Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH2:4]1.[CH3:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[S-:35].[Na+]>>[CH3:9][C:7]1([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH2:4][C@@H:3]([CH2:2][S:35][C:27]2[N:26]([CH3:25])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=2)[O:8]1
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Reactant: Cn1c([S-])nc2ccccc21
Agent: [Na+]
Product: Cn1c(SC[C@@H]2C[C@H](CC(=O)OC(C)(C)Cc3ccccc3)OC(C)(C)O2)nc2ccccc21

Procedure:
The procedure was carried out in the same manner as in Example 11, except that 3.5 g of 2-methyl-1-phenylpropan-2-yl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate was used in place of 30 g thereof, and sodium 1-methyl-1H-benzo[d]imidazole-2-thiolate (3.7 g) prepared in Example 9 was used in place of sodium 1-phenyl-1H-tetrazole-5-thiolate. The title compound was obtained (4.7 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I:28]C1C=C(C=CC=1)C(C(=CNC1C=CC=CC=1)C#N)=O.CCN(C(C)C)C(C)C>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([I:28])[CH:26]=1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2ccccc2)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(I)c2)c1N
Temperature: 160 °C
Yield: 70 %

Procedure:
To a stirred solution of N-cyclopropyl-3-hydrazino-4-methyl-benzamide, trifluoroacetic acid salt 6 (648 mg, 1.74 mmol, 1.0 eq) in 2 mL of ethanol was added 2-(3-iodo-benzoyl)-3-phenylamino-acrylonitrile 2 (550 mg, 1.74 mmol, preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84) and DIEA (0.50 mL, 2.9 mmol). The mixture was heated to 160° C. for 40 min using microwave. The mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc/hex, gradient 1/1 to 2/1) to give 3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 7 (589 mg, 70%) as a white solid. MS m/z 497 [M+H]+; 1H NMR (300 MHz, CDCl3) δ0.60 (m, 2H), 0.86 (m, 2H), 2.24 (s, 3H), 2.87 (m, 1H), 5.81 (bs, 2H), 6.35 (bs, 1H), 7.25 (dd, J1=J2=7.8 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.69 (d, J=1.7 Hz, 1H), 7.80 (m, 3H), 7.89 (m, 1H), 8.00 (s, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1.[C:20](Cl)(=[O:22])[CH3:21]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:20](=[O:22])[CH3:21])[CH:9]=[C:10]2[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2cccc(CCCNC(C)=O)c2c1
Product: COc1ccc2cc(C(C)=O)cc(CCCNC(C)=O)c2c1

Procedure:
By reacting N-[3-(7-methoxy-1-naphthyl)propyl]acetamide obtained in Example 1 with acetyl chloride, the compound of the title is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13]C)=O)[C:5]=2[CH:4]=[CH:3]1.[ClH:15].[NH2:16][C:17]([NH2:19])=[NH:18].C[O-].[Na+]>CO>[ClH:15].[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([NH:18][C:17]([NH2:19])=[NH:16])=[O:13])[C:5]=2[CH:4]=[CH:3]1
Reactant: COC(=O)c1cccc2c1ccn2C
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1ccc2c(C(=O)NC(=N)N)cccc21
Yield: 66.1 %

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 0.85 g (4.49 mmol) of methyl 1-methyl-4-indolecarboxylate, 4.29 g (44.9 mmol) of guanidine hydrochloride and 50 ml of a methanol solution of 2.43 g (44.9 mmol) of sodium methoxide. Thus 0.75 g (66.1%) of 1-methyl-4-indoloylguanidine hydrochloride was obtained.
Reaction SMILES: CN(C(ON1N=NC2[CH:12]=[CH:13][CH:14]=[N:15]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:27]=[C:28]([C:36]([OH:38])=O)[CH:29]=[C:30]2[C:35]=1[N:34]=[CH:33][CH:32]=[CH:31]2.C(N(C(C)C)CC)(C)C.C1(N)CC1>CN(C=O)C.O>[Br:25][C:26]1[CH:27]=[C:28]([C:36]([NH:15][CH:14]2[CH2:12][CH2:13]2)=[O:38])[CH:29]=[C:30]2[C:35]=1[N:34]=[CH:33][CH:32]=[CH:31]2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Br)c2ncccc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CC1)c1cc(Br)c2ncccc2c1
Reaction time: 2 h

