Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Br:20][C:21]1[CH:29]=[C:28]([C:30](Cl)=[O:31])[C:24]2[O:25][CH2:26][CH2:27][C:23]=2[CH:22]=1>C1COCC1>[Br:20][C:21]1[CH:29]=[C:28]([C:30](/[N:12]=[C:6]2\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\2[CH2:4][CH2:3][O:2][CH3:1])=[O:31])[C:24]2[O:25][CH2:26][CH2:27][C:23]=2[CH:22]=1
Reactant: O=C(Cl)c1cc(Br)cc2c1OCC2
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cc(Br)cc2c1OCC2
Yield: 35.5 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and 5-bromo-2,3-dihydrobenzo[b]-furan-7-carbonyl chloride (Maybridge, 0.42 g, 1.6 mmol) in 35 mL THF were processed as in Example 126B. The resulting crude material was purified via flash column chromatography (SiO2, 7:3 hexanes:EtOAc) to afford the title compound (0.16 g, 0.39 mmol, 36% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.24 (s, 3H), 2.28 (s, 3H), 3.23 (t, J=8.5 Hz, 2H), 3.33 (s, 3H), 3.78-3.87 (m, 2H), 4.45-4.56 (m, 2H), 4.70-4.81 (m, 2H), 7.35-7.39 (m, 1H), 8.09 (d, J=20 Hz, 1H); MS (DCI/NH3) m/z 411, 413 (M+H)+; Anal. calculated for C17H19BrN2O3S.0.3H2O: C, 49.00; H, 4.74; N, 6.72. Found: C, 48.91; H, 4.36; N, 6.57.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([CH2:36][C:37](=[O:39])[NH2:38])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:32]([CH2:36][C:37]([NH2:38])=[O:39])[CH2:31]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: NC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Agent: Cl
Agent: [Li+]
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3CC(N)=O)sc2CN1

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[carbamoylmethyl]piperazine hydrochloride
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(C1C=CC=CC=1B1OC(C)(C)C(C)(C)O1)(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[C:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C4CCCC4)cc(Br)c3O2)cc1
Reactant: Cc1ccccc1B(O)O
Agent: CC(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C4CCCC4)cc(-c4ccccc4)c3O2)cc1
Yield: 99 %

Procedure:
To a solution of 4-cyclopentylphenol (3.0 g, 18.0 mmol) in acetonitrile (30 mL) cooled to 0° C. was slowly added N-bromosuccinimide (3.29 g, 18 mmol) generally according to the procedure described for Example 309 afforded 3.75 g (84%) of 2-bromo-4-cyclopentylphenol Treatment of 2-bromo-4-cyclopentylphenol (3.75 g, 16.0 mmol) with potassium carbonate (5.4.0 g, 40 mmol) and allyl bromide (2.38 g, 20.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-cyclopentylphenol. Treatment of 2-allyl-6-bromo-4-cyclopentylphenol (3.0 g, 10.0 mmol) with 3-chloroperoxybenzoic acid (3.49 g, 12.0 mmol, 77%) followed by potassium carbonate (3.7 g, 25.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.68 g, (53%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.68 g, 4.6 mmol) with p-toluenesulfonyl chloride (0.96 g, 5.0 mmol) generally according to the procedure described for Intermediate 10 gave 1.78 g (70%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.1 mmol) and 2-methylphenylboronic acid (0.45 g, 3.3 mmol) generally according to the procedure described for Intermediate 35 afforded 0.51 g, (99%) of (5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.239 g, 3.67 mmol) generally according to the procedure described for Intermediate 98 afforded 0.16 g (65%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.24 g, 0.48 mmol) according to the procedure described in Example 154 afforded 0.126 g (50%) of (±)-[(5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 190-193° C. (dec).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21]Br>ClCCl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:21][CH2:20][CH2:19][Br:18])(=[O:3])[CH3:2]
Reactant: BrCCCBr
Reactant: CC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)Nc1cccc(OCCCBr)c1
Reaction time: 24 h

