Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:7][P:8]([CH:13](O)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)(=[O:12])[O:9][CH2:10][CH3:11])[CH3:6].C(Cl)[Cl:23].N1C=CC=CC=1>O>[CH2:5]([O:7][P:8]([CH:13]([Cl:23])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)(=[O:12])[O:9][CH2:10][CH3:11])[CH3:6]
Reactant: CCOP(=O)(OCC)C(O)c1ccc(Cl)cc1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOP(=O)(OCC)C(Cl)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 97.5 %

Procedure:
9.2 g (0.0768 mol) of thionyl chloride were added to a mixture of 20.2 g (0.0725 mol) of 4-chloro-α-hydroxybenzylphosphonic acid diethyl ester, 65 g of methylene chloride and 5.8 g (0.0725 mol) of pyridine at 20°-40° C. in the course of about 1 hour, while cooling slightly with water. The reaction mixture was then heated under reflux for 3 hours and subsequently stirred for 12 hours, without further action of heat. The mixture was poured onto about 100 g of ice-water and the organic phase was separated off and dried. After distilling off the solvent, the residue was concentrated under 6 mm Hg and at 45° C. 21 g (97.7% of theory) of 4-chloro-α-chloro-benzylphosphonic acid diethyl ester were obtained as a yellow viscous oil with a purity of 98.6% (gas chromatogram) and a refractive index of nD24 : 1.5250.
Reaction SMILES: N[C:2]1[C:6]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[OH-:14].[Na+].C.Cl>O>[OH:11][C:7]1[C:6]2[C:2](=[O:14])[NH:3][S:4](=[O:13])(=[O:12])[C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: NC1=NS(=O)(=O)c2cccc(O)c21
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1NS(=O)(=O)c2cccc(O)c21
Yield: 92 %

Procedure:
5 gm (25.2 mmols) of 3-amino-4-hydroxy-1,2-benzoisothiazole-1,1-dioxide and 2.02 gm (50.5 mmols) of sodium hydroxide were refluxed in 15 ml of water for 6.5 hours. Subsequently, the solution was treated with activated charcoal at 60° C. and filtered. At 60° C. the filtrate was acidified with concentrated aqueous hydrochloric acid (about 5 ml, 0.06 mol). The resulting precipitate was filtered off, dried and recrystallized from water. 4.62 gm (92% of theory) of 4-hydroxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([OH:18])=O)[C:9]=3[N:8]=2)=[CH:3][CH:2]=1.[B-](F)(F)(F)F.C[CH2:25][O:26][C:27]([C:29]([C:39]#N)=[N:30]OC(N(C)C)=[N+](C)C)=[O:28].[CH:41](N(C(C)C)CC)([CH3:43])[CH3:42]>CN(C=O)C>[CH3:25][O:26][C:27](=[O:28])[C@H:29]([CH2:39][CH:41]([CH3:43])[CH3:42])[NH:30][C:16]([C:15]1[C:9]2[N:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[NH:11][C:10]=2[CH:12]=[CH:13][CH:14]=1)=[O:18]
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: O=C(O)c1cccc2[nH]c(-c3ccncc3)nc12
Reactant: CCN(C(C)C)C(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1cccc2[nH]c(-c3ccncc3)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
120 mg (0.5 mmol) of 2-(pyrid-4-yl)-1H-benzimidazole-4-carboxylic acid (1d) and 84 mg (0.5 mmol) of H-(L)-leucine methyl ester were dissolved in 5 ml of DMF. 164 mg (0.5 mmol) of TOTU and 0.086 ml of diisopropylethylamine were added and the mixture was stirred at RT for 3 h. The precipitate was filtered off and the filtrate was concentrated. The residue was dissolved in ethyl acetate, the solution was washed with water, and the organic phase was dried using anhydrous sodium sulfate and concentrated. Yield: 180 mg (98%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:30][OH:31]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=[C:19]3[C:18]2=[O:28])[CH2:13][C:14]([NH:30][OH:31])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(C)cc3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(C)cc3C2=O)ccc1OC
Yield: 87.8 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-methylphthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(4-methyl-phthalimido)propanoic acid (2.40 g, 6.26 mmol), N,N′-carbonyldiimidazole (1.12 g, 6.91 mmol) and hydroxylamine hydrochloride (530 mg, 7.62 mmol) in tetrahydrofuran (8 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-methylphthalimido)propionamide as a white solid (2.19 g, 88% yield): mp, 180.0–181.5° C.; 1H NMR (DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H, CH3), 2.49 (s, 3H, CH3), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.97 (q, J=7.0 Hz, 2H, CH2), 5.65 (t, J=7.9 Hz, 1H, NCH), 6.89 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.61–7.74 (m, 3H, Ar), 8.78 (br s, 1H, OH), 10.57 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 14.67, 21.33, 34.31, 50.14, 55.45, 63.72, 111.75, 112.33, 119.61, 123.03, 123.52, 128.63, 131.32, 131.61, 134.88, 145.54, 147.67, 148.52, 166.02, 167.62, 167.73; Anal Calcd for C21H22N2O6: C, 63.31; H, 5.57; N, 7.03. Found: C, 63.29; H, 5.69; N, 6.86.
Reaction SMILES: [CH3:1][CH:2]([C:16](=[O:28])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1>[Pd].C(OCC)(=O)C>[CH3:1][CH:2]([C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)[C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1
Reactant: COc1cc(C=CC(=O)C(C)C(=O)C=Cc2ccc(O)c(OC)c2)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CCC(=O)C(C)C(=O)CCc2ccc(O)c(OC)c2)ccc1O
Yield: 41.4 %

