Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[O:11]C1C=CC=CC=1.O.[NH2:22][NH2:23]>C(O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([NH:22][NH2:23])=[O:11]
Reactant: O=C(Nc1ccccc1C(F)(F)F)Oc1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)Nc1ccccc1C(F)(F)F

Procedure:
Phenyl (2-trifluoromethylphenyl)carbamate (12.1 g) was dissolved in ethanol (150 mL). Hydrazine monohydrate (16.7 mL) was added and the mixture was heated under reflux for 2.25 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (7.5 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:29]=1.[C:31](OCC)(=[O:34])[NH:32][NH2:33]>>[CH3:1][C:2]1[C:3]([CH3:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8]3[N:7]([C:31](=[O:34])[NH:32][N:33]=3)[C:6]=2[CH:29]=1
Reactant: CCOC(=O)NN
Reactant: Cc1cc2c(cc1C)N(C(=O)CN1CCN(CCO)CC1)c1ncccc1C(=S)N2
Product: Cc1cc2c(cc1C)-n1c(n[nH]c1=O)-c1cccnc1N2C(=O)CN1CCN(CCO)CC1

Procedure:
In the manner given in Example 11, 8,9-dimethyl-6,11-dihydro-11-[[4-(2-hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione is heated to about 200° C. with ethyl carbazate to give 6,7-dimethyl-2,9-dihydro-9-[[4-(2-hydroxyethyl)piperazino]acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin- 3-one.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].[C:23](O)([CH3:26])([CH3:25])[CH3:24].C1CCN2C(=NCCC2)CC1.C([O-])(O)=O.[Na+]>CN(C=O)C>[OH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[C:13]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
CDI (2.40 g, 14.79 mmol) was added to a solution of salicylic acid (2.02 g, 14.62 mmol) in DMF (20 mL). The reaction mixture was stirred at 50° C. for 30 min and tert-butyl alcohol (2.80 mL, 29.84 mmol) and DBU (4.4 mL, 29.45 mmol) were dropwise added. The reaction mixture was stirred at 50° C. for 16 h and allowed to reach r.t. It was poured into NaHCO3 (100 mL, saturated aqueous solution) and extracted with EtOAc (70 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 2.089 g of tert-butyl 2-hydroxybenzoate (colourless oil, yield: 73%).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH2:8][CH3:9].[SH:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[N:12]=1.C(N(CC)CC)C>C(O)C>[CH2:8]([C:4]1[N:5]=[CH:6][S:7][C:3]=1[CH2:2][S:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]([F:21])([F:19])[F:20])[N:12]=1)[CH3:9]
Reactant: CCc1ncsc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A mixture of 5-(bromomethyl)-4-ethyl-1,3-thiazole (5.2 mmol), 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (700 mg, 3.6 mmol), and triethylamine (1.5 mL, 11 mmol) in absolute ethanol (40 mL) was stirred at room temperature overnight. The mixture was evaporated. The residue was treated with diethyl ether (100 mL). The solid material was removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-4% MeOH/CH2Cl2), affording the title compound (900 mg, 78% yield); 1H NMR (500 MHz, DMSO-d6): δ 1.19 (t, 2H, J=7.5 Hz), 2.76 (m, 2H, J=7.5 Hz), 4.65 (s, 2H), 6.65 (s, 1H), 8.88 (s, 1H); M+322.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:10]([OH:12])=O)=[CH:7][O:8][CH:9]=1)=[O:4].[F:13][C:14]([F:24])([F:23])[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[F:23][C:14]([F:13])([F:24])[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:10]([C:6]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:9][O:8][CH:7]=2)=[O:12])[CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cocc1C(=O)O
Reactant: Nc1cccc(SC(F)(F)F)c1
Product: COC(=O)c1cocc1C(=O)Nc1cccc(SC(F)(F)F)c1
Yield: 78 %

