Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:17][C:18](=O)[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=O)OC.O.[NH2:26][NH2:27]>>[CH3:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]1[N:26]=[N:27][C:2]2[CH:1]3[CH2:8][CH2:7][CH:4]([C:3]=2[CH:17]=1)[CH2:5][CH2:6]3
Reactant: O=C1C(=O)C2CCC1CC2
Reactant: NN
Reactant: COP(=O)(CC(=O)CC(C)(C)C)OC
Solvent: O
Product: CC(C)(C)Cc1cc2c(nn1)C1CCC2CC1

Procedure:
White solid MS (ESI): 231.1 (MH+). Prepared from bicyclo[2.2.2]octane-2,3-dione, (4,4-dimethyl-2-oxo-pentyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[OH:13][C:14]1[CH:15]=[C:16]([CH:43]=[CH:44][C:45]=1[OH:46])[C:17]([NH:19][NH:20][S:21]([NH:24][C:25]([N:27]1[CH2:30][C@H:29]([NH:31]C(=O)OCC2C=CC=CC=2)[C:28]1=[O:42])=[O:26])(=[O:23])=[O:22])=[O:18].[H][H]>C(#N)C.[Pd]>[NH2:31][C@H:29]1[CH2:30][N:27]([C:25]([NH:24][S:21]([NH:20][NH:19][C:17](=[O:18])[C:16]2[CH:43]=[CH:44][C:45]([OH:46])=[C:14]([OH:13])[CH:15]=2)(=[O:22])=[O:23])=[O:26])[C:28]1=[O:42]
Reactant: [H][H]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)c2ccc(O)c(O)c2)C1=O)OCc1ccccc1
Agent: [Pd]
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CC#N
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)c2ccc(O)c(O)c2)C1=O
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
7.4 ml of bis(trimethylsilyl)acetamide (0.03 mol) was added to a suspension of 2.47 g (0.005 mol) of (S)-[1-[[[[2-(3,4-dihydroxybenzoyl)hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (see Example 3A) in 40 ml of acetonitrile. After stirring for 15 minutes, a clear solution was obtained. One gram of palladium on charcoal (10%) was added and hydrogen was passed through the solution with stirring. The catalyst was filtered off and 2 ml of methanol were added to the solution, followed by a few drops of acetic acid. The mixture was stirred for 2 hours with cooling (ice/water) and the precipitate was filtered off, washed with acetonitrile and petroleum ether to yield 1.5 g of (S)-3-amino-N-[[2-(3,4-dihydroxybenzoyl)hydrazino]sulfonyl]-2-oxo-1-azetidinecarboxamide.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH3:4].[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:20][C:19](=[O:21])/[CH:18]=[CH:17]/[C:6]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])[C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCc1c(/C=C/C(=O)O)ccc2c(OC)cccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)ccc2c(OC)cccc12
Yield: 75.6 %

Procedure:
As in Example 113, (E)-3-(1-butyl-5-methoxy-2-naphthalenyl)-2-propenoic acid (1.4 g) was reacted with 4-nitrophenol (0.76 g) in dichloromethane (25 mL) in the presence of 1,3-dicyclohexylcarbodiimide (1.02 g) to give 1.51 g of (E)-3-(1-butyl-5-methoxy-2-naphthalenyl)-2-propenoic acid 4-nitrophenyl ester. Crystallization of a portion from diethyl ether afforded the analytical sample, mp 115°-116° C. Anal. Calcd for C24H23NO5 : C, 71.10; H, 5.72; N, 3.45 Found: C, 71.25; H, 5.75; N, 3.39
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=1.C(N(CC)CC)C>ClCCl>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([NH:14][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[CH:16][C:17]=1[C:23]([F:24])([F:25])[F:26])#[N:20]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccccc1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Isopropoxy-benzoyl chloride was condensed with 4-Amino-2-trifluoromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-Isopropoxy-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]=C)=[CH:7][N:6]=1)([F:4])[CH3:3].N1C(C)=CC=CC=1C.C1C[O:24]CC1>O.[Os](=O)(=O)(=O)=O>[F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]=[O:24])=[CH:7][N:6]=1)([F:4])[CH3:3]
Reactant: C1CCOC1
Reactant: C=Cc1cnc(C(C)(F)F)nc1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CC(F)(F)c1ncc(C=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
2-(1,1-difluoroethyl)-5-vinylpyrimidine (110 mg, 0.646 mmol) was dissolved in THF (5 ml) and water (2 ml). NaIO4 (571 mg, 2.67 mmol), 2,6-lutidine (143 mg, 0.155 ml, 1.3 mmol) and osmium tetraoxide (138 mg, 0.17 ml, 0.013 mmol, 0.078 molar in tBuOH) was added. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with diethyl ether. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. 1H NMR showed a mixture of aldehyde and lutidine, which was used directly in the next reaction, (166 mg, 42% yield, 28% pure). 1H NMR (CDCl3 500 MHz): δ 10.24 (s, 1H), 9.30 (s, 2H), 2.12 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+].C(O)(=O)C.[Br:18][CH:19]([CH:22]=O)[CH:20]=O>C(O)C>[Br:18][C:19]1[CH:20]=[N:1][C:2]2[N:6]([N:5]=[CH:4][C:3]=2[C:7]([OH:9])=[O:8])[CH:22]=1
Reactant: O=CC(Br)C=O
Reactant: CCOC(=O)c1cn[nH]c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1cnn2cc(Br)cnc12
Temperature: 70 °C
Yield: 50.9 %

