Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:22][C@@H:21]3[C@@:16]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([N:17]=[C:18]([NH:23]C(=O)C4C=CC=CC=4)[S:19][CH2:20]3)[CH2:15]2)=[N:12][CH:13]=1.Cl.CON>C(O)C>[F:7][C:8]1[CH:13]=[N:12][C:11]([N:14]2[CH2:22][C@@H:21]3[C@@:16]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([N:17]=[C:18]([NH2:23])[S:19][CH2:20]3)[CH2:15]2)=[N:10][CH:9]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NC1=N[C@@]2(c3ccccc3)CN(c3ncc(F)cn3)C[C@H]2CS1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Pyridine (20 mL, 197 mmol) is added to a mixture of N-[(4aR,7aS)-6-(5-fluoropyrimidin-2-yl)-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (9.5 g, 22 mmol), O-methylhydroxylamine hydrochloride (15 g, 175 mmol) in ethanol (85 mL) and the mixture is stirred at 60° C. for 2 hours. The mixture is cooled to ambient temperature and concentrated. The mixture is diluted with water (100 mL) and ethyl acetate (100 mL) and the pH to 2 using 1 M hydrochloric acid. The aqueous layer is separated and the pH is adjusted to 10 using 2 M sodium hydroxide. The resulting aqueous solution is extracted with ethyl acetate (2×100 mL). The organic layers are combined, dried over magnesium sulfate, filtered, and concentrated. The crude product is purified over silica gel using a 5% solution of dichloromethane/2 M ammonia in methanol. Chiral Analysis of the product; column: Chiralpak AD 0.46×15 cm, 5 μm; eluent: 100% (methanol with 0.2% dimethylethylamine); flow: 0.75 mL/min at UV 254 nm; Rt=6.9 minutes. (4.6 g, 64%, >98% ee). ES/MS (m/e): 330 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](OC)=[O:32])[CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:31]2=[O:32])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCCCCCc1cccnc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCCCc2cccnc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 7-(pyridin-3-yl)heptanoate (2.0 eq., prepared in Synthetic Example 14) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[5-(3-pyridyl)pentyl]-1,8-naphthyridin-2(1H)-one, mp 155° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl:25][S:26](O)(=[O:28])=[O:27]>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:18]1[CH:23]=[CH:22][C:21]([S:26]([Cl:25])(=[O:28])=[O:27])=[CH:20][CH:19]=1)[CH3:24]
Reactant: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(O)Cl
Product: CC1(c2ccc(S(=O)(=O)Cl)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(1-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (0.50 g., 0.0014 mole) is added portionwise with stirring to chlorosulfonic acid (5 ml.) in an ice-water bath. The reaction mixture is stirred at 0° C. for 2 hours, left to come to ambient temperature for 2 hours, then slowly added to crushed ice to precipitate 0.51 g. of [1-oxo-2-(4-chlorosulfonylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid which melts at 209°-210° C. after crystallization from acetic acid:water, 3:2.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]=1[CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=O)C1C=CC=CC=1>CO>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][C:18]1[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:17]=1[CH2:16][CH:12]1[CH2:13][CH2:14][CH2:15][NH:11]1)[CH3:32]
Reactant: CCOC(=O)C=Cc1oc2ccccc2c1CC1CCCN1C(=O)OCc1ccccc1
Solvent: CO
Product: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1
Yield: 91.5 %

Procedure:
A mixture containing 47 (1.0 g, 2.3 mmol) and 10% Pd-on-carbon (˜1 g) in anhydrous MeOH (20 mL) was placed under a hydrogen atmosphere (45 PSI) and shaken using a Parr apparatus for 1 h. The catalyst was removed by filtration and the solids were washed with EtOAc and MeOH. The clarified filtrate was concentrated to afford 634 mg (91%) of 48 as an orange oil which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ7.51-7.49 (m, 1H), 7.38-7.35 (m, 1H), 7.21-7.17 (m, 2H), 4.16-4.09 (m, 2H), 3.68-3.59 (m, 2H), 3.12-3.07 (m, 2H), 2.88-2.73 (m, 4H), 1.84-1.69 (m, 4H), 1.43-1.39 (m, 1H), 1.26-1.20 (m, 3H) ppm.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].[OH:21][C:22]1([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CN(C)C=O>[OH:21][C:22]1([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:24][CH2:23]1
Reactant: O=C(CCCCCBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1(O)CCN(CCCCCC(=O)c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
6-Bromo-1-phenyl-1-hexanone (2.9 g) and potassium carbonate (3 g) were added to a solution of 4-hydroxy-4-tert-butoxycarbonylaminomethylpiperidine (2.5 g) in dimethylformamide (40 ml), and the mixture was stirred at 60° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 3.74 g of 4-hydroxy-1-(6-oxo-6-phenylhexyl)-4-tert-butoxycarbonylaminomethylpiperidine.
