Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1NNC(=O)C=1CC1C=CC=CC=1OCC1C=CC=CC=1C)(C)C.CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH:56]([C:59]1[NH:63][N:62]=[C:61]([O:64][C@@H:65]2[O:82][C@H:81]([CH2:83][O:84]C(=O)C)[C@@H:76]([O:77]C(=O)C)[C@H:71]([O:72]C(=O)C)[C@H:66]2[O:67]C(=O)C)[C:60]=1[CH2:88][C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][C:90]=1[O:95][CH2:96][C:97]1[CH:102]=[CH:101][CH:100]=[CH:99][C:98]=1[CH3:103])([CH3:58])[CH3:57].C[O-].[Na+].Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.ClCCl.O.O1CCCC1.CO>[C@@H:65]1([O:64][C:61]2[C:60]([CH2:88][C:89]3[CH:94]=[CH:93][CH:92]=[CH:91][C:90]=3[O:95][CH2:96][C:97]3[CH:102]=[CH:101][CH:100]=[CH:99][C:98]=3[CH3:103])=[C:59]([CH:56]([CH3:58])[CH3:57])[NH:63][N:62]=2)[O:82][C@H:81]([CH2:83][OH:84])[C@@H:76]([OH:77])[C@H:71]([OH:72])[C@H:66]1[OH:67]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccccc2OCc2ccccc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: C[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccccc1COc1ccccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-isopropyl-4-[2-(2-methylbenzyloxy)-benzyl]-1,2-dihydropyrazol-3-one (68 mg), acetobromo-α-D-glucose (92 mg) and benzyl tri(n-butyl)ammonium chloride (63 mg) in dichloromethane (2 mL) was added a solution of potassium carbonate (140 mg) in water (0.5 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give a residue containing 5-isopropyl-4-[2-(2-methylbenzyloxy)benzyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole. To a solution of the residue in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added sodium methoxide (28% methanol solution, 0.187 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 2 mol/L hydrochloric acid and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (51 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:10])/[N:3]=[C:4](\[CH3:9])/[C:5]([F:8])([F:7])[F:6].C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.[F:39][C:40]1[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=1/[C:47](=[N:50]\[S@@:51]([C:53]([CH3:56])([CH3:55])[CH3:54])=[O:52])/[CH2:48][F:49].C[Al](C)C.[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1>[F:39][C:40]1[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=1[C:47]([NH:50][S@@:51]([C:53]([CH3:56])([CH3:55])[CH3:54])=[O:52])([CH2:9]/[C:4](=[N:3]/[N:2]([CH3:10])[CH3:1])/[C:5]([F:8])([F:7])[F:6])[CH2:48][F:49]
Reactant: C/C(=N\N(C)C)C(F)(F)F
Reactant: CC(C)(C)[S@@](=O)/N=C(/CF)c1cccc(F)c1F
Agent: CC(C)[N-]C(C)C
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CN(C)/N=C(/CC(CF)(N[S@](=O)C(C)(C)C)c1cccc(F)c1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a cooled (−78° C.) solution of (E)-1,1-dimethyl-2-(1,1,1-trifluoropropan-2-ylidene)hydrazine (12.78 g, 83 mmol) in THF (80 mL) was added N-1,N-1,N-2,N2-tetramethylethane-1,2-diamine (9.64 g, 83 mmol) followed by lithium diisopropylamide, 2.0M solution in heptane/tetrahydrofuran/ethylbenzene (41.5 mL, 83 mmol) via syringe, and stirred for 60 min. In a second flask, a solution of (R,E)-N-(1-(2,3-difluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (11.5 g, 41.5 mmol) in toluene (50 mL) was treated with trimethylaluminum solution, 2.0M in toluene (20.74 mL, 41.5 mmol) at −78° C. After stirred for 10 min, this solution was cannulated to the solution containing hydrazone at −78° C. The reaction mixture was stirred at this temperature for 3 h. Saturated NH4Cl solution was added to quench the reaction. The resulted suspension was allowed to warm to room temperature and then filtered through a pad of celite. The filtrate was extracted with EtOAc (3×). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column (0-50% EtOAc/hexane) to afford (R)-N-((Z)-2-(2,3-difluorophenyl)-4-(2,2-dimethylhydrazono)-1,5,5,5-tetrafluoropentan-2-yl)-2-methylpropane-2-sulfinamide (9.0 g, 20.5 mmol) as yellow oil. The ratio of the two diastereoisomers was about 9:1 based on LCMS. MS m/z=432.2 [M+H]+. Calculated for C17H23F6N3OS: 431.4
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:18]([O:25][C:8]1[CH:9]=[C:2]([F:1])[C:3]([C:4]#[N:5])=[C:6]([F:11])[CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1c(F)cc(OCc2ccccc2)cc1F
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a suspension of 2,4,6-trifluorobenzonitrile (314 mg, 2.00 mmol) and potassium carbonate (828 mg, 6.00 mmol) in dry N,N-dimethylformamide (3 mL) at 100° C. was added a solution of benzyl alcohol (216 mg, 2.00 mL) in dry N,N-dimethylformamide (1 mL) using a syringe pump over 4 h and the resulting mixture was stirred at 100° C. for 1 h. The reaction mixture was stirred at room temperature overnight and water and ethyl acetate were added and the phases separated. The organic phase was washed with 1.2 M hydrochloric acid (3×) and the combined organic phases were back-extractted with ethyl acetate (3×). The organic phases were dried (sodium sulfate), filtered, concentrated in vacuo and the residue was purified by flash chromatography (silica gel, hexanes-ethyl acetate 15:1) to give a white solid, mixture of regioisomers. The title product was obtained as a white solid (51 mg, 10%) by HPLC purification (reversed phase).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:12][C:13]1[N:14]=[C:15]([O:21][CH:22]([CH3:27])[CH2:23][N:24]([CH3:26])[CH3:25])[C:16]([C:19]#[N:20])=[N:17][CH:18]=1.CC(C)([O-])C.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][N:24]([CH3:25])[CH2:23][CH:22]([O:21][C:15]1[C:16]([C:19]#[N:20])=[N:17][CH:18]=[C:13]([NH:12][C:2]2[N:3]=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:14]=1)[CH3:27]
Reactant: CC(CN(C)C)Oc1nc(N)cnc1C#N
Reactant: Clc1cc2ccccc2cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(CN(C)C)Oc1nc(Nc2cc3ccccc3cn2)cnc1C#N
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 7.2 %

