Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][S:10][CH3:11])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2.[OH:21]O.N>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][S:10]([CH3:11])=[O:21])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2
Reactant: COc1cc(CSC)ccc1-c1nc2ncccc2[nH]1
Reactant: OO
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(CS(C)=O)ccc1-c1nc2ncccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A quantity of 1.4 gm (4.9 mmol) of 2-(2'-methoxy-4'-methylthiomethyl-phenyl)-imidazo[4,5-b]pyridine was dissolved in 30 ml of glacial acetic acid and mixed with 3 ml of 30% hydrogen peroxide. After stirring for two hours at ambient temperature, the solution was diluted with 200 ml of water, made alkaline with concentrated ammonia solution, saturated with sodium chloride, and extracted three times with 30 ml of methylene chloride. The organic extracts were concentrated by evaporation, and the solid residue was purified by column chromatography (200 gm of silica gel; eluant: methylene chloride with 2 to 10% of ethanol).
Reaction SMILES: Br[C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[CH:8]=[O:9].C(=O)([O-])O.[Na+].[ClH:15]>>[Cl:15][C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[CH:8]=[O:9]
Reactant: Cl
Reactant: Cc1nc(C=O)c(Br)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc(C=O)c(Cl)[nH]1

Procedure:
5-Bromo-2-methylimidazole-4-carbaldehyde (400 mg) was dissolved in conc. hydrochloric acid (6 ml), and the mixture was refluxed under heating for 24 hr. Saturated aqueous sodium hydrogencarbonate solution was added under ice-cooling until the mixture assumed weak alkalinity and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and then brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. Hexane was added to the residue and the crystals were collected by filtration to give 5-chloro-2-methylimidazole-4-carbaldehyde (222 mg) as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])C=CC=CC=1.[OH:10][C:11]1C2C=CC=CC=2C=CC(=O)[CH:12]=1.[OH:23][C:24]1[C:34](=[O:35])[CH:33]=[CH:32][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:26]=2[CH:25]=1.COC(=O)C=O>>[CH2:11]([O:10][C:2](=[O:1])[C:3]([O:23][C:24]1[C:34](=[O:35])[CH:33]=[CH:32][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:26]=2[CH:25]=1)=[O:9])[CH3:12]
Reactant: O=c1cccccc1O
Reactant: O=c1ccc2cnccc2cc1O
Reactant: O=c1ccc2ccccc2c(O)c1
Agent: COC(=O)C=O
Product: CCOC(=O)C(=O)Oc1cc2ccncc2ccc1=O

Procedure:
In the same manner using the appropriate compound of formula III and replacing 2-hydroxy-2,4,6-cycloheptatrien -1-one with an equivalent amount of 5-hydroxy-7H-benzocyclohepten -7-one, 6-hydroxy-7H-cyclohepta[c]pyridin-7-one, 2-hydroxy-3H-6,7-dihydrocyclobutacyclohepten-3-one, 1-hydroxy-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-3-one, and 2-hydroxy-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-3-one, the following compounds are obtained respectively: [(7H-7-oxobenzocyclohepten -6yl)oxy] oxo-acetic acid methyl ester (I; R1, R5 and R6 = H, R3 and R4 together form a --CH=CH--CH=CH-- chain and R2 = O--CO--COOCH3), [(7-oxo-7H-cyclohepta[c]pyridin-6-yl)oxy]oxo-acetic acid ethyl ester (I; R1, R2 and R5 = H, R3 and R4 together form a --CH2 =CH2 --N=CH-- chain and R6 = O--CO--COOC2H5), [(3-oxo-3H-6,7-dihydrocyclobutacyclohepten-2-yl)oxy]oxo-acetic acid ethyl ester (I; R2, R5 and R6 = H, R3 and R4 together form a --CH2 --CH2 -- chain and R1 = O--CO--COOC2H5), [(3-oxo-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-1-yl)oxy]oxo-acetic acid ethyl ester (I; R1, R2 and R6 = H, R3 and R4 together form a --(CH2)6 -- chain and R5 = O--CO--COOC2H5) and [(3H-6,7,8,9,10,11,12,13-octahydro-3-oxocycloheptacyclodecen-2-yl)oxy]-oxo-acetic acid methyl ester (I; R1, R2 and R5 = H, R3 and R4 together form a --(CH2)8 -- chain and R6 = O--CO--COOCH3).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCC(N2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3-Dimethyl-6-nitroindoline (0.8 g) was dissolved in CH2Cl2 (50 mL), N-methyl-4-piperidone (1 g) was added to the mixture, followed by 2.5 g NaBH(OAc)3 and glacial AcOH (1 mL). The mixture was stirred at RT overnight. Saturated NaHCO3 solution (50 ml) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCO3 solution and once with brine, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 9:1 EtOAc:MeOH to afford the title compound as an orange oil. MS: 290 (M+1). Calc'd. for C16H23N3O2−289.37.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[I-].[Na+].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>CC(C)=O>[ClH:15].[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24][CH2:25][N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCCBr
Reactant: CCNCC
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCCN(CC)CC
Product: Cl

