Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]3[CH:23]=[CH:22][C:17](C(OC)=O)=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[OH-:26].[Na+].[O:28]1[CH2:32]CCC1.Cl>O.CO>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:22][C:23]=3[C:32]([OH:28])=[O:26])=[N:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)s2)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1-c1nnc(-c2ccc(C(F)(F)F)cc2)s1
Yield: 83 %

Procedure:
A mixture of methyl 4-[5-(4-trifluoromethylphenyl)-1,3,4-thiadiazol-2-yl]benzoate (0.838 g), 1 M aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (100 ml) and methanol (50 ml) was heated under reflux for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid was added to acidify the mixture. The mixture was extracted with ethyl acetate-tetrahydrofuran (1:1, volume ratio). The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from tetrahydrofuran to give 4 [5-(4-trifluoromethylphenyl)-1,3,4-thiadiazol-2-yl]benzoic acid (0.672 g, yield 83%) as a colorless crystalline powder. melting point: >300° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccccc1[N+](=O)[O-]
Yield: 94.2 %

Procedure:
To a stirred solution of 2-nitrophenol (1) (1.4 g, 10 mM) and ethyl 4-bromobutyrate (2.1 g, 1.57 mL, 11 mM) in 35 mL of dry acetone is added 2 g (14.5 mM) of anhydrous, ground potassium carbonate. The resultant colored mixture is then heated under a nitrogen atmosphere at gentle reflux until the color due to the phenol anion has dissipated and a yellow mixture remains. Concentration of the cooled and filtered mixture yields an oil which on flash chromatography (silica gel, ethyl acetate/hexane- or methylene chloride as eluant) yields 2.4 g (96% yield) of the title compound (3) as an oily liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1)[NH2:24]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2cc1OCC

Procedure:
In the manner of Example 141 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3-chloro-4-(1-methyl-2-imidazolylthio)aniline (WO-9615118) gave the title compound as a tan solid, mp 285-290° C.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[C:4]([NH:6][C@H:7]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH:17]=[CH:16]2)[C:8]([O:10]C)=[O:9])=[O:5].[Cl:36][C:37]1[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[C:38]=1[C:39]([NH:41][C@@H:42]([CH2:47][C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][CH:57]=1)[N:54]=[C:53]([C:58]1[C:63]([Cl:64])=[CH:62][CH:61]=[CH:60][C:59]=1[Cl:65])[CH:52]=[CH:51]2)[C:43]([O:45]C)=[O:44])=[O:40].ClC1C=CC=C(Cl)C=1C(NC(CC1C=C2C(=CC=1)N=C(C1C(Cl)=CC=CC=1Cl)C=C2)C(O)=O)=O>>[Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[C:4]([NH:6][C@H:7]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH:17]=[CH:16]2)[C:8]([OH:10])=[O:9])=[O:5].[Cl:36][C:37]1[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[C:38]=1[C:39]([NH:41][C@@H:42]([CH2:47][C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][CH:57]=1)[N:54]=[C:53]([C:58]1[C:63]([Cl:64])=[CH:62][CH:61]=[CH:60][C:59]=1[Cl:65])[CH:52]=[CH:51]2)[C:43]([OH:45])=[O:44])=[O:40]
Reactant: COC(=O)[C@@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Agent: O=C(NC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cccc1Cl
Product: O=C(N[C@@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cccc1Cl
Product: O=C(N[C@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cccc1Cl

Procedure:
Hydrolysis at RT of methyl (2R)-2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 36 and methyl (2S)-2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 37 (as described in example 1.1 for the synthesis of compound 38) gives respectively (2R)-2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoic acid 40 and (2S)-2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoic acid 39.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9]([Cl:16])[N:8]=[CH:7][N:6]=1.C(N(CC)CC)C>COCCOC.O>[Cl:16][C:9]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:5]([N:2]([CH3:3])[CH3:1])[N:6]=[CH:7][N:8]=1
Reactant: CNC
Reactant: COC(=O)Cc1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1c(Cl)ncnc1N(C)C
Reaction time: 1 h

