Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N(CC)CC)C.[CH2:14]([O:16][CH2:17]Cl)[CH3:15]>ClCCl>[C:1]([O:6][CH2:17][O:16][CH2:14][CH3:15])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCOCCl
Reactant: C=C(C)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCOCC
Yield: 90.5 %

Procedure:
To a 500-mL, 3-necked round bottomed flask equipped with a thermocouple temperature monitor, 250-mL addition funnel, nitrogen inlet and a magnetic stirrer was added 150 mL of dichloromethane, and 18.9 g (0.22 mol) of methacrylic acid. The addition funnel was charged with a mixture of 22.3 g (0.23 mol) of triethylamine and 25 mL of dichloromethane which was then added in a thin stream to the flask with stirring in an ice-bath. Upon completion of the addition, the addition funnel was recharged with a mixture of 18.9 g (0.2 mol) of chloromethyl ethyl ether and 25 mL of dichloromethane which was subsequently added dropwise to the reaction mixture with cooling over about 15 minutes. The ice bath was removed and the mixture stirred at room temperature overnight. The resulting suspension was filtered and the filtrate washed several times with saturated bicarbonate, water and brine and dried over anhydrous magnesium sulfate. Filtration and removal of the solvent by evaporation on a rotary evaporator provided 26.1 g of a yellowish oil which was distilled at reduced pressure to provide 20.3 g (70%) of the title compound as a clear, colorless oil.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([CH3:20])=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1)C.[C:24]1([C:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([CH3:34])[CH:31](O)[OH:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:24]1([C:30]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:31][O:32][CH:4]([C:5]3[CH:6]=[CH:7][C:8]([CH:11]=[CH:12][C:13]([CH3:20])=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=3)[O:3][CH2:34]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(c1ccccc1)(c1ccccc1)C(O)O
Reactant: CCOC(=O)C=C(C)C=Cc1ccc(C(OCC)OCC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(C)C=Cc1ccc(C2OCC(c3ccccc3)(c3ccccc3)CO2)cc1

Procedure:
The following are placed in a 250 ml reactor fitted with Dean-Stark apparatus: 70 ml of toluene, 3.5 g (0.011 M) of ethyl 5-(4-diethoxymethylphenyl)-3-methylpenta-2,4-dienoate, 5.0 g (0.011 M) of 2,2-diphenylpropanediol and finally 0.5 g of para-toluenesulphonic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[O:17]1CCC[CH2:18]1.C([Li])CCC>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH:18]=[O:17])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(-c2cc3ccccc3s2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2sc3ccccc3c2C=O)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(4-methylphenyl)benzo[b]thiophene (896 mg) in freshly distillated tetrahydrofuran (15 ml) was added n-butyllithium (2.75 ml, 1.6 mol solution in n-hexane) through a syringe at -78° C. The solution was stirred at -78° C. for 10 minutes and then at ambient temperature for half an hour. To the deep red colored solution was added N,N-dimethylformamide (365mg) at 5° C. The mixture was stirred at ambient temperature for one hour, quenched with aqueous saturated ammonium chloride solution, and extracted with diethyl ether. The organic layer was washed with aqueous saturated ammonium chloride solution, dried, and concentrated in vacuo to give a yellow residue, which was purified by flash column chromatography on silica gel eluted with 50% n-hexane in dichloromethane to yield 2-(4-methylphenyl)benzo[b]thiophene-3-carbaldehyde (285 mg) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].O[C:13]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][C:14]=1[CH:15]=O.C1(P(Cl)(Cl)=O)C=CC=CC=1.C(N(CC)CC)C>ClCCCl>[CH3:24][O:23][C:19]1[C:20]([O:21][CH3:22])=[C:13]2[C:14]([CH:15]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9](=[O:11])[O:10]2)=[CH:17][C:18]=1[N+:25]([O-:27])=[O:26]
Reactant: Cc1ccccc1CC(=O)O
Reactant: COc1c([N+](=O)[O-])cc(C=O)c(O)c1OC
Agent: O=P(Cl)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1c([N+](=O)[O-])cc2cc(-c3ccccc3C)c(=O)oc2c1OC