Procedure:
A mixture of palladium (II) acetate (24 mg, 0.11 mmol) and (±)-2,2″-bis(diphenylphosphino)-1,1″-binaphthalene (140 mg, 0.22 mmol) in toluene (2 mL) was degassed under a stream of nitrogen gas with stirring for 10 minutes. After addition of 3-chloroisoquinoline (59 mg, 0.36 mmol), 5-amino-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2-carbonitrile (80 mg, 0.36 mmol) in DMF (0.5 mL), and sodium tert-butoxide (42 mg, 0.43 mmol), the mixture was degassed for a further 5 minutes and then heated at 140° C. for 30 minutes in a microwave reactor. Upon cooling, the mixture was diluted with methanol and isolated by SPE using a MP-TsOH cartridge, washing with methanol and then eluting with 2 M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. Preparative HPLC gave the title compound (8.9 mg, 0.026 mmol, 7%). 1H NMR (d6-DMSO, 400 MHz) δ 9.22 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.09 (d, 1H, J=9.1 Hz), 7.84 (d, 1H, J=8.1 Hz), 7.77-7.73 (m, 1H), 7.58-7.54 (m, 1H), 5.53-5.49 (m, 1H), 2.67-2.63 (m, 1H), 2.34-2.32 (m, 1H), 2.21 (s, 6H), 1.46 (d, 3H, J=6.3 Hz). LC-MS (2) Rt=2.93 min m/z (ESI−) 347 (M−H).
Reaction SMILES: O1CCCC1.[C:6]([O:10][C:11]([N:13]([CH2:38][C:39]1[CH:48]=[CH:47][C:42]2[O:43][CH2:44][CH2:45][O:46][C:41]=2[CH:40]=1)[CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[C:25]([C:34]([OH:36])=O)=[CH:24][C:23]2=[O:37])[CH2:16][CH2:15]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(Cl)(=O)OCC(C)C.[NH2:57][CH2:58][C:59]1[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=1>O.C(OCC)(=O)C.C(N(CC)CC)C>[O:43]1[C:42]2[CH:47]=[CH:48][C:39]([CH2:38][N:13]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=5)[C:25]([C:34]([NH:57][CH2:58][C:59]5[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=5)=[O:36])=[CH:24][C:23]4=[O:37])[CH2:16][CH2:15]3)[C:11](=[O:12])[O:10][C:6]([CH3:8])([CH3:9])[CH3:7])=[CH:40][C:41]=2[O:46][CH2:45][CH2:44]1
Reactant: NCc1cccnc1
Reactant: COc1ccc2c(C(=O)O)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(C(=O)NCc3cccnc3)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 2 h

