Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([OH:17])=O)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][N:25]([CH3:40])[CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]([NH2:39])[CH2:34][CH2:33][CH2:32]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([NH:39][CH:35]2[C:36]3[C:31](=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:25]([CH3:40])[CH3:24])=[CH:38][CH:37]=3)[CH2:32][CH2:33][CH2:34]2)=[O:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Reactant: CN(C)CCOc1ccc2c(c1)CCCC2N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)CCOc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1

Procedure:
To a 20 mL vial equipped with stirring was added 3-(3,4-dichloro-benzenesulfonylamino)-3-phenyl-propionic acid (128 mg, 0.34 mmol), 6-(2-dimethylamino-ethoxy)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (40 mg, 0.17 mmol), EDC (Aldrich, 49 mg, 0.26 mmol), HOBt (Aldrich, 23 mg, 0.17 mmol), and CH2Cl2 (1 mL). The reaction was stirred at RT overnight and diluted with CH2Cl2 (50 mL). The organic phase was washed with saturated NaHCO3, and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (4%-6% MeOH—CH2Cl2) to afford the title compound as a white solid. MS (ESI): 590 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:37])[C:7]([CH3:36])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:36][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[N:14]=1)([CH3:8])[C:6]([OH:37])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(N3CCN(c4ccccc4)CC3)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCOc2ccc(N3CCN(c4ccccc4)CC3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.2 %

Procedure:
2-Methyl-2-[(4-{2-[4-(4-phenylpiperazin-1-yl)phenoxy]ethyl}-1,3-thiazol-2-yl)thio]propionic acid tert-butyl ester (490 mg) obtained in Example 148-1 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (330 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]=2)(=[O:20])=[O:19])[N:7]([CH3:30])[N:6]=1.[H-].[Na+].[Br:33][C:34]1[CH:35]=[N:36][C:37](Cl)=[N:38][CH:39]=1>C1COCC1.CC(N(C)C)=O>[Br:33][C:34]1[CH:35]=[N:36][C:37]([O:1][CH2:2][CH2:3][O:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:8]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:28])[CH3:29])=[CH:23][N:22]=3)(=[O:19])=[O:20])[N:7]([CH3:30])[N:6]=2)=[N:38][CH:39]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reaction time: 0.08 h
Yield: 45.8 %

Procedure:
To a solution of N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (Example 40) (1.00 g) in anhydrous THF (10 ml) at 0° C. and under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 195 mg) and the mixture was stirred for 5 minutes. To the mixture was added 5-bromo-2-chloropyrimidine (Liquid Crystals, 1993, 14(3), 741) (1.12 g) in dimethylacetamide (3 ml). After stirring for 1 hr, the reaction mixture was partitioned between ethyl acetate (100 ml) and saturated ammonium chloride solution (100 ml). The organic fraction was washed with brine (100 ml), followed by drying over magnesium sulfate, filtering and concentration under reduced pressure. Purification of the residue by preparative HPLC on a Phenomenex Magellen column using a 0.1M ammonium acetate:acetonitrile gradient (95:5 to 50:50 over 5 minutes) afforded the title compound as a white solid (625 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[NH:12][C:11]([C:20]([F:23])([F:22])[F:21])=[C:10]2C(O)=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].O.C(Cl)Cl.CCOCC.C(OCC)C.CCCCCC>CN1CCCC1=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[NH:12][C:11]([C:20]([F:23])([F:21])[F:22])=[CH:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(C2C3=C(CCCC3=O)NC(C(F)(F)F)=C2C(=O)O)c1
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: N#Cc1cccc(C2C=C(C(F)(F)F)NC3=C2C(=O)CCC3)c1
Yield: 99 %

