Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([C:27]45[CH2:36][CH:31]6[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]6)[CH2:28]4)[CH2:34]5)[CH:20]=3)[CH:15]=2)[CH:10]=1)[Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCN(C(C)C)C(C)C.[C:64]1([CH3:74])[CH:69]=[CH:68][C:67]([S:70](Cl)(=[O:72])=[O:71])=[CH:66][CH:65]=1>C1COCC1.CCOC(C)=O.CN(C1C=CN=CC=1)C>[C:27]12([C:21]3[CH:20]=[C:19]([C:14]4[CH:15]=[C:16]5[C:11](=[CH:12][CH:13]=4)[CH:10]=[C:9]([O:1][S:70]([C:67]4[CH:68]=[CH:69][C:64]([CH3:74])=[CH:65][CH:66]=4)(=[O:72])=[O:71])[CH:18]=[CH:17]5)[CH:24]=[CH:23][C:22]=3[O:25][CH3:26])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(-c2ccc3cc(O[Si](C)(C)C(C)(C)C)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3cc(OS(=O)(=O)c4ccc(C)cc4)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-tert-butyl-dimethylsiloxy-6-(3-adamantan-1-yl-4-methoxyphenyl)-naphthalene (14 g, 28 mmol) in THF (160 ml) was added TBAF (28 ml, 28 mmol) and the reaction stirred at RT for 5 min. The reaction mixture was diluted with EtOAc and washed with 1N HCl, brine, and dried over Na2SO4. The crude product was concentrated in vacuo and the residue was dissolved in DCM (200 ml). DMAP (0.2 equiv), DIEA (1.2 equiv) and toluene-4-sulfonyl chloride (1 equiv) were added and the reaction was stirred at RT for 30 minutes. The solvent was removed, the residue was dissolved in EtOAc, washed with 1N HCl, brine, and dried over Na2SO4. The solvent was removed and the crude product was recrystallized from acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)[CH:7]=1.[F:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>C1COCC1>[Cl:18][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:8]([C:6]3[C:5]([CH3:22])=[CH:4][C:3]([F:23])=[C:2]([NH:1][C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=4)=[O:33])[CH:7]=3)[C:9](=[O:21])[N:10]2[CH2:19][CH3:20])=[CH:15][N:14]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(Cl)cc21
Reactant: O=C=Nc1cccc(F)c1
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2C)cc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.1 %

Procedure:
A solution of Example A6 (0.200 g, 0.603 mmol) and TEA (0.126 mL, 0.904 mmol) in THF (6 mL) was treated with 3-fluorophenyl isocyanate (0.083 ml, 0.723 mmol) and stirred at RT for 4 h. The mixture was concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex). The material was treated with DCM and the solid collected via filtration. The filtrate was concentrated to dryness, re-purified via silica gel chromatography (MeOH/DCM) and combined with the isolated solid to afford 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea (88 mg, 31% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.23 (s, 1H), 8.77 (s, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.00 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.46 (dt, J=12.0, 2.3 Hz, 1H), 7.28 (m, 1H), 7.18 (d, J=12.2 Hz, 1H), 7.05 (ddd, J=8.2, 2.0, 0.9 Hz, 1H), 6.77 (td, J=8.3, 2.5 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 2.07 (s, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 469.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)[C:9]2=O)=[CH:4][CH:3]=1.[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].CCOC(C)=O>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)[C:9]2=[N:26][S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(N)=O
Reactant: COC1CCC2(CCc3ccc(Br)cc3C2=O)CC1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC1CCC2(CCc3ccc(Br)cc3C2=NS(=O)C(C)(C)C)CC1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
7′-Bromo-4-methoxy-3′,4′-dihydro-1′H-spiro[cyclohexane-1,2′-naphthalen]-1′-one (Intermediate 9, 2.26 g, 6.99 mmol), 2-methylpropane-2-sulfinamide (1.27 g, 10.5 mmol) and titanium ethoxide (2.88 mL, 14.0 mmol) were dissolved in 2-Me THF (15 mL) and heated to reflux over the weekend. The reaction was stopped and cooled to r.t. EtOAc (30 mL) and water (15 mL) were added under stirring. The mixture was then let to stand without stirring for 1 h. The organic phase was collected by filtration, dried using a phase separator and concentrated in vacuo. The product was purified by flash column chromatography using a gradient of 0-100% EtOAc in heptane to give the title compound (0.61 g, 20% yield): MS (ES+) m/z 426.11 [M+H]+.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.CO.C(OCC)(=O)C>[OH:3][C:2]1[CH2:4][O:5][C:6](=[O:7])[C:1]=1[C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O=C1COC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCC/C=C\CCCCCCCC(=O)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 36 %

