Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:6]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[N:7]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: Cc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1c(CSc2ncnc3[nH]cnc23)nc2cccc(Cl)c2c1=O
Yield: 52.6 %

Procedure:
Prepared according to Procedure C using Intermediate 2j (200 mg, 0.626 mmol), 6-mercaptopurine monohydrate (93 mg, 0.546 mmol), K2CO3 (95 mg, 0.689 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 125 mg of an off-white solid (46%), mp 213.9° C. 1H NMR (DMSO-d6) δ: 13.53 (br s, 1H); 8.49 (s, 1H); 8.44 (s, 1H); 7.78 (t, J=7.9 Hz, 1H); 7.63 (d, J=8.2 Hz, 1H); 7.59 (d, J=7.7 Hz, 1H); 7.49 (d, J=6.9 Hz, 1H); 7.24-7.41 (m, 3H); 4.32-4.45 (m, 2H); 2.14 (s, 3H). 13C NMR (DMSO-d6) ppm: 158.9, 157.2, 154.2, 151.5, 149.7, 149.6, 143.5, 136.1, 135.9, 135.1, 133.2, 131.3, 130.3, 130.0, 129.9, 129.1, 127.6, 127.1, 117.8, 32.4, 17.5. MS (ES): m/z 438.0 (M+). Anal. calcd. for C21H15ClN6OS: C, 58.00; H, 3.48; Cl, 8.15; N, 19.32; S, 7.37. Found: C, 58.05; H, 3.38; Cl, 8.89; N, 18.38; S, 7.00.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.CCO.[NH2:17][C:18]1[CH:52]=[CH:51][C:21]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[CH:29]=[C:30]([C:32]4[N:37]=[CH:36][C:35]([CH2:38][N:39]([CH2:47][CH2:48][O:49][CH3:50])[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:34][CH:33]=4)[S:31][C:24]=23)=[C:20]([F:53])[CH:19]=1>C1(C)C=CC=CC=1>[F:53][C:20]1[CH:19]=[C:18]([NH:17][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[S:13])[CH:52]=[CH:51][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]2[CH:29]=[C:30]([C:32]3[N:37]=[CH:36][C:35]([CH2:38][N:39]([CH2:47][CH2:48][O:49][CH3:50])[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[CH:34][CH:33]=3)[S:31][C:24]=12
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a suspension of isothiocyanate 2 (5.50 g, 28.2 mmol) in a mixture of toluene (20 mL)/EtOH (20 mL) in a 500 mL round-bottom flask was added aniline 13 (10 g, 19.06 mmol) in a mixture of toluene (50 mL)/EtOH (50 mL). After 30 min, additional amount of isothiocyanate 2 (1 g, 5.12 mmol) in a mixture toluene (5 mL)/EtOH (5 mL) was added to the reaction mixture which was stirred at r.t. for an additional 45 min. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated with MeOH (40 mL) to dryness. Finally MeOH (80 mL) was added to the dry residue to produce a precipitate that was stirred at room temperature for 14 h, collected by filtration, dried for 2 h under vacuum to afford 14 as beige solid (7 g, 51% yield). MS (m/z): 720.3 (M+1)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][C:23]=2[Cl:25])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: O=S(=O)(NCCCCCO)c1ccc(-c2ccc(Cl)cc2Cl)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 2,4-dichlorophenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 22.6, 29.0, 32.0, 42.7, 60.5, 126.5, 127.8, 129.5, 130.0, 132.3, 132.7, 133.7, 137.4, 140.3 and 141.3.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+:12]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:16]=1[C:17](Cl)=[O:18])([O-:14])=[O:13].O>CN(C)C=O>[N+:12]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:16]=1[C:17]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:18])([O-:14])=[O:13]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (4.63 grams; 0.025 mole) dissolved in dimethylformamide (50 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. 2-Nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride (9.5 grams; 0.025 mole) was added and the reaction mixture was stirred at room temperature overnight. After this time the mixture was poured into water and was thereafter extracted with toluene. The toluene extract was evaporated to dryness leaving a dark reddish solid. This solid was recrystallized from toluene to yield the desired product N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl]phthalimide as a white powder melting at 160° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:13][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[N:4]2[C:3]1=[O:14].O=[C:16]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17]([OH:19])=[O:18].[OH-].[Na+].C([BH3-])#N.[Na+]>O>[C:17]([CH:16]([NH:1][CH:2]1[CH2:13][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[N:4]2[C:3]1=[O:14])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:19])=[O:18]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: NC1CN2CCCC(C(=O)O)N2C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(CCc1ccccc1)NC1CN2CCCC(C(=O)O)N2C1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 32.4 %

Procedure:
