Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:18])[CH2:13][CH2:14][C:15](O)=[O:16])[CH:9]=[CH:10][CH:11]=1.C([N:26](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N>CN(C=O)C>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([NH2:26])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)O)c1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cccc(C(=O)CCC(N)=O)c1

Procedure:
To a solution of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid (Step D) in DMF, add triethylamine and BOP, after couple of hours of stirring, reaction mixture can be added to liquid ammonia at −40° C. and the resulting mixture can be warmed for 16 hours to give title compound.
Reaction SMILES: [CH:1]([S:3]([OH:6])(=[O:5])=[O:4])=[CH2:2].ClCCS(Cl)(=O)=O.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>>[CH:1]([S:3]([O:6][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])=[O:4])=[CH2:2]
Reactant: Oc1ccccc1
Reactant: C=CS(=O)(=O)O
Agent: Cl
Agent: O=S(=O)(Cl)CCCl
Product: C=CS(=O)(=O)Oc1ccccc1

Procedure:
The aryl ester of vinylsulfonic acid can be prepared by several available techniques. One method, described in U.S. Pat. No. 3,121,730 to Distler, involves reacting a beta-chloro-ethanesulfonic acid chloride with phenol in an aqueous medium at a pH of between 7.5 and 11.5. The reaction proceeds with a loss of 2 mols of hydrogen chloride to yield phenyl vinylsulfonate. An alternative method, described in U.S. Pat. No. 3,133,948, also to Distler, involves reacting carbyl sulfate with an aromatic hydroxy compound in an aqueous alkaline medium at a pH between 7.5 and 11.5 to yield a phenyl vinylsulfonate.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[C:17]([CH2:23]Br)[CH:16]=1>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:23]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: BrCc1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3ccc(Br)cc3C2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
In 70 ml of N,N-dimethylformamide was suspended 3.97 g of sodium hydride (purity: 60%), and 50 ml of an N,N-dimethylformamide solution containing 8.49 g of p-toluenesulfonamide was added thereto, after which the resulting mixture was stirred at 60° C. for 30 minutes. To the reaction mixture was added a solution of 17.0 g of 1-bromo-3,4-di(bromomethyl)benzene in 50 ml of N,N-dimethylformamide at 60° C., and the resulting mixture was stirred at 60° C. for one hour. The reaction mixture obtained was added to 500 ml of ice water and the precipitate was collected by filtration, and purified by a column chromatography (eluent: chloroform), to obtain 15.2 g of colorless, crystalline 5-bromo-2-(p-toluenesulfonyl)isoindoline.
Reaction SMILES: [CH2:1]([C@H:8]([NH:20][C:21](=[O:31])[O:22][C@@H:23]1[C@H:30]2[C@H:26]([O:27][CH2:28][CH2:29]2)[O:25][CH2:24]1)[C@H:9]([OH:19])[CH2:10][NH:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:40][C:35]=2[O:34][CH2:33]1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41]([N:11]([O:12][CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:10][C@@H:9]([OH:19])[C@@H:8]([NH:20][C:21](=[O:31])[O:22][C@@H:23]3[C@H:30]4[C@H:26]([O:27][CH2:28][CH2:29]4)[O:25][CH2:24]3)[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:42])=[O:43])=[CH:40][C:35]=2[O:34][CH2:33]1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc2c(c1)OCO2)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230), 1,3-benzodioxole-5-sulfonyl chloride (Eur. Pat. Appl. 583960, 23 Feb. 1994, 56 mg, 0.253 mmol) and diisoproylethylamine (0.042 mL, 0.242 mmol) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. A catalytic quantity of dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately 2 hours. An additional quantity of 1,3-benzodioxole-5-sulfonyl chloride (11 mg, 0.050 mmol) was added and the reaction was heated for an additional hour. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. After separating the phases, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 μM) eluting with 1:1 ethyl acetate:hexane. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate (123 mg, 87%) as a white solid. H1-NMR (chloroform-D3): 1.32 (m, 6H), 1.70 (m, 5H), 2.14 (m, 2H), 3.00 (m, 4H), 3.18 (b, 1H), 3.74 (m, 2H), 3.97 (m, 4H), 4.27 (m, 1H), 4.90 (m, 1H), 5.07 (m, 1H), 5.70 (d, 1H), 6.15 (s, 2H), 6.95 (d, 1H), 7.30 (m, 7H). MS(ESI): 641(M+Na).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Br)(C)C.[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][C:15]=1[CH:16]=[O:17].Cl>O1CCCC1.O>[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:18][C:15]=1[CH:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:17]
Reactant: Brc1ccccn1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1F
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccn1)c1cc(OC(F)(F)F)ccc1F
Reaction time: 2 h

