Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:12](O)[CH2:13][CH2:14][OH:15]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]2[O:15][CH2:14][CH2:13][CH2:12][O:8]2)[CH:9]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1C1OCCCO1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture of 5-bromo-2-methoxybenzaldehyde (52.3 g, 243 mmol), 1,3-propanediol (30 ml, 31.6 g, 415 mmol), and 4-toluenesulphonic acid (0.3 g) in toluene (350 ml) was heated to reflux in a Dean-Stark apparatus for 20 h. The mixture was cooled to RT, washed with saturated NaHCO3 solution (100 ml), then the organic layer was separated and combined with a CH2Cl2 solution (100 ml). The extract was washed (brine; 50 ml), dried (Na2SO4), and concentrated in vacuo to give a brown oil (66.2 g). The crude product was distilled to afford the title compound (58.2 g) as a colourless viscous oil b.p. 115-120° C., 0.02 mmHg δH (80 MHz; CDCl3) 1.2-1.5 (1H, br m, CH2CHHCH2), 1.9-2.4 (1H, m, CH2CHHCH2), 3.78 (3H, s, OMe), 3.6-4.4 (4H, m, CH2CH2CH2), 5.76 (1H, s, OCH), 6.67 (1H, d, J 8.8 Hz, ArH ortho to OMe), 7.33 (1H, dd, J 8.8, 2.3 Hz, ArH para to acetal), and 7.68 (1H, d, J 2.3 Hz, ArH ortho to acetal); m/z (El) 274 (44%), 273 (31), 272 (45), 271 (27), 216 (34), 215 (47), 214 (35), 213 (44), 193 (34), 135 (22), and 87 (100).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[N:14]1[C:18](=[O:19])[C:17]2=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=[C:16]2[C:15]1=[O:25])[CH3:2].[H][H]>C(OCC)(=O)C.[Rh]>[CH2:1]([O:3][CH2:4][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[N:14]1[C:18](=[O:19])[C:17]2=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=[C:16]2[C:15]1=[O:25])[CH3:2]
Reactant: CCOCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Reactant: [H][H]
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CCOCc1cc(N)ccc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
The solution of 300 mg of N-(2-ethoxymethyl-4-nitrophenyl)-4-chlorophthalimide in 40 ml of ethyl acetate is hydrogenated with 200 mg of 5% rhodium on carbon at 2.5 atmospheres of hydrogen pressure for 3 hours. After filtration from the catalyst the residue is refluxed for 24 hours in 5 ml of xylene, the solution evaporated and the residue crystallized from diethyl ether, to give the N-(2-ethoxymethyl-4-aminophenyl)-4-chlorophthalimide melting at 154°-156°.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:5]=1.[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:20][CH:9]1[C:4](=[O:3])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]1
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of tert-butyl 4-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (64.4 g, 237 mmol) in anhydrous ACN (1.5 L) at ambient temperature was added Selectfluor (92.5 g, 261 mmol) portion wise over 10 minutes, during which a slight exotherm (to 40° C.) was observed. The mixture was stirred for 2 hours, then concentrated to dryness and partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to afford 51 g (99%) of desired product as a solid.
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:18]=[CH:17][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=2)[CH:6]=[N:5][N:4]=[N:3]1.[OH-].[Na+].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O.C(OCC)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:7]([N:2]3[CH:6]=[N:5][N:4]=[N:3]3)=[CH:18][CH:17]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: NCCCCOc1ccc(-n2cnnn2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(NCCCCOc1ccc(-n2cnnn2)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.7 g of 4-[4-(1H-tetrazol-1-yl)phenoxy]butaneamine hydrochloride (Example 39) in 100 ml of water is treated successively with 3.5 ml of 10N NaOH and a solution of 2.7 g of 4-bromobenzenesulfonyl chloride in 100 ml of diethyl ether. The mixture is stirred at room temperature for 1.5 hours, the precipitate collected, washed with diethyl ether and water, and air dried. Recrystallization from ethanol gives the pure compound, m.p. 109°-110° C.; yield, 1.6 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:13][C:14]([CH:19]([CH3:21])[CH3:20])([CH3:18])[C:15](=[O:17])[N:16]=1)=[O:5])[CH3:2].Cl[C:23]([O:25][CH3:26])=[O:24]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]([C:23]([O:25][CH3:26])=[O:24])[C:14]([CH:19]([CH3:20])[CH3:21])([CH3:18])[C:15](=[O:17])[N:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccccc1C1=NC(=O)C(C)(C(C)C)N1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1C1=NC(=O)C(C)(C(C)C)N1C(=O)OC
Reaction time: 1 h
Yield: 89.7 %

