Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:10][S:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:9]2[C:8]([C:6]([OH:7])=[O:5])=[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:11][N:10]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)c1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
To a solution of 11 (2.35 g) in CH2Cl2 (25 ml) is added 25 ml of TFA and the mixture is stirred at room temperature for 24 h. The mixture is then concentrated and the residue is dissolved in ether (250 ml). Water (225 ml) is added followed by 1N NaOH (25 ml). After washing and separation, the basic water layer is extracted once more with ether. The water layer is acidified with conc. HCl and the precipitated product is extracted with ether (2×150 ml). The combined organic layers are washed with brine, dried and concentrated. 1.85 g of 12 is obtained as a cream colored solid.
Reaction SMILES: O[C:2]1[C:3]([OH:18])=[C:4](O)[C:5](O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[OH-].[Na+].C1([O-:27])C=CC=CC=1.[Na+].[Na+].C1([O-])C=CC=CC=1.ClC([SiH2]OC)Cl>>[OH:18][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:27])=[CH:11][CH:10]=2)=[O:8])=[CH:15][CH:2]=1
Reactant: [O-]c1ccccc1
Reactant: O=C(c1ccccc1)c1cc(O)c(O)c(O)c1O
Agent: CO[SiH2]C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
Synthesis I: A solution of tetrahydroxybenzophenone (Aldrich Chemical) is treated with sufficient caustic, i.e. sodium hydroxide, to prepare a disodium phenolate salt. This salt solution is mixed at a two to one molar ratio with dichloromethylmethoxysilane (Aldrich, United Chemicals) to yield 2,2′ di-(dimethoxymethylsilyoxy), 4,4′dihydroxy-benzophenone having the structure shown in FIG. 8(a).
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]=[O:20])[CH:14]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]3)[CH2:5]1.C(N(CC)CC)C.[C:32](SCC)(=[S:34])[CH3:33]>CO>[CH3:22][C:21]([CH:14]1[CH2:13][C:12]2[C:16](=[CH:17][CH:18]=[C:10]([N:6]3[CH2:5][C@H:4]([CH2:3][NH:2][C:32](=[S:34])[CH3:33])[O:8][C:7]3=[O:9])[CH:11]=2)[N:15]1[CH:19]=[O:20])([CH3:24])[CH3:23]
Reactant: CCSC(C)=S
Reactant: CC(C)(C)C1Cc2cc(N3C[C@H](CN)OC3=O)ccc2N1C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=S)NC[C@H]1CN(c2ccc3c(c2)CC(C(C)(C)C)N3C=O)C(=O)O1
Yield: 45.6 %

Procedure:
The amine hydrochloride salt (200 mg, 0.566 mmol) prepared in Step 12 is stirred in a mixture of methanol (4 ml) and triethylamine (0.234 ml, 1.683 mmol). To this solution is added ethyl dithioacetate (0.08 ml, 0.70 mmol) and the mixture heated to reflux for 2 hours then allowed to cool. The precipitate is filtered to afford the thioamide as white needles (97 mg, 46%): mp 219-221° C. Anal: Calcd. for C19H25N3O3S: C, 60.78; H, 6.71; N, 11.19. Found: C, 60.63; H, 6.80; N, 11.12.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:6])[CH2:4][OH:5].[CH3:7]CN(CC)CC.[C:14]1(C)[C:15]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1>C(Cl)Cl>[CH3:7][C:18]1[CH:19]=[CH:14][C:15]([S:20]([O:5][CH2:4][C@H:3]([O:2][CH3:1])[CH3:6])(=[O:21])=[O:22])=[CH:16][CH:17]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CO[C@H](C)CO
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@H](C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a stirred solution of crude (R)-2-methoxypropan-1-ol (4.30 g, 47.7 mmol) in DCM (200 mL) was added Et3N (10.0 mL, 71.6 mmol). A solution of toluene sulfonyl chloride (10.9 g, 57.3 mmol) in DCM (80 mL) was added dropwise at 0° C. under nitrogen. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (hexanes:EtOAc, 10:1 to 4:1) to give (R)-2-methoxypropyl 4-methylbenzenesulfonate (6.43 g, 55% for three steps).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=O)[CH2:6][C:7](=O)[CH3:8])[CH3:2].Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1>C(O)C.O>[CH2:1]([O:3][C:4]([C:5]1[N:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:22]=[C:7]([CH3:8])[CH:6]=1)=[O:11])[CH3:2]
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(C)nn1-c1ccc(OC)cc1
Temperature: 80 °C