Procedure:
To a stirring solution of 1.07 g (10.72 mmol) of tetronic acid in 30 mL of dimethylformamide is added 1.64 mL (11.97 mmol) of triethylamine and 428 mg of 4-dimethylaminopyridine at 0° C. Next, 2.44 g (12.77 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3.0 g (11.79 mmol) of palmitoleic acid are added and the reaction is stirred for 3 days at room temperature. The reaction is acidified with 1.0N HCl and extracted with four 100 mL portions of ethyl acetate. The combined organic layers are dried over MgSO4 and concentrated in vacuo affording crude compound. Pure material was obtained by flash chromatography with 10% methanol/ethyl acetate as eluant affording 1.3 g (36%) of 4-hydroxy-3-((Z)-1-oxo-9-hexadecenyl)-2(5H)-furanone.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Mg]Br>CCOCC>[OH:18][CH:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)[CH3:19]
Reactant: C[Mg]Br
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCOCC
Product: CC(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of N-(benzyloxycarbonyl)-4-formyl-piperidine (1 g, 3.92 mmol) in Et2O (40 mL) at −78° C. was treated with methylmagnesium bromide (3M in Et2O, 3.2 mL, 9.60 mmol). The reaction mixture was stirred at −78° C. for 2 h, quenched with saturated aqueous NH4Cl and extracted with Et2O. The combined organic extract was washed with brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a colorless oil. The crude product was purified by flash chromatography on an ISCO silica gel column using 0 to 70% EtOAc/hexanes to give 0.64 g (62%) of (±)-phenylmethyl 4-(1-hydroxyethyl)-1-piperidinecarboxylate as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.40-7.25 (m, 5H), 5.11 (s, 2H), 4.30-4.15 (m, 2H), 3.65-3.55 (m, 1H), 2.80-2.65 (m, 2H), 1.90-1.80 (m, 1H), 1.80-1.70 (m, 1H), 1.70-1.55 (m, 1H), 1.30-1.10 (m, 5H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.O[C:9]1[C:10]([C:19]([NH2:21])=[O:20])=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.N1CCOCC1>C1(C)C=CC=CC=1.CO.C(OCC)(=O)C>[NH:1]1[CH2:6][CH2:5][C:4]2([NH:21][C:19](=[O:20])[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][C:9]=3[O:7]2)[CH:16]=[CH:15][CH:14]=[CH:13]4)[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: NC(=O)c1cc2ccccc2cc1O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Product: O=C1NC2(CCNCC2)Oc2cc3ccccc3cc21

Procedure:
A mixture of 26 mg (0.083 mmol) of N-[4,8-dimethoxyquinoline-2-yl)carbonyl]-4-piperidone (prepared as described in Example 44), 15.5 mg (0.083 mmol) of 3-hydroxy-2-naphthalenecarboxamide, and 0.020 mL of morpholine in a mixture of 0.2 mL of toluene and 0.6 mL of methanol is refluxed for 20 hr. The reaction mixture is diluted with ethyl acetate, and washed with water, brine, and dried over Na2SO4. After solvent removal by rotoevaporation, the crude product is purified by preparative TLC to give 11 mg (0.023 mmol, 27% yield) of 1′-[4,8-dimethoxyquinoline-2-yl)carbonyl]spiro[2H-naphtho[2,3-e]-1,3-oxazin-2,4′-piperidin]-4-(3H)-one (Compound 159): 1H NMR (DMSO-d6): δ 3.95 (s, 3H), 4.07 (s, 3H), 7.20 (s, 1H), 7.23 (d, 1H), 7.44 (d of d, 1H), 7.55 (m, 3H), 7.67 (d, 1H), 8.04 (d, 1H), 8.46 (s, 1H), and 9.09 ppm (s, 1H). MS m/z: 484.0 (M+H)+, 506.0 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:10])=[N:4][C:5](Cl)=[N:6][C:7]=1[CH3:8].[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1>>[CH3:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11]2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Cl)nc(O)c1C
Reactant: c1ccc2c(c1)CCNC2
Product: Cc1nc(N2CCc3ccccc3C2)nc(O)c1C
Yield: 80.8 %

