Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([S:19]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][C:4]=1[C:30]1[O:31][CH:32]=[CH:33][CH:34]=1.[C:36](O)(=[O:40])[CH2:37][CH2:38][CH3:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH3:1][N:2]([CH3:35])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([S:19]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH2:26][CH2:25]3)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][C:4]=1[C:30]1[O:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCCC(=O)O
Reactant: CN(C)c1ccc(NS(=O)(=O)c2cccc(S(=O)(=O)NCC3CCNCC3)c2)cc1-c1ccco1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)N1CCC(CNS(=O)(=O)c2cccc(S(=O)(=O)Nc3ccc(N(C)C)c(-c4ccco4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 373.7 %

Procedure:
To a solution (1.5 ml) of Y516 (60 mg, 0.098 mmol) produced in Example 35 in dimethylformamide were added n-butanoic acid (butyric acid) (20 μl, 0.02 mmol), HBTU (N,N,N′,N′-tetramethyl-O— (benzotriazol-1-yl)uronium Hexafluorophosphate) (40 mg, 0.1 mmol) and DIEA (N,N-diisopropylethylamine) (30 ml, 0.18 mmol), and the mixture was stirred at room temperature for 18 hr. Then, the reaction mixture was cooled, poured into cold water, and extracted with chloroform. The obtained chloroform extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol (40:1)) to give the title compound (Y639) (44 mg, 77%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Clc1ncccn1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1cnc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)nc1

Procedure:
1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.3 g, 8.0 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloropyrimidine (0.914 g, 8.0 mmol) were stirred in anhydrous DMF (15 mL) at 140° C. for 24 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous NH4Cl solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (2×80 mL) and dried with MgSO4. The solvents were evaporated and the product was isolated by column chromatography (silica gel, EtOAc:Hexane=1:9) as a yellowish solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.C[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(C2CN=C(c3ccccn3)O2)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc(C2=NCC(c3cccc(OCc4ccc5ccccc5n4)c3)O2)nc1
Yield: 21.8 %

Procedure:
A solution of 4,5-dihydro-5-(3-hydroxyphenyl)-2-(2-pyridyl)-1,3-oxazole (7.3 g, 0.03 mol) and 2-(chloromethyl)quinoline (5.4 g, 0.03 mol) in dimethylformamide (200 ml) is heated to 90° for 16 hours in the presence of sodium methoxide (1.6, 0.03 mol). The mixture is dissolved in ethyl acetate and water. The aqueous layer is extracted twice with ethyl acetate. The combined ethyl acetate solutions are washed twice with dilute aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to obtain an oil. This material is chromatographed on a Water Prep Pak 500 silica column with methylene chloride/methanol 99/1 (v/v) as mobile phase to obtain 2.5 g of purified material as a viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH2:18][OH:19])([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:20])[CH:3]=1.[C:21]([C:25]1[CH:30]=[C:29]([CH2:31][OH:32])[C:28]([CH3:33])=[CH:27][C:26]=1[S:34]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:24])([CH3:23])[CH3:22].CCN(CC)CC>C(#N)C>[C:21]([C:25]1[CH:30]=[C:29]([CH2:31][OH:32])[C:28]([CH3:33])=[CH:27][C:26]=1[S:34][C:3]1[C:4](=[O:20])[O:5][C:6]([CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH2:18][OH:19])([CH:8]([CH3:9])[CH3:10])[CH2:7][C:2]=1[OH:1])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: CC(C)C1(CCc2ccsc2CO)CC(O)=CC(=O)O1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(SC2=C(O)CC(CCc3ccsc3CO)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16b using 4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-24; 1 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.05 mmol), NEt3 (2.2 mmol) in acetonitrile (5 mL). The product was chromatographed over silica gel using 97.5:2.5 CH2Cl2:MeOH, mp 87-90° C. MS (APCI): 503 (M−H).
Reaction SMILES: [Br:1]Br.[CH:3]1([O:9]/[N:10]=[C:11](/[C:17](=[O:19])[CH3:18])\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH2:15]([O:14][C:12](=[O:13])/[C:11](=[N:10]\[O:9][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)/[C:17](=[O:19])[CH2:18][Br:1])[CH3:16]
Reactant: CCOC(=O)/C(=N\OC1CCCCC1)C(C)=O
Reactant: BrBr
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)/C(=N\OC1CCCCC1)C(=O)CBr
Reaction time: 2 h