Procedure:
Ethyl-2,4-dioxovalerate (0.555 g, 3.5 mmol) and 4-methoxyphenylhydrazine hydrochloride (0.67 g, 3.8 mmol) were mixed in ethanol and heated to 80° C. overnight. The reaction was cooled, diluted with water and extracted with EtOAc. Organic layers were combined and washed with water, 10% HCl, sat. NaHCO3, dried over MgSO4 and concentrated under reduced pressure. The residue was purified on silica gel (20% EtOAc in hexanes to 30% EtOAc in hexanes). Two regioisomers were isolated, the title regioisomer being the more polar (yield 492 mg). LC-MS (C14H16N2O3 calculated 260) m/z 261 (M+H).
Reaction SMILES: [C:1]([O:10][CH2:11][CH2:12][CH:13]1[O:18][CH2:17][CH2:16][CH2:15][O:14]1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH2:11][CH2:12][CH:13]2[O:14][CH2:15][CH2:16][CH2:17][O:18]2)=[O:9])[N:22]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: O=C(OCCC1OCCCO1)c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)OCCC2OCCCO2)n1
Reaction time: 1 h

Procedure:
0.84 Gram of 2-(1,3-dioxan-2-yl)ethyl salicylate and 0.73 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine was dissolved in 10 ml of N,N-dimethylformamide, and 0.51 g of anhydrous potassium carbonate was added thereto. The resulting solution was stirred at 100° to 110° C. for 1 hour. The reaction solution was allowed to cool, poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer separated from the aqueous layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (mfd. by Merck & Co., Inc., solvent: chloroform) to obtain 0.50 g of 2-(1,3-dioxan-2-yl)ethyl 2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoate [present compound (V-1)].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([C:5]2[S:1][C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH:3][CH:4]=2)=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(O)Cc1cccs1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(O)Cc1ccc(C(=O)c2ccc(Cl)cc2)s1

Procedure:
Using the procedure of Example 1, thiophene-2-acetic acid and p-chlorobenzoyl chloride were reacted to obtain 5-(p-chlorobenzoyl)-thiophene-2-acetic acid melting at 165° C.
Reaction SMILES: [CH2:1]([C:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH2:11][OH:12])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20]I>>[CH2:13]([C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:11][O:12][CH3:20])[CH2:9][OH:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CI
Reactant: OCC(CO)(Cc1ccccc1)Cc1ccccc1
Product: COCC(CO)(Cc1ccccc1)Cc1ccccc1

Procedure:
2,2-Dibenzyl-3-methoxy-1-propanol was prepared from 2,2-dibenzyl-1,3-propandiol and methyl iodide through the same procedure as described above.
Reaction SMILES: C(O)(=O)C.[CH:5]1([NH:8][NH2:9])[CH2:7][CH2:6]1.Cl.[CH:11](=O)[C:12]([CH3:14])=[O:13]>O>[CH:5]1([NH:8][N:9]=[CH:11][C:12](=[O:13])[CH3:14])[CH2:7][CH2:6]1
Reactant: CC(=O)C=O
Reactant: NNC1CC1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C=NNC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Acetic acid (1.71 mL, 29.9 mmol) was slowly added to a solution of cyclopropylhydrazine.HCl (2.5 g, 18.1 mmol) in H2O (30 mL), and was then quickly added dropwise to a solution of pyruvaldehyde (40%, 2.36 mL, 14.5 mmol) in H2O (240 mL). This solution was stirred overnight at room temperature. The aqueous layer was salted and extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give 1.04 g of crude product as a reddish oil. The crude product was purified via flash chromatography (silica gel) eluting with a gradient of ethyl acetate/hexanes (25:75 to 50:50) to afford 637 mg (35%) of 2-oxopropanal cyclopropylhydrazone as a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([CH:6]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7]1)C.CC[O:18]C(C)=O>O1CCOCC1.O.C(O)CCC.O=[Os](=O)(=O)=O>[O:15]=[C:12]1[N:11]2[CH:6]([CH2:4][CH2:3][CH2:2][CH:1]=[O:18])[CH2:7][CH2:8][CH2:9][C:10]2=[N:14][O:13]1
Reactant: CCOC(C)=O
Reactant: CCCC(C)C1CCCc2noc(=O)n21
Agent: O=[Os](=O)(=O)=O
Solvent: C1COCCO1
Solvent: O
Solvent: CCCCO
Product: O=CCCCC1CCCc2noc(=O)n21

