Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1C=N[C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.[CH:28](N(CC)C(C)C)(C)[CH3:29].[C:37]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1)(=[O:39])[CH3:38]>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][S:47]([C:44]6[CH:45]=[CH:46][C:41]([NH:40][C:37](=[O:39])[CH3:38])=[CH:42][CH:43]=6)(=[O:49])=[O:48])=[C:7]5[CH:28]=[CH:29]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1C=CC(N)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)NC2=c3ccc4c5c([nH]c(=O)c-5c3N(C)C=C2)=CCN4c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stock solution of Example 14e and N,N-diisopropylethylamine (0.08 M and 0.16 M in dichloromethane, respectively, 500 μL, 0.042 mmol Example 14e and 0.083 mmol N,N-diisopropylethylamine), and 4-acetamidobenzene-1-sulfonyl chloride (0.40 M in dichloromethane, 239 μL, 0.096 mmol) were mixed and stirred at ambient temperature overnight. The reaction mixture was concentrated, dissolved in methanol (1 mL) and injected on the reverse phase HPLC(C8, acetonitrile/water (0.1% TFA), 5-100%) to yield the title compound as an impure mixture. The material was dissolved in methanol (1 mL) and manually injected into the HPLC(C8, acetonitrile/water (0.1% TFA), 5-100%) to give 0.0071 g (32%) of the title compound as the TFA salt. 1H NMR (400 MHz, DMSO-d6/D2O) δ 7.75 (q, J=9.16 Hz, 4H), 7.57 (s, 1H), 7.48 (d, J=2.44 Hz, 1H), 7.11 (d, J=8.54 Hz, 1H), 7.02 (s, 1H), 6.95 (dd, J=8.54, 2.44 Hz, 1H), 6.80 (m, J=8.85, 8.85 Hz, 2H), 6.37 (m, 2H), 4.97 (s, 1H), 4.12 (m, 1H), 4.04 (s, 3H), 2.06 (s, 3H). MS (APCI+) m/z 558.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: NC1CCc2ccc(F)cc2NC1=O
Product: CC(C)(CC(=O)NC1CCc2ccc(F)cc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step E by the procedure described in Example 1, Step F. 1H NMR (300MHz, CDCl3): 1.35 (s,6H), 1.41 (s,9H), 1.93 (m,1H), 2.4-2.9 (m,5H), 4.54 (m,1H), 5.19 (br s,1H), 6.73 (m,2H), 6.88 (dt;2,8Hz;1H), 7.19 (dd;6,8Hz;1H), 8.07 (m,1H). FAB-MS: calculated for C20H28FN3O4 393; found 394 (M+H,56%).
Reaction SMILES: C(N(CC)[C:4](=[O:15])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[CH:6]=1)C.Br[CH2:19][C:20]([CH3:22])=[CH2:21].CC(CSC[C@H]1O[C@@H](N2C3NC=NC(=O)C=3N=C2)[C@H](O)[C@@H]1O)C>>[CH3:12][O:11][C:9]1[CH:8]=[C:7]([O:13][CH3:14])[CH:6]=[C:5]2[C:10]=1[CH:19]=[C:20]([CH3:22])[CH:21]=[C:4]2[OH:15]
Reactant: C=C(C)CBr
Reactant: CCN(CC)C(=O)c1cc(OC)cc(OC)c1
Agent: CC(C)CSC[C@H]1O[C@@H](n2cnc3c(=O)nc[nH]c32)[C@H](O)[C@@H]1O
Product: COc1cc(OC)c2cc(C)cc(O)c2c1
Yield: 50 %

Procedure:
5,7-Dimethoxy-3-methyl-1-naphthol is synthesized from N,N-diethyl-3,5-dimethoxybenzamide and 3-bromo-2-methylpropene according to the method described by Sibi et al. (J. Org. Chem. 1986, Vol. 51, pp. 271-273). The yield is approximately 50%.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24](=O)[C:25]#[CH:26])[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1.Cl.[OH:31][C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[NH:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][N:35]=[C:33]([C:32]([OH:31])([CH3:37])[CH3:36])[N:34]=3)[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1