Procedure:
A stirred solution of (-)-4-(3-cyanophenyl)-2-trifluoromethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid (3.93 g, 10.85 mmol) in N-methylpyrrolidin-2-one (24 mL) was placed in a preheated oil bath at 210° C. for 20 minutes. The cooled reaction mixture was then poured into water (200 mL) and extracted twice with ethyl ether. The combined ether extracts were washed twice with water, dried (MgSO4), filtered and the solvent removed to yield an off-white solid. Chromatography (eluent: methylene chloride/ether 9:1) and trituration with ethyl ether/hexane provided the title compound (3.42 g, 79%) as a white solid mp 187°-189° C. NMR: 1.88-1.91 (m, 2H, CH2), 2.21-2.25 (m, 2H, CH2), 2.53-2.64 (m, 2H, CH2), 4.68(d, 1H, J=5.3 Hz, CH), 5.61 (d, 1H, J=5.3 Hz, CH), 7.50-7.54 (m, 2H, Ar), 7.61-7.66 (m, 2H, Ar), 9.42 (s, 1H, NH); MS: m/z=319(M+1); [α]D23 =-606.8° (c=0.665, methanol). Analysis for C17H13F3N2O: Calculated C, 64.14; H, 4.12; N, 8.80; Found: C, 64.07; H, 4.24; N, 8.78.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7]([OH:10])=[CH:8][CH:9]=1)[CH2:2][CH3:3]>[Cu]>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:6][C:7](=[O:10])[CH2:8][O:11][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(O)c(O)c1
Agent: [Cu]
Product: CCCc1ccc2c(c1)OCC(=O)CO2

Procedure:
This compound was prepared using known reactions, starting from 97% pure 4-propyl-1,2- benzenediol. This starting product, having an odor of the copper, phenolic, slightly fatty type, was converted in an analogous way to that described in U.S. Pat. No. 3,799,892 to give a crude product which, after purification and crystallization in heptane at -20° C., gave 7-propyl-2H,4H-1,5-benzodioxepin-3-one with a purity above 99%, showing the following spectral data:
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH2:25])[C:6](=[O:22])[CH:7]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:8]C=C)[CH2:3][CH2:2]1.CS(C)=O>C1(C)C=CC=CC=1.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH:1]1([CH2:4][N:5]2[CH:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:24]=[CH:25][CH2:8][CH:7]([N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[C:6]2=[O:22])[CH2:3][CH2:2]1
Reactant: C=CCC(C(=O)N(CC1CC1)C(C=C)c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)CC=CC(c2ccccc2)N1CC1CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a solution of (N-(cyclopropylmethyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-(1-phenylprop-2-en-1-yl)pent-4-enamide (4c) (210 mg) dissolved in Toluene (25 mL) at 80° C. under N2 was added Grubbs catalyst (2nd generation) (21 mg) and the reaction mixture was stirred at 80° C. for 1 h, then cooled to RT. DMSO (0.1 mL) was added to the reaction mixture which was stirred for 2 h, then concentrated. The crude product was directly purified via flash chromatography (gradient—5%, 10% and 15% EtOAc/hexanes) to give a diastereomeric mixture (1.5:1) of the title compound (128 mg, 66%). 1H NMR (300 MHz, CDCl3) δ 0.03-0.09 (m, 1H), 0.22-0.34 (m, 2H), 0.46-0.57 (m, 1H), 0.66-0.72 (m, 0.6H), 1.03-1.09 (m, 0.4H), 2.42-2.48 (m, 1H), 2.98 (dd, 0.6H), 3.20 (dd, 0.4H), 3.55 (dd, 0.6H), 3.61-3.74 (m, 1H), 3.94 (dd, 0.4H), 5.09 (dd, 0.4H), 5.28 (bd, 0.4H), 5.57 (dd, 0.6H), 5.77(d, 0.6H), 6.00-6.08 (m, 1H), 6.26-6.35 (m, 1H), 7.35-7.48 (m, 5H), 7.65-7.88 (m, 4H). MS APCI, m/z=387 (M+1). LC/MS 2.66 min., Method A.
Reaction SMILES: C[O:2][C@H:3]1[C@@H:7]2[CH2:8][C@H:9]3[C@H:14]([C@H:15](/[CH:16]=[CH:17]/[C@@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([CH3:24])[N:19]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:6]2[C@@H:5]([CH3:32])[O:4]1)[CH2:13][CH2:12][CH2:11][CH2:10]3.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[CH3:32][C@H:5]1[O:4][C:3](=[O:2])[C@@H:7]2[CH2:8][C@H:9]3[C@H:14]([C@H:15](/[CH:16]=[CH:17]/[C@@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([CH3:24])[N:19]4[C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C@H:6]12)[CH2:13][CH2:12][CH2:11][CH2:10]3
Reactant: CO[C@@H]1O[C@H](C)[C@H]2[C@@H](/C=C/[C@@H]3CCC[C@@H](C)N3C(=O)OC(C)(C)C)[C@@H]3CCCC[C@H]3C[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@@H]1CCC[C@@H](/C=C/[C@H]2[C@@H]3CCCC[C@H]3C[C@H]3C(=O)O[C@H](C)[C@@H]23)N1C(=O)OC(C)(C)C
Yield: 97.4 %