Procedure:
A mixture of 2-methylphenyl acetic acid (0.60 g), 2-hydroxy-3,4dimethoxy-5-nitro-benzaldehyde (0.91 g), PhPOCl2 (0.60 ml) and triethyl amine (1.7 ml) were reacted in 1,2-dichloroethane as described in example 4. Yield: 0.68 g.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(#N)C>C(N(CC)CC)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:37](=[O:46])[C:38]2=[CH:45][CH:44]=[CH:43][CH:42]=[C:39]2[C:40]1=[O:41])=[O:25])[CH3:28]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Reactant: CCOC(=O)C(Br)CCCCCCCN1C(=O)c2ccccc2C1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 13.4 %

Procedure:
A mixture of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine-5-acetate (2.1 g), ethyl 2-bromo-9-phthalimidononanoate (3 g), acetonitrile (100 ml) and triethylamine (0.96 g) is heated at 80° C. for 3 days. After evaporation of the solvent, ethyl acetate (200 ml) and water (150 ml) are added to the residue. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily residue is chromatographed on silica gel using hexane-ethyl acetate (2:1-1:1) as an eluent. Evaporation of the first eluate gives tert-butyl 3(S)-[1(R)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.6 g) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22]CC)=[O:21])[O:14][N:13]=1.O>O1CCOCC1>[F:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([OH:22])=[O:21])[O:14][N:13]=1
Reactant: CCOC(=O)[C@@](C)(CCc1cc(-c2cccc(OC)c2F)no1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2cc(CC[C@](C)(C(=O)O)S(C)(=O)=O)on2)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
Sodium hydroxide (1.0 M aqueous solution, 4.7 mL, 4.7 mmol, 4.0 equiv) was added to solution of ethyl(2R)-4-[3-(2-fluoro-3-methoxyphenyl)isoxazol-5-yl]-2-methyl-2-(methylsulfonyl)butanoate (0.47 g, 1.2 mmol, 1.0 equiv) in 1,4-dioxane (10 mL), and the reaction was allowed to stir overnight (18 h) at room temperature. Water (5 mL) was added, and the mixture was extracted with diethyl ether (25 mL). The aqueous phase was acidified to pH=3 with 1.0 M hydrochloric acid and then extracted with ethyl acetate (2×50 mL). The combined ethyl acetate phases were dried over potassium carbonate, filtered and concentrated under reduced pressure to provide a light tan solid (0.42 g, 96%). MS (LCMS) m/z 372.1 (M+1). 1H NMR (400 MHz, METHONAL-d4) δ1.68 (s, 3H) 2.26-2.41 (m, 1H) 2.61-2.74 (m, 1H) 2.85-3.00 (m, 1H) 3.04-3.15 (m, 1H) 3.16 (s, 3H) 3.92 (s, 3H) 6.65 (d, J=3.12 Hz, 1H) 7.18-7.24 (m, 2H) 7.36-7.44 (m, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:20]([NH2:21])[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[CH:37](OCC)[CH2:38][N:39]=[C:40]=[N:41][Si](C)(C)C)C>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:20]([NH:21][C:40]3[NH:39][CH:38]=[CH:37][N:41]=3)[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: CCOC(CN=C=N[Si](C)(C)C)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1
Reaction time: 0.17 h
Yield: 42 %