Procedure:
In accordance with the same procedure as in Step 2 of Example 57, except that 5,6-dimethyl-2-chloro-4-hydroxypyrimidine (6.0 g, 37.8 mmol) prepared in the Step 2 of Example 65 and 1,2,3,4-tetrahydroisoquinoline(10 ml, 79.9 mmol) were used as starting materials, 7.8 g of the titled compound was prepared. (Yield: 81%)
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[C:10]([Mg]Br)([CH3:12])=[CH2:11].[Cl-].[NH4+]>C1COCC1>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1])[C:11]#[C:10][CH3:12]
Reactant: C=C(C)[Mg]Br
Reactant: CC(=O)CCC=C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CC(C)(O)CCC=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of LaCl3.2LiCl (0.6 M in THF, 80 ml; 133 mmol) was added rapidly to neat 6-methyl-5-hepten-2-one (60.6 g; 480 mmol), at room temperature under nitrogen. After 1 hour, the reaction was cooled into an ice-water bath and a solution of isopropenylmagnesium bromide (0.5 M in THF; 800 ml; 400 mmol) was added over a 3 hour period. The reaction was then warmed up to room temperature and stirred for 3 hours. After cooling back to 0° C., a saturated aqueous ammonium chloride solution (500 ml) was added slowly with vigorous stirring. After warming up to room temperature, the reaction was filtered through celite, thoroughly rinsing with diethyl ether. The filtrate was transferred to a sep. funnel and the phases separated. The aqueous phase was re-extracted with diethyl ether. Each organic phase was washed with brine. Combined extracts were dried over sodium sulfate. The product was purified by fractional vacuum distillation through a 20-cm Widmer column. The boiling point of the pure product was 53° C./0.004 mbar. 294 mmol of product were obtained (yield: 74%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C)C=O.[CH2:12]([O:14][C:15]([C:17]1[N:18]=[CH:19][N:20]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH:31]([CH3:33])[CH3:32])[CH:26]=C3)[CH:21]=1)=[O:16])[CH3:13]>ClCCl>[CH2:12]([O:14][C:15]([C:17]1[N:18]=[CH:19][N:20]([C:22]2[CH:30]=[C:29]3[C:28](=[CH:24][CH:23]=2)[N:27]([CH:31]([CH3:32])[CH3:33])[CH:26]=[C:2]3[CH:1]=[O:5])[CH:21]=1)=[O:16])[CH3:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cn(-c2ccc3c(ccn3C(C)C)c2)cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cn(-c2ccc3c(c2)c(C=O)cn3C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To anhydrous dichloromethane (30 mL) was added oxalyl chloride (0.03 mL, 0.36 mmol). N,N-dimethylformamide (0.03 mL, 0.36 mmol) was added at 0° C., which was then stirred for 30 min at 0° C. To this solution was added 1-(1-isopropylindol-5-yl)-imidazole-4-carboxylic acid ethyl ester (0.09 g, 0.3 mmol) obtained in Preparation 27, and the mixture was stirred for 1 h at room temperature. The solvent was removed, tetrahydrofuran (30 mL) and 20% aqueous ammonium acetate solution (30 mL) were added to the residue, and the mixture was heated for 30 min while being stirred under reflux. The reaction solution was cooled, ethyl acetate was added, and washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was filtered, washed with ethyl acetate and dried to give the title compound (0.09 g, 92% Yield).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:31])[CH:28]([SH:30])[CH3:29]>>[CH3:25][O:26][C:27](=[O:31])[CH:28]([S:30][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1)[CH3:29]
Reactant: COC(=O)C(C)S
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: COC(=O)C(C)Sc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1
Yield: 27.9 %

Procedure:
{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid methyl ester (125 mg, 28%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol), and mercapto-propionic acid methyl ester (240 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CC(C)([O-])C.[K+]>O.CN1CCCC1=O>[CH3:18][C:17]1[C:12]([NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccnc1N
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccnc1Nc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 36.9 %

