Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1c(Cl)cc(Cl)cc1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,4,6-Trichlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,4,6-trichlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:31])[CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=2)[CH2:20]1.[C:32](OCC)(=[O:34])C>>[CH3:11][O:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[NH:1][C:32](=[O:34])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH3:31])[CH:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=4)[CH2:20]3)[CH2:13][CH2:12][C:3]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC(N(C)CCCNCCc1cc(OC)c(OC)cc1N)CC2
Reactant: CCOC(C)=O
Product: COc1ccc2c(c1)CC(N(C)CCCN1CCc3cc(OC)c(OC)cc3NC1=O)CC2

Procedure:
Here, 1-[2-(2-amino-4,5-dimethoxy-phenyl)-ethyl amino]-3-[N-methyl-N-(7-methoxy-1,2,3,4-tetrahydro naphth 2-yl)-amino]-propane (2.0 g, 0.005 mol) and N,N'-carbonyldiimidazole (1 g, 0.006 mol) are reflxed for 60 minutes in absolute ethyl acetate (40 ml). After extraction with saturated potassium carbonate solution and with water, the product which has been evaporated in vacuo is dissolved in methylene chloride and precipitated with petroleum ether. yield: 1.2 g. Mp: 163°-165° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[OH:10][CH2:11][CH2:12][O:13][C:14](=[O:38])[CH2:15][C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[N:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:17]=1[CH3:37].[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:39][S:40]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:38])[CH2:15][C:16]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[N:18]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:17]=1[CH3:37])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(CC(=O)OCCO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(CC(=O)OCCOS(C)(=O)=O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
DMAP (0.03 mmol) and diisopropylethylamine (DPEA) (0.5 mmol) are added to a solution of 2-hydroxyethyl-2-[1-phenyl-2-methyl-5-(4-methylsulphonylphenyl)-1H-pyrrol-3-yl)acetate in DCM (10 ml), at 0° C., MsCl (0.6 mmol) is added and it is stirred for 3 h, at RT. Then H2O is added (5 ml) and it is stirred for 1 h, the phases are separated and the organic phase is washed with NaHCO3 and then with H2O. It is dried and concentrated. The raw product is purified by chromatography (silica; hexane/EtOAc). Oil, yield 76%. 1H NMR 200 MHz (CDCl3) δ (ppm): 2.05 (s, 3H), 2.96 (s, 6H), 3.50 (s, 2H), 4.13-4.33 (m, 4H), 6.51 (s, 1H), 7.08-7.14 (m, 4H), 7.37-7.41 (m, 3H), 7.62 (d, 2H, J=8.6). MS-ESI: m/z 515 (M+Na+).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15](NC(=O)OCC)[NH:16][C:17](=O)[O:18]CC)=[C:11]([F:28])[CH:10]=1)#[N:8]>C1(C)C=CC=CC=1>[Cl:2][CH:15]([N:16]=[C:17]=[O:18])[C:12]1[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][C:11]=1[F:28]
Reactant: CCOC(=O)NC(NC(=O)OCC)c1ccc(C#N)cc1F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(Cl)N=C=O)c(F)c1

