Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[CH3:28][NH2:29]>CO>[CH3:28][NH:29][C:1]([C:3]1[CH:4]=[C:5]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:26])[NH:19][C:20]3[C:25]\2=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)=[NH:2]
Reactant: CN
Reactant: N#Cc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Agent: Cl
Solvent: CO
Product: CNC(=N)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 62 from (Z)-3-[1-(3-cyanophenylamino)-1-phenyl-methylidene]-2-indolinone, methanolic hydrochloric acid and methylamine in methanol.
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:2]3[CH:18]=[CH:17][C:5]4[N:6]([CH2:10][CH2:11][N:12]5[CH2:16][CH2:15][CH2:14][CH2:13]5)[C:7](=[O:9])[NH:8][C:4]=4[CH:3]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: O=c1[nH]c2cc(I)ccc2n1CCN1CCCC1
Product: O=c1[nH]c2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2n1CCN1CCCC1

Procedure:
Prepared according to general working method II from 5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one (140 mg, 0.39 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (83 mg, 0.39 mmol).
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[C:15](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[CH:14][C:13]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([NH:43][CH3:44])[N:38]=2)=[CH:12][N:11]=1.C(=O)(O)[O-].[Na+]>CO>[N:24]1([C:21]2[CH:20]=[CH:19][C:18]([CH:17]=[CH:16][C:15]3[C:10](=[O:9])[NH:11][CH:12]=[C:13]([C:37]4[CH:42]=[CH:41][N:40]=[C:39]([NH:43][CH3:44])[N:38]=4)[CH:14]=3)=[CH:23][CH:22]=2)[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1
Reactant: CNc1nccc(-c2cnc(OC)c(/C=C/c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CNc1nccc(-c2c[nH]c(=O)c(C=Cc3ccc(N4CCNCC4)cc3)c2)n1
Temperature: 150 °C
Yield: 95.2 %

Procedure:
Pyridine hydrochloride (2 g) was added to tert-butyl 4-(4-((E)-2-(2-methoxy-5-(2-(methylamino)pyrimidin-4-yl)pyridin-3-yl)vinyl)phenyl)piperazine-1-carboxylate (168 mg, 0.33 mmol) and the mixture was heated at 150° C. for 30 min. The reaction mixture was dissolved in MeOH (30 mL) and solid sodium bicarbonate was added until bubbling ceased. The suspension was filtered and the filtrate was concentrated. Purification by column chromatography (DCM/MeOH/aq. NH3 gradient) gave the title compound (122 mg, 94%) as a yellow solid.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([C:17]2[N:21]([S:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])[C:20]([CH3:31])=[C:19]([C:32]([O:34]CC)=[O:33])[CH:18]=2)[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:13]([C:11]1[CH:10]=[C:9]([C:17]2[N:21]([S:22]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:24])=[O:23])[C:20]([CH3:31])=[C:19]([C:32]([OH:34])=[O:33])[CH:18]=2)[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(S(=O)(=O)N2CCCCC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1S(=O)(=O)N1CCCCC1
Yield: 89.4 %

Procedure:
To a solution of NaOH (2.72 g, 67.8 mmol) in H2O was added to compound 4c (800 mg, 1.7 mmol) in MeOH (60 mL) and refluxed for 3 h, evaporated, diluted with H2O, acidified with conc. HCl to pH ˜2, extracted with EA (3×30 mL), washed by brine, dried with Na2SO4 and concentrated to get the compound 4d (700 mg, 90%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:28]=1[CH2:29][NH:30][C:31](=[O:37])[C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C@H:9]1[C:10]([N:33]1[CH2:34][CH2:35][CH2:36][C@H:32]1[C:31]([NH:30][CH2:29][C:28]1[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:27]=1[CH2:26][NH:25][C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:24])=[O:37])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C)C1C(=O)O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1N(C(=O)OC(C)(C)C)CCC1(C)C