Procedure:
A solution of ethyl 5-amino-1H-pyrazole-4-carboxylate (2 g, 12.89 mmol) and sodium hydroxide (19.34 mL, 38.7 mmol) (aqueous, 2M) in ethanol (30 mL) was heated at 80° C. overnight. The reaction mixture was concentrated in vacuo to give a crude mixture of carboxylate and sodium hydroxide. The crude mixture was dissolved in ethanol (4 mL) and acetic acid (14 mL, 245 mmol). Whilst stirring the mixture, bromomalonaldehyde (1.947 g, 12.90 mmol) was added and then the mixture heated to 70° C. for 1 h. The reaction mixture was allowed to cool and the precipitate was filtered and washed with ethanol. The solid product was dried in a vacuum oven to give the title compound (1.589 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.[N+]([NH:19][C:20](N)=[O:21])([O-])=O.O>CC(C)=O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]2[CH2:9][N:10]([C:20]([NH2:19])=[O:21])[CH2:11]2)=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
A solution of 9.6 g (0.025 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine 56.66% (contains diphenylmethane) in 50 ml of acetone was treated with 4.22 g (0.045 mole) of nitrourea and 5 ml of water. The mixture was heated on a hot plate until a clear solution was obtained then allowed to cool to ambient temperature during the next 4 hr. The reaction mixture was diluted with 200 ml of ice water and an oil separated (diphenylmethane) which was dissolved in 30/60 petroleum ether and separated. Upon standing, a fine white precipitate formed in the aqueous solution. Filtration yielded 3.6 g of fine white crystals, m.p. 176°-178° C. After drying under 0.5 mm Hg vacuum at 80° C., the product weight was reduced to 3.1 g (47.7%), m.p. 178°-179° C.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH2:13][CH2:14][C:15](OC)=[O:16])=O)=[CH:9][C:8]=1[OH:21])[CH:5]=[CH2:6]>C(O)(=O)C>[CH2:4]([C:7]1[CH:20]=[CH:19][C:10]([C:11]2[CH2:13][CH2:14][C:15](=[O:16])[NH:2][N:3]=2)=[CH:9][C:8]=1[OH:21])[CH:5]=[CH2:6]
Reactant: NN
Reactant: C=CCc1ccc(C(=O)CCC(=O)OC)cc1O
Solvent: CC(=O)O
Solvent: O
Product: C=CCc1ccc(C2=NNC(=O)CC2)cc1O
Yield: 94.4 %

Procedure:
Hydrazine hydrate (4.5 ml, 0.09 mole) was added to a stirred solution of methyl 3-(4-allyl-3-hydroxybenzoyl)propionate (5.6 g, 0.023 mole) in glacial acetic acid (60 ml) and the mixture heated under reflux for one hour. Evaporation under reduced pressure gave a residue which was triturated with water to give 6-(4-allyl-3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (5 g, m.p. 175°-178°C, 96%). The pure pyridazinone, recrystallised from ethanol had m.p. 178°-180°C.
Reaction SMILES: N1C=C[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.COC(C)=C.[C:23]([O:27][C:28]([N:30]1[CH2:34][C@H:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH2:32][C@@H:31]1[C@@H:45]([OH:60])[C@@H:46]([NH:56][C:57](=[O:59])[CH3:58])[CH2:47][C:48]1[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClCCl.CC(C)=O>[C:23]([O:27][C:28]([N:30]1[CH2:34][C@H:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[CH2:32][C@@H:31]1[C@H:45]1[O:60][C:3]([CH3:4])([CH3:2])[N:56]([C:57](=[O:59])[CH3:58])[C@H:46]1[CH2:47][C:48]1[CH:49]=[C:50]([F:55])[CH:51]=[C:52]([F:54])[CH:53]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(CO[C@@H]2C[C@H]([C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(C)=O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: c1ccncc1
Agent: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc(CO[C@@H]2C[C@H]([C@H]3OC(C)(C)N(C(C)=O)[C@H]3Cc3cc(F)cc(F)c3)N(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 1 h
Yield: 607.3 %

