Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)([O-:22])=[O:21]>[OH-].[K+].C(O)C>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc([N+](=O)[O-])cc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 67.7 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.19 g, 0.74 mmol) was reacted with 4-nitrobenzaldehyde (0.112 g, 0.74 mmol) in 1.5 mL of 4% KOH in ethanol for 3 hours at room temperature to afford 0.195 g (68%) of the title compound as a fine tan powder, mp 184-185° C.: CI-MS m/e 389 (M+), 390 (M++1);
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[Si:9]([N:16]1[C@H:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:18]([C@H:25]([OH:27])[CH3:26])[C:17]1=[O:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(N(CC)CC)C>>[Si:9]([N:16]1[C@H:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:18]([C@H:25]([O:27][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[CH3:26])[C:17]1=[O:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
t-Butyldimethylchlorosilane (940 mg, 6.25 mmol) is added in one portion to a solution of (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-carbomethoxymethylazetidin-2-one (1.88 g, 6.25 mmol) and triethylamine (1.27 g, 6.25 mmol) in 15 ml of anhydrous diemthylformamide at 0° C. After 15 min. at 0° C. the cooling bath is removed and the reaction mixture is stirred at room temperature for 24 hrs. Ether (100 ml) is added and the mixture is filtered, then washed with 2.5N hydrochloric acid (20 ml), water (3×20 ml) and brine. The organic phase is dried over magnesium sulfate, then concentrated in vacuo. The residue is chromatographed on silica gel (7:3 petroleum ether:ether) to yield (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-carbomethoxymethylazetidin-2-one. n.m.r. (CDCl3) δ4.1(m, 2), δ3.68(S, 3), δ3.03(dd, 1, J=4.3, 2.7), δ2.8(ABq, 2), δ1.17(d, 3, J=6.6), δ0.98(s, 9), δ0.89(s, 9), δ0.23(s, 6), δ0.1(s, 6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][N:15]([C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:32]([F:31])[CH:33]=3)=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Reactant: O=C(Cl)c1cccc(F)c1
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C#Cc4ccc(Cl)cc4)cc3)C(=O)c3cccc(F)c3)ccc2O1

Procedure:
The titled compound was prepared following the procedure E using 6-({4-[(4-chlorophenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-fluorobenzoyl chloride as a yellow oil (96%). M+ (ESI): 540.2. HPLC, Rt: 5.71 min (Purity: 97.4%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH:10]([C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)=O.CC(O)=O.C[N:39](C)C=O>>[O:30]1[C:27]2[CH:28]=[CH:29][C:24]([C:10]3[CH:11]=[C:12]([C:14]4[CH:23]=[CH:22][C:21]5[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH:15]=4)[N:39]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])[CH:9]=3)=[CH:25][C:26]=2[O:32][CH2:31]1
Reactant: CN(C)C=O
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc2c(c1)OCO2)c1ccc2ccccc2c1
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cc(-c2ccc3c(c2)OCO3)cc(-c2ccc3ccccc3c2)n1
Temperature: 100 °C