Procedure:
Methyl 4-(3-(trifluoromethylthio)phenylcarbamoyl)furan-3-carboxylate is prepared from 4-(methoxycarbonyl)furan-3-carboxylic acid and 3-(trifluoromethylthio) aniline following Method G (yield=78%). 1H NMR (300 MHz, CHCl3) δ 11.66 (s, 1H), 8.29 (s, 1H), 8.22-8.09 (m, 1H), 7.96-7.82 (m, 2H), 7.50-7.37 (m, 2H), 3.99 (s, 3H); ESI(−) calcd. for C14H9F3NO4S (344.02). Found 344.0
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([CH2:12][NH:13][C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[N:25]1.[OH-].[Li+]>ClCCl>[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([CH2:12][N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[S:29]([C:26]2[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=2)(=[O:31])=[O:30])=[CH:10][CH:9]=1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: Oc1cccc(NCc2ccc(Cl)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(O)c2)n1
Temperature: 50 °C
Reaction time: 48 h
Yield: 77.6 %

Procedure:
Pyridine (520 μl, 6.4 mmol) was added to a stirred solution of 3-(4-chloro-benzylamino)-phenol (500 mg, 2.2 mmol) and 1-methylpyrazole-3-sulfonyl chloride (181 mg, 4.5 mmol) in anhydrous dichloromethane (22 ml). The reaction was stirred under nitrogen at 50° C. for 48 hours and then quenched with water (50 ml). The reaction was extracted with dichloromethane (3×25 ml), and the organics combined, washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulphate and then concentrated in vacuo. The crude product was dissolved in a solution of tetrahydrofuran/methanol/water (1:1:1) (25 ml), treated with lithium hydroxide (271 mg, 6.45 mmol) and the mixture was stirred at 85° C. for 2 hours. The reaction was cooled, quenched with 2M hydrochloric acid (aq) until slightly acidic and extracted with ethyl acetate (2×50 ml). The organic extracts were combined, washed with water (100 ml), dried over anhydrous sodium sulphate and concentrated in vacuo to obtain a white solid (645 mg, 27% yield). HPLC retention time 5.59 min Mass spectrum (ES+) m/z 378 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[O:5][C:4](=[O:14])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:14][CH2:4][CH2:3][C:2]([C:11]1[C:10]([CH3:12])=[CH:9][C:8]([CH3:13])=[CH:7][C:6]=1[OH:5])([CH3:15])[CH3:1]
Reactant: Cc1cc(C)c2c(c1)OC(=O)CC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(C)(C)CCO)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
The product of Example 436A (4.00 g, 0.0196 mol) in tetrahydrofuran (75 mL) was added dropwise to a solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 20.6 mL, 0.0206 mol) in tetrahydrofuran (105 mL) at room temperature over a period of 30 minutes then stirred an additional one hour at ambient temperature. The stirred reaction was quenched by dropwise addition of saturated aqueous ammonium chloride (5 mL) after 15 minutes, the precipitate was removed by vacuum filtration. The filtrate was concentrated by rotary evaporation and the residue purified by silica gel flash chromatography eluting with 4:96 methanol/methylene chloride to afford the title compound as a white solid (2.94 g, 0.014 mol, 72%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.44 (s, 6 H) 2.00-2.07 (m, 2 H) 2.08 (s, 3 H) 2.36 (s, 3 H) 3.11-3.28 (m, 2 H) 4.09 (t, J=4.78 Hz, 1 H) 6.29 (s, 1 H) 6.42 (s, 1 H) 8.95 (s, 1 H). MS (ESI+) m/z 209 (M+H)−, 226 (M+NH4)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[C:8]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:21]O>C(=O)(O)[O-].[Na+]>[CH3:21][O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][C:7]1[C:8]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1
Reactant: CO
Reactant: NC(Cc1csc2ccc(Cl)cc12)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1csc2ccc(Cl)cc12
Temperature: 25 °C

Procedure:
To a mixture of 2-Amino-3-(5-chloro-benzo[b]thiophen-3-yl)-propionic acid (255.7 mg, 1.0 mmol) in methanol was added thionyl chloride (0.08 mL) at 0° C. The resulting mixture was heated at reflux for 7 h, allowed to cool to room temperature, diluted with saturated sodium bicarbonate and extracted with ethyl acetate (2×30 mL). The organic extracts were combined, washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oil (2-amino-3-(5-chloro-benzo[b]thiophen-3-yl)-propionic acid methyl ester).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>O1CCCC1.[Pd]>[NH2:17][C:16]1[C:7]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCCCCO
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N)c1NCCCCO
Yield: 98.8 %