Procedure:
Similarly to Referential example 4, 156.0 mg(0.35 mmol) of (2S,6R)-tert-butyl 2-[(E)-2-[(1R,3R,3aS,4S,4aR,8aS,9aR)-1-methoxy-3-methyl-dodecahydronaphtho[2,3-c]furan-4-yl]vinyl]-6-methyl-1-piperidinecarboxylate were reacted with 0.90 ml of Jones reagent to obtain 147.1 mg of (2S,6R)-tert-butyl 2-[(E)-2-[(3R,3aS,4S,4aR,8aS,9aR)-3-methyl-1-oxo-dodecahydronaphtho[2,3-c]furan-4-yl]vinyl]-6-methyl-1-piperidinecarboxylate, and then 1.00 ml of trifluoroacetic acid was reacted to obtain 113.0 mg of crude (3R,3aS,4S,4aR,8aS,9aR)-3-methyl-4-[(E)-2-[(2S,6R)-6-methylpiperidine-2-yl]vinyl]-3-methyl-decahydronaphtho[2,3-c]furan-1(3H)-one(yield after 2 processes 98%). Then, 0.30 ml of 37% formaldehyde solution and 47.1 mg (2.2 equivalents) of sodium cyanoboronhydride were reacted to obtain 100.8 mg of (3R,3aS,4S,4aR,8aS,9aR)-4-[(E)-2-[(2S,6R)-1.6-dimethylpiperidine-2-yl]vinyl]-3-methyl-decahydronaphtho[2,3-c]furan-1(3H)-one (ent-himbacine)(yield after 3 processes 84%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([Cl:13])=[C:6]([O:14][CH2:15][CH3:16])[CH:5]=1.[Sn](Cl)(Cl)(Cl)Cl>CO.Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([O:14][CH2:15][CH3:16])[C:7]([Cl:13])=[C:8]([NH2:10])[CH:9]=1
Reactant: CCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Product: CCOc1cc(C(=O)OC)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-chloro-3-ethoxy-5-nitro-benzoic acid methyl ester (1.0 g, 3.85 mmol, 1.0 equiv) in methanol (20 mL) was added dropwise under stirring at 0° C. a solution of tin chloride (2.92 g, 15.41 mmol, 4.0 equiv) in 37% HCl (7.5 mL). After the addition was completed the cooling bath was removed and the reaction mixture stirred at rt for 18 h. The solution was concentrated by evaporation under reduced pressure and the solution extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material purified by recrystallization from dichloromethane yielding 0.88 g (100%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.28 (t, J=7.0 Hz, 3H), 3.75 (s, 3H), 4.01 (q, J=7.0 Hz, 2H), 5.57 (br s, 2H), 6.71 (d, J=1.7 Hz, 1H), 7.03 (d, J=1.7 Hz, 1H). 13C NMR (75 MHz, DMSO): δ 14.51, 52.09, 64.31, 100.87, 108.93, 110.33, 128.52, 145.93, 154.51, 166.10. MS (ISP): 230.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[CH3:14][O:15][C:16](=[O:22])[C@H:17]([CH:19]([CH3:21])[CH3:20])[NH2:18]>>[CH3:14][O:15][C:16](=[O:22])[CH:17]([NH:18][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: Cl
Product: COC(=O)C(NC(=O)CCc1ccc(O)cc1)C(C)C
Yield: 89.5 %

Procedure:
Following the same procedure of Example 4 except that 3-(4-hydroxyphenyl)propionic acid (1.0 g, 6.0 mmol) and valine methyl ester hydrochloride (1.1 g, 6.6 mmol) were used, 1.5 g of the title compound was obtained. The compound was finally purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: hexane/EtOAc (1/1)). The results of analyses of the compound are as follows:
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)C.O.[OH-].[K+]>C(O)CO.CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:23])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: OCCO
Product: O=C(O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Temperature: 25 °C
Yield: 3.3 %