Procedure:
4-Methyl-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (6a, 0.20 g, 0.5 mmol) and palladium on activated carbon (0.25 g, 10%) were combined in ethyl acetate (100 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 2 hr at room temperature. The resulting mixture was filtered through celite and the solvent evaporated to afford an oil. The crude oil was twice chromatographed on silica gel with ethyl acetate/hexane to give a semi-solid. The crude semi-solid was distilled bulb to bulb to give 80 mg (38%) of a pale yellow oil; 1H NMR: δ enol form: 1.69 (s, 3H), 2.72 (m, 8H), 3.83 (s, 6H), 5.48 (s, 2H), 6.69 (m, 4H), 6.79 (d, 2H, J=7.5 Hz); keto form: 1.23 (d, 3H, J=7.2 Hz), 2.72 (m, 8H), 3.57 (q, 1H, J=7.0 Hz), 3.83 (s, 6H), 5.48 (s, 2H), 6.69 (m, 4H), 6.79 (d, 2H, J=7.5 Hz); 13C NMR: δ 12.5, 29.2, 43.3, 55.9, 61.4, 111.0, 114.2, 120.7, 132.4, 143.9, 146.3, 206.1; Exact mass calcd for C22H26O6: 386.1729, observed (M+H) 387.1783.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]1(=O)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[O:8]1.C([O-])(=O)C.[K+]>C(O)(=O)C.C(OCC)(=O)C>[O:8]=[C:7]1[C:11]2[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9](=[O:16])[N:1]1[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into a 3-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-aminopropanoic acid (20 g, 224.48 mmol, 1.00 equiv) and 1,3-dihydro-2-benzofuran-1,3-dione (33.28 g, 224.69 mmol, 1.00 equiv) in acetic acid (1,200 mL). This was followed by the addition of potassium acetate (66.0 g, 672.49 mmol, 3.00 equiv) in several batches at 0° C. The resulting solution was stirred for 3 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 150 mL of water. The solids were collected by filtration. This resulted in 40 g (81%) of 3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propanoic acid as a white solid. Rf: 0.15 (in ethyl acetate:petroleum ether=1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[C:26](Cl)(=[O:29])[CH2:27][CH3:28].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.20 g of (3-amino-5-bromo-phenyl)-pyridin-3-yl-methanone (0.72 mmol) in 10 mL of dichloroethane was added 0.25 mL of diisopropylethylamine and 0.065 mL of propionyl chloride. The reaction was stirred 1 h at ambient temperature, then poured into saturated aqueous sodium bicarbonate. The phases were separated and the aqueous phase was washed once with methylene chloride, dried over sodium sulfate, filtered and concentrated to give 0.24 g (quantitative yield) of N-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-propionamide.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[C:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C(Cl)=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[N:37]1[S:38][N:39]=[C:40]2[C:45]([NH2:46])=[CH:44][CH:43]=[CH:42][C:41]=12>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11](=[O:13])[CH:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:8]([C:18]([NH:46][C:45]2[C:40]3[C:41](=[N:37][S:38][N:39]=3)[CH:42]=[CH:43][CH:44]=2)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: Nc1cccc2nsnc12
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCON=C1C[C@@H](C(=O)Nc2cccc3nsnc23)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 2,1,3-benzothiadiazol-4-amine the title compound was obtained in 46% purity by LC/MS. MS(ESI+): m/z=512.4.
Reaction SMILES: [BH4-].[Na+].CC1C=[C:6]([C:21](=O)[CH:22]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)C)C=CC=1O[Si](C(C)C)(C(C)C)C(C)C.C([OH:41])C>>[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:27]2([OH:30])[CH2:28][CH2:29][N:24]([CH:22]([OH:41])[CH2:21][CH3:6])[CH2:25][CH2:26]2)=[CH:32][CH:33]=1
Reactant: Cc1cc(C(=O)C(C)N2CCC(O)(c3ccc(F)cc3)CC2)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: CCC(O)N1CCC(O)(c2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
A mixture of sodium borohydride (0.564 g, 14.92 mmol) and ethanol (60 mL) was stirred 10 minutes and then 1-(3-methyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (7.66 g, 14.92 mmol in 10 mL of ethanol) was added with two 30 mL ethanol rinses. The reaction mixture was stirred at ambient temperature overnight. The white solid that precipitated was collected by filtration and dried to yield 5.72 g (74%) of (1R*, 2R*)-1-(3-methyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl-propan-1-ol, which was suitable for use without further purification and had: m.p. 188-189° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:15])[C:11]([CH3:14])([OH:13])[CH3:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH:35]2[CH2:37][CH2:36]2)(=[N:25][S:26]([CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])(=[O:28])=[O:27])=[O:24])=[CH:19][CH:18]=1.Cl>C(#N)C.O1CCOCC1.O>[Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:15])[C:11]([OH:13])([CH3:14])[CH3:12])=[N:4][C:5]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH:35]3[CH2:37][CH2:36]3)(=[N:25][S:26]([CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])(=[O:27])=[O:28])=[O:24])=[CH:19][CH:18]=2)=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCS(=O)(=O)N=S(=O)(c1ccc(N)cc1)C1CC1
Reactant: C[C@@H](Nc1nc(Cl)ncc1Br)C(C)(C)O
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Nc1nc(Nc2ccc(S(=O)(=NS(=O)(=O)CC[Si](C)(C)C)C3CC3)cc2)ncc1Br)C(C)(C)O

