Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]([NH2:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.[CH3:14][S:15][C:16]1[N:21]=[C:20]([Sn](CCCC)(CCCC)CCCC)[CH:19]=[CH:18][N:17]=1>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][C:10]([NH2:13])([CH3:12])[C:9]#[C:8][C:5]1[CH:4]=[CH:3][C:2]([C:18]2[CH:19]=[CH:20][N:21]=[C:16]([S:15][CH3:14])[N:17]=2)=[CH:7][N:6]=1
Reactant: CC(C)(N)C#Cc1ccc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2ccc(C#CC(C)(C)N)nc2)n1

Procedure:
3-(5-Bromo-pyridin-2-yl)-1,1-dimethyl-prop-2-ynylamine (1.05 g, 4.4 mmol), 2-methylthio-4-tri-butylstannylpyrimidine (1.83 g, 4.4 mmol) and PdCl2(PPh3)2 (154 mg, 0.22 mmol) in toluene (22 ml) were refluxed under argon for 2 hours. A second portion of 2-methylthio-4-tri-n-butylstannylpyrimidine (1.83 g, 4.4 mmol) was added and the mixture refluxed for 1 hour. The reaction mixture was filtered, evaporated and purified via chromatography on silicagel (TBME/MeOH/ammonia:97/2.7/0.3 to 95/4.5/0.5) to give the title compound as orange-brown solid, which was recrystallized form ether/hexanes. Yield: 500 mg (40%).
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:24])[CH2:9][C@@H:10]([OH:23])[C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.Cl>N1C=CC=CC=1>[CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:24])[CH2:9][CH:10]([O:23][C:25]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])[C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@H](O)C[C@]12C
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3C(OC(=O)CCC(=O)O)C[C@]12C

Procedure:
According to the general principles outlined by Erlanger et al. (Method in Immunology and Immunochemistry Vol. I, p. 148, Ed. C. A. Williams and M. W. Chase. Academic Press N.Y., 1967), and by Buzby et al. (J. Med. Chem. 10:199, 1967), a solution of 11α-hydroxyprogesterone (10 g) (Sigma Chem. Co., St. Louis, MO) and of succinic anhydride (10 g) in dry pyridine (100 ml) was prepared and refluxed under nitrogen atmosphere for 20 hours. The cooled reaction mixture was poured into cold aqueous hydrochloric acid (3 N, 500 ml) containing crushed ice, and extracted with chloroform. After evaporation of the chloroform, the residue was recrystallized repeatedly from acetone-hexane, and from acetone yielding 4.5 gm of white crystals, melting point 148°-152° C. Absorption maximum in 0.1 NaOH was at 243 nm. These characteristics were consistent with those described in the literature (Lindner et al., Steroids 19:357-375, 1972) for 11α-hydroxyprogesterone hemisuccinate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>>[Cl:9][C:10]1[CH:17]=[C:16]([S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: Sc1cccc(Cl)c1
Reactant: O=Cc1ccc(F)cc1Cl
Product: O=Cc1ccc(Sc2cccc(Cl)c2)cc1Cl

Procedure:
3-Chlorobenzenethiol and 2-chloro-4-fluorobenzaldehyde were reacted according to the same experiment procedures as in Reference Example 1 of the pamphlet of WO 03029205 to obtain the target product as a colorless oil.
Reaction SMILES: O=[C:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH2:21]([SH:24])[CH2:22][SH:23].O>ClCCl>[CH2:14]([C:2]1([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[S:24][CH2:21][CH2:22][S:23]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCC(=O)CCCCCCCC(=O)OC
Reactant: SCCS
Solvent: O
Solvent: ClCCl
Product: CCCCCCCC1(CCCCCCCC(=O)OC)SCCS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, methyl 9-oxo-hexadecanoate (No. 4984860; 2.39 g, 8.40 mmol) was dissolved in dichloromethane (47 mL), and the solution was cooled to 0° C. While maintaining the temperature at 0° C., 1,2-ethanedithiol (840 μL, 10.1 mmol), and borontrifluoride-ethylether complex (1.24 mL, 10.1 mmol) were sequentially added, and the mixture was stirred at 0° C. for 5 minutes and at room temperature for 2 hours. Water was added to the reaction solution to stop the reaction, and the solution was extracted with dichloromethane. The organic layer was sequentially washed with a saturated sodium bicarbonate aqueous solution and a saturated brine, and dried over anhydrous sodium sulfate. After the organic layer was filtered and the solvent was distilled off, the resulting residue was purified with SP1 (SiO2 cartridge, 5.0% ethyl acetate/n-hexane, Rf=0.5) to obtain methyl 8-(2-heptyl-[1,3]dithiolan-2-yl)-octanoate (No. 5553355; 2.57 g, 85% yield).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:12][O:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(N)=O)c(O)c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc(C)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 617.5 %