Procedure:
Dimethylamine (50 ml of a 40% aqueous solution) is added dropwise to a solution of methyl 4,6-dichloropyrimidin-5-yl-acetate (80 g, 0.36 mol) in 1,2-dimethoxyethane (300 ml) and triethylamine (56 ml, 0.4 mol) at room temperature with cooling. After stirring for 1 hour the mixture is diluted with water and the product extracted with diethyl ether. Drying (MgSO4), evaporation of the solvent and distillation gives the methyl 4-chloro-6-dimethylamino-pyrimidin-5-yl-acetate as a colorless solid (74 g), b.p. 135°-138° C./1.5 torr, m.p. 30°-32° C.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[O:9])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Nicotinoyl chloride hydrochloride (286 mg, 1.61 mmol, 1.0 eq) was added at room temperature to a stirred solution of (S)-3-amino-1-N-BOC-pyrrolidine (300 mg, 1.61 mmol, 1.0 eq) in CH2Cl2 (9 mL), followed by triethylamine (337 μL, 2.42 mmol, 1.5 eq). After stirring overnight at room temperature, the reaction mixture was extracted and the organic layer was dried over Na2SO4, filtered and evaporated to afford 457 mg of the expected compound.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([CH2:25][O:26][C:27](=[O:43])[C@H:28]([CH:40]([CH3:42])[CH3:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:21][C:22]([OH:24])=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:62][CH2:63]I>O1CCOCC1>[Cl:62][CH2:63][O:23][C:22](=[O:24])[CH2:21][CH:20]([CH2:25][O:26][C:27](=[O:43])[C@H:28]([CH:40]([CH3:42])[CH3:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:19][O:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)O
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OCCl

Procedure:
3,3-bis(N-CBz-L-valyloxymethyl)-propionic acid (3 g, 5 mmole) was dissolved in dioxane (20 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40%, 3.11 ml, 4.8 mmole). The solution was dried in vacuo, and it was coevaporated with toluene several times. The residue was dissolved in methylene chloride (15 ml) and then chloroiodomethane (7.3 ml, 100 mmole) was added to the solution. The reaction solution was refluxed for 18 hr and then evaporated and the product was isolated with silica gel column chromatography. 900 mg.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]([CH3:11])[CH2:7]2.[Cl-:15].[NH4+]>CO.O.[Fe]>[ClH:15].[I:1][C:2]1[CH:3]=[C:4]([NH2:12])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[CH:7]2
Reactant: CC1Cc2cc([N+](=O)[O-])cc(I)c2N1
Reactant: [Cl-]
Agent: [Fe]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cc1cc2cc(N)cc(I)c2[nH]1
Product: Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A solution of 7-iodo-2-methyl-5-nitro-2,3-dihydro-1H-indole XIV (4.75 g, 0.0156 mol) in methanol (150 mL) at 25° C. was treated with a solution of ammonium chloride (5.22 g, 0.0976 mol) in water (150 mL) and iron powder (3 g, 0.0534 mol). The mixture was heated to 100° C. under a nitrogen atmosphere for 6 h. The reaction mixture was filtered hot through a pad of celite and washed with hot methanol. The filtrate was concentrated in vacuo and the residue partitioned between methylene chloride and water. The layers were separated and the pH of the aqueous layer was adjusted to pH=10 with ammonium hydroxide. The aqueous layer was extracted with methylene chloride and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to a volume of 50 mL. The resulting solution was treated with a 4.0M aqueous hydrochloric acid solution in dioxane and then stirred at 25° C. for 1 h. The precipitate was collected by filtration and washed with methylene chloride and petroleum ether to afford 7-iodo-2-methyl-1H-indol-5-ylamine hydrochloride XV (4.37 g, 81%) as a gray solid: LRMS for freebase C9H11IN2 (M+H)+ at m/z=275.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][NH:9]2)=[CH:4][CH:3]=1.F[C:20](F)(F)S(OC)(=O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][N:9]2[CH3:20])=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1c[nH]n(-c2ccc(F)cc2)c1=O
Product: CCOC(=O)c1cn(C)n(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 67 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (2.2 g, 8.9 mmol) and methyl trifluoromethanesulfonate (3 mL) was stirred at 80° C. for 40 min. The mixture was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=70/30→100/0) to give the title compound (1.6 g, 67%) as a pale-yellow solid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[CH:19]([Cl:22])(Cl)Cl>>[CH2:15]([O:14][C:12]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:12](=[N:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[C:11]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:9][CH:10]=2)=[CH:18][CH:17]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: ClC(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(N=C(Nc2ccc(C(=O)OCC)cc2)c2ccc(Cl)cc2)cc1

