Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C@@H:7]1[O:16]S(C)(=O)=O)(C)(=O)=O>C1(C)C=CC=CC=1.[OH-].[K+].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:16]1[C@@H:7]2[CH2:8][CH2:9][C:10]3[C:15]([C@H:6]12)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CS(=O)(=O)O[C@H]1CCc2ccccc2[C@H]1OS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CC[C@H]1O[C@@H]21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
One mole equivalent of (1R,2S)-1,2-dimesyloxy-1,2,3,4-tetrahydronaphthalene was dissolved in 180 volume equivalents of toluene and 30 volume equivalents of 10% aqueous caustic potash was added together with 0.05 weight equivalents of tetrabutylammonium bromide. The mixture was stirred vigorously at ambient temperature for 4 hours when the reaction was judged essentially complete by GLC analysis. The organic layer was separated and washed three times with 0.25 volume equivalents of water. The solvent was removed by vacuum rotary distillation to give a crude brown oily product. The product was purified by column chromatography using Silica Gel 60 and a mixture of hexane and dichloromethane as eluent. The first fraction, after evaporation of the solvent, gave 0.26 mole equivalents of (1S,2R)-1,2-epoxy-1,2,3,4-tetrahydronaphthalene which had an optical rotation [α]D22 =-133° (C=0.21,CHCl3). This compares with the literature value (see below) for (1R,2S)-1,2-epoxy-1,2,3,4-tetrahydronaphthalene of [α]D 32 +133° (C=0.39,CHCl3). Chiral GLC analysis showed the product to be >99.8% enantiomeric excess. Melting point 47°-48° C. J.Chem.Soc.Perkin.Trans I, 1979, 2437 quotes 45°-48° C. 1HNMR: H1=3.95,d,1H; H2=3.75,dt,1H; H3=1.65 and 2.3,m,2H; H4=2.55,m,2H; H5-H8=7.1-7.5,m,4H.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]([OH:12])=[O:11])=[CH:8][CH:9]=1)=[O:4].[H][H]>C(OCC)(=O)C.[Rh]>[CH3:1][O:2][C:3]([CH:5]1[O:6][CH:7]([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)O)o1
Reactant: [H][H]
Agent: [Rh]
Solvent: CCOC(C)=O
Product: COC(=O)C1CCC(C(=O)O)O1
Yield: 100.2 %

Procedure:
A mixture of furan-2,5-dicarboxylic acid monomethyl ester (1.95 g) and 5% rhodium on carbon (400 mg) in ethyl acetate (50 ml) was hydrogenated until hydrogen uptake ceased. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were evaporated to give (2.00 g) of the title compound: νmax (film) 3170, 1765 and 1720 cm-1 ; δH (CDCl3) 1.95-2.65 (4H, m), 3.85 (3H, s) and 4.55-4.8 (2H, m).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([I:30])[C:21]=3[C:31]3[CH:32]=[C:33]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([O:46]C)=[O:45])=[CH:40][C:39]=4[CH3:48])[CH:34]=[CH:35][C:36]=3[Cl:37])[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O[Li].O.CCOC(C)=O.CCCCCC>O1CCOCC1>[F:51][C:2]([F:1])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([I:30])[C:21]=3[C:31]3[CH:32]=[C:33]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([OH:46])=[O:45])=[CH:40][C:39]=4[CH3:48])[CH:34]=[CH:35][C:36]=3[Cl:37])[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(Cl)c(-c3c(I)cc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1-c1ccc(Cl)c(-c2c(I)cc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the title compound from Step B (30 mg, 0.035 mmol) in dioxane (2 ml) at room temperature, an aqueous solution of LiOH.H2O (7.36 mg, 0.175 mmol) was added. The mixture was stirred at room temperature for overnight. TLC (EtOAc:hexane/2:8) showed no starting material. The solvent was removed. 1N HCl (1 ml) was added. The mixture was extracted with methylene chloride (3×10 ml). The combined methylene chloride layers were dried over sodium sulfate. The title compound was obtained by preparative reverse phase HPLC as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH:38]=[CH2:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:40]>O1CCOCC1>[NH2:40][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH:38]=[CH2:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Reactant: N
Solvent: C1COCCO1
Product: C=C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(N)ncnc21
Temperature: -78 °C