Procedure:
A solution of bromine (4.5 ml) in carbon tetrachloride (50 ml) was added dropwise to a mixture of ethyl (Z)-2-(cyclohexyloxyimino)-3-oxobutyrate (20.0 g), hydrogen bromide in acetic acid (45%, 1.0 ml) and carbon tetrachloride (150 ml) over 1.5 h, at room temperature. The mixture was stirred for 2 h, then the solvent removed in vacuo.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[F:6][C:7]1[CH:13]=[C:12](I)[CH:11]=[CH:10][C:8]=1[NH2:9]>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:2]([C:12]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([F:6])[CH:13]=1)[CH2:3][CH2:4][CH3:5]
Reactant: [Li]CCCC
Reactant: Nc1ccc(I)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCCCc1ccc(N)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.1 %

Procedure:
ZnCl2 (5. 17 g, 38.0 mmol) was weighed into a flask, which was then flame dried and flushed with N2. Anhydrous THF (20 ml) was then added at 0° C., followed by 2.5 M nBuLi (15.2 ml, 38.0 mmol). The reaction mixture was stirred at 0° C. for 15 min, after which 2-fluoro-4-iodoaniline (3.00 g, 12.7 mmol) in anhydrous THF (10 ml) and Pd(PPh3)4 (0.74 g, 0.64 mmol) were added sequentially. The mixture was allowed to warm to RT and stirred for a further 6 h. The mixture was poured into ice/Et2O, the organic layer separated and the aqueous layer further extracted with Et2O. The combined organic fractions were washed with sat. NaHCO3, dried (Na2SO4) and concentrated under reduced pressure. The resulting solid was removed from the mixture by filtration and the filtrate purified by flash chromatography on silica (12.5% EtOAc/Hexane as eluant) to give the desired product (30%, 3.7 mmol). 1H NMR [400 MHz, CDCl3]δ 6.80 (dd, J=12.1, 1.8 Hz, 1 H), 6.76-6.65 (m, 2 H), 3.65 (br s, 2 H), 2.49 (t, J=7.7 Hz, 2 H), 1.57-1.49 (m, 2 H), 1.32 (sextet, J=7.3 Hz, 2 H), 0.91 (t, J=7.3 Hz, 3 H). LCMS (ACPI+) 168 (100%). Step B: Preparation of 2-(4-butyl-2-fluoroanilino)-3,4-difluorobenzoic acid
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][C:6]3[C:11]([CH:2]12)=[CH:10][CH:9]=[CH:8][CH:7]=3.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[OH:1][C@@H:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C@H:2]1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: c1ccc2c(c1)CCC1OC21
Solvent: CCO
Product: O[C@@H]1CCc2ccccc2[C@H]1N1CCCC1

Procedure:
A mixture of 1,2-epoxy-1,2,3,4-tetrahydronaphthalene (19.8 g), pyrrolidine (15 ml) and ethanol (75 ml) was stirred at reflux for 2 hours and evaporated of the volatiles under reduced pressure. The residue was dissolved in ether and the solution was extracted with IN hydrochloric acid (200 ml). The acid extract was washed with ether and basified with 1N sodium hydroxide aqueous solution with cooling. The mixture was extracted with ether (2X) and the combined ether extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residual viscous liquid was distilled under vacuum to yield trans-1,2,3,4-tetrahydro-2-hydroxy-1-(pyrrolidin-1-yl)naphthalene (16.5 g), b.p. 128°-135°/0.25 torr.
Reaction SMILES: O[CH:2]([CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)[CH3:3].C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]([F:43])([F:42])[C:35]1[CH:36]=[C:37]([SH:41])[CH:38]=[CH:39][CH:40]=1>CCOCC.ClCCl>[F:43][C:34]([F:33])([F:42])[C:35]1[CH:36]=[C:37]([S:41][CH:2]([CH:4]2[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]2)[CH3:3])[CH:38]=[CH:39][CH:40]=1
Reactant: FC(F)(F)c1cccc(S)c1
Reactant: CC(O)C1CN(C(=O)OC(C)(C)C)C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(Sc1cccc(C(F)(F)F)c1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To 100 ml round bottom flask was added tert-butyl 3-(1-hydroxyethyl)azetidine-1-carboxylate (2.06 g, 10.2 mmol), triethylamine (4.2 ml, 30.7 mmol) and 40 ml dichloromethane. Methanesulfonyl chloride (0.955 ml, 12.3 mmol) was added at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 1 hour. It was then diluted with 100 ml ether, washed with 2×50 ml saturated sodium carbonate solution. The organics were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 30 ml dimethylformamide. Potassium carbonate (3.75 g, 26.8 mmol) and 3-(trifluoromethyl)benzenethiol (1.91 g, 10.7 mmol) were added. The resulting reaction mixture was heated at 75° C. overnight. It was diluted with 120 ml ether, washed sequentially with 150 ml water, and 75 ml saturated sodium carbonate. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with hexane to 1:9 ethyl acetate/hexane to give 2.65 g desired product as colorless oil.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].S(Cl)([Cl:7])=O.[C:9](O)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1>O1CCCC1>[ClH:7].[OH:3][CH2:2][CH2:1][O:4][C:9]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:16]
Reactant: O=C(O)c1cccnc1
Reactant: OCCO
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cl
Product: O=C(OCCO)c1cccnc1
Temperature: 60 °C

