Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].Cl[C:21]1[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C:21]3[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=3)[CH:12]=2)[CH2:9][CH2:10]1
Reactant: COCCN1CCN(c2cc(N)ncn2)CC1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: COCCN1CCN(c2cc(Nc3ncc(C#N)s3)ncn2)CC1

Procedure:
6-[4-(2-methoxyethyl)piperazin-1-yl]pyrimidin-4-amine 5-3 (0.25 g, 1.05 mmol), sodium hydride (0.842 g, 2.11 mmol), and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.15 g, 1.05 mmol) were treated as in Scheme 4 above. The product 5-4 was purified on a C18 preparative hplc and isolated via lyophilization from dioxane. Hi-Res MS: calc: 346.1445 found: 346.1445. 1H-NMR (DMSO): 9.97 ppm (s, 1H); 8.51 ppm (s, 1H); 8.28 ppm (s, 1H); 6.32 ppm (s, 1H); 4.35 ppm (m, 2H); 3.68 ppm (m, 2H); 3.59 ppm (m, 2H); 3.37 ppm (m, 7H); 3.12 ppm (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[C:23]([CH3:25])=[CH2:24])C1C=CC=CC=1.O.[H][H]>C(O)C.[Pd]>[CH:23]([C:10]1[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=1[OH:8])([CH3:25])[CH3:24]
Reactant: C=C(C)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(O)cc1O
Reaction time: 16 h

Procedure:
2,4-Bis-benzyloxy-1-isopropenyl-benzene was taken up in solution in ethanol and added to 10% palladium on carbon, which had been pre-wetted with water. Hydrogen was introduced to the flask and the mixture was allowed to shake for 16 hours. The catalyst was filtered from the reaction mixture, by a suitable method, and the liquor was concentrated in vacuo, to give 4-isopropyl-benzene-1,3-diol as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C(Cl)(=O)C([Cl:20])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]([Cl:20])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1ccc(CC(=O)O)cc1OCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(CC(=O)Cl)cc1OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (3,4-diethoxy-phenyl)-acetic acid (2.0 g, 8.9 mmol) in DCM (6 ml) were successively added oxalylchloride (1.13 ml, 13.4 mmol) and a catalytic amount of DMF (0.069 ml, 0.89 mmol) at 0° C. (ice bath). The reaction mixture was stirred at 0° C. for 1 h then evaporated to dryness under vacuum to yield the crude (3,4-diethoxy-phenyl)-acetyl chloride (2.2 g, 8.9 mmol, quant.) as a brownish oil which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH:3]=[O:4].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[S:14])[S-:13].C([NH+](CC)CC)C>CN(C)C=O>[OH:4][CH:3]1[CH2:2][S:14][C:12](=[S:13])[N:11]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1
Reactant: S=C([S-])Nc1ccccn1
Reactant: O=CCCl
Agent: CC[NH+](CC)CC
Solvent: CN(C)C=O
Product: OC1CSC(=S)N1c1ccccn1
Temperature: 2 °C
Reaction time: 16 h
Yield: 34.8 %

Procedure:
A 50% by weight aqueous solution of chloroacetaldehyde (37.7 g) is added at 10° C., to a solution of triethylammonium pyrid-2-yldithiocarbamate (65.4 g) in dimethylformamide (300 cc). The reaction is allowed to proceed for 16 hours at 20° C. After evaporating off the solvents under pressure (0.1 mm Hg) at 50° C., the residual oil is treated with chloroform (750 cc). The chloroform solution is washed twice with distilled water (200 cc in total), dried over sodium sulphate and evaporated. The oily residue (38 g) is dissolved in boiling ethanol (180 cc), and boiling isopropyl ether (180 cc) and decolourising charcoal (1 g) are added. After filtering the boiling solution and then cooling for 2 hours at 2° C., the crystals which have appeared are filtered off, washed with an ice-cooled mixture (50 cc in total) of ethanol (25 cc) and isopropyl ether (25 cc) and dried under reduced pressure (0.1 mm Hg) at 45° C. 4-Hydroxy-3-(pyrid-2-yl)thiazolidine-2-thione (17.8 g), which melts at 110° C., is thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: CCc1ccc(O)c(Br)c1
Product: CCc1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from 2-bromo-4-ethyl-phenol (example B.a5) and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless oil after distillation at 10 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10][C:11]1[NH:15][CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[CH:12]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10][C:11]1[NH:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=1
Reactant: COC(=O)c1c[nH]c(Sc2cc(Cl)c(Cl)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2cc(Cl)c(Cl)cc2Cl)c1
Reaction time: 2.5 h