Reaction SMILES: [Br:1][C:2]1[C:6](Br)=[C:5]([Br:8])[NH:4][N:3]=1.[CH2:9]([O:11]CC)C.C([Li])CCC.CN(C)C=O>O>[Br:8][C:5]1[C:6]([CH:9]=[O:11])=[C:2]([Br:1])[NH:3][N:4]=1
Reactant: Brc1n[nH]c(Br)c1Br
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(Br)n[nH]c1Br
Temperature: -75 °C
Reaction time: 1.5 h

Procedure:
81.7 g (0.268 mol) of 3,4,5-tribromopyrazole are introduced with stirring into 1500 cm3 of diethyl ether at a temperature in the region of 20° C. and under an argon atmosphere. The mixture is cooled to a temperature in the region of −78° C. and 335 cm3 (0.536 mol) of n-butyllithium at 1.6 mol/l are then added dropwise over 3 hours 15 minutes. The reaction mixture is stirred for 1.5 hours at a temperature in the region of −75° C., followed by dropwise addition of 100 cm3 (1.34 mol) of dimethylformamide, while keeping the temperature below −70° C. Stirring is continued for 2 hours at a temperature in the region of −75° C., and then for 15 hours at a temperature in the region of 20° C. The reaction medium is then cooled in an ice bath and 1000 cm3 of water are added. After separation of the phases by settling, the aqueous phase is extracted with 500 cm3 of diethyl ether and with 3 times 500 cm3 of ethyl acetate. The aqueous phase is then acidified with citric acid solution to pH 3 (the formation of a precipitate is observed) and extracted with twice 1000 cm3 of diethyl ether. The organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa), and the yellow solid obtained is taken up in 300 cm3 of water and stirred for 2 hours at a temperature in the region of 20° C. The mixture is then filtered and the solid is washed with twice 50 cm3 of water, dried under a ventilated hood and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 51.3 g of 3,5-dibromo-1H-pyrazole-4-carboxaldehyde are thus obtained in the form of a yellow powder melting at 173° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:33][C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29](=[O:31])[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C1CCNC1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)N1CCCC1
Yield: 59.3 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.54 mmol) was reacted with pyrrolidine (0.45 ml, 5.4 mmol) to give the title compound (160 mg, 59%) as a solid, except that the mixture was heated at 55° C. for 20 hours and purified by chromatography on silica gel (eluant: 1-5% methanol in DCM); NMR Spectrum 1.61 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.47-3.30 (m, 3H), 3.77 (m, 1H), 5.63 (q, 1H), 6.04 (s, 2H), 7.27 (d, 1H), 7.35 (d, 1H), 7.65 (d, 1H), 7.74 (m, 3H), 7.88 (dd, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.56 (s, 1H), 11.09 (br s, 1H); Mass spectrum 500.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.018 mole), 1,1'-carbonyldiimidazole (3.1 g, 0.019 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 3 hours. The nitrogen flow was stopped and a solution of piperidine (1.7 g, 0.020 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue triturated in potassium bicarbonate solution (100 ml) and filtered. The filter cake was washed with water and recrystallized from isopropyl alcohol-isopropyl ether to give 5.9 g (82%) of white flakes, mp 175°-176° C.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:29]=1[NH:30][CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])=[CH:27][CH:26]=[CH:25][CH:24]=2>C(#N)C>[CH2:2]([C:1]1[N:30]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[C:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:19]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Reactant: CCCCC(OC)(OC)OC