Procedure:
Add p-toluene sulfonic acid pyridine salt (0.245 g, 1 mmol) and 2-methoxypropene (4.6 mL, 49 mmol) to a solution of (2R,4R)-2-[(1S,2S)-2-acetylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-4-(4-methoxy-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.64 g, 10.55 mmol) in dichloromethane (25 mL) and acetone (25 mL). Stir 60 min and concentrate under reduced pressure. Dissolve residue in ethyl acetate and wash with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry magnesium sulfate and purify on silica gel with hexanes/ethyl acetate mixtures to give the desired compound as a foam (3.49 g, 61%).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21]O.[CH:23]([OH:25])=[O:24]>>[CH:1]([O:20][OH:24])=[O:19].[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:24][C:23]([O:21][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]([OH:20])=[O:19])=[O:25]
Reactant: OO
Reactant: O=CO
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCC(OC(=O)O)C(=O)O
Product: O=COO

Procedure:
The reaction was carried out in the manner of Example 1, Step 1 with the exception that 10 g of laboratory grade oleic acid were used as the substrate. The reactant peroxyformic acid was prepared in situ by mixing 30 mL of formic acid with 20 mL of 30% by weight hydrogen peroxide solution. Oleic acid as a substrate produced monohydroxy formoxy stearic acid only. The product was a white, hard substance. Gas chromatographic analysis showed the absence of starting material (oleic acid) .
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>[OH-].[Na+].O.O1CCCC1>[C:9]([OH:23])(=[O:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)O
Yield: 23.7 %

Procedure:
Hydroquinone (55 g) was dissolved in a solution of sodium hydroxide (20 g) in water (300 ml) and to the resulting solution was added dropwise a solution of tetradecanoyl chloride (123 g) in tetrahydrofuran (150 ml) with cooling. The precipitate formed was filtered off and the filtrate was extracted with ethyl acetate. The extract was thoroughly washed with water to remove unreacted hydroquinone and the solvent was removed. The residue was recrystallized from n-hexane to give hydroquinone monomyristate (20 g). m.p. 75°-78° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=O)[C:6]=2[CH2:5][CH2:4][N:3]1[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18].Cl.[NH2:23][C@@H:24]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:25]([OH:39])[CH2:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.O>[CH2:40]([C@H:24]([NH:23][C:12]([C:7]1[C:6]2[CH2:5][CH2:4][N:3]([CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[C:2](=[O:1])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:14])[C@H:25]([OH:39])[CH2:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCCC(CCC)N1CCc2c(C(=O)O)cccc2C1=O
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(CCC)N1CCc2c(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNCc3cccc(C(F)(F)F)c3)cccc2C1=O
Reaction time: 20 h
Yield: 110.4 %