Procedure:
To a stirred solution of t-butyl 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate (164 mg.) in anhydrous CH2Cl2 at room temperature was added a molar solution of anhydrous toluene-p-sulphonic acid in CH2Cl2 (0.5 ml.) and then 1-(2,2-diethoxyethyl)-3-trimethylsilylcarbodiimide (125 μl.). Stirring was continued for 10 minutes and the solvent was evaporated. The residue, t-butyl 3-acetoxymethyl-7-[2-(2,2-diethoxyethyl)-3-trimethylsilyl]guanidinoceph-3-em-4-carboxylate, was dissolved in acetonitrile and 12N aqueous HCl (42 μl.) added. The mixture was stirred for 1.5 hours at room temperature, and the solvent evaporated. To the residue, t-butyl 3-acetoxymethyl-7-(imidazol-2 -yl)aminoceph-3-em-4-carboxylate, was added trifluoracetic acid and the mixture was stirred for 15 minutes. The solvent was evaporated and the residue was precipitated from a solution in the minimum of CH2Cl2 with ether. The precipitate was dissolved in CH2Cl2 /MeOH and the solvent evaporated to give 3-acetoxymethyl- 7-(imidazol-2-yl)aminoceph-3-em-4-carboxylic acid (262 mg. of 42% strength), identical with the product obtained in Example 2 (yield from 7-amino derivative 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C[C:11]1[CH:12]=[C:13]([CH:15]=[C:16](C)[CH:17]=1)N>>[CH3:9][C:8]1[CH:7]=[CH:6][C:4]([NH:5][C:11]2[CH:12]=[CH:13][CH:15]=[CH:16][CH:17]=2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1ccc(N)cc1C
Reactant: Cc1cc(C)cc(N)c1
Product: Cc1ccc(Nc2ccccc2)cc1C
Yield: 84 %

Procedure:
The procedure of Example IV is repeated with the exception that 3,4-dimethylaniline was substituted for 3,5-dimethylaniline. After a reaction time of 3.5 hours, the crude reaction product was recrystallized once from hexane to give an 84 percent yield of 3,4-dimethyldiphenylamine having a melting point of 55°-55.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=[O:24])=[CH:17]2)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.FC(F)(F)C(O[C:40]1[C:45]([F:46])=[C:44]([F:47])[C:43]([F:48])=[C:42]([F:49])[C:41]=1[F:50])=O>CN(C=O)C>[F:46][C:45]1[C:40]([O:24][C:23]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:12](=[O:13])[NH:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:22][CH:21]=3)=[O:25])=[C:41]([F:50])[C:42]([F:49])=[C:43]([F:48])[C:44]=1[F:47]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 32 (0.154 g, 0.44 μmol) in DMF (5 mL) in the presence of DIEA (93 ml, 0.53 mmol) was added dropwise pentafluorophenyl trifluoroacetate (92 μl, 0.53 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature overnight. HPLC showed that the reaction was completed. The solvent was then evaporated to dryness, and the residue was carefully washed with ether to give compound 33 in quantitative yield.
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[CH2:14][CH2:13][C:6]2=[C:7]([C:10]([OH:12])=[O:11])[S:8][CH:9]=[C:5]2[CH2:4]1)[CH3:2].[Li][CH2:18]CCC.CI>CC#N>[CH2:15]([C:3]1([CH2:1][CH3:2])[CH2:14][CH2:13][C:6]2=[C:7]([C:10]([OH:12])=[O:11])[S:8][C:9]([CH3:18])=[C:5]2[CH2:4]1)[CH3:16]
Reactant: CCC1(CC)CCc2c(csc2C(=O)O)C1
Reactant: [Li]CCCC
Solvent: CC#N
Solvent: CI
Product: CCC1(CC)CCc2c(C(=O)O)sc(C)c2C1

Procedure:
5,5-Diethyl-3-methyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid is prepared from 5,5-diethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid by treatment with tert.-BuLi followed by methyliodide in analogy to Example C; LC-MS: tR=1.03 min, [M+1+CH3CN]=294.27.
Reaction SMILES: C([O:8][C:9](=[O:28])[C@@H:10]([NH:14][C:15](=[O:27])[C@@H:16]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH3:17])[CH:11]([CH3:13])[CH3:12])C1C=CC=CC=1.[OH-].[Li+]>C1COCC1.CO.O>[C:23]([O:22][C:20]([N:18]([CH3:19])[C@@H:16]([CH3:17])[C:15]([NH:14][C@@H:10]([CH:11]([CH3:12])[CH3:13])[C:9]([OH:28])=[O:8])=[O:27])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.7 %