Reactant: CC(C)(O)C(=N)N
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(F)n3)c(Cl)c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(OCc2cccc(F)n2)c(Cl)c1=O
Temperature: 75 °C
Yield: 30.8 %

Procedure:
To a solution of 5-chloro-6-(6-fluoro-pyridin-2-ylmethoxy)-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-3H-pyrimidin-4-one of Step D (78 mg, 0.19 mmol) in acetonitrile (3 mL) was added 2-hydroxy-2-methylpropionamidine HCl (39 mg, 0.28 mmol) and potassium carbonate (78 mg, 0.57 mmol) and the slurry heated at 75° C. for eighteen hours. After cooling to room temperature the reaction was filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a yellow oil (29 mg, 31% yield). MS (M+H): 496; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.15 (s, 3H), 2.21 (s, 3H), 5.54-5.65 (m, 2H), 6.90 (d, J=7.83 Hz, 1H) 7.48 (d, J=6.65 Hz, 1H), 7.55-7.57 (m, 2H), 7.85-7.93 (m, 2H), 8.14 (d, J=8.22 Hz, 1H), 8.78 (d, J=5.09, 1H).
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:13]([N:15]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=2[N:38]([CH2:41][C@H:42]2[CH2:47][CH2:46][C@H:45]([CH2:48][C:49]([OH:51])=[O:50])[CH2:44][CH2:43]2)[CH2:39][CH3:40])[C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25][CH3:26])=[CH:18][N:17]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:54](O)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.CCN=C=NCCCN(C)C.Cl.O>ClC(Cl)C.CN(C1C=CN=CC=1)C>[CH2:54]([O:50][C:49](=[O:51])[CH2:48][C@H:45]1[CH2:46][CH2:47][C@H:42]([CH2:41][N:38]([C:29]2[CH:30]=[CH:31][C:32]([C:34]([F:36])([F:37])[F:35])=[CH:33][C:28]=2[CH2:27][N:15]([CH:13]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:52])[F:53])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[CH3:14])[C:16]2[N:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][S:25][CH3:26])=[CH:20][N:21]=2)[CH2:39][CH3:40])[CH2:43][CH2:44]1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: OCc1ccccc1
Reactant: CCN(C[C@H]1CC[C@H](CC(=O)O)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCN(C[C@H]1CC[C@H](CC(=O)OCc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere, a solution of the (S)-isomer-dominant semi-chiral compound (4) of trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid (744.1 g, 0.95 mol) obtained in Step 2 in anhydrous dichloroethane (11.6 L) was added with benzyl alcohol (113.1 g, 1.05 mol), WSC.HCl (200.5 g, 1.05 mol) and DMAP (11.9 g, 98 mmol) under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was added with water (10 L), and the mixture was extracted with chloroform (19 L, 14 L). The organic layer was washed with saturated brine (12 L), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel: 28 g, developing solvent: heptane/ethyl acetate=6/1) to obtain a semi-chiral compound (5) of trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid benzyl ester (yellow oil, 745.8 g, yield: 90%).
