Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=O.C([O-])([O-])=O.[K+].[K+].Cl.[NH2:29][OH:30]>CCO.O>[OH:30]/[N:29]=[CH:1]/[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(/C=N/O)cc2)CC1
Reaction time: 8 h

Procedure:
To a suspension of tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate (3.89 g, 13.41 mmol, prepared as described in Example 10) and K2CO3 (1.02 g, 7.38 mmol) in EtOH (50 mL) was added hydroxylamine hydrochloride (1.4 g, 20.1 mmol) in water (saturated, approx. 2 mL) and the reaction mixture stirred overnight. The reaction was filtered, concentrated in vacuo, water was added and the product filtered to afford tert-butyl 4-{4-[(E)-(hydroxyimino)methyl]phenyl}piperazine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1>C(O)C.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:12][CH:13]([OH:15])[CH2:14]2)=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CC(O)C2)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-nitrophenyl)azetidin-3-ol (160 mg, 0.75 mmol, 1.0 eq) in ethanol (10 mL) was added 10% Pd—C (20 mg) and stirred under H2 gas balloon at RT for 5 h. The reaction mixture was passed through celite and concentrated to obtain 1-(4-amino-2-fluorophenyl)azetidin-3-ol (110 mg, 80.0%, viscous oil) (TLC: EtOAc/PE (1:1), Rf: 0.1).
Reaction SMILES: [CH2:1]([N:8]1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:26][CH:25]=1.C(N)C1C=CC=CC=1>>[CH2:1]([NH:8][C:40]([C:36]1[S:35][C:34]([N:31]2[CH2:32][CH2:33][N:29]([CH2:28][C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:45][CH:44]=3)[C:30]2=[O:43])=[N:38][C:37]=1[CH3:39])=[O:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 16 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white powder in 16% yield: mp 192-193° C.; 1H NMR (300 MHz, CDCl3) δ 7.37-7.21 (m, 7H), 7.04-6.98 (m, 2H), 5.95 (s, 1H), 4.54 (d, J=5.7 Hz, 2H), 4.41 (s, 2H), 4.03 (t, J=8.1 Hz, 2H), 3.42 (t, J=8.1 Hz, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.1, 162.3, 157.2, 155.3, 152.9, 137.9, 133.8, 131.3, 129.9, 128.7, 127.7, 117.3, 115.9, 47.2, 44.0, 42.0, 41.6, 17.2; MS (ES+) m/z 425.2 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4](C2C=CC(CCC)=CC=2)[CH2:3]1.Br[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=2)[CH:19]=1>>[CH3:29][O:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([N:4]1[CH2:5][CH2:6][NH:7][C@H:2]([CH3:1])[CH2:3]1)[CH:27]=[CH:26]2
Reactant: CCCc1ccc(N2CCN[C@H](C)C2)cc1
Reactant: COc1ccc2cc(Br)ccc2c1
Product: COc1ccc2cc(N3CCN[C@H](C)C3)ccc2c1