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C

Procedure:
Trimethyl orthovalerate (3.6 mL, 21 mmol) and pyridine hydrochloride (0.22 g, 1.9 mmol) were added to a solution of 1-[(3-aminoquinolin-4-yl)amino]-2-methylpropan-2-ol (prepared as described in Part A of Example 8, approximately 4.4 g, 19 mmol) in acetonitrile (96 mL). The reaction mixture was heated at reflux for 1 hour, then was allowed to cool to room temperature and was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to yield 4.1 g of 1-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white foam.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][C:7]([CH3:11])(O)[CH:8]=[CH2:9])([CH3:3])[CH3:2].[C:12](O)(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(OC=C)C.C([O-])(=O)C.[Hg+]>[CH:1]([O:4][CH2:5][CH2:6][C:7]([CH3:11])=[CH:8][CH2:9][CH2:13][CH:12]=[O:14])([CH3:3])[CH3:2]
Reactant: C=CC(C)(O)CCOC(C)C
Reactant: CC(=O)O
Agent: C=COCC
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: CC(=CCCC=O)CCOC(C)C

Procedure:
15.8 g (0.1 mol) of 5-isopropoxy-3-methyl-1-penten-3-ol (produced in accordance with Example 63) and 20.0 g of mercury acetate are kept in 180 cc of ethylvinyl ether at reflux temperature during the course of 4 days. 0.9 cc of glacial acetic acid is added at 20° to the solution which has rendered turbid. 150 cc of 5% potassium carbonate solution are added after 3 hours and the mixture is extracted with hexane. The hexane extract is evaporated and the residue is heated to 165°-168° during 11/2 hours in an atmosphere of nitrogen and without further purification; the residue is subsequently distilled at reduced pressure. B.P. of 7-isopropoxy-5-methyl-4-heptenal: 70°-73°/0.8 mm. nD20 = 1.4476
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH:24]=[CH2:25])[CH2:11][CH2:10][CH:9]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Rh](Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1(/[CH:23]=[CH:24]/[CH3:25])[CH2:7][CH2:8][CH:9]([N:12]2[C:13](=[O:22])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]2=[O:21])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C=CCC1(C(=O)OCC)CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: Cl[Rh](Cl)Cl
Solvent: CCO
Product: C/C=C/C1(C(=O)OCC)CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 75 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
1-Allyl-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-cyclohexanecarboxylic acid ethyl ester (Intermediate 73, 975 mg, 2.86 mmol) was dissolved in ethanol (13.900 mL) in a roundbottom flask with reflux condensor. The flask was charged with rhodium(III) chloride (32.5 mg, 0.143 mmol), and the reaction mixture was heated to 75° C. and stirred for 18 hr, then filtered and concentrated in vacuo to yield the title compound as a brown oil (965 mg, 99%) which was taken to the next step without further purification.
