Azzindani/Open_Reaction_Data huggingface dataset:
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[NH:14][CH2:15][CH2:16]O)([O-:3])=[O:2].S(Cl)([Cl:20])=O>ClC(Cl)Cl>[Cl:20][CH2:16][CH2:15][NH:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCl
Reaction time: 2 h

Procedure:
To a stirred mixture of 12.5 parts of 2-{[2-nitro-4-(trifluoromethyl)phenyl]amino}ethanol and 150 parts of trichloromethane are added dropwise 7.5 parts of sulfinyl chloride. Upon completion, stirring is continued for 2 hours at reflux temperature. The reaction mixture is evaporated and the residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding N-(2-chloroethyl)-2-nitro-4-(trifluoromethyl)benzenamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:18][C:10]1[O:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][C:11]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: BrBr
Reactant: CCOC(=O)c1coc(-c2ccc(F)cc2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccc(F)cc2)oc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)oxazole-4-carboxylate (7.44 g) in chloroform (100 ml) was added dropwise bromine (8.1 ml) at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes and then refluxed for 8 hours. After cooling the reaction mixture, 10% aqueous sodium thiosulfate solution was added to the mixture and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate:n-hexane=1:9) to obtain ethyl 5-bromo-2-(4-fluorophenyl)-oxazol-4-carboxylate (9.21 g) as pale yellowish powder.
Reaction SMILES: [NH2:1][C:2]([CH:12]=[CH2:13])([CH2:6][C:7]1[NH:11][CH:10]=[N:9][CH:8]=1)[C:3]([OH:5])=[O:4].[ClH:14].[CH3:15]O>>[ClH:14].[CH3:15][O:4][C:3](=[O:5])[C:2]([NH2:1])([CH:12]=[CH2:13])[CH2:6][C:7]1[NH:11][CH:10]=[N:9][CH:8]=1
Reactant: CO
Reactant: C=CC(N)(Cc1cnc[nH]1)C(=O)O
Agent: Cl
Product: C=CC(N)(Cc1cnc[nH]1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1.81 g (0.01 mole) of 2-amino-2-vinyl-3-(5-imidazolyl)propionic acid in 50 ml of methanol saturated with anhydrous HCl is stirred overnight at 25° C. then evaporated to give 2-amino-2-vinyl-3-(5-imidazolyl)propionic acid methyl ester hydrochloride. The ester hydrochloride is suspended in 50 ml of methylene chloride and treated with 2.8 g (0.02 mole) of benzoyl chloride followed by treatment with 3.6 g (0.035 mole) of triethylamine. The mixture is stirred for 24 hours at 25° C., then washed with water, dried and evaporated. The residue is recrystallized from methanol to give methyl N,N'-dibenzoyl-2-amino-3-(5-imidazolyl)-2-vinylpropionate.
Reaction SMILES: Br[CH2:2][C:3]([CH2:5][O:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:4].C[Si]([C:30]#[N:31])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CC#N>[C:8]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:6][CH2:5][C:3](=[CH2:4])[CH2:2][C:30]#[N:31])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C(CBr)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: C1CCOC1
Product: C=C(CC#N)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
