Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:3][C:4](=[NH:12])OC1C=CC=CC=1)#[N:2].[CH:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>CCOCC>[C:1]([NH:3][C:4](=[NH:12])[NH:23][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)#[N:2]
Reactant: NC1CCCc2ccccc21
Reactant: N#CNC(=N)Oc1ccccc1
Solvent: CCOCC
Product: N#CNC(=N)NC1CCCc2ccccc21
Temperature: 220 °C

Procedure:
A 25 ml round bottom flask containing a mixture of 4.8 g of N-cyano-O-phenylisourea and 6 g of 1,2,3,4-tetrahydro-1-naphthylamine was placed in an oil bath preheated to 190° C. The bath temperature was raised to 220° C. over 20 minutes and maintained at 220° C. for 8 minutes. Upon cooling, the reaction mixture had a glass-like appearance. The product was isolated from the reaction mixture by thorough shaking of the reaction mixture with ether to remove the remaining starting materials and phenol, and decanting the ether solution which left the crude product as a white gummy residue. The crude product was further purified by chromatography on a column packed with silica gel and eluting initially with toluene then with toluene-ethyl acetate mixtures with gradual increase in the ethyl acetate content. This gave 4.61 g of the desired compound that had satisfactory data in spectroscopic analysis.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][C@@H:23]1OS(=O)(=O)[N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]1>CN(C=O)C>[C:33]([O:32][C:30]([NH:25][CH2:24][C@@H:23]([N:3]1[C:7]2=[N:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:22])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n([C@@H](C)CNC(=O)OC(C)(C)C)c2n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
To a suspension of 60% sodium hydride in mineral oil (503 mg, 12.6 mmol) in DMF (10 mL) cooled to 0° C. is added a solution of diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (Intermediate D, 3.00 g, 11.4 mmol) in DMF (10 mL), dropwise. The mixture is stirred at 0° C. for 30 min after which a solution of tert-butyl (5S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (2.71 g, 11.4 mmol) in DMF (10 mL) is added. The mixture is allowed to warm and stir at room temperature for 16 h. The reaction is quenched with H2O and is stirred for 15 min. The mixture is extracted with ethyl acetate and the combined organic phases are washed with brine and are dried (Na2SO4). The solvent is removed in vacuo and the crude material is purified via flash column chromatography using a gradient elution of 0-30% ethyl acetate/heptane to afford the title compound (3.00 g, 63%). LCMS: 442.86 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])=[O:4].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[O:10][CH3:12])=[O:4]
Reactant: COC(=O)c1scc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1scc(Br)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 129.3 %

Procedure:
Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (˜200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on high vacuum, yielding 13.7 g (100%) of methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH+=251.0).
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:22]=2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:34]([O:38][C:39](=[O:45])[NH:40][CH2:41][CH2:42][CH2:43]Br)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:45])[NH:40][CH2:41][CH2:42][CH2:43][N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:11](=[O:12])[C:10]2[CH:20]=[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[CH:22]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][CH:32]=3)[CH:9]=2)[CH2:19][CH2:18]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCNCC3)c2)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Product: CC(C)(C)OC(=O)NCCCN1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 85 %

Procedure:
Following procedure of Example 11(e) 3,5-bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide 0.35 g (0.79 mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester (0.188 g, 0.79 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.38 (9H, s), 1.52 (4H, m), 1.75 (2H, m), 1.90 (2H, m), 2.28 (2H, m), 2.82 (1H, m), 2.92 (2H, m), 3.74 (1H, brs), 3.68 (1H, m), 6.79 (1H, brs), 7.18 (1H, t), 7.26 (4H, d), 7.52 (2H, s), 7.88 (4H, d), 8.38 (1H, d).
Reaction SMILES: C(N(CC)CC)C.[O:8]([C@H:16]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([CH:28]=[O:29])[CH2:17]1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[N+:30]([CH3:33])([O-:32])=[O:31]>>[O:8]([C@H:16]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([CH:28]([OH:29])[CH2:33][N+:30]([O-:32])=[O:31])[CH2:17]1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)C[N+](=O)[O-]
Yield: 65.5 %

