Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.CSC>O>[OH:8][C:9]1[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:17]=1
Reactant: CCOC(=O)/C=C/c1ccc(Cc2ccccc2OCc2ccccc2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: CCOC(=O)/C=C/c1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of triethyl phosphonoacetate (0.89 mL) in tetrahydrofuran (30 mL) was added potassium tert-butoxide (0.50 g), and the mixture was stirred at room temperature for 15 minutes. A solution of 4-(2-benzyloxybenzyl)benzaldehyde (1.0 g) in tetrahydrofuran (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. To the resulting mixture was added dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1) to give ethyl (E)-3-[4-(2-benzyl-oxybenzyl)phenyl]acrylate (0.86 g). To the obtained ethyl (E)-3-[4-(2-benzyloxybenzyl)phenyl]acrylate (0.86 g) were added trifluoroacetic acid (9.5 mL), water (0.5 mL) and dimethyl sulfide (1.0 mL), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give ethyl (E)-3-[4-(2-hydroxybenzyl)phenyl]acrylate (0.51 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][OH:8].[H-].[Na+].[H][H].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>O1CCCC1.C(OCC)(=O)C>[CH:13]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:8][CH2:7][C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])([CH3:15])[CH3:14]
Reactant: Cc1ccsc1CO
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccsc1CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 2 h

Procedure:
A solution of (3-methylthien-2-yl)methanol (3.20 g) in tetrahydrofuran (10 ml) was added to a mixture of sodium hydride (60% dispersion in mineral oil, 1.05 g) in tetrahydrofuran (40 ml). After the evolution of hydrogen had subsided triisopropylsilyl chloride (5.2 ml) was added. The reaction mixture was stirred for 2 hours then diluted with ethyl acetate. The mixture was extracted with water, 2M aqueous sodium hydroxide, water and dried with brine and over sodium sulfate. The crude product was purified by Biotage chromatography® using 100:1 petroleum ether:ethyl acetate as eluent to give the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[C:27]#[C:28][C:29](O)=[O:30]>ClCCl.CO>[CH2:14]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:29](=[O:30])[C:28]#[C:27][C:18]2[CH:19]=[CH:20][C:21]([C:23]([F:25])([F:24])[F:26])=[CH:22][C:17]=2[Cl:16])=[CH:11][CH:12]=1)[CH3:15]
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 69 mg (0.33 mmol) of 4-(2-diethylaminoethoxy)phenylamine and 75 mg (0.30 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 70 mg (53% of theory); melting point: 194° C.-197° C.; C22H22ClF3N2O2 (M=438.88); calc.: molecular ion peak (M+H)+: 439/441; found: molecular ion peak (M+H)+: 439/441; Rf value: 0.35 (silica gel, dichloromethane/methanol=(9:1)).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7].N1C(C)=CC=CC=1C.[F:28][C:29]([F:42])([F:41])[S:30]([O:33]S(C(F)(F)F)(=O)=O)(=[O:32])=[O:31].O>CN(C)C1C=CN=CC=1.ClCCl>[F:28][C:29]([F:42])([F:41])[S:30]([OH:33])(=[O:32])=[O:31].[CH3:19][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][S:30]([C:29]([F:42])([F:41])[F:28])(=[O:32])=[O:31])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7]
Reactant: COC(=O)c1cc(O)cc(C(=O)NCCN(C)C)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)NCCN(C)C)c1
Product: O=S(=O)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of methyl 3-[(2-dimethylaminoethyl)carbamoyl]-5-hydroxybenzoate (11.9 g), 2,6-lutidine (6.25 ml) and 4-(dimethylamino)pyridine (0.84 g) in dichloromethane (240 ml) was added dropwise trifluoromethanesulfonic anhydride (9.02 ml) at -30° C. over 30 minutes. After stirring at room temperature for 4 hours, water (100 ml) was added to the reaction mixture. Two phases were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diethyl ether and the crystalline was collected and washed with diethyl ether to give methyl 3-[(2-dimethylaminoethyl)carbamoyl]-5-trifluoromethylsulfonyloxybenzoate trifluoromethanesulfonate (16.02 g).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[C:9]([SH:15])=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Br[C:17]1[C:22]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:21][CH:20]=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>CN(C=O)C>[F:7][C:8]1[C:9]([S:15][C:19]2[CH:20]=[CH:21][C:22]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:17][C:18]=2[N+:27]([O-:29])=[O:28])=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[F:7][C:8]1[C:9]2[S:15][C:19]3[C:20](=[CH:21][C:22]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:17][CH:18]=3)[O:14][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)Oc1cccc([N+](=O)[O-])c1Br
Reactant: Oc1cccc(F)c1S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Sc2c(O)cccc2F)c([N+](=O)[O-])c1
Product: CC(C)Oc1ccc2c(c1)Oc1cccc(F)c1S2
Temperature: 80 °C
Yield: 8 %
Yield: 45 %

