Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=O.O[NH:16][C:17](=[NH:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([I:28])[CH:19]=1.C(Cl)CCl.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([I:28])[CH:19]=3)[N:29]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCOc1ccc(C(=O)O)cc1Cl
Reactant: CC(C)Oc1ccc(C(=N)NO)cc1I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 47.4 %

Procedure:
A mixture of 3-chloro-4-propoxybenzoic acid (0.298 g, 0.93 mmol), the product of Step A (0.2 g, 0.93 mmol) and EDC (0.214 g, 1.1 mmol) in anhydrous DMF (3 ml) was stirred overnight at 45° C. 1M TBAF in THF (0.3 ml) was added and this was stirred for 2.5 h at 110° C. The reaction mixture was diluted to 20 ml with H2O and extracted with EtOAc (2×15 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrate was distilled off and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.22 g, 47.4%), as a colourless solid. 1H-NMR (CDCl3) 8.56 (d, 1H, J=2.04 Hz); 8.21 (d, 1H, J=2.37 Hz); 8.07-8.02 (m, 2H); 7.00 (d, 1H, J=8.73 Hz); 6.87 (d, 1H, J=8.67 Hz); 4.68-4.63 (m, 1H); 4.08 (t, 2H, J=6.45 Hz); 1.93-1.87 (m, 2H); 1.36 (d, 6H, J=6.06 Hz); 1.09 (t, 3H, J=7.44 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:10]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([CH2:8][N:9]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH2:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CN(N)CC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
The compound (5.8 g, 15 mmol) obtained in step 1 was dissolved in methanol (60 mL), 10% palladium/carbon (M) (3.0 g) was added, and the mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered through a filter cell, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol=9/1) to give the title compound (2.9 g, 11 mmol, 76%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[Cl:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21](SC)=[N:22][CH:23]=2)=[CH:15][CH:14]=1>C(O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)=[N:22][CH:23]=2)=[CH:27][CH:28]=1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Reactant: NCCCNc1ccccn1
Solvent: CCO
Product: O=c1[nH]c(NCCCNc2ccccn2)ncc1Cc1ccc(Cl)cc1

Procedure:
2-(3-Aminopropylamino)pyridine (0.91 g) and 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (1.33 g) were fused together on a oil bath at 160° C. for 2.5 hr. The mixture was dissolved in hot ethanol. Cooling afforded a white solid which on recrystallisation from ethanol gave 5-(4-chlorobenzyl)-2-[3-(pyrid-2-ylamino)propylamino]-4-pyrimidone, (1.24 g; 67%) m.p. 168°-71° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][NH:8][C:9]2=[O:14])([O-])=O.[H][H]>[Pd].C(OCC)(=O)C.C(N(CC)CC)C>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][NH:8][C:9]2=[O:14]
Reactant: O=c1[nH]ncc2c([N+](=O)[O-])cccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1cccc2c(=O)[nH]ncc12
Yield: 100450.6 %

Procedure:
980 mg of 5-nitro-phthalazin-1-one (Example 66) and 100 mg of palladium on activated carbon are suspended in 50 ml of ethyl acetate and 1 ml of triethylamine, and it is hydrogenated with hydrogen under normal pressure. It is filtered through diatomaceous earth, and the solvent is removed in a vacuum. 830 g of 5-amino-phthalazin-1-one as a solid is obtained as a crude product.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]([OH:24])[CH:22]=[CH2:23])[CH:18]=[CH:19][CH:20]=1>>[C:4]([Si:1]([O:24][CH:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=1)[CH:22]=[CH2:23])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC(O)c1cccc(Cl)c1
Agent: c1c[nH]cn1
Product: C=CC(O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 22.4 g (133 mmol) of 1-(3-chlorophenyl)prop-2-en-1-ol in 90 mL anhydrous DMF (from Step A) was added t-butyldimethylsilyl chloride (20.0 g, 133 mmol) and imidazole (18.1 g, 266 mmol) and the resulting solution was stirred overnight under nitrogen at room temperature. Wash with water and extract with ethyl acetate. Separate organics, dry over magnesium sulfate, filter, and concentrate under vacuum. The residue was purified by flash silica gel column eluting with a gradient eluent of 0-15% ethyl acetate in hexane to afford the title compound (16.6 g, 46%). m/z (ES) 282, 284 (M, M+2)+; 151, 153 (M-OTBS, M-OTBS+2)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Fc1ccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401 (c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 4-fluorobenzeneboronic acid (Avocado Chemical Company) (35 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (3:1 hexane:EtOAc), the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 323 (M+1). Mp: 134.5-135.0° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[CH:19]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([S:25]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:12])[CH2:4][CH2:3]2)(=[O:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Product: O=C(CCCN1CCC(NS(=O)(=O)C2CCCCC2)CC1)c1ccccc1