Procedure:
Phosphorous pentachloride (9.63 g, 46.2 mmol) is added to a mixture of diethyl (4-cyano-2-fluorophenyl)methylenedicarbamate (intermediate 26, 6.50 g, 21.0 mmol) in toluene (25.0 mL), and the mixture is heated at reflux for 3 h. The toluene is evaporated, and the mixture is then purified by distillation under reduced pressure. The first fraction (ca. 35° C., ca. 0.2 mbar) is discarded. The second fraction (ca. 112° C., ca. 0.1 mbar) is collected. Yield: 1.90 g.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:14]([O:16]CCCC)=[CH2:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CC#N.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:16])[CH3:15]
Reactant: C=COCCCC
Reactant: COC(=O)c1ccc(OC)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(OC)cc1C(C)=O
Temperature: 97 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
A mixture of methyl 2-bromo-4-methoxybenzoate (4) (5.9 g, 23.9 mmol), butyl vinyl ether (15.4 mL, 119.4 mmol), Ph3P (939.0 mg, 3.6 mmol), Et3N (4.3 mL, 31.0 mmol), and Pd(OAc)2 (343.0 mg, 1.8 mmol) in MeCN (45 mL) is stirred under argon at 97° C. for 18 h, cooled to room temperature, diluted with H2O (50 mL), and filtered through Celite® (H2O rinse). The filtrate is concentrated to dryness at reduced pressure. The residue plus tetrahydrofuran (140 mL) and 10% HCl (140 mL) were stirred for 2 h. After tetrahydrofuran removal at reduced pressure, the residue is extracted with dichloromethane (3×70 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (16.7% to 33.3% ethyl acetate/hexane) to give 4.8 g (96%) of 5 as a yellow solid, mp 48-50° C. IR 2962, 1733, 1688, 1258 cm−1; 1H NMR (CDCl3) δ 2.50 (s, 3H, CH3CO), 3.86 (s, 6H, CH3O, CO2CH3), 6.76 (d, J=2.0 Hz, 1H, 3-PhH), 6.93 (dd, J=7.2, 2.0 Hz, 1H, 5-PhH), 7.90 ppm (d, J=7.2 Hz, 1H, 6-PhH).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[O:22]1[CH:24]([CH2:25][CH2:26][CH3:27])[CH2:23]1>>[OH:22][CH:24]([CH2:25][CH2:26][CH3:27])[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Reactant: CCCC1CO1
Product: CCCC(O)COc1cccc(OCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Alkylation reaction of phenol 24 with 1,2-epoxypentane gave 2-(2-(3-(2-hydroxypentyloxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil. Yield (1.1 g, 84%): 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=6.8 Hz, 1H), 7.44-7.56 (m, 2H), 7.12-7.16 (m, 1H), 6.68-6.73 (m, 1H), 6.46-6.52 (m, 3H), 4.10 (t, J=5.2 Hz, 2H), 3.90-4.0 (m, 2H), 3.77-3.82 (m, 3H), 1.32-1.56 (m, 4H), 0.94 (t, J=6.8 Hz, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[C:13]([OH:21])[CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(Cl)Cl>[CH:5]1([C:11]2[C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[C:13]([OH:21])[CH:12]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(O)Cc1ccc(C2CCCCC2)cc1O
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: O=C(O)Cc1cc([N+](=O)[O-])c(C2CCCCC2)cc1O
Reaction time: 0.17 h

Procedure:
1.06 ml of 100% nitric acid are slowly added dropwise at -10° to a solution of 5.9 g of 4-cyclohexyl-2-hydroxy-phenylacetic acid in 100 ml of absolute methylene chloride. The mixture is finally stirred for 10 minutes without further cooling, the methylene chloride solution washed several times with water, dried over sodium sulphate and evaporated to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])=[CH:23][CH:22]=1>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][N:16]([C:21]3[CH:26]=[CH:25][C:24]([C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])=[CH:23][CH:22]=3)[CH2:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(OC3CNC3)cc2)cc1
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(OCc4ccccc4)cc3)C2)cc1
Temperature: 30 °C
Reaction time: 48 h

Procedure:
Example 8.5 is prepared analogously to 8.1. 3-(4-Benzyloxy-phenoxy)-azetidine and (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1) are used as starting materials. Reaction conditions are stirring for 2 days at 30° C.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6].C(=O)([O-])[O-].[F:23][C:24]([F:29])([F:28])[C@@H:25]1[CH2:27][O:26]1>C1COCC1>[F:23][C:24]([F:29])([F:28])[C@@H:25]([OH:26])[CH2:27][N:14]1[CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:18]=[CH:17][C:11]=2[CH2:12][CH2:13]1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Agent: O=C([O-])[O-]
Solvent: O=[N+]([O-])O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CCN(C[C@H](O)C(F)(F)F)CC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitric acid salt (2.01 g, 7.88 mmol, 1.0 eq), was placed in THF (100 mL) and MP-carbonate (7.1 g) was added. The reaction was stirred in a sealable vessel for 1 hour and then (S)-2-trifluoromethyl-oxirane (1.30 g, 11.59 mmol, 1.00 mL, 1.47 eq) was added. The reaction vessel was sealed, stirred at room temperature for 1 hour, and then heated at 50° C. overnight. The reaction was then cooled to room temperature and filtered. The resin was washed with CH2Cl2 (150 mL) and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain (S)-1,1,1-trifluoro-3-(7-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propan-2-ol as an orange solid (2.27 g, 95%). m.p.=82-85° C.; LCMS (m/e) 305 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.06-7.99 (m, 2H), 7.31-7.26 (m, 1H), 4.16-4.02 (m, 2H), 3.15-2.97 (m, 4H), 2.96-2.81 (m, 3H), 2.81-2.67 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.Cl.[N:18]#[C:19]N.[OH-].[Na+]>O.CN(C)C=O.ClC(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=[C:19]2[NH2:18])=[CH:6][CH:7]=1
Reactant: Nc1ccccc1NCc1ccc(F)cc1
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc2ccccc2n1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 9.5 %

