Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[OH:23][CH:24]([C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([F:57])([F:56])[F:55])=[CH:49][CH:48]=1)[C:25]1[C:26]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:27]2[C:32](=[CH:33][C:34]=1[CH:35]([CH3:37])[CH3:36])[O:31][C:30]([CH3:39])([CH3:38])[CH2:29][C:28]2=[O:40]>ClCCl>[CH:35]([C:34]1[CH:33]=[C:32]2[C:27]([C:28](=[O:40])[CH2:29][C:30]([CH3:39])([CH3:38])[O:31]2)=[C:26]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:25]=1[C:24](=[O:23])[C:47]1[CH:48]=[CH:49][C:50]([O:53][C:54]([F:55])([F:56])[F:57])=[CH:51][CH:52]=1)([CH3:37])[CH3:36]
Reactant: CC(C)c1cc2c(c(-c3ccccc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)c1cc2c(c(-c3ccccc3)c1C(=O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 4 h

Procedure:
At 0° C., 166 mg (390 μmol) of 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one are added to a solution of 95 mg (197 μmol) of rac-6-{hydroxy[4-(trifluoromethoxy)phenyl]methyl}-7-iso-propyl-2,2-dimethyl-5-phenyl-2,3-dihydro-4H-chromen-4-one (Example 31A) in 3 ml of dichloromethane, and the mixture is stirred at this temperature for 4 h. The mixture is then diluted with dichloromethane and washed three times with 1 M aqueous sodium hydroxide solution. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=[N:13]O)=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:15])=[N:9]2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[OH-].[Na+]>>[OH:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(O)c(C=NO)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2ccc(O)c(C#N)c2n1
Temperature: 144 °C
Reaction time: 7.5 h
Yield: 60 %

Procedure:
Referring to FIG. 19, compound 7 (0.160 g, 0.792 mmol) was added to acetic anhydride (3.5 mL) and the resulting mixture was stirred at 144° C. under nitrogen atmosphere for 7.5 h. Concentrated NaOH solution (50%) was added to the mixture slowly with stirring until the reaction reached pH 12. The solvent was evaporated and the resulting dark brown residue was purified by column chromatography (1:1 EtOAc/hexane) to yield 5b (0.0874 g, 0.475 mmol, 60%) as a yellow solid: 1H NMR (acetone-d6) δ 8.20 (1H, J=8.0 Hz), 8.04 (1H, d, J=8.8 Hz), 7.37 (1H, d, J=8.4 Hz), 7.36 (1H, d, J=9.2 Hz), 2.69 (3H, s); 13C NMR (acetone-d6) δ 163.1, 161.7, 149.1, 136.6, 133.9, 121.0, 117.3, 114.8, 95.7, 24.7; FTIR (neat) 3111, 2922, 2229, 1620, 1577, 1508, 1446, 1342, 1271, 1143, 844 cm−1; MS (ESI) m/z calculated for (C11H8N2O+H)+ 185, found 185; HRMS (ESI) m/z calculated for (C11H8N2O+H)+ 185.0716, found 185.0766.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH:26]=2)[C:21](O)=[O:22])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:63]([N:65]1[CH:69]=[CH:68][C:67]([NH2:70])=[N:66]1)[CH3:64]>CN(C=O)C>[CH3:35][C:34]([Si:31]([CH3:33])([CH3:32])[O:30][CH2:29][C@@H:28]([O:27][C:25]1[CH:24]=[C:20]([CH:19]=[C:18]([O:17][CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:26]=1)[C:21]([NH:70][C:67]1[CH:68]=[CH:69][N:65]([CH2:63][CH3:64])[N:66]=1)=[O:22])[CH3:38])([CH3:37])[CH3:36]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: CCn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
DIPEA (3.11 mL, 18.03 mmol) was added to a solution of 3-{(phenylmethyl)oxy}-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (3.00 g, 7.21 mmol), HATU (3.41 g, 9.01 mmol) and 1-ethyl-1H-pyrazol-3-amine [Chem. Heterocycl. Compd. (Engl. Transl.), 11, 1975, 212] (1.20 g, 10.8 mmol) in DMF (10 mL). The resulting mixture was stirred at ambient temperature for 3 hours. The DMF was removed in vacuo. The solvent was evaporated and the residue was dissolved in 5% w/v citric acid (50 mL), ethyl acetate (30 mL) and diethyl ether (30 mL) and the organic layer was further washed with sat. aqueous NaHCO3 (30 mL) and brine (30 mL). The organic layer was separated, then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:5 to 1:2 ethyl acetate:hexanes, afforded the title compound as a colourless oil (2.40 g, 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:17]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>C(OCCO)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:7][C:6]=2[CH:17]=1