0.51 g of 2-amino-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (racemate B) was dissolved in 4 ml of water. 1.37 g of 2-oxo-4-phenylbutyric acid were added and the mixture was adjusted to pH 6 using 2N aqueous sodium hydroxide solution. 0.33 g of sodium cyanoborohydride was then added and the mixture was left to stir at room temperature for 22 hours. The product was absorbed on to a strong acidic ion-exchange resin and eluted with water containing 2% pyridine to give 0.62 g of crude product. Crystallization from water gave 0.3 g (32%) of 2-(1-carboxy-3-phenylpropylamino)-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (2 racemates: racemates C and D) in the form of a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:3]1=[O:21].[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C@:38](S(C)(=O)=O)([CH2:44][CH2:45][CH2:46][CH3:47])C(OCC)=O)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:44][CH2:45][CH2:46][C@H:47]([NH:1][C@@H:2]2[CH2:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:3]2=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCCC[C@](C(=O)OCC)(C1CCN(C(=O)OCc2ccccc2)CC1)S(C)(=O)=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Product: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H]1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 90 °C
Yield: 47.4 %

Procedure:
A mixture of 0.32 g of tert-butyl (RS)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate and 0.2 g of ethyl (R)-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonylhexanoate is heated at 90° C. for 30 minutes. After cooled, the mixture is separated and purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to give 0.14 g of tert-butyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate as colorless oil from the first fraction.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[Cl:11])[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.O.[CH3:22][N:23]1CCN(C)C1=O>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[N:4]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:3]=[C:2]([C:22]#[N:23])[C:10]=12
Reactant: CN1CCN(C)C1=O
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cn(S(=O)(=O)c2ccccc2)c2nccc(Cl)c12
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
To the solution of 3-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine in 1,3-dimethyl-2-imidazolidinone was added Zn(CN)2 and tetrakis(triphenylphosphine)palladium(0) at ambient temperature. This was stirred at 140° C. for 1.5 hours. The reaction was cooled and was added water, extracted with EtOAc. The organic layer was washed with brine and was dried over MgSO4 and evaporated. Resultings were purified by silica gel column chromatography to afford 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile as white powder.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:20])=[O:19])=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1Br
Yield: 34 %

Procedure:
4-Nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-nitrobenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 146-149° C., yield 34%.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21]C(OC(C)(C)C)=O)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29].CCOCC>O1CCOCC1>[ClH:29].[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH2:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarboxylate (0.78 g, 2.0 mmol) in dioxane (10 mL) was added 4M HCl in dioxane (5 mL) at 0° C. The reaction mixture was stirred at rt for 1 h, then, Et2O (10 mL) was added. The solid precipitation was collected by filtration, washed with Et2O (2×), and dried under vacuum to provide (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide hydrochloride (0.65 g, 99%), which was used directly in the next step. ESI-MS (EI+, m/z): 291.19 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][N:15]([CH3:23])[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[NH2:22].C(N(CC)CC)C>>[CH3:14][N:15]([CH3:23])[C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][C:7]([C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)=[O:8]
Reactant: CN(C)C1CCCCC1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