Procedure:
Potassium tert-butoxide (360 mg, 3.2 mmol) was added to a stirred, degassed, solution of 3-fluoro-2-mercaptophenol (390 mg, 2.7 mmol) and 2-bromo-3-isopropoxy-nitrobenzene in 20 mL anhydrous DMF and the resulting burgandy-colored reaction heated at 80° C. under N2 overnight (17 h). After cooling to room temperature 10% aqueous HCL (100 ml) was added and the reaction mixture washed with EtOAc (2×75 ml). The combined organics were rinsed with water (2×200 ml), and brine (200 ml), dried (Na2SO4), and concentrated in vacuo to a viscous orange-brown oil. Purification by column chromatography afforded 390 mg (45% from O-2-(4-methoxybenzyl)thio-3-fluorophenyl N,N-diethylcarbamate) of 3-fluoro-2-((4-isopropoxy-2-nitrophenyl)thio)phenol as a yellow solid along with 60 mg (8%) of 1-fluoro-7-isopropoxyphenoxathiin.
Reaction SMILES: O.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])([CH3:5])([CH3:4])[CH3:3].[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CC(C)C[C@H](NC(=O)OC(C)(C)C)C(N1CCN(C2C=CC=CN=2)CC1)=O>>[CH3:14][CH:12]([CH3:13])[CH2:11][C@H:10]([NH:9][C:7](=[O:8])[O:6][C:2]([CH3:3])([CH3:4])[CH3:5])[C:15]([N:27]1[CH2:28][CH2:29][N:24]([C:19]2[N:18]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:25][CH2:26]1)=[O:17]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: c1cnc(N2CCNCC2)nc1
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccccn2)CC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ncccn2)CC1
Yield: 71 %

Procedure:
Tert-butoxycarbonyl-L-leucine monohydrate (12.5 g) and 1-(2-pyrimidinyl)piperazine (8.21 g) were condensed in the same manner as employed in the preparation of tertbutyl (s)-3-methyl-1-[4-(2-pyridyl)piperazine-1-yl-carbonyl]-butylcarbamate to yield 13.4 g of tert-butyl (s)-3-methyl-1-[4-(2-pyrimidinyl)piperazine-1-yl carbonyl]butylcarbamate (yield: 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccn1
Reactant: Nc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccccn2)cc1
Reaction time: 6 h
Yield: 9.9 %