Reactant: NCc1cccnc1
Reactant: Cc1ccc2c(c1)NC(=S)c1ccccc1N2
Solvent: CCOCCO
Product: Cc1ccc2c(c1)N=C(NCc1cccnc1)c1ccccc1N2
Yield: 48.9 %

Procedure:
A solution of 0.32 g (1.3 mmol) of 8-methyl-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione (Hunziker F., et al., Helv. Chim. Acta, 50:1588 (1967)) in 10 mL 2-ethoxyethanol was treated with 0.3 mL (2.9 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed two times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Recrystallization from EtOAc/hexane gave 0.2 g (50% yield) of the pure product as a light yellow solid, mp 186-187° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =315.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[O:19][CH3:20])[CH:3]=1.P([O-])(O)(O)=[O:22].[Na+].CC(=CC)C.Cl([O-])=O.[Na+].Cl.S([O-])([O-])=O.[Na+].[Na+]>CC(O)(C)C.O.C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:5]([C:6]([OH:22])=[O:7])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[O:19][CH3:20])[CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: COc1cc(F)ccc1Oc1cc(Cl)c(Cl)cc1C=O
Agent: CC=C(C)C
Agent: Cl
Agent: O=S([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: COc1cc(F)ccc1Oc1cc(Cl)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzaldehyde (3.3 g, 10.47 mmol) in tBuOH (33.00 mL), water (19.80 mL) and acetonitrile (19.80 mL) was added sodium dihydrogen phosphate (655.9 μL, 10.47 mmol), 2-methylbut-2-ene (5.54 mL, 52.35 mmol) and sodium chlorite (2.84 g, 31.41 mmol). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was acidified with 1N HCl and diluted with ethyl acetate. Sodium sulfite was added to remove the faint yellow color. The two layers were separated and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The solid was triturated with hexanes and filtered to provide 4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoic acid (2.94 g, 85%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.37 (br s, 1H), 7.96 (s, 1H), 7.18-7.12 (m, 2H), 6.86-6.80 (m, 2H), 3.76 (s, 3H) ppm.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:10]=[C:9]([N:11]2[CH2:14][CH:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[C@H:17]([CH3:22])[CH2:16]3)[CH2:12]2)[C:8]([F:23])=[CH:7][CH:6]=1)C>C(O)=O>[CH3:22][C@H:17]1[N:18]([CH3:21])[CH2:19][CH2:20][N:15]([CH:13]2[CH2:12][N:11]([C:9]3[N:10]=[C:5]([CH:4]=[O:3])[CH:6]=[CH:7][C:8]=3[F:23])[CH2:14]2)[CH2:16]1
Reactant: CCOC(OCC)c1ccc(F)c(N2CC(N3CCN(C)[C@H](C)C3)C2)n1
Solvent: O=CO
Product: C[C@@H]1CN(C2CN(c3nc(C=O)ccc3F)C2)CCN1C
Yield: 99.9 %

Procedure:
To (2R)-4-(1-(6-(diethoxymethyl)-3-fluoropyridin-2-yl)azetidin-3-yl)-1,2-dimethylpiperazine (157 mg, 0.428 mmol) described in Production Example 24-1-2 was added formic acid (5.00 mL) at room temperature. The resultant mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under a reduced pressure, to give a crude product (125 mg) of the title compound. The product was used in the subsequent reaction without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]1[C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH:21]1[CH2:28]O.[Br:30]C(Br)(Br)Br>ClCCl>[Br:30][CH2:28][CH:21]1[CH2:22][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:20]1
