Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:34])[N:11]([CH:21]2[CH2:33][CH2:32][C:24]3([O:28][C@H:27]4[CH2:29][O:30][CH2:31][C@H:26]4[O:25]3)[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].C([BH3-])#N.[Na+].O1CCCC1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:34])[N:11]([C@H:21]2[CH2:22][CH2:23][C@H:24]([O:25][C@H:26]3[C@@H:27]([OH:28])[CH2:29][O:30][CH2:31]3)[CH2:32][CH2:33]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)O[C@H]2COC[C@H]2O3)c2ncnn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O[C@@H]3COC[C@@H]3O)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of 3′-fluoro-4′-({5-oxo-7-propyl-4-[(3a′R,6a′S)-tetrahydrospiro[cyclohexane-1,2′-furo[3,4-d][1,3]dioxol]-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.3 g), sodium cyanoborohydride (2.9 g), boron trifluoride-diethyl ether complex (5.9 mL) and tetrahydrofuran (50 mL) was stirred at 70° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.39 g, 30%).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([O:13][CH2:14][O:15][CH3:16])[CH:5]=1)([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+].C(=O)=O>O1CCCC1.CO>[CH:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[C:6]([O:13][CH2:14][O:15][CH3:16])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: COCOc1cc(C(C)C)ccc1C(=O)O
Agent: CCOC(=O)Cl
Agent: O=C=O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: COCOc1cc(C(C)C)ccc1CO
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
To a solution of 4-isopropyl-2-(methoxymethoxy)benzoic acid, which may be prepared as described in Exmple 6-B, (2.40 g, 11.0 mmol) and 4-methylmorpholine (1.18 mL, 11.0 mmol) in 50 mL dry tetrahydrofuran at −10° C. was added dropwise ethyl chloroformate (1.02 mL, 11.0 mmol). After stirring at −10° C. for 20 min, sodium borohydride (1.21 g, 33.0 mmol) was added all at once. Methanol (150 mL) was cautiously added dropwise. Once the vigorous evolution of carbon dioxide had significantly decreased, the remaining methanol was added. Stirring was continued for 30 min, and the reaction was quenched with 10% acetic acid in water. The volatile solvents were removed, and the remaining material was diluted with ether. The ether was extracted with saturated NaHCO3 (2×), water (2×), brine (1×), and dried over MgSO4. The crude