Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][C:18]([O:20][C@H:21]3[CH2:25][CH2:24][O:23][CH2:22]3)=[O:19])[CH:11]=2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH2:40])[CH:32]=[CH:33][C:34]=1[C:35]1[O:39][CH:38]=[N:37][CH:36]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:40][C:8](=[O:26])[NH:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][NH:17][C:18](=[O:19])[O:20][C@H:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[CH:32]=[CH:33][C:34]=1[C:35]1[O:39][CH:38]=[N:37][CH:36]=1
Reactant: O=C(Nc1cccc(CNC(=O)O[C@H]2CCOC2)c1)Oc1ccccc1
Reactant: COc1cc(N)ccc1-c1cnco1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)Nc2cccc(CNC(=O)O[C@H]3CCOC3)c2)ccc1-c1cnco1
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Added 2e (15 g, 1.0 eq) and 2g (8.58 g, 1.07 eq) into a jacketed reactor of suitable size before adding ethyl acetate (225 ml, 15 vol) and diisopropylethylamine (5.43 g, 1.0 eq), then heated the mixture to reflux (75-85° C.) for 24 hours. Once the reaction was complete, the mixture was cooled to room temperature and stirred for an additional 1 hour. Precipitated solid was filtered, washed with EtOAc 2 times (45 ml, 3 vol each wash), then dried at 58° C. for 18 hours (until a LOD is achieved of less than 1%) to give 17.46 g of crude 2h (90.4% yield, 98.46% a/a) as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4]/[C:5](/[C:19]([O:21]C)=[O:20])=[CH:6]\[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3](=[O:23])/[C:4](=[CH:24]/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[C:5](/[C:19]([OH:21])=[O:20])=[CH:6]\[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)C/C(=C\c1cc(OC)c(OC)c(OC)c1)C(=O)OC
Product: COC(=O)C(=C/c1ccccc1)/C(=C\c1cc(OC)c(OC)c(OC)c1)C(=O)O

Procedure:
(E)-3-Methoxycarbonyl-4-(3,4,5-trimethoxyphenyl) -3-butenoic acid methyl ester and benzaldehyde are treated in the same manner as in Example 1-(1) to give (E)-2-[(E) -benzylidene]-3-carboxy-4-(3,4,5-trimethoxyphenyl)-3-butenoic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([S:11][CH3:12])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH2:8])=[C:4]([S:11][CH3:12])[CH:3]=1
Reactant: CSc1cc(F)ccc1C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CSc1cc(F)ccc1CN
Temperature: 25 °C

Procedure:
A slurry of 4-fluoro-2-(methylthio)benzamide (9 g, 48.6 mmol) in diethyl ether (500 mL) was cooled to 0° C. under nitrogen and lithium aluminum hydride (5.53 g, 145.8 mmol, 1.0 M in diethyl ether) was added dropwise. The reaction was allowed to stir with slow warming to 25° C. overnight. The reaction was quenched via the addition of water (5.53 mL), 15% NaOH (5.53 mL) and water (16 mL). The mixture was stirred, the lithium salts precipitated out and were filtered off. The organic filtrate was washed with saturated sodium bicarbonate (300 mL) and brine (300 mL), dried over Na2SO4, filtered and reduced to a small volume. The resulting brown oil was placed under high vacuum to give the desired compound as a free base.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[CH2:3]1.[S:11]1[CH:15]=[CH:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[S:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:6]1[C:7](=[O:8])[CH2:9][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]=1[OH:5]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: C1=CSCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)CC(=O)C(C2CCCS2)=C(O)C1
Reaction time: 0.5 h

Procedure:
A mixture of 7 parts of dimedone, 7 parts of 2,3-dihydrothiophene, 150 parts by volume of benzene and 0.7 parts of p-toluenesulfonic acid was refluxed by heating while stirring for 1 hour and 30 minutes and then allowed to stand at room temperature for 12 hours. The reaction mixture was washed with 50 parts by volume of water and then treated three times with 50 parts by volume of a 10% aqueous solution of sodium hydroxide. The aqueous layer was collected and the pH was adjusted to 2.0 with the addition of 6 N hydrochloric acid while maintaining the temperature thereof below 10° C. The light yellow colored crystals thus deposited were collected and purified by passing through a column containing a silica gel using a solvent mixture of chloroform and benzene (1:1) as a spreading agent to obtain 2-(2-tetrahydrothienyl)-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one in a form of colorless fine crystals. The melting point was 97° to 99° C. The yield was 8 parts.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][S:22]C3C=CC=CC=3C(OC)=O)[C@@H:18]([OH:33])[C@H:17]2[OH:34])[CH2:2]1.S[C:36]1[O:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1.C(C1C=CC=CC=1S)(OC)=O>>[O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:17]([OH:34])[C@H:18]([OH:33])[C@@H:19]([CH2:21][S:22][C:36]3[O:37][C:38]4[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=4[N:40]=3)[O:20]2)[CH2:2]1
Reactant: COC(=O)c1ccccc1SC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Reactant: Sc1nc2ccccc2o1
Agent: COC(=O)c1ccccc1S
Product: O[C@@H]1[C@H](O)[C@@H](CSc2nc3ccccc3o2)O[C@H]1n1cnc2c(N[C@@H]3CCOC3)ncnc21