Procedure:
A mixture of 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-5-(naphthalen-2-yl)-1,5-pentanedione on Wang resin (2.7 g, 1.68 mmol), NH4OAc (1.0 g), and AcOH (1.5 mL) in dimethylformamide (40 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-(4-benzo[1,3]dioxol-5-yl-6-naphthalen-2-yl-pyridin-2-yl)-phenol; mp 195-196° C.; 1H NMR (DMSO-d6) d 6.17 (s, 2H), 6.99 (m, 2H), 7.17 (d, J=8.2 Hz, 1H), 7.37 (m, 1H), 7.63 (m, 2H), 7.71 (dd, J=8.2, 1.9 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H), 8.03 (m, 1H), 8.12 (m, 2H), 8.24 (dd, J=8.6, 1.8 Hz, 1H), 8.35 (m, 2H), 8.42 (d, J=1.1 Hz, 1H), 8.74 (s, 1H), 14.55 (s, 1H); IR (KBr) 1605 cm−1; MS [M+H]+ m/z=418. Anal. calcd for C28H19NO3: C, 80.56; H, 4.59; N, 3.36; Found: C, 80.13; H, 4.49; N, 3.18.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14](SC)=[N:13][C:12]2=[O:19])=[CH:7][C:6]=1[O:20][CH3:21].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:14]2[CH:15]=[CH:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([OH:1])([CH3:23])[CH3:22])=[C:6]([O:20][CH3:21])[CH:7]=3)[C:12](=[O:19])[N:13]=2)=[CH:27][CH:26]=1
Reactant: COc1cc(-n2ccc(SC)nc2=O)ccc1OCC(C)(C)O
Reactant: OCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1cc(-n2ccc(OCc3ccc(Cl)cc3)nc2=O)ccc1OCC(C)(C)O
Temperature: 145 °C

Procedure:
A stirred mixture of 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(methylthio)pyrimidin-2(1H)-one Part C of Procedure 1 (10 mg, 0.03 mmol), (4-chlorophenyl)methanol (85 mg, 0.6 mmol) and K2CO3 (12 mg, 0.09 mmol) in NMP (0.1 mL) was heated at 145° C. for 60 min, diluted with CH2Cl2, washed with water, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (silica gel/hexane-EtOAc 100:0:0 to 0:100 gradient) to afford the title compound 4-(4-chlorobenzyloxy)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one A-8 (5 mg, 36% yield) as a white solid. LC/MS 431 (M+H)+, tR 0.9 min (method 5); 1H NMR (400 MHz, chloroform-D) δ 7.53 (1H, d, J=7.03 Hz), 7.40 (2H, d, J=8.53 Hz), 7.37 (2H, d, J=8.78 Hz), 6.96 (1H, d, J=8.53 Hz), 6.91 (1H, d, J=2.26 Hz), 6.85 (1H, dd, J=8.53, 2.51 Hz), 6.00 (1H, d, J=7.03 Hz), 5.45 (2H, s), 3.86 (3H, s), 3.85 (2H, s), 1.35 (6H, s).
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].Cl[C:7](Cl)([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[S:1]([N:5]=[C:7]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:3])(=[O:2])[NH2:4]
Reactant: ClC(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: NS(N)(=O)=O
Solvent: CC#N
Product: NS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of sulfamide (100.9 mg, 1.05 mmol) in anhydrous acetonitrile (3.3 mL) is slowly added dichlorodiphenoxymethane (269.1 mg, 1.00 mmol) at 0° C. The reaction mixture is stirred at room temperature overnight before removal of the solvent. The residue is purified by chromatography to provide diphenyl sulfamoylcarbonimidate (280.2 mg, 96% yield) as a white solid product; HPLC-MS calculated for C13H12N2O4S (M+H+) 293.1, found 293.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]1([NH:27][OH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[OH:28])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: ONc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)N(O)c1ccccc1
Yield: 26.4 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and N-phenylhydroxylamine (80 mg, 0.73 mmol) to give 50 mg of the title compound (26%) after silica gel column chromatography with 2% acetic acid/ethyl acetate: mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.04 (s, 1H), 10.01 (s, 1H), 7.56 (d, 2H, J=7.9 Hz), 7.30 (t, 2H, J=7.9 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 7.05 (t, 1H, J=7.4 Hz), 5.17~5.26 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.58~2.62 (m, 2H), 2.09 (dm, 1H, J=13.5 Hz), 1.81~1.95 (m, 1H).
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].O.O.O.C([O-])(=O)C.[Na+].[Cl:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH2:23]Cl.Cl>O.C(#N)C>[Cl:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH2:23][NH:9][C:6]1[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=S(=O)(O)c1ccc(NCc2ccc(Cl)cc2Cl)cc1
Yield: 55.3 %

