Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:2]=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].C(N1C=CC(N)=N1)CC.N1C(C)=CC=CC=1C>C(Cl)Cl.C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH2:48][CH2:1][CH3:2])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: CCCn1ccc(N)n1
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
Triphenylphosphine (173 mg, 0.66 mmol) was dissolved in methylene chloride (8 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (133 mg, 0.75 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 146 mg, 0.44 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 30 min. The mixture was chilled to 0° C. and 1-propyl-1H-pyrazol-3-ylamine (54 mg, 0.43 mmol) was added followed by 2,6-lutidine (154 μL, 1.32 mmol). The mixture was continued to stir at 0° C. for 30 min and then at 25° C. for 3 h. The reaction was diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and saturated aqueous brine solution (2×20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-propyl-1H-pyrazol-3-yl)-propionamide (104 mg, 55%) as a white foam: ESI-LRMS m/e calcd for C21H28ClN3O3S [M+] 437.2, found 438.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.85 (t, J=7.4 Hz, 1H, CH3), 1.04-1.16 (m, 2H, CH2), 1.38-1.93 (m, 10H, 5×CH2), 2.10-2.41 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.59 (t, J=7.5 Hz, 1H, CH), 3.89 (t, J=7.0 Hz, 2H, NCH2), 6.61 (d, J=2.2, 1H, Ar), 7.23 (d, J=2.2, 1H, Ar), 7.44 (dd, Jo=8.2, Jm=1.3 Hz. 1H, Ar), 7.57 (d, Jm=1.3 Hz, 1H, Ar), 8.02 (d, Jo=8.2 Hz, 1H, Ar), 8.61 (s, 1H, NH).
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]#[N:25])=[CH:21]2)=[CH:16][CH:15]=1.[Br:26]N1C(=O)CCC1=O>>[Br:26][CH2:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]#[N:25])=[CH:21]2)=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc(C#N)cc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: N#Cc1ccc2ccc(CBr)cc2c1
Temperature: 80 °C
Yield: 73.1 %

Procedure:
2,2′-azobisisobutyronitrile (491 mg, 3 mmol) and normalbutyronitrile (50 ml) were added to 7-methyl-2-naphthalene carbonitrile (5.0 g, 30 mmol) at room temperature. N-bromosuccinimide (5.3 g, 30 mmol) was added thereto, and the mixture was heated at an internal temperature of 80° C. for 2 hours. After that, the experiment was conducted in the same way as Example 12. Analysis by reversed-phase chromatography by use of the obtained product from Example 11 as a standard sample revealed that 5.4 g of the title compound was obtained (74% yield).
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.S(C)C.[F:25][C:26]([F:45])([F:44])[C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][C:33]3[CH2:42][CH2:41][CH2:40][C:39](=[O:43])[C:34]=3[CH:35]=2)[CH2:30]1)=[O:28]>C1(C)C=CC=CC=1.C1COCC1>[F:45][C:26]([F:25])([F:44])[C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][C:33]3[CH2:42][CH2:41][CH2:40][C@H:39]([OH:43])[C:34]=3[CH:35]=2)[CH2:30]1)=[O:28]
Reactant: O=C1CCCc2cc3c(cc21)CCN(C(=O)C(F)(F)F)C3
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CSC
Product: O=C(N1CCc2cc3c(cc2C1)CCC[C@@H]3O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-methyl-CBS-oxazaborolidine (1M solution in toluene, 0.56 mL, 0.56 mmol) in 15 mL of toluene at −10° C. was added BH3.SMe2 (1.27 mL, 13.38 mmol). To this stirred solution was then added 2-(2,2,2-trifluoroacetyl)-1,2,3,4,8,9-hexahydrobenzo[g]-isoquinolin-6(7H)-one(3.31 g, 11.15 mmol)in 5 mL of dry THF dropwise while keeping the temperature around −10° C. After stirring at room temperature for 2 h, the reaction mixture was cooled down to −10° C. and was quenched with 6 mL of MeOH and was then evaporated to dryness and directly submitted to flash chomatography (SiO2, hexane/EtOAc=3:1 to 2:1 to 1:1) to afford (S)-2,2,2-trifluoro-1-(6-hydroxy-3,4,6,7,8,9-hexahydrobenzo[g]isoquinolin-2(1H)-yl)ethanone as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:8]=[C:7](C(O)=O)[C:6]=2[CH2:5][CH2:4][NH:3]1.C1N=CN([C:24]([N:26]2C=NC=C2)=[O:25])C=1.[C:31]([OH:35])([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1>[O:1]=[C:2]1[C:11]2[C:6](=[C:7]([NH:26][C:24](=[O:25])[O:35][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:8]=[C:9]([O:12][CH:13]([CH3:14])[CH3:15])[CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CC(C)Oc1cc(C(=O)O)c2c(c1)C(=O)NCC2