The titled amide was prepared according to general procedure B using p-trifluoromethyl-benzoyl chloride (4.17 g.; 0.02 mole), N,N-dimethylcyclohexane-1,2-diamine (2.84 g.; 0.02 mole) and triethylamine (2.02 g., 0.02 mole). The crude solid was crystallized from ether to give 4.766 g. (77% yield) of colorless needles, m.p. 141°-142°, raised to 141.5°-142.5° on recrystallization. uv λmax 222 nm (ε11,450); sh 245 (5,550); sh 260 (3,400); sh 276 (1.750). ir NH 3310; =CH 3030; N-alkyl 2770, 2740; C=O 1635; C=C 1575, 1510; amide II 1550; CF3 /ether 1330, 1990, 1165, 1130, 1105, 1065, 1020; aromatic 860; nmr in CDCl3 at 100 MHz was in accord. Mass spectrum M+ 314.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:7][CH:8]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[CH:17]([O:16][CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH3:29])=[CH:21][CH:22]=2)=[O:28])[CH:4]=1)[C:11]([OH:13])=[O:12])([CH3:18])[CH3:19]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CCOC(=O)C(Cc1cccc(CO)c1)OC(C)C
Product: Cc1ccc(NC(=O)OCc2cccc(CC(OC(C)C)C(=O)O)c2)cc1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)phenyl]-2-isopropoxypropanoate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)[C:5]2[N:6]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>O>[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:2]2[CH:3]=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=3)[C:5]3[N:6]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=3)[N:7]=2)[CH2:26][CH2:25]1
Reactant: CCOc1ccc(Nc2cc(Cl)nn3c(C)c(C)nc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Product: CCOc1ccc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C)c(C)nc23)cc1
Reaction time: 96 h

Procedure:
In a 2 dram reaction vial was added crude 6-chloro-N-(4-ethoxyphenyl)-2,3-dimethylimidazo[1,2-b]pyridazin-8-amine (0.013 g, 0.04 mmol) from 1b and trans-1,4-diaminocyclohexane (1.0 g, 8.0 mmol). The mixture was allowed to melt at 160° C. for 4 days. The melt was then cooled, diluted with water and extracted with dichloromethane. The organic layer was concentrated and then diluted with MeOH and then purified by preparative HPLC. This gave 0.005 g of the titled compound as a TFA salt. 1H NMR (500 MHz, MeOD) δ ppm 7.24 (2H, d, J=8.25 Hz), 7.00 (2H, d, J=8.80 Hz), 6.17 (1H, s), 4.05 (2H, q, J=6.96 Hz), 3.62-3.83 (1H, m), 3.02-3.21 (1H, m), 2.47 (3H, s), 2.42 (3H, s), 2.18-2.29 (2H, m, J=11.55 Hz), 2.03-2.14 (2H, m, J=12.65 Hz), 1.45-1.62 (2H, m), 1.39 (3H, t, J=6.87 Hz), 1.26-1.36 (2H, m). LC/MS, m/e 395 (M+1). HPLC Rt, 2.49 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: C(O)C.[BH4-].[Na+].[F:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][N:23]([CH:25]([CH:31]=[O:32])[C:26](OCC)=[O:27])[CH:24]=2)[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:37])([C:33]([F:36])([F:35])[F:34])[C:9]=2[CH:8]=1>O1CCCC1>[F:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][N:23]([CH:25]([CH2:31][OH:32])[CH2:26][OH:27])[CH:24]=2)[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:37])([C:33]([F:36])([F:35])[F:34])[C:9]=2[CH:8]=1
Reactant: CCOC(=O)C(C=O)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCC(CO)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 17 h
Yield: 61.4 %

Procedure:
To a mixture of ethanol (80 ml) and sodium borohydride (16.2 g), a solution of an optically active form (13.2 g) of ethyl 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-oxo-propionate in tetrahydrofuran (80 ml) was added dropwise over 25 min. At this time, the temperature of the reaction mixture was controlled with an ice-bath not to exceed 30° C. The ice-bath was changed to a water-bath, and the mixture was stirred for 17 hr. Then, the water-bath was removed and the mixture was further stirred for 4 hr. The reaction mixture was ice-cooled, 2N hydrochloric acid was added and the mixture was stirred. To this mixture were added ethyl acetate and water, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl acetate, and the extract was combined with the organic layer obtained earlier. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1 to 15/1) to give the title compound (7.38 g, 84%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[N:25]=[C:24]([N:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[N:28]=[CH:27]2)[CH:23]=[CH:22][CH:21]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:29]3[N:28]=[CH:27][N:26]([C:24]4[CH:23]=[CH:22][CH:21]=[C:20]([CH3:19])[N:25]=4)[CH:30]=3)=[O:32])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1cccc(-n2cnc(C(=O)O)c2)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: Cc1cccc(-n2cnc(C(=O)N[C@@H](C)Cn3ccc(-c4ccc(C#N)c(Cl)c4)n3)c2)n1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (220 mg, 0.844 mmol) and 1-(6-methylpyridin-2-yl)-1H-imidazole-4-carboxylic acid (223 mg, 1.097 mmol). The product was triturated with acetonitrile. Yield 153 mg (40%). 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 1.45 (s, 3H), 2.59 (s, 1H), 4.28-4.45 (m, 2H), 4.55-4.64 (m, 1H), 6.62 (d, 1H), 7.16 (d, 1H), 7.19 (d, 1H), 7.52 (d, 1H), 7.67 (d, 1H), 7.75 (t, 1H), 7.80 (m, 1H), 7.89 (d, 1H), 8.12 (d, 1H), 8.21 (d, 1H).