Procedure:
8 g (0.028 mole) of 2-(2-ethoxycarbonylphenyl)-5-isopropyl-5-methyl-4-oxo-2-imidazoline are dissolved in 30 ml of absolute pyridine, and 5.3 g (0.056 mole) of methyl chloroformate are added at room temperature. After 1 hour, the mixture is poured onto ice and extracted twice with 100 ml of toluene each time and the organic phase is washed twice with water, dried and evaporated. 8.7 g (90% of theory) of 2-(2-ethoxycarbonylphenyl)-5-isopropyl-1-methoxycarbonyl-5-methyl-4-oxo-2-imidazoline are obtained as a colorless oil.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10]O)[CH2:5][CH2:4]1)=[O:2].[SH:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O.O>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][S:12][C:13]2[NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: O=CN1CCN(CCO)CC1
Reactant: Sc1nc2ccccc2[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Yield: 75.4 %

Procedure:
To a solution containing 1-formyl-4-(2-hydroxyethyl)piperazine (1.58 g, 10 mmol), 2-mercaptobenzimidazole (5.56 g, 37 mmol), and triphenylphosphine (9.26 g, 35.3 mmol) in dimethylformamide (100 mL), diethyl azodicarboxylate (5.19 g, 29.8 mmol) was added dropwise over 5 minutes with ice-cooling and stirring under argon. The mixture was stirred for 80 minutes at room temperature, and then water (2 mL) was added to the mixture so as to deactivate the reagent. The reaction mixture was concentrated under reduced pressure, and chloroform (200 mL) was added to the residue. Insoluble material was removed through filtration, and the filtrate was concentrated under reduced pressure. 2N Hydrochloric acid (20 mL) and ethyl acetate (100 mL) were added to the residue, and the liquid was partitioned. The organic layer was extracted with 2N hydrochloric acid (20 mL×2). The aqueous extract and the aqueous layer were combined, and the mixture was washed with chloroform (50 mL×2) . The pH of the mixture was adjusted to about 9 through addition of potassium carbonate, followed by extraction with chloroform (50 mL×3), washing the organic layer with saturated brine, drying over sodium sulfate anhydrate, and removing the solvent. The thus-formed crude product was crystallized from acetone-diethyl ether, thereby yielding 2.19 g of 1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (yield: 76%) as a colorless crystalline powder. The crystallization mother liquor was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (eluent: chloroform:methanol=50:1 to 20:1), thereby yielding 0.42 g of 1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (yield: 14%) as a colorless crystalline powder. The overall yield was 90%.
Reaction SMILES: Cl.[Cl:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH:6]=NOC.C=O.CC(C)=[O:20]>O.CCCCCC>[Cl:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH:6]=[O:20]
Reactant: CC(C)=O
Reactant: CON=CCCC(Cl)c1ccccc1
Agent: C=O
Agent: Cl
Solvent: CCCCCC
Solvent: O
Product: O=CCCC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.1 mL of 2 mol/L hydrochloric acid was added to a mixture of 82 mg of (4-chloro-4-phenylbutylidene)(methoxy)amine, 0.32 mL of a 36% formalin aqueous solution and 4 mL of acetone, and the obtained mixture was then stirred at room temperature for 0.5 hours. Thereafter, hexane and water were added to the reaction mixture, and the water layer was then removed. The solvent was distilled away under reduced pressure, so as to obtain 61 mg of 4-chloro-4-phenylbutanal in the form of a colorless oily product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:20](=[O:32])[C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1
Yield: 58.4 %

Procedure:
4-[5-(4-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.45 mmol) was dissolved at rt in a mixture of 30% TFA in CH2Cl2. The reaction mixture was stirred until TLC indicated consumption of starting material (30 min). The mixture was then partitioned between EtOAc and water. The water layer was basified with solid NaOH to pH 12. The organic layer was separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was washed with water, dried over Na2SO4, filtered and concentrated to afford the product (89 mg, Yield: 56%). HRMS m/z calcd for C20H26N4O [M+H]+: 339.2180. Found: 339.2180.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([N:12]=[C:13](SC)SC)[S:9][C:7]=2[N:8]=1.Cl.Cl.[NH2:20][CH2:21][C@@:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([NH:12][C:13]3[O:30][C@:22]4([CH2:21][N:20]=3)[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]4)[S:9][C:7]=2[N:8]=1
Reactant: COc1ncc2nc(N=C(SC)SC)sc2n1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Yield: 64.5 %

