CC)=[O:27])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CCCCCC>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)[C:10]([C:25](=[O:31])[C:26]([OH:28])=[O:27])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2c(-c3ccc(F)c(Cl)c3)cccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2c(-c3ccc(F)c(Cl)c3)cccc12
Yield: 64.3 %

Procedure:
[1-Benzyl-7-(3-chloro-4-fluorophenyl)-1H-indol-3-yl](oxo)acetic acid was prepared from ethyl 2-[1-benzyl-7-(3-chloro-4-fluorophenyl)-1H-indol-3-yl]-2-oxoacetate (0.139 g, 0.319 mmol), and potassium hydroxide (0.076 g, 1.35 mmol) in THF (2.5 mL) and water (2.5 mL) following the procedure described in Step 4 of Example 5. Following work-up, and trituration of the residue with hexane, a solid was obtained. Drying for 12 hours at 82° C. yielded the title compound as a yellow solid (0.0836 g, 64%), mp: 153-156° C. Mass spectrum (−ESI, [M−H]−) m/z 406; 1HNMR (500 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.65 (s, 1H), 8.35 (m, 1H), 7.3-7.35 (m, 2H), 7.05-7.2 (m, 5H), 7.0 (s, 1H, J=7.1 Hz), 6.35 (d, 2H, J=6.9 Hz), 5.35 (d, 1H, J=16.6 Hz), and 5.15 ppm (d, 1H, J=16.6 Hz). Elemental Analysis for C23H15ClFNO3: Calculated: C, 67.74; H, 3.71; N, 3.43. Found: C, 67.53; H, 3.9; N, 3.3.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([OH:12])[CH2:9][CH2:10][CH3:11].S([O-])([O-])(=O)=O.[Mg+2]>[Bi](Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH2:6]([O:7][C:1]1([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:1][CH2:2][CH3:3]
Reactant: CCCCO
Reactant: O=C1CCCCC1
Agent: Cl[Bi](Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CCCCOC1(OCCCC)CCCCC1
Temperature: 10 °C
Reaction time: 10 h
Yield: 182.2 %

Procedure:
In a 300-ml three-necked flask, 98 g of cyclohexanone, 148 g of n-butanol, 50 g of anhydrous magnesium sulfate, 2 mg of bismuth chloride and 80 g of toluene were charged. The resulting mixture was stirred at 10° C. under atmospheric pressure for 10 hours in a nitrogen atmosphere. After magnesium sulfate was removed from the reaction mixture, the solvent (toluene) and unreacted starting materials were distilled off under reduced pressure. Distillation of the residue under reduced pressure gave 207.7 g of cyclohexanone dibutyl acetal (yield: 89.4%).