Procedure:
Ex-28) The product of Example 27 (0.42 g; 2 mmol) and NaIO4 (0.86 g; 4 mmol) were dissolved in a mixture of 12 mL of dioxane and 8 mL of H2O. Two drops of a 2% solution of OsO4 in n-butanol was added to the mixture. The reaction mixture was stirred until tlc (100% EtOAc) indicated that the starting material was consumed. A precipitate had formed and was filtered. This solid was washed with dioxane. The filtrate was concentrated and the residue was partitioned between H2O/CH2Cl2. The organic layer was dried over MgSO4 and concentrated to afford the title compound as an oil.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([N:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[CH:2][CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: Nc1ccc(N2C(=O)C=CC2=O)cc1
Temperature: 23 °C
Reaction time: 22 h
Yield: 98.6 %

Procedure:
The solution of 21.6 g (200 mmol) of 1,4-phenylenediamine in 200 ml of tetrahydrofuran is mixed over 1.5 hours with the solution of 19.6 g of maleic acid anhydride, and it is stirred for 22 hours at 23° C. It is filtered, rewashed with tetrahydrofuran, and the filtrate is dried. 37.1 g (197 mmol, 98%) of the title compound is isolated as a crystalline solid.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:15]=[O:16])C.O=P(Cl)(Cl)Cl>>[C:1]1([N:7]2[CH:11]=[C:10]([CH:15]=[O:16])[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: c1ccc(-n2cccn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn(-c2ccccc2)c1
Temperature: 106 °C
Reaction time: 0.17 h
Yield: 112.7 %

Procedure:
1-Phenyl-1H-pyrazole (250 mg, 1.7 mmol) was added to a cold (0-4° C.) solution of DMF (1.5 g, 1.6 mL, 9.7 mmol) and POCl3 (1.86 g, 1.1 mL, 19.2 mmol) and stirring continued for 10 minutes. The resulting mixture was heated at 106° C. for 2.5 hrs. The reaction mixture was cooled and quenched with ice cold water, basified with 20% aqueous NaOH solution, filtered the solid precipitated to afford 330 mg (crude) of 1-Phenyl-1H-pyrazole-4-carbaldehyde. 1H NMR (CDCl3): δ 10.0 (s, 1H), 8.45 (s, 1H), 8.2 (s, 1H), 7.75 (d, 2H), 7.55 (t, 2H), 7.45 (t, 1H).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[CH:12][C:13]([N+:26]([O-])=O)=[C:14]([CH:25]=1)[C:15]([NH:17][CH2:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[O:16])[CH2:3][CH2:2]2.[H][H]>CO.[Pd]>[NH2:26][C:13]1[CH:12]=[CH:11][C:10]([N:4]2[CH:5]3[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3]2)=[CH:25][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[O:16]
Reactant: CC(C)NC(=O)CNC(=O)c1cc(N2CCN3CCC2CC3)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)NC(=O)CNC(=O)c1cc(N2CCN3CCC2CC3)ccc1N
Yield: 98.9 %

Procedure:
5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (Intermediate 4A) (7.0 g, 18.0 mmol) was dissolved in methanol (120 mL) and palladium on carbon (0.7 g) added. The resulting solution was hydrogenated at room temperature under 4 bar pressure of hydrogen overnight. The reaction mixture was filtered through a celite pad, washed with methanol and dichloromethane, and concentrated to afford 2-amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(2-(isopropylamino)-2-oxoethyl)benzamide (6.4 g, 17.8 mmol).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].C(COC)OC.C(C1N(CC2C(F)=CC=CC=2Cl)C(/C=C(/C2NN=NN=2)\[CH2:40][C:41]2[S:42][CH:43]=[CH:44][CH:45]=2)=CN=1)CCC.[C:60]([O:63]CC)(=[O:62])[CH3:61]>C(C1N(CC2C(F)=CC=CC=2Cl)C(/C=C(\CC2SC=CC=2)/C(OC)=O)=CN=1)CCC>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[C:7](/[CH:10]=[C:61](\[CH2:40][C:41]2[S:42][CH:43]=[CH:44][CH:45]=2)/[C:60]([OH:63])=[O:62])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(C)=O
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)c2nnn[nH]2)n1Cc1c(F)cccc1Cl
Reactant: CCCCc1ncc(C=O)n1Cc1c(F)cccc1Cl
Agent: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OC)n1Cc1c(F)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1c(F)cccc1Cl