Procedure:
N,N'-Bis(4-ethoxycarbonylphenyl)-4-chlorobenzamidine (12) was prepared from ethyl 4-[N-(4-chlorobenzoyl)] aminobenzoate, phosphorus pentachloride, and ethyl 4-aminobenzoate; white crystals: mp 171.0°-172.5° C. 1H-NMR (CDCl3) 8.0-6.9 (m, 13H), 4.2 (q, 4H, J=7 Hz), 1.5 (t, 6H, J=7 Hz); IR (CHCl3) 3420, 3330, 1705, 1590; MS (m/e) 450, 452 (M+), 286 (base).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]([CH:19]3[CH2:21][CH2:20]3)[O:10][C:11]=2[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=1)=O.COCCO[AlH2-]OCCOC.[Na+]>O1CCCC1.CC(OC)(C)C>[CH:19]1([CH:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:5]=3[CH2:3][OH:2])[O:10]2)[CH2:20][CH2:21]1
Reactant: COC(=O)c1cc(OC)c(OC)c2c1C=CC(C1CC1)O2
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(CO)c2c(c1OC)OC(C1CC1)C=C2
Temperature: 40 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
Methyl ester 2 (2 g, 6.2 mmol) was dissolved in 30 ml tetrahydrofurane and 2.7 ml of a 3.5-M solution of Red-Al (9.4 mmol) was added. The mixture was stirred at 40° C. for 3 hours. The solution was diluted with 100 ml of TBME and slowly quenched by addition of 50 ml of a 30% potassium-tartrate solution. The layers were separated and the organic solution was washed with brine (2 times 30 ml), dried over magnesium sulfate and concentrated. The pure alcohol 4 (1.34 g, 5.1 mmol) was obtained as a white-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([S:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[N-:25]=[C:26]=[S:27].O1CC[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([S:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:26]([NH:25][CH2:29][CH3:30])=[S:27])=[CH:22][CH:23]=2)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: [N-]=C=S
Reactant: Nc1ccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Reactant: C1CCOC1
Product: CCNC(=S)Nc1ccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1

Procedure:
A solution of 1-[4-(4-chlorophenyl)-2-(4-aminophenylthio)-n-butyl]imidazole (680 mg) and 1 ml of ethyl)isothiocyanate in 20 ml of tetrahydrofuran was heated overnight under gentle reflux. The solvent was then evaporated and the residue chromatographed on silica gel eluting with 2.2% water in ethyl acetate to give 1-[4-(4-chlorophenyl)-2-(4-ethylaminothiocarbonylaminophenylthio)-n-butyl]imidazole.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCC[CH2:39][C:40]([OH:42])=[O:41])C(=O)C[C@H]1O.C1CCC([NH:53]C2CCCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([NH:53][CH2:39][C:40]([OH:42])=[O:41])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)O