Procedure:
Triethylamine (1.27 ml, 9.55 mmol) was added to a solution of (2S,4R)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonylprolinal (19.1 g, 57.87 mmol) in nitromethane (95 ml) under stirring and cooling with ice. This solution was left to stand at room temperature for hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel™ C-300, 350 g, hexane-ethyl acetate 9:1) to obtain oily (2S,4R)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonyl-2-(1-hydroxy-2-nitroethyl)pyrrolidine (14.81 g, yield: 65.5%). IR(KBr)cm-1 : 3420, 1675, 1700, 1560, 1415, 1255, 1165, 840, 780
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@H:15]1[CH2:19][N:18](C(OC(C)(C)C)=O)[C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]1)=[O:13])[CH2:7]2)=[CH2:2].[ClH:31].O1CCOCC1>>[ClH:31].[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@@H:15]1[CH2:16][C@@H:17]([C:27]([O:29][CH3:30])=[O:28])[NH:18][CH2:19]1)=[O:13])[CH2:7]2)=[CH2:2]
Reactant: C=Cc1cccc2c1CN(C(=O)O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)C2
Agent: Cl
Solvent: C1COCCO1
Product: C=Cc1cccc2c1CN(C(=O)O[C@H]1CN[C@H](C(=O)OC)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
A mixture of 1-t-butyl 2-methyl (2S,4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (18.0 g, 43.2 mmol) and HCl/dioxane (4 M) (43.2 mL, 173 mmol) was stirred at RT for 2h. The reaction mixture was concentrated to remove the dioxane followed by concentration from Et2O to give (3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate hydrochloride as an off-white solid (15 g) which was used without further purifcation. LRMS (ESI) m/z 317 [(M+H)+; calcd for C17H21N2O4: 317].
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:9][CH2:10][CH:11]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12]2)[CH:2]=1.[CH3:31][O:32][C:33](=[O:44])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42]Br)=[CH:36][CH:35]=1>>[CH3:31][O:32][C:33](=[O:44])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][N:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH:11]2[CH2:10][CH2:9][CH:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:7][C:3]2[CH:2]=[C:1]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:6]=[CH:5][CH:4]=2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2cccc(-c3ccccc3)c2)O[Si](C)(C)C(C)(C)C)cc1
Yield: 74.2 %

Procedure:
Analogous to the procedure described for Compound 1A, Step D, 5-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (5.116 g, 12.08 mmol) was alkylated with 4-(3-bromo-propyl)-benzoic acid methyl ester (3.41 g, 13.3 mmol) over 20 h. Purification by medium pressure chromatography using a solvent gradient (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 4-(3-{2-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (5.38 g). 1H NMR (CDCl3) δ 7.93 (d, 2H), 7.56 (d, 2H), 7.43 (m, 3H), 7.34 (m, 3H), 7.23 (m, 2H), 7.12 (m, 1H), 3.89 (m, 1H), 3.87 (s, 3H), 3.64 (m, 1H), 3.49 (m, 1H), 2.95-2.61 (m, 5H), 2.30 (m, 2H), 2.01 (m, 1H), 1.89-1.70 (m, 3H), 1.59-1.24 (m, 4H), 0.84 (s, 9H), −0.04 (d, 3H), −0.16 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:20])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:5](O)=[O:6].[CH3:21][S:22]([NH2:25])(=[O:24])=[O:23]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:20])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:5]([NH:25][S:22]([CH3:21])(=[O:24])=[O:23])=[O:6]
Reactant: O=C(O)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Yield: 67.6 %