Reaction SMILES: [C:1]([C:3]1[C:4]([S:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:5][CH:6]=[C:7]([CH2:9][Br:10])[CH:8]=1)#[N:2].[CH2:21]([P:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24].CCOCC>O1CCCC1>[Br-:10].[C:1]([C:3]1[C:4]([S:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:5][CH:6]=[C:7]([CH2:9][P+:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=1)#[N:2]
Reactant: N#Cc1cc(CBr)cnc1Sc1ccc([N+](=O)[O-])cc1
Reactant: CCCCP(CCCC)CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[P+](CCCC)(CCCC)Cc1cnc(Sc2ccc([N+](=O)[O-])cc2)c(C#N)c1
Product: [Br-]

Procedure:
Alternatively, 3-cyano-2-(4-nitrophenylthio)-5-bromomethylpyridine is allowed to react in tetrahydrofuran with tri-(n-butyl)phosphine for ten hours. Following the addition of ether, the solid which forms is collected by filtration and washed with 1:1 tetrahydrofuran:ether to yield [3-cyano-2-(4-nitrophenylthio)pyridin-5-ylmethyl]-tri-(n-butyl)phosphonium bromide as a white solid; mp 175°-176° C.; NMR CDCl3, 80 MHz) d 0.85-2.63(m, 27H), 4.76(d, 2H, J=15.4 Hz), 7.74(d, 2H, J=9.0 Hz), 8.26(d, 2H, J=9.0 Hz), 8.55(brs, 1H), 8.79(brs, 1H); IR (KBr) 2950, 2860, 2220, 1595, 1575, 1515, 1390, 1340, 1075 and 845 cm-1 ; HRMS 471.2116(M+ -HBr), Calc'd. for C25H34N3O2PS471.2109.
Reaction SMILES: [Na].[OH:2][C:3]1[C:4](=[O:11])[CH:5]=[C:6]([CH2:9][OH:10])[O:7][CH:8]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[OH:10][CH2:9][C:6]1[O:7][CH:8]=[C:3]([O:2][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:11])[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: O=c1cc(CO)occ1O
Agent: [Na]
Solvent: CO
Product: O=c1cc(CO)occ1OCc1ccccc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
69 g (3 mol) of sodium were dissolved in 5 1 of methanol. Subsequently 425.3 g (3 mol) of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one was added and stirred at 30° C. until a clear solution was obtained. 595 g (3.5 mol) of benzyl bromide was then added and stirred for 1 hour under reflux. The warm and very dark colored solution was poured into 15 1 of ice water. The product crystallized immediately. The crystals were collected and washed first with 8 1 of water and then twice with 2.5 1 of ether. The product was left to stand overnight and finally dried at 50° C. for 16 hrs. Yield: 646 g=92.6%.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:8][CH:7]=1)=[O:5])C.O[Li].O.CCOC(C)=O.Cl>C1COCC1.O>[C:25]([O:24][C:22]([NH:21][CH2:20][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1cnc(CNC(=O)OC(C)(C)C)c2c(OC)cc(OC)cc12
Agent: Cl
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 95.6 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (520 mg, 1.34 mmol) in THF (10 ml) and H2O (10 ml) under nitrogen, LiOH—H2O (95 mg, 2.3 mmol) was added. The reaction was stirred at 50° C. for 3.5 hours and at then at room temperature for 18 hours. EtOAc and water were then added and the pH was adjusted to 5 by dropwise addition of 6N HCl. The layers were then separated and the aqueous phase was extracted with EtOAc. The combined organic layers were then washed with brine, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to give 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid as a solid (464 mg, 96%). H1-NMR (DMSO): δ, 8.84 (s, 1H), 7.96 (s, 1H), 6.91 (t, 1H, J=5.4 Hz), 6.77 (s, 1H), 4.80 (d, 2H, J=5.43 Hz), 3.95 and 3.88 (s, 3H each), 1.36 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][C:4]=1[F:13])#[N:2].S(C)C>C1COCC1>[F:13][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][OH:11])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccc(CC(=O)O)cc1F
Solvent: C1CCOC1
Solvent: CSC