Procedure:
A solution of methyl 2-[(4-hydroxybutyl)amino]-3-nitrobenzoate (66.5 g, 248 mmol) in tetrahydrofuran (1600 mL) was stirred in the presence of 10% palladium on carbon (50% wet; 6.80 g) under hydrogen atmosphere at room temperature for 5 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (58.4 g, 245 mmol, 99%).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].N12CC3CC(CC(C3)C1)C2.O.[C:27]([O-])([O-])=[O:28].[K+].[K+]>C(O)(C(F)(F)F)=O>[C:10]1([C:2]([C:4]2[CH:9]=[CH:8][C:7]([CH:27]=[O:28])=[CH:6][CH:5]=2)([CH3:1])[CH3:3])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: C1C2CC3CC1CN(C2)C3
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(c1ccccc1)c1ccc(C=O)cc1
Temperature: 100 °C

Procedure:
A suspension of propane-2,2-diyldibenzene (3.93 g, 20 mmol) and 1-aza-tricyclo[3.3.1.1*3,7*]decane (2.80 g, 20 mmol) in TFA (35 mL) was heated at 100° C. for 16 h. The reaction mixture was allowed to cool to RT, poured onto cold water and made alkaline (pH=9) with solid K2CO3. The aqueous solution was extracted with Et2O (3×250 mL) and the separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether:EtOAc 95:5) affording the title compound (3.47 g, 15.46 mmol).
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6].[CH3:8][C:9]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N:17]=[C:18]=[O:19]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:6][CH2:5][C:4]([O:7][C:18](=[O:19])[NH:17][C:10]1[CH:11]=[CH:12][C:13]([S:15][CH3:16])=[CH:14][C:9]=1[CH3:8])=[N:3][O:2][CH3:1]
Reactant: CSc1ccc(N=C=O)c(C)c1
Reactant: CONC(=O)CCl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CON=C(CCl)OC(=O)Nc1ccc(SC)cc1C
Temperature: 25 °C

Procedure:
N-Methoxychloroacetamide (12.3 grams; 0.1 mole), benzene (60 ml) and dibutyltin dilaurate (1 drop) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Methyl-4-methylthiophenylisocyanate (21.5 grams; 0.12 mole) dissolved in benzene (30 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-[N-(2-methyl-4-methylthiophenyl)carbamoyloxy]-2-methoxyiminoethane.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([NH:22][C:23]([C:25]2[C:26]([CH3:32])=[N:27][N:28]([CH3:31])[C:29]=2[CH3:30])=[O:24])[CH:10]=[CH:11][C:12]=1[CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:4]([CH3:6])[CH3:5].[C:33](Cl)(=[O:35])[CH3:34].Cl>O1CCCC1>[C:33]([N:22]([C:9]1[CH:10]=[CH:11][C:12]([CH:13]([C:14]([F:17])([F:15])[F:16])[C:18]([F:19])([F:20])[F:21])=[C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=1)[C:23]([C:25]1[C:26]([CH3:32])=[N:27][N:28]([CH3:31])[C:29]=1[CH3:30])=[O:24])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1nn(C)c(C)c1C(=O)Nc1ccc(C(C(F)(F)F)C(F)(F)F)c(CC(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C(=O)c1c(C)nn(C)c1C)c1ccc(C(C(F)(F)F)C(F)(F)F)c(CC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
Sodium hydride (38 mg, 60%, 0.96 mmol) was suspended in tetrahydrofuran (10 ml), and a solution of N-{3-isobutyl-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl}-1,3,5-trimethylpyrazole-4-carboxamide (300 mg, 0.64 mmol) in tetrahydrofuran (5 ml) was added dropwise. After stirring at room temperature for 30 min, a solution of acetyl chloride (75 mg, 0.96 mmol) in tetrahydrofuran (2 ml) was added, and the mixture was stirred for one day. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to give the desired compound (90 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3](=O)[CH2:4][CH3:5].[CH3:9][C@@H:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>C1C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[C:11]1([C@H:10]([NH:17][C@H:3]([CH2:4][CH3:5])[C:2]([CH3:8])([CH3:7])[CH3:1])[CH3:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC(=O)C(C)(C)C
Reactant: C[C@@H](N)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC[C@@H](N[C@H](C)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54505 %