Reactant: CC(C)(C)O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CC(C)Oc1cc(NC(=O)OC(C)(C)C)c2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a suspension of 1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (77a, 1.76 g, 7.06 mmol) in anhydrous dioxane (100 mL) was added CDI (1.43 g, 8.83 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then stirred at 100° C. for 30 minutes. After cooling down to room temperature, TMSA (1.50 mL, 10.8 mmol) was added. After stirring the reaction mixture for 2 hours, t-butanol (25.0 mL) was added. The resulting mixture was stirred at 100° C. overnight. After cooling to room temperature and concentrating under vacuum, the resulting residue was purified by column chromatography (0-100% EtOAc/heptanes) to give tert-butyl [1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]carbamate (77b, 958 mg, 42%) as a solid.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1[C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.48 g, 1.6 mmol) and (3-fluorophenyl)boronic acid (0.27 g, 2.0 mmol) in 1,4-dioxane (10 mL) was added a 1N solution of sodium carbonate in water (2.1 mL, 2.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.080 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, concentrated, and purified on silica gel (0-50% ethyl acetate/hexanes) to give the desired compound (0.32 g, 63%). LCMS calculated for C14H11FN5OS (M+H)+: m/z=316.1. Found: 316.0.
Reaction SMILES: C1COCC1.[C:6]([NH:9][CH2:10][CH:11]([O:14][C:15](=[O:17])C)[CH2:12]Cl)(=[O:8])[CH3:7].C(OC(=O)[NH:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:39]=[CH:38][C:37](=[O:40])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)C1C=CC=CC=1>CN(C=O)C.CO>[O:17]=[C:15]1[N:27]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:35]=[CH:36][C:37](=[O:40])[CH2:38][CH2:39]3)=[CH:30][CH:29]=2)[CH2:12][CH:11]([CH2:10][NH:9][C:6](=[O:8])[CH3:7])[O:14]1
Reactant: CC(=O)NCC(CCl)OC(C)=O
Reactant: O=C1C=CN(c2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.0 M LiOBu-t in THF (5 mL, 5 mmol) is added dropwise with stirring to a solution of acetic acid 1-(acetylamino-methyl)-2-chloro-ethyl ester (0.600 g, 3.10 mmol) in DMF (1 mL) and MeOH (0.127 mL) under nitrogen atmosphere at 0° C. [4-(4-Oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-carbamic acid benzyl ester (0.500 g, 1.55 mmol; prepared as described for Example 8), is added, and the mixture is allowed to gradually warm up to r.t. and stirred for additional 24 h. The mixture is quenched with saturated aq. NH4Cl (20 mL), diluted with aq. NaCl, and extracted with EtOAc (3×). The organic layers are combined and washed with brine, and dried over MgSO4. The solvent is removed under vacuum, and the crude product purified by silica gel flash chromatography (gradient 20% to 100% EtOAc—hexanes) to afford the title compound as a white solid. Yield 137 mg (26%). MS (m/z): 330 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.24 (br. t, J=5.8 Hz, 1H), 7.72 (d, J=7.7, 1H), 7.53 (d, J=9.1, 2H), 7.27 (d, J=9.1, 2H), 4.97 (d, J=7.7 Hz, 1H), 4.72–4.67 (m, 1H), 4.10 (t, J=9.1 Hz, 2H), 3.75–3.69 (m, 1H), 3.40 (t, J=5.5 Hz, 2H), 2.50–2.49 (m, 2H), 1.82 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>CN(C=O)C.O>[N:16]1([C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: N#Cc1ncccc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncccc1-n1cncn1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of 