Procedure:
The procedure of Example 1, Method A, is used. 2-n-Butyl-1-(2-chloro-6-fluorophenyl)methyl-1H-imidazole-5-carboxaldehyde, trimethyl 3-(2-thienyl)-2-phosphonopropionate, sodium hydride and glyme are held at 60° C. for 1 hour to give, after chromatography over silica gel with 50% of hexanes in ethyl acetate, methyl (E)-[2-n-butyl-1-{(2-chloro-6-fluorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate and corresponding cis or (Z)-isomer. The (E)-isomer is hydrolyzed to afford (E)-3-[2-n-butyl-1-{(2-chloro-6-fluorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14](=[O:31])[C@@H:15]([NH2:30])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:13][C:14](=[O:31])[C@@H:15]([NH:30][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cccc(O)c2)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2cccc(O)c2)cc1)NC(=O)c1cc(Cl)ccc1N
Yield: 36.2 %

Procedure:
A solution of 2-amino-5-chloro-benzoic acid (1.95 g, 11.38 mmol) in DMF (10.0 mL) was reacted with (2S)-amino-3-(3′-hydroxy-biphenyl-4-yl)propionic acid methyl ester (3.50 g, 11.38 mmol), HBTU (3.98 g, 10.50 mmol), and DIEA (6.08 mL, 34.15 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silical gel using DCM/hexane 85:15 and increasing the gradient to DCM and finally DCM containing 0.25% methanol, to give 1.75 g of (2S)-(2-amino-5-chloro-benzoylamino)-3-(3′-hydroxy-biphenyl-4-yl)propionic acid methyl ester as a white solid.
Reaction SMILES: C([Li])(C)(C)C.I[C:7]1([CH2:10][C@@H:11]2[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]2)[CH2:9][CH2:8]1.[S:18]([Cl:21])(Cl)=[O:19].CC[O:24]CC>>[CH3:16][C:13]1([CH3:17])[O:12][C@H:11]([CH2:10][C:7]2([S:18]([Cl:21])(=[O:19])=[O:24])[CH2:9][CH2:8]2)[CH2:15][O:14]1
Reactant: CC1(C)OC[C@@H](CC2(I)CC2)O1
Reactant: O=S(Cl)Cl
Reactant: CCOCC
Agent: [Li]C(C)(C)C
Product: CC1(C)OC[C@@H](CC2(S(=O)(=O)Cl)CC2)O1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
tert-Butyl lithium (0.2 mL, 0.34 mmol, 1.7M) was added to a solution of (R)-4-(1-iodocyclopropyl)methyl)-2,2-dimethyl-1,3-dioxolane (step G, 45 mg, 0.16 mmol) in ether (1 mL) at −78° C. and the mixture stirred at −78° C. for 30 mins. A solution of thionyl chloride (26 μL) in ether (0.5 mL) was then added. The resulting orange solution was warmed to room temperature and concentrated under reduced pressure. The residue was dissolved in chloroform, filtered and dried under reduced pressure to afford (R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonyl chloride (23.7 mg, 57%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[CH3:35][S:36]([NH:39][C:40](=O)[O:41]CC)(=[O:38])=[O:37].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:32][C:40]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:41])=[CH:33][CH:34]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)NS(C)(=O)=O
Reactant: Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of compound 10b (82 mg, 0.18 mmol) and compound 12a (0.14 g, 0.86 mmol) in DMF (2 mL) was added DIEA (0.16 mL, 0.91 mmol). The mixture was stirred at 100° C. for 2 h. The solution was cooled down, and diluted with DCM (10 mL). The organic layer was washed with 1 N HCl solution (10 mL) and brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash column chromatography on silica gel (0-10% CH3OH/DCM) to give the title compound 50 as a red solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.96 (s, 1H), 8.31 (d, J=8.6 Hz, 1H), 8.12 (d, J=5.6 Hz, 1H), 7.94 (dd, J=13.6, 8.2 Hz, 2H), 7.83 (d, J=8.6 Hz, 1H), 7.66-7.77 (m, 5H), 7.57-7.63 (m, 2H), 7.51-7.57 (m, 1H), 6.40 (d, J=5.9 Hz, 1H), 4.03-4.14 (m, 4H), 3.83-3.92 (m, 4H), 3.17 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H27N7O4S: 570.2 (M+H). Found 570.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:19][CH2:20][CH:21]1[O:23][CH2:22]1.[OH-].[NH4+]>C(Cl)(Cl)(Cl)Cl>[Cl:19][CH2:20][CH:21]1[CH2:22][O:23][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:2][CH3:1])=[O:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:17]1
Reactant: ClCC1CO1
Reactant: COC(=O)c1ccccc1C(=O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1C1(c2ccccc2)OCC(CCl)O1
Reaction time: 0.33 h