Procedure:
The compound from Step B (80, mg) was dissolved in the minimum amount of 1,4-dioxane and placed in a stainless steel bomb. The bomb was cooled to −78° C. and liquid ammonia was added. The bomb was sealed and heated at 90° C. for 24 h. The ammonia was allowed to evaporate and the residue concentrated to a white solid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([Cl:3])Cl.[CH3:4][CH:5]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=C[CH:18]=[CH:17]2)[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].C1C=C(Cl)C=C(C(OO)=O)C=1>CCOC(C)=O>[Cl:3][C:1]1[CH:18]=[CH:17][C:16]2[C:21](=[C:12]([O:11][CH:5]([CH3:4])[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:13]=[CH:14][CH:15]=2)[N:20]=1
Reactant: ClCCl
Reactant: CC(CC(C)(C)C)Oc1cccc2cccnc12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CC(CC(C)(C)C)Oc1cccc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL round bottom flask charged with 2 mL of CH2Cl2, 0.500 g (2.07 mmol) of 8-(1,3,3-trimethylbutoxy)quinoline was slowly added with gentle heating in order to dissolve the material. To this was added 1.8 equiv m-CPBA (50–70% by weight) in three portions. After stirring for 30 min, the dense solution became a brown solid. The solid was dissolved in 25 mL EtOAc and the resulting solution was washed with 10% aqueous NaHSO3, saturated aqueous NaHCO3, and the organic layer evaporated in vacuo. After co-evaporation with toluene, the residue was dissolved in POCl3 (5 mL) and the flask fitted with a reflux condenser. The reaction flask was then placed in an oil bath that had been preheated to 95° C. for 15 min. After cooling to room temperature, the solution was concentrated down to a red oil, which was then dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 until the aqueous layers became basic. The organic layer was evaporated in vacuo and the residue was purified by silica gel column chromatography (EtOAc/hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.37 (d, 1H), 7.55 (m, 3H), 7.34 (m, 1H), 4.70–4.93 (m, 1H), 1.90 (dd, 1H), 1.53 (dd, 1H), 1.30 (d, 3H), 0.94 (s, 9H); MS (DCI/NH3) m/z 277 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[CH:7]=1)=[O:5])C.[OH-].[K+].Cl>CCO.O>[CH3:21][O:20][C:15]1[CH:14]=[C:13]([CH:12]=[CH:11][C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:10][N:9]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: CCOC(=O)c1cc(C=Cc2ccc(O)c(OC)c2)n[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C=Cc2cc(C(=O)O)[nH]n2)ccc1O
Temperature: 25 °C
Yield: 67.8 %

Procedure:
Ethyl-3-[β-(3-methoxy-4-hydroxyphenyl)ethenyl]-1H-pyrazole-5-carboxylate (0.49 g, 1.7 mmoles) is added to a solution of KOH (0.38 g, 6.8 mmoles) in 50 ml EtOH. The reaction is warmed to reflux overnight. After cooling to room temperature, the reaction is diluted to 200 ml with H2O, and acidified to pH≈4 with HCl. A white precipitate forms, and it is collected by filtration. Drying in vacuum in the presence of P2O5 gives 0.3 g (68%) of the desired product, mp=270°-271° C. (dec).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[CH2:10]([O:12][C:13](=[O:23])[NH:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=S)[CH3:11].Cl.Cl.[NH2:26][CH:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:28]([NH:30][C:31]1([C:38]#[N:39])[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)=[O:29].C(N(CC)C(C)C)(C)C>ClCCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:10]([O:12][C:13](=[O:23])[N:14]=[C:15]([NH:26][CH:27]([C:28](=[O:29])[NH:30][C:31]1([C:38]#[N:39])[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]1)[CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH3:11]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: CCOC(=O)NC(=S)N1CCOCC1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N=C(NC(CC1CCCCC1)C(=O)NC1(C#N)CCN(C)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 25.7 %