Product: N#Cc1ccc(CCO)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-cyano-3-fluorophenyl)acetic acid (25.6 g, 143 mmol) in 150 mL of dry THF was cooled by ice/water, and then BH3/Me2S (10 M, 15.7 mL, 157 mmol) was added slowly. The reaction was warmed to ambient temperature and stirred overnight. The mixture was quenched with MeOH and concentrated to dryness. The residue was partitioned between water and EtOAc. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford 2-fluoro-4-(2-hydroxyethyl)benzonitrile. 1H-NMR (400 MHz, CDCl3)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])(=O)=O.Cl>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[CH:24]([O:29][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[C:25]([F:27])([F:28])[F:26])=[O:21])[C:15]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a suspension of 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide (1.13 g) and 2,6-lutidine (0.5 mL) in dichloromethane (5 mL) at 0° C. was added tert-butyldimethylsilyl trifluoromethanesulfonate (0.73 mL). The mixture was allowed to stir for 1.5 h. over which time the suspension became a solution. The mixture was poured into 1N hydrochloric acid and extracted into ether. The organic layer was washed (water), dried and evaporated to give an oil, which crystallized upon addition of ether:hexane to give a white solid. The solid was collected and washed with hexane to yield 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide as a white solid (1.1 g); MS: m/z=647(M+1).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]([N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][CH:20]([O:25]C(=O)C3C=CC=CC=3)[CH2:19][C:18]2([CH3:35])[CH3:34])[N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]([N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][CH:20]([OH:25])[CH2:19][C:18]2([CH3:35])[CH3:34])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(NCCCC)nc(N2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCNc1nc(NCCCC)nc(N2C(C)(C)CC(O)CC2(C)C)n1

Procedure:
10 g of 2,4-bis-butylamino-6-(2,2,6,6-tetramethyl-4-benzoyloxypiperidin-1-yl)1,3,5-triazine (prepared according to Example 8) are heated at reflux for 6 hours with 50 ml of methanol and 50 ml of twenty per cent sodium hydroxide solution. The methanol is distilled off from the reaction mixture in vacuo. 100 ml of toluene and 50 ml of water are added to the residue, shaken thoroughly, the aqueous phase is separated off and the toluene solution is washed three times, each with 50 ml of water. After evaporating the toluene solution, 2,4-bis-butylamino-6-(2,2,6,6-tetramethyl-4-hydroxypiperidin-1yl)-1,3,5-triazine is obtained as a yellowish viscous material. Colorless crystals which melt at 90° C. are obtained by crystallization from acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][C:12]=1[CH:13]=O.C[Si]([C:27]#[N:28])(C)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>ClCCl.O.C(OCC)(=O)C>[C:27]([CH:13]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:12]1[CH:15]=[C:16]([O:21][CH3:22])[CH:17]=[C:18]([O:19][CH3:20])[C:11]=1[F:10])#[N:28]
Reactant: C[Si](C)(C)C#N
Reactant: COc1cc(C=O)c(F)c(OC)c1
Reactant: N#Cc1ccc(N)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(F)c(C(C#N)Nc2ccc(C#N)cc2)c1

Procedure:
After adding 1.23 g of 4-aminobenzonitrile [CAS No. 873-74-5], 1.92 g of 2-fluoro-3,5-dimethoxybenzaldehyde [CAS No. 113984-71-7], 1.0 g of MS3A and 2.77 ml of trimethylsilyl cyanide to a solution of 0.645 g of Yb(OTf)3 in 20 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 20 hours. After then adding 500 ml of ethyl acetate and 300 ml of water to the reaction mixture, it was filtered through celite and the celite was washed with 500 ml of ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (2.59 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccccc1N1CCN(C(=S)Nc2nc3ccccc3nc2OC)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate (215 mg, 0.69 mmol) and 1-(2-methoxyphenyl)piperazine (154 mg, 0.69 mmol) were dissolved in anhydrous tetrahydrofuran (25 ml) and thereto DBU (105 mg, 0.69 mmol) was added. The mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.C(Cl)(=O)[C:21](Cl)=[O:22].[I:26][C:27]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[C:28]=1C(O)=O>>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:21](=[O:22])[C:35]4[CH:34]=[C:33]([O:36][CH3:37])[C:32]([O:38][CH3:39])=[CH:28][C:27]=4[I:26])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(I)c(C(=O)O)c1OC