Procedure:
To a solution of 2-bromopyridine (380 mg) in anhydrous tetrahydrofuran (3 mL) is slowly added a 1M solution of isopropylmagnesium bromide in tetrahydrofuran (2.64 mL) at room temperature. After stirring for 2 hours, 2-fluoro-5-(trifluoromethoxy)benzaldehyde (0.50 mL) is added and the reaction mixture stirred for 2 hours. After hydrolysis with water and 3N hydrochloric acid, the mixture is washed with diethyl ether, basified with concentrated sodium hydroxide and extracted with ethyl acetate twice. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (heptane/ethyl acetate 2/1) to afford (2-fluoro-5-trifluoromethoxyphenyl)pyridin-2-ylmethanol as an orange oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[C:11]2[NH:12][C:13](=[O:15])[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[F:5][C:6]1[C:11]2[NH:12][C:13](=[O:15])[O:14][C:10]=2[CH:9]=[C:8]([N+:1]([O-:4])=[O:2])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2c(F)cccc2o1
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2c(F)cc([N+](=O)[O-])cc2o1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Nitric acid (70%, 2.50 ml, 0.0389 mol) is added dropwise at −10° C. to a solution of 4-fluoro-1,3-benzoxazol-2(3H)-one (Step 4, 5.95 g, 0.0389 mol) in concentrated sulfuric acid (60 ml). The reaction is stirred at −10° C. for 30 minutes and then poured into ice water. The resulting precipitate is collected by filtration and dried under reduced pressure to give desired product contaminated with approximately 10-15% of the undesired 5-nitro isomer (7.2 g, 93%); mp 177-9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13].[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].C[O-].[Na+]>CO.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([C:16]([O:18][CH3:19])=[O:17])([C:12]([O:14][CH3:15])=[O:13])[CH2:22][CH2:21][C:20]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Reactant: C=CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCC(C(=O)OC)(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Reaction time: 40 h
Yield: 84.7 %

Procedure:
To a solution of the nitro diester, Dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (86) (0.44 g, 1.62 mmol) and methyl acrylate (0.22 mL, 2.43 mmol) in absolute methanol (5 mL) was added a catalytic amount of sodium methoxide at 21° C. under argon. The reaction mixture was stirred for 40 h at the same temperature and then diluted with dichloromethane (50 mL). The resulting mixture was washed with water, brine and dried. The residue obtained upon evaporation of the solvents was purified on a silica gel (hexane:ethyl acetate, 8:1) to give Trimethyl 1-(2-fluoro-4-nitrophenyl)propane-1,1,3-tricarboxylate (85) (0.49 g, 85%): 1H NMR δ 8.04 (dd, 1H, J=8.7, 2.3 Hz), 7.95 (dd, 1H, J=10.9, 2.3 Hz), 7.57 (dd, 1H, J=8.7, 7.5 Hz), 3.81 (s, 6H), 3.62 (s, 3H), 2.64-2.69 (m, 2H), 2.35-2.40 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:3]1=[O:20].[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>>[Br:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:6]1[C:2]([CH3:21])([CH3:1])[C:3](=[O:20])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:5]1=[O:7]
Reactant: BrCc1ccccc1Br
Reactant: CSc1ccc(N2C(=O)NC(C)(C)C2=O)cc1C(F)(F)F
Product: CSc1ccc(N2C(=O)N(Cc3ccccc3Br)C(C)(C)C2=O)cc1C(F)(F)F