Procedure:
Using an analogous procedure to Example 2 4-amino-1-(4-phenyl-4-oxobutyl)piperidine may be reacted with cyclohexanesulphonyl chloride to give the title compound.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:41])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[S:21][CH:22]=[C:23]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:26])[N:24]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>C(O)(=O)C.[Pt]=O>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:41])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[S:21][CH:22]=[C:23]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:26])[N:24]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1csc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)n1)C(=O)OCC
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@H](NC(=O)c1csc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)n1)C(=O)OCC
Reaction time: 24 h
Yield: 36.2 %

Procedure:
To a 50 mL round bottom flask were charged 0.25 g (0.43 mmol) of diethyl N-{2-[2-pivaloylamino4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl]-4-thiazolylcarbonyl}-L-glutamate dissolved in 8 mL of glacial acetic acid, followed by the addition of 0.25 g of platinum oxide catalyst. The reaction was then stirred under hydrogen at 1 atmosphere for 24 hours The catalyst was then filtered away, and the filtrate was removed in vacuo. The residue was then purified using silica gel flash chromatography eluting with 2% methanol/chloroform to give 0.092 g (36%) of diethyl N-{2-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-4-thiazolylcarbonyl}-L-glutamate, m.p. 63-166° C., as a yellow solid. Rf =0.28 (5% methanol/chloroform); 1H NMR (300 MHz, DMSO d6) δ 1.09-1.23 (m, 15H), 1.73-1.77 (m, 3H), 1.97-2.10 (m, 4H), 2.34 (t, J=7.2 Hz, 2H), 2.50-2.62 (m, 2H), 2.86-2.95 (m, 1H), 3.08-3.12 (m, 2H), 3.964.11 (m, 4H), 4.43-4.45 (m, 1H), 6.46 (s, 1H), 8.14 (s, 1H), 8.48 (d, J=8.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH3:18])[CH2:10][C:11](OC(C)(C)C)=[O:12].[BH4-].[Li+].CO>C1COCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH2:10][CH2:11][OH:12])[CH3:18]
Reactant: CC(C)(C)OC(=O)CC(C)(N[S@](=O)C(C)(C)C)c1cccc(F)c1F
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(CCO)(N[S@](=O)C(C)(C)C)c1cccc(F)c1F
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(2,3-difluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)butanoate (17.9 g, 47.7 mmol) in THF (250 mL) at ambient temperature was added lithium borohydride, 2m solution in THF (47.7 mL, 95 mmol) followed by MeOH (12 mL, slightly exothermic reaction. added slowly via syringe). After stirred for 2 h, the reaction was carefully quenched by the addition of saturated ammonium chloride, followed by water and EtOAc. The separated organic phase was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and dried in vacuum to afford (R)-N-(2-(2,3-difluorophenyl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide as light yellow foam. It was carried to next step without purification. MS m/z=306.1 [M+H]+. Calculated for C14H21F2NO2S: 305.4
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[C:37]([NH:44][NH2:45])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].CN(C=O)C>C(Cl)Cl.CCOC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:45][NH:44][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:22])=[CH:23][CH:24]=3)=[C:8]([C:12]([F:13])([F:14])[F:15])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1