Procedure:
Methyl 5-(2,4,5-trichlorophenylthio)pyrrole-3-carboxylate (2.1 g.) was combined with 20 ml. of methanol and 20 ml. of 1 N sodium hydroxide and heated to reflux. Additional 1 N sodium hydroxide was added in an amount sufficient to obtain a solution. Reflux was continued for 2.5 hours, the methanol was then allowed to evaporate, and the aqueous residue was diluted with approximately one volume of water and extracted twice with ether. The aqueous phase was cooled in an ice-water bath and acidified with conc. hydrochloric acid. Crude product (1.65 g., m.p. 210°-215° C.) was recovered by filtration. Recrystallization from methanol/water afforded purified 5-(2,4,5-trichlorophenylthio)pyrrole-3-carboxylic acid (1.01 g., m.p. 215°-217° C.).
Reaction SMILES: O[C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:11][CH:12]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C=C(C)c1ccc(-c2ccc(Cl)cc2)cc1
Yield: 91 %

Procedure:
To a solution of crude ethyl 3-hydroxy-3-(4′-chloro-[1,1′-biphenyl]-4-yl)-butanoate (2g) in benzene (200 ml) was added p-toluenesulfonic acid (3 gm) and was refluxed for 3 h 30 minutes. The reaction mixture was cooled, neutralized with NaHCO3 solution, diluted with water and organic layer was extracted. Organic layer was washed with water, dried (NaHCO3) and concentrated. Crude product was purified by column chromatography on silica gel to furnish 5.27 g (47.=91% yield) of ethyl 3-(4′-chloro-[1,1′-biphenyl]-4-yl)-but-2-enoate (3g, formula 3, R=p-Cl—C6H4) m.p. 91-94° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3C(=O)C4=CC=CC=C4C3=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCN(c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCN1CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of N-[3-(4-phenyl-1-piperazinyl)propyl]phthalimide (18.3 g) in ethanol (300 ml) was added 100% hydrazine hydrate (5.3 g). The resulting mixture was refluxed with stirring for 2 hours. The reaction mixture was evaporated under reduced pressure. After the addition of dil. aqueous solution of sodium hydroxide to the residue, the mixture was extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and then evaporated under reduced pressure to give 3-(4-phenyl-1-piperazinyl)propylamine (11.2 g).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:40][CH2:41][CH3:42])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:47]=[C:48]=[O:49])(C)C>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([C:48]([NH2:47])=[O:49])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:40][CH2:41][CH3:42])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)N=C=O
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 160, [(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (example 185) was reacted with trimethylsilyl isocyanate (TCI-US) to give the title compound. HR-MS (ES, m/z) calculated for C34H41Cl2N6O3 [(M+H)+] 651.2612, observed 651.2608.
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11](O)=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)CCl.C1C=[N:23]C2N(O)N=NC=2C=1.C(=O)([O-])O.[NH4+]>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([C:11](=[O:12])[NH2:23])[CH3:10])[CH3:14])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: On1nnc2cccnc21
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H](C(N)=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
Boc-N-methyl-L-alanine (3.12 g, 15.3 mmol), EDC (2.94 g, 15.3 mmol), HOAt (2.09 g, 15.3 mmol) and ammonium hydrogencarbonate (3.63 g, 45.9 mmol) were added to DMF (20 mL) and stirred at ambient temperature overnight. The mixture was partitioned between EtOAc and water. The EtOAc layer was washed with aqueous potassium hydrogen sulfate solution (×2), dilute aqueous sodium carbonate solution and brine. The EtOAc was evaporated to give the title compound as a white solid (1 g). 1H NMR (400 MHz, DMSO-d6): 7.19 (1H, br), 6.95 (1H, br), 4.60-4.20 (1H, m), 2.73 (3H, s), 1.39 (9H, s), 1.24 (3H, d).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:7]=[C:8]([N:19]2[CH:23]=[C:22]([CH2:24]OS(C)(=O)=O)[N:21]=[N:20]2)[CH:9]=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1>CN(C=O)C.C(OCC)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([N:19]2[CH:23]=[C:22]([CH2:24][N:1]=[N+:2]=[N-:3])[N:21]=[N:20]2)[CH:9]=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Temperature: 90 °C
Yield: 45 %