Procedure:
A mixture of dimethyl 5-methoxythiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (100 mg, 0.349 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (80 mg, 0.349 mmol) and cesium carbonate (228 mg, 0.698 mmol) in DMF (1.7 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and the solids were collected by filtration to afford (R)—N-(5-methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (78 mg, 64% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.12 (br. s., 1H) 8.63 (s, 1H) 3.95-4.18 (m, 4H) 3.71 (d, J=9.77 Hz, 1H) 3.41 (d, J=15.26 Hz, 1H) 2.74-3.10 (m, 5H) 2.11-2.27 (m, 2H) 1.71-1.86 (m, 1H) 1.50-1.70 (m, 2H). MS (LC/MS) R.T.=1.66; [M+H]+=347.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15])([O-:3])=[O:2].[Cl:18][C:19]1[C:28]([NH2:29])=[C:27]2[C:22]([C:23]([O:30][CH3:31])=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1>N1C=CC=CC=1>[Cl:18][C:19]1[C:28]([NH:29][S:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:16])=[O:15])=[C:27]2[C:22]([C:23]([O:30][CH3:31])=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1
Reactant: COc1ccnc2c(N)c(Cl)ccc12
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccnc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3[N+](=O)[O-])c(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
2-Nitro-4-(trifluoromethyl)benzenesulfonyl chloride (839 mg, 2.9 mmol) was added to a solution of 7-chloro-4-methoxy-quinolin-8-ylamine (Intermediate 70) (550 mg, 2.6 mmol) in pyridine(10 ml) and the mixture was stirred at room temperature for 18 h. The solvent was removed in vacuo. The residue was dissolved EtOAc (100 ml), washed sat. sodium bicarbonate solution, dried (MgSO4) and concentrated in vacuo to give the title compound (830 mg, 69%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:27](I)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:20]=[CH:21][C:22]([Br:25])=[CH:23][N:24]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCI
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(Br)cn2)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
2-[(4-{2-[(5-Bromopyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (3.27 g) synthesized in Example 162-1 and heptyl iodide (1.77 g) were dissolved in N,N-dimethylformamide (36 mL), potassium tert-butoxide (0.80 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (2.80 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[C:17](Cl)=[O:18].C(N(CC)CC)C>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[C:17]([NH:12][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH3:11])=[N:8][C:7]=2[C:2]=1[Cl:1])=[O:18]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2c(Cl)c(NC(=O)c3cc(Cl)cc(Cl)c3)ccc2s1
Yield: 60 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 3,5-dichlorobenzoyl chloride (122 mg, 0.56 mmol) in presence of triethylamine (0.5 mL) according to method A gave 3,5-Dichloro-N-(4-chloro-2-methyl-benzothiazol-5-yl)-benzamide (66 mg, 0.15 mmol, 60% yield) as a off-white powder after crystallisation in hexane/DCM.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[S:27].C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[F:18])=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccccc1N=C=S
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccccc1NC(=S)Nc1ncccc1OCc1c(F)cccc1Cl

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (7.48g, 0.03 mol), 2fluorophenyl isothiocyanate (5.0 g, 0.033 mol) and toluene (30 ml) was heated under reflux for 1.5 hours, then cooled and diluted with ether to induce crystallisation of the product. Yield 7.9 g (59 %), m.p. 145°-147 ° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12].[NH3:14]>O.C(O)C>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH3:10])[C:3]([N+:11]([O-:13])=[O:12])=[C:2]([NH2:14])[CH:7]=1
Reactant: CNc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Reactant: N
Solvent: O
Solvent: CCO
Product: CNc1cc(Cl)cc(N)c1[N+](=O)[O-]

Procedure:
0.034 mole (7.5 g) of 2,4-dichloro-6-methylaminonitrobenzene is added to 100 ml of a 28% solution of ammonia in water and 50 ml of ethanol in an autoclave. The reaction medium is heated for 12 hours at 145°-150° C., the pressure being 12 kg/cm2. The product expected precipitates from the reaction medium on cooling. After draining and re-impasting in water, it is dried by heating under vacuum in the presence of phosphorous pentoxide. Recrystallized from isopropanol, it melts at 129° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[F:7])(=O)[CH3:2].[CH2:9]1C[O:12][CH2:11][CH2:10]1.C(OCC(Br)F)(=[O:16])C.C1COCC1.C(OC(C)C)(C)C>O>[F:7][CH:6]([CH:11]([OH:12])[CH2:10][CH3:9])[C:5]([O:4][CH2:1][CH3:2])=[O:16]
Reactant: CC(=O)OCC(F)Br
Reactant: C1CCOC1
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C(F)C(O)CC
Reaction time: 0.33 h
Yield: 85 %