Procedure:
1-(tert-Butoxycarbonyl)-3,3-dimethylprolyl-N-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)-L-prolinamide was prepared as a mixture of diastereomers from 1-(tert-butoxycarbonyl)-3,3-dimethyl-D,L-proline (73 mg, 0.30 mmol) and L-prolin-N-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)amide (111 mg, 0.30 mmol) essentially according to the EDC coupling procedure described in Step 3 of Example 46. The diastereomeric products were separated by reverse phase HPLC as described in Step 3 of Example 46. Diastereomer A: LCMS RT=2.44 min. LCMS (M+H)=593.4. Diastereomer B: LCMS RT=2.58 min. LCMS (M+H)=593.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.[C:29]([O:33][C:34]([NH:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40]O)=[O:35])([CH3:32])([CH3:31])[CH3:30].N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>C(Cl)Cl.C1COCC1>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:27])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[C:37]([NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH:38]=3)=[CH:24][CH:25]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(OCc3cccc(NC(=O)OC(C)(C)C)c3)cc2)cc1
Yield: 83 %

Procedure:
2-(2-(4-(4-Hydroxyphenoxy)phenyl)acetylamino)benzoic acid methyl ester obtained by the Reference Example 24 (315 mg, 0.83 mmol) was dissolved in 20 ml of methylene chloride-THF mixture (1:1 v/v), added with 3-(tert-butoxycarbonylamino)benzyl alcohol (465 mg, 2.1 mmol), 1,1′-azobis(N,N′-dimethylformamide) (359 mg, 2.08 mmol) and tri-n-butyl phosphine (520 ml, 2.1 mmol) and the reaction mixture was stirred over a night. After completing the reaction, the solvent was removed under reduced pressure and the obtained crude residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate 75:25 v/v) to obtain the subject compound (404 mg, 0.693 mmol) in the form of a colorless gummy substance. The result of 1H-NMR was consistent with the above structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1.[CH2:43]([O:45][CH2:46][CH2:47][C:48](Cl)=[O:49])[CH3:44]>>[CH2:43]([O:45][CH2:46][CH2:47][C:48]([NH:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:17][CH:18]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:8]1)=[O:49])[CH3:44]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(N)c2)cc1
Reactant: CCOCCC(=O)Cl
Product: CCOCCC(=O)Nc1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
Analogously to Example 116b, 1.81 g of tert-butyl 3-(3-aminobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 118c) and 0.612 g of 3-ethoxypropionyl chloride are reacted. The title compound is obtained as a colourless oil. Rf=0.22 (1:1 EtOAc-heptane); Rt=5.77.
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[C:20]=1[Br:25]>>[Br:25][C:20]1[C:21]([CH3:24])=[N:22][O:23][C:19]=1[NH:18][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Reactant: Cc1noc(N)c1Br
Product: COc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 1. Reaction of 5-chlorosulfonyl-2-(4-methoxyphenyl)thiophene with 5-amino-4-bromo-3-methylisoxazole gave N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamide in 50% yield, m.p. 128-130° C.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14](=[O:16])[CH3:15])=[C:8]([F:17])[CH:7]=1.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CCOCC>[CH2:22]([O:21][C:19](=[O:20])[C:18](=[O:24])[CH2:15][C:14](=[O:16])/[CH:13]=[CH:12]/[C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][C:8]=1[F:17])[CH3:23]
Reactant: CC(=O)/C=C/c1ccc(Cl)cc1F
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1F
Temperature: -5 °C
Reaction time: 48 h
Yield: 86.5 %