Procedure:
To 3-acetamidophenol (15.1 g) in dichloromethane (500 ml, dry) was added potassium carbonate (20 g) and then 1,3-dibromopropane (30 g). The resulting mixture was heated at reflux for 6 hours and then overnight at room temperature. After an additional 24 hours, the reaction was complete. Solids were filtered from the reaction mixture, and the solution was concentrated to an oil, which was purified to yield 3-(3-acetamidophenoxy)propyl bromide, 13.2 g.
Reaction SMILES: [H][H].Cl[C:4]1[C:9]([O:10][CH3:11])=[C:8](Cl)[N:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][CH:14]=2)[N:5]=1.C(N(CC)CC)C.C(O)C>[Pd].O>[CH3:11][O:10][C:9]1[CH:8]=[N:7][C:6]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:5][CH:4]=1
Reactant: COc1c(Cl)nc(-c2ccc(OCc3ccccc3)cc2)nc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: COc1cnc(-c2ccc(O)cc2)nc1
Temperature: 40 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
Hydrogen gas was blown into a mixture of 21 g of 4,6-dichloro-5-methoxy-2-(4-benzyloxyphenyl)pyrimidine, 18.1 g of triethylamine, 3.15 g of 10% palladium-on-carbon, 210 ml of ethanol, and 11 ml of water, followed by stirring at 40° C. for 6 hours. The catalyst was removed by filtration, and the filtrate was poured into 300 ml of water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and distilled to remove ethyl acetate to afford 8.93 g (percent yield: 90.9%) of 5-methoxy-2-(4-hydroxyphenyl)pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>ClCCl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: COc1ccc(Br)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(Br)c(CBr)c1
Reaction time: 4 h
Yield: 72.1 %

Procedure:
To a stirred solution of 4-bromo-3-methylanisole (100 g, 497 mmol) in dry dichloromethane (500 mL) was added N-bromosuccinimide (97 g, 545 mmol) followed by benzoyl peroxide (6 g, 25 mmol). The reaction was gently refluxed with a 150 watt flood lamp with reflector placed approximately 12 inches from the reaction flask. After 24 h the reaction was concentrated by rotary evaporation to half its volume and allowed to sit for 4 h. The white precipitate which formed was filtered off and rinsed with a small volume of dichloromethane. The filtrate was concentrated to dryness and the remaining solid was triturated with hexanes and filtered. Drying under vacuum gave the title compound (100.25 g, 72%) as white needles: GC tR=6.56 min (HP 530 μm×20 m methylsilicone column, He carrier flow 20 mL/min, 100° C. initial temp., 1 min initial time, 10° C./min rate, 200° C. final temp., 1 min final time); 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J=10 Hz, 1 H), 6.99 (d, J=3 Hz, 1 H), 6.73 (dd, 1H), 4.55 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[C:5](N)=[N:6][C:7]=1[CH3:8].N([O-])=[O:15].[Na+]>FC(F)(F)C(O)=O.O>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([OH:15])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1Br
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1nc(O)c([N+](=O)[O-])c(C)c1Br
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-4,6-dimethyl-3-nitro-2-pyridinylamine (Heitsch, H.; et al. Bioorg. Med. Chem. 1997, 5, 673, 2.0 g, 8.1 mmol) in trifluoroacetic acid/water (v/v, 2:1, 30 mL) was added sodium nitrite (1.1 g, 16 mmol) in small portions at room temperature, and then the reaction mixture was stirred overnight. The resulting precipitates were collected by filtration, washed with water, and dried under reduced pressure to give 2.2 g (quant.) of the title compound: 1H-NMR (CDCl3) δ 2.53 (3H, s), 2.38 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7](=O)[CH:8]([CH3:18])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[H-].[Na+].P(Cl)(OCC)(OCC)=O.[N+:33]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])#[C-:34].[H-].[Na+].C1COCC1>C1COCC1>[CH2:39]([O:38][C:36]([C:35]1[N:33]=[CH:34][N:6]2[C:7]=1[CH:8]([CH3:18])[N:9]=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[C:4]1[CH:3]=[C:2]([Br:1])[CH:21]=[CH:20][C:5]2=1)=[O:37])[CH3:40]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC1N=C(c2ccccc2F)c2cc(Br)ccc2NC1=O
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccc1F)c1cc(Br)ccc1-2
Temperature: -10 °C
Reaction time: 3 h