Procedure:
A mixture of 2-hydroxy-4-methyl-benzamide (15.1 g, 0.1 mol) and K2CO3 (41.7 g, 0.3 mol) in 1000 mL of acetone was heated to reflux for 1 hour before Me2SO4 was added at that temperature. The resulting mixture was refluxed overnight. The reaction mixture was then filtered and the filtrate was concentrated. The resulting residue was dissolved in 1000 mL of methanol/ammonia (1:1) and stirred at room temperature for 3 hours. After removal of the solvent, the residue was recrystallized from EtOAc/PE to afford 102 g of 2-methoxy-4-methyl-benzamide (yield 61%). 1H NMR (400 MHz, DMSO-d6): δ 7.72 (d, J=7.6 Hz, 1H), 7.57 (br s, 1H), 7.46 (br s, 1H), 6.92 (s, 1H), 6.81 (d, J=7.6 Hz, 1H), 3.85 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[C:10](=[O:28])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:33][S:34][CH3:35]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:33][S:34][CH3:35])[C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)=[CH:17][CH:16]=2)[C:10](=[O:28])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(=O)N(Cc2ccc(Nc3ncccn3)cc2)CCN1Cc1ccccc1
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Yield: 86.45 %

Procedure:
In 40 ml of N,N-dimethylformamide was dissolved 3.0 g of 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine, and 0.372 g of sodium hydride (purity 52%) was added thereto, after which the resulting mixture was subjected to reaction at 80° C. for 30 min. with stirring. The reaction mixture was then cooled, and 0.72 ml of chloromethylmethylsulfide was added thereto, after which the resulting mixture was subjected to reaction at 50° to 60° C. for 2 hours. After the completion of the reaction, the reaction mixture was distilled under reduced pressure and the residue thus obtained was extracted with chloroform and then washed with water. The solution thus obtained was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure. The crystals thus obtained were recrystallized from isopropyl alcohol to obtain 3.0 g (86.45% yield) of white crystalline 1-benzyl-4-{4-[N-methylthiomethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine having a melting point of 156° C.
Reaction SMILES: Cl.[S:2]1[C:6]2=[CH:7][CH:8]=[CH:9][NH:10][CH:5]2[CH2:4][CH2:3]1.[CH3:11][O:12][C:13](=[O:23])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:12][C:13]([C@@H:14]([N:10]1[CH2:9][C:8]2[CH:7]=[CH:6][S:2][C:3]=2[CH2:4][CH2:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:23]
Reactant: COC(=O)C(Br)c1ccccc1Cl
Reactant: C1=CNC2CCSC2=C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1