Procedure:
This compound was prepared in a manner similar to that of 23 substituting 2-mercaptobenzoxazole for 2-carbmethoxy thiophenol (M+1)=471.4.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](OCC)=[O:14])[N:10]=[C:9]2[S:18][CH3:19])=[CH:4][CH:3]=1.[Li+].[BH4-].O.CCOC(C)=O>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:9]2[S:18][CH3:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(-c2ccc(I)cc2)c(SC)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1nc(CO)cn1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of ethyl 1-(4-iodophenyl)-2-(methylthio)-1H-imidazole-4-carboxylate (0.49 g, 1.26 mmol) in anhydrous THF (10 mL) at room temperature, LiBH4 (2M in THF, 3.2 mL, 6.4 mmol) was added. The mixture was stirred at room temperature overnight. H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methanol (0.41 g).
Reaction SMILES: Br[CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: CCOC(OCC)/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(OCC)/C(C)=C/COc1ccc(NC(C)=O)cc1
Reaction time: 96 h
Yield: 57.9 %

Procedure:
A solution of 1.0 g (E)-4-bromo-1,1-diethoxy-2-methyl-2-butene in 10 ml of sieve dried dimethyl formamide is treated with 0.7 g of p-acetylaminophenol and 0.64 g anhydrous potassium carbonate. The suspension is stirred under nitrogen for four days and the mixture is then poured into 100 ml water and the hazy solution extracted with two 100 ml portions of benzene. The benzene extract is washed with water and dried with sodium sulfate. The benzene extract is concentrated and vacuum dried to give 0.75 g of (E)-4-(4-acetylaminophenoxy)-1,1-diethoxy-2-methyl-2-butene which is dissolved in about 5 to 10 ml acetone and treated with about 1 ml water and a spatula of p-toluenesulfonic acid monohydrate. The resulting solution is agitated occasionally for 30 minutes and the solution is evaporated at room temperature giving a solid, ethylether insoluble residue. The residue is dissolved in about 150 ml methylene chloride and washed twice with water. The residue is dried with sodium sulfate and concentration gave 0.45 g of a solid. The material is filtered in about 50 ml of hot carbon tetrachloride-benzene then boiled down to about 10 ml. The product is filtered and washed with room temperature carbon tetrachloride giving 0.2 g white solid, m.p. 127°-30° C. Elemental Analysis. Calculated for C13H15NO3 : C,66.94; H,6.48; N,6.00. Found: C,66.64; H,6.29; N,5.75.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.O[CH2:10][C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH:5]=[N:6][CH:7]=1
Reactant: Oc1cncc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-chloropyridin-3-ol (1.46 g, 11.28 mmol), (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.27 g, 11.28 mmol), and triphenylphosphine (2.96 g, 11.28 mmol) in THF (50 mL) was added di-tert-butyl azodicarboxylate (DTAD) (2.60 g, 11.28 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and warmed to room temperature. After being stirred at room temperature for 2 days, the mixture was concentrated in vacuo to afford a dark brown viscous oil. The residual oil was crystallized from isopropyl ether (IPE)-hexane, and formed precipitate was removed by filtration. The filtrate was concentrated in vacuo to afford a dark brown oil. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:9 to 1:5) to afford crude 5.15 g (quant.) of the title compound as a colorless gel. The crude title compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH3:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([CH2:28][CH2:29][CH2:30][CH:31]2[NH2:34])=[CH:26][CH:25]=1>>[CH2:1]([C:3]1[C:4]([NH:34][CH:31]2[C:32]3[C:27](=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:33]=3)[CH2:28][CH2:29][CH2:30]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: COc1ccc2c(c1)C(N)CCC2
Product: CCc1cnc(CC)c(NC2CCCc3ccc(OC)cc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.67, 7.08, 6.92, 6.81, 5.42, 4.54, 3.75, 2.84-2.77, 2.68, 2.56, 2.10, 1.88, 1.36-1.27; (MS/CI) calcd for C19H25N3O+H 312.4, found 312.1.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:28])([F:27])[F:26])=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:10]2)[CH:7]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:38].[K+]>O>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:15]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([CH2:8][C:6]2[CH:7]=[C:2]([I:38])[CH:3]=[CH:4][C:5]=2[C:25]([F:28])([F:27])[F:26])[N:10]=1)=[O:24]
Reactant: Nc1ccc(C(F)(F)F)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(Nc1ccn(Cc2cc(I)ccc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of N-(1-{[5-amino-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-2,6-difluorobenzamide (for a preparation see Intermediate 41)(0.6 g, 1.51 mmol) in water (6 ml) in an ice-water bath (internal temperature at 5° C.) was added concentrated sulphuric acid specific gravity 1.84 (1 ml, 18.8 mmol). To the slight suspension was added a solution of sodium nitrite, super free flowing (0.125 g, 1.82 mmol, Aldrich) in water (3 ml) dropwise. The suspension was stirred in an ice-water bath for 20 min. To the mixture was added a solution of potassium iodide, extra pure briquettes (0.377 g, 2.27 mmol, Acros) in ice-cold approximately 1 M sulphuric acid (5.5 ml). The mixture was allowed to warm to ambient temperature and then heated to 80° C. for 30 min under nitrogen. The tarry suspension was partitioned between ethyl acetate (130 ml) and water (50 ml). The phases were separated and the organic phase washed with saturated aqueous sodium hydrogen carbonate (2×50 ml), dried (MgSO4), filtered and the solvent removed at reduced pressure to leave a dark red foam (0.77 g). The sample was loaded in dichloromethane and purified on silica 100 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (0.412 g); LCMS: (System 4) MH+=508 tRET=3.10 min.
Reaction SMILES: [I:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.Cl>B(Br)(Br)Br>[I:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[S:10][C:6]=2[CH:5]=[C:4]([OH:19])[CH:3]=1
Reactant: COc1ccc(-c2nc3c(I)cc(OC)cc3s2)cc1
Agent: BrB(Br)Br
Agent: Cl
Product: Oc1ccc(-c2nc3c(I)cc(O)cc3s2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Iodo-6-methoxy-2-(4-Methoxy-phenyl)-benzothiazole (175 mg, 0.44 mmol) [Compound of Example 1d] was suspended in boron tribromide (1M in methylene chloride, 3.5 mL) and stirred at room temp under nitrogen for 72.0 hr. Reaction was poured into aqueous hydrochloric acid (1M) and extracted with ethyl acetate. Ethyl acetate extracts were washed with: 1) hydrochloric acid (1.0M), 2) saturated brine and concentrated in vacuo. Washed solid was further purified by flash chromatography on silica affording the title compound (158 mg, 97%) as a yellow solid. MH+=370
Reaction SMILES: [CH3:1][CH2:2][NH:3][C:4]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:15]([OH:29])[CH2:14][C@@H:13]1[OH:30])=[O:5].Cl[C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39])=[O:33]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:32](=[O:33])([O:29][CH:15]1[CH2:14][CH:13]([OH:30])[C@H:12]([CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][C:4]([NH:3][CH2:2][CH3:1])=[O:5])[C@H:16]1/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39]
Reactant: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Reactant: O=C(Cl)OCCCCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)CCC/C=C\C[C@H]1C(O)CC(OC(=O)OCCCCCl)[C@@H]1/C=C/[C@@H](O)CCc1ccccc1
Reaction time: 72 h

