Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>CN(C)C=O>[CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:15]([N:14]([CH3:18])[CH3:13])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(O)c2ccccc2n1
Solvent: CN(C)C=O
Product: Cc1cc(OC(=O)N(C)C)c2ccccc2n1

Procedure:
24 g (0,15 mole) of 2-methyl-4-hydroxyquinoline were dissolved in 200 ml of dimethylformamide (anhydrous and free from amine), 23 g (0,22 mole) of triethylmine were added and, subsequently, 24 g (0,22 mole) of dimethylcarbamic acid chloride added dropwise.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([C:30](C)([CH3:33])[CH2:31]O)[CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(N1CCC(S)CC1)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:23][CH:24]5[CH2:25][CH2:26][N:27]([CH:30]([CH3:33])[CH3:31])[CH2:28][CH2:29]5)[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)CO)CC3)ccc1OCC2
Agent: [Pd]
Agent: CC(C)N1CCC(S)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Temperature: 120 °C
Yield: 90.2 %

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 1 (400 mg, 1.07 mmol), 1-isopropylpiperidine-4-thiol (340 mg, 2.14 mmol), Pd2(dba)3 (50 mg, 5 mol %), XantPhos (61 mg, 10 mol %) and DIPEA (0.745 mL, 4.28 mmol) in dioxane (10 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The reaction mixture was diluted with DCM (200 mL) and purified by column chromatography (Si-PCC, 0-13% MeOH in DCM) then (C18, 20-45% MeOH in 0.003M HCl/H2O). The product containing fractions were combined and concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 176 as a colorless solid (437 mg, 90%). LCMS: RT 3.01 min [M+H]+ 453.3. 1H NMR (MeOD, 400 MHz): δ 8.54 (1H, d, J=2.36 Hz), 7.93 (1H, s), 7.77 (1H, s), 7.36 (1H, dd, J=8.49, 2.37 Hz), 7.02 (1H, d, J=8.49 Hz), 5.96-5.86 (1H, m), 4.55-4.46 (4H, m), 3.11-3.05 (1H, m), 2.94-2.84 (2H, m), 2.75-2.63 (1H, m), 2.28 (2H, t, J=11.32 Hz), 2.05-1.95 (2H, m), 1.69-1.53 (8H, m), 1.04 (6H, d, J=6.57 Hz)
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:7]=2)[CH2:2]1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:22][CH:21]=1.N12CCN(CC1)CC2>CN(C)C=O.C(OCC)(=O)C>[Si:30]([O:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:7]=2)=[CH:21][CH:22]=1)([C:43]([CH3:45])([CH3:46])[CH3:44])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)[Si](OCCCc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(OCC2CO2)cc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(OCC(O)COc2ccc(CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Temperature: 70 °C
Yield: 58.7 %