Procedure:
Tetrahydrothienopyridine hydrochloride from Example 1 was reacted with α-bromo-2-chlorophenyl acetic acid methyl ester in acetone in the presence of potassium carbonate to give racemic clopidogrel. After inorganic salt filtration, the product was recovered as bisulfate, by addition of sulfuric acid.
Reaction SMILES: [F:1][CH:2]([F:33])[N:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([O:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:14])=[CH:9][CH:10]=2)[C:5]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=2[O:31][CH3:32])=[CH:4]1.Cl.C(N=C=N)C.[C:40]1([CH3:50])[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46]([NH2:49])(=[O:48])=[O:47].CO.C(Cl)Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:33][CH:2]([F:1])[N:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([O:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:14])=[CH:9][CH:10]=2)[C:5]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH:49][S:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[CH3:50])(=[O:47])=[O:48])=[O:28])=[CH:24][C:23]=2[O:31][CH3:32])=[CH:4]1
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C(F)F)c2ccc(NC(=O)OC3CCCC3)cc12
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C(F)F)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a solution of 4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (1.10 grams, 2.37 mmol), 4-dimethylaminopyridine (0.44 grams, 3.63 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1,2-dichloroethane) (0.70 grams, 3.64 mmol) in methylene chloride (100 mL) was added o-tolylsulfonamide (0.41 grams, 2.42 mmol). The resulting solution was stirred for 16 hours at room temperature. The solution was diluted with methylene chloride and washed with 1 M hydrochloric acid (ag) and brine. The organics were dried over sodium sulfate and concentrated. Chromatography on silica gel (5% methanol/methylene chloride gave 4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide (1.10 grams, 76% yield). HRMS calcd. for C31H31N3O6F2S: 611.1902. Found: 611.1924.
Reaction SMILES: [CH2:1]([C@H:3]1[C:7](=[O:8])[NH:6][C:5]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[S:4]1)[CH3:2].FC(F)(F)C(O)=[O:18].OO>O>[CH2:1]([CH:3]1[C:7](=[O:8])[NH:6][C:5]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[S@:4]1=[O:18])[CH3:2]
Reactant: CC[C@@H]1SC2(CCN(C)CC2)NC1=O
Reactant: O=C(O)C(F)(F)F
Agent: OO
Solvent: O
Product: CCC1C(=O)NC2(CCN(C)CC2)[S@]1=O
Temperature: 0 °C

Procedure:
A solution of AF267B (1.72 gr, 0.008 mol) in water (2.5 ml) was cooled (ice-water bath) and trifluoroacetic acid (3.5 ml) was added. To the cold stirred obtained mixture was added hydrogen peroxide (30%, 0.57 ml, 0.008 mol), the cooling bath was removed and the reaction mixture was stirred at room temperature over night Sodium sulfite was added and the pH of the solution was adjusted to 9 with a saturated solution of sodium carbonate. The aqueous phase was extracted with dichloromethan (2×100 ml) and then with ethyl acetate (1×50 ml). The organic extracts were combined, dried (MgSO4) and the solvent was evaporated. Flash chromatography (silica-gel 60, 230-400 mesh, Merck 1.09385, elution with methanol/chloroform/ammonium hydroxide 10:89:1 v/v) gave AF300. 1H NMR (CDCl3) δ 1.19 (t, j=7.3 Hz, 3H, CH3), 1.85-2.0 (m, 5H), 2.17 (m, 1H), 2.27 (m, 1H), 2.34 (s, 3H, NCH3), 2.6 (m, 2H), 3.30 (dd, j=3.56, 11.13 Hz,: CH3CH2CH), 6.37 (br NH) ppm; MS (EI) m/e 230 (M+).
Reaction SMILES: [CH2:1]([CH:5]([O:10][C:11]1[CH:28]=[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:20](=[O:27])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:13](=[C:14]23)[CH:12]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].[Br:29]N1C(=O)CCC1=O.CN(C=O)C>C(Cl)(Cl)Cl>[Br:29][C:28]1[C:11]([O:10][CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:12][C:13]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20](=[O:27])[C:19]3[C:14]=2[C:15]=1[CH:16]=[CH:17][CH:18]=3
Reactant: CC(C)CC(CC(C)C)Oc1cc2c3c(cccc3c1)C(=O)c1ccccc1-2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)CC(CC(C)C)Oc1cc2c3c(cccc3c1Br)C(=O)c1ccccc1-2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 500 ml three neck round bottom flask was equipped with a mechanical stirrer, heating mantle and condenser. To the flask was added 45 g (0.12 mole) of 2-(1-isobutyl-3-methylbutoxy)-7H-benzo[de]anthracene-7-one, 23.6 g (0.13 mole) N-bromosuccinimide and 265 g DMF. The mixture was agitated well, heated to 50° C. and held at 50° C. for two hours. Some of the DMF was stripped from the reaction using heat and vacuum and then 300 g chloroform were added to the flask. The resulting solution was washed three times with 250 g deionized water. The solvent was removed using a rotary evaporator; the yield was 52.5 g of a dark brown oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21]C)=O)[C:11](=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:24][NH2:25]>COCCO>[CH3:24][N:25]1[C:11](=[O:23])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]2[C:19](=[O:21])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:3]2[CH2:2]1
Reactant: COC(=O)c1ccccc1-n1c(CCl)nc2ccccc2c1=O
Reactant: CN
Solvent: COCCO
Product: CN1Cc2nc3ccccc3c(=O)n2-c2ccccc2C1=O
Yield: 82.5 %