Procedure:
To a solution of bimatoprost (Cayman Chemicals 16820, Lot 188757; 123 mg, 0.30 mmol) in DCM (3 mL) at 0° C. was added DMAP (39 mg, 0.31 mmol) followed by the slow addition of 4-chlorobutyl chloroformate (43 uL, 0.31 mmol). After 3 days at ambient temperature, the mixture was diluted with DCM and washed with water (1×) and brine (1×). The DCM layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude mixture of regioisomers and diacylated products was submitted to column chromatography (ethyl acetate-hexane 25-100%, followed by methanol-dichloromethane (5-15%) to provide as the major component isolated, 11-acylated chloride g-1 (25 mg, 15%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:24][C:25]1[C:26]([CH3:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[CH3:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[C:11]([NH:24][C:25]2[C:30]([CH3:31])=[CH:29][CH:28]=[C:27]([OH:32])[C:26]=2[CH3:33])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(C)c1N
Reactant: Cc1cc(C(=O)O)cc(-c2cccc(F)c2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2c(C)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution of 3-(3-fluorophenyl)-5-methyl-benzoic acid (300 mg, 1.30 mmol, 1.1 eq) (III(q)) in CH2Cl2 (10 mL) was added (COCl)2 (610 mg, 4.81 mmol, 3.3 eq) and DMF (5 drops). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to remove the solvent and excess reagent. The residue obtained was dissolved in THF (10 mL) and added dropwise to a mixture of 3-amino-2,4-dimethylphenol (intermediate X(c)) (163 mg, 1.18 mmol, 1.0 eq) and NaHCO3 (612 mg, 7.30 mmol, 5.0 eq) in THF (20 mL) at 0° C. After addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The resulting mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and evaporated in vacuo. The crude product obtained was purified by column chromatography (CH2Cl2: MeOH, 500:1 to 300:1) to give the title compound as a white solid (290 mg, 57%).
Reaction SMILES: [C:1]([NH:14][CH:15]([CH2:19][CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+].[Cl-].[Ca+2:26].[Cl-]>O>[Ca+2:26].[C:1]([NH:14][CH:15]([CH2:19][CH2:20][CH2:21][CH3:22])[C:16]([O-:18])=[O:17])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:1]([NH:14][CH:15]([CH2:19][CH2:20][CH2:21][CH3:22])[C:16]([O-:18])=[O:17])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)NC(CCCC)C(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCC(=O)NC(CCCC)C(=O)[O-]