Procedure:
Sodium azide (1.10 g, 16.90 mmol) was added to the mixture of methanesulfonic acid 1-(3,5-difluoro-4-thiomorpholin-4-yl-phenyl)-1H-[1,2,3]triazol-4-ylmethyl ester and methanesulfonic acid 3-(3,5-difluoro-4-thiomorpholin-4-yl-phenyl)-3H-[1,2,3]triazol-5-ylmethyl ester, obtained in Example 9, in DMF (10 mL) and heated to 90° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL). The solution was washed with water (100 mL×2) followed by brine (50 mL) and dried over sodium sulfate. Removal of volatiles and purification of the residual material by silica gel column chromatography (eluent, 1:9–3:7 ethyl acetate/hexane) yielded compounds 1-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-1H-1,2,3-triazol-4-ylmethyl azide (13A) (800 mg, 45%) followed by 1-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-1H-1,2,3-triazol-5-ylmethyl azide (13B) (850 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1([C:9]#[N:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.ClCCCl.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2C(=O)C3(CCOCC3)N(CCCC(O)=O)[C:24]2=[O:40])=[CH:19][C:18]=1[C:41]([F:44])([F:43])[F:42])#[N:16]>C(N(CC)CC)C>[NH:10]=[C:9]1[C:2]2([CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)[NH:1][C:24](=[O:40])[N:23]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[C:18]([C:41]([F:42])([F:43])[F:44])[CH:19]=1
Reactant: N#Cc1ccc(N2C(=O)N(CCCC(=O)O)C3(CCOCC3)C2=O)cc1C(F)(F)F
Reactant: CN1CCC(N)(C#N)CC1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN1CCC2(CC1)NC(=O)N(c1ccc(C#N)c(C(F)(F)F)c1)C2=N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Using the procedure of Stage 2 of Example 20, 153 mg of the product of Stage 1 of Example 20, 1.5 ml of 1,2-dichlorethane and 0.1 ml of triethylamine were reacted and the solution was placed in an ice-cooled water bath. 1 ml of the product of Example 7 of European Patent Application EP 0,494,819 was added and the mixture was allowed to return to ambient temperature. The reaction medium stood for one hour, was dried and the residue was purified on silica with methylene chloride-methanol: 7-3 as eluant to obtain 277 mg of the expected product (white crystals) melting at 199°-200° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=2)[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccc(F)c(C)c2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-{1-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-{1-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid as off-white solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:6])[CH2:5][CH2:4]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1>C1COCC1.O>[CH:3]1([S:6][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4]1
Reactant: SC1CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
1.78 g (44.6 mmol) of sodium hydride (60%) was added in portions to a solution of 3.00 g (40.5 mmol) of cyclopropane thiol (preparation according to: E. Block et al., J. Am. Chem. Soc. 1992, 114, 3492) in 100 ml THF/100 ml diethyl ether and was stirred for 30 minutes at room temperature. Then 6.00 g (38.7 mmol) of 1-fluoro-4-nitrobenzene was added in portions. The mixture was stirred for 2 hours at 40° C. After it had cooled, the mixture was put in water and was extracted with benzene (3×). The combined organic phases were concentrated by evaporation and the residue was purified chromatographically (hexane/ethyl acetate 95:5). 4.6 g (23.6 mmol; yield: 61%) of the product was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][Mg]Br>C1COCC1>[Cl:1][C:2]1[C:3]([C:4](=[O:6])[CH3:11])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloronicotinic acid (B-1) (7.88 g, 50.0 mmol) in THF (100 mL) was added methyl magnesium bromide (42 mL, 3-Methyl ether solution) dropwise under 0° C. Upon completion of the addition, the reaction mixture was stirred at 0° C. for 0.5 h and then at room temperature overnight. The reaction mixture was added into ice/water (150 mL), and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated to afford the title compound 1-(2-chloropyridin-3-yl)ethanone (B-2). MS (m/z): 156 (M+1)+.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41])[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[C:24]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]([N:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:15][CH:16]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:46]1[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=1)=[O:35]
Reactant: Oc1ccc(F)cc1
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCCO)cc1OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCCOc2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
5-[4-(9H-9-Carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]-1-pentanol (0.12 g, 0.22 mmol) prepared in Example 135 was mixed with 4-fluorophenol (50 mg, 0.44 mmol), tetrahydrofuran (4 ml), diethyl azodicarboxylate (69 μl, 0.44 mmol) and triphenylphosphine (0.11 g, 0.44 mmol), followed by stirring overnight at room temperature. After distilling off the solvent, the residue was partitioned between ethyl acetate and water, and the organic layer was washed with water, dried over anhydrous magnesium sulfate and then evaporated to remove the solvent. The residue was applied to silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/10) to give the titled compound (0.13 g, yield: 93%) as a white crystal (cis:trans=4:1).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([OH:22])=[O:21])[CH2:14][O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[ClH:33]>CO>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:20]([OH:22])=[O:21])[CH2:14][O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[ClH:33]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](COC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CO
Product: C[C@@H](OC(C)(C)C)[C@H](N)C(=O)N[C@@H](COC(C)(C)C)C(=O)O