Procedure:
To a mixture of 52.0 g (0.30 mole) of sulfanilic acid in 225 ml of warm water was added 83 g (0.61 mole) of sodium acetate trihydrate and 75 ml of acetonitrile. Then a solution of 37.1 g (0.19 mole) of 2,4-dichlorobenzyl chloride in 75 ml of acetonitrile was added and the resulting solution refluxed for 31/2 hrs, followed by the dropwise addition of 50 ml of conc. HCl while simultaneously removing 75 ml of acetonitrile by distillation. The reaction mixture was filtered while hot (80° C.) and the same purification sequence utilized as described in the previous example, which gave 34.91 g (55.3% yield) of purified 4-(((2,4-dichlorophenyl)methyl)amino)benzenesulfonic acid as a white powder having a melting point greater than 275° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]#[N:26])=[CH:17][CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:34]>ClCCl>[ClH:34].[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]#[N:26])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(C#N)c2ccccc12
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(N2C[C@@H]3C[C@H]2CN3)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
165RL03 (207 mg, 0.59 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added and the mixture was shaken in a vial at rt for 3 hours. TLC showed no more starting material. Hydrochloric acid (1 M, 5 mL) was added and the mixture was washed with ethyl acetate (2×10 mL). The aqueous layer was made alkaline with sodium hydroxide (2 M) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness to give an off-white solid (146 mg, 99%). The product was converted to the corresponding hydrochloride salt as described above.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH:5]([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)C.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:13][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C(C)Cc1ccccn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(Cc1ccccn1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-2-methyl-3-pyridin-2-yl-propionic acid ethyl ester (250 mg, 1.29 mmol, 1.0 eq.) in dioxane (8 mL), lithium hydroxide monohydrate (67 mg, 1.55 mmol, 1.2 eq.) in water (5 mL) was added in portions keeping the temperature below 30° C. The resulting solution was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo The residue was dissolved in water (3 mL), MeCN (1 mL) and formic acid (0.5 mL). The solution was directly purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions, extremely polar method) and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [SH:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[CH3:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([S:1][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[NH:11][C:10]2=[O:12]
Reactant: Cc1cccc2c(=O)[nH]c(S)nc12
Reactant: ClCc1ccncc1
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(SCc3ccncc3)nc12
Yield: 44 %

Procedure:
The title compound was prepared in a yield of 44.0%, using 2-mercapto-8-methyl-4(3H)-quinazolinone in place of 2-mercapto-3-phenyl-4(3H)-quinazolinone and 4-chloromethylpyridine hydrochloride in place of 2-chloromethyl4-methylpyridine hydrochloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][C:6](=[N:23][OH:24])[C:5]1=[O:25].[CH2:26]([N:29]=[C:30]=[O:31])[CH2:27][CH3:28].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][C:6](=[N:23][O:24][C:30]([NH:29][CH2:26][CH2:27][CH3:28])=[O:31])[C:5]1=[O:25]
Reactant: CCCN=C=O
Reactant: COCN1C(=O)C(=NO)CN(c2ccccc2)c2ccc(OC)cc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCNC(=O)ON=C1CN(c2ccccc2)c2ccc(OC)cc2N(COC)C1=O
Temperature: 25 °C
Yield: 62.4 %

Procedure:
1-Methoxymethyl-2-oxo-3-hydroxyimino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.0 g) was dissolved in tetrahydrofuran (10 ml), propyl isocyanate (0.62 g) and triethylamine (0.74 g) were added thereto, the mixture was refluxed for 2 hours and 30 minutes. The reaction mixture was allowed to cool to room temperature, crystals so precipitated were collected by filtration, and the crystals were washed with diisopropyl ether, to thereby obtain 0.78 g of the titled compound as white crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([N:18]([CH2:25][C:26]([N:28]([CH3:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:27])[C:19](=[O:24])[CH2:20][N:21]=[C:22]=[O:23])[CH:15]=[CH:16][CH:17]=1>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:6][C:22](=[O:23])[NH:21][CH2:20][C:19]([N:18]([CH2:25][C:26]([N:28]([CH3:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:27])[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=2)=[O:24])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(N(CC(=O)N(C)c2ccccc2)C(=O)CN=C=O)c1
Reactant: Nc1cccc(CO)c1
Product: COc1cccc(N(CC(=O)N(C)c2ccccc2)C(=O)CNC(=O)Nc2cccc(CO)c2)c1
Yield: 61.1 %