Procedure:
To 120 mL cold (-10° C.) ethylene glycol, 16 mL of thionyl chloride were added dropwise. Upon completion of the addition, 24.6 g (0.2 mol) of nicotinic acid were added portionwise and the reaction mixture was heated overnight at 60° C. Then, 700 mL of hot tetrahydrofuran were added and the mixture was cooled. The solid which formed was removed by filtration and washed with ether to give 28.5 g of the title compound as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl.FC(F)(F)S(O[C:33]1[C:45]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1)(=O)=O>O1CCOCC1.O>[CH:36]1[C:37]2[NH:38][C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:45]=2[C:33]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=2)=[CH:34][CH:35]=1
Reactant: O=S(=O)(Oc1cccc2[nH]c3ccccc3c12)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(-c2cccc3[nH]c4ccccc4c23)cn1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
0.72 g of 2-cyano-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)pyridine, 3.3 g of caesium carbonate and 92 mg of 1,1′-bis(diphenyl-phosphino)ferrocenepalladium(II) dichloride as a complex with dichloromethane (1/1) [PdCl2(dppf).CH2Cl2] are successively added, under argon, to a solution of 0.8 g of 4-trifluoromethanesulphonyloxycarbazole, obtained in stage 1 of Example 1, in a mixture of 37 ml of dioxane and 12 ml of water. The reaction mixture is refluxed for 4 hours, cooled to ambient temperature, filtered through celite and concentrated under reduced pressure. The residue is subsequently purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (85/15 by volume), so as to give 0.24 g of 5-(9H-carbazol-4-yl)pyridine-2-carbonitrile in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.N1([C:25](N2C=CN=C2)=[O:26])C=CN=C1>O1CCCC1>[Br:1][C:2]1[N:3]=[C:4]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[C:25](=[O:26])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncc(Br)nc1NCc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: O=c1[nH]c2ncc(Br)nc2n1Cc1cccc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of 5-bromo-N3-(3-nitrobenzyl)pyrazine-2,3-diamine (100 mg, 0.31 mmol) in anhydrous tetrahydrofuran (10 mL) was added diimidazol-1-ylmethanone (250 mg, 1.51 mmol) at room temperature. After stirring overnight, the reaction was concentrated under reduced pressure. Purification of the resultant residue by flash chromatography [silica gel; hexanes/ethyl acetate (2:1)] afforded 6-bromo-1-(3- nitrobenzyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one as a red-brown solid (95 mg, 88%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][O:25]1>>[O:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: BrCC1CCCO1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC3CCCO3)CC1)O2

Procedure:
Compound 117 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-(bromomethyl)tetrahydrofuran and conditions outlined in procedure V. M.p.=155-159° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 4.1 (m, 1H), 3.9 (m, 1H), 3.75 (m, 1H), 3.0-2.8 (m, 4H), 2.6-2.4 (m, 4H), 2.2-2.1 (m, 2H), 2.1-1.8 (m, 5H), 1.5 (m, 1H); LCMS: 386 [M+H].
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O)(=O)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C@H:39]([NH2:41])[CH3:40])[CH:36]=[CH:37][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:41][C@@H:39]([C:35]2[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH3:31])[CH:34]=2)[CH3:40])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: COc1cccc([C@@H](C)N)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc([C@@H](C)N[C@H]2CCN(Cc3ccccc3)C2)c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 28.4 %