Procedure:
7-Bromo-5-(2′-fluorophenyl)-3-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 137 (3.78 g, 10.88 mmol) was suspended in dry THF (150 mL) and cooled to −10° C. Sodium hydride (60% dispersion in mineral oil, 0.52 g, 13.07 mol) was added into the suspension in one portion. The reaction mixture was allowed to stir and then warm to rt over 3 h period. The reaction mixture was again cooled to −10° C. and diethyl chlorophosphate (2.65 mL, 17.42 mmol) was added. The cooling bath was then removed and stirring continued for 3 h. During this time, sodium hydride (60% dispersion in mineral oil, 0.61 g, 15.24 mmol) was suspended in dry THF (60 mL) at −10° C. in another flask. Ethyl isocyanoacetate (1.43 mL, 13.07 mmol) was added to the NaH/THF suspension and this mixture allowed to stir for 3 h. After 3 h the first flask was cooled to −30° C. with a cooling bath and the mixture in the second reaction flask was added to the first flask via a cannula. The reaction mixture was allowed to stir for 24 h, after which it was cooled to 0° C. with an ice-water bath and slowly quenched with acetic acid (5 mL). Water was then added to the reaction mixture and this was extracted with EtOAc. The EtOAc layers were combined, washed with aq NaHCO3, brine and dried (Na2SO4). After removal of the solvent under reduced pressure the solid was purified by flash chromatography (silica gel, EtOAc:hexane: gradient elution 1:2, 1:1, 2:1). The ethyl ester 138 was a white solid (1.82 g, 38%). mp 190-192° C.; IR (KBr, cm−1) 3316, 2925, 1693, 1621, 1485, 1448, 1371; 1H NMR (CDCl3) δ 7.92 (s, 1H), 7.72 (dd, J=8.5, 1.5 Hz, 1H), 7.6 (t, J=6.9 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.42-7.49 (m, 2H), 7.23-7.29 (m, 1H), 7.05 (t, J=9.3 Hz, 1H), 6.71 (q, J=7.3 Hz, 1H), 4.41 (m, 2H), 1.42 (t, J=7.1 Hz, 3H), 1.29 (d, J=7.2, 3H). MS (EI) m/e (relative intensity) 442 (M+, 5), 428 (7), 381 (58), 355 (100), 303 (37); [α]26D=−10.9 (c 0.54, EtOAc).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9][C:8]2[CH:23]=[CH:24][CH:25]=[N:26][C:7]1=2.Cl.C([OH:32])(C)C>>[NH2:9][C:8]1[C:7]([N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:27])[CH3:1])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:32])=[N:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)O
Reactant: CN(C)CCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Agent: Cl
Product: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1N

Procedure:
A solution of N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine in isopropyl alcohol is treated with 25% hydrochloric acid at 0° C. to give a solution of the title compound.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2>O.C(O)(=O)C>[CH3:20][O:19][C:11]1[C:12]([O:17][CH3:18])=[CH:13][C:14]2[C:15]3[CH:16]=[N:1][NH:5][C:6]=3[CH:7]=[N:8][C:9]=2[CH:10]=1
Reactant: O=N[O-]
Reactant: COc1cc2ncc(N)c(C)c2cc1OC
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2ncc3[nH]ncc3c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
Sodium nitrite (1.28 g, 18.60 mmol), dissolved in water (2.5 ml), is added to a solution of 3-amino-6,7-dimethoxy-4-methylquinoline (2.70 g, 12.39 mmol) in glacial acetic acid (90 ml). The reaction mixture is stirred at room temperature for 3 h. When the reaction is complete, the mixture is evaporated in vacuo. The residue is taken up in water, filtered and rinsed with water. The filtrate is evaporated to dryness in vacuo. The residue obtained is filtered off with suction a number of times through a little flash silica gel in a frit with cyclohexane/ethyl acetate 4:1 (parts by volume) in order to remove impurities. The filtrate is discarded. The filter cake is subsequently washed with ethyl acetate/0-10% by vol. of ethanol, and the filtrate is evaporated to dryness in vacuo, giving 7,8-dimethoxy-3H-pyrazolo[3,4-c]-quinoline (2.29 g, purity 85%, 8.48 mmol) as a solid. MS: 230.0 (M+H+), TLC (HPTLC): Rf=0.45 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:24]=[C:23]([C:25]4[S:32][C:31]([CH3:33])=[C:30]5[C:26]=4[CH2:27][C@H:28]4[C:34]([CH3:36])([CH3:35])[C@H:29]45)[O:22][N:21]=3)=[CH:15][C:14]=2[CH3:37])([N+:8]([O-:10])=[O:9])[CH2:4][O:3]1.[OH-].[Na+]>C1COCC1.C(O)(C(F)(F)F)=O.O.C(O)(C(F)(F)F)=O.O>[CH3:19][C:18]1[CH:17]=[C:16]([C:20]2[N:24]=[C:23]([C:25]3[S:32][C:31]([CH3:33])=[C:30]4[C:26]=3[CH2:27][C@H:28]3[C:34]([CH3:35])([CH3:36])[C@H:29]34)[O:22][N:21]=2)[CH:15]=[C:14]([CH3:37])[C:13]=1[O:12][CH2:11][C:5]([N+:8]([O-:10])=[O:9])([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCC1([N+](=O)[O-])COC(C)(C)OC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCC(CO)(CO)[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 4.5 h
Yield: 98.8 %