Procedure:
4-Aminothiophenol (0.065 moles, 8.1 g) in 275 ml DMF was stirred at room temperature for 1 hr with sodium hydride (0.065 moles previously washed with hexane). 2-Chloropyridine (0.06 moles, 6.8 g) was added and the reaction mixture was stirred for 6 hr. An additional 5.2 g of 4-aminothiophenol was added and the reaction stirred at room temperature for 16 hr. Water was added and the product extracted with ethyl acetate. The solution was washed thoroughly with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 30% ethyl acetate/hexane to yield 2-(4-aminophenylthio)pyridine 1.2 g, 10%. Mass spec (FD) 202. Calculated for C11H10N2S: C, 65.32; H, 4.98, N, 13.85 Found: C, 65.23; H, 5.09; N, 13.63.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][S:4](=[O:7])([OH:6])=[O:5].S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[CH3:15][O:9][C:8](=[O:10])[C@H:2]([CH2:3][S:4](=[O:6])([OH:7])=[O:5])[NH2:1]
Reactant: O=S(Cl)Cl
Reactant: N[C@@H](CS(=O)(=O)O)C(=O)O
Reactant: CO
Product: COC(=O)[C@@H](N)CS(=O)(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
L-cysteic acid (300 mg, 1.77 mmol) was dissolved in methanol (12 mL), and thionyl chloride (2.5 mL, 34 mmol) was slowly added at 0° C. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure, and the obtained residue was suspended in diisopropyl ether. The suspension was filtered to give the title compound as white crystals (291 mg, 1.33 mmol, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[CH:17][C:3]=1[NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][CH3:15])[N:8]=[C:7](Cl)[N:6]=1.Cl.[CH3:36][NH:37][CH3:38].C(N(CC)C(C)C)(C)C>C(#N)C.O>[Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[CH:17][C:3]=1[NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][CH3:15])[N:8]=[C:7]([N:37]([CH3:38])[CH3:36])[N:6]=1
Reactant: COc1cc(Cl)c(Nc2nc(Cl)nc(OC)c2[N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: COc1cc(Cl)c(Nc2nc(N(C)C)nc(OC)c2[N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A mixture of 2-chloro-N-(2-chloro-6-methoxy-5-nitropyrimidin-4-yl)-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.1 g), dimethylamine hydrochloride (41 mg) and N,N-diisopropylethylamine (0.13 mL) in acetonitrile (2 mL) was stirred at 60° C. for 2 hours. The reaction mixture was diluted with water, and the precipitated crystals were collected by filtration. The crystals were washed with water and diethyl ether, and dried under reduced pressure to give 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-N-(6-methoxy-2-dimethylamino-5-nitropyrimidin-4-yl)-4-methoxyaniline (86 mg). The title compound was prepared in a similar manner to that described in Example 171 using this material instead of ethyl 2-[4-chloro-2-(2-fluoro-6-methoxybenzyloxy)-4-(6-methoxy-2-methoxymethyl-5-nitropyrimidin-4-ylamino)phenoxy]acetate.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.Cl>C(O)C.O.[OH-].[Na+]>[Br:1][C:2]1[C:3]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: CCOC(=O)COc1cc2onc(-c3ccccc3F)c2cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1cc2onc(-c3ccccc3F)c2cc1Br

Procedure:
A suspension of 4 g of ethyl {[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate in 125 ml of ethanol, 50 ml of water and 4 ml of 50% sodium hydroxide solution is refluxed for several hours, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract is dried, the solvent is removed and the residue is recrystallized from acetonitrile to give {[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 223°-224° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[C:34](F)=[CH:33][C:29]([C:30]([OH:32])=O)=[C:28]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)[CH:27]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:30]([C:29]1[CH:33]=[CH:34][C:26]([F:25])=[CH:27][C:28]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:32]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: O=C(O)c1cc(F)c(F)cc1-n1nccn1
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 318.4 (M+H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:29](=[O:30])[N:16]2[C:17]([C:26]([OH:28])=[O:27])=[C:18]([CH2:21][O:22][C:23](=[O:25])[NH2:24])[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([NH:13][CH:14]1[C:29](=[O:30])[N:16]2[C:17]([C:26]([OH:28])=[O:27])=[C:18]([CH2:21][O:22][C:23](=[O:25])[NH2:24])[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csnn1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csnn1
Yield: 45.6 %

Procedure:
2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer)(0.65 g) and 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (0.96 g) were reacted according to similar manners to those of Examples 12 and 15 to give 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)(0.7 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.B(O)(O)[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[N:7][C:6]=3[C:8]=2[CH3:23])[CH2:13][CH2:14]1)=[O:22]
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: OB(O)c1cccnc1
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3cccnc3)nc12
Yield: 85.4 %