Procedure:
3,5-Dibromo-4-(3-bromobenzyloxy)benzoic acid (0.15 mmol) was coupled with methanesulphonamide (0.77 mmol) using the procedure described in Example 31. Purification on column (silica gel, chloroform/methanol 9:1) gave 55 mg (67%) of N-[3,5-dibromo-4-(3-bromobenzyloxy)benzoyl]methanesulphonamide.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([OH:14])[C@H:11]([OH:13])[CH3:12].N1C(C)=CC(C)=CC=1C>ClCCl>[C:1]([O:14][CH2:10][C@H:11]([OH:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H](O)CO
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: C[C@@H](O)COC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
Benzoyl chloride (10.98 mL, 94.62 mmol) was added dropwise to a solution of (R)-(−)-1,2-propanediol (6.00 g, 78.85 mmol) and 2,4,6-collidine (7.22 mL, 54.67 mmol) in 100 mL of anhydrous dichloromethane at −78° C. The reaction was stirred at −78° C. for three hours and at room temperature for 1 hr, before quenching with water (10 mL) for 15 minutes. The quenched mixture was washed with 0.5N HCl (4×50 mL) until the dark color diminished, and then with saturated NaHCO3 solution (4×50 mL) and brine. The organic layer was separated, dried over Na2SO4 and concentrated. Chromatography (silica gel 230-400 Mesh, 1:9 ethyl acetate/Hexane) of the residue afforded 8.9 g (63%) of (2R)-2-Hydroxypropyl benzoate as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.13 (d, J=6.4 Hz, 3H), 3.93 (m, 1H), 4.10 (m, 2H), 4.95 (d, J=4.8 Hz, 1H), 7.51 (t, J=7.2 Hz, 2H), 7.64 (t, J=7.6 Hz, 1H), 7.99 (d, J=6.8 Hz, 2H); MS (ESI) m/z 181 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:16][C:17]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][C:20]1[N:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:26][C:23]4[CH:24]=[N:25][C:20]([O:19][C:18]5[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:17]=5[CH3:16])=[CH:21][CH:22]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cccc(Oc2ccc(N)cn2)c1C
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: c1ccncc1
Product: Cc1cccc(Oc2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cn2)c1C
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 6-(2,3-dimethylphenoxy)pyridin-3-amine (43 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 402.4, found 403.1 (M+1)+. Retention time 3.11 minutes.
Reaction SMILES: [Na].[Br:2][C:3]1[NH:4][C:5]([Br:9])=[C:6]([Br:8])[N:7]=1.[H-].[Na+].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18]Br>CN(C)C=O.O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][N:4]1[C:5]([Br:9])=[C:6]([Br:8])[N:7]=[C:3]1[Br:2]
Reactant: Brc1nc(Br)c(Br)[nH]1
Reactant: BrCCCCOCBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCOCn1c(Br)nc(Br)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
To a solution of a sodium salt, prepared from 1.22 g of 2,4,5-tribromoimidazole and 0.16 g of 60% oil-based sodium hydride, in 5 ml of N,N-dimethylformamide was added dropwise 1.23 g of 4-bromobutoxymethyl bromide at room temperature. After stirring at room temperature for 3 hours, 50 ml of water was added to the reaction mixture which was then extracted with three 30-ml portions of ether. The ether layer was dried over magnesium sulfate and concentrated. The oily product obtained was purified by column chromatography on silica gel to obtain 0.74 g of 1-(4-bromobutoxymethyl)-2,4,5-tribromoimidazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)#[N:2].[NH:20]1[C:28]2[C:23](=[C:24]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:12][N:8]1[C:9]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[C:6]([CH:13]2[CH2:18][CH2:17][CH:16]([N:32]3[CH2:33][CH2:34][N:29]([C:24]4[C:23]5[CH:22]=[CH:21][NH:20][C:28]=5[CH:27]=[CH:26][CH:25]=4)[CH2:30][CH2:31]3)[CH2:15][CH2:14]2)=[CH:7]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cn1cc(C2CCC(N3CCN(c4cccc5[nH]ccc45)CC3)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A solution of 4-(5-cyano-1-methyl-3-indolyl)-cyclohexanone (0.75 g, 3 mmol), 1-(indol-4-yl)piperazine (0.6 g, 3 mmol), sodium triacetoxyborohydride (0.95 g, 4.5 mmol) and acetic acid (0.34 ml, 6 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml) and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.73 g (56%) of product as a white solid: mp 274-275° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:6][C@@H:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
A suspension of L-serine-methyl ester hydrochloride (5 g, 32.13 mmol) in CH2Cl2 (100 mL) was added with TEA (1.1 mol eq, 4.9 mL) and the mixture was stirred at r.t. for 10 minutes. Then 4-chlorobenzensulfonyl chloride (1 mol eq, 6.81 g) and additional TEA (1.1 mol eq) were added and the solution hated at 50° C. for 5 h. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase extracted with EtOAc (3×40 mL). The combined organic phases were dried over Na2SO4 and evaporated to reduced pressure. The residue was recrystallized from ethyl ether to afford 2C as white solid (8.6 g, 91% yield). 1HNMR (DMSO, 200 MHz) δ 3.51 (s, 3H), 3.60 (m, 2H), 3.91 (t, 1H), 5.17 (t, 1H), 7.50 (d, 2H, J=8), 7.89 (d, 2H, J=7.8)), 8.35 (bs, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][C:12]#[N:13]
Reactant: OCc1cccc(O)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: N#CCOc1cccc(CO)c1