Procedure:
43 mg of 1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid are dissolved in 2.5 cm3 of dichloromethane under an inert atmosphere at a temperature close to 20° C. 62 mg of (2R,3S)-3-amino-4-phenyl-1-{[3-(trifluoromethyl)benzyl]amino}butan-2-ol hydrochloride (2:1), 3 mg of hydroxybenzotriazole and 34 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to the solution. 0.124 cm3 of N,N-diisopropylethylamine is poured into the reaction medium. This medium is kept stirring for 20 h at a temperature close to 20° C. 10 cm3 of dichloromethane are added to the reaction mixture, then 10 cm3 of water. After decantation, the organic phase is washed with 5 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 100 mg of colorless oil obtained are purified by flash chromatography over silica (column: 7 g; particle size: 20-40 μm spherical; flow rate: 20 cm3/min; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 40 mg of N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14]CC)=O)[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].C(OC([N:28]1[CH2:32][C@H:31]([CH:33]([C:38]([CH3:43])([CH3:42])[CH:39]([CH3:41])[CH3:40])[O:34][SiH:35]([CH3:37])[CH3:36])OS1(=O)=O)=O)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.ClCCl>[CH3:37][SiH:35]([CH3:36])[O:34][CH:33]([C:38]([CH3:42])([CH3:43])[CH:39]([CH3:40])[CH3:41])[C@H:31]1[N:9]2[C:10]3[CH:11]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=[CH:5][C:6]=3[CH:7]=[C:8]2[C:12](=[O:14])[NH:28][CH2:32]1
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C(C)(C)C(O[SiH](C)C)[C@@H]1CNC(=O)c2cc3ccc(C(F)(F)F)cc3n21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of 0.700 g ethyl 6-(trifluoromethyl)indole-2-carboxylate in 7 ml DMF was added 0.13 g sodium hydride 55% in oil and the mixture was stirred at room temperature for 30 min. To the resulting solution was added 1.30 g (R)-5-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester and the mixture was stirred at room temperature for 18 h. The reaction mixture was distributed between 10% citric acid and dichloromethane and the organic phase was purified by chromatography on silica gel with dichloromethane. The product (1.15 g) was taken up in 11 ml TFA was stirred at 0° C. for 45 min. The solvent was evaporated and the residue was taken up in 10 ml methanol. To the resulting solution was added 1.00 g potassium carbonate and the mixture was stirred at room temperature for 3 h. The reaction mixture was purified by chromatography on silica gel with ethyl acetate to yield 0.36 g of the tiltle compound (m.p.: 143–144° C.) and 0.117 g of its desilylated analog (m.p.: 184–185° C.)
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:14]([C:15]2[CH2:19][CH2:18][O:17][N:16]=2)=[C:13]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:14]([C:15]2[CH2:19][CH2:18][O:17][N:16]=2)=[C:13]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:12]=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C1=NOCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1C1=NOCC1
Temperature: 110 °C

Procedure:
74.8 g (0.63 mol) of thionyl chloride in 50 ml of dry toluene were added dropwise at 50° C. to a solution of 139.0 g of 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoic acid, 1 ml of dimethylformamide and 1 l of dry toluene. After the mixture had been heated for 6 hours at 110° C., the solvent was distilled off. This gave 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl chloride in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:23][C:6]2[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1.[C:34](=O)(O)[O-].[K+]>CO.S(=O)(=O)(O)O.O>[CH3:34][O:32][C:31](=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1
Reactant: COc1cc2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2cc1OCCCCCC(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)CCCCCOc1cc2c(cc1OC)nc(-c1ccccc1)n2-c1ccc(C)cc1
Reaction time: 2 h

Procedure:
40 mg of 6-[[5-methoxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid was dissolved in 2 ml of methanol, mixed with 1 drop of concentrated sulfuric acid, and the mixture was stirred for 2 hours. It was mixed with saturated potassium bicarbonate solution, diluted with water, extracted with ethyl acetate, the extracts were dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was crystallized from diisopropyl ether.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[O:33][CH3:34]>C(Cl)Cl>[F:22][C:2]([F:21])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:32]([O:33][CH3:34])=[O:35])=[CH:19][CH:20]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2ccc(OC(F)(F)F)cc2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
To a solution of methyl 2-(4-(trifluoromethoxy)benzyl)piperidine-4-carboxylate (8.19 g, 25.81 mmol) in DCM (100 mL) was added DIPEA (5.40 mL, 30.97 mmol) followed by methyl carbonochloridate (2.236 mL, 28.39 mmol). The reaction mixture was stirred at room temperature for 30 min. The solvents were evaporated and the residue partitioned between ethyl acetate and 3.8 M HCl. After phase separation the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated to give a yellow oil. Dimethyl 2-(4-(trifluoromethoxy)benzyl)piperidine-1,4-dicarboxylate (9.72 g, 100%) was isolated. MS m/z 376 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C@@H:28]([CH3:31])[CH2:29][OH:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C@@H:28]([CH3:31])[CH2:29][OH:30])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: C[C@H](N)CO
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: C[C@@H](CO)NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (S)-2-amino-1-propanol via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1-hydroxypropan-2-yl)terephthalamide. MS (Q1) 445 (M)+.
Reaction SMILES: [F:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH2:30][CH2:31][CH2:32][OH:33])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH2:30][CH2:31][CH2:32][OH:33])[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)Nc2cc(OCCCO)nc(SCc3cccc(F)c3F)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(OCCCO)nc(SCc2cccc(F)c2F)n1)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 4-({[2-[(2,3-difluorobenzyl)thio]-6-(3-hydroxypropoxy)pyrimidin-4-yl]amino}sulfonyl)piperazine-1-carboxylate (the product from step ii), 0.83 g) in DCM (5 ml) was added TFA (5 ml) slowly. The reaction was then stirred at room temperature for 18 h. The reaction was reduced in vacuo and the residue purified by prep HPLC to give the title compound as a white solid. Yield 160 mg