Procedure:
(S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 27 mg of pyridin-3-yl-3-boronic acid via General Procedure A to give 56.2 mg of 206. MS (Q1) 483.3 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]2[C:8](N3CCOCC3)([C:9](=[O:21])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[N:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:6]=1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[CH2:12][CH2:11][N:10]([C:14]3[CH:15]=[CH:16][C:17]([I:20])=[CH:18][CH:19]=3)[C:9](=[O:21])[C:8]=2[N:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)C1=NN(c2ccc(Cl)cc2)C2(N3CCOCC3)C(=O)N(c3ccc(I)cc3)CCC12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nn(-c2ccc(Cl)cc2)c2c1CCN(c1ccc(I)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(4-chloro-phenyl)-6-(4-iodo-phenyl)-7a-morpholin-4-yl-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid methyl ester (52, 595 mg, 1.0 mmol) in methylene chloride (CH2Cl2, 4 mL) was treated with trifluoroacetic acid (TFA, 1.0 mL) at 25° C., and the resulting reaction mixture was stirred at 25° C. for an additional 30 min. When HPLC and TLC showed the reaction was complete, the solvents were removed in vacuo. The residue was directly purified by flash column chromatography (SiO2, 5–20% EtOAc/hexane gradient elution) to afford the desired elimination product (53, 467 mg, 508 mg theoretical, 92%) as a pale-yellow oil, which solidified upon standing at room temperature in vacuo. For 53, CIMS m/z 508/510 (M++H, C20H15ClIN3O3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C[C:24]1[CH:32]=[C:31]([C:33]([OH:35])=[O:34])[CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=O.Cl.[CH2:37](N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:26]([C:25]2[CH:24]=[CH:32][C:31]([C:33]([O:35][CH3:37])=[O:34])=[CH:30][CH:29]=2)=[O:28])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C(=O)O)ccc1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (100 mg) and commercially available monomethylterephthalic acid (130 mg) were dissolved in N,N-dimethylformamide (4 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (227 mg) was added, and the admixture was stirred at room temperature for 18 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 99 mg of the title compound (yield: 64%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[ClH:13].[C:14]([C:16]1[CH:29]=[CH:28][C:19]([CH2:20][N:21]2[C:25]([CH:26]=[O:27])=[CH:24][N:23]=[CH:22]2)=[CH:18][C:17]=1[O:30][CH3:31])#[N:15]>>[ClH:13].[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([N:7]2[CH2:19][CH2:20][NH:21][CH2:25][C:26]2=[O:27])[CH:8]=[CH:9][CH:10]=1.[ClH:13].[ClH:13].[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([N:7]2[CH2:19][CH2:20][N:21]([CH2:26][C:25]3[N:21]([CH2:20][C:19]4[CH:28]=[CH:29][C:16]([C:14]#[N:15])=[C:17]([O:30][CH3:31])[CH:18]=4)[CH:22]=[N:23][CH:24]=3)[CH2:25][C:26]2=[O:27])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: COc1cc(Cn2cncc2C=O)ccc1C#N
Agent: Cl
Product: COc1cc(Cn2cncc2CN2CCN(c3cccc(OC(F)(F)F)c3)C(=O)C2)ccc1C#N
Product: O=C1CNCCN1c1cccc(OC(F)(F)F)c1

Procedure:
1-(3-trifluoromethoxy-phenyl)-2-piperazinone hydrochloride was prepared from 3-trifluoromethoxyaniline using Steps F-J of Example 1. This amine (1.75 g, 5.93 mmol) was coupled to the aldehyde from Step I of Example 6 (1.57 g, 6.52 mmol) using the procedure outlined in Step H of Example 1. Purification by flash column chromatography through silica gel (60%-100% acetone CH2Cl2) and conversion of the resulting white foam to its dihydrochloride salt provided the titled product as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=N[CH:5]=[CH:6][N:7]=1.Cl.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1.[C:23]([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH3:10])[CH:12]=3)[CH2:18]2)=[CH:23][CH:5]=[CH:6][N:7]=1
Reactant: Cc1cccc(C2CCCNC2)c1
Reactant: O=C([O-])[O-]
Reactant: Clc1nccnc1Cl
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C2CCCN(c3cccnc3Cl)C2)c1
Temperature: 50 °C
Yield: 119 %