Procedure:
A mixture of 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid (synthesis is described in PCT/US2010/024035) (1 equiv.), EDCI (1 equiv.), and BocNHNH2 (1 equiv.), in DCM and DMF (1:1) is stirred at 25° C. overnight, followed by an aqueous/EtOAc workup. Purification if necessary by column chromatography on silica gel to give the product.
Reaction SMILES: CN1C(CCC)=CC(C2SC=CC=2C)=N1.[CH3:16][N:17]1[C:21]([C:22]2[S:23][CH:24]=[CH:25][C:26]=2[CH3:27])=[CH:20][C:19]([CH2:28][CH2:29][CH3:30])=[N:18]1.[I:31]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].IC1C(C2SC=CC=2C)=NN(C)C=1CCC>CN(C)C=O>[I:31][C:20]1[C:19]([CH2:28][CH2:29][CH3:30])=[N:18][N:17]([CH3:16])[C:21]=1[C:22]1[S:23][CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: CCCc1cc(-c2sccc2C)n(C)n1
Reactant: O=C1CCC(=O)N1I
Agent: CCCc1c(I)c(-c2sccc2C)nn1C
Agent: CCCc1cc(-c2sccc2C)nn1C
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCc1nn(C)c(-c2sccc2C)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a mixture of 1-methyl-3-(3-methyl-2-thienyl)-5-propyl-1H-pyrazole and 1-methyl-5-(3-methyl-2-thienyl)-3-propyl-1H-pyrazole (85:15, 3.7 mmol) in 10 mL dry N,N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (4.6 mmol) in small portions. The reaction mixture was stirred at room temperature overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 928 mg of a mixture of 4-iodo-1-methyl-3-(3-methyl-2-thienyl)-5-propyl-1H-pyrazole and 4-iodo-1-methyl-5-(3-methyl-2-thienyl)-3-propyl-1H-pyrazole (85:15; 61% yield) that was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].F[B-](F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18].[OH-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:11])[N:6]([CH2:17][CH3:18])[N:7]=2)[CH:3]=1
Reactant: CC[O+](CC)CC
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCn1nc2ccc(Br)cc2c1C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-3-methyl-1H-indazole (8.44 g) in ethyl acetate (100 ml) was added dropwise triethyloxonium tetrafluoroborate (1 M dichloromethane solution, 60 ml) at room temperature, and the mixture was stirred at the same temperature overnight. To the reaction mixture was added a 1 M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (1.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:26])[C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:26])[C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(OC(F)(F)F)cc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 4-[hydroxy-(4-trifluoromethoxy-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 32) (604 mg, 1.61 mmol) in CH2Cl2 (8 mL) was added SiO2 (2 g) followed by PCC (1.04 g, 4.82 mmol), and the mixture was stirred at room temperature for 3 h to give 4-(4-trifluoromethoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester as colourless crystals (601 mg, 100%) after purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][C:4]1([C:13]([F:16])([F:15])[F:14])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5]1.[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>C(Cl)Cl>[N+:19]([C:11]1[CH:10]=[CH:9][C:7]2[O:8][C:4]([CH2:3][C:2]([F:1])([F:17])[F:18])([C:13]([F:15])([F:14])[F:16])[O:5][C:6]=2[CH:12]=1)([O-:21])=[O:20]
Reactant: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 54.4 g of 2-(2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole in 75 ml of methylene chloride was added dropwise to a mixture of 40 ml of 65% strength by weight nitric acid and 40 ml of concentrated sulphuric acid at i0° C. The mixture was subsequently stirred at room temperature for 1 hour and then poured onto ice-water, the organic phase was separated off and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with water, dried and freed from readily volatile constituents. 95 g of the product (=86% of theory) with a melting point of 87° to 88° C. remained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([CH:25]=O)[CH:24]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])C(=O)OC(C)(C)C)=O.[NH2:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C.[BH4-].[Na+].[OH-].[Na+]>CCOC(C)=O.CO>[CH2:18]([NH:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH2:1][NH:35][CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29][CH2:28][NH2:27])[CH:24]=[C:23]([CH2:25][NH:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH:22]=1)[CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)CN(CCCOc1cc(C=O)cc(C=O)c1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCNCCCN
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CNCCCOc1cc(CNCCCNCCCN)cc(CNCCCNCCCN)c1
Reaction time: 24 h

Procedure:
tert-Butyl (3-(3,5-diformylphenoxy)propyl)-(isobutyl)carbamate (0.15 g, 0.42 mmol) and MeOH (10 mL) were added to a round-bottom flask. To the solution was added tert-butyl (3-((3-aminopropyl)amino)propyl)carbamate (0.20 g, 0.84 mmol) and the reaction mixture was stirred for 24 h. Sodium borohydride (0.06 g, 1.69 mmol) was added and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aqueous NaOH (10%, 50 mL) and EtOAc (50 mL) were added, the layers separated and the aqueous layer was extracted with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product as clear oil which was used without further purification.
Reaction SMILES: [Si]([O:18][C:19]1[CH:55]=[CH:54][C:22]([O:23][CH2:24][C@@H:25]([OH:53])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:52]=[CH:51][C:33]([NH:34][C:35]3[C:40]([NH:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:43])=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:45]([NH:44][C:42]([NH:41][C:40]1[C:35]([NH:34][C:33]2[CH:51]=[CH:52][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:53])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:55][CH:54]=3)=[CH:31][CH:32]=2)=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:43])[CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCNC(=O)Nc1cccnc1Nc1ccc(CCNC[C@H](O)COc2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCNC(=O)Nc1cccnc1Nc1ccc(CCNC[C@H](O)COc2ccc(O)cc2)cc1
Yield: 87.8 %