Procedure:
(S)-2-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyric acid benzyl ester (7 g, 18 mmol) and 1 M aqueous lithium hydroxide (40 mL, 40 mmol) was added to THF/MeOH/H2O (3:1:1; 200 mL) to give a yellow solution. The reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was dissolved in water and then acidified to pH 2 using first 6 M and then 1 M aqueous HCl. The mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to give crude (S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyric acid (5.7 g) which was used directly in the next step without further purification, m/z=303 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([S:24]C#N)[CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:13])[CH2:3]1.SCC(C(CS)O)O>P([O-])(O)(O)=O.[K+]>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([SH:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:13])[CH2:5]1
Reactant: C[C@@H]1CN(CCNC(=O)Nc2nc3ccc(SC#N)cc3s2)C[C@H](C)O1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Product: C[C@@H]1CN(CCNC(=O)Nc2nc3ccc(S)cc3s2)C[C@H](C)O1
Yield: 99.6 %

Procedure:
The 1-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea was prepared according to the method described in Example 1 b, but using 640 mg of 2-[({2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}carbamoyl)amino]-1,3-benzothiazol-6-yl thiocyanate, 7 mg of potassium dihydrogen phosphate and 729 mg of DL-dithiothreitol. 597 mg of 1-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C.O>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: NCc1ccccn1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Reaction time: 1 h

Procedure:
A mixture of 2,4-Dichloro-5-phenyl-thieno[2,3-d]pyrimidine (1.77 g, 6.3 mmol), 2-aminomethylpyridine (Aldrich, 782 μl, 7.6 mmol), and triethylamine (VWR, 1.06 ml, 7.63 mmol) were refluxed in ethanol (30 ml) for 3 hrs. On cooling, the reaction was poured into water (300 ml) and stirred for 1 hr. The resulting precipitate was filtered, washed with water (2×30 ml) and dried under vacuum at 40° C. to give (2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine as a pale-yellow solid. Yield=(1.55 g, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18]>C(O)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:17][OH:18])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C(c1ccccc1)c1ccc(Br)cc1
Yield: 94 %

Procedure:
A mixture of 4-bromobenzophenone (10.0 g, 0.0383 mol) and hydroxylamine hydrochloride (13.3 g, 0.192 mol) was heated in a mixture of ethanol (250 mL) and pyridine (50 mL) at reflux for 2 hours under an atmosphere of nitrogen. The solvents were removed under the reduced pressure and the residue was partitioned between water (300 mL) and dichloromethane (300 mL). The water phase was further extracted with dichloromethane twice (180 mL each) and the combined organic extracts were dried over magnesium sulfate. The solvent was removed under the reduced pressure and the residue was purified by flash chromatography on silica gel using ethyl acetate/n-heptane (1:9) as mobile phase to yield (4-bromophenyl)(phenyl)methanone oxime as a white solid (9.93 g, 0.036 mol): 1H NMR (DMSO-d6, 400 MHz) 7.66 (d, 1H), 7.57(d, 1H), 7.33 (m, 7H)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[CH:30][C:16]=1[O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:35][CH2:34][C:32]3[CH:31]=[CH:30][C:16]([O:17][C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:27])([F:28])[F:29])[CH:19]=4)=[C:15]([F:14])[CH:33]=3)[CH:3]=2)[CH2:9][CH:10]1[CH3:13]
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2F)cc1C(F)(F)F
Product: CC1Cn2c(cc(OCc3ccc(Oc4ccc(C#N)c(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and 4-(2-fluoro-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile.
Reaction SMILES: [C:1]([S:4][C@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:30])[C:16]([C:20]1[N:21]=[C:22]([NH:25]C(=O)CCl)[S:23][CH:24]=1)=[N:17][O:18][CH3:19])(=[O:3])[CH3:2].[Na+:31].C(=S)(SC)N.[Na]>O>[C:1]([S:4][C@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:30])[C:16]([C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1)=[N:17][O:18][CH3:19])(=[O:3])[CH3:2].[Na+:31]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1SC(C)=O)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1SC(C)=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.7 %