Procedure:
0.3 g of 4-fluoronitrobenzene, 0.46 g of 2-amino-3-methylpyridine, and 0.353 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 1 hour and 0.286 g of potassium tert-butoxide was then added. Heating was then continued for 6 hours and, after cooling to room temperature, the reaction medium was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 0.18 g of 3-methyl-N-(4-nitrophenyl)pyrid-2-amine (7) was obtained.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1>[CH:1]([N:14]1[CH2:17][CH:16]([N:27]2[C:26](=[O:28])[C:25]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]3[C:23]2=[O:33])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 20 °C
Yield: 67.4 %

Procedure:
A mixture of 0.362 mol of 1-benzhydryl-3-mesyloxyazetidine (J. Org. chem. 1972, 37, 3953-3955), 0.44 mol of potassium phthalimide and 0.045 mol of hexadecyltributylphosphonium bromide in 500 ml of anhydrous toluene is heated at reflux for 5 hours, then it is cooled at 20° C. The precipitate is filtered, washed with 400 ml of ethyl acetate and discarded. The organic solution is washed with water, dried on anhydrous sodium sulfate, filtered on charcoal and concentrated under reduced pressure. The oily residue is crystallized from 600 ml of diisopropyl ether. Thus, 80 g (Yield: 67.4% of the theoretic) of 1-benzhydryl-3-phthalimidoazetidine are obtained; m.p. 118°-120° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:16])=[N:12][NH:13][C:14]=2[NH2:15])=[CH:6][CH:5]=1.CN(C)[CH:21]=[CH:22][CH:23]=O>C(O)C.C(O)(=O)C>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([NH2:15])=[N:13][N:12]3[CH:23]=[CH:22][CH:21]=[N:16][C:11]=23)=[CH:6][CH:5]=1
Reactant: CN(C)C=CC=O
Reactant: Nc1n[nH]c(N)c1-c1ccc(OC(F)(F)F)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1
Yield: 107.5 %

Procedure:
In a microwave vessel containing the product from Example 1B (0.4 g, 1.549 mmol) and 3-(dimethylamino)acrylaldehyde (0.155 g, 1.549 mmol) in ethanol (5 mL) was added two drops of acetic acid. The mixture was irradiated with microwave at 140° C. for 15 minutes and concentrated. The resulting solid was purified by flash chromatography on silica gel, eluting with EtOAc/Hexanes (40-70% gradient), to yield the title compound (0.49 g, 59%). MS ESI+ m/z 295.5 [M+H]+.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=1.NN>C(O)C>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(CCCCN)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To tert-butyl 4-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl]benzoate (33.2 g) in ethanol (600 mL) was added hydrazine (16.9 g). The reaction was heated to reflux and stirred for 2 h. The reaction was then cooled to r.t. and filtered. The solids were washed with ethanol (4×200 mL). The combined organic extracts were concentrated and then dissolved in CH2Cl2 and insoluble material removed by filtration. The organic extracts were concentrated to afford 17.1 g of tert-butyl 4-(4-aminobutyl)benzoate: 1H NMR (CDCl3, 400 MHz) 7.90 (d, 2H, J=8.2 Hz), 7.2 (d, 2H, J=8.0 Hz), 2.7 (m, 2H,), 1.7 (m, 4H), 1.60 (s, 9H), 1.4 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@H:14]2[CH2:15][C@@H:3]1[CH2:4][CH2:5][C:6]12[CH2:8][CH:7]1[C:9]([O:11]CC)=[O:10].C1(C(OCC)=O)C2(CCCCC2)C1>>[CH3:1][C:2]1([CH3:16])[C@H:14]2[CH2:15][C@@H:3]1[CH2:4][CH2:5][C:6]12[CH2:8][CH:7]1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C1CC12CC[C@H]1C[C@@H]2C1(C)C
Agent: CCOC(=O)C1CC12CCCCC2
Product: CC1(C)[C@H]2CCC3(CC3C(=O)O)[C@@H]1C2