Reaction SMILES: [C:1](OCC)(=O)C(OCC)=O.[C:11]1([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-]CC.[Na+].C=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[C:18]([O:20][CH2:21][CH3:22])(=[O:19])[C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:1]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: C=O
Agent: CC[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of diethyl oxalate (75 g, 513 mmole) and ethyl phenylacetate (108 g, 658 mmol) in 300 mL of dry toluene was slowly charged with solid sodium ethoxide (33.3 g, 489 mmol). A mild exothermic reaction was observed and the reaction mixture turned orange. Precipitation of the salt started within 1 hour and the reaction was left at room temperature overnight. The salt was filtered and washed thoroughly with dry ether. The solid was suspended in 200 mL of ether then acidified to pH2 with 5% aqueous hydrochloric acid. The aqueous layer was separated followed by additional extraction with ether (2×50 mL). The combined etheral solution was successively washed with a saturated solution of sodium bicarbonate (50 mL), water (2×50mL) and brine (50 mL), dried over magnesium sulfate and evaporated in vacuum at room temperature (to prevent possible decarboxylation). The resulting yellow oil was charged with water (250 mL) and formaldehyde (81 mL, 37% aqueous solution, 1 mole) and then it was cooled to 0° C. The resulting mixture was charged, very slowly, with potassium carbonate (72 g, 521 mmol), over 30 minutes. The temperature in the reaction flask was not allowed to exceed 15° C. The reaction mixture was stirred at room temperature for an additional two hours. The aqueous solution was extracted with ether (2×50 mL) and the combined ethereal solution was washed with water (2× 50 mL) and brine (50 mL), dried over magnesium sulfate and evaporated. The resulting yellow oil was purified by Kugelrohr distillation (80°-85° C., 0.5 mmHg) to yield 82.3 g (91%). 300MHz 1H NMR (CDCl3)δ7.46-7.31 (m,5 H), 6.37 (d, J=1.17 Hz, 1H), 5.91 (d, J=1.17 Hz, 1H), 4.31 (q, J=7.15 Hz, 2 H), 1.35 (t, J=7.15 Hz, 3 H). IR (neat)2995, 1740, 1610, 1500, 1450, 1405, 1370, 1310, 1200 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](O)=[O:26])[C:13]2=[O:31])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:26])[C:13]2=[O:31])[CH:9]([CH3:10])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)C(=C1C(=O)N(Cc2cccc(C(=O)O)c2)c2ccccc21)c1ccc(Cl)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)C(=C1C(=O)N(Cc2cccc(C(=O)NS(C)(=O)=O)c2)c2ccccc21)c1ccc(Cl)cc1
Reaction time: 72 h
Yield: 38.5 %

Procedure:
A mixture of 3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid (0.22 g, 0.51 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.20 g, 1.02 mmol), methylsulfonamide (97 mg, 1.02 mmol), DMAP (12.2 mg, 0.10 mmol) in dichloromethane (20 ml) was stirred for 72 hours. The organic solution washed with brine (10 ml) then dried over sodium sulfate. After removal of solvent, the residue was dissolved in 2 ml DMF for prepared HPLC to give the product N-(3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide (100 mg, 38%) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=6.82 Hz, 6H) 3.50 (s, 3H) 5.00-5.12 (m, 1H) 5.17 (s, 2H) 5.52 (s, 1H) 5.84 (d, J=7.83 Hz, 1H) 6.75 (t, J=7.83 Hz, 1H) 6.85 (d, J=7.83 Hz, 1H) 7.17 (t, J=7.20 Hz, 1H) 7.28 (d, J=8.59 Hz, 2H) 7.60 (t, J=7.71 Hz, 1H) 7.65 (d, J=8.34 Hz, 2H) 7.70 (d, J=7.83 Hz, 1H) 7.94 (d, J=7.83 Hz, 1H) 8.02 (s, 1H). MS calcd. for C27H25ClN2O4S 508.5, obsd. (ESI+) [(M+H)+] 509.2.
Reaction SMILES: O.CC#[N:4].N[C@H:6]([CH2:13][C:14]([OH:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C(N)(CO)CO.Cl>[NH2:4][C@H:13]([C:14]([OH:16])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N[C@H](CC(=O)O)c1ccccc1
Reactant: CC#N
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 18 h

Procedure:
The standard PAM activity assay mixture contains 5 mM L-α-phenylalanine, 1 to 10 μg enzyme in 50 mM Tris-HCl buffer (pH 7.5) in a final volume of 0.5 ml. Enzyme reactions were carried out at 28° C., 150 rpm for 18 hours and terminated by addition of 50 μl ethanol to precipitate proteins. After centrifugation for 5 minutes, the supernatants were analyzed by a reverse phase HPLC method. The formation of β-phenylalanine was quantified based on peak area compared to the β-phenylalanine standard curve. Enzyme activity is expressed as μg β-phenylalanine formed per hour per mg protein. HPLC analysis used a YMC Ph column (4.6×150 mm; Waters, Milford, Mass.), and a flow rate of 1.2 ml/minutes. Absorbance was monitored at 210 nm. The method employed two solvents A, water; and B, CH3CN and a gradient consisting 0% to 12% B for 6 minutes, 12% to 90% in 1 minute and returning to 0% in 1 minute. Retention times of L-α-phenylalanine and β-phenylalanine are 4.3 minutes and 3.5 minutes, respectively.