Procedure:
NH2 --(R)--CH(Et)CMe3 : To a cooled solution (0°) of 4,4-dimethyl-3-pentanone (106 g, 0.92 mmol) and (R)-α-methylbenzylamine (111 g, 0.92 mmol) in benzene (1 L), a solution of TiCl4 (50.5 mL, 0.46 mmol) in benzene (200 mL) was added at a rate that kept the temperature of the mixture below 10°. Thereafter, the mixture was stirred mechanically for 3 h at 40°, cooled to room temperature and filtered through diatomaceous earth. The diatomaceous earth was washed with Et2O. The combined filtrate and wash was concentrated. The residue was dissolved in dry MeOH (2 L). The solution was cooled to 0° and NaBH4 (20 g, 0.53 mmol) was added portionwise while maintaining the temperature of the mixture below 5°. The methanol was evaporated. The residue was dissolved in Et2O. The solution was washed with brine, dried (MgSO4) and evaporated to dryness to give a reddish oil (a 18:1 mixture of diastereoisomers as indicated by NMR). The oil was purified by flash chromatography (SiO2, eluent: EtOAc/hexane, 7:93) to afford N-(1(R)-phenylethyl)-1(R)-ethyl-2,2-dimethylpropyl-amine as a liquid (110 g, 54%). This material was dissolved in hexane (1.5 L). 6N HCl in dioxane (90 mL) was added to the solution over a period of 15 min. The resulting white solid was collected on a filter and then washed with hexane to provide N-(1(R)-phenyl-ethyl)-1(R)-ethyl-2,2-dimethylpropylamine hydrochloride (125 g, 97%). 1H NMR(CDCl3) δ 0.55 (t, J=7.5 Hz, 3H), 1.14 (s, 9H), 1.54-1.95 (m, 2H), 2.23 (d, J=6.5 Hz, 3H), 2.36-2.44 (m, 1H), 4.31-4.49 (m, 1H), 7.30-7.48 (m, 3H), 7.74-7.79 (m, 2H).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([O-:7])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][C:17]=1[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1)=[O:26].Cl>C(Cl)(Cl)Cl.CN(C)C=O.N1C=CC=CC=1>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:25]([C:17]2[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:16]=2[NH:15][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]([O:9][CH3:10])=[O:8])=[O:26])=[N:29][CH:30]=1
Reactant: Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Reactant: COC(=O)CCCC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)CCCC(=O)Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
Monomethyl glutarate (3.32 g) is dissolved in chloroform (50 ml) and thereto are added thionyl chloride (1.75 ml) and N,N-dimethylformamide (one drop). After stirring for 1.5 hours at the same temperature, the reaction solution is cooled, and thereto are added 3-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (5.00 g) obtained in Reference Example 80 and pyridine (7.0 ml). After stirring for 2.5 hours at room temperature, the reaction solution is poured into 5% hydrochloric acid and extracted with chloroform. The organic layer is washed successively with saturated brine, a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in diisopropyl ether and the precipitates are collected by filtration to give methyl 5-[(2-{[(5-chloropyridin-2-yl)amino]carbonyl}benzofuran-3-yl)amino]-5-oxopentanoate (6.16 g). APCI-MS M/Z:416/418[M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:33])([CH3:32])[C:14]([C:16]2[S:17][C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:19][C:20]=2[CH3:21])=O)=[CH:9][C:8]=1[CH3:34])[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:32])([CH3:33])[CH2:14][C:16]2[S:17][C:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=3)=[CH:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:34])[CH3:2]
Reactant: CCOC(=O)COc1ccc(C(C)(C)C(=O)c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc(C(C)(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1C
Temperature: 50 °C