Procedure:
To a solution of 0.10 g of sodium (3R,4R)-4-acetylthio-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate in 5 ml of water is added under ice-cooling 0.030 g of sodium monomethyl dithiocarbamate, and the mixture is stirred for 3 hours at room temperature. The same procedure as Example 3B yields 0.016 g of sodium (3R,4R)-4-acetylthio-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[CH2:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]=[O:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=CNc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CNc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Reaction time: 1.25 h

Procedure:
To a solution of N-(2-hydroxy-5-nitrophenyl)-formamide (26 g, 0.143 mol) in DMF (180 mL) is added potassium carbonate (22 g, 0.159-mol), followed by benzyl bromide (27 g, 0.158 mol) at 60° C. The mixture is stirred for 1.25 h. The mixture is diluted with water. The precipitated solid is separated by filtration and washed with 1N HCl, water and hexanes, and air dried for 18 h to afford N-(2-benzyloxy-5-nitrophenyl)-formamide as a white solid: (M−H)−=271.1.
Reaction SMILES: [CH:1]([CH2:3][C:4]([O:6]C(=O)CC=O)=[O:5])=O.[OH:12][C:13]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:14]=1[C:15]([CH2:17][C:18]#[N:19])=[O:16]>N1C=CC=CC=1>[C:4]([OH:6])(=[O:5])[CH3:3].[OH:24][C:22]1[CH:21]=[CH:20][C:14]2[C:15](=[O:16])[C:17]([C:18]#[N:19])=[CH:1][O:12][C:13]=2[CH:23]=1
Reactant: N#CCC(=O)c1ccc(O)cc1O
Reactant: O=CCC(=O)OC(=O)CC=O
Solvent: c1ccncc1
Product: CC(=O)O
Product: N#Cc1coc2cc(O)ccc2c1=O
Temperature: -10 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To a mixture of 105 g (1.2 mol) of formyl acetic anhydride and 40 ml of pyridine cooled to -10°C was added 16.5 g (0.1 mol) of 2,4-dihydroxybenzoylacetonitrile. This mixture was stirred overnight, allowing the reaction to warm to room temperature. The mixture was evaporated in vacuo and the residue was triturated with ethanol and filtered to give 23.3 g of crude material. Recrystallization of this solid from absolute ethanol gave 5.3 g of 7-hydroxy-4-oxo-4H-1-benzopyran-3 -carbonitrile acetate, mp 178°-180°C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[K].[CH3:16]C(C)([O-])C.CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH3:16][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[C:8]([C:13]#[N:14])=[CH:9]1
Reactant: N#Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Reactant: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: Cn1cc(C#N)c2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h

Procedure:
1.6 g 6-nitro-1H-indole-3-carbonitrile are dissolved in 45 ml of tetrahydrofuran, combined with 1 g potassium-tert.-butoxide and stirred for 30 minutes. Then a solution of 560 μl methyl iodide in 5 ml of tetrahydrofuran is slowly added dropwise and the mixture is stirred for 5 hours. The solvents are eliminated in vacuo, water is added and the pH is adjusted to 4 by the addition of citric acid. The solid is suction filtered and washed with water and some cold methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:7][C:6]=2[CH:25]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].P(OCC)(OCC)[O:37]CC>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([OH:37])([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:7][C:6]=2[CH:25]=1
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)C1C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C1(O)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A solution of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (15 g, 41.7 mmole) in 780 ml of tetrahydrofuran was cooled to -78° C. and 147 ml (167 mmole in tetrahydrofuran) of potassium hexamethyldisilazide solution was added. After stirring for 1 hour, 28.7 ml of triethyl phosphite (166.7 mmole) was added and anhydrous oxygen gas was rapidly bubbled through the resulting solution. The reaction temperature was then raised to 0° C. and allowed to stir for an additional hour. Oxygenation was then discontinued and the reaction was quenched by the addition of 50 ml of acetic acid. The reaction mixture was then concentrated and the residue dissolved in ethyl acetate. The organic solution was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate, and brine and then dried over anhydrous sodium sulfate. Concentration of the dried organic solution afforded a solid which, upon trituration in hexane, gave 14.8 g of the title compound.