Reaction SMILES: C([N:8]1[C:17](=[O:18])[C:16]([CH:19]([CH3:21])[CH3:20])=[C:11]2[S:12][CH2:13][CH2:14][CH2:15][N:10]2[C:9]1=[O:22])C1C=CC=CC=1.B(Br)(Br)Br.CO>C1(C)C=CC=CC=1>[CH:19]([C:16]1[C:17](=[O:18])[NH:8][C:9](=[O:22])[N:10]2[CH2:15][CH2:14][CH2:13][S:12][C:11]=12)([CH3:21])[CH3:20]
Reactant: CC(C)c1c2n(c(=O)n(Cc3ccccc3)c1=O)CCCS2
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)c1c2n(c(=O)[nH]c1=O)CCCS2
Reaction time: 0.5 h

Procedure:
To a solution of 4.75 g (15 mmol) of 7-benzyl-9-isopropyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione in 120 ml of toluene, 7.52 g (30 mmol) of boron tribromide was added under ice cooling conditions, followed by refluxing for 16 hours. After the reaction mixture was cooled, 50 ml of methanol was added, followed by stirring for 30 minutes. After this mixture was concentrated to dryness, methanol-diethyl ether was added to the residue. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to yield 1.95 g (57.4%, light white powder) of the desired product.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:11])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][C:32](Br)=[O:33].O>C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][N:7]([C:8]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:11])[C:32](=[O:33])[CH2:31][Br:30])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNc1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
A mixture of 2.5g (0.0074 M) of 2-(2-acetoxyethylamino)-5-chloro-2'-fluorobenzophenone and 5g (0.0362 M) of potassium carbonate in 25 ml of dry chloroform was treated with 2.0g (0.0096 M) of bromoacetyl bromide over a 20 minute period with stirring. The mixture was stirred for 1 hour at room temperature when 25 ml of water was added, and the chloroform layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was dissolved in 10 ml of benzene, and chromatographed over 100g of Florisil. Elution with 1 l. of benzene gave 0.2g of an oil and elution with 1.5 l. of ether and 1 l. of ethyl acetate gave 1.8g and 1.0g, respectively of a colorless oil which were combined and recrystallized from a mixture of dichloromethane and petroleum ether to give the above named product as white prisms, m.p. 84°-88°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:9]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:41][S:42]([C:45]1[CH:46]=[C:47]([CH:52]=[CH:53][CH:54]=1)[C:48]([NH:50][NH2:51])=[O:49])(=[O:44])=[O:43]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([NH:51][NH:50][C:48](=[O:49])[C:47]2[CH:52]=[CH:53][CH:54]=[C:45]([S:42]([CH3:41])(=[O:43])=[O:44])[CH:46]=2)=[O:15])=[CH:11][C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:9]1
Reactant: CS(=O)(=O)c1cccc(C(=O)NN)c1
Reactant: COC(=O)c1cc(C(=O)O)n(-c2ccccc2Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)NNC(=O)c2cccc(S(C)(=O)=O)c2)n(-c2ccccc2Cl)n1
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
To a stirred solution of compound 7 (500 mg, 1.78 mmol) in DMF (20 mL at 0° C., EDCI (500 mg, 2.6 mmol) was added and stirred for 15 min. HOBt (351 mg, 2.6 mmol) was added to the reaction mixture and after 30 min stirring 3-(methylsulfonyl)benzohydrazide 3 from Example 1 (450 mg, 2.1 mmol) was added. Reaction mixture was allowed to attain room temperature and stirred for over night. Water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL×4). Combined organic layer was washed with water, brine, dried over sodium sulphate and concentrated. The crude product on column chromatographic purification using 2% methanol in dichloromethane afforded the title compound 8 (452 mg, 52%).