Reaction SMILES: B(Br)(Br)Br.ClCCl.C[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=2)=[CH:12][CH:11]=1>O>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=2)=[CH:12][CH:11]=1
Reactant: CCCCCc1ccc(-c2ccc(OC)cc2)s1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCCCc1ccc(-c2ccc(O)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A solution of boron tribromide (3.2 cm3) and dichloromethane (30 cm3) was added dropwise to a solution of 2-(4-methoxyphenyl)-5-pentylthiophene (10.0 g) and dichloromethane (70 cm3) at 0° C. under an atmosphere of nitrogen. The reaction solution was stirred overnight at room temperature and water (100 cm3) added. The organic layer was separated off and the aqueous layer extracted with dichloromethane (2×100 cm3). The combined organic layers were washed with brine (2×100 cm3) and then dried (MgSO4), filtered and evaporated down. The residue was purified by column chromatography on silica gel using a 4:1 hexane/dichloromethane mixture as eluent and recrystallisation from hexane to yield 7.7 g of g 2-(4-hydroxyphenyl)-5-pentylthiophene, K 100-102° C., I.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[Si:14]([O:31][CH2:32][CH2:33][C@@H:34]([OH:55])[C@H:35]([C:46]1[CH:51]=[C:50]([F:52])[C:49]([F:53])=[C:48]([F:54])[CH:47]=1)[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCCl>[Si:14]([O:31][CH2:32][CH2:33][C@@H:34]([O:55][CH2:10][O:11][CH3:12])[C@H:35]([C:46]1[CH:51]=[C:50]([F:52])[C:49]([F:53])=[C:48]([F:54])[CH:47]=1)[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COCCl
Reactant: CC(C)(C)[Si](OCC[C@@H](O)[C@@H](C(=O)OCc1ccccc1)c1cc(F)c(F)c(F)c1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCO[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](C(=O)OCc1ccccc1)c1cc(F)c(F)c(F)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
IPEA (0.742 mL) and chloromethyl methyl ether (0.324 mL) were added to a solution of benzyl (2S,3R)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoate (840 mg) in 1,2-dichloroethane (20 mL) at 0° C. The reaction solution was stirred at 60° C. for 4 hours and then left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and a saturated ammonium chloride solution were added to the residue, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 875 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CS(C)=O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([NH:11][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCCCCc1ccc(N)cc1
Solvent: CS(C)=O
Product: CCCCCCc1ccc(Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Yield: 53.5 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser, and a nitrogen inlet was added 4-n-hexylaniline (49.1 grams, 0.283 moles), 1-fluoro-4-nitrobenzene (13.3 grams. 0.094 moles) and anhydrous methyl sulfoxide (80 ml). The contents of the flask were heated at 100° C. for 4 days; cooled to room temperature; partitioned between diethyl ether (300 ml) and water (100 ml). The ether extract was washed with water (4×100 ml) followed by brine (3×50 ml). The ether extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield a brown liquid. The brown liquid was recrystalized from hexane (500 ml) to yield 15.0 grams of product as a yellow solid. 1H NMR (CDCl3) δ 8.1(d, 2H), 7.2(d, 2H), 7.15(d, 2H),6.9(d, 2H), 6.3(bs, 1H), 2.6(t, 2H), 1.6(pent, 2H), 1.2-1.4(m, 6H), 0.9(t, 3H).