Procedure:
95 mg (0.32 mmol) of (R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol is dissolved in 2 ml of acetonitrile and mixed with 116 mg (0.32 mmol) of (RS)—S-(4-aminophenyl)-S-cyclopropyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide. After 0.08 ml of an approximately 4N solution of HCl in dioxane and 0.08 ml of water are added, the mixture is heated in a sealed vessel for 16 hours to 75° C. The suspension is filtered, and the filtrate is separated by flash chromatography (dichloromethane—dichloromethane/ethanol 95:5, 15 ml/min) The fractions, 43-51 min, contain 50 mg (25% of theory) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[C:11]([CH:10]=1)[C:12]#[N:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C#N)cc1OCc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(C#N)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of 3-benzyloxy-4-methoxybenzonitrile (43.8 g, 0.18 mol) in glacial acetic acid (87 ml) was added dropwise to concentrated nitric acid (70% w/w, 244 ml) with periodic cooling to maintain the reaction temperature below 30° C. Once the addition was complete, the reaction was stirred for a further 30 minutes, after which time the mixture was poured into water (11) and stirred for 30 minutes. The resulting precipitate was isolated by filtration, washed with water and dried under reduced pressure at 50° C. to afford the subtitle compound as a white solid (35.1 g, 68%). Rf 0.70 (EtOAc:hexane 1:1, v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([Cl:13])[CH3:12].[O-:14][C:15]#[N:16].[K+].O>COCCOCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([Cl:13])[CH3:12].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:15](=[O:14])[NH:16][C:11]([CH3:12])=[N:10]1
Reactant: N#C[O-]
Agent: CC(Cl)=NNc1ccc(Cl)cc1Cl
Agent: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: Cc1nn(-c2ccc(Cl)cc2Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 5.1 grams (0.0214 mole) of N-(2,4-dichlorophenyl)ethanehydrazonoyl chloride (A), prepared as in Example 1, 2.1 grams (0.0257 mole) potassium cyanate, and 3 mL of water in 51 mL of diglyme was stirred at ambient temperature for about 22 hours. After this time, the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in about 500 mL of ethyl acetate and washed with three 25 mL portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was triturated with hexane and the resultant solid was collected by filtration. The solid was dried, yielding 4.5 grams (85.2% yield from (A)) of subject compound (1).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])NC1SC(SCC(C)(C)C(O)=O)=CN=1.[NH2:36][C:37]1[S:38][C:39]([S:42][C:43]2([C:47]([OH:49])=[O:48])[CH2:46][CH2:45][CH2:44]2)=[CH:40][N:41]=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:36][C:37]1[S:38][C:39]([S:42][C:43]2([C:47]([OH:49])=[O:48])[CH2:44][CH2:45][CH2:46]2)=[CH:40][N:41]=1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: Nc1ncc(SC2(C(=O)O)CCC2)s1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCOCc2ccccc2Cl)C(=O)Nc2ncc(SC3(C(=O)O)CCC3)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 1-(2-amino-thiazol -5-ylsulfanyl)-cyclobutanecarboxylic acid prepared using the procedure for the preparation of 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[N:7][C:6]=1[CH3:29])C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=2)=[N:7][C:6]([CH3:29])=[C:5]([CH:10]=1)[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2Cl)c(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2Cl)cc1C(=O)O
Reaction time: 16 h