2-cyano-3-fluoro-pyridine (2.99 g, 24.49 mmol, preparation described in Sakamoto et. al., Chem. Pharm. Bull. 1985, 33(2), 565–571) in DMF (30 ml) is added cesium carbonate (2.03 g, 29.39 mmol) and 1,2,4-triazole (2.03 g, 29.39 mmol) and the reaction mixture is stirred at 65° C. for 4 h. After cooling to room temperature, the mixture is diluted with water and extracted with EtOAc 3 times. The aqueous layer is saturated with LiCl and further extracted with EtOAc. The combined organic layer is dried on sodium sulfate, concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, 2% MeOH containing 10% NH4OH in CH2Cl2 to 6%) to give 3-[1,2,4]triazol-1-yl-pyridine-2-carbonitrile. 1H NMR (CDCl3, 400 MHz) δ 8.95 (s, 1H); 8.8 (d, J=4 Hz, 1H); 8.24 (s, 1H); 8.22 (d, J=8.5 Hz, 1H); 7.75 (dd, J=4, 8.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:39])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:35])([CH3:34])[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[NH:10][CH:9]2[C:36](O)=[O:37])[CH:5]=[CH:6][CH:7]=1.CC1(C)[O:45][C@@H:44]([CH2:46][CH2:47][NH2:48])[CH2:43][O:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:45][C@H:44]([CH2:43][OH:42])[CH2:46][CH2:47][NH:48][C:36]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:39])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:35])([CH3:34])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[NH:10]1)=[O:37]
Reactant: COc1ccc(CC(C)(C)CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)cc1
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(C)(C)CC2NC(C(=O)NCC[C@H](O)CO)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)cc1
Yield: 27.8 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid prepared in Example 126c (0.5 g, 0.87 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.25 g, 1.7 mmol), HATU (0.6 g, 1.7 mmol) and iPr2NEt (0.45 mL, 2.6 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.16 g, 29%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]([NH2:8])=[S:7])[CH3:4].[Cl:9][CH2:10][C:11](=O)[CH2:12]Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[ClH:9].[Cl:9][CH2:10][C:11]1[N:8]=[C:6]([CH2:5][N:3]([CH3:4])[CH3:2])[S:7][CH:12]=1
Reactant: O=C(CCl)CCl
Reactant: CN(C)CC(N)=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)Cc1nc(CCl)cs1
Reaction time: 8 h

Procedure:
To a 3-liter flask were added 1170 ml. of 1,2-dichloroethane, 308 g. of dimethylaminothioacetamide, hydrochloride, 279 g. of 1,3-dichloropropanone and 370 g. of sodium bicarbonate. The mixture was stirred for 8 hours, and 500 ml. of additional 1,2-dichloroethane was added and the mixture stirred for a short time more. It was then filtered, the filter cake was washed with 670 ml. of 1,2-dichloroethane, and the filtrates were combined and chilled in an ice bath. To the filtrate was added 157 ml. of thionyl chloride, dropwise, with good stirring. It was then warmed and stirred overnight at ambient temperature, and then for 30 minutes at 65°-70°. It was then cooled and filtered, and the solids were washed with 500 ml. of additional 1,2-dichloroethane and dried to obtain 427 g. of the desired product. The product was confirmed to be substantially identical to the product of Example 5 by nuclear magnetic resonance analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].CS[C:15](SC)=[N:16][C:17]#[N:18].C([O-])([O-])=O.[K+].[K+].[NH2:27][NH2:28]>C1COCC1>[NH2:18][C:17]1[NH:28][N:27]=[C:15]([NH:12][S:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:11])[N:16]=1
Reactant: CSC(=NC#N)SC
Reactant: NS(=O)(=O)c1c(Cl)cccc1Cl
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1nc(NS(=O)(=O)c2c(Cl)cccc2Cl)n[nH]1
Temperature: 30 °C
Reaction time: 72 h
Yield: 91.3 %

Procedure:
A mixture of 90.1 g (0.398 mol) of 2,6-dichlorobenzenesulfonamide, 64.7 g (0.398 mol) of dimethyl N-cyanodithioiminocarbonate and 58.3 g (0.420 mol) of powdered anhydrous K2CO3 in 800 ml of THF was heated at reflux for 3 hours. After cooling to 30° C., 25.3 ml (25.6 g, 0.798 mol) of anhydrous hydrazine was added dropwise over 30 minutes. The resulting mixture was stirred for 3 days at ambient temperature and filtered. The solid collected was washed with THF, suspended in 400 ml of water and acidified with 180 ml of acetic acid. The resulting mixture was filtered, and the solid collected was washed with water and dried to yield 112 g (91 percent) of the desired product as a white solid, mp 300° C. (decomp.) IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6](=[O:11])([O:8][CH2:9][CH3:10])[NH2:7]>COC1C=CC(O)=CC=1.ClC=C(Cl)Cl>[CH3:4][CH:3]([NH:7][C:6]([O:8][CH2:9][CH3:10])=[O:11])[CH2:2][CH:1]([NH:7][C:6]([O:8][CH2:9][CH3:10])=[O:11])[NH:7][C:6]([O:8][CH2:9][CH3:10])=[O:11]
Reactant: CCOC(N)=O
Reactant: C/C=C/C=O
Agent: COc1ccc(O)cc1
Solvent: ClC=C(Cl)Cl
Product: CCOC(=O)NC(C)CC(NC(=O)OCC)NC(=O)OCC
Reaction time: 0.5 h
Yield: 52 %

Procedure:
35 g of crotonaldehyde are added dropwise at 60°-83° C. to a mixture of 133.5 g of ethyl carbamate, 15 g of acid ion exchanger resin (Duolite C 265), 0.2 g of hydroquinone monomethyl ether and 200 ml of trichloroethylene in the course of 20 minutes, and the mixture is thereafter left at 80° C. for 30 minutes. The catalyst is filtered off, the solvent is distilled off and the residue is crystallized from ethyl acetate/petroleum ether. This gives 83 g (52% yield, based on starting crotonaldehyde) of 3-methyl-1,1,3-tri(ethoxycarbonylamino)propane having a melting point of 103°-105° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:20])=[C:8]([C:10]2[CH:11]=[C:12]([CH2:17][CH:18]=[CH2:19])[CH:13]=[CH:14][C:15]=2[OH:16])[CH:9]=1.[H-].[Na+].[H][H].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1>CN(C=O)C>[CH2:3]([C:4]1[CH:5]=[CH:6][C:7]([OH:20])=[C:8]([C:10]2[CH:11]=[C:12]([CH2:17][CH:18]=[CH2:19])[CH:13]=[CH:14][C:15]=2[O:16][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[CH:9]=1)[CH:2]=[CH2:1]
Reactant: C=CCc1ccc(O)c(-c2cc(CC=C)ccc2O)c1
Reactant: [H][H]
Reactant: ICCCCCCCCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCc1ccc(O)c(-c2cc(CC=C)ccc2OCCCCCCCCCCOC2CCCCO2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 26.8 %

Procedure:
A solution was prepared by dissolving 0.53 g of Magnolol into DMF. The solution, wherein 80 mg of sodium hydride (60% oiliness) was added, was stirred at room temperature until generation of hydrogen gas stopped. The reaction mixture, added 1.0 g of 2-(10-iododecyloxy)tetrahydropyrane, was heated to 70° C. with stirring for 3 hours. The solvent in the reaction mixtures was removed under reduced pressure, and an aqueous solution of ammonium chloride was added into the residue to extract with diethylether. The extract was washed with an aqueous solution saturated with NaCl, dried with sodium sulfate and concentrated. The concentrate was purified by a silica gel column-chromatography (n-hexane:ethyl acetate=10:1) to yield 0.27 g of 4-allyl-2-[5-allyl-2-(10-tetrahydropyranyloxydecyloxy)phenyl]phenol. The subject thus obtained was dissolved into 10 ml of ethanol, 1 ml of hydrochloric acid was added thereinto and stirred for 3 hours at room temperature. The reactant, wherein 100 ml of water was added, was extracted with diethylether. The extract was washed with water, sodium hydrogencarbonate and an aqueous solution saturated with NaCl in turn, dried with sodium sulfate and concentrated. The concentrate was purified by a silica gel column-chromatography (n-hexane:ethyl acetate=15:1) to yield 0.16 g of 4-allyl-2-[5-allyl-2-(10-hydroxy-decyloxy)phenyl]phenol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([I:17])[C:11]=1[OH:18])(=[O:9])[CH3:8].[CH3:19][O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35]I)=[CH:31][CH:30]=2)[CH:23]=1.C(OCC)(=O)C>CC(C)=O.ClCCl>[CH3:19][O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:7](=[O:9])[CH3:8])=[C:11]([OH:18])[C:12]=3[I:17])=[CH:33][CH:34]=2)[CH:23]=1