Procedure:
Sodium pellets (2.88 g, 0.125 mol) were slowly added to absolute ethyl alcohol (EtOH, 125 mL). After the sodium had reacted, the solvent was removed under reduced pressure, and anhydrous ether (200 mL) was added. The reaction mixture was cooled to −5° C., and a solution of (E)-4-(4-chloro-2-fluorophenyl)-but-3-en-2-one (1; 24.75 g, 0.125 mol) and diethyl oxalate (21.9 g, 0.15 mol) in anhydrous ether (25 mL) was added over 30 min. After stirring 2 days (d) at room temperature, the yellow solid was filtered and washed with ether. After 1 hour (h) of drying at room temperature, the solid was partitioned between CH2Cl2 (200 mL) and 1 N sulfuric acid (H2SO4, 150 mL). The organic layer was dried (MgSO4), and the solvent was removed to give (E)-6-(4-chloro-2-fluoro-phenyl)-2,4-dioxo-hex-5-enoic acid ethyl ester (3; 32.3 g, 86%) as a yellow solid. A small sample was recrystallized from EtOH to yield yellow crystals: mp 84-85° C.; 1H NMR (400 MHz, CDCl3) δ 14.72 (s, 1H), 7.76 (d, J=16.1 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.24-7.12 (m, 2H), 6.73 (d, J=16.1 Hz, 1H), 6.53 (s, 1H), 4.38 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C14H12ClFO4, 298.041. found, 298.041.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([C:14]([F:13])([F:24])[F:25])[CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccc(C(F)(F)F)c1
Yield: 71.5 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 3-(trifluoromethyl)benzoic acid (347 mg, 1.83 mmol), BOP-Cl (465 mg, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethyl)benzamide (250 mg, 71% yield) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C2CCCCO2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=2)[CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=3)[CH:16]=2)=[C:2]([CH3:1])[CH:7]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(OC4CCCCO4)cc3C)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccc(O)cc3C)c2)cc1
Yield: 98.4 %

Procedure:
A solution of methyl 3-(4-{[2′-methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methoxy}phenyl)propanoate (3.78 g, 8.21 mmol) and p-toluenesulfonic acid monohydrate (0.156 g, 0.821 mmol) in methanol (60 mL) was stirred at room temperature for 2 hrs. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound (3.04 g, yield 98%) as a colorless viscous oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[CH3:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[S:23][CH3:22])[CH2:35][CH2:34]2)=[O:21])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CSc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3SC)CC2)c(OC)nc1C
Yield: 56 %

Procedure:
Phenyl N-(5-ethyl-6-methyl-2-methoxypyridin-3-yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:5][CH:4]=1.[O:36]([CH2:43][CH2:44]Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:1][CH2:44][CH2:43][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:4][CH:5]=2)[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]1[CH2:12][CH2:13]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(CO)cc1)C2
Reactant: BrCCOc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(COCCOc3ccccc3)cc1)C2

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (1RS,2RS,3RS,5SR)-3-(4-hydroxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate [Example 86(eee)] with phenoxy-ethyl bromide there was obtained tert-butyl (1RS,2RS,3RS,5SR)-2-(naphthalen-2-ylmethoxy)-3-[4-(2-phenoxy-ethoxymethyl)-phenyl]-8-aza-bicyclo[3.2.1]octane-8-carboxylate as a colourless oil; MS: 611 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]3)=[O:30])=[CH:25][CH:24]=2)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:10]1=[O:21].C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>ClCCl>[Cl:22][C:6]1[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:38])([F:40])[F:39])[CH2:33][CH2:32]3)=[O:30])=[CH:25][CH:24]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][S:49]([CH3:48])(=[O:51])=[O:50])[CH2:16][CH2:15]2)[C:10]1=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@H](O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve (R)-3-[3,5-Dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one (Preparation 23) (0.419 g, 0.70 mmol) in 10 ml of dry dichloromethane at 0° C. Add triethylamine (0.18 ml, 1.41 mmol) followed by methanesulfonyl chloride (0.06 ml, 0.77 mmol). Stir at room temperature for 5 hours. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with 1N HCl, NaHCO3 and brine. Dry over magnesium sulfate, filter, and concentrate. Filter through a short silica plug to receive 0.45 g (95%) of the title compound: Mass spectrum (apci) m/z=675 (M+H).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2O.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[N:13]1[C:9](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]1=[O:14]
Reactant: O[C@H]1C[C@H]2CC[C@@H]1C2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H]2CC[C@@H]1C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.1 %