Procedure:
A solution of 2.9 g of 5-(2,4-Dichloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid ethyl ester and 230 mg of LiOH in 10 ml of THF and 10 ml of water was stirred at room temperature for 16 h. After 16 h, the mixture was brought to pH 2 by addition of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The residue was codistilled twice with dichloromethane and twice with toluene The isolated crude product was used in the next reaction step. Yield: 3 g.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].Cl.[NH2:35][C:36]1([C:47]2[N:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27]([NH:35][C:36]1([C:47]2[N:48]=[CH:49][CH:50]=[CH:51][N:52]=2)[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]1)=[O:28]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Reactant: CC(C)(C)OC(=O)N1CC(N)(c2ncccn2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)CN(C(=O)OC(C)(C)C)C4)c(OC)cc3C)c(F)c12
Reaction time: 8 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (50 mg, 0.111 mmol) and tert-butyl 3-amino-3-(pyrimidin-2-yl)azetidine-1-carboxylate hydrochloride (31.8 mg, 0.111 mmol) in DMF (1 ml) in a 25 ml round-bottomed flask was added PyBOP (69.2 mg, 0.133 mmol) and then triethylamine (0.046 ml, 0.332 mmol). The reaction mixture was stirred overnight, and then diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The crude product was then purified by column chromatography (2% methanol in chloroform) to afford tert-butyl 3-(5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzamido)-3-(pyrimidin-2-yl)azetidine-1-carboxylate. Yield: 40 mg (53%). LCMS: (ES+) m/z observed=584.2 (M+H)+ of 4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(3-(pyrimidin-2-yl)azetidin-3-ylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[N:17]([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:24]>Cl.O>[ClH:24].[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:11][NH2:17])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NNc1ccc(C2CCCCC2)cc1
Temperature: -5 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
To a slurry a 4-cyclohexylaniline (350.6 g) and ethanol (330 ml) in 30% HCl (1470 ml) was added a solution of sodium nitrite (151.8 g) in water (735 ml), while maintaining the temperature between -8 to -2° C. The reaction was stirred for an additional four hours at -2 to 10° C. A solution of tin (II) chloride dihydrate (1353.8 g) in 30% HCl (1470 ml) was added slowly, and the resulting white suspension was cooled overnight. The crude product was collected by vacuum filtration and washed with 1 N hydrochloric acid, and ether. Recrystallization in 6 L of methanol gave 300 g of the desired product as fine long needles, m.p. 251-254° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CS(OO[CH2:29][CH2:30][CH:31]([F:40])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=O)=O>>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:29][CH2:30][C@H:31]([F:40])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:20][CH:21]=2)=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCC(F)CCOOS(C)(=O)=O
Product: CCCCCCCCOc1cnc(-c2ccc(OCC[C@H](F)CCCCCCCC)cc2)nc1
Yield: 19.5 %

Procedure:
The titled compound was synthesized from 5-octyloxy-2-(4-hydroxyphenyl)pyrimidine and 3-fluoroundecyloxy methanesulfonate.
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1.[CH3:18]C(C)=O.O[O:23][S:24]([O-:26])=O.[K+]>O>[CH3:18][S:24]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:17])=[O:16])=[CH:13][CH:14]=1)(=[O:26])=[O:23]
Reactant: O=S([O-])OO
Reactant: CSc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.977 g (0.004 mole) of 2′-(methylthio)-1,1′-biphenyl-4-carboxylic acid of Example 14, Step A, in 25 mL of water and 75 mL of acetone was added 10 g. (0.163 mole) of oxone. The mixture was stirred overnight at room temperature. The acetone was removed in vacuo, and the residue was collected (0.80 g) and washed with water to provide a solid, m.p. 273-275° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH2:19]([O:31][CH2:32][CH:33]1[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>N1C=CC=CC=1.CCOCC>[CH2:19]([O:31][CH2:32][CH:33]1[NH:34][CH2:35][CH2:36][N:37]([C:10]2[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:14])[CH2:38]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: CCCCCCCCCCCCOCC1CNCCN1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1

Procedure:
A 710 mg portion of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was suspended in 5 ml of pyridine and 2 g of 2-[(dodecyloxy)methyl]-piperazine added. This mixture was heated at 80°-85° C. for 4 hours, then cooled and diluted with ether. The solid was collected, washed with ether and dried, giving 1.3 g of the desired product, mp 125°-127° C.