Procedure:
The reaction of 114.1 with 2-bromobenzyl bromide afforded 1-(2-bromobenzyl)-5,5-dimethyl-3-(4-methylsulfanyl-3-trifluoromethylphenyl)imidazolidine-2,4-dione (115.2). The further reaction with methyl 4-aminobenzoate under conditions as described for the preparation of compound I afforded methyl 4-{2-[5,5-dimethyl-3-(4-methylsulfanyl-3-trifluoromethylphenyl)-2,4-dioxoimidazolidin-1-ylmethyl]phenylamino}benzoate; molecular weight 557.15 (C28H26F3N3O4S); retention time Rt=2.22 min. [B]; MS (ESI): 558.21 (MH+).
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[CH:34]1([CH2:37][NH2:38])[CH2:36][CH2:35]1>>[CH:34]1([CH2:37][NH:38][C:3](=[O:5])[CH:2]([OH:1])[CH:6]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[N:22]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:23]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:36][CH2:35]1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: NCC1CC1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCC1CC1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with cyclopropylmethylamine; ESI-MS [M+H]+: 496.2
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:16][CH2:17][CH2:18][OH:19]>C(Cl)Cl>[OH:19][CH2:18][CH2:17][CH2:16][S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Sc1ccncc1
Reactant: OCCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
In 250 ml of methylene chloride was dissolved 22.2 g (200 mmol) of 4-mercaptopyridine and 27.9 ml (200 mmol) of triethylamine. Thereto was added 18.1 g (200 mmol) of 3-bromo-1-propanol. The mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with a 1N aqueous solution of sodium hydroxide and water and dried. Then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 21.3 g of the desired compound (yield: 62.9%, yellow oil).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=O)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1.O1CCOCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[S:40])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(Cl)nc2)c2ncccc2c1=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(Cl)nc2)c2ncccc2c1=S
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-[(6-chloropyridin-3-yl)methyl]-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (490 mg, 1.42 mmol) was suspended in toluene (5 mL) and dioxane (5 mL) and placed into a preheated oil bath at 110° C. The mixture was treated with Lawesson's Reagent (316 mg, 0.782 mmol, 0.55 equiv) portionwise over 45 minutes and stirred for an addition 30 minutes at 110° C. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 50:50; hexanes:ethyl acetate), providing the titled compound as a brown foam.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].C(=O)([O-])[O-].[Na+].[Na+].[Cl:17]Cl>C1C(Cl)=CC=C(Cl)C=1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([Cl:17])=[O:10]
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: ClCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccc(Cl)cc1
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of 48 g of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 195 ml of dichlorobenzene under protective gas are added 39.8 g of sodium carbonate. Subsequently, while illuminating with a mercury lamp, 24 g of chlorine gas are introduced at 20° C. within 3.5 hours. After the gas introduction has ended, the reaction solution is stirred with illumination at 20° C. for a further 20 minutes. The solid is filtered off and washed with a little dichlorobenzene. After the solvent has been removed, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 87%.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[C:25]([O:27][CH3:28])=[O:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c(C(=O)OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
A mixture of dimethyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]isophthalate (2.01 g, 5.11 mmol), TFA (20 mL), and CH2Cl2 (25 mL) was stirred for 1.5 hr at room temp. The resulting mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mixture was extracted with CH2Cl2, washed with brine, dried over Na2CO3, and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (9:1, v/v) as eluent to give 0.80 g (53%) dimethyl (S)-4-(2-pyrrolidinylmethoxy)isophthalate as a yellow oil. 1H-NMR (CDCl3) δ 1.71 (m, 1 H), 1.89 (m, 2 H), 2.00 (m, 1 H), 3.05–3.13 (m, 2 H), 3.67 (m, 1 H), 3.90 (s, 3 H), 3.91 (s, 3 H), 4.05–4.18 (m, 2 H), 7.00 (d, 1 H, J=8.8 Hz), 8.14 (dd, 1 H, J=2.4, 8.8 Hz), 8.50 (d, 1 H, J=2.4 Hz).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:21]1([C:31](Cl)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:31]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:32])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: COc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CC(NC(=O)c2cccc3ccccc23)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol (450 mg, 1.64 mmol) in ethyl acetate (15 ml) were added 1-naphthoyl chloride (369 ml, 2.45 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (622 mg, 89%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].Br[CH2:28][CH2:29][CH2:30]Br>>[N:1]1([C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:30][CH2:29][CH2:28]1
Reactant: BrCCCBr
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCC1

Procedure:
The title compound, light yellow solid, MS: m/e=425.2 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 1,3-dibromopropane.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH2:19][C:20]#[CH:21])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:8][CH2:9][CH2:10][N:11]([CH2:19][C:20]#[CH:21])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: C#CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#CCN(CCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.9 %