Procedure:
To a solution of (1R,2S,4S)-bicyclo[2.2.1]heptane-2-ol (1.0 g) in tetrahydrofuran (10 ml) were added phthalimide (1.4 g) and triphenylphosphine (2.6 g), and diethylazodicarboxylate (1.5 ml) dropwise under ice cooling. The mixture was warmed to ambient temperature and stirred for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate)=100:0 to 95:5) to obtain 2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-1H-isoindole-1,3(2H)-dione (1.4 g) as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH:19]([C:23]#[N:24])[CH2:18]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[ClH:25].[CH3:26][OH:27]>>[ClH:25].[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH:19]([C:23](=[NH:24])[O:27][CH3:26])[CH2:18]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CO
Reactant: CCn1c2ccccc2c2cc(CN3CCCC(C#N)C3)ccc21
Agent: Cl
Product: CCn1c2ccccc2c2cc(CN3CCCC(C(=N)OC)C3)ccc21
Temperature: -5 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A 100-mL 3-necked round-bottomed flask was charged with 1-((9-ethyl-9H-carbazol-3-yl)methyl)piperidine-3-carbonitrile (1.31 g, 4.05 mmol, 1.00 equiv, 98%) from Example 13 in anhydrous MeOH (20 mL). Then, this was treated with HCl gas. The resulting solution was allowed to stir at −5° C. for 3 hours, followed by at −20° C. for overnight. Resulting precipitate was collected by filtration and dried to afford methyl 1-((9-ethyl-9H-carbazol-3-yl)methyl)piperidine-3-carbimidate hydrochloride as white solid (1.44 g, 92%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C:21]([F:24])([F:23])[F:22])[C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:27]>>[CH2:1]([O:8][C@H:9]([C:21]([F:23])([F:22])[F:24])[C@@H:10]([NH:13][C:14]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:20])[C:11]([OH:27])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)[C@H](OCc1ccccc1)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)[C@H](OCc1ccccc1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (2S,3S)-3-(benzyloxy)-4,4,4-trifluoro-1-hydroxybutan-2-ylcarbamate (1.47 g, 4.2 mmol) in acetone (80 mL) was added Jone's reagent (8.2 mL) at 0° C. The mixture was stirred at the same temperature for 3 h until the starting material was completely consumed, then the reaction was quenched by adding isopropanol (5 mL). The reaction mixture was extracted with EtOAc. The extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave the crude (2R,3S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid (1.56 g), which was used directly for the following reaction. 1H NMR (400 MHz, CD3OD, δ in ppm) 7.25˜7.34 (m, 5H), 4.76 (d, J=10.9 Hz, 1H), 4.70 (d, J=10.9 Hz, 1H), 4.53 (d, J=6.4 Hz, 1H), 4.32 (m, 1H), 1.41 (s, 9H).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].N1C=CC=CC=1.[F:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[OH:21].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>ClCCl>[F:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[O:21][C:2](=[O:3])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: O[C@H]1CCCC[C@@H]1F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)O[C@H]1CCCC[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-chloroethyl chloroformate (1.0 mL), pyridine (1.0 mL), and dichloromethane (30 mL), (1S,2S)-2-fluorocyclohexanol [CSA No. 292150-03-9] (900 mg) dissolved in dichloromethane (10 mL) was added at −78° C. After stirring the resulting mixture overnight at room temperature, dichloromethane (30 mL) was added to the mixture. The resulting mixture was sequentially washed with 0.5 N hydrochloric acid and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (480 mg).
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[C:6]([O:25][CH3:26])=[CH:7][C:8]2[CH2:9][CH:10]3[CH2:24][NH:23][CH2:22][CH2:21][N:11]3[CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O.C(Cl)(Cl)Cl>[ClH:1].[ClH:1].[CH3:3][O:4][C:5]1[C:6]([O:25][CH3:26])=[CH:7][C:8]2[CH2:9][CH:10]3[CH2:24][N:23]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:22][CH2:21][N:11]3[CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[CH:14]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNCC1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(c1ccccc1)N1CCN(Cc3ccccc3)CC1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
8,9-Dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline dihydrochloride (the compound obtained in Example 1-(6)) (2 g) is dissolved in N,N-dimethylformamide (10 ml), and thereto are added potassium carbonate (2.8 g) and benzyl bromide (0.7 ml), and the mixture is stirred at room temperature for 3 hours. The reaction solution is diluted with chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitates (1.2 g) are dissolved in chloroform, and thereto is added a 4M hydrochloric acid in ethyl acetate, and the solvent is removed by evaporation under reduced pressure. The resultant is recrystallized from ethanol to give 8,9-dimethoxy-2-benzyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline dihydrochloride (1.2 g).