Procedure:
A solution of N-[3-[(4-fluorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (70.0 g, 0.2205 mole) in ethylene glycol was refluxed for 2 hours, cooled and 14% of the solution was removed. To the remaining solution (0.19 mole) was added 88 ml of water and solid potassium hydroxide pellets (21.4 g, 0.38 mole). The solution was heated at reflux for an additional 11/4 hours, filtered into ice water (2 liter) and acidified with 3N hydrochloric acid. The resulting solid was collected by filtration, washed with water and dried under high vacuum at 60° C. overnight to give 45.5 g of crude title compound (88% yield). A 3.5-g porton of the solid was dissolved in hot methanol and filtered while hot, and water was added to the cloud point. Upon cooling to room temperature, solid precipitated which was collected and recrystallized again from methanol/water to give 2.00 g of title compound after drying under high vacuum at 50° C., mp >250° C.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C(C3C(C)=NN(C)C=3C)N=CC=4)=CC=2)CCC1.[O:37]=[C:38]1[C:47]2[C:42](=[C:43]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:44]=[CH:45][CH:46]=2)[O:41][C:40]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[C:39]1[C:60]1[CH:65]=[CH:64][C:63]([C:66]2([NH:70]C(=O)OC(C)(C)C)[CH2:69][CH2:68][CH2:67]2)=[CH:62][CH:61]=1>>[NH2:70][C:66]1([C:63]2[CH:62]=[CH:61][C:60]([C:39]3[C:38](=[O:37])[C:47]4[C:42]([O:41][C:40]=3[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[C:43]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:44]=[CH:45][CH:46]=4)=[CH:65][CH:64]=2)[CH2:69][CH2:68][CH2:67]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5ccccc5)nccc4c3=O)cc2)CCC1
Agent: Cc1nn(C)c(C)c1-c1nccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5ccccc5)nccc4c3=O)cc2)CCC1
Yield: 15 %

Procedure:
Following the procedure used to prepare 3-(4-(1-aminocyclobutyl)phenyl)-2-phenyl-8-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4H-pyrano[2,3-c]pyridin-4-one, tert-butyl (1-(4-(4-oxo-2,8-diphenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutyl)carbamate was reacted give the title compound (5 mg, 15%). 1H NMR (500 MHz, CD3OD): δ 8.65 (d, J=5.1 Hz, 1H), 7.96 (d, J=5.1 Hz, 1H), 7.89-7.85 (m, 2H), 7.46-7.15 (m, 12H), 2.69-2.63 (m, 2H), 2.49-2.52 (m, 2H), 2.20-2.11 (m, 1H), 1.92-1.78 (m, 1H). LCMS (Method I): RT=4.67 min, [M+2]+=446.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[Br:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1)=[O:20]
Reactant: Nc1ccc(N)cc1
Reactant: O=C(Cl)CCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1ccc(NC(=O)CCBr)cc1
Temperature: 80 °C
Yield: 64.7 %

Procedure:
A solution of 7.02 g of p-aminoaniline in 150 ml of toluene was added 9.12 ml of triethylamine and stirred at 80° C. while adding dropwise a solution of 11 g of β-bromopropionyl chloride in 30 ml of toluene. After the mixture was reacted for 30 minutes colored resinous substance which formed was removed, and the reaction mixture was washed with water and dried. Removal of the solvent by distillation gave 10.1 g of N-(β-bromopropionyl)-p-aminoaniline as oily product. Production of the compound was confirmed by IR and NMR spectra.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)[CH2:3][OH:4].[N:17]#[C:18]Br>>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2([CH2:6][CH2:5][C@H:2]3[CH2:3][O:4][C:18]([NH2:17])=[N:1]3)[CH2:9][CH2:8]2)=[CH:15][CH:14]=1
Reactant: N[C@H](CO)CCC1(c2ccc(Cl)cc2)CC1
Reactant: N#CBr
Product: NC1=N[C@@H](CCC2(c3ccc(Cl)cc3)CC2)CO1