To a solution of 11 (1.45 g; 3.69 mmol) and in dry CH3CN (37 mL) was added trimethylsilyl cyanide (0.49 mL; 3.69 mmol). Then 1 M tetrabutylammonium fluoride (TBAF) in THF solution (3.69 mL, 3.69 mmol) was added slowly at room temperature and the reaction was stirred for 20 min. Most solvents were evaporated and ethyl acetate (100 mL) and saturated aqueous NaHCO3 (30 mL) were added. The organic layer was washed by saturated aqueous NaCl and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by flash column chromatography over silica gel using acetate-hexane (1:10) as the eluent to afford 12 as white solid (1.01 g; 64% yield): 1H NMR (400 MHz, CDCl3) δ 7.39-7.45 (m, 6H, six of ArH), 7.21-7.34 (m, 9H, nine of ArH), 5.31 (s, 2H, C═CH2), 3.64 (s, 2H, Ph3COCH2), 3.11 (s, 2H, CH2CN); 13C NMR (100 MHz, CDCl3) δ 143.3, 135.5, 128.2, 127.7, 126.9, 116.8, 114.7, 87.0, 65.7, 21.9, (10).
Reaction SMILES: [CH2:1]([N:4]([C:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1[N:28]([C:32](=[O:34])C)C(=O)C)(C(OCC)=O)C(OCC)=O)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].O>[O-]CC.[Na+].C(O)C>[CH2:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH:8]1[CH2:19][C:20]2[C:21](=[C:22]([O:26][CH3:27])[CH:23]=[CH:24][CH:25]=2)[NH:28][C:32]1=[O:34])[CH2:6][CH3:7]
Reactant: CCCN(CCC)C(Cc1cccc(OC)c1N(C(C)=O)C(C)=O)(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCN(CCC)C1Cc2cccc(OC)c2NC1=O
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
Diethyl (dipropylamino){(2-(diacetylamino)-3-methoxyphenyl)methyl}propanedioate (6.34 g) was dissolved in sodium ethoxide in ethanol (150 mL of 1.4 M). After 20 min, the solution was heated under reflux for 15 hours; water was added to the reaction after 1 hour (1 mL), 3 hours (2 mL), 4 hours (5 mL) and 5 hours (15 mL). The solution was filtered to remove precipitated inorganic material and the solvents were removed trader reduced pressure, and the residue was partitioned between ethyl acetate and water. The oil obtained after evaporation of the ethyl acetate was chromatographed on silica gel to give 3.3 g of 3-(dipropylamino)-3, 4-dihydro-8-methoxy-2(1H)quinolinone. The product was crystallized from pentane to give 2.0 g of product, mp 50°°-54° C. Anal Calcd for C16H24N2O2 : C, 69.53; H, 8.75; N, 10.14. Found: C, 69.56; H, 8.98; N, 10.24.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:40]1([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:47]1[CH2:48][CH2:49][N:44]([CH:40]3[CH2:43][CH2:42][CH2:41]3)[CH2:45][CH2:46]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: C1CC(N2CCNCC2)C1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCN(C4CCC4)CC3)ccc2[nH]1
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 1-cyclobutylpiperazine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown solid (62%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[O:7].[CH3:17]CCCC.C(OCC)C>>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:6]2[O:7][CH2:17]2)[CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCCCC
Solvent: CCOCC
Product: FC(F)(F)c1cc(C2CO2)cc(C(F)(F)F)c1