Procedure:
A solution of HATU (1.2 eq), 8-bromoquinoline-6-carboxylic acid (1 eq), diisopropylethylamine (2.5 eq) and cyclopropylamine (1.1 eq) was stirred at rt for 1 h in DMF (0.2 M). The reaction mixture was diluted with water, stirred for 2 h and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was crystallized in EtOAc and title product isolated by filtration as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(OCC)(=O)C.CCCCCC>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH:4][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cl
Reactant: Nc1c(F)cc(F)cc1Br
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1c(F)cc(F)cc1Br
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To a vigorously stirred solution of 2-bromo-4,6-difluoro aniline (100 g, 0.48 mol) in pyridine (400 mL), at 0° C., is added ethyl chloroformate (70 ml, 0.73 mol) at a rate to keep the temperature below 5° C. When addition is complete, the mixture is stirred at 0° C.–5° C. an additional 2 hours while monitoring by TLC (20% ethyl acetate/hexane, UV). The reaction is then allowed to warm to room temperature, filtered and the filtrate concentrated. The residue is dissolved in diethyl ether/ethyl acetate (500 ml/250 ml) and washed with H2O, 2.5 N HCl, aqueous NaHCO3, brine, dried (Na2SO4), filtered, concentrated, and triturated with petroleum ether to give 126 g of 2-bromo-4,6-difluoro-N-carbethoxy aniline (94%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C.[C-]#N.[K+].COC1C=CC(O)=CC=1>>[C:1]([O:6][CH2:7][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: COc1ccc(O)cc1
Agent: [C-]#N
Agent: [K+]
Product: C=C(C)C(=O)OCCCCCCCCCCCCCCCCCC
Temperature: 75 °C
Reaction time: 3.5 h

Procedure:
300 g of methyl methacrylate (3 mole), 135 g of stearyl alcohol (0.5 mole), 4.35 g of KCN (1%) and 0.108 g of hydroquinone methyl ether (250 ppm) are added to a 1 liter round-bottomed flask. The mixture is heated to about 75° C. by conducting air through it and the methyl methacrylate/methanol-azeotrope is removed at a temperature of 65° C. at the head of the column by way of a 1 m vigreux column. The trans-esterification is completed after 3.5 hours. After cooling down of the flask, the sump is filtered to remove the potassium cyanide, and the filter residue is washed with a little methyl methacrylate. The filtrate is concentrated at 40° C. under a water jet vacuum. A white, crystalline residue of stearyl methacrylate of 162 g = 96% will result.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6](C)=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([N:18]3[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:20][C:19]3=[O:35])[CH3:17])=[CH:12][CH:11]=2)=[N:3]1.Cl[C:37]1C(C)=CC(=O)N(C)N=1>>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:37])[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([N:18]3[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:20][C:19]3=[O:35])[CH3:17])=[CH:12][CH:11]=2)=[N:3]1
Reactant: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn(C)c1=O
Reactant: Cc1cc(=O)n(C)nc1Cl
Product: Cc1cc(=O)n(C)nc1-c1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1

Procedure:
The title compound was prepared from 3-{(S)-1-[4-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and 6-chloro-2,5-dimethylpyridazin-3(2H)-one following a procedure analogous to that described in Example 17. Mass spectrum (ESI+): m/z=476 [M+H]+
Reaction SMILES: C([C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:13]=1[O:26][CH3:27])([CH2:9][CH2:10][CH3:11])[C:4]([O:6]CC)=[O:5])#N.[OH-].[K+]>C(O)C.O>[CH3:27][O:26][C:13]1[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][CH:16]=[CH:17][C:12]=1[CH:3]([CH2:9][CH2:10][CH3:11])[C:4]([OH:6])=[O:5]
Reactant: CCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2Cl)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC(C(=O)O)c1cccc(Oc2ccccc2Cl)c1OC
Yield: 62.9 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenoxy)phenyl]valerate (7 g) and potassium hydroxide (5 g) in ethanol (80 ml) and water (40 ml) was treated in a similar manner to that of Example 14-(7) to give oily 2-[2-methoxy-3-(2-chlorophenoxy)phenyl]valeric acid (3.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][CH:27]([OH:30])[CH2:28][NH2:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:29][CH2:28][CH:27]([OH:30])[CH3:26])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and DL-1-amino-2-propanol employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.81 (1H, t, J=5.6 Hz), 10.81 (1H, br s), 10.10 (1H, br s), 8.18 (0.48H, s), 8.14 (052.H, s), 7.36-7.23 (3H, m), 7.14-7.08 (2H, m), 4.74 (1H, t, J=4 Hz), 3.98 (2H, s), 3.75-3.65 (1H, m), 3.29-3.15 (2H, m), 1.07-1.04 (3H, m); HRMS calcd for C19H18FN3O4+H+: 372.1360. Found 372.1364.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[C:32]=1[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[C:35]([O:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:31]=3[O:30][CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(OC)c1C=O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1cccc(OC)c1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,6 dimethoxybenzaldehyde. MS (ESI) m/z 529.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=O)C.[NH2:14][C@@H:15]1[CH2:24][CH2:23][C:22]2[C:17](=[C:18]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:19]=[CH:20][CH:21]=2)[CH2:16]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:31][N:28]1[CH2:29][CH2:30][N:25]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH2:16][C@H:15]([NH:14][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:5]([OH:4])[CH:6]=2)[CH2:24][CH2:23]3)[CH2:26][CH2:27]1
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2cccc(O)c2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-acetoxybenzoic acid (130 g, 0.69 mol) in thionyl chloride (400 mL) was stirred at ambient temperature for 4 days. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (100 mg, 0.52 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.50 mmol) and triethylamine (100 μL, 0.75 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in 99.5% ethanol (25 mL) and concentrated hydrochloric acid (5 mL) was added. After 17 h, the pH was adjusted to 8 and the solvent evaporated in vacuo. The residue was partitioned between water and methylene chloride. The organic phase was separated, dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 93 mg (51%) of the title compound as white crystals: mp 117° C. decomp, [α]21D −10° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 365 (22, M+).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[CH:7]1[CH:12]=[N:11][CH:10]=[C:9](CO)[CH:8]=1.[C:15]([O:19][C:20](=[O:34])[NH:21][CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[C:32](Cl)=[N:31][CH:30]=[CH:29][N:28]=2)[CH2:23]1)([CH3:18])([CH3:17])[CH3:16]>C(O)(C)(C)C>[C:15]([O:19][C:20](=[O:34])[NH:21][CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]([O:4][CH2:2][C:8]3[CH:7]=[CH:12][N:11]=[CH:10][CH:9]=3)=[N:31][CH:30]=[CH:29][N:28]=2)[CH2:23]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nccnc2Cl)C1
Reactant: CC(C)(C)[O-]
Reactant: OCc1cccnc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC1CCN(c2nccnc2OCc2ccncc2)C1
Yield: 11.8 %