Procedure:
Using a procedure similar to that described in Example 31, but starting with 3-(hydroxymethyl)aniline (1.1 g) and 2-[N-(3-methoxyphenyl)isocyanatoacetamido]-N-methyl-N-phenylacetamide (3.2 g), and after recrystallisation in ethyl acetate, 2-[2-{3-[3-(hydroxymethyl)phenyl]ureido}-N-(3-methoxyphenyl)acetamido]-N-methyl-N-phenylacetamide (2.6 g), m.p. 142° C., is obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:20]([CH3:23])=[N:21][S:22][C:10]=2[C:9]=1[OH:24])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]2[C:20]([CH3:23])=[N:21][S:22][C:10]=2[C:9]=1[O:24][C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(-c2ccccc2)c2c(C)nsc2c1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2c(C)nsc2c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A mixture of 7-Hydroxy-3-methyl-4-phenyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester (1.15 mmol), trimethylacetyl chloride (1.39 mmol), Et3N (1.74 mmol), and CH2Cl2 (5.7 mL) was stirred at r.t. for 2 h. The mixture was then quenched with water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. Eluting with 0-20% EtOAc/CH2Cl2 gave the title compound (392.8 mg) as a colorless oil: MS (m/z) 427.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:28][CH:27]=[C:26]([CH:29]=O)[CH:25]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34]([CH2:37][CH2:38][NH2:39])(=[O:36])=[O:35]>>[CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:28][CH:27]=[C:26]([CH2:29][NH:39][CH2:38][CH2:37][S:34]([CH3:33])(=[O:36])=[O:35])[CH:25]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1coc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)c1
Product: CS(=O)(=O)CCNCc1coc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)c1

Procedure:
Prepared according to Procedure D from 5-(4-{4-benzyloxyanilino}-6-quinazolinyl)-furan-3-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz, d6DMSO 9.51 (bs, 2H), 9.11 (s, 1H), 8.79 (s, 1H), 8.29 (d, 1H), 8.06 (s, 1H), 7.90 (d, 1H), 7.60 (d, 2H), 7.5-7.3 (m, 5H), 7.11 (d, 2H), 5.14 (s, 2H), 4.14 (bs, 2H), 3.6-3.5 (m, 3H), 3.12 (s, 3H); MS m/z 529 (M+1).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][C:14]=1[NH2:15]>CCOC(C)=O>[CH3:11][O:12][C:13]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([C:22]([F:24])([F:23])[F:25])=[CH:16][C:14]=1[NH:15][C:8]([NH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:9]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: COc1cc(OC)c(C(F)(F)F)cc1N
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(C(F)(F)F)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 18 h
Yield: 89.9 %