Procedure:
2-Chloro-N-methylpyridinium iodide (680 mg, 2.66 mmol), was added to a solution of (Morpholine-4-carbothioyl)-carbamic acid ethyl ester (450 mg, 2.06 mmol), 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt (745 mg, 2.04 mmol), and N,N-diisopropylethylamine (1.10 mL, 6.3 mmol) in dichloromethane (8.0 mL). The reaction was stirred at room temperature for 2.5 h then taken up in 10% citric acid solution and washed with EtOAc. The aqueous phase was then basified with saturated sodium carbonate and extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated to provide the desired product as a white solid (250 mg, 26%). This material was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to 90% acetonitrile in water. MS, m/z 477=M+1.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22]Br)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22][N:10]1[CH2:11][CH2:12][CH:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1CCC(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A mixture of 4-piperidinopiperidine (Aldrich) (2.0 g, 11.88 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester [Eur. J. Med. Chem. Chim. Ther. 37 (2002) 573-584] (3.96 g, 16.63 mmol), dimethyl formamide (130 mL) and potassium carbonate (1.64 g, 11.88 mmol) was stirred at room temperature overnight, then concentrated in vacuo. The residue was dissolved in water (150 mL), extracted with dichloromethane (3×150 mL), the combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated. The crude product was submitted to column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and chloroform:methanol:NH4OH=10:1:0.1 as eluent to yield 2.27 g (59%) of the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1)([O-:15])=[O:14].O>C(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:23](=[O:24])[CH2:22][C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1
Reactant: NCCCO
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)NCCCO
Temperature: 25 °C
Yield: 11.4 %

Procedure:
To a stirred solution of 3-hydroxypropylamine (507 mg, 6.76 mmol) and triethylamine (1.88 mL, 0.013 mol) in DCM (10 mL) at 0° C. was added (4-nitro-phenyl)-acetyl chloride (1.35 g, 6.76 mmol) in DCM (10 mL) dropwise. The dark red solution was allowed to warm to room temperature and then poured into water (50 mL). The layers were separated and the organic layer was dried (Na2SO4) and concentrated in vacuo. The crude material was purified by preparative thin layer chromatography (TLC) (5%-MeOH—CHCl3) to afford 183 mg (11%) of the title compound as a solid. 1H-NMR (CDCl3; 400 MHz): δ 8.12 (d, 2H, J=8.7 Hz), 7.39 (d, 1H, J=8.7 Hz), 6.09 (br s, 1H), 3.58 (s, 2H), 3.57-3.54 (m, 2H), 3.40 (br s, 1H), 3.36-3.31 (m, 2H), 1.63-1.57 (m, 2H).
Reaction SMILES: [C:1](O[K])(C)(C)C.P(=O)(OC=[N+]=[N-])OC.[CH3:15][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]1[CH:22]=[C:23]([CH:27]=O)[CH:24]=[N:25][CH:26]=1>C1COCC1>[C:27]([C:23]1[CH:24]=[N:25][CH:26]=[C:21]([CH:17]2[CH2:18][CH2:19][CH2:20][N:16]2[CH3:15])[CH:22]=1)#[CH:1]
Reactant: CC(C)(C)O[K]
Reactant: CN1CCC[C@H]1c1cncc(C=O)c1
Agent: CO[PH](=O)OC=[N+]=[N-]
Solvent: C1CCOC1
Product: C#Cc1cncc(C2CCCN2C)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of tBuOK in THF (0.08 mL, 0.08 mmol) cooled at −78° C. was added dropwise a solution of methyl diazomethyl phosphonate in THF (0.1 mL, 0.08 mmol). The solution was stirred at −78° C. for 5 min, then a solution of 5-(1-methylpyrrolidin-2-yl)pyridine-3-carbaldehyde (V) (0.0126 g, 0.066 mmol) in THF (1 mL) was added via a double tipped needle. The reaction mixture was stirred at −78° C. for 16 h then allowed to warn to RT over 2 h. After evaporation of the solvent under reduced pressure, the crude material was purified by RPLC (silica gel, 10% EtOAC/hexanes) to afford 0.0061 g (51%) of 3-ethynyl-5-(1-methylpyrrolidin-2-yl)-pyridine (VI) as a clear oil. The data were identical to those described in the literature (Bleicher, L. S.; Cosford, N. P. D.; Herbault, A.; McCallum, J. S.; McDonald, I. A. J. Org. Chem. 1998, 63, 1109).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]=[CH:9][CH:10]2[C:15](=[O:16])OC(C)(C)OC2=O)[CH:5]=[N:6][CH:7]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:15]([OH:16])=[CH:10][CH:9]=[N:8]2)=[N:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(C=Nc2cncc(Br)c2)C(=O)O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1ccnc2cc(Br)cnc12
Temperature: 236.5 °C
Yield: 76 %