Procedure:
The title compound was prepared following the procedure of Intermediate 17, but starting from 2-bromo-6-methoxynaphthalene. Purification by chromatography (DCM/MeOH 80/20) afforded the title compound as an off white solid (43%). HPLC (Condition A), Rt: 2.2 min (HPLC purity: 98.4%). M+(ESI): 257.2
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:26][N:27](C)[C:28](=O)OC(C)(C)C)=[CH:4][N:5]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:6]=1[C:7]1[C:8]([C:13]([F:16])([F:15])[F:14])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:42]>C(O)C>[ClH:42].[F:1][C:2]1[C:3]([CH2:26][NH:27][CH3:28])=[CH:4][N:5]([S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:19])[C:6]=1[C:7]1[C:8]([C:13]([F:15])([F:14])[F:16])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2C(F)(F)F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of tert-butyl ({4-fluoro-1-(phenylsulfonyl)-5-[2-(trifluoromethyl)pyridin-3-yl]-1H-pyrrol-3-yl}methyl)methylcarbamate (389 mg) in ethanol (4 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 188 mg, 55%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][N:18]2C(=O)C3C(=CC=CC=3)C2=O)[N:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO>[NH2:18][CH2:17][C:15]1[N:16]=[C:12]([NH:11][C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[S:13][CH:14]=1
Reactant: O=C(NCc1ccccc1)Nc1nc(CN2C(=O)c3ccccc3C2=O)cs1
Agent: NN
Solvent: O
Solvent: CO
Product: NCc1csc(NC(=O)NCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Benzyl-N′-{4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,3-thiazol-2-yl}urea 20c (3 g; 7.64 mmol) was suspended in 50 ml of CH3OH and then, after addition of 2 g of hydrazine hydrate, stirred at RT for 2 h. The resulting solid was filtered off, and the resulting mother liquor was evaporated and triturated with 0.5 N HCl. Renewed filtration and concentration of the mother liquor led to enrichment of the required product, and this purification step was therefore repeated 3×. 0.78 g; ESI-MS [M+H+]=263.05
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].F[C:8]1[CH:23]=[C:22]([C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11].[F:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([O:39][CH3:40])[CH:33]=1.O.C(OCC)(=O)C>CN1C(=O)CCC1>[F:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:8]2[CH:23]=[C:22]([C:24]([F:30])([F:29])[C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:9]=2[C:10]([NH:12][C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[O:11])=[C:34]([O:39][CH3:40])[CH:33]=1
Reactant: COc1cc(F)ccc1O
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(F)ccc1Oc1cc(C(F)(F)C(F)(F)F)ccc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
Cs2CO3 (69.8 mg, 0.21 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide (25 mg, 0.07 mmol) and 4-fluoro-2-methoxyphenol (24.4 μL, 0.2 mmol) in NMP (0.3 mL) and the reaction was stirred at 100° C. for 45 minutes. The reaction mixture was poured into water: ethyl acetate (9:1). The mixture was shaken, and the solid was filtered off, washed with ether, then triturated with ethyl acetate and dried to give the desired product. The mother liquors were filtered and washed with ethyl acetate to give a second crop of material. Both solids were combined and dried under vacuum to give 2-(4-fluoro-2-methoxy-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (111) (15.4 mg, 45%) as a white solid. ESI-MS m/z calc. 472.08. found 473.3 (M+1)+; Retention time: 1.62 minutes. 1H NMR (400 MHz, DMSO) δ 11.32 (s, 1H), 10.62 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.39-7.27 (m, 2H), 7.17 (dd, J=10.7, 2.8 Hz, 1H), 6.88 (dd, J=11.3, 5.7 Hz, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.43 (d, J=7.1 Hz, 1H), 3.73 (s, 3H) ppm.
Reaction SMILES: CC1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:7][C:6]2=[O:15].S(=O)(=O)(O)O.[Cr](O)(O)(=O)=O.[C:26]([OH:29])(=[O:28])[CH3:27]>O>[C:27]1([C:26]([OH:29])=[O:28])[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:7][C:6]2=[O:15]
Reactant: CC(=O)O
Reactant: Cc1cnn2c(=O)[nH]c3ccccc3c12
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cnn2c(=O)[nH]c3ccccc3c12
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To 40 g (0.19 mole) of 1-methyl-pyrazolo[1,5-c]quinazolin-5(6H)-one in a rapidly stirring mixture of 350 g of concentrated sulfuric acid and 100 g of acetic acid is added, dropwise a solution of 100 g of chromic acid in 175 g water and 50 g acetic acid. After 12 hours, the reaction is poured into 2 l. of ice water. The reaction mixture is concentrated, cooled and the title compound filtered off and dried.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:11][C:10]=2[C:36]([NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:37])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O.ClCCl>[NH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:10]([CH:11]=1)[C:36]([NH:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)=[O:37]
Reactant: CC(C)(C)OC(=O)N(CCOCCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCOCCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bis(1,1-dimethylethyl) (2-{[2-({4-[(phenylmethyl)oxy]-3-[(3-pyridinylamino)carbonyl]phenyl}oxy)ethyl]oxy}ethyl)imidodicarbonate (may be prepared as described in Description 77; 340 mg, 0.56 mmol) was treated with trifluoroacetic acid/dichloromethane (v/v 40%, 10 ml). The mixture was stirred at 25° C. for 1 h. The solvent was removed under reduced pressure. The residue was purified twice by reverse phase HPLC using a gradient of acetonitrile and 0.1% aqueous ammonia as the eluent. Evaporation of the product-containing fractions yielded the title compound as a white solid. 86 mg.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:8][C:9]=1[N:10]([CH:23]([C:30]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:11]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([Cl:21])=[CH:16][C:15]=1[CH3:22])(=[O:13])=[O:12])=[O:4].O[Li].O>C1COCC1.CO.O>[O:34]1[C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[CH:31]=[C:30]1[CH:23]([N:10]([S:11]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([Cl:21])=[CH:16][C:15]=1[CH3:22])(=[O:12])=[O:13])[C:9]1[CH:8]=[C:7]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(c1ccccc1)c1cc2ccccc2o1)S(=O)(=O)c1cc(C)c(Cl)cc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(S(=O)(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C(c2ccccc2)c2cc3ccccc3o2)c(C)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.9 %