Procedure:
To a round-bottom flask purged with N2 was charged with Potassium t-butoxide (7.6 g, 68.4 mmol) and t-butanol (140 mL). The mixture was flushed with N2 for approximately 5 min., while stirring. To this mixture was added pyridylcarbinol (7.4 g, 68.4 mmol), followed by [1-(3-chloro-pyrazin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (6.8 g, 22.8 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, and then diluted with water and extracted with EtOAc three times. The organic layer was washed with water and brine, dried over sodium sulfate, and then concentrated in vacuo. Purification of the crude by column chromatography afforded {1-[3-(pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (1 g, 12% yield).
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([OH:36])=O)[CH2:28][CH2:27]1.CS(N)(=O)=O.[N:55]1([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:58][CH2:57][CH2:56]1>>[N:55]1([S:59]([NH:62][C:34](=[O:36])[C:33]2[CH:37]=[C:29]([CH:26]3[CH2:28][CH2:27]3)[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]=2[F:38])(=[O:61])=[O:60])[CH2:58][CH2:57][CH2:56]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC(F)(F)CC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(COc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2C2CC2)CCC(F)(F)CC1

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained (0.17 g, 56%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.72-8.59 (m, 1H), 7.69-7.61 (m, 1H), 6.64-6.52 (m, 1H), 4.31-4.19 (m, 4H), 3.76 (s, 2H), 2.35-2.20 (m, 2H), 2.08-1.73 (m, 7H), 1.69-1.58 (m, 2H), 1.17 (s, 3H), 0.99-0.89 (m, 2H), 0.71-0.61 (m, 2H); MS (ES+) m/z 461.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]=1Br)=[O:5])[CH3:2].C([Li])(C)(C)C.CN([CH:34]=[O:35])C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]=1[CH:34]=[O:35])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1Br
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (I-5d, 4.4 g, 0.01 mmol) in anhydrous THF (100 ml) and under a N2 atmosphere at −78° C. was slowly added tert.-butyl lithium (13 ml of 1.7 M solution in pentane, 0.22 mol). After 1 hour at −78° C., DMF (7.7 ml, 0.1 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 2.5 hours, quenched with sat'd aq. NH4Cl (10 ml), allowed to slowly warm to room temperature, and finally poured into sat'd aq. NaCl. The aqueous solution was extracted with Et2O (3×) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified via flash chromatography using a solvent gradient of 1:3 EtOAc/hexanes to 1:1 EtOAc/hexanes to give the desired product I-5e as a pale yellow amorphous glass (2.0 g): +APCI MS (M+1) 389.2; 1H NMR (CD2Cl2) δ 1.41 (3H, t), 4.45 (2H, q), 7.09-7.14 (2H, m), 7.24-7.39 (7H, m), 10.50 (1H, s).
Reaction SMILES: CS(C)=O.[CH3:5][Si](Cl)(C)C.[CH:10]1([CH2:13][N:14]2[CH2:34][CH2:33][C@@:21]34[C:22]5[C:27]6[CH2:28][C@@H:15]2[C@H:16]3[CH2:17][C@H:18]([C@:36]([OH:42])([C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:37])[C@H:19]([OH:35])[C@@H:20]4[O:32][C:23]=5[C:24]([OH:31])=[C:25]2CC[C:26]2=6)[CH2:12][CH2:11]1.[CH2:43]1COC[CH2:44]1>>[C:38]([C@:36]1([CH3:37])[C@@H:18]2[C@@:19]3([CH2:44][CH2:43][C@:16]4([CH2:17]2)[C@@:21]25[C:22]6[C:27](=[CH:26][CH:25]=[C:24]([OH:31])[C:23]=6[O:32][C@@H:20]32)[CH2:28][C@H:15]4[N:14]([CH2:13][CH:10]2[CH2:11][CH2:12]2)[CH2:34][CH2:33]5)[O:35][CH2:5][O:42]1)([CH3:39])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[C@@](C)(O)[C@H]1C[C@@H]2[C@H]3Cc4c5c(c(O)c6c4[C@@]2(CCN3CC2CC2)[C@@H](O6)[C@H]1O)CC5
Reactant: C1CCOC1
Reactant: C[Si](C)(C)Cl
Solvent: CS(C)=O