Procedure:
To 3.0 mL of tetrahydrofuran suspension containing 0.15 g of 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, 39 μL of triethylamine was added at room temperature, 36 μL of isobutyl chlorocarbonate was added dropwise under ice-cooling. After the reaction mixture was stirred at the same temperature for 2 hours, 26 μL of 3-(aminomethyl)pyridine was added, further 39 μL of triethylamine was added and stirred at the same temperature for 3 hours. To the reaction mixture, ethyl acetate and water were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [gradient elution of chloroform:methanol=100:0-90:10], to give 0.12 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxo-4-(((pyridin-3-ylmethyl)amino)carbonyl)quinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C([Li])CCC.Br[CH2:22][CH2:23][CH2:24][Cl:25]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:22][CH2:23][CH2:24][Cl:25])[C:4]=2[CH:3]=1
Reactant: ClCCCBr
Reactant: Brc1ccc2c(c1)Nc1ccccc1S2
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: ClCCCN1c2ccccc2Sc2ccc(Br)cc21

Procedure:
A solution of 2-bromophenothiazine (41.72 g., 0.05 mole) in 200 ml. of dry toluene was added to a stirred solution of 9.6 g. (0.15 mole) of n-butyllithium in 100 ml. of dry toluene. The stirred solution was warmed for about 2.0 hours at 45°-50° C. and then 31.5 g. (0.20 mole) of bromopropylchloride in 50 ml. of dry toluene was added. The mixture was refluxed for 15 hours. The cooled reaction mixture was washed with water, dried over sodium sulfate and the dried solution concentrated at reduced pressure. The residual oil was distilled to give the product, 2-bromo-10-(3-chloropropyl)phenothiazine.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:10])=O)=[CH:4][C:3]1=[O:11].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:10])=[CH:4][C:3]1=[O:11]
Reactant: Cn1ccc(C(N)=O)cc1=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cn1ccc(C#N)cc1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a cold solution of 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (7.2 g, 47.3 mmol, Journal of Organic Chemistry, 1959, 24, 196) in DCM (70 mL) was added TEA (13.19 mL, 95 mmol) and TFAA (8.02 mL, 56.8 mmol) at about 0° C. The reaction mixture was stirred for about 2 h at about 0° C. The reaction mixture was filtered and the filtrate was diluted with DCM (100 mL). The organic layer was washed successively with water (2×70 mL) and brine (1×70 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford 1-methyl-2-oxo-1,2-dihydropyridine-4-carbonitrile as a white solid 3.3 g, (52.0%), 1H NMR (400 MHz, DMSO) δ: 7.94-7.92 (d, J=7.2 Hz, 1H), 7.00 (s, 1H), 6.53-6.50 (dd, J=2 Hz, 1 Hz), 3.45 (s, 3H), LC/MS (Table 1, Method d) Rt=0.77 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:21][CH3:22])[NH:9][C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[H-].[Na+].I[CH3:26]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([O:20][CH3:26])[N:9]=[C:8]([S:21][CH3:22])[N:7]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1nc(SC)[nH]c(=O)c1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(SC)nc(OC)c1OCc1ccccc1
Yield: 9 %