Procedure:
To a stirred mixture of 23.5 parts of N-(4-fluorophenylmethyl)-1,2-benzenediamine and 14.4 parts of concentrated hydrochloric acid were added dropwise 9 parts of cyanamide at 100° C. After stirring for 3 hours at 100° C., there were added dropwise 10.5 parts of a sodium hydroxide solution 50%. Upon completion, stirring was continued overnight at reflux temperature. The reaction mixture was cooled and taken up in a mixture of water, trichloromethane and N,N-dimethylformamide. The organic phase was separated, dried, filtered and evaporated. The residue was stirred in trichloromethane. The product was filtered off and crystallized from trichloromethane, yielding 2.5 parts (9.5%) of 1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine; mp. 189.5° C. (int. 31).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH:9]=[CH:10][CH2:11]Cl>C(#N)C>[Cl:8][CH:9]=[CH:10][CH2:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: ClC=CCCl
Solvent: CC#N
Product: ClC=CCNc1ccccc1

Procedure:
1 mole of aniline was dissolved in 200 mL acetonitrile, and 0.7 mole 1,3-dichloropropene was added. The reaction was heated to reflux overnight with mechanical stirring. The reaction was then filtered and concentrated. Upon distillation, N-(3-chloro-2-propenyl)aniline was obtained as a yellow solid. The main distillation cut contained 65% N-(3-chloro-2-propenyl)aniline by weight.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([CH3:17])C(OC)=O.[Cl-].[Li+].[BH4-].[Na+].[NH4+].[Cl-].C[CH2:25][OH:26].C1COCC1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:17][CH2:25][OH:26]
Reactant: COC(=O)C(C)c1ccccc1-c1cccs1
Reactant: CCO
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1ccccc1-c1cccs1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a cold (0° C.) solution of methyl 2-(2-thienyl)phenylpropionate (387 mg, 1.57 mmol) and anhydrous lithium chloride (353 mg, 8.32 mmol) in an EtOH/THF mixture (4:3; 28 mL) was added sodium borohydride (315 mg, 8.32 mmol). The reaction mixture was then stirred at room temperature for 20 h. Aqueous NH4Cl (50 mL) was added and the crude product was extracted with EtOAc (2×50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography (5% EtOAc in hexane) to yield 2-(2-thienyl)phenpropyl alcohol as a light yellow oil.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])=[N:6][C:5]=1[CH3:21])(=[O:3])[CH3:2].Br[CH2:23][CH2:24][CH2:25][CH3:26].CC(C)([O-])C.[K+]>CN(C)C=O>[C:1]([C:4]1[S:8]/[C:7](=[N:9]\[C:10](=[O:20])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])/[N:6]([CH2:23][CH2:24][CH2:25][CH3:26])[C:5]=1[CH3:21])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1nc(C)c(C(C)=O)s1
Reactant: CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(C)c(C(C)=O)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of Example 238A (0.40 g, 1.2 mmol), 1-bromobutane (0.16 mL, 1.5 mmol), and potassium t-butoxide (0.22 g, 1.9 mmol) in 5 mL N,N-dimethylformamide was warmed to 65° C. and stirred for 20 hours. The mixture was cooled to ambient temperature quenched with 5 mL of saturated aquesous NH4Cl and diluted with 5 mL of ethyl acetate. The layers were separated and the aqueous phase was extracted twice with 5 mL of ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 40% hexanes in ethyl acetate) afforded the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 1.04 (t, J=7.3 Hz, 3H), 1.42-1.55 (m, 2H), 1.77-1.90 (m, 2H), 2.51 (s, 3H), 2.76 (s, 3H), 3.88 (s, 3H), 4.32-4.41 (m, 2H), 7.10 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.7 Hz, 1H), 7.99 (d, J=3.1 Hz, 1H); MS (DCI/NH3) m/z 381 (M+H)+. Anal. Calculated for C18H21ClN2O3S: C, 56.76; H, 5.56; N, 7.35. Found: C, 56.68; H, 5.49; N, 7.26.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C:13]([CH2:19][N:20]([C:22]1[CH:27]=[N:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:23]=1)[CH3:21])=[CH:14]2)C1C=CC=CC=1.C(O)C>[C].[Pd].C(OCC)(=O)C>[C:28]1([C:25]2[N:26]=[CH:27][C:22]([N:20]([CH2:19][CH:13]3[CH2:12][CH2:11][C:10]4[C:15](=[CH:16][CH:17]=[CH:18][C:9]=4[OH:8])[CH2:14]3)[CH3:21])=[N:23][C:24]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN(CC1=Cc2cccc(OCc3ccccc3)c2CC1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(CC1CCc2c(O)cccc2C1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 31 h
Yield: 66.9 %