Procedure:
To a solution of 8.0 g of (R)-1-benzyl-3-pyrrolidinol and 16.5 ml of diisopropylethylamine dissolved in 400 ml of methylene chloride was added dropwise a solution of 13.4 g of anhydrous trifluoromethanesulfonic acid in 50 ml of a methylene chloride at −20° C. or lower. The reaction mixture was stirred for 15 minutes while maintaining it to −20° C., then, a solution of 9.88 g of (R)-1-(3-methoxyphenyl)ethylamine in 100 ml of methylene chloride was added dropwise to the mixture at −20° C. or lower, and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=1:0→50:1) and NH silica gel column chromatography (hexane:ethyl acetate=25:1→10:1) to obtain 3.98 g of (S)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]amine. MS•APCI (m/z): 311 [M+H]+ (2) To a solution of 3.67 g of (S)-(1-benzylpyrrolidin-3-yl)-[(R)-1-(3-methoxyphenyl)ethyl]amine dissolved in 100 ml of methanol were added 830 mg of palladium hydroxide and 8.85 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was shaked under hydrogen atmosphere at 3 atm at room temperature for 3 days. Palladium hydroxide was removed, and the solvent was evaporated. To the residue was added methanol, and the resulting precipitates were collected by filtration, washed with methanol and dried to obtain 1.14 g of (S)-3-[(R)-1-(3-methoxyphenyl)-ethylamino]pyrrolidine dihydrochloride (the following Reference example Table, Reference example 1.001).
Reaction SMILES: C([C@H](NC(=O)C1C=C[C:28](F)=[C:27]([N:32]2[CH2:36][CH2:35][CH2:34][C:33]2=[O:37])C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH2:39]([C@H:46]([NH:61][C:62](=[O:72])[C:63]1[CH:68]=[C:67]([O:69][CH3:70])[CH:66]=[C:65](Br)[CH:64]=1)[C@@H:47]([OH:60])[CH2:48][C@H:49]([C:51](=[O:59])[NH:52][CH2:53][CH2:54][C:55](C)([CH3:57])[CH3:56])[CH3:50])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[C:73]1(=O)NCCCC[CH2:74]1>>[CH2:39]([C@H:46]([NH:61][C:62](=[O:72])[C:63]1[CH:64]=[C:65]([N:32]2[CH2:27][CH2:28][CH2:36][CH2:35][CH2:34][C:33]2=[O:37])[CH:66]=[C:67]([O:69][CH3:70])[CH:68]=1)[C@@H:47]([OH:60])[CH2:48][C@H:49]([C:51](=[O:59])[NH:52][CH:53]1[CH2:54][CH:55]2[CH2:56][CH:73]1[CH2:74][CH2:57]2)[CH3:50])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C1CCCCCN1
Reactant: COc1cc(Br)cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)c1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(F)c(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: COc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCCCC2=O)c1

Procedure:
Prepared in an analogous manner to E1, from N-[(1S,2S,4R)-1-benzyl-4-(3,3-dimethylbutylcarbamoyl)-2-hydroxypentyl]-3-bromo-5-methoxybenzamide (D17) and ε-caprolactam.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 69% overall yield. FDMS m/e=366 (M+ of free base). α[D]589 =-10.45 (c=0.61, methanol).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[NH2:44][C@H:45]([C:53]([O:55]C)=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CO>[CH3:1][NH:44][C@H:45]([C:53]([OH:55])=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C@H:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)/C(=N\OC1CCNC1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CO
Solvent: C1COCCO1
Product: CN[C@@H](Cc1ccccc1)C(=O)O
Product: O=C(O)/C(=N\O[C@H]1CCNC1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
30 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetic acid and 60 ml of methanol are added to 100 ml of dioxane containing 0.5 g of methyl L-phenylalaninate, and the mixture is heated at 50° C. to dissolve said acid therein. 700 ml of dioxane are added to the solution, and the mixture is stirred at room temperature for 5 hours. Crystalline precipitates are collected by filtration (the filtrate is hereinafter referred to as "Filtrate I"), and 14.3 g of the crude product thus obtained are dissolved in 24 ml of methanol. 280 ml of dioxane are added to the methanol solution. The mixture is stirred at room temperature for 4 hours, and crystalline precipitates are collected by filtration (the filtrate is hereinafter referred to as "Filtrate II"). 12.2 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]acetic acid methyl L-phenylalaninate salt are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[CH2:18](Br)[C:19](=[CH2:21])[CH3:20].NC1C(C(N)=O)=CC2C3C(=CC=CC=3)N(C(C)C)C=2N=1>>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:20][C:19]([CH3:21])=[CH2:18])[C:6]=2[N:14]=1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Reactant: C=C(C)CBr
Agent: CC(C)n1c2ccccc2c2cc(C(N)=O)c(N)nc21
Product: C=C(C)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Yield: 58.9 %

Procedure:
2-Amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 196 mg, 0.866 mmol) was alkylated with methallyl bromide (0.131 mL, 1.30 mmol) according to the procedure detailed in the synthesis of 13 to afford 2-amino-9-(2-methylprop-2-en-1-yl)-9H-pyrido[2,3-b]indole-3-carboxamide (xii-a, 143 mg, 59%).