Procedure:
3-[(3-Benzofuran-2-yl-benzyl)-(4-chloro-2,5-dimethyl-benzenesulfonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (20 mg, 0.031 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 3 mL) and then added 1N aqueous solution of LiOH.H2O (0.20 mL, 0.186 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and methanol (9:1) to obtain 3-[(3-Benzofuran-2-yl-benzyl)-(4-chloro-2,5-dimethyl-benzene-sulfonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (14 mg, 70%) as a white solid. 1H NMR (DMSO, 400 MHz): δ7.93 (s, 1H), 7.84 (s, 1H), 7.74 (bd, 1H), 7.65-7.22 (m, 14H), 4.95 (s, 2H), 2.33, 2.23 (2s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH:10]([CH3:23])[N:9]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:25])[CH:10]([CH3:23])[N:9]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=S

Procedure:
2.6 g of (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 40 ml of dioxane and treated with 1.6 g of phosphorus pentasulfide and 0.7 ml of triethylamine. The mixture is then heated to reflux for 20 minutes, cooled with ice and concentrated on a rotary evaporator. The residue is treated with 10% bicarbonate solution and ethyl acetate, and the ethyl acetate phase is washed twice with 10% bicarbonate solution, dried with sodium sulfate, filtered and concentrated. The residue is purified on a 60 g silica gel column using methylene chloride and methylene chloride/ethyl acetate (20:1) for the elution and then crystallised from methylene chloride/petroleum ether. There is obtained (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-thione which melts at 258°-260° C and which exhibits a rotation of [α]25D =+160,6° (in methylene chloride, 1%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1.[BrH:10]>>[Br:10][CH2:2][C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1
Reactant: Br
Reactant: O=c1ccc(CO)c[nH]1
Product: O=c1ccc(CBr)c[nH]1
Temperature: 100 °C

Procedure:
To 5-hydroxymethyl-2-pyridone (114.9 mg, 0.9 mmol) was added 3.0 ml of 48% hydrobromic acid. The mixture was heated at 100° C. for 20 minutes. The excess hydrobromic acid was then evaporated in vacuo to give the corresponding 5-bromomethyl-2-pyridone. This compound was used without purification. HRMS: m/e, M+found; 186.9626, 7.4% Calc. for C6H6BrNO: 186.9633, −3.9 ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:21](N=C(N(C)C)N(C)C)([CH3:24])([CH3:23])[CH3:22].BrCC(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:22][CH:21]([CH3:24])[CH3:23])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NS(=O)(=O)c2ccc(F)cc2)nc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: CC(C)CBr
Product: CC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(F)cc1
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 24.6 %