Procedure:
Dichloropyrazine (100 mg, 0.454 mmol), 3-(3-methylphenyl)piperidine hydrochloride (85 mg, 0.454 mmol), and K2CO3 (157 mg, 1.136 mmol) were combined in a 25-mL round bottom flask with a stirbar. DMF (4.48 mL) was added, and the reaction mixture was heated to 50° C. for 4 h. The reaction mixture was diluted with EtOAc (20 mL), and washed sequentially with sat. aq. NaHCO3 (20 mL) and brine (20 mL). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as a brown gum (155 mg, 76%), which was used in the subsequent step without further purification. Data for H-1: LC/MS: rt=3.17 min, m/z (M+H)=288.15 found; 288.79 required.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O)C.C([O-])(=O)/C=C/C([O-])=O>O>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:7]([O:20][CH3:21])=[CH:8][C:9]3[O:14][C:13](=[O:15])[C:12]4[CH2:16][CH2:17][CH2:18][C:11]=4[C:10]=3[CH:19]=2)[CH2:31][CH2:30]1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Reactant: Fc1ccccc1N1CCNCC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: O
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ccccc2F)CC1)CCC3
Yield: 59 %

Procedure:
Method B (50 h at 60° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(2-fluorophenyl)piperazine; yield 59%; fusion point 148°-150° C. (from ethanol). Fumarate (×H2O): method E; yield 78%; the fusion point being 205°-210° C. (from water).
Reaction SMILES: [N:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[S:3][C:2]=1[C:15]([OH:17])=[O:16].[C:18](Cl)(=O)[C:19](Cl)=O.[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[NH:35][CH3:36])[C:28]([NH:30][CH3:31])=[O:29].C(=O)(O)[O-].[Na+]>ClCCl.CN(C=O)C.C(#N)C>[CH2:18]([O:16][C:15]([C:2]1[S:3][C:4]2[CH2:5][CH2:6][O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]=2[N:1]=1)=[O:17])[CH3:19].[Cl:24][C:25]1[CH:26]=[C:27]([C:28](=[O:29])[NH:30][CH3:31])[CH:32]=[CH:33][C:34]=1[N:35]([CH3:36])[C:15]([C:2]1[S:3][C:4]2[CH2:5][CH2:6][O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]=2[N:1]=1)=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1nc2c(s1)CCOc1ccccc1-2
Reactant: CNC(=O)c1ccc(NC)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1nc2c(s1)CCOc1ccccc1-2
Product: CNC(=O)c1ccc(N(C)C(=O)c2nc3c(s2)CCOc2ccccc2-3)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
4,5-Dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester was prepared according to Example 136 for 226, and hydrolyzed to the corresponding acid using General Procedure B. To a suspension of 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (130 mg) in dry dichloromethane (10 mL) was added oxalyl chloride (78 μL) and DMF (1 drop). After 1 hour the solvent was reduced in vacuo and the residue was dissolved in acetonitrile (10 mL) and to this was added 3-chloro-N-methyl-4-methylamino-benzamide from Example 21 (116 mg) and sodium bicarbonate (49 mg). The reaction mixture was warmed to 60° C. After 3 hours the reaction mixture was cooled, diluted with dichloromethane, washed with water, dried (MgSO4) and the solvent removed in vacuo. The residue was recrystallized form ethyl acetate/methanol/hexane to yield 121 (132 mg). NMR: (CDCl3): 3.04 (3H, d), 3.31 (2H, t), 3.48 (3H, s), 4.28-4.31 (2H, m), 6.05 (1H, sbr.), 6.81-6.83 (1H, m), 6.96 (1H, d), 7.05-7.15 (2H, m), 7.48 (1H, d), 7.78 (1H, dd), 7.93 (1H, s). MS: (ESI+) MH+ 428