Product: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a solution of DMSO (2.1 ml, 28.7 mMol) in THF (10 ml), at ambient temperature, was added trimethylsilyl chloride (TMSCl) (2.7 ml, 20.8 mMol). After 30 minute agitation, a solution of compound 2 (1.5 g, 3.3 mMol) in THF (12.5 ml) was added and the mixture was stirred at ambient temperature. After 24 h reaction time at ambient temperature, the reaction conversion was about 85% at which point the reaction was quenched by addition of saturated aqueous NaHCO3 solution (100 ml). The resulting mixture was extracted with EtOAc (2×100 ml). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give 2.7 g of crude product. After purification by column chromatography on silica gel, 0.52 g of the title compound 3 (34.4% yield) was obtained with a purity of >99%.
Reaction SMILES: ClC1C=C(CCC[N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])NC2SC(SCC(O)=O)=CN=2)C=CC=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][C:43](O)=O)=[CH:36][CH:35]=1.C([O:48][C:49](=[O:60])[C:50]([S:53][C:54]1[S:58][C:57]([NH2:59])=[N:56][CH:55]=1)([CH3:52])[CH3:51])C>>[CH3:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH2:42][CH2:43][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:59][C:57]2[S:58][C:54]([S:53][C:50]([CH3:51])([CH3:52])[C:49]([OH:48])=[O:60])=[CH:55][N:56]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: COc1ccc(CCCCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(4-methoxy-phenyl)-butyric-acid and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [Br:1][CH:2]([C:10](Cl)=[O:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.Cl>C(OCC)C>[Br:1][CH:2]([C:10]([O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CCCC(Br)C(=O)Cl
Reactant: Oc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCC(Br)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To a solution of methyl 5-bromo-5-chloroformylpentanoate (2.57 g) in diethyl ether (15 ml) was added a mixture of phenol (0.94 g) and diisopropylethylamine (1.30 g) in diethyl ether (10 ml). The mixture was stirred at room temperature for 15 minutes and poured into ice water and diluted hydrochloric acid. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (5:1) to give methyl 5-bromo-5-phenoxycarbonylpentanoate as an oil (2.33 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)=[O:4].[I-].[Na+].[N-:15]=[N+]=[N-].[Na+]>CC(C)=O>[ClH:1].[NH2:15][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cl
Product: NCC(=O)c1ccc(O)c(O)c1
Temperature: 40 °C
Yield: 50.4 %

Procedure:
10 g (53.6 mmol) of 2-chloro-3',4'-dihydroxyacetophenone was dissolved in 50 ml of acetone, and 600 mg (4.0 mmol) of sodium iodide and 5.23 g (80.5 mmol) of sodium azide were added thereto. The mixture was refluxed for 24 hours. The insolubles in the reaction solution were removed by filtration, and the filtrate was concentrated under reduced pressure. To the reaction solution, ethyl acetate was added, and the mixture was washed sequentially with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the oily residue was dissolved in 100 ml of methanol and 13.6 ml of concentrated hydrochloric acid. 1.5 g of 10% palladium carbon catalyst was added to the solution, and the mixture was stirred under heating at 40° C. under a hydrogen gas stream for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. To the concentrated residue, actone was added, and the precipitated crystals were collected by filtration to obtain 5.5 g (yield: 50.4%) of 2-amino-3',4'-dihydroxyacetophenone hydrochloride.