Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]12[CH2:11][O:10][CH2:9][CH:8]1[S:7][C:6]([NH2:12])=[N:5]2)[CH3:2].[CH2:13]([O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19])[CH3:14]>>[CH2:13]([O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:12]=[C:6]1[N:5]([CH2:2][CH2:1][O:3][CH3:4])[C:4]2([O:3][CH2:1][CH3:2])[CH2:11][O:10][CH2:9][CH:8]2[S:7]1)=[O:19])[CH3:14]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: CCOC12COCC1SC(N)=N2
Product: CCOc1ccccc1C(=O)N=C1SC2COCC2(OCC)N1CCOC

Procedure:
The product from Example 125B and 2-ethoxybenzoyl chloride were processed as described for example 118A to afford the title compound. MS (ESI+) m/z 395 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1.C(N(CC)CC)C.[C:16](=O)([O-:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>CN(C)C1C=CN=CC=1.ClCCl>[OH:8][CH2:7][CH2:6][C:4]1[CH:5]=[N:1][N:2]([C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[CH:3]=1
Reactant: CC(C)(C)OC(=O)[O-]
Reactant: OCCc1cn[nH]c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1cc(CCO)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.10 g (9.81 mmol) 2-(1H-pyrazol-4-yl)-ethanol, 0.20 g (1.64 mmol) 4-dimethylaminopyridine and 1.50 ml (10.3 mmol) triethylamine were placed in 30 ml dichloromethane, the reaction mixture was cooled to 0° C. and 2.20 g (9.88 mmol) tert. butyl carbonate was slowly added. The mixture was stirred for 2 h at ambient temperature and then overnight at ambient temperature. It was diluted with 50 ml dichloromethane and washed with 10% citric acid solution and 15% potassium carbonate solution, the organic phase was dried, filtered and the solvent was eliminated from the filtrate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]([NH2:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]([C:33](O)=[O:34])[CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:22])[CH:9]([NH:21][C:33]([CH:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24](=[O:23])[CH2:25]2)=[O:34])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1CC(C(=O)O)c2ccccc21
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C1CC(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine (150 mg, 0.42 mmol) in acetonitrile (10 ml) were added 3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid (73 mg, 0.42 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.62 mmol) and 1-hydroxy-1H-benzotriazole (63.6 mg, 0.42 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from ethyl acetate-hexane to give a highly polar isomer (61 mg, 31%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)([N:13]1C=CN=C1)=O>C(Cl)Cl>[CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:13])=[O:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ncccc1C(=O)O
Solvent: ClCCl
Product: Cc1ncccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To a stirred mixture of 2-methylnicotinic acid (15.0 g, 0.111 mol) and 1,1'-carbonyldiimidazole (36.0 g, 0.222 mol) was added 300 mL of methylene chloride dropwise. The reaction mixture was stirred at room temperature overnight. Ammonia gas was distilled into the reaction mixture for 30 minutes using a dry ice condenser and the mixture was stirred at room temperature for an additional hour. Solvent was removed under vacuum and the residue was dissolved with 500 mL of acetonitrile. The solution was concentrated to half volume at low temperature and the product precipitated out as white solid. The crude mixture was recrystallized from ethanol/ether to give 11.5 g of 2-methylnicotinamide as a colorless crystal (76%): mp 160°-163° C. Anal. Calc'd. For C7H8N2O: C, 61.75, H, 5.92, N, 20.57. Found: C, 61.44, H, 6.14, N, 20.66.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:38])=[C:4]([C:24]([NH:26][CH2:27][CH:28]([O:34]C(=O)C)[CH2:29][O:30]C(=O)C)=[O:25])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17]C(=O)C)[CH2:12][O:13]C(=O)C)=[O:8].[C:39](Cl)(=[O:62])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]#[C:49][C:50]#[C:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61].C(OCC)(=O)C>ClCCl>[OH:17][CH:11]([CH2:12][OH:13])[CH2:10][NH:9][C:7](=[O:8])[C:6]1[C:21]([I:22])=[C:2]([NH:1][C:39](=[O:62])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]#[C:49][C:50]#[C:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[C:3]([I:38])=[C:4]([C:24]([NH:26][CH2:27][CH:28]([OH:34])[CH2:29][OH:30])=[O:25])[C:5]=1[I:23]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Amino,N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide (2.19 g, 2.5 mmol) and 10,12-tricosadiynoyl chloride (1.82 g, 5 mmol) were dissolved in 20 ml dichloromethane. The solution was stirred for 3 days at ambient temperature under a nitrogen atmosphere. TLC (ethyl acetate) indicated that the reaction was complete. The reaction mixture was evaporated and dissolved in a mixture of methanol (30 ml) and 1M sodium hydroxide solution (15 ml). After 1 hour TLC (methanol/chloroform) indicated that the reaction was complete. The solution was neutralized with concentrated hydrochloric acid. The residue was dissolved in chloroform and filtered. The solvent was removed and the reaction mixture was purified through silica gel with methanol/chloroform (1:3) to give the title compound. 1H NMR (300 MHz, DMSO): δ0.8 (CH3, t), 1.2-1.7 (17×CH2, m), 2.2-2.3 (2×CH2, t), 3.1-3.2 (2×CH2NH, m), 3.3-3.5 (2×CH2OH, m), 3.6-3.8 (2×CHOH), 4.4-4.7 (4×OH, m), 8.4-8.5 (2×CONH, m), 9.8 (2×ArNHCO, s).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[C:29]([Si:33]([O:36][C:37]1[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][C:38]=1[F:44])([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.O.CC(O)=O>[Si:33]([O:36][C:37]1[C:38]([F:44])=[C:39]([B:16]([OH:21])[OH:17])[CH:40]=[CH:41][C:42]=1[CH3:43])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:35])[CH3:34]
Reactant: Cc1cccc(F)c1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(B(O)O)c(F)c1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL flask vial were added a stir-bar, 2.1 mL dry THF, and 2,2,6,6-tetramethylpiperidine (0.22 mL, 1.0 mmol). The flask was cooled to −78° Celsius and then treated with n-BuLi (0.48 mL, 1.9 mmol, 2.5 M in hexanes) over 2 minutes. The resultant mixture was stirred for 5 min and then warmed to 0° Celsius. After 30 min, the mixture was re-cooled to −78° Celsius and treated with B(O-iPr)3 (0.26 mL, 1.1 mmol) over 4 min. After 15 min, a solution consisting of tert-butyl(2-fluoro-6-methylphenoxy)dimethylsilane (247 mg, 1.03 mmol) in dry THF (2.1 mL) was added over the course of 6 min and stirring continued for 1 hour at −78° Celsius. The mixture was then warmed to rt, treated with HOAc (0.5 mL), and then poured into water (100 mL) and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (3×100 mL), the combined extracts dried over Na2SO4, filtered, and concentrated to dryness to give the title compound, which was used directly in the next synthetic step.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:26][C:27]([C:29]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:26][C:27]([C:29]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)(=[O:19])=[O:18])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)#[N:1]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)cc2)C(N)=O)CCOCC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4′-(morpholinosulfonyl)biphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 27, step (i), 0.24 g) in dichloromethane (10 mL) was treated with Burgess' reagent (0.185 g) and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica eluting with ethyl acetate/isohexane (1:1) to afford the sub-titled compound (210 mg).
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][NH:8]1.ClC1C=C(Cl)C=C(Cl)C=1[O:47][S:48](=O)(=[O:50])[NH2:49].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][N:8]1[S:48]([NH2:49])(=[O:50])=[O:47]
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Reactant: NS(=O)(=O)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1cc(F)c(F)cc1F
Yield: 43.8 %