Procedure:
p-Tolyl isocyanate (0.16 mL, 1.24 mmol) was added to a solution of 2,4-dimethoxy-5-(trifluoromethyl)aniline (0.25 g, 1.13 mmol) in EtOAc (3 mL) and the resulting mixture was stirred at room temp. for 18 h. The resulting precipitate was washed with Et2O to give the title compound as a white solid (0.36 g): 1H-NMR (CDCl3) δ 2.21 (s, 3H), 3.97 (s, 3H), 3.86 (s, 3H), 6.88 (s, 1H), 7.05 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 8.13 (s, 1H), 8.33 (s, 1H), 9.09 (s, 1H); FAB-MS m/z 355 ((M+1)+). B1e. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:40])[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[N:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)[CH2:18][CH2:17]1)(C)(C)C>C(Cl)Cl>[C:38]([C:34]1[CH:33]=[C:32]([C:30]2[N:31]=[C:22]([CH:19]3[CH2:18][CH2:17][CH:16]([O:15][CH2:14][C:13]([OH:40])=[O:12])[CH2:21][CH2:20]3)[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:37]=[CH:36][CH:35]=1)#[N:39]
Reactant: CC(C)(C)OC(=O)COC1CCC(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2nc(C3CCC(OCC(=O)O)CC3)cc3cccnc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (TFA) (2 ml) is added to a solution of {4-[8-(3-cyano-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexyloxy}-acetic acid tert-butyl ester (182 mg, 0.41 mmol) in CH2Cl2 (2 ml) at 0° C. The solution is stirred at room temperature for 1 hour, concentrated, and azeotroped with toluene (×3). Purification by chromatography on silica gel, eluting with 7% methanol in CH2Cl2 gives the product. MS (ES+) [M+H]+ 388.04
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]>O1CCCC1.[Pd].CO>[NH2:11][C:4]1[C:5]([O:9][CH3:10])=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: COc1nc(C)c(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(C)c(C)cc1N
Reaction time: 3 h
Yield: 98 %

Procedure:
5,6-Dimethyl-2-methoxy-3-nitropyridine (1-013-06) (2.56 g) was dissolved in tetrahydrofuran (41 mL), and to the reaction mixture was added a suspension of 5% palladium on carbon (450 mg) in methanol (41 mL), and then the catalytic reduction was carried out. After 3 h, catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-amino-5,6-dimethyl-2-methoxypyridine (1-013-07) (2.096 g, 97.9%, m.p.: 56-58° C.) as a blackish brown crystal.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]2[NH:21][N:22]=[N:23][C:19]=2[CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[N:21]1[C:20]2[CH:24]=[CH:25][C:17]([NH:16][C:2]3[C:11]4[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])=[CH:18][C:19]=2[NH:23][N:22]=1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3ccc4nn[nH]c4c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 141, 218.6 mg (1 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 161.0 mg (1.2 mmol) of 5-aminobenzotriazole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was heated at 100° C. for 1 hr. The work up gave 213.5 mg (67.6%) of the product as a yellow solid, m.p.>250 C., mass (electrospray, m/e): M+H 316.9. HRCIMS: calcd 316.107 for C17H12N6O (M+), obsd 316.1079.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C:5]1[CH:9]([C:10]([CH3:12])=[CH2:11])[CH2:8][CH2:7][C:6]=1[CH3:13])=[O:2].CC(C)=[O:16].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([CH2:3][CH2:4][C:5]1[CH:9]([C:10]([CH3:12])=[CH2:11])[CH2:8][CH2:7][C:6]=1[CH3:13])([OH:16])=[O:2]
Reactant: C=C(C)C1CCC(C)=C1CCC=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C=C(C)C1CCC(C)=C1CCC(=O)O

Procedure:
A solution of 25 g of 2-(2-formylethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene in 1200 ml of acetone was treated at -10° C with 55 ml of Jones reagent. The resulting brown mixture was poured on to ice/sodium bicarbonate solution. Ether extraction, washing neutral with sodium bicarbonate solution, saturated sodium chloride solution and water, drying of the extract with magnesium sulphate and removal of the solvent under reduced pressure yielded 20 g (80%) of a weakly yellow oily crude product from which there were obtained by distillation 15 g of pure 2-(2-carboxyethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene; boiling point 0.01 = 102° C; IRfilm : νmax = 3600-2400, 1720, 1645, 1450, 1420, 1380, 1330, 1290, 1220, 1085, 945 and 900 cm-1. The compound has a woody, spicy, weakly sweetish and somewhat musty fragrance.