Reactant: OCC1CC2(C1)OCCO2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCC1CC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triphenylphosphine (6.28 gm, 24 mmol) in dichloromethane was added drop wise to a solution of 5,8-dioxaspiro[3.4]oct-2-ylmethanol (2.3 gm, 16 mmol) (step d) and tetrabromomethane (6.62 gm, 20 mmol) in dichloromethane. The reaction mixture was stirred at room temperature for about 6 hours. The solvent was removed under reduced pressure and the residue was extracted with diethyl ether. The organic layer was concentrated under reduced pressure to get a crude product, which was purified by column chromatography.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3].I[CH2:26][CH2:27][CH3:28]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:26][CH2:27][CH3:28]
Reactant: CCCI
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Product: CCCCCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3

Procedure:
Following the procedure for the preparation of 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and substituting 1-iodohexane for 1-iodopropane while making non-critical variations the title compound was obtained as 360 mg (66%) of a yellow foam: 1H NMR (400 MHz, CDCl3) δ 7.83 (br s, 1H), 7.36-7.27 (m, 3H), 7.17-7.13 (m, 1H), 7.05-7.01 (m, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.93 (d, J=7.2 Hz, 1H), 3.95-3.85 (m, 2H), 3.06-3.01 (m, 1H), 2.98-2.93 (m, 2H), 2.90-2.85 (m, 1H), 2.82-2.79 (m, 1H), 2.42-2.37 (m, 2H), 1.57-1.51 (m, 2H), 1.22-1.16 (m, 6H), 0.83 (t, J=6.9 Hz, 3H); HRMS (FAB) calcd for C24H30N2O+H1: 363.2436 found 363.2444.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH2:37]([O:44][CH2:45][C:46]([CH3:50])([CH3:49])[C:47]#[CH:48])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[NH2:51][C:52]1[C:57]([F:58])=[CH:56][C:55]([NH:59][CH2:60][C@@H:61]([OH:71])[CH2:62][O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[C:54](Br)[CH:53]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[NH2:51][C:52]1[C:57]([F:58])=[CH:56][C:55]([NH:59][CH2:60][C@@H:61]([OH:71])[CH2:62][O:63][CH2:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)=[C:54]([C:48]#[C:47][C:46]([CH3:50])([CH3:49])[CH2:45][O:44][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:53]=1
Reactant: Nc1cc(Br)c(NC[C@@H](O)COCc2ccccc2)cc1F
Reactant: C#CC(C)(C)COCc1ccccc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(C)(C#Cc1cc(N)c(F)cc1NC[C@@H](O)COCc1ccccc1)COCc1ccccc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Palladium acetate (0.01 eq), dppb (0.015 eq), CuI (0.015 eq) and potassium carbonate (3 eq) are suspended in acetonitrile (1.2 vol). After stirring for 15 minutes, a solution of 4-benzyloxy-3,3-dimethylbut-1-yne (1.1 eq) in acetonitrile (0.2 vol) is added. The mixture is sparged with nitrogen gas for 1 h and then a solution of (R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol free base (1 eq) in acetonitrile (4.1 vol) is added. The mixture is sparged with nitrogen gas for another hour and then is heated to 80° C. Reaction progress is monitored by HPLC and the reaction is usually complete within 3-5 h. The mixture is cooled to room temperature and then filtered through Celite. The cake is washed with acetonitrile (4 vol). The combined filtrates are azeotroped to dryness and then the mixture is polish filtered into the next reactor. The acetonitrile solution of (R)-1-((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol thus obtained is used directly in the next procedure (cyclization) without further manipulation.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][C:17]([NH2:19])=[O:18])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:5]2.C[O:21][C:22](=O)[C:23]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[CH:26]=1)=O.[K].CC([O-])(C)C.[K+]>C1COCC1>[Cl:1][C:2]1[C:3]([C:16]2[C:17](=[O:18])[NH:19][C:22](=[O:21])[C:23]=2[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[CH:26]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH2:12][N:13]([CH3:14])[CH3:15])=[CH:5]2
Reactant: COC(=O)C(=O)c1cn(C)c2ccccc12