Procedure:
A solution of 567 mg (1.09 mmol) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine, 302 mg (1.09 mmol) sulfamic acid 2,4,6-trichloro-phenyl ester [Hedayatullah, M. & Hugueny, J. Phosphorus, Sulfur Silicon Relat. Elem. (1991), 61(1–2), 19–25.] and 0.15 ml triethylamine in 2 ml CH2Cl2 was heated for 1 h at reflux, evaporated and purified by flash column chromatography on silica gel with hexane/EtOAc (9:1 to 1:1) to give 286 mg (44%) (2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-sulfonic acid amide. [Hedayatullah, M. & Hugueny, J. Phosphorus Sulfur (1985), 25(1), 33-8.] MS: 621 (M+Na+).
Reaction SMILES: C(=[N:14][C:15]1[C:28]2[O:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[C:29]3[CH2:35][CH:34]4[N:36](C(=O)C(F)(F)F)[CH:31]([CH2:32][CH2:33]4)[CH2:30]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO.[OH-].[Na+]>CO.O.C(Cl)Cl>[CH:31]12[NH:36][CH:34]([CH2:33][CH2:32]1)[CH2:35][C:29](=[C:20]1[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:14])[C:28]=3[O:27][C:26]3[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:30]2
Reactant: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3c(N=C(c4ccccc4)c4ccccc4)cccc31)C2)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Nc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 1-{3-[4-(benzhydrylidene-amino)-xanthen-9-ylidene]-8-aza-bicyclo[3.2.1]oct-8-yl}-2,2,2-trifluoroethanone in methanol (0.1 to 1 M solution) may be treated with sodium acetate (2 to 4 equiv) and hydroxylamine hydrochloride (1 to 3 equiv) and stirred at rt for 1 to 4 days. Sodium hydroxide may be added to make the solution basic, and the solution may be stirred at rt for 1 to 5 hr. Methylene chloride and water may be added, and the organic layer may be separated. After drying over a suitable drying agent such as potassium carbonate, filtration, and evaporation, the residue may be purified via reverse phase column chromatography to yield Compound 2c.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21](F)=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][Br:12])=[O:4].ClC1C=CC=CC=1C=O>>[Br:12][CH2:11][C:10]1[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7][C@@H:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Agent: O=Cc1ccccc1Cl
Product: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccccc1Cl