Reactant: CC(=O)c1ccc(O)c(I)c1O
Reactant: COC(=O)c1cccc(Cc2ccc(CI)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Cc2ccc(COc3ccc(C(C)=O)c(O)c3I)cc2)c1
Temperature: 50 °C
Yield: 61 %

Procedure:
Potassium carbonate (675 mg, 4.88 mmol) is added to a solution of 4-acetyl-3-hydroxy-2-iodo-phenol (925 mg, 3.33 mmol) and 3-(4-iodomethyl-benzyl)-benzoic acid methyl ester (1.21 g, 3.30 mmol) in acetone (65 mL). The resulting suspension is heated at 50° C. for 16 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. The residue is taken up in dichloromethane, washed with 1N hydrochloric acid, brine, dried over magnesium sulfate, filtered and concentrated to give a yellow solid. This solid is dissolved in dichloromethane and a white precipitate forms upon addition of ethyl acetate. The white solid is filtered off and the mother liquor is purified by flash chromatography, eluting with 20% ethyl acetate in hexanes. The precipitate and chromatographed materials are combined to give 1.04 g of the title compound as a pale yellow solid: MS (m/z) 517 (M+1), 515 (M−1); 1H NMR δ (CDCl3); 13.58 (s, 1H), 7.93 (m, 2H), 7.74 (d, J=9.0 Hz, 1H), 7.45-7.38 (m, 4H), 7.25 (d, J=8.0 Hz, 2H), 6.50 (d, J=9.0 Hz, 1H), 5.27 (s, 2H), 4.07 (s, 2H), 3.94 (s, 3H), 2.63 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.C([Li])CCC.[CH:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-:36]>C1COCC1>[Cl:36][C:4]1[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=[C:2]([CH:27]([OH:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: [Cl-]
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(C(O)c4ccccc4)cc3c2C1
Reaction time: 0.33 h
Yield: 56 %

Procedure:
A solution of the product of Example 29 step B (1.0 g, 2.58 mmol) in dry THF (15 mL) was cooled to −78° C. under a nitrogen atmosphere and n-butyl lithium (1.6 M in hexane, 1.0 mL, 1.54 mmol) was added dropwise over 10 min. The reaction mixture was stirred for 20 min and a solution of benzaldehyde (137 mg, 1.29 mmol) in THF (1 mL) was added over 5 min. The reaction was stirred for 1 h at −78° C., poured into saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated in vacuo and the residue purified by flash column chromatography (SiO2, 85:15 hexanes/ethyl acetate) to afford tert-butyl 6-chloro-8-(hydroxy(phenyl)methyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.6 g, 56%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.42-7.26 (m, 7H), 5.91 (d, J=3.3 Hz, 1H), 4.51 (s, 2H), 3.87-3.75 (m, 2H), 2.93-2.83 (m, 2H), 2.28 (d, J=3.3 Hz, 1H), 1.49 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[CH2:5]2.N1CCCCC1.Cl[C:20]([C:22]([O:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])=[O:21]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:20]([C:22]([O:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])=[O:21])[NH:7][C:6](=[O:12])[CH2:5]2
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CC(=O)OC(C)(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: -40 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A stirred solution of 5-fluoro-6-amino-1,3-dihydro-indol-2-one (410 mg, 2.46 mmol) in 10 ml of tetrahydrofuran was added with piperidine (0.3 ml). The mixture was cooled to −40° C. in an acetone-dry ice bath and added with acetic acid 1-chlorocarbonyl-1-methyl-ethyl ester (405 mg, 2.46 mmol) in 10 ml of tetrahydrofuran dropwise. Upon the completion of the addition, the resulting mixture was stirred at the room temperature overnight until the precipitate was formed. The solid was filtered, washed with water and recrystallized from methanol to give acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-1-methyl-ethyl ester (720 mg, 99.5%) as a white solid.