Procedure:
16.4 g (0.05 mol) of 2-chloromethyl-3-(2-methoxycarbonyl-phenyl)-4H-quinazolin-4-one and 10 ml of liquid methylamine in 100 ml of ethylene glycol monomethyl ether are heated to 40° C. for 2 hours in an autoclave. After cooling the mixture, the colourless crystals are filtered off and washed several times with ethanol. 12 g (82.5% of theory) of 6-methyl-6,7-dihydro-5H,13H-quinazolino[3,2-a][1,4]benzodiazepine-5,13-dione are obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH:8]1[C:17]([OH:19])=O.C[N:21](C)C=O>O1CCCC1.O>[O:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH:8]1[C:17]([NH2:21])=[O:19]
Reactant: CN(C)C=O
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C1CCc2ccccc2O1
Temperature: 25 °C
Yield: 97 %

Procedure:
Oxalyl chloride (11.0 mL, 126 mmol) was added dropwise to a cooled (0° C.) solution of the compound from Example 20 (15 g, 84.3 mmol) and N,N-dimethylformamide (1 mL) in tetrahydrofuran (250 mL). Upon completion of gas evolution the mixture was warmed to room temperature and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (450 mL). The solution was cooled to -78° C. and ammonia condensed onto the mixture. After 30 minutes the mixture was warmed to room temperature, diluted with water, and extracted with ethyl acetate (2×). The combined organic phase was washed with saturated aqueous sodium chloride solution (2×), dried (MgSO4), and concentrated to give a solid. The solid was triturated with 1:1 diethyl ether/hexanes and dried at 50° C. in vacuo to give a colorless solid (14.5 g, 97%). Mp 125-127° C.; 1H NMR (acetone-d6, 300 MHz) δ 7.08 (m, 3 H), 6.86 (m, 2 H), 6.75 (br s, 1 H), 4.47 (dd, 9.2 Hz, 2.9 Hz, 1 H), 2.76 (m, 2 H), 2.28 (m, 1 H), 0.96 (m, 1 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:31])=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: C1COCCN1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)N2CCOCC2)cc1
Yield: 67.1 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with morpholine (available from Aldrich Chemical Company, Inc.; 54 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(morpholine-4-carbonyl)-biphenyl-2-carboxylic acid (76 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.44-7.51 (m, 4H), 3.60-3.67 (m, 4H), 3.26-3.30 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH3:15][NH:16][CH2:17][CH2:18][OH:19]>>[CH3:15][N:16]([CH2:17][CH2:18][OH:19])[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: CNCCO
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Product: Cc1oc(-c2ccccc2)nc1CN(C)CCO