Procedure:
Compound C-2 was prepared in analogy to compound C by using 2-chlorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([SH:11])[C:4]2=[CH:3][CH:2]=1.[H-].[Na+].[O:14]1[CH2:16][CH:15]1[CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>CN(C)C=O>[C:10]1([S:11][CH2:16][CH:15]([OH:14])[CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: c1cncc(CCC2CO2)c1
Reactant: Sc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CCc1cccnc1)CSc1cccc2ccccc12
Yield: 34.5 %

Procedure:
Prepared according to the method described in Example 1 from 1-thionaphthol (0.150 g), sodium hydride (0.044 g) and (±)-3-(2-oxiranylethyl)pyridine (0.150 g) in dimethylformamide (3 ml) at room temperature to give the title compound as an oil (0.100 g).
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[N:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:4]1.[CH2:15]([CH:18]([C:21]#[N:22])[C:19]#[N:20])[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:15]([C:18]([CH2:2][N:3]1[CH:7]=[N:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:4]1)([C:21]#[N:22])[C:19]#[N:20])[CH:16]=[CH2:17]
Reactant: FC(F)(F)C(F)(F)c1ncn(CCl)n1
Reactant: C=CCC(C#N)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(C#N)(C#N)Cn1cnc(C(F)(F)C(F)(F)F)n1

Procedure:
1-(chloromethyl)-3-(pentafluoroethyl)-1H-1,2,4-triazole and 1.02 g of allyl malononitrile were dissolved in 28 ml of N,N-dimethylformamide. 2.76 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and then subjected to preparative high performance liquid chromatography to obtain 0.54 g of allyl {[3-(pentafluoroethyl)-1H-1,2,4-triazole 1-yl]methyl}malononitrile (referred as the compound of the present invention (35), hereinafter) shown by below formula.
Reaction SMILES: C([NH:8][C:9]1[C:17]2[O:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[C:13]=2[C:12]([CH3:27])=[C:11]([CH3:28])[C:10]=1[CH3:29])C1C=CC=CC=1>CCCCCC.C(OCC)(=O)C>[CH:24]([C:21]1[CH:20]=[CH:19][C:18]([CH:14]2[C:13]3[C:12]([CH3:27])=[C:11]([CH3:28])[C:10]([CH3:29])=[C:9]([NH2:8])[C:17]=3[O:16][CH2:15]2)=[CH:23][CH:22]=1)([CH3:26])[CH3:25]
Reactant: Cc1c(C)c(NCc2ccccc2)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c(N)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Yield: 80 %