Procedure:
4-fluoro-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (400 mg, 1.359 mmol) was dissolved in acetonitrile (4 mL), 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (284 μL, 1.36 mmol) added and the mixture stirred for 20 minutes. 1-Bromo-2-methylpropane (296 μL, 2.72 mmol) was then added and the reaction vessel sealed and heated by microwaves to 150° C. for 1 hour. The reaction was cooled and concentrated in vacuo, then the crude product was extracted to the organic phase of an aqueous work up between ethyl acetate and water. The organic phase was passed through a hydrophobic frit, concentrated in vacuo and purified by mass directed autoprep (formic acid modifier) to give the title compound (117 mg). LCMS (2 min, formic) Rt 1.38 min, m/z (ES+) 351 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10](O)(=O)[CH:11]([CH:13]([C:15](O)=O)[OH:14])[OH:12]>Cl>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[C:10]1[CH:11]([OH:12])[CH:13]([C:15]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=1)[OH:14]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CNc1ccccc1N
Agent: Cl
Product: Cn1c(C(O)C(O)c2nc3ccccc3n2C)nc2ccccc21
Temperature: 25 °C
Yield: 50 %

Procedure:
N-Methylbenzene-1,2-diamine (13.5 g, 85.4 mmol) and tartaric acid (6.4 g, 42.6 mmol) were dissolved in 4 N aqueous HCl (100 mL), and the solution was stirred at reflux overnight. After cooling to room temperature, the precipitate was collected by vacuum filtration and re-dissolved in water (200 mL), and the pH of the resulting mixture was adjusted to 8 with aqueous NH4OH solution. The precipitate was collected by vacuum filtration and dried to give 6.86 g of the desired product, which was used for the next step without further purification. LC-MS: m/z 323 (M+H+).
Reaction SMILES: [CH2:1]([C:7]1[CH:18]=[CH:17][C:10]2[O:11][CH2:12][C:13](=[O:16])[CH2:14][O:15][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5]C.[CH2:19](C1C=CC2OCC(=O)COC=2C=1)C=C.CC(C)CCC1C=CC2OCC(=O)COC=2C=1>>[CH3:19][CH:4]([CH3:5])[CH2:3][CH2:2][CH2:1][C:7]1[CH:18]=[CH:17][C:10]2[O:11][CH2:12][C:13](=[O:16])[CH2:14][O:15][C:9]=2[CH:8]=1
Reactant: C=CCc1ccc2c(c1)OCC(=O)CO2
Reactant: CCCCCCc1ccc2c(c1)OCC(=O)CO2
Agent: CC(C)CCc1ccc2c(c1)OCC(=O)CO2
Product: CC(C)CCCc1ccc2c(c1)OCC(=O)CO2

Procedure:
Odor: Marine, floral-aldehyde odor. -IR (film): ν=1502/1418/1466/1580 cm−1 (ν C═C, Ar), 1265/1304/1201 cm−1 (ν ring), 1050 cm−1 (ν C—O—C), 1741 cm−1 (ν C═O). -1H-NMR (CDCl3): δ=0.88 (2d, J=6.4 Hz, 6H, 4′-Me2), 1.18-1.24 (m, 2H, 3′-H2), 1.53-1.61 (m, 4H, 2′-H2, 4′-H), 2.50 (t, J=7.8 Hz, 2H, 1′-H2), 4.69 (d, J=8.0 Hz, 4H, 2-,4-H2), 6.78 (dd, J=8.0, 4.0 Hz, 1H, 8-H), 6.82 (d, J=4.0 Hz, 1H, 6-H), 6.90 (d, J=8.0 Hz, 1H, 9-H). -13C-NMR (CDCl3): δ=22.44 (2q, 4′-Me2), 27.74 (d, C-4′), 29.07 (t, C-2′), 35.14 (t, C-1′), 38.39 (t, C-3′), 75.35/75.63 . (2t, C-2,-4), 120.30/120.48 (2d, C-6,-9), 123.50 (d, C-8), 138.86 (s, C-7), 146.03/147.83 (2s, C-5a,-9a), 204.76 (s, C-3). -MS (EI): m/z (%)=77 (13) [C6H5+], 91 (8) [C7H7+], 135 (7) [M+-C5H11—C2H2O], 149 (16) [M+-C5H11—CO], 177 (100) [M+-C5H11], 191 (1) [M+-C4H9], 205 (3) [M+-C3H7], 248 (38) [M+].
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([CH2:33][O:34][CH3:35])[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:36])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:37][CH2:38][CH2:39]Cl)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[I-].[Na+].[C:43]([O-:46])(=[O:45])[CH3:44].[Na+]>CN(C=O)C>[C:43]([O:46][CH2:39][CH2:38][O:37][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:14]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([CH2:33][O:34][CH3:35])[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=1)[C:13]2=[O:36])(=[O:45])[CH3:44]
Reactant: CC(=O)[O-]
Reactant: CCCCc1nc2ccc(OCCCl)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccc(OCCOC(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 68.3 %