Procedure:
5-Benzyloxy-2-methylsulfanyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (6.190 g, 19.32 mmol) in dry N,N-dimethylformamide (60 ml) was reacted at 10° C. with sodium hydride (0.90 g of a 60% dispersion in mineral oil, 22.5 mmol) and iodomethane (1.4 ml, 21.7 mmol) and chromatographed to give first 0.581 g (9% yield) of 5-benzyloxy-6-methoxy-2-methylsulfanyl-pyrimidine-4-carboxylic acid ethyl ester as white crystals; mp 48–49° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.32 (3H, t, J=7.1 Hz, CH3), 2.56 (3H, s, SCH3), 4.07 (3H, s, OCH3), 4.36 (2H, q, J=7.1 Hz, CH2), 5.04 (2H, s, OCH2), 7.3–7.45 (5H, m, aromatics). HRMS (FAB POS) calculated for C16H19N2O4S [M+H+]: 335.106554. found: 335.106641, δ −0.3 ppm. The following fractions then gave 5.836 g (90% yield) of the title ester as white needles; mp 84–85° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.33 (3H, t, J=7.0 Hz, CH3), 2.62 (3H, s, SCH3), 3.57 (3H, s, NCH3), 4.35 (2H, q, J=7.0 Hz, CH2), 5.22 (2 H, s, OCH2), 7.3–7.5 (5H, m, aromatics). Anal. Calcd for C16H18N2O4S: C 57.47, H 5.43, N 8.38. Found: C 57.37, H 5.42, N 8.36.
Reaction SMILES: [C:1]([C:3]1([C:13](OC)=[O:14])[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)#[N:2].CO.[BH4-].[Li+]>O1CCCC1>[OH:14][CH2:13][C:3]1([C:1]#[N:2])[CH:4]2[CH2:12][CH:8]3[CH2:7][CH:6]([CH2:11][CH:10]1[CH2:9]3)[CH2:5]2
Reactant: COC(=O)C1(C#N)C2CC3CC(C2)CC1C3
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: N#CC1(CO)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a solution of methyl 2-cyanoadamantane-2-carboxylate (1.33 g, 6.07 mmol) in anhydrous tetrahydrofuran (50 mL) was added anhydrous methanol (0.49 mL, 12 mmol) and lithium borohydride (4.0 M solution in tetrahydrofuran, 3.0 mL, 12 mmol). The mixture was heated to reflux under a nitrogen atmosphere for 7 hours, cooled to ambient temperature and quenched with careful addition of saturated aqueous ammonium chloride (10 mL). The mixture was diluted with ethyl acetate (200 mL), washed with a 3:1 mixture of saturated aqueous ammonium chloride and water (2×200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1.06 g, 91%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 3.92 (s, 2H), 2.24-2.20 (m, 2H), 2.10-1.97 (m, 4H), 1.86-1.84 (m, 5H), 1.73-1.64 (m, 4H); MS (ES−) m/z 192.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[S:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1)(=[O:15])(=[O:14])[NH2:13]>>[S:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][N:23]=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:20][CH:21]=1)(=[O:15])(=[O:14])[NH2:13]
Reactant: COc1ccc(C=O)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: COc1ccc(C=NNc2ccc(S(N)(=O)=O)cc2)cc1
Yield: 62 %

Procedure:
A solution of 4-methoxybenzaldehyde (5 mmol) and 4-sulfamylphenyl-hydrazine hydrochloride was to the General Procedure. The title compound, melting point 228–231° C., was obtained in 62% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([CH:16]=[O:17])=[C:4]([N:18](CC2C=CC(OC)=CC=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1.C1(CO)CCCCC1.C(#N)C>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([CH:16]=[O:17])=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(N)nc(OCC3CCCCC3)c2C=O)cc1
Agent: OCC1CCCCC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNc2nc(N)nc(OCC3CCCCC3)c2C=O)cc1

Procedure:
The mixture of 2-Amino-4-cyclohexylmethoxy-6-di(4-methoxybenzyl)amino-5-pyrimidine carbaldehyde and cyclohexylmethanol obtained previously was stirred in trifluoroacetic acid (2 ml) for 18 h. Excess trifluoroacetic acid was removed, and the residue extracted with ethyl acetate and water (50 ml each) Further ethyl acetate was added to the aqueous layer, and the organic components combined, dried and evaporated. The residual brown oil was applied to a silica column, eluting with 20% EtOAc/petrol (40:60). A pale yellow oil was obtained. Addition and removal of acetonitrile gave a solid which was recrystallised from a petrol/ethyl acetate mixture (0.091 g; 0.34 mmol) M.p. 97° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Br)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[CH:26]2[CH2:30][CH2:31][CH2:32][CH2:33][CH:25]12.[Na]>CN(C)C=O>[C:24]1(=[O:34])[N:28]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:28]2[C:27](=[O:29])[CH:26]3[CH2:30][CH2:31][CH2:32][CH2:33][CH:25]3[C:24]2=[O:34])([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:27](=[O:29])[CH:26]2[CH2:30][CH2:31][CH2:32][CH2:33][CH:25]12
Reactant: O=C(c1ccccc1)C(OCCBr)(OCCBr)c1ccccc1
Reactant: O=C1NC(=O)C2CCCCC12
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1C2CCCCC2C(=O)N1CCOC(OCCN1C(=O)C2CCCCC2C1=O)(C(=O)c1ccccc1)c1ccccc1
Yield: 91.2 %

Procedure:
Benzil-di-(β-bromoethyl)ketal (13.26 g) and 11.55 g of sodium hexahydrophthalimide were dissolved in 100 ml of N,N-dimethylformamide, and heated at 50° to 60° C. for 5 hours with stirring. The reaction mixture was worked up in the same way as in Example 4 to afford 16.05 g (yield 89.5%) of benzil-di-(β-hexahydrophthalimidoethyl)ketal. Recrystallization from a mixture of ethanol and chloroform afforded crystals having a melting point of 115°-116° C.
Reaction SMILES: C(O[C:4](=[O:19])[CH2:5][C@H:6]([CH3:18])[CH2:7][CH2:8][CH2:9][C@@H:10]([CH3:17])[CH2:11][CH2:12][CH:13](C)[CH2:14][CH3:15])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:26]COCC>>[CH3:18][C@H:6]([CH2:7][CH2:8][CH2:9][C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:26])[CH2:5][CH2:4][OH:19]
Reactant: CCOCC
Reactant: CCOC(=O)C[C@H](C)CCC[C@@H](C)CCC(C)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCO
Reaction time: 2 h
Yield: 97.4 %