Procedure:
To a solution of 950 mg of 10c in 5 ml of THF was added 5 ml of 1M tetra-n-butyl ammonium fluoride in THF. The mixture was stirred for 1 hr at RT and then poured into 50 ml of water and extracted with ethyl acetate. The crude product thus obtained was chromatographed on silica gel (using a gradient of heptane/ethyl acetateas eluent) and provided 700 mg of 10d, as a colorless oil; Rf 0.35 (heptane/ethyl acetate 1/1);
Reaction SMILES: [C:1]1([CH:7]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:8][N:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:30]=2[Cl:39])[CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:27])([CH3:26])[CH:16]([CH:20]([CH3:25])[C:21]([O:23]C)=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO.O.[OH-].[Na+]>[C:1]1([CH:7]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:8][N:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[C:30]=2[Cl:39])[CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:26])([CH3:27])[CH:16]([CH:20]([CH3:25])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)C1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)C1(C)C
Yield: 92 %

Procedure:
A solution of methyl N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-2,2-dimethyl-3-(3-aminopropoxy)phenylpropionate (195 mg, 0.3 mmole) in 10 mL of MeOH, 1 mL of H2O and 2 mL 2.5N NaOH was refluxed for 5 hours. The reaction was cooled, diluted with H2O and acidified with 3N HCl to pH 5.1. The mixture was extracted with EtOAc, the extracts were washed with H2O, dried and evaporated, and gave the titled compound, 172 mg (92% yield). MS (ESI) 625 (MH+).
Reaction SMILES: [O:1]1[CH2:29][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[O:15][C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[OH:1][CH:2]([CH2:29][NH:33][CH:30]([CH3:32])[CH3:31])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([C:14]2[O:15][C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: CC(C)N
Reactant: O=S(=O)(c1ccc(OCC2CO2)cc1)c1oc2ccccc2c1-c1ccccc1
Product: CC(C)NCC(O)COc1ccc(S(=O)(=O)c2oc3ccccc3c2-c2ccccc2)cc1

Procedure:
Treatment of 2-[(4-(2,3-epoxypropoxy)phenylsulfonyl]-3-phenylbenzofuran with isopropylamine as described in Example 3 gives the title compound.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24]1>>[C@@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21][C:30](=[O:31])[CH2:29][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Product: CN1CCN(CC(=O)Nc2cccc3nc(N[C@H]4CCc5ccccc54)ccc23)CC1

Procedure:
The title compound, light yellow oil, MS: m/e=416.4 (M+H+), was prepared in accordance with the general method of example 32 from (R)—N2-indan-1-yl-quinoline-2,5-diamine (example 16) and commercially available (4-methyl-piperazin-1-yl)-acetic acid.
Reaction SMILES: [OH-].[Na+].CO.[F:5][C:6]([F:38])([CH:12]([OH:37])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([NH:25][C:26]3[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=3)[CH:22]=[C:21]([CH3:36])[CH:20]=2)=[CH:15][N:14]=1)[C:7]([O:9]CC)=[O:8]>C1COCC1>[F:38][C:6]([F:5])([CH:12]([OH:37])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([NH:25][C:26]3[N:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][N:27]=3)[CH:22]=[C:21]([CH3:36])[CH:20]=2)=[CH:15][N:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(F)(F)C(O)c1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(O)C(F)(F)C(=O)O)nc2)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Sodium hydroxide (1 M, 0.190 mL, 0.190 mmol) and methanol (0.300 mL) were added to a solution of ethyl 2,2-difluoro-3-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoate (17.8 mg, 0.037 mmol) in THF (0.500 mL). The mixture was stirred at 40° C. for 2 hours and then cooled to room temperature and the crude reaction mixture was directly purified by reverse phase HPLC to afford 2,2-difluoro-3-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoic acid. MS APCI C20H16F5N4O3 [M+H]455. found 455.0. 1H NMR (500 MHz, DMSO-d6)) δ10.28 (s, 1H), 8.83 (d, J=5.3 Hz, 1H), 8.74 (d, J=2.2 Hz, 1H), 8.08 (d, J=11.1 Hz, 1H), 7.96 (s, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.27 (d, J=5.2 Hz, 1H), 7.21 (s, 1H), 5.17 (t, J=12.7 Hz, 1H), 2.36 (s, 3H).