Procedure:
A mixture of 1,2-epoxy-3-[4-(tert-butoxycarbonyl)phenoxy]propane (5.11 g, 20.4 mmol) [S. P. Connors, et al., J. Med. Chem., 1991, 34, 1570] and 3-(4-hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy)propane (7.97 g, 20.4 mmol) in N,N-dimethylformamide (50 ml) was treated with 1,4-diazabicyclo[2,2,2]octane (0.45 g) and the resulting mixture was heated at 70° C. for 48 hours. The cooled mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 95:5) gave 7.67 g (58%) of the title material as oil.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17]C)(=[O:5])[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.C(C1C=NC2C(C=1Cl)=CC=CC=2O)(=O)CCC.[F:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[C:43]([CH3:48])[CH:42]=1>ClCCl.O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:45][C:44]1[CH:46]=[CH:47][C:41]([F:40])=[CH:42][C:43]=1[CH3:48])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1cc(F)ccc1N
Agent: BrB(Br)Br
Agent: CCCC(=O)c1cnc2c(O)cccc2c1Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of 3-butyryl-4-chloro-8-methoxyquinoline (131.9 g, 0.5 mol) in dichloromethane (1 liter) was cooled to -78°, then boron tribromide (142 ml, 1.5 mol) added slowly over 10 minutes. The mixture was warmed slowly to 0°, stirred 2 hours, then allowed to warm to room temperature overnight. After recooling in ice the reaction was quenched cautiously with water, then the resulting solid filtered off and dried. This was heavily contaminated with boron-containing impurities, but was used without purification. Crude 3-butyryl-4-chloro-8-hydroxyquinoline (64 g) and 4-fluoro-2-methylaniline (16.7 ml, 0.15 mol) were dissolved in dioxan (300 ml), heated on a steam bath for 2 hours, then left to stand overnight. The dioxan was evaporated, dichloromethane and aqueous sodium bicarbonate added, the mixture stirred until all the solid had dissolved, then the organic layer dried and evaporated. Recrystallisation from methanol gave 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxy-quinoline (37 g), m.p. 121°-122°.
Reaction SMILES: [Cl:1][C:2]1[C:17]([N:18](S(CCC)(=O)=O)[S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:16][CH:15]=[C:14]([F:31])[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Cl.C(=O)(O)[O-].[Na+]>C1COCC1.[Li+].[OH-]>[Cl:1][C:2]1[C:17]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:20])=[O:21])=[CH:16][CH:15]=[C:14]([F:31])[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5]
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)OCc2ccccc2)c1Cl)S(=O)(=O)CCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)OCc2ccccc2)c1Cl
Temperature: 25 °C
Yield: 53.8 %

Procedure:
Benzyl 2-chloro-6-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (413.2 mg, 0.840 mmol) was dissolved in THF (8.4 mL) and 2.0M aqueous LiOH (1.26 mL). The mixture was refluxed for 16 hours and then allowed to cool to ambient temperature. The mixture was acidified to a pH of 0 with 1.0M HCl (5.0 mL) and then adjusted to a pH of 4 using saturated sodium bicarbonate. The mixture was extracted with EtOAc (2×). The extracts were washed with water (2×) and brine (1×), dried over sodium sulfate and concentrated to afford benzyl 2-chloro-6-fluoro-3-(propylsulfonamido)benzoate (174.5 mg, 0.4523 mmol, 53.9% yield). MS (APCI-neg) m/z=384.1 (M-H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:20]([O:22]C)=[O:21])[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Na+].O.Cl>CO>[C:20]([C:11]1[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:17])[CH3:18])[N:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)[CH:10]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1cc(-c2ccc(C)c(F)c2)nn(CC(C)C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)c(=O)n(CC(C)C)n2)cc1F
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
To a suspension of 6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one (5.27 g, 16.6 mmol) in methanol (50 mL) was added a 2 mol/L aqueous sodium hydroxide (50 mL), and the mixture was stirred at 60° C. for 15 minutes. The temperature of the reaction mixture was allowed to drop back to room temperature, and then, water was added. After the system was acidified with concentrated hydrochloric acid, the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-hexane to yield the title compound as colorless fine-needles (4.73 g, 93.8%).
Reaction SMILES: CC(C(C1C=CC=CC=1)=O)=CC1C=CC=CC=1.O.NN.[C:21]1([C:27]2[NH:28][NH:29][CH:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:31]=2[O:32][CH3:33])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CC=CN1>[Pd]>[C:21]1([C:27]2[C:31]([O:32][CH3:33])=[C:30]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC1=C(c2ccccc2)NNC1c1ccccc1
Agent: [Pd]
Agent: C1=CNNC1
Agent: CC(=Cc1ccccc1)C(=O)c1ccccc1
Solvent: O
Product: COc1c(-c2ccccc2)n[nH]c1-c1ccccc1