Procedure:
In a procedure similar to those described in Production Examples 4 and 5, 20 g of N-lauroylaminohexanoic acid, 2.6 g of sodium hydroxide, 180 g of ion exchanged water and 71 g of 10% by weight aqueous solution of calcium chloride were used. Thus, 21.1 g of the target N-lauroylaminohexanoic acid calcium salt was obtained as white crystals (yield: 99.6%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17](=[O:33])[N:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH:19]=2)=[CH:11][CH:10]=1>ClCCl>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17](=[O:33])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:19]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2cn(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cn(C3CCNCC3)c(=O)[nH]2)cc1
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (0.600 mL) was added to a solution tert-butyl 4-[4-(4-methylphenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]piperidine-1-carboxylate (178.4 mg, 0.50 mmol) in dichloromethane (3 mL). After 16 h, the reaction was concentrated and purified by reverse phase HPLC (C-18 column, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title product. MS 258.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10]([N:40]1[CH2:41][CH2:42][CH:37]([CH3:36])[CH2:38][CH2:39]1)=[O:12])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(CCc1ccccc1Cl)C(=O)O
Reactant: CC1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
A mixture of 1.7 g (5.4 mmol) of 2-[(tert-butoxycarbonyl)amino]-4-(2-chlorophenyl)butanoic acid, 2.1 g (11 mmol) of EDC, 1.5 g (11 mmol) HOBt, and 1.9 mL (11 mmol) of iPrNEt in 25 mL of CH2Cl2 is stirred for 10 min, and 0.77 mL (6.5 mmol) of 4-methylpiperidine is added. After stirring overnight, the mixture is washed twice with 10% citric acid, and once each with water, saturated NaHCO3, water, and brine. The extract is concentrated to provide 1.8 g (85%) of tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=3)[O:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:9]=2)[N:4]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:3]=1.[CH2:41]([N:49]1[CH:53]=[C:52](B2OC(C)(C)C(C)(C)O2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:41]([N:49]1[CH:53]=[C:52]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=4)[O:14][CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)[CH:9]=3)[N:4]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH:3]=2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4cccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 75.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)piperidine-1-carboxylate (intermediate 13) (150 mg, 0.222 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 59) (100 mg, 0.334 mmol) using Pd(PPh3)2Cl2 (8 mg, 0.011 mmol) and sodium carbonate (59 mg, 0.557 mmol) in toluene/ethanol/water (4/1/1 ml) to afford 120 mg (75.0% yield) of the titled compound after column purification using 1% methanol in DCM as eluent. MS: m/z=718.4 (M+1).
Reaction SMILES: Cl[CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[C:3]#[N:4].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>O>[C:3]([CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)#[N:4]
Reactant: c1c[nH]cn1
Reactant: N#CC(Cl)Sc1ccc(Cl)cc1
Solvent: O
Product: N#CC(Sc1ccc(Cl)cc1)n1ccnc1
Temperature: 25 °C
Yield: 53.4 %

Procedure:
Into a 125 ml three-necked round bottom flask are placed 33 g (0.15 mole) of α-chloro-α-p-chlorophenylthioacetonitrile and 33 g (0.48 mole) of imidazole. The mixture is heated to 60° when an exothermic reaction sets in (110°). It is then cooled to room temperature, poured into water and extracted with ether. The combined ether extracts are evaporated to give 20 g of a brown solid which when triturated with ether gives 7 g of pure product, mp 120°-2°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(S(F)(F)[F:25])CC)C>ClCCl>[C:1]1([CH2:7][CH2:8][S:9][CH:11]([F:25])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(CCc1ccccc1)CCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FC(Cc1ccccc1)SCCc1ccccc1

Procedure:
According to the procedure of McCarthy et. al. (J. Amer. Chem. Soc. 1985, 107, 735), the resultant compound of Example 2 was treated with diethylaminosulfur trifluoride in dichloromethane to give the desired compound.