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 15A for the product from Example 1A. MS m/z 212 (M+NH4)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>ClCCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nccs2)CC1
Agent: Cl
Solvent: ClCCCl
Product: c1csc(NC2CCNCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
810 mg (2.85 mmol) tert-butyl-4-(thiazol-2-ylamino)piperidine-1-carboxylate was dissolved in DCE (10 ml) and an ethereal HCl soln (10 ml) was added. After 3 h of stirring at RT, the solvent was removed in vacuo. The residue was taken up by water and adjusted to a pH of 11 with a 10% aq. NaOH soln. Extraction then took place with chloroform. The organic phase was washed with water and sat. aq. NaCl soln, dried over MgSO4 and filtered, and the solvent was removed in vacuo. 483 mg (2.64 mmol, 93%) N-(piperidin-4-yl)thiazol-2-amine was thus obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[S:24](N)([NH2:27])(=[O:26])=[O:25]>O1CCOCC1>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([S:24]([NH2:27])(=[O:26])=[O:25])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(N)(=O)=O
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Solvent: C1COCCO1
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(S(N)(=O)=O)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To a solution of COMPOUND 249 (0.1882 g, 0.61 mmol) in 1,4-dioxane (25 mL) was added sulfamide (0.5826 g, 6.06 mmol), and stirred at 100° C. for 4 hours. The mixture was concentrated and water (20 mL) was added and extracted with CH2Cl2 (2×75 mL). The combined organic extracts were washed with water (2×30 mL), dried (Na2SO4), filtered and concentrated. Purification of the crude material by column chromatography on silica gel (33:1:1 CH2Cl2-MeOH—NH4OH) provided 0.1461 g (59%) of COMPOUND 342 as a white solid. 1H NMR (CDCl3) δ 1.80-1.88 (m, 2H), 1.95-2.00 (m, 2H), 2.08 (s, 6H), 2.48-2.58 (m, 3H), 3.76-3.82 (m, 6H), 4.76 (s, 2H), 7.06-7.11 (m, 2H), 7.37 (d, 2H, J=7.2 Hz), 8.33 (d, 2H, J=3.0 Hz). 13C NMR (CDCl3) δ 21.23, 30.29, 50.70, 58.21, 61.67. ES-MS m/z 390.4 (M+H). Anal. Calcd. for C19H27N5O2S.0.2(CH2Cl2): C, 56.73; H, 6.79; N, 17.23. Found: C, 56.44; H, 7.06; N, 17.08.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:6]=1)C.[C:36]1([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][NH2:50])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:4](=[O:3])[C:5]2[CH:6]=[C:7]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=3)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[CH:10]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: NCCCCCCCCc1ccccc1
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
N-(8-phenyl-octyl)-3,5-bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide was prepared as a white solid (0.331 g, 74%) from 3,5-bis-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester and phenyloctyl amine using a procedure similar to step 2 of Example 1. 1H NMR (CDCl3) δ 7.96-7.50 (m, 10H); 7.35-7.10 (m, 5H); 6.28 (m, 1H); 3.45 (m, 2H); 3.31 (m, 4H); 2.60 (m, 2H); 1.60 (m, 4H); 1.33 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=NN=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:16][C:17]([Cl:38])([Cl:37])[C:18]1[N:23]=[C:22]([C:24]([Cl:27])([Cl:26])[Cl:25])[N:21]=[C:20]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](Cl)=[O:32])[N:19]=1>N1C=CC=CC=1>[Cl:27][C:24]([Cl:25])([Cl:26])[C:22]1[N:23]=[C:18]([C:17]([Cl:38])([Cl:16])[Cl:37])[N:19]=[C:20]([C:28]2[CH:29]=[C:30]([C:31]3[O:32][C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:15][N:14]=3)[CH:34]=[CH:35][CH:36]=2)[N:21]=1
Reactant: O=C(Cl)c1cccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)c1
Reactant: COc1ccc(-c2nnn[nH]2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(-c2nnc(-c3cccc(-c4nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n4)c3)o2)cc1OC

Procedure:
5-(3,4-Dimethoxyphenyl)-tetrazole (20 pbw) and 3-(4,6-bis-trichloromethyl-s-triazin-2-yl)benzoyl chloride (44 pbw) are heated in 400 pbv of pyridine. The mixture is further processed as indicated above.