Procedure:
25 g (55.24 mmoles) of Z-Thr(But)-Ser(But)-OH are dissolved in 200 ml of methanol and are hydrogenated catalytically (at pH 4.5) using an autotitrator, with addition of a solution of HCl in methanol. After completion of the hydrogenation, the Pd/BaSO4 catalyst is filtered off, the filtrate is concentrated and the residue is dried in a high vacuum. Yield 1.1 g of an amorphous product
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[C:7](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[CH2:8][O:9][Si](C(C)(C)C)(C)C)(=[O:3])[CH3:2]>CC#N.C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5]/[C:6](/[C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1)=[C:7](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[CH2:8][OH:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(=C(\CO[Si](C)(C)C(C)(C)C)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(=O)OC/C(=C(\CO)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a solution of 50.5 g of (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-enyl acetate in 125 mL of MeCN, 10 mL of PyHF was added and the resulted mixture was stirred at rt for 1.5 h. The reaction mixture was diluted with 600 mL of toluene and then loaded on silica gel column and eluted with EtOAc. The solvent was evaporated to afford 38.3 g of the titled compound. 1H NMR (acetone-d6, 500 MHz): δ 7.68 (d, 2H), 7.32 (d, 2H), 7.15-7.00 (m, 5H), 5.20 (s, 2H), 4.62 (d, 2H), 4.09 (t, 1H, OH), 3.02 (s, 3H), 1.92 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([CH2:23][OH:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:3][CH2:2]1.[C:30](Cl)(=[O:32])[CH3:31]>>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([CH2:23][OH:24])[CH2:22][CH2:21][N:20]([C:30](=[O:32])[CH3:31])[CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:3][CH2:2]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3(CO)CCNCC3)ccc2n1CC1CC1
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(CO)(S(=O)(=O)c2ccc3c(c2)nc(CC(C)(C)C)n3CC2CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in STEP D of Example 6 using (4-(1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)piperidin-4-yl)methanol (STEP G) and acetyl chloride instead of methanesulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O>O>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CCO
Reactant: CC(C)=CC=O
Solvent: O
Product: CC(C)=CCCC(C)=CC=O
Temperature: 140 °C
Yield: 76 %

Procedure:
Air is blown for five minutes through a mixture of 100 parts of 3-methyl-2-buten-1-ol (prenol) and 100 parts of 3,3-dimethylacrolein. The reaction mixture containing peroxide is then heated for six hours at 140° C. The water formed in the reaction is removed continuously by injecting pentane into the reaction chamber. The reaction product is worked up by distillation. 59.2 parts of citral having a boiling point of 103° to 106° C. at 12 mm is obtained, equivalent to a yield of 76% of theory based on 3,3-dimethylacrolein at a conversion of 43%.
Reaction SMILES: N#N.[NH2:3][C:4]1[C:8]([Br:9])=[CH:7][NH:6][N:5]=1.CN(/[CH:13]=[C:14](\[Cl:19])/[CH:15]=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)C>C(O)(=O)C>[Br:9][C:8]1[CH:7]=[N:6][N:5]2[CH:15]=[C:14]([Cl:19])[CH:13]=[N:3][C:4]=12
Reactant: Nc1n[nH]cc1Br
Reactant: CN(C)/C=C(\Cl)C=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N#N
Solvent: CCO
Solvent: CC(=O)O
Product: Clc1cnc2c(Br)cnn2c1
Temperature: 70 °C
Yield: 80.8 %

Procedure:
A 5 L 4-neck round bottom flask equipped with mechanical stirrer, thermocouple, condenser and N2 bubbler was charged with 3-amino-4-bromopyrazole (40.0 g, 240 mmol), 2-Chloro-1,3-bis(dimethylamino)trimethinium hexafluorophosphate (77.0 g, 252 mmol) in acetic acid (390 ml)/ethanol (580 ml). The reaction mixture was heated to 70° C. for 8 hrs. Cool to 0° C. Filter off solids. Wash solids with 500 ml water then 500 ml MeOH and dried under high vac to afford the title compound (45.1 g, 194 mmol). LRMS (APCI) calc'd for (C6H3BrClN3) [M+H]+, 231.9; found 231.9. 1H NMR (CDCl3, 500 MHz) δ 8.74 (s, 1H), 8.52 (s, 1H), 8.14 (s, 1H).