Procedure:
3.13 g (0.01157 mol) of 3(R),7(R),10-trimethyl-dodecanoic acid ethyl ester in dry ether (35 ml) was added dropwise to a mixture of lithium aluminum hydride (3.0 g) in 150 ml of dry diethyl ether. The mixture was refluxed with stirring for 21/2 hr. The flask was cooled in an ice-bath and the excess of lithium aluminum hydride was destroyed by carefully adding water, followed by 450 ml of 2 N H2SO4. The aqueous phase was extracted with diethyl ether (3×150 ml). The ether extract was washed with water (3×50 ml), saturated aqueous NaHCO3 (3×50 ml), water (3×50 ml) and dried over anhydrous magnesium sulfate. Evaporation of ether to dryness at reduced pressure yielded 2.70 g of crude material which on distillation (Kugelrohr oven, 104°-110°/0.10 mmHg) afforded 2.572 g (97.4%) of 3(R),7(R),11-trimethyl-dodecanol as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:13])[CH2:11][OH:12])([O-:3])=[O:2].C(N(CC)CC)C.O=C(Cl)[O:23][C:24](Cl)(Cl)[Cl:25]>O1CCCC1>[Cl:25][C:24]([O:12][CH2:11][CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:13])=[O:23]
Reactant: CC(CO)c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 130 %

Procedure:
A solution of 2-(2-nitrophenyl)propanol (16.12 g, 89 mmol) and triethylamine (12.4 mL, 89 mmol) in anhydrous tetrahydrofuran (THF) (96 mL) was added to a cold solution (0° C.) of diphosgene (10.7 mL, 89 mmol) m anhydrous THF (40 mL) over a period of 15 min with stirring and under nitrogen. After 30 min the cooling bath was removed and stirring was continued at room temperature for 3 h. The mixture was filtered and washed with THF. The solvent was removed in vacuo to give 28.20 g of 2-(2-nitrophenyl)propyl chloroformate as light brown oil that was directly used for the next reaction step. TLC: 20% ethyl acetate in hexanes, Rf=0.66.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([CH3:20])[C:9](=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1.Br[CH2:23][CH2:24][Cl:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][N:2]([CH2:3][C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([CH3:20])[C:9](=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:23][CH2:24][Cl:25]
Reactant: ClCCBr
Reactant: CNCc1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)oc2c(CN(C)CCCl)cccc2c1=O
Reaction time: 12 h

Procedure:
A mixture of 22 g of Intermediate XX, 66 ml of 1-bromo-2-chloroethane and 11 g of anhydrous potassium carbonate in 88 ml of dimethylformamide was stirred at 20°-25° C. for 12 hours. The reaction mixture was then poured into 600 ml of water and extracted with dichloromethane. The organic layer was washed with water, dried on anhydrous sodium sulfate and acidified with ethanolic hydrogen chloride. The solvent and the excess 1-bromo-2-chloroethane were distilled off in vacuo at 70°-80° C. The residue was taken up in cold 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic solution was washed with water, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo at 25°-30° C. The crude title product was purified by flash chromatography on silica gel, eluting with ethyl acetate:petroleum ether (7:3), to give 18 g of the title compound melting at 118°-120° C. after crystallization from ethanol.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:3].C(O)(=O)C.[CH:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1)=O>C(O)C>[CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:3]=[CH:14][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1
Reactant: CN(N)c1ccccc1
Reactant: O=Cc1ccnc2ccccc12
Solvent: CC(=O)O
Solvent: CCO
Product: CN(N=Cc1ccnc2ccccc12)c1ccccc1
Temperature: 0 °C

Procedure:
One equivalent of methylphenylhydrazine (4.1 g; 0.033 mol, compound 2 was diluted in 25 ml of ethanol and 0.5 ml of glacial acetic acid in a three-necked flask on which was mounted a condenser. The reaction medium was then stirred at 0° C. 1 equivalent of 4-formylquinoline (5.28 g; 0.033 mol, compound 14) was added by spatula. After adding the aldehyde, the reaction medium was heated at 70° C. (oil bath temperature) for 4 hours.