Procedure:
5-{[(5-Bromopyridin-3-yl)imino]methyl}-2,2-dimethyl-1,3-dioxane-4,6-dione (59 g, 0.18 mol) was slowly added to DOWTHERM A heat transfer fluid (2000 mL) over a period of 5 minutes at 235-238° C. Following addition, the reaction was maintained for an additional 5 minutes and then allowed to cool to 40° C. A brown precipitate formed, which was filtered and washed with hexanes (150 mL). The brown solid was suspended in an ethanol/water mixture (90:10, 1500 mL), heated to a boil for 30 minutes, isolated by filtration, and washed with ethanol (200 mL) to yield 30.8 g of 7-bromo[1,5]naphthyridin-4-ol as a dark brown powder.
Reaction SMILES: [NH2:1][NH2:2].O.[C:4]([CH:7]([CH2:12][CH2:13][CH3:14])[CH2:8][C:9](O)=[O:10])(=O)[CH3:5]>CCO>[CH3:5][C:4]1[CH:7]([CH2:12][CH2:13][CH3:14])[CH2:8][C:9](=[O:10])[NH:1][N:2]=1
Reactant: CCCC(CC(=O)O)C(C)=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCC1CC(=O)NN=C1C
Temperature: 85 °C

Procedure:
NH2NH2—H2O (6.94 ml, 143 mmol) is added to a solution of 3-acetyl-hexanoic acid (18.8 g, 119 mmol) in EtOH (150 ml), and the mixture is refluxed (oil bath 85° C.) for 4 hours. The solvent is removed in vacuo and water (100 ml) and EtOAc (100 ml) are added to the residue. The layers are separated and the aqueous layer is extracted with EtOAc (3×100ml). The combined extracts are washed with brine (150 ml), dried (Na2SO4) and evaporated. 6-methyl-5propyl-4,5-dihydropyridazin-3-one is obtained as a light yellow oil, and is used in the next step.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1.[CH:20]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1)([CH3:22])[CH3:21]>C(Cl)Cl.CO>[CH:20]([N:23]1[CH2:24][CH2:25][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:17](=[O:19])[CH2:16][C:13]3[CH:12]=[CH:11][C:10]([N:5]4[CH:6]=[N:7][C:8]5[C:4]4=[N:3][CH:2]=[N:1][CH:9]=5)=[CH:15][CH:14]=3)=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:27][CH2:28]1)([CH3:22])[CH3:21]
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3cncnc32)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cncnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-purin-9-yl-phenyl)-acetic acid and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (disclosed in WO 03/099771). Title compound: ES-MS: 538.1 [M+H]+; tR=2.93 min (System 1); Rf=0.12 (CH2Cl2/MeOH/NH3aq, 94:5:1).
Reaction SMILES: O.C([O-])=O.[Na+].C(O)(=O)C.C([O:17][C:18]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:38][C:19]=1[C:20]([NH:22][C:23]1[CH:32]=[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])=[O:21])C1C=CC=CC=1>[C].[Pd].O1CCOCC1>[O:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[C:31]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([NH:22][C:20](=[O:21])[C:19]2[CH:38]=[C:39]([N:42]3[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]3)[CH:40]=[CH:41][C:18]=2[OH:17])[CH:32]=1
Reactant: COC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cc(N2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
Water (0.20 mL), sodium formate (0.045 g), acetic acid (0.043 mL) and 10% palladium-carbon (8 mg) were added to a dioxane (1 mL) solution of methyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-(furan-2-yl)benzoate (0.085 g), followed by stirring at room temperature for 3 hours and 30 minutes and then at 60° C. for 50 minutes. To the reaction mixture, 10% palladium-carbon (8 mg) was added, followed by stirring at 70° C. for 50 minutes. After cooling the reaction mixture to room temperature, the insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.048 g of methyl 4-(furan-2-yl)-2-(2-hydroxy-5-(piperidin-1-yl)benzamido)benzoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:14]([N+:25]([O-])=O)=[CH:13][CH:12]=3)=[O:5])[CH3:2]>O1CCCC1.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:14]([NH2:25])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])c(N3CCCCC3)c12
Agent: [Ti+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N)c(N3CCCCC3)c12
Reaction time: 0.1 h
Yield: 79.3 %