Procedure:
To 800 mg of 5-(benzyloxy)-2-{[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]methyl}-3,4-dihydronaphthalene, 18 ml of ethanol, 15 ml of ethyl acetate and 80 mg of 10% palladium-carbon were added and, after the mixture was hydrogenated under 3 atm at room temperature for 31 hours, the reaction was continued at 30° C. for 23 hours. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 443 mg of the desired compound as a pale yellow oily substance.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([OH:19])=[C:15]([CH:18]=1)[CH2:16][OH:17]>>[OH:17][CH2:16][C:15]1[CH:18]=[C:11]([Br:10])[CH:12]=[CH:13][C:14]=1[O:19][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: ClCCN1CCCC1
Reactant: OCc1cc(Br)ccc1O
Agent: Cl
Product: OCc1cc(Br)ccc1OCCN1CCCC1
Yield: 52 %

Procedure:
The title compound was prepared in 52% yield by essentially following the procedures outlined in Example 3, Part D, from 1-(2-chloroethyl)pyrrolidine hydrochloride and 5-bromo-2-hydroxybenzyl alcohol.
Reaction SMILES: [Br-].[Br:2][CH:3]([CH3:26])[C:4](=[O:25])[CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O1CCCC1.O>[Br:2][CH:3]([CH3:26])[C:4](=[O:25])[CH:5]=[P:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(Br)C(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(Br)C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 96.8 %

Procedure:
A mixture of (3-bromo-2-oxobutyl)triphenylphosphonium bromide (30 g) in ethyl acetate (150 ml), tetrahydrofuran (50 ml) and water (150 ml) was adjusted to pH 10 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was triturated with diisopropyl ether and collected by filtration to give (3-bromo-2-oxobutylidene)triphenylphosphorane (24.27 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:46]=[O:47]>O1CCCC1>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([S:25]([NH:24][C:15]2[N:14]([CH3:38])[N:13]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][C:2]([CH:46]=[O:47])=[CH:7][N:6]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:27])=[O:26])=[CH:29][CH:30]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncc(C=O)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: -78 °C

Procedure:
To N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 3) (332 mg) in tetrahydrofuran (10 ml) at −78° C. under an atmosphere of nitrogen was added n-butyllithium in hexanes (0.69 ml of 1.6M). Dimethylformamide (86 μl) was added dropwise to the solution after 20 minutes of stirring at −78° C. After a further 20 minutes of stirring at −78° C., the mixture was quenched with saturated ammonium chloride solution (2 ml). The mixture was diluted with ammonium chloride (50 ml), extracted with ethyl acetate (50 ml), dried over magnesium sulphate, filtered and the filtrate was evaporated to dryness. Purification of the residue by column chromatography on silica gel (32 g), eluting with an ethyl acetate:hexane gradient (1:1 to 3:1) yielded the title compound as a cream solid (52 mg).
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([N+:35]([O-])=O)[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[H][H]>[Pd].C1COCC1.CN(C=O)C>[C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([NH2:35])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N(CC(=O)O)CC(=O)O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 4 h
Yield: 44.2 %

Procedure:
A mixture of 0.6 g of N-(carboxymethyl)-N-[3-nitro-5-(octadecyloxy)phenyl]glycine and 0.2 g of 10% palladium on carbon in 170 ml of THF and 10 ml of DMF was stirred in a hydrogen atmosphere at room temperature until uptake ceased after 4 hours. The reaction mixture was heated to dissolve the precipitated product and the catalyst was removed by filtration. The filtrate was concentrated at reduced pressure and the solid residue was dissolved in THF and the solution was passed through a SEP-PAK silica cartridge (Waters Associates). The eluent was concentrated at reduced pressure to a solid which was triturated with ethyl acetate and filtered to give 0.25 g (44% yield, mp 185°-195°) of N-(carboxymethyl)-N-[3-amino-5-(octadecyloxy)phenyl]glycine. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [H-].[Na+].[C:3](Cl)(=[O:5])[CH3:4].[F:7][C:8]1[CH:29]=[CH:28][C:11]([NH:12][C:13]2[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=2[CH3:27])[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:10][CH:9]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[C:16]([C:15]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:13]([N:12]([C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:29][CH:28]=2)[C:3](=[O:5])[CH3:4])[CH:14]=1)(=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(F)cc1)c1cc(C(=O)c2ccccc2)ccc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
60% sodium hydride 79 mg and acetyl chloride 0.14 mL were added to N,N-dimethylformamide 5.0 mL solution of 3-(4-fluoroanilino)-4-methylbenzophenone 0.50 g under ice cooling sequentially, and it was stirred at room temperature for 4 hours. After the reaction mixture was cooled to ice temperature,60% sodium hydride 79 mg and acetyl chloride 0.14 mL were added sequentially, and it was stirred at room temperature for 5 hours and 30 minutes. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=2:1] to give N-(5-benzoyl-2-methylphenyl)-N-(4-fluorophenyl)acetamide 82 mg of orange oil.