Procedure:
To a reactivial containing ethyl[4-(1,1-dimethyl-2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}-2-oxoethyl)-2-methylphenoxy]acetate (intermediate 106, 36 mg) was added trifluoroacetic acid (0.22 ml) and triethylsilane (0.11 ml). The vial was then sealed and heated at 50° C. for 18 hours. The reaction was then allowed to cool to room and concentrated in vacuo. Purification by flash column chromatography eluting cyclohexane-1% EtOAc/cyclohexane yielded the title compound as a colourless oil.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])[S:10][C:9]=12.[NH2:38][C:39]([NH2:41])=[S:40]>C(#N)C.CN(C=O)C>[OH:35][C@@H:33]([C@H:32]1[C:31](=[O:36])[N:16]2[C:17]([C:18]([OH:20])=[O:19])=[C:13]([C:11]3[S:10][C:9]4=[C:5]([S:4][CH2:3][CH2:2][NH:41][C:39](=[NH:38])[SH:40])[N:6]=[CH:7][N:8]4[CH:12]=3)[C@H:14]([CH3:37])[C@H:15]12)[CH3:34]
Reactant: NC(N)=S
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCBr)c4s3)[C@H](C)[C@H]12
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(c3cn4cnc(SCCNC(=N)S)c4s3)[C@H](C)[C@H]12
Temperature: 50 °C
Reaction time: 18 h
Yield: 14.7 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-(2-bromoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (128 mg) was dissolved in 3 ml of acetonitrile and 0.5 ml of DMF. Thiourea (222 mg) was added to the solution. The mixture was stirred at 50° C. for 18 hr. The reaction solution was concentrated under the reduced pressure. The residue was purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1), followed by a reaction and purification in the same manner as in Example 1c). Thus, 14.5 mg of the title compound was prepared.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:11][CH3:12])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])[CH3:2].[Br:13]N1C(=O)CCC1=O>CO>[Br:13][C:7]1[C:8]([CH3:9])=[C:3]([CH2:1][CH3:2])[C:4]([O:11][CH3:12])=[N:5][C:6]=1[CH3:10]
Reactant: CCc1c(C)cc(C)nc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: CCc1c(OC)nc(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
A mixture of 3-ethyl-2-methoxy-4,6-dimethylpyridine (265 mg, 1.61 mmol), N-bromosuccinimide (346 mg, 1.93 mmol) and methanol (5 mL) is stirred at room temperature for 5 hr. The solvent is removed and the residue is purified by chromatography eluting with dichloromethane. Product containing fractions are combined and concentrated to afford 5-bromo-3-ethyl-2-methoxy-4,6-dimethylpyridine (285 mg, 73%) as a white semi-solid. LC/MS: MS m/e=244/246 (M+H); RT 4.78 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22]Cl)=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:27][OH:28]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][O:28][CH3:27])=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1c(CCl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Reactant: CO
Product: COCc1c(C)n(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O
Temperature: 60 °C

Procedure:
1.14 g of isopropyl 2-chloro-4-fluoro-5-[5-chloromethyl-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate are dissolved in 10 ml of methanol and the solution is heated at 60° C. for 45 minutes. The reaction mixture is evaporated to dryness under reduced pressure and the residue is dissolved in ethyl acetate and shaken with aqueous sodium bicarbonate solution. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure, and the residue is purified by chromatography on a silica gel column using diethyl ether/ethyl acetate (15:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-methoxymethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.82 ppm (d, 1H), 7.33 ppm (d, 1H), 5.23 ppm (m, 1H), 4.40 ppm (d, 1H), 4.33 ppm (d, 1H), 3.49 ppm (s, 3H), 3.39 ppm (s, 3H), 2.43 ppm (s, 3H), 1.35 ppm (d, 6H).
Reaction SMILES: COC1C=CC([C@@H]2C(=O)N([C@@H]([C@H](C3C=CC=CC=3)C)C([NH:18][C:19]3[S:20][CH:21]=[C:22]([C:24](=[O:27])CC)[N:23]=3)=O)C(=O)N2)=CC=1.[CH3:37][O-:38].[Na+]>CO>[CH3:37][O:38][C:24]([C:22]1[N:23]=[C:19]([NH2:18])[S:20][CH:21]=1)=[O:27]
Reactant: C[O-]
Reactant: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OC)cc3)C2=O)n1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1csc(N)n1

Procedure:
2-Amino-thiazole-4-carboxylic acid ethyl ester (38 g) (prepared as described in Example 4) in methanol (400 mL) was cooled in an ice bath and to it was added 25% sodium methoxide over 0.5 hours. The ice bath was removed after 0.5 hours. A small amount of isoluble material was removed by filtration and to the yellow solution was added saturated aqueous ammonium chloride and the reaction mixture concentrated to remove excess methanol. The mixture was basified to pH=9.0 with saturated aqueous sodium bicarbonate and extracted with 1:1 ether/tetrahydrofuran (3×200 mL). The combined organic extracts were washed with water. The organic solution was dried over sodium sulfate and concentrated to give a pale yellow solid which still contained some residual solvent. The solid was suspended in hexanes, filtered on a 5.5 cm funnel then dried in vacuo to give 2-amino-thiazole-4-carboxylic acid methyl ester (15.6 g) as a pale yellow solid.