Procedure:
Following General Procedure EC and using 3,5-bis-(trifluoromethyl)benzaldehyde (Lancaster), the title compound was isolated after flash chromatography with 10:1 pentane/diethylether.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[NH:7][C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([C:11](=[O:14])[CH2:12]Cl)[C:4]=2[CH:3]=1.[CH2:22]([N:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)[CH2:25][CH3:26])[CH3:23]>O1CCOCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[NH:7][C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([C:11](=[O:14])[CH2:12][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH:28]3[CH2:27][N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2cc(Cl)ccc21
Reactant: CCN(CC)CC1CCCCN1
Solvent: C1COCCO1
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2cc(Cl)ccc2C(=O)Nc2cccnc21

Procedure:
5.6 g (0.0174 mole) of 9-chloro-11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one were suspended in 100 ml of anhydrous dioxane and, after addition of 6.0 g (0.035 mol) of 2-[(diethylamino)methyl]piperidine, the mixture was boiled under reflux for 12 hours.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH2:6][CH2:5][C:4]1=[O:60])[CH3:2].[C:61]([O:64][CH2:65][C:66](Cl)=[O:67])(=[O:63])[CH3:62]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:66](=[O:67])[CH2:65][O:64][C:61](=[O:63])[CH3:62])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH2:6][CH2:5][C:4]1=[O:60])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC(=O)COC(C)=O)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-phenoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (42 mg) in dry methylene chloride (0.4 ml) is cooled to 0° C. To this solution is added a solution of acetoxyacetyl chloride (9 mg) in methylene chloride (0.5 ml). The reaction mixture is stirred at 0° C. for 30 minutes, and quenched with a drop of methanol. Purification by preparative tlc on silica gel gives the title compound.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[NH:4][N:3]=1.[CH:11]1(Br)[CH2:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[N:3]=1
Reactant: Brc1n[nH]c2cccnc12
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1nn(C2CCC2)c2cccnc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-1H-pyrazolo[4,3-b]pyridine (200 mg) in DMF (10 ml) were added cyclobutyl bromide (0.19 mL) and Cs2CO3 (395 mg) at room temperature. After stirring overnight at 60° C., the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) to give the title compound (181 mg).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>O1CCCC1>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH2:25][CH2:26][O:27][CH3:28])[N:15]=[CH:14][N:13]=[C:12]2[S:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:3]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a suspension of sodium hydride (422 mg, 17.6 mmol) in anhydrous tetrahydrofuran (100 mL) cooled to 0° C., 3-aminothiophenol (125 mg, 16.8 mmol) was added dropwise as a solution in tetrahydrofuran (5 mL). The mixture was stirred at 0° C. for 30 minutes. 4-Chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline, previously synthesized, was added and the resulting mixture heated to 50° C. overnight. After removal of the solvent the residue was taken into ethyl acetate/water, the organic layer separated and the aqueous phase extracted twice. The organics were combined, dried (MgSO4) and concentrated under reduced pressure. The residue was triturated in methanol to give 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline (2.8 g, 49%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.33 (d, 2H), 7.16-7.10 (m, 1H), 6.81 (s, 1H), 6.75-6.67 (m, 2H), 5.35 (bs, 2H), 4.33 (bs, 2H), 4.02 (s, 6H), 3.77 (bs, 2H); LC-MS (ESI) m/z 358 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]([OH:12])=[CH:10][C:9]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)=[C:8]([F:24])[CH:7]=1>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:7]=[C:8]([F:24])[C:9]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)=[C:10]([N+:1]([O-:4])=[O:2])[C:11]=1[OH:12]
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(O)c(Cl)cc(F)c1-c1ncc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 10 h
Yield: 79 %

Procedure:
0.24 ml (5.8 mmol) of 100% strength nitric acid was added to 1.9 g (5.8 mmol) of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-chloro-5-trifluoromethylpyridine in 50 ml of concentrated sulfuric acid. The reaction mixture was stirred at about 20° C. for 10 hours and then poured into 100 ml of ice-water. The solids were subsequently removed and dried at 40° C. in a vacuum drying cabinet. Yield: 79%; m.p.: 67-72° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:4][CH2:3][C@@H:2]([NH2:1])[CH:5]([CH3:7])[CH3:6])[C:10]=1[C:11]#[N:12]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)[C@H](N)CO
Product: CC(C)[C@H](N)COc1cccc(N)c1C#N