Procedure:
After a 500 mL reaction vessel which had been sufficiently dried inside by vacuum heating was replaced with dry nitrogen, and placed in an ice bath, 24.2 g (370 mmol/1.5 equivalent) of activated metal zinc and 300 mL of THF (dehydrated) were added into the reaction vessel. Thereto was added a bromofluoroethyl acetate/THF solution (46.91 g (253.6 mmol/1.0 equivalent) of bromofluoroethyl acetate and 80 mL of THF (dehydrated)) dropwise over 5 min. After the dropwise addition, the temperature of the mixture was elevated to the room temperature, followed by stirring for 20 min. Thereto was added a propionealdehyde/THF solution (17.76 g (305.8 mmol/1.2 equivalent) of propionealdehyde and 80 mL of THF (dehydrated)), and the mixture was stirred for 60 min at a room temperature. Thereafter, water and diisopropyl ether were added thereto, and two-layer separation was carried out. The organic layer thus obtained was washed with diluted hydrochloric acid and water, and the moisture was eliminated using magnesium sulfate, followed by filtration. Then diisopropyl ether was distilled off to give 35.4 g (yield: 85%) of ethyl 2-fluoro-3-hydroxy-pentanoate represented by the following formula.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:35])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH3:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:35])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH3:34])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: Cc1cc(Cl)ccc1/C(C#N)=C/c1cccc(Cl)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1F
Yield: 48.8 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methyl-phenyl)-acrylonitrile (2.3 g, 7.5 mmol) prepared in Example 57a, AgF (1.3 g, 10 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.9 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH:18]([Mg]Br)=[CH2:19]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH:18]=[CH2:19])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: C=C[Mg]Br
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (326 mg) in THF (10 mL)-78° C. was added vinyl magnesium bromide (2.42 mL of 1.0 M in THF) dropwise. The resulting mixture was then stirred at 0° C. for 2 hr. The resulting mixture was quenched with H2O and 1 N HCl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow gum. The yellow gum was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([CH3:10])[N:4]=1.[CH3:11][N:12]([CH3:16])[C:13](Cl)=[S:14]>>[CH3:11][N:12]([CH3:16])[C:13](=[S:14])[O:9][C:7]1[N:6]=[C:5]([CH3:10])[N:4]=[C:3]([CH2:2][Cl:1])[CH:8]=1
Reactant: Cc1nc(O)cc(CCl)n1
Reactant: CN(C)C(=S)Cl
Product: Cc1nc(CCl)cc(OC(=S)N(C)C)n1

Procedure:
4-Chloromethyl-6-hydroxy-2-methyl-pyrimidine is reacted with N,N-dimethylthiocarbamoyl chloride analogously to the process described in Example 86 in order to produce 4-chloromethyl-2-methyl-6-pyrimidinyl N,N-dimethylthiocarbamate which is required as the starting material in Example 30. This product is obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[CH2:14][C@@H:15]([OH:31])[C@@H:16]([NH:24][C:25](=[O:30])[C@H:26]([CH2:28][SH:29])[NH2:27])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32](O)(=[O:43])[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[CH2:14][C@@H:15]([OH:31])[C@@H:16]([NH:24][C:25](=[O:30])[C@H:26]([CH2:28][SH:29])[NH:27][C:32]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1)=[O:43])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CS
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CS)NC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 64 h
Yield: 41.3 %

Procedure:
A solution of 650 mg of N-tert.butyl-1-[3(S)-[(L-cysteinyl)amino]-2(R)-hydroxy-4-phenylbutyl]-2(S)-piperidinecarboxamide and 242 mg of quinaldic acid was cooled in an ice/salt mixture. 189 mg of hydroxybenzotriazole, 161 mg of N-ethylmorpholine and 317 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 64 hours. The mixture was diluted with ethyl acetate and filtered, and the filtrate was then evaporated. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution. The organic phase was washed with sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using dichloromethane/methanol (19:1) for the elution to give 350 mg of N-tert.butyl-1-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-cysteinyl]amino]butyl]-2(S)-piperidinecarboxamide as a white solid; MS: m/e 620 [M+H]+.