Procedure:
N-{2-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-3-pyridinyl}-N′-hexylurea (0.15 g, 0.197 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.09 g, 0.173 mmol).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Mg].C(I)C.CC.Cl[CH2:18][CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21]>CCOCC.C(O)(=O)C.C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:18][CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]1)=[O:21])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=C(CCCl)N1CCN(c2ccccc2)CC1
Agent: CC
Agent: [Mg]
Solvent: CCI
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1[nH]c2ccccc2c1CCC(=O)N1CCN(c2ccccc2)CC1

Procedure:
2-methylindole (26.2 g) dissolved in dry ether (100 ml) was added dropwise to the Grignard reagent prepared from 4.9 g of magnesium and 31.2 g of ethyl iodide in 100 ml of dry ether at 20°-25°C and the mixture was gently refluxed until the evolution of ethane ceased. 1-(β-Chloropropionyl)-4-phenylpiperazine (55.6 g) dissolved in dry ether (100 ml) was then slowly added to the resulting reaction mixture at a temperature below 20°C. At first the addition of the latter caused the precipitation of yellowish viscid solid, which finally became cherry-red. After the addition was completed, ether was distilled off under ordinary pressure and the viscid solid mass which remained was heated on a steam bath for 3 hours, and then cooled. The resulting reaction mixture was agitated vigorously with 250 ml of benzene and 200 ml of a 5 % aqueous solution of acetic acid. The benzene layer which was separated was washed with a 10 % aqueous solution of sodium carbonate and water, dried over anhydrous sodium sulfate and concentrated to dryness. The residual solid was recrystallized from ethanol to give 1-[β-(2-methyl-3-indolyl)propionyl]-4-phenylpiperazine, melting at 121°-122°C.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C@@H:3]([N:5]([CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13])[C:6](=[O:9])[O:7][CH3:8])[CH3:4].[Br-].[CH2:24]1[CH2:28]OC[CH2:25]1>>[CH3:22][C:2]([CH3:21])([CH3:1])[C@@H:3]([N:5]([CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)([OH:13])[CH2:28][CH:24]=[CH2:25])[C:6](=[O:9])[O:7][CH3:8])[CH3:4]
Reactant: COC(=O)N(CCC(=O)c1ccc(F)cc1)[C@@H](C)C(C)(C)C
Reactant: C1CCOC1
Agent: [Br-]
Product: C=CCC(O)(CCN(C(=O)OC)[C@@H](C)C(C)(C)C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of (S)-methyl 3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (4.5 g, 0.015 mol) in THF (60 mL) was added allymagnesium bromide (1 M, 30 mL, 0.03 mol) dropwise at −78° C. under N2. After adding completely, the reaction mixture was stirred at rt overnight. The reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give methyl (S)-3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-hydroxyhex-5-enyl)carbamate (4.80 g, 92%), which was used for the next step without further purification.
Reaction SMILES: [OH:1][CH2:2]C(CO)OCN1C=C(C=C)C(=O)NC1=O.ClN1C(=O)CCC1=O.[OH:26][CH2:27][CH2:28][O:29][CH2:30][N:31]1[CH:38]=[C:37]([CH:39]([N:42]=[N+:43]=[N-:44])[CH2:40][Cl:41])[C:35](=[O:36])[NH:34][C:32]1=[O:33]>ClCCl.CO>[OH:26][CH2:27][CH:28]([CH2:2][OH:1])[O:29][CH2:30][N:31]1[CH:38]=[C:37]([CH:39]([N:42]=[N+:43]=[N-:44])[CH2:40][Cl:41])[C:35](=[O:36])[NH:34][C:32]1=[O:33]
Reactant: C=Cc1cn(COC(CO)CO)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=NC(CCl)c1cn(COCCO)c(=O)[nH]c1=O
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CO
Product: [N-]=[N+]=NC(CCl)c1cn(COC(CO)CO)c(=O)[nH]c1=O
Yield: 57 %

Procedure:
Reaction of 9a with N-chlorosuccinimide, using the procedure outlined for the preparation of 2b, and purification of the product by silica gel column chromatography using dichloromethane-methanol (90:10, v/v) as eluent yielded 10b as a syrup (75 mg, 57%).