Procedure:
Using N-benzyl-3-(4-isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-amine synthesized in Reference Example 287, the title compound was synthesized in the same manner as in Reference Example 30. Yield 80%. Melting point: 122-123° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[C:9]([C:27]([O:29][CH3:30])=[O:28])([CH2:10][N:11]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)=[O:15])[N:12]=3)[CH2:8][CH2:7][C:6]=2[CH:31]=1.C(N(CC)CC)C.Cl[S:40][N:41]([CH3:51])[C:42](=[O:50])[O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[C:9]([C:27]([O:29][CH3:30])=[O:28])([CH2:10][N:11]([C:14]([N:16]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=4)[S:40][N:41]([CH3:51])[C:42]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:50])=[O:15])[N:12]=3)[CH2:8][CH2:7][C:6]=2[CH:31]=1
Reactant: CCCCCCOC(=O)N(C)SCl
Reactant: COC(=O)C12CCc3cc(Cl)ccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCOC(=O)N(C)SN(C(=O)N1CC2(C(=O)OC)CCc3cc(Cl)ccc3C2=N1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of the title compound of Step E above (2.2 g, 0.005 mol) in 25 ml methylene chloride cooled to 0° C. was added triethylamine (1.0 g) and hexyl (chlorosulfenyl)(methyl)carbamate, (prepared in a manner similar to Example 1, Step D), (2.5 g 75% pure) dropwise at 0° C. The mixture was stirred at room temperature for additional one hour. The reaction mixture was concentrated under high vacuum and subjected to silica gel column chromatography using hexane-ether (1:1) as an eluent. The title compound (2.5 g) was obtained, melting point 128°-129° C. in high purity.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:12][CH:13]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:22]=[C:23]3[C:28]=2[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH3:36])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][O:11][C:7]3[C:8]([CH3:10])=[CH:9][C:4]([C:3]([OH:37])=[O:2])=[CH:5][C:6]=3[CH3:36])=[C:28]3[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:22]2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1cc(C)c(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(C)c1OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3,5-dimethyl-benzoic acid methyl ester (example 39) was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as off-white solid. MS: m/e=507.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I>O>[Br:1][C:2]1[N:3]=[C:4]([I:15])[C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Br)nc1I

Procedure:
A 4.125 g sample of 2-bromo-5-hydroxypyridine (from step 28c) and 5.28 g of Na2CO3 were dissolved in 75 mL of water. To this solution was added 6.02 g of I2, and the mixture was stirred until the iodine color disappeared. The reaction mixture was then adjusted to pH 5, and extracted with EtOAc. The extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on silica gel, eluting with 97:3 CHCl3 :MeOH to give 4.3 g of the title compound: 1H NMR (CDCl3, 300 MHz) δ 7.08-7.11 (d, 1H, J=8.5 Hz), 7.29-7.32 (d, 1H, J=8.5 Hz); MS m/z: 300 (M+H)+, 317 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(OCC)(=O)C.O1CCCC1>CN(C)C=O.O>[C:17]1([O:16][C:14](=[O:15])[NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1nccs1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
After dissolving 2-aminothiazole (5.01 g, 50.0 mmol) and pyridine (7.91 g, 100 mmol) in dimethylformamide (50 ml), phenyl chloroformate (8.22 g, 52.5 mmol) was added while cooling on ice, and the mixture was stirred at room temperature for 1 hour. The reaction solution was distributed between an ethyl acetate-tetrahydrofuran mixed solvent and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. After adding ethyl acetate and then hexane to the obtained crude product, the precipitated crystals were filtered out and blow-dried to obtain the title compound (10.6 g, 48.1 mmol, 96%) as colorless crystals.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([C:31]5[C:32]6[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=6)[N:28]=[CH:29][CH:30]=5)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound, white solid (80 mg, 66%), MS (ISP) m/z=486.6 [(M+H)+], mp 222° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and quinoline-4-carboxylic acid.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C:12](O)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C:12]([Cl:23])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COS(=O)(=O)c1ccc(-c2ccccc2)cc1
Product: O=C(Cl)COS(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
A mixture of acid 17 (200 mg, 0.685 mmol) and thionyl chloride (1 ml) was heated at reflux for 1.5 h. The excess thionyl chloride was removed in vacuo and the residue dried under high vacuum at 50° C. for 1.5 h. The product acid chloride 18 was used without further purification.