Procedure:
A solution of 8.7 g. of 2-(4-bromobutyl)-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 40 ml. of acetone is treated with 3.0 g. of sodium iodide and 1.6 g. of diethylamine and stirred in the dark at room temperature for 20 hours. After concentration under reduced pressure, the residue is treated at 0°-2° C. with 40 ml. of 1-N sodium hydroxide solution and then extracted with ether. The ethereal extract is immediately shaken with 40 ml. of 0.5-N hydrochloric acid and the acidic aqueous phase is made alkaline at 0°-2° C. with 1-N sodium hydroxide solution. The mixture is immediately extracted with methylene chloride and the organic phase, shielded from daylight, is dried over sodium sulfate. After concentration, the resulting oil is dissolved in ether and treated with ethereal hydrochloric acid. The crystallized hydrochloride is removed by filtration and washed with ether, and there is obtained 5-chloro-2-[4-(diethylamino)butyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 137°-140° C. Recrystallization from methylene chloride/ether does not increase the melting point.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@@H:16]([CH2:24][CH3:25])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[CH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[C:29]=12)=O>ClCCCl.C(O)(=O)C>[O:18]=[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C@@H:16]([NH:15][CH2:26][C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[C:29]=12)[CH2:24][CH3:25]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC[C@H](N)C(=O)N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC[C@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
A mixture of sodium triacetoxyborohydride (279 mg, 1.315 mmol) and (S)-2-amino-1-(pyrrolidin-1-yl)butan-1-one (123 mg, 0.789 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (200 mg, 0.657 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (83 mg, 28.4%). [M+H] calc'd for C23H32N4O5, 445; found, 445.5.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[CH3:13])(=O)=O.O[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[C:27]([CH3:38])[C:26]=1[CH3:39]>>[F:14][C:12]([C:11]1[S:10][N:9]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:6][O:5][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:38])[C:26]=1[CH3:39])([F:15])[CH3:13]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CCc1ccc(-c2nsc(C(C)(F)F)c2COS(C)(=O)=O)cc1
Product: CCc1ccc(-c2nsc(C(C)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Step 5 and 6 by coupling [5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazol-4-yl]methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H-NMR (300 MHz, CD3OD) δ 7.58 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 5.02 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.68 (q, J1=15.2 Hz, J2=7.5 Hz, 2H), 2.52 (t, J=8.1 Hz, 2H), 2.24 (s, 3H), 2.13 (t, J=18.6 Hz, 3H), 2.09 (s, 3H), 1.24 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C25H27F2NO3S, 460.2 (M+H). found 460.2.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([CH3:31])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>CN(C)C=O.O.ClCCl>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([CH3:31])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: C[C@@H](N)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 140 °C
Yield: 75 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (75 mg, 0.234 mmol) and 3-(R)-amino-butyric acid (103 mg, 1.0 mmol) were placed in a CEM 10 mL Microwave vessel and dissolved in anhydrous N,N-dimethylformamide (2 mL.) Sodium methoxide (54 mg, 1.0 mmol) was added to solution and the vessel was sealed. The reaction was heated to 140° C. in a CEM microwave apparatus for four hours. Upon completion, the reaction mixture was diluted with water and treated with 1N hydrochloric acid. The precipitate was dissolved in dichloromethane and dried over anhydrous sodium sulfate. The crude product was purified by MPLC (methylene chloride-ethyl acetate) to provide the title compound as a light-yellow solid in 75% yield. MS ESI(−) m/e: 390.091 (M−1).
Reaction SMILES: O[Li].O.C(OC(N(C)[C@@H](C)C(N[C@H]1C2(CCOCC2)OC2C=CC=CC=2N(C[C:33]2[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[C:39]3[C:34]=2[CH:35]=[CH:36][C:37]([C:45]([O:47]C)=[O:46])=[CH:38]3)C1=O)=O)=O)(C)(C)C.Cl>O.C1COCC1>[CH3:44][O:43][C:42]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([C:45]([OH:47])=[O:46])[CH:36]=[CH:35]2
Reactant: COC(=O)c1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C4(CCOCC4)Oc4ccccc43)c(OC)ccc2c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cc(C(=O)O)ccc2c1
Reaction time: 18 h
Yield: 281.9 %