Procedure:
Prepared as in Example 24d from (S)-2-amino-3-methylbutan-1-ol and 2-amino-6-fluoro-benzonitrile as brown solid (71%). MS 220 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:35])=[C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:35])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(Cl)nc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(5-chloro-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propanoate (383 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (328 mg, 93%) as a white solid.
Reaction SMILES: [N:1](OCCC(C)C)=O.[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([NH2:28])=[C:23]([CH3:29])[C:22]=1[CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].C([O-])(=O)C.[K+]>C(O)(=O)C>[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[C:22]([CH2:30][O:31][C:32](=[O:34])[CH3:33])=[C:23]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:28][N:1]=[CH:29]2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)C[C@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)C(=O)OCC
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
Isoamyl nitrite (700 μL, 5.2 mmol), was added dropwise to an ice cold solution of 2-(S)-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-succinic acid diethyl ester (1.91 g, 4.8 mmol) in 5% acetic acid in tolune (81.2 mL). Mixture stirred at 0° C. for 45 minutes. Potassium acetate (1.50 g, 15.3 mmol) was added to the mixture. Reaction was stirred at room temperature for 14 hours. Mixture was quenched with water. Mixture was extracted with ethyl acetate (30 mL). Mixture was washed 2× saturated aqueous sodium bicarbonate. Organic was dried (magnesium sulfate) filtered and concentrated. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 80% yield as an amber oil. 1H NMR (300 MHz, CDCl3): δ=8.23 (s, 1H), 7.26 (s, 1H), 5.45 (s, 2H), 4.09 (q, J=7.0, 4H), 3.20 (dd, J1=7.32, J2=13.2, 1H), 3.10 (m, 1H), 2.97 (dd, J1=7.0, J2=13.3, 1H), 2.73 (dd, J1=8.4, J2=16.8, 1H), 2.44 (dd, J1=5.5, J2=16.8, 1H), 2.08 (s, 3H), 1.18 (m, 6H). MS m/e (M+H)+=411.0.
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[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)/[C:24]#[N:25])=[C:19]([F:34])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:34])([C:24]#[N:25])[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: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 25.2 %

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)-2-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-acrylonitrile (2.3 g, 8 mmol) prepared in Example 64a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.02 g, 25%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6]2([C:16]([O:18][CH3:19])=[O:17])[N:8]([C:9]([O:11][C:12]([CH3:15])(C)C)=[O:10])[CH:3]1[CH2:4][CH2:5]2.C(O)(C(F)(F)F)=O.C(Cl)(OC[C:31]1[CH:36]=[CH:35]C=[CH:33][CH:32]=1)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][C:6]2([C:16]([O:18][CH3:19])=[O:17])[N:8]([C:9]([O:11][CH2:12][C:15]3[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=3)=[O:10])[CH:3]1[CH2:4][CH2:5]2
Reactant: COC(=O)C12CCC(C(=O)C1)N2C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C12CCC(C(=O)C1)N2C(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 30 %

Procedure:
A mixture of O7-tert-butyl O4-methyl 2-oxo-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate (prepared according to the literature: Org. Lett., Vol. 9, No. 7, 2007 p 1235-p 1238) (0.34 g, 1.27 mmol), TFA (1.5 ml) in DCM was stirred for 2 hours. After removal of solvent and TFA under reduced pressure, the residue was dissolved into DCM (5 mL). To it was added TEA (0.51 g, 5.08 mmol) and CbzCl (0.43 g, 2.54 mmol). After 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography to give O7-benzyl O4-methyl 2-oxo-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate 148b. Yield:30%. MS: calc'd (MH +) 304, measured (MH +) 304.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:16]([OH:19])[CH2:17][CH3:18])[C:3]=1[C:20]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:21].[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:28]([O:19][CH:16]([C:4]1[C:3]([C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[C:2]([OH:1])[C:11]2[C:6](=[C:7]([C:12]([F:14])([F:13])[F:15])[CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:17][CH3:18])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCC(O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Reactant: O=C(O)c1ccccc1
Product: CCC(OC(=O)c1ccccc1)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Yield: 73.7 %

Procedure:
Using the procedure of Example 5, 5 g of 4-hydroxy-2-(1-hydroxypropyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide and 1.7 g of benzoic acid were reacted to obtain 4.65 g of 2-[1-(benzoyloxy)-propyl]-4-hydroxy-N-(2-thiazolyl)-8-(trifluoromethyl)-3-quinoline carboxamide melting at 230° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[CH:23]=[C:22]([C:33]([F:36])([F:35])[F:34])[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[CH:23]=[C:22]([C:33]([F:35])([F:36])[F:34])[N:21]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:25]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.6 %

Procedure:
To a cooled and stirred solution of 5-{3-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid tert-butylamide (example 169) (0.175 g, 0.32 mmol) in dichloromethane (4 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.12 g, 75%). MS (ISN) 494.1 [(M−H)−]; mp 226° C.