Procedure:
A mixture of 2-butyl-6-(2-chloroethyloxy)-3-[[2'-(N-methoxymethyltetrazol-5-yl)biphenyl-4-yl]methyl]-4(3H)-quinazolinone (0.59 g), sodium iodide (0.16 g) and sodium acetate (0.87 g) in DMF (15 ml) was stirred at 80° C. for 3 days. The reaction mixture was concentrated to dryness and the residue was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give a colorless oil (0.42 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:5]=1.[CH:15]1([C:19]2[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]3[CH:27]=[C:28]([NH2:32])[CH:29]=[CH:30][CH:31]=3)[S:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26](/[CH:25]=[CH:24]/[C:21]3[S:22][CH:23]=[C:19]([CH:15]4[CH2:18][CH2:17][CH2:16]4)[N:20]=3)[CH:27]=2)=[O:13])[CH:5]=1
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reactant: COC(=O)c1cccc(CC(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)c1
Reaction time: 16 h
Yield: 77.5 %

Procedure:
A solution composed of 1.0 g of 3-carboxymethyl benzoic acid methyl ester, 1.3 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 1.0 g of N-ethyl-N-(dimethylaminopropyl) carbodiimide, 2.4 g of 4-dimethylaminopyridine and 75 ml of methylene chloride was stored at 0° C. After 16 hr., the reaction mixture was washed with 75 ml of water, dried (MgSO4) and the solvents removed by rotary evaporation. The residual materials were triturated with ethyl acetate/hexane to yield 1.7 g of (E)-3-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester; m.p. 119°-120° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:21]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH2:21]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: c1cncc(C2CCNC2)c1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCC(c4cccnc4)C3)c(F)cc2c1=O
Yield: 82 %

Procedure:
Starting from 7-chloro-1-cyclopropyl-6-fluoro -1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.24 g, 4.4 mmol) and 3-(3-pyrrolidinyl) pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.43 g, 82%) as a light beige solid, mp 226°-228° C.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][C:12](=[O:15])[O:13][CH3:14].[CH2:16]1[O:26][C:19]2([CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[O:18][CH2:17]1.O>C1COCC1.CCOC(C)=O>[OH:25][C:22]1([C:10]2[S:6][C:7]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[N:8][CH:9]=2)[CH2:23][CH2:24][C:19]2([O:18][CH2:17][CH2:16][O:26]2)[CH2:20][CH2:21]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COC(=O)Nc1nccs1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Nc1ncc(C2(O)CCC3(CC2)OCCO3)s1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
A solution of n-butyllithium (10.0 mL of 1.6 M solution in hexane, 15.93 mmol) was added to methyl 1,3-thiazol-2-ylcarbamate (1.05 g, 6.64 mmol) in THF (10 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, a solution of 1,4-cyclohexanedione mono-ethylene ketal (1.84 g, 11.75 mmol) in THF (10 mL) was added to the lithiated compound solution via syringe at −78° C. The reaction mixture was allowed to warm to room temperature slowly and stirred overnight. water and EtOAc were added. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl, dried (MgSO4), concentrated and flash chromatographed (50% EtOAc/hexane t0 75% EtOAc/hexane) to give 0.744 g of the title compound in 51% yield. MS (EI) calcd: (M+H)+=315.1; found: 315.0.