Procedure:
A solution of LiOH.H2O (35.0 mg, 835 μmol, Eq: 5) in H2O (4 mL) was added to a solution of methyl 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-5 (4H)-yl)methyl)-6-methoxy-2-naphthoate (110.5 mg, 167 μmol, Eq: 1.00) in THF (3 mL). After 18 h, the mixture was poured into 1 M HCl (20 mL) and extracted with EtOAc. The combined organic extracts were washed with H2O, brine, dried over Na2SO4 and concentrated. The residue was dissolved in MeCN/H2O, and lyophilized to afford 5-((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-5 (4H)-yl)methyl)-6-methoxy-2-naphthoic acid (95.2 mg, 88%) of white solid which was used without purification. MS m/z 648.2 (MH+)
Reaction SMILES: C[O:2][C:3]1[C:11]2[S:10][C:9]([C:12]([F:15])([F:14])[F:13])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br.CO.O>ClCCl>[F:15][C:12]([F:13])([F:14])[C:9]1[S:10][C:11]2[C:3]([OH:2])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: COc1cccc2nc(C(F)(F)F)sc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Oc1cccc2nc(C(F)(F)F)sc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 7-methoxy-2-(trifluoromethyl)-1,3-benzothiazole (C26) (398 mg, 1.71 mmol) in dichloromethane (10 mL) at −78° C. was treated with boron tribromide (1 M in dichloromethane, 3.41 mL, 3.41 mmol), warmed to room temperature and stirred for 18 hours. Methanol (3.0 mL) was added to the mixture at −78° C. and the mixture was warmed to room temperature. Water (30 mL) was added and the mixture was extracted with dichloromethane (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% methyl tert-butyl ether in heptanes) afforded the title compound as a colorless solid. Yield: 251 mg, 1.15 mmol, 67%. GCMS m/z 219 (M+). 1H NMR (400 MHz, CDCl3) δ 6.44 (br s, 1H), 6.95 (d, J=7.8 Hz, 1H), 7.47 (dd, J=8.2, 8.0 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12](=[O:18])OC(C)(C)C)=[CH:10][C:5]=2[N:4]([CH2:19][CH3:20])[CH:3]=1.ClC([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)=O>Cl.O1CCOCC1>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)=[O:18])=[CH:10][C:5]=2[N:4]([CH2:19][CH3:20])[CH:3]=1
Reactant: CCn1cc(Br)c2cnc(NC(=O)OC(C)(C)C)cc21
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCn1cc(Br)c2cnc(NC(=O)c3ccc(C(=O)OC)cc3)cc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A mixture of tert-butyl 3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (3C, 340 mg, 0.99 mmol) in 4M HCl in dioxane (3 ml) was stirred at room temperature for 1 h and 70° C. for 2 h. The mixture was concentrated in vacuo and dissolved in pyridine (3 ml). To the mixture, methyl 4-(chlorocarbonyl)benzoate (220 mg, 1.1 mmol) was added and stirred at room temperature for 3 h. The mixture was extracted with EtOAc/H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (basic-SiO2, hexanes:EtOAc=3:1) to give methyl 4-(3-bromo-1-ethyl-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamoyl)benzoate (3D, 350 mg, 0.87 mmol, 87% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (t, J=1.00 Hz, 3H) 3.90 (s, 3H) 4.21 (q, J=7.16 Hz, 2H) 7.72 (s, 1H) 7.99-8.11 (m, 2H) 8.11-8.20 (m, 2H) 8.35 (d, J=0.76 Hz, 1H) 8.52 (d, J=1.01 Hz, 1H) 10.96 (s, 1H).
Reaction SMILES: CN(C)CCO.C([Li])CCC.[C:12]1([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Br)(Br)(Br)[Br:25]>CCCCCC.O>[Br:25][C:22]1[CH:23]=[C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=[CH:20][N:21]=1
Reactant: BrC(Br)(Br)Br
Reactant: c1ccc(-c2ccncc2)cc1
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: Brc1cc(-c2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 2-dimethylaminoethanol (5.60 g, 62.8 mmol) in hexane (80 ml) was added dropwise 1.6N hexane solution of n-butyl lithium (78.5 ml, 125 mmol) under ice-cooling, and stirred at 0° C. for 30 minutes. Then, 4-phenylpyridine (3.24 g, 20.8 mmol) was added thereto, and stirred at 0° C. for 1 hour. After cooling the reaction solution to −78° C., a solution of carbon tetrabromide (25.0 g, 75.4 mmol) in hexane (40 ml) was added thereto, and stirred at −78° C. for 1 hour, then at room temperature for 1 hour. To the reaction solution was added water under ice-cooling, and extracted with ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the titled compound 2.21 g (45.4%) as solid product.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>O1CCOCC1.C(OCC)(=O)C>[Br:2][CH2:14][CH2:13][CH2:12][CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCCCCc1ccccc1
Reactant: BrP(Br)Br
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: BrCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Phosphorus tribromide (17.6 ml, 186 mmol) was added dropwise to a solution of 4-phenyl-1-butanol (10.0 g, 66.6 mmol) in dioxane (200 ml). The reaction mixture was stirred for 1 hour at room temperature. Another portion of phosphorus tribromide (17.6 ml, 186 mmol) was added dropwise. The reaction mixture was stirred for 16 hours at room temperature. It was cooled to 0° C. Water (130 ml) was added dropwise. The reaction mixture was stirred for 30 min at room temperature. It was diluted with ethyl acetate (200 ml) and washed with 1 N hydrochloric acid (200 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (200 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using ethyl acetate/heptane 1:3 as eluent, to give 8.54 g of (4-bromobutyl)benzene.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:18][CH2:17][C@@H:16]([O:19][CH3:20])[CH2:15]3)[CH:11]=[CH:10][C:9]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:4][CH2:3]1.[CH:28](=O)[CH2:29][CH2:30][CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:28]([N:24]1[CH2:23][CH2:22][N:21]([C:9]2[CH:10]=[CH:11][C:12]([N:14]3[CH2:18][CH2:17][C@@H:16]([O:19][CH3:20])[CH2:15]3)=[CH:13][C:8]=2[CH:5]2[CH2:4][CH2:3][C:2]([CH3:27])([CH3:1])[CH2:7][CH2:6]2)[CH2:26][CH2:25]1)[CH2:29][CH2:30][CH3:31]
Reactant: CO[C@@H]1CCN(c2ccc(N3CCNCC3)c(C3CCC(C)(C)CC3)c2)C1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCN1CCN(c2ccc(N3CC[C@@H](OC)C3)cc2C2CCC(C)(C)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a mixture of the crude product of (R)-1-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazine produced in Example (98b) (160 mg), butyraldehyde (0.052 mL, 0.584 mmol) and tetrahydrofuran (7 mL) were added sodium triacetoxyborohydride (164 mg, 0.774 mmol) and acetic acid (0.022 mL, 0.384 mmol) in that order, followed by stirring for 1 hour at room temperature. Ethyl acetate and saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 170 mg of (R)-1-butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazine as a light brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[O:20][C:19]([CH:21]=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Product: Oc1ccccc1N=Cc1ccc(-c2ccc(Cl)cc2)o1