Procedure:
The title compound was prepared from 4-chloromethyl-5-methyl-2-phenyloxazole (10 g) and 2-(methylamino)ethanol (36 ml) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].Cl.[CH3:9][NH:10][O:11][CH3:12].C(N(CC)CC)C>ClCCl>[CH3:12][O:11][N:10]([CH3:9])[C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1]
Reactant: CNOC
Reactant: CC(C)=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3,3-Dimethylacryloyl chloride (28.2 mL, 0.253 mol) was slowly added to a mixture of N,O-dimethylhydroxylamine hydrochloride (27.2 g, 0.278 mol) and triethylamine (75 mL, 0.519 mol) in dichloromethane (300 mL) at 0° to 30° C. and stirred 1 h at 0° C. The resultant mixture was washed with 1 N hydrochloric acid and then with 1 N sodium hydroxide and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue vacuum distilled (60° to 70° C. at 0.2 mm Hg) to give the product, 26.8 g (74%) as a colorless oil; IR(neat): 2938 and 1660 cm-1 : MS: m/z 144 (MH+); 1H NMR(CDCl3): δ 1.91 (d, J=1.2 Hz, 3H), 2.14 (d, J=0.9 Hz, 3H), 3.20 (s, 3H), 3.68 (s, 3H), and 6.12 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[NH:10][CH2:9]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].O.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[N:10]([C:28](=[O:31])[CH:29]=[CH2:30])[CH2:9]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CNc3c(ccc4ccccc34)S2)cc1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To a mixture of 3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (1.50 g), sodium hydrogen carbonate (1.0 g), methylene chloride (30 ml) and water (15 ml) is added dropwise with stirring a solution of acryloyl chloride (0.90 g) in methylene chloride (10 ml) under ice cooling. The mixture is stirred at room temperature for 3 hours. The organic layer is separated, washed, dried and distilled to remove the solvent. The residue is chromatographed on silica gel (toluene: acetone =50 : 1) to give 3-(4-chlorophenyl)-1-propenoyl-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (1.37 g, 78%) as powder.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)C(C)C)(C)C.[F:20][C:21]([F:36])([F:35])[C:22]([O:25][C:26](=O)[O:27]C1C=CC=CN=1)([CH3:24])[CH3:23]>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C@@H:2]([NH:1][C:26]([O:25][C:22]([CH3:24])([CH3:23])[C:21]([F:36])([F:35])[F:20])=[O:27])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(OC(=O)Oc1ccccn1)C(F)(F)F
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C(F)(F)F)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To an ice-cooled solution of (S)-methyl 2-amino-3,3-dimethylbutanoate (0.411 g, 2.262 mmol) in DCM (20 mL) was added N,N-Diisopropylethylamine (1.182 mL, 6.79 mmol). The formed solution was stirred for 5 min before addition of carbonic acid pyridin-2-yl ester 2,2,2-trifluoro-1,1-dimethyl-ethyl ester (1.24 g, 4.98 mmol, from step 1a) in DCM (10 mL). The final light yellow solution was stirred at room temperature overnight. The reaction mixture was washed with 5% citric acid aqueous solution, 0.1 M NaOH aqueous solution, and brine, then dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by silica gel column, eluted with (4:1) hexane-EtOAc to afford a colorless oil as the product (673 mg, 99%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:37])[N:16]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:17]2[C:22]([C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:13])[CH3:10]>>[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:37])[N:16]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:17]2[C:22]([C:23]=1[N:24]1[CH2:25][CH2:26][N:27]([C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:28][CH2:29]1)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1c(N2CCNCC2)c2cccnc2n(Cc2ccccc2)c1=O
Reactant: O=C(Cl)c1cccs1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cccnc2n(Cc2ccccc2)c1=O

Procedure:
In the above-described reaction, 2-thiophene carbonyl chloride is reacted with 1-benzyl-2-oxo-4-piperazin-1-yl-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester to yield the target compound, 1-benzyl-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester, depicted by formula (6) in Scheme 4. If it is preferred that the substitutent R is other than 2-thiophene, another carbonyl chloride compound can be substituted in the reaction.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=[O:14])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17]Br>C(O)(=O)C>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:16])[CH2:12][C:13]([CH2:15][Br:17])=[O:14])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CC(=O)Nc1nnc(C(C)(C)C)s1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(C)c1nnc(NC(=O)CC(=O)CBr)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A reaction flask was charged with 14.3 g (0.059 mole) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)acetoacetamide dissolved in 230 ml of acetic acid. With efficient stirring, there was added dropwise 9.4 g (0.059 mole) of bromine dissolved in 55 ml of acetic acid while controlling the temperature at 20°-25°. The reaction solution was allowed to stir overnight at ambient temperature. On the following morning a sample of the precipitated solids was withdrawn. By N.M.R. analysis, the material was determined to be the corresponding 2-bromoacetoacetamide, m.p. 128°-30°. The reaction mixture was heated at 75°-80° for twelve hours. The solution was cooled to 20° and the precipitated solid was collected on a vacuum filter. After washing the filter cake with water, the material was stirred with aqueous sodium bicarbonate. The product was isolated and dried. There was obtained 8.8 g (46.6%) of authentic N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-4-bromoacetoacetamide, m.p. 144°-46°. N.M.R. (CDCl3) ∂ 1.4 [C(CH3)3 ], 4.4 (CH2), 6.3 (CH, enol).