Procedure:
A suspension of 3-[4-(2,2-dimethyl-5-nitro-[1,3]dioxan-5-ylmethoxy)-3,5-dimethyl-phenyl]-5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazole (85 mg, 0.158 mmol) in THF:TFA:water 20:4:1 (12.5 mL) is stirred at 65° C. for 4.5 h. The mixture is further diluted with TFA:water 2:1 (1.5 mL) and stirring is continued at 65° C. for 3 h. The mixture is cooled to rt, poured onto 2N aq. NaOH and extracted twice with DCM. The organic extracts are dried over MgSO4 and evaporated to give 2-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxymethyl}-2-nitro-propane-1,3-diol (78 mg) as a beige resin; LC-MS: tR=1.17 min, [M+1]+=500.89.
Reaction SMILES: [NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]O)[CH2:11][C@H:10]2[O:18][CH3:19])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.[Cl:25]C(Cl)Cl.[Cl-]>N1C=CC=CC=1>[OH2:7].[NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][Cl:25])[CH2:11][C@H:10]2[O:18][CH3:19])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCO)C[C@H]1OC
Reactant: ClC(Cl)Cl
Agent: [Cl-]
Solvent: c1ccncc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCl)C[C@H]1OC
Product: O
Temperature: 50 °C

Procedure:
To a stirred solution of 5.01 parts of cis-4-amino-5-chloro-N-[1-(2-hydroxyethyl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide in 112.5 parts of trichloromethane were added 1.33 parts of pyridine and 2 parts of thioyl chloride.. The whole was stirred and heated for 7 hours at 50° C. and subsequently stirred overnight at room temperature. The reaction mixture was washed with a sodium hydroxide solution and water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 9 parts of cis-4-amino-5-chloro-N-[1-(2-chloroethyl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate as a residue (interm. 15).
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.[K].S(O[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A mixture of potassium phthalimide (5.59 g, 30.2 mmoles) and 200 ml of dried N,N-dimethylformamide was heated to 110° C. To this mixture was added dropwise methyl 20-tosyloxyeicosanoate (10.0 g, 20.1 mmoles) dissolved in 300 ml of N,N-dimethylformamide and the resulting mixture was heated at 110° C. with stirring for 2 hours. After the completion of the reaction, the reaction mixture was treated in the same manner as in Reference Example 2 to give methyl 20-phthalimidoeicosanoate (8.97 g, 95%) having the following properties.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9]C=1.CCCCCC.[CH:27]([Br:30])(Br)[Br:28]>O>[Br:28][C:27]1([Br:30])[CH2:1][C:14]1([C:13]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C(=Cc1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: BrC(Br)Br
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Product: BrC1(Br)CC1(c1ccccc1)c1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
Under a nitrogen atmosphere, potassium tert-butoxide (14.8 g, 132 mmol), diphenylethylene (13.2 g, 73.3 mmol) and hexane (75 ml) were placed in a reaction flask and cooled to −5° C. To this, bromoform (24.1 ml, 95.4 mmol) was added gradually, and the mixture was stirred at the same temperature for 30 minutes. Then, water was added to the reaction mixture and the organic layer was extracted with toluene. The toluene extract was dried over anhydrous magnesium sulfate and then the solvent was removed under reduced pressure. The residue was recrystallized from a mixed solvent of isopropanol and toluene to give the title compound (14.4 g, 56%) as white crystal.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na+].Cl[CH2:29][CH2:30][CH2:31][CH2:32][OH:33].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Reactant: OCCCCCl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCCCCO)cc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 7.66 g of sodium 4-(n-hexadecylamino)benzoate, 7.55 g of 4-chloro-1-butanol, and 20.0 ml of hexamethylphosphoramide is stirred at 150° C for two hours, allowed to cool, and poured into water. The solid is collected by filtration and then is dissolved in methylene chloride. The solution is washed with water, dried, and evaporated. The residual solid is crystallized from hexane to yield 4-hydroxybutyl 4-(n-hexadecylamino)benzoate as a white solid, mp 61°-63° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([C@H:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH2:19][C@@H:18]2[CH2:29][OH:30])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[C:11]1([C@H:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:28])[C:24]([F:26])([F:27])[F:25])[CH2:19][C@@H:18]2[CH:29]=[O:30])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(N1CC[C@H](c2ccccc2)[C@@H](CO)C1)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C[C@H]1CN(C(=O)C(F)(F)F)CC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 110.2 %

Procedure:
A solution of 1.37 mL of DMSO in 20 mL of dichloromethane was cooled to −78° C., and added dropwise 0.845 mL of oxalyl chloride (internal temperature −60° C. or lower). After stirring at the same temperature for 20 minutes, a solution of 1.46 g of rel-[(3R,4S)-4-phenyl-1-(trifluoroacetyl)piperidin-3-yl]methanol in 20 mL of dichloromethane was added dropwise thereto, followed by stirring for additional 20 minutes. 4.40 mL of triethylamine was added dropwise thereto, and the reaction temperature was then elevated to −30° C., followed by stirring for additional 15 minutes. To the reaction mixture was added a saturated ammonium chloride solution to stop the reaction, followed by warming to room temperature, and then extraction with chloroform. The organic layer was washed with water, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 1.597 g of rel-(3R,4S)-4-phenyl-1-(trifluoroacetyl)piperidine-3-carbaldehyde as a crude product.