Procedure:
Following the procedure of Example 1 but substituting α-methoxychalcone for α-methylchalcone, and reacting the same with hydrazine hydrate, there is prepared 3,5-diphenyl-4-methoxypyrazoline. The so-formed pyrazoline is then reacted with Pd/C at reflux to obtain 3,5-diphenyl-4-methoxypyrazole in good yield.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:9])([CH3:8])[N+:5](=[O:6])[C:4]([CH3:11])([CH3:10])[N:3]=1.NN.O.NN>CO>[OH:6][N:5]1[C:7]([CH3:9])([CH3:8])[C:2]([CH3:1])=[N:3][C:4]1([CH3:11])[CH3:10]
Reactant: CC1=NC(C)(C)[N+](=O)C1(C)C
Agent: NN
Solvent: CO
Solvent: O
Product: CC1=NC(C)(C)N(O)C1(C)C
Reaction time: 12 h

Procedure:
1.5 g (0.01 mole) of 2,2,4,5,5-pentamethyl-3-imidazoline-1-oxyl prepared as described in either of Examples 4 and 5 was solved in 10 ml methanol and treated with 1.5 ml (0.03 mole) of hydrazine or hydrazine-hydrate at ambient temperature. This solution was stored for 12 hours and over this period the methanol evaporated and the color of the solution disappeared. The partly crystallized residue was stirred with acetone and the colorless crystals were filtered and rinsed with acetone. 1.32 g of the isolated crystals with a yield of 88% were crystallized from ethyl acetate producing 1-hydroxy-2,2,4,5,5-pentamethyl-3-imidazoline having a melting point of 127°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11]C(C)([O-])C.[K+].CI>O1CCCC1.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Clc1ccc2cc[nH]c2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cn1ccc2ccc(Cl)cc21
Reaction time: 1 h
Yield: 67 %

Procedure:
A mixture of 6-chloroindole (22.0 g, 0.145 mole) and potassium t-butoxide (KOt-Bu) (20.0 g 0.179 mole) in tetrahydrofuran at room temperature is treated dropwise with methyl iodide (11.2 mL, 0.179 mole), allowed to stir at ambient temperatures for about 1 hour and diluted with a mixture of pet ether and water. The phases are separated. The organic phase is washed with 1 N HCL and water, dried over Na2SO4 and concentrated to a brown oil. After chromatography (silica gel/4:1 hexanes:ethyl acetate), the oil is distilled to afford the title product as a colorless oil, 16.25 g (67% yield), bp 110°-115° C./4 mm Hg, identified by IR, 1HNMR, 13CNMR, mass spectral and microanalyses.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH3:13].[CH2:14](I)[CH2:15][CH3:16].[Cl-].[NH4+]>CN(C)C=O>[Br:3][C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[C:7]([CH3:13])[N:8]([CH2:14][CH2:15][CH3:16])[N:9]=2)[CH:5]=1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: CCCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCn1nc2ccc(Br)cc2c1C
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (85 mg) in N,N-dimethylformamide (10 ml) was added a solution of 5-bromo-3-methyl-1H-indazole (500 mg) in N,N-dimethylformamide (1 ml) at 0° C., and the mixture was stirred at the same temperature for 30 min. To the obtained reaction mixture was added propyl iodide (0.35 ml), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (100 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][C:17](O)=[O:18])(=[O:13])=[O:12].[CH3:26][O:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]2[CH:38]([NH2:39])[CH2:37][S:36](=[O:41])(=[O:40])[N:35]([CH3:42])[C:34]=2[CH:43]=1)=[O:29]>>[CH3:26][O:27][C:28]([C:30]1[CH:31]=[CH:32][C:33]2[CH:38]([NH:39][C:17](=[O:18])[CH2:16][CH:15]([NH:14][S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:13])=[O:12])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:37][S:36](=[O:41])(=[O:40])[N:35]([CH3:42])[C:34]=2[CH:43]=1)=[O:29]
Reactant: COC(=O)c1ccc2c(c1)N(C)S(=O)(=O)CC2N
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Product: COC(=O)c1ccc2c(c1)N(C)S(=O)(=O)CC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
The title compound was prepared from 3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionic acid Example 1, Step H and 4-amino-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2λ6-benzo[c][1,2]thiazine-7-carboxylic acid methyl ester (Step B) similar to that described in Example 1, Step F. MS (+APCI, m/z): 608 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][C@H:12]([C:14]([NH:16][CH:17]1[C:23](=[O:24])[N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]2[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=2[N:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:18]1=[O:41])=[O:15])[CH3:13]>>[CH:1]1([CH2:6][C:7]([NH:11][C@H:12]([C:14]([NH:16][CH:17]2[C:18](=[O:41])[N:19]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:20]3[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=3[N:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:23]2=[O:24])=[O:15])[CH3:13])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCCC1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O
Agent: Cl
Product: C[C@H](NC(=O)CC1CCCC1)C(=O)NC1C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O

Procedure:
Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-W), the title compound was prepared as an amorphous white solid. Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1). Rf=0.44 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([CH3:30])([CH2:24]OS(C)(=O)=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([CH3:30])([CH2:24][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC1(COS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1OCC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
After dissolving 541 mg of 2-methylphenol in 10 ml of N,N-dimethylformamide, 171 mg of sodium hydride (70% suspension in oil), 1.00 g of 1-(tert-butoxycarbonyl)-4-methyl-4-(methanesulfonyloxymethyl)piperidine and tetra n-butylammonium iodide (catalytic amount) were added and the mixture was stirred at 120° C. overnight. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (816 mg, 78% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(OCC)(=O)C>[CH2:13]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc2ccccc2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Oc1ccc2ccccc2c1OCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
1,2-Dihydroxynaphthalene (70 mg) was dissolved in acetone (1 ml), the solution was added with benzyl bromide (74.7 mg) and potassium carbonate (72.5 mg), and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was added with distilled water and ethyl acetate, the layers were separated, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:acetone:triethylamine=50:10:0.2) to obtain the title compound (20.7 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](O)=[O:8].S1C=CC=C1[Cl:18]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([Cl:18])=[O:8]
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Reactant: Clc1cccs1
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1cccc(Br)c1
Yield: 99 %

Procedure:
A mixture of trans 3-bromocinnamic acid (m.p. 177°-179° C; 11.4 g), thienyl chloride (11.9 g) and dry benzene (150 ml) was heated at reflux for 2 hours. Solvent and excess thienyl chloride were removed by distillation under reduced pressure leaving trans 3-bromocinnamoyl chloride (12.2 g), b.p. 100°-100.5°C/0.2 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[K].CC(C)([O-])C.[CH2:33](Br)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CS(C)=O.O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCBr
Reactant: CCCCCCc1ccc(-c2cnc(-c3ccc(O)c(F)c3)cn2)cc1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCOc1ccc(-c2cnc(-c3ccc(CCCCCC)cc3)cn2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
0.35 g of the crude 2-(3-fluoro-4-hydroxyphenyl)-5(4-n-hexylphenyl)pyrazine was dissolved in 3 ml of dimethyl sulfoxide and 3 ml of tetrahydrofuran. To the resulting solution, was added 0.12 g of potassium-tertbutoxide. The obtained mixture was stirred at room temperature for 30 minutes and then 0.22 g of n-nonyl bromide was added thereto. The mixture was stirred at room temperature for additional five hours. Then the reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and with a 30% aqueous solution of sodium hydroxide and the repeatedly washed with water until the washing liquor showed a pH value of approximately 7. Then the ethyl acetate phase was dehydrated over sodium sulfate and the solvent was distilled off. Thus 0.48 g of a crude reaction product was obtained. The crude reaction product was purified by silica gel column chromatography and recrystallized from acetone. Thus 0.41 g of the title compound was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]([CH:17]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]([OH:25])=O)[CH2:18]3)=[O:16])[CH:12]=2)[NH:7][N:6]=1)=[O:4].CNC(C1C2C(=CC=C(N)C=2)NN=1)=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[N:62]1([C:68]2[S:69][C:70]([C:73]3[N:78]=[CH:77][CH:76]=[CH:75][N:74]=3)=[CH:71][N:72]=2)[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]([CH:17]3[CH2:21][CH2:20][N:19]([CH2:22][C:23](=[O:25])[N:65]4[CH2:66][CH2:67][N:62]([C:68]5[S:69][C:70]([C:73]6[N:78]=[CH:77][CH:76]=[CH:75][N:74]=6)=[CH:71][N:72]=5)[CH2:63][CH2:64]4)[CH2:18]3)=[O:16])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: c1cnc(-c2cnc(N3CCNCC3)s2)nc1
Reactant: CNC(=O)c1n[nH]c2ccc(NC(=O)C3CCN(CC(=O)O)C3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CNC(=O)c1n[nH]c2ccc(N)cc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1n[nH]c2ccc(NC(=O)C3CCN(CC(=O)N4CCN(c5ncc(-c6ncccn6)s5)CC4)C3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of [3-(3-methylcarbamoyl-1H-indazol-5-ylcarbamoyl)-pyrrolidin-1-yl]-acetic acid (15 mg, 0.043 mmol, prepared by a procedure similar to that of Example 98 using the indazole of Example 85 instead of indazole 65) and HOBt (7 mg, 0.052 mmol) in DMF (0.5 mL) at 0° C., EDCl (10 mg, 0.052 mmol) was added and the resulted reaction mixture was stirred at this temperature for 0.5 hour. To this solution was added 2-(2-piperazin-1-yl-thiazol-5-yl)-pyrimidine (18 mg, 0.052 mmol) made from previous step, followed by DIEA (7 μL). The reaction was stirred at 0° C. for 1 hour and was gradually warm up to room temperature and was continuously stirred for overnight. Ethyl acetate (5 mL) was then added, followed by water (10 mL). The organic layer was collected, dry over sodium sulfate, evaporate of solvent and residue was purified using prep-HPLC. To the solution obtained from HPCL, HCl (1N, 2 mL) was added and the solution was brought to dryness under vacuum. The formed residue was then dissolved in acetonitrile/water (3:1) and was lyophilized to give desired product (10 mg, 38% yield) as hydrochloride salt.
Reaction SMILES: [CH3:1][CH:2]([NH2:5])[CH2:3][CH3:4].C(O)C(N)(CO)CO.Cl.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=C(CC(=O)C)[CH:20]=[CH:21][CH:22]=1.C1([C@H](N)C)C=CC=CC=1.C(O)(=O)CCCCCCC/C=C\CCCCCCCC>>[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=[C:4]([CH2:3][C@H:2]([NH2:5])[CH3:1])[CH:20]=[CH:21][CH:22]=1
Reactant: CCC(C)N
Reactant: CC(=O)Cc1cccc(C(F)(F)F)c1
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: C[C@@H](N)c1ccccc1
Agent: Cl
Product: C[C@@H](N)Cc1cccc(C(F)(F)F)c1
Yield: 65 %

Procedure:
The Arthrobacter species KNK168 strain was subjected to shaking culture in the same manner as in Example 6 using (RS)-1-methylpropylamine as an enzyme inducer. The cells harvested from one liter of the culture were suspended in one liter of a 0.1 M Tris-hydrochloric acid buffer (pH 8.5), and 30 g of 1-(3-trifluoromethylphenyl)-2-propanone, 18 g of (R)-1-phenylethylamine, and 44 g of oleic acid were added thereto. The components were reacted at 30° C. for 40 hours with stirring. After the reaction, the resulting mixture was subjected to extraction and distillation in the same manner as in Example 6, to give 19.5 g of (R)-1-(3-trifluoromethylphenyl)-2-aminopropane. The optical purity was 100% ee, and the yield was 65%.