Procedure:
A mixture of 3-hydroxymethyl phenol (0.081 mol), bromoacetonitrile (0.081 mol) and anhydrous potassium carbonate (0.081 mol) in acetone (160 ml) and dimethylformamide (20 ml) is heated at reflux for 48 hrs. The reaction mixture is filtered and evaporated. The residue is diluted with ethyl acetate (150 ml), washed with 10% aqueous sodium hydroxide solution (3×100 ml) and then with brine (3×100 ml). The ethyl acetate solution is dried (magnesium sulfate) and chromatographed using a silica gel column (ca. 100 g) and eluted with 1:1 petroleum ether:ethylacetate (21). The resultant oil is used directly in the next step.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[C@H:13](O)[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:35])CC)C>ClCCl>[CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[C@H:13]([F:35])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N(Cc2ccccc2)Cc2ccccc2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)[C@H](N(Cc2ccccc2)Cc2ccccc2)C1
Yield: 67.8 %

Procedure:
To a dichloromethane solution (8.7 mL) of tert-butyl (3R,4R)-3-(dibenzylamino)-4-hydroxypyrrolidine-1-carboxylate (320 mg, 0.92 mmol) synthesized in Reference Synthesis Example 71, (diethylamino)sulfur trifluoride (295 mg, 1.84 mmol) was added at 0° C. and the resultant solution was stirred at room temperature. After completion of the reaction, the reaction solution was washed with water and saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product (240 mg) of the title compound. The crude product was used in the next reaction as it was.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]#[N:10].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([O:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>CN(C=O)C>[C:9]([C:8]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH:7]=1)[O:5][CH2:4][CH2:3][NH:2][C:40](=[O:41])[C:39]1[CH:38]=[CH:37][C:36]([O:35][CH:32]2[CH2:31][CH2:30][N:29]([C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:28])[CH2:34][CH2:33]2)=[CH:44][CH:43]=1)#[N:10]
Reactant: N#Cc1ccc(OCc2ccccc2)c(OCCN)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)NCCOc3cc(C#N)ccc3OCc3ccccc3)cc2)CC1
Reaction time: 8 h

Procedure:
1.06 g (3.50 mmol) of 3-(2-aminoethoxy)-4-benzyloxybenzonitrile hydrochloride was dissolved in 15 ml of DMF. 1.23 g (3.84 mmol) of 4-(1-t-butoxycarbonyl-4-piperidyloxy)benzoic acid, 710 mg (4.2 mmol)) of 2-chloro-1,3-dimethylimidazonium chloride and 1.45 ml (5.19 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. After the treatment with dichloromethane as the extraction solvent in an ordinary manner, the solvent was evaporated, and the obtained residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1.[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:18]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: OCCCCCCCl
Reactant: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(O)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(OCCCCCCCl)cc2)cc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 74.9 %

Procedure:
7.35 g (22.5 mmol) 4-pentoxyphenyl (2E)-3-{4-hydroxyphenyl}acrylate, 3.36 g (24.6 mmol) 6-chloro-1-hexanol and 6.45 g (24.6 mmol) of triphenylphosphine were dissolved in 100 ml of tetrahydrofurane. The colourless solution was subsequently cooled to 0° C. and 4.28 g (24.6 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene were added dropwise thereto over a period of 25 minutes. The mixture was subsequently allowed to react for 4 h at 0° C. The reaction mixture was reduced in volume by evaporation. The resulting residue was added to a mixture of methanol and water (3:2) and was then extracted with a mixture of tert.-butyl-methylether:hexane 1:1. The tert.-butyl-methylether:hexane phase was washed repeatedly with water, dried over magnesium sulphate, filtered and concentrated by rotary evaporation to yield 7.5 g 4-pentoxyphenyl (2E)-3-{4-(6-chlorohexyloxy)phenyl}acrylate as yellowish crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH:15]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1N1CCC(N2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2-methoxy-5-nitrophenyl)piperidin-4-one (Preparation Example 502) (296 mg), 1-methylpiperazine (0.20 mL) and 1,2-dichloroethane (11 mL), sodium triacetoxyborohydride (385 mg) was added and stirred overnight at room temperature. After addition of water and saturated aqueous sodium hydrogen carbonate, the reaction liquid was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=100:0 to 10:1) to give 1-[1-(2-methoxy-5-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0.40 g) as a brown oil.