Procedure:
140 mg of 5-piperidino-6-nitro-beta-carboline-3-carboxylic-acid-ethylester in 10 ml of tetrahydrofuran is mixed with the four-fold molar amount of titanium trichloride in water. After 6 minutes, the substance is neutralized, filtered and evaporated. The residue is extracted with methylene chloride, and the extracts are concentrated and recrystallized from glacial acetic acid. 102 mg of 5-piperidino-6-amino-beta-carboline-3-carboxylic-acid-ethylester with a m.p. of 188°-190° C. is obtained.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42]CO)=[CH:36][CH:35]=1)([O-:33])=[O:32]>C(Cl)Cl>[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][CH2:1][Br:5])=[CH:36][CH:35]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(CCCCO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
Part A.Carbon tetrabromide (34.01 gm, 102.55 mmol), pyridine (8.3 mL, 102.55 mmol) and triphenylphosphine (25.52 gm, 112.55 mmole) were added sequentially to a solution of 4-(4-nitrophenyl) butanol (20.0 gm, 102.55 mmol) in 400 mL of CH2Cl2 (precooled to 0° C.) and was allowed to stir overnight with warming to room temperature. The volatiles were removed under vacuum and the residue dissolved in ethyl acetate, filtered through a plug of silica and concentrated to dryness. The resulting oil was purified by flash chromatography eluting hexane:ethyl acetate(v:v, 4:1) to give 4-(4-nitrophenyl)butyl bromide as an oil 23.51 gm (88%). 1H NMR (CDCl3) 1.95-1.81 (m, 4H), 2.78 (t, 2H), 3.45 (t, 2H), 7.37 (d, 2H), 8.15 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][CH2:9][C:8](=O)[C:7]=2[CH:14]=1.C[O-].[Na+].Cl.[BH4-].[Na+].CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1.[C:37](=O)([O:40]C)[O:38][CH3:39]>C1COCC1.O.C(N(CC)CC)C.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][C:9]([C:37]([O:38][CH3:39])=[O:40])=[CH:8][C:7]=2[CH:14]=1
Reactant: COC(=O)OC
Reactant: COc1ccc2c(c1)C(=O)CCCS2
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CO
Product: COC(=O)C1=Cc2cc(OC)ccc2SCC1
Reaction time: 1 h

Procedure:
A suspension of 7-methoxy-3,4-dihydro-1-benzothiepin-5(2H)-one (3.87 g) and sodium methoxide (5.0 g) in dimethyl carbonate (50 ml) was heated at reflux for 4 hours. The reaction mixture was mixed with 1 N hydrochloric acid (100 ml) and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to obtain a yellow oily substance (4.96 g). Into a mixture of the thus-obtained oily substance, sodium borohydride (0.7 g) and THF (50 ml) was added dropwise at −40° C. methanol (5 ml), and the resulting mixture was stirred at −10° C. to −20° C. for one hour. The reaction mixture was mixed with water and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to obtain a yellow oily substance (4.80 g). Into a solution of the thus-obtained oily substance and triethylamine (7.5 ml) in THF (50 ml) was added at 0° C. methanesulfonyl chloride (2.09 ml), and the resulting mixture was stirred at 0° C. for 0.5 hour and at room temperature for one hour. To this reaction mixture was added 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) (4.0 ml), and the resulting mixture was stirred for 2.5 hours. The reaction mixture was mixed with water and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:5) to obtain methyl 7-methoxy-2,3-dihydro-1-benzothiepine-4-carboxylate (3.00 g) as a yellow oily substance.