Reactant: CN(C)Cc1cc2c(CC(N)=O)c(Cl)ccc2cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Product: CN(C)Cc1cc2c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)c(Cl)ccc2cn1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(6-chloro-3-dimethylaminomethyl-isoquinolin-5-yl)-acetamide (47 mg, 0.17 mmol) and (1-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (56 mg, 0.26 mmol) in anhydrous THF was added dropwise a 1 M solution of potassium t-BuOK in THF (1.8 mL) under an argon atmosphere at 0° C. The resulting deep red reaction mixture was stirred for 1.5 h at 0° C., quenched with a saturated aqueous NH4Cl solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure. Purification by flash column chromatography (silica gel, EtOAc/water/acetic acid 7:1:1) afforded the title compound as its acetate salt (61 mg, 0.12 mmol, 70%). MS (ES+): 445 (M(C25H2135ClN4O2)+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[C:14]([CH2:16][CH3:17])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:18].C([BH3-])#N.[Na+].[Cl:23][C:24]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:25]=1[O:26][CH:27]([CH3:30])[CH:28]=O>CO.O>[CH2:16]([C:14]1[C:12](=[O:13])[NH:11][C:9](=[O:10])[N:8]([CH:15]=1)[C@@H:6]1[O:7][C@H:3]([CH2:2][NH:1][CH2:30][CH:27]([O:26][C:25]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:24]=2[Cl:23])[CH3:28])[C@@H:4]([OH:18])[CH2:5]1)[CH3:17]
Reactant: CC(C=O)Oc1ccc(Cl)cc1Cl
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNCC(C)Oc3ccc(Cl)cc3Cl)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.2 %

Procedure:
To a solution, cooled in ice, of 0.45 g of 5'-amino-2',5'-dideoxy-5-ethyluridine in 28 ml of methanol and 9 ml of water were added 0.17 g of sodium cyanoborohydride followed by 0.5 g of 2-(2,4-dichlorophenoxy)propionaldehyde. The mixture was allowed to warm to room temperature and was then stirred at room temperature for 3 days. The solution was concentrated in order to remove methanol, diluted with 20 ml of water and extracted three times with 15 ml of methylene chloride. The combined extracts were dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride (1:12) for the elution. There was obtained 0.26 g of 2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2,4-dichlorophenoxy)-propylamino]uridine, mp 51°-61° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][N:32]3[CH2:33][CH2:34][CH:29]([C:25]4[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=4)[CH2:30][CH2:31]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COc1ccc(Oc2ccc(C=O)cc2)cc1
Product: COc1ccc(Oc2ccc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)cc2)cc1

Procedure:
Prepared by Procedure F and Scheme R using 4-(4-methoxyphenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 459.2 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[C:22]([F:21])([F:32])[F:33])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Agent: Cl
Product: O=C(CNC(=O)c1ccccc1C(F)(F)F)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 2-trifluoromethylbenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C1COCC1>CO.[Pd]>[NH2:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([N:6]([CH3:8])[CH3:7])=[O:5])=[C:2]([CH3:1])[CH:12]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)N(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(N)ccc1C(=O)N(C)C

Procedure:
A solution of 1.7 g (8.16 mmol) 2,N,N-trimethyl-4-nitro-benzamide in 45 ml MeOH:THF=1:1 is hydrogenated in the presence of 0.2 g 10% Pd/C (Fluka 75990). The reaction mixture is filtered (2 glass fiber filters used) and the filtrate is concentrated in vacuo to afford the crude title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][O:14][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(c2ccc(Br)cc2)CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred of [1-(4-bromophenyl)-cyclopentyl]-methanol (226) (47.0 g, 184.19 mmol) in dichloromethane (300 mL) was added Et3N (51.3 mL, 368.39 mmol) followed by dropwise addition of mesyl chloride (17.1 mL, 221.03 mmol) at 0° C., and the reaction mixture stirred at room temperature for 1 h. The reaction was quenched by the addition of water, extracted with dichloromethane, washed with water, dried over Na2SO4 and concentrated. The crude product was purified by 100-200 silica column chromatography using 5% ethyl acetate in hexane as the eluent to give methanesulfonic acid 1-(4-bromophenyl)-cyclopentylmethyl ester (227) (52.8 g, 86%) as a white solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH2:15][CH2:14]2)[N:8]=1.CN([CH:19]=[O:20])C>C1COCC1>[CH:13]1([C:9]2[N:8]=[C:7]([CH:19]=[O:20])[CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:14]1
Reactant: CN(C)C=O
Reactant: Brc1cccc(C2CC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(C2CC2)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A flame dried flask was charged with dry THF (75 mL) and chilled to −78° C. To this was added n-BuLi (9.90 mL, 24.7 mmol, 2.5 M in hexanes), followed by the slow addition of a THF (25 mL) solution of the 2-bromo-6-cyclopropylpyridine (4.90 g, 24.7 mmol) over a 15 minute period). The mixture was stirred at −78° C. for 15 minutes, and neat DMF (2.87 mL, 37.1 mmol) was added. The mixture was stirred for 15 minutes at −78° C., then quenched with saturated ammonium chloride solution (50 mL) and allowed to warm to ambient temperature. The mixture was diluted with water, extracted with EtOAc, dried over sodium sulfate and concentrated to 3.5 g (96%) of an orange oil/liquid.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13].[K].[CH2:16]([NH:20][C:21]1[N:26]=[C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:24]=[C:23](Cl)[N:22]=1)[CH2:17][CH2:18][CH3:19]>C(#N)C.O.C1(C)C=CC=CC=1>[CH2:10]([NH:14][C:23]1[N:24]=[C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:26]=[C:21]([NH:20][CH2:16][CH2:17][CH2:18][CH3:19])[N:22]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN
Reactant: CCCCNc1nc(Cl)nc(NCCCC)n1
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [K]
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCCCNc1nc(NCCCC)nc(NCCCC)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
18.5 g (0.1 mol.) of cyanuric chloride were dissolved in 150 mL of acetonitrile. The mixture solution was cooled to 0° C. The cooled solution was dropwise added with a solution of 14.6 g (0.2 mol.) of butylamine in 20 mL of water over one hour while stirring in such a manner that the temperature did not raise over 5° C. While further continuing the stirring, a solution of 20.0 g (0.2 mol.) of potassium hydrogenecarbonate in 100 mL of water was dropwise added to the solution at the same temperature. Thereafter, the reaction temperature was gradually raised and the stirring was continued at 45° C. for eight hours. After the completion of the conversion of the resulting product into 2,4-bis(butylamino)-6-chloro-1,3,5-triazine was recognized by a high-performance liquid chromatography, the obtained produt was cooled and separated through filtration. After the filtrated cake was fully wahsed with a large amount of water, the obtained 2,4-bis(butylamino)-6-chloro-1,3,5-triazine was suspended in 100 mL of water and added with 29.2 g (0.4 mol.) of butylamine and further reacted for six hours under heat-reflux. After cooling, the resulting product was added with 200 mL of toluene and vigorously stirred. Thereafter, the aqueous layer was separated. After the toluene layer was further washed thrice with each 150 mL of water, toluene was distilled off from the organic layer under heating and reduced pressure to obtain 28.2 g of 2,4,6-tris(n-butylamino)-1,3,5-triazine (yield: 96%).