Procedure:
2.23 g of Z-Ile-OH-dicyclohexylammonium salt are suspended in ethyl acetate and acidified with 0.2 M citric acid. The resulting ethyl acetate solution is washed until neutral, dried and evaporated to dryness. The residue is dissolved in 15 ml of acetonitrile, and 750 mg of H-Gly-OMe.HCl are added to the solution followed at 0° C., with stirring, by 0.84 ml of triethylamine. After 10 minutes 1.24 g of dicyclohexylcarbodiimide are added and the mixture is stirred overnight at 0° C. The precipitate is filtered off, the filtrate evaporated to dryness, and the residue taken up in 30 ml of ethyl acetate and filtered. The ethyl acetate solution is washed with 0.2 M citric acid and saturated sodium bicarbonate solution, dried and concentrated to about 10 ml in vacuo. After adding 25 ml of hexane the protected dipeptide crystallises out; melting point 120°-122° C. Rf = 0.53 in the system chloroform-methanol (95:5) in a thin layer chromatogram on silica gel.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[CH:3][CH:2]=1.[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:38])[F:37])[N:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>CS(C)=O.O>[CH3:21][CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[C:33]([CH2:34][NH:35][C:12]([NH:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[O:20])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:37])[F:38])[N:29]=2)[CH2:26][CH2:27]1
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CN)CC1
Reactant: O=C(Nc1ccnc2ccccc12)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)Nc2ccnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Phenyl quinolin-4-ylcarbamate (crude 139 mg, 0.53 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (144 mg, 0.53 mmol) were dissolved in dimethyl sulfoxide. Then triethylamine (0.15 mL, 1.06 mmol) was added to it. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([O:13][CH3:14])=[C:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=O.ClC(Cl)(O[C:19](=[O:25])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:34]1([C@H:40]([NH2:42])[CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:14][O:13][C:4]1[S:3][C:2]2[NH:1][C:19](=[O:25])[N:42]([C@@H:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:41])[C:7](=[O:9])[C:6]=2[C:5]=1[CH3:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(=O)c1c(N)sc(OC)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1sc2[nH]c(=O)n([C@H](C)c3ccccc3)c(=O)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
To a solution (30 mL) of ethyl 2-amino-5-methoxy-4-methylthiophene-3-carboxylate (1.0 g) in methylene chloride were added triphosgene (1.8 g) and triethylamine (3.0 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added (1R)-1-phenylethanamine (1.7 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (15 mL), sodium methoxide (1.0 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.62 g, 42%).
Reaction SMILES: [NH:1]([C:19]([O:21]CC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([CH2:17][F:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Br.[C:30](O)(=O)[CH3:31]>>[NH:1]([C:19]([CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:30][CH3:31])=[O:21])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([CH2:17][F:18])=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)CF
Reactant: CC(=O)O
Agent: Br
Product: CCCCCCCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)CF
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
The Z-Leu-Leu-CH2F (0.39 g) obtained in Example 3 was dissolved in acetic acid (5 ml) including a 25% anhydrous hydrogen bromide and the mixture was agitated at room temperature for 3 hours. After the end of the reaction, the solvent was distilled off and the resultant residue was dissolved in anhydrous methylene chloride (5 ml). To this, under ice water, were added triethylamine (0.23 g) and octanoylchloride (0.2 g) to dissolve it, then this was washed with a 10% aqueous citric acid solution, a 5% sodium hydrogencarbonate, then a saturated saline water in this order, then was dried on anhydrous sodium sulfate and the solvent distilled off under reduced pressure. The residue was purified by silica gel medium pressure column chromatography to obtain the above-referenced compound Octanoyl-Leu-Leu-CH2F (200 mg, 0.52 mmole) at a yield of 52%.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:3]=1[C:4]([N:6]([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]([C:26]1[CH:38]=[CH:37][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)=[CH:28][CH:27]=1)#[N:25]>CN(C)C=O>[C:24]([C:26]1[CH:38]=[CH:37][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:17][C:15]2[CH:14]=[CH:13][C:3]([C:4]([N:6]([CH:10]([CH3:11])[CH3:12])[CH:7]([CH3:8])[CH3:9])=[O:5])=[C:2]([OH:1])[CH:16]=2)=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(OCCCCCBr)cc1
Reactant: CC(C)N(C(=O)c1ccc(O)cc1O)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)C(C)C
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A solution of 2,4-dihydroxy-N,N-bis(1-methylethyl)benzamide (3 g, 12.7 mmol) in 30 mL of N,N-dimethylformamide is treated with cesium carbonate (4.97 g, 15.2 mmol), and 5-(4-cyanophenoxy)pentyl bromide (3.4 g, 1.27 mmol) and stirred at 40° C. for 24 hours. The reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford a yellow foam. This material is purified by chromatography on silica gel (30 g) with 30-70% ethyl acetate/hexane as the eluent to afford 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide as colorless foam.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([O:13][CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)(=[O:17])=[O:16]
Reactant: OCCC#Cc1cccc(CF)n1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCC#Cc1cccc(CF)n1
Yield: 75.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(B), from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-ol (2.60 g, 15 mmol) and methanesulfonyl chloride (1.50 mL, 19 mmol) to afford 2.90 g of 4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl methanesulfonate (Yield: 78%) as a pale yellow oil which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl.C1(C)C=CC=CC=1.CCOCC>[O:1]([CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To an ice-cold solution of the compound from Step 1 (2.60 g, 12.9 mmol), phenol (3.64 g, 38.7 mmol), and triphenylphosphine (6.77 g, 25.8 mmol) in DCM (50 mL) was added a solution of diisopropyl azodicarboxylate (5.22 g, 25.8 mmol) in toluene (30 mL). After stirring at room temperature for 60 hours it was diluted with ether and the solution was extracted with aqueous 3N NaOH. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The intermediate tert-butyl (R)-2-(phenoxymethyl)pyrrolidine-1-carboxylate was obtained from the residue by column chromatography (silica gel, cHex/EtOAc 29:1); yield: 1.82 g (51%).