Procedure:
To a solution of 33 g (0.138 mol) of 2-benzoyl benzoic acid methyl ester in 200 ml of dry carbon tetrachloride was added 10.1 ml (0.13 mol) of 1-chloro-3,4-epoxypropane. The reaction was cooled in an ice bath and a solution of 1.5 ml (0.013 mol) of stannic chloride in 10 ml of carbon tetrachloride was added with stirring over a 20 min period. The reaction was allowed to stand over the weekend, and then the same quantities of 1-chloro-2,3-epoxy-propane and stannic chloride were added. After 18 hours the reaction was cooled in an ice bath, and neutralized with concentrated ammonium hydroxide. The precipitate was filtered off and washed with dichloromethane and the combined filtrates were washed with 150 ml of water, dried with sodium sulfate and evaporated. The resulting oil was dissolved in 100 ml of dichloromethane and chromatographed through 500 g of neutral alumina. Elution with 3 l of dichloromethane gave the end product as an oil which was about 95% pure by TLC. Crystallization and recrystallization of a small sample from ether/petrol gave white rods, mp 90°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](=[NH:10])[O:7][CH2:8][CH3:9])=[C:4]([F:13])[CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:10]=[C:6]([O:7][CH2:8][CH3:9])[C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][C:4]=1[F:13])=[O:19]
Reactant: CCOC(=N)c1ccc(Cl)cc1F
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1ccc(Cl)cc1F

Procedure:
starting from ethyl 4-chloro-2-fluorobenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-2-fluoro-4-chlorobenzimidate and therefrom with methylhydrazine there is obtained 3-(4-chloro-2-fluorophenyl)-1-methyl-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 109.5°-112° C.;
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:21][C:22]1([F:35])[O:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:30]([S:31]([Cl:34])(=[O:33])=[O:32])[C:24]=2[O:23]1>>[ClH:34].[N:11]1([C:14]2[CH:19]=[C:18]([NH:20][S:31]([C:30]3[C:24]4[O:23][C:22]([F:35])([F:21])[O:26][C:25]=4[CH:27]=[CH:28][CH:29]=3)(=[O:32])=[O:33])[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Reactant: O=S(=O)(Cl)c1cccc2c1OC(F)(F)O2
Product: Cl
Product: O=S(=O)(Nc1cccc(N2CCNCC2)c1)c1cccc2c1OC(F)(F)O2

Procedure:
The compound was prepared as described for Example 28 by reaction of 4-(5-aminophenyl)-piperazine-1-carboxylic acid tert-butyl ester with commercially available 2,2-Difluorobenzo[1,3]dioxole-4-sulfonyl chloride followed by deprotection under acidic conditions.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].N[CH:6]([C:19]1[CH:23]=[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])[O:21][CH:20]=1)[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([N:30](CC)CC)C>ClCCl>[CH3:1][N:2]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:19]1[CH:23]=[C:22]([Si:24]([CH3:26])([CH3:27])[CH3:25])[O:21][CH:20]=1)[C:3]([NH2:30])=[O:4]
Reactant: CCCCCCCCCCCCC(N)c1coc([Si](C)(C)C)c1
Reactant: CCN(CC)CC
Reactant: CN=C=O
Solvent: ClCCl
Product: CN(CCCCCCCCCCCCCc1coc([Si](C)(C)C)c1)C(N)=O
Reaction time: 48 h

Procedure:
A solution of methylisocyanate (23ul, 0.38 mmol) in dichloromethane (0.5 ml) was added to a solution of 3-(1-aminotridecyl)-5-trimethylsilylfuran (85.5 mg, 0.25 mmol) and triethylamine (53 microliter, 0.3 mmol) in dichloromethane (2 ml) at room temperature. Stirring was continued for two days and the reaction mixture was quenched with water. Extraction (dichloromethane) and evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by preparative TLC (20×20 CM, 1000ul; developed with 40% ethyl acetate/hexane) to give the titled urea as a colorless oil.