Procedure:
In analogy to example 1d (S)-2-amino-4-[1-(4-chloro-phenyl)-cyclopropyl]-butan-1-ol was reacted with cyanogen bromide to give (S)-4-{2-[1-(4-chloro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine. White solid. MS (ISP): 265.1 ([M+H]+))
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+].CCOC(C)=O>CCO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:16]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(-c2ccc(-c3ccc(OC)cc3)c(-c3ccc(OCc4ccccc4)cc3)n2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2ccc(-c3ccc(OC)cc3)c(-c3ccc(O)cc3)n2)cc1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
The 2-(4-benzyloxyphenyl)-3,6-bis(4-methoxyphenyl)pyridine (3.0 g, 6.3 mmol), ammonium formate (2.0 g, 31 mmol), and 5% Pd/C (1.0 g, 0.5 mmol Pd) were combined in 150 mL of EtOH, and the reaction mixture was stirred at 50°-55 ° C. and followed by TLC (EtOAc/ Tol, 1:9). After 1 h, more ammonium formate (0.5 g, 8 mmol) was added and reaction mixture stirred at 50° C. for 30 min and no starting material remained. After cooling, the reaction mixture was filtered, concentrated, and the residue triturated with Et2O/ pet. ether. The white ppt was filtered and dried in vacuo to give 2.35g (97% yield) of product: mp 204°-205° C.; 1H NMR (CDCl3) d 3.83 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.85 (s, 1H, ArOH), 6.71-6.74 (d, 2H, J=9 Hz, ArH), 6.83-6.86 (d, 2H, J=9 Hz, ArH), 7.00-7.03 (d, 2H, J=9 Hz, ArH), 7.14-7.17 (d, 2H, J=9 Hz, ArH), 7.37-7.40 (d, 2H, J=9 Hz, ArH), 7.68-7.70 (m, 2H, ArH), 8.08-8.11 (d, 2H, J=9 Hz, ArH); MS(FD) 383(M+). Anal. Calcd for C25H21NO3 : C, 78.31; H, 5.52; N, 3.65. Found: C, 78.07; H, 5.79; N, 3.95.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:11]3[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=3[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:36])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1>CS(C)=O>[CH3:24][O:25][C:26](=[O:36])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:15]2[C:10]3[C:9]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)[O:17][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:30]=1
Reactant: Clc1ncnc2oc(-c3ccc(Br)cc3)c(-c3ccccc3)c12
Reactant: COC(=O)COc1cccc(N)c1
Solvent: CS(C)=O
Product: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccc(Br)cc4)c(-c4ccccc4)c23)c1

Procedure:
Heat 400 mg (1.04 mmol) of 6-(4-bromophenyl)-4-chloro-5-phenylfuro[2,3-d]pyrimidine (preparation according to WO 03/018589) and 225.5 mg (1.25 mmol) of 3-aminophenoxyacetic acid methyl ester to 150° C. in an oil bath for 1.5 h. After cooling, take up the residue in DMSO and filter through silica gel (eluent: cyclohexane/ethyl acetate 2:1). 140 mg (25.5% of theory) of the target compound are obtained as a yellowish solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=2)[C:26]([OH:28])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38](I)[CH2:39]C>>[C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([N:32]([CH2:37][CH2:38][CH3:39])[S:33]([CH3:36])(=[O:34])=[O:35])[CH:31]=2)[C:26]([OH:28])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(c1cc(C(=O)O)cc(-c2nnc(C(C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Reactant: CCCI
Product: CCCN(c1cc(C(=O)O)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O

Procedure:
Prepared using a procedure similar to that employed for the synthesis of Intermediate VI, substituting propyl iodide in the place of methyl iodide in Step B of the Intermediate III synthesis.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[CH3:14][O:15][CH2:16][C:17](O)=O>>[CH3:14][O:15][CH2:16][C:17]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1
Reactant: NC(C(=O)O)C(O)c1ccccc1
Reactant: COCC(=O)O
Product: COCc1nc(C(=O)O)c(-c2ccccc2)o1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures Y, Z with methoxyacetic acid, Z1 and Z2. LC-MS-conditions 02: tR=0.81 min; [M+H]+=234.45.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:52][C:53]1[CH:54]=[N:55][C:56]2[C:61]([CH:62]=1)=[CH:60][CH:59]=[CH:58][CH:57]=2.C(N(CC)CC)C>CN(C=O)C>[O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([NH:52][C:53]4[CH:54]=[N:55][C:56]5[C:61]([CH:62]=4)=[CH:60][CH:59]=[CH:58][CH:57]=5)=[O:18])[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12
Reactant: Nc1cnc2ccccc2c1
Reactant: O=C(O)c1ccc2cc3n(c2n1)CCCNC3=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cnc2ccccc2c1)c1ccc2cc3n(c2n1)CCCNC3=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A solution of 6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxylic acid (Intermediate E, 75 mg, 0.31 mmol) and PyBOP (175 mg, 0.34 mmol) in DMF (2 mL) is stirred for 30 min. 3-Aminoquinoline (49 mg, 0.34 mmol) and triethylamine (171 μL, 1.22 mmol) are added and the reaction is stirred at room temperature for 16 h. The mixture is purified via preparative HPLC using a gradient elution from 10-75% acetonitrile/H2O with 0.1% TFA to afford the title compound (93 mg, 82%). LCMS: 372.20 (M+H+). (Method V)