Reactant: CN(C)CCNc1ccnc2cc3c(cc12)OCO3
Product: COc1cc(I)c(C(=O)N(CCN(C)C)c2ccnc3cc4c(cc23)OCO4)cc1OC
Yield: 71 %

Procedure:
Prepared from N′-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimethylethane-1,2-diamine (1.0 g, 3.84 mmol) in 71% yield with a reaction time of 3 h, from the acid chloride prepared using 10 mmol of oxalyl chloride and 4.8 mmol of 2-iodo-5,6-dimethoxybenzoic acid. Compound 7a had: IR(CHCl3) 1652; 1H NMR (CDCl3) δ 2.74 (s, 6H), 2.66 (t, 2.H, J=7.0), 3.33 (s, 3H), 3.74 (s, 3H), 3.96 (m, 1H), 4.49, (m, 1H), 6.15 (s, 2H), 6.41 (s, 1H), 7.03 (s, 1H), 7.34 (d, 1H, J=4.8), 7.37 (s, 1H), 7.44 (s, 1H), 8.56 (d, 1H, J=4.8); 13C NMR (CDCl3) δ 45.7, 46.9, 55.5, 56.1, 56.6, 82.7, 98.5, 102.2, 106.7, 110.2, 120.2, 121.5, 122.9, 121.5, 122.9, 133.8, 145.9, 148.0, 148.3, 148.5, 149.0, 149.6, 151.0, 170.0; HRMS calcd for C23H24IN3O5H, 550.0839; found 550.0823.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[NH:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:14]([C:19](O)=[O:20])[CH2:15][C:16](=[O:18])[NH2:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1.O.C(OCC)(=O)C>[NH:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:14]([C:19]([NH:1][C@H:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:20])[CH2:15][C:16](=[O:18])[NH2:17]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.9 %

Procedure:
5.00 Grams of H-Leu-OEt.HCl, 5.95 g of Boc-Asn-OH and 4.11 g of HOBT.H2O were suspended in 100 ml of THF. To this suspension was added 4.70 ml of WSC with ice-cooling. The mixture was stirred for 7 hours at room temperature. To the reaction mixture were added 100 ml of ethyl acetate and 200 ml of water to effect extraction. The ethyl acetate layer was washed with 50 ml of a saturated aqueous sodium bicarbonate solution three times, 50 ml of a saturated aqueous sodium chloride solution once, 50 ml of 1N hydrochloric acid three times and 50 ml of a saturated aqueous sodium chloride solution once in this order, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was solidified with isopropyl ether to obtain 7.00 g (yield: 72.9%) of the above objective compound. Melting point: 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:24])[N:17]([CH2:21][CH2:22]Cl)[CH2:18][CH2:19]Cl)([CH3:14])([CH3:13])[CH3:12].[H-].[Na+]>CN(C)C=O>[C:11]([O:15][C:16]([N:17]1[CH2:21][CH2:22][C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)([C:7]#[N:8])[CH2:19][CH2:18]1)=[O:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Temperature: 60 °C
Yield: 53.6 %

Procedure:
To 1.26 g (8.37 mmol) 4-chloro-benzylcyanide was added bis-(2-chloroethyl)-carbamic acid tert-butyl ester (2.02 g, 8.37 mmol) in 25 ml N,N-dimethylformamide. The resulting mixture was stirred and cooled in an ice bath, then sodium hydride (60% suspension in mineral oil) (1.1 g, 42 mmol) was added portionwise. The reaction was brought to room temperature and then heated in an oil bath at 60° C. for 16 hours. The reaction mixture was quenched by addition of ice water and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed twice with water, once with brine, dried with magnesium sulfate and concentrated in vacuo. The residual brown oil was purified by silica gel chromatography eluting with hexane-ethyl acetate (9:1) to give the title compound (1.44 g, 54%).