Procedure:
Using 2-aminophenol and 5-(4-chlorophenyl)furan-2-carbaldehyde, 3.18 g of 2-{[5-(4-chlorophenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:13].O>C(OCC)C>[Br:13][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: BrP(Br)Br
Reactant: OCCCc1ccc(F)cc1
Solvent: O
Solvent: CCOCC
Product: Fc1ccc(CCCBr)cc1

Procedure:
Compound 20-1 (9.39 g) was dissolved in diethyl ether (100 ml), phosphorus tribromide (8.58 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 3.5 hr. To the reaction mixture was slowly added water, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (4.93 g) as a pale-yellow oil.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:25][CH2:24]1
Reactant: BrCC1CC1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC2CC2)c1
Yield: 49.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and bromomethyl cyclopropane were reacted by the same way with the example 1 to obtain the titled compound (170 mg, yield: 49.4%).
Reaction SMILES: [CH2:1]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:24])[CH:18]=2)=[CH:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:25](Cl)(=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CC(C)=O.CO>N1C=CC=CC=1>[CH2:1]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:19]([F:24])[CH:18]=2)=[CH:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC(=O)Cl
Reactant: CCCCCCCCCCc1ncc(-c2ccc(O)c(F)c2)cn1
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: CO
Product: CCCCCCCCCCc1ncc(-c2ccc(OC(=O)CCCCCC)c(F)c2)cn1
Temperature: 0 °C
Yield: 61.6 %

Procedure:
0.80 g (2.42 mmol) of 2-decyl-5-(3-fluoro-4-hydroxyphenyl) pyrimidine was dissolved in 10 ml of pyridine before 0.62 ml (4.00 mmol) of heptanoylchloride was added dropwise thereto while being cooled with ice and stirred. Then, the solution was cooled with ice and stirred for 15 minutes before it was heated and stirred for another 20 minutes in a water bath having a temperature maintained at 45° to 56° C. After the reaction had been completed, the solution was injected into 150 ml of ice water so as to filter and wash with water the deposited crystal. The thus obtained crystal was dissolved in toluene and the resultant toluene layer was washed with water and dried with dried mirabilite. The solvent was removed by lowering the pressure and distillation. The residue was purified by the silica gel column chromatography method which uses toluene as the eluate before it was recrystallized twice by an acetone-methanol mixed solvent so that 0.66 g (yield 61.6%) of 2-decyl-5-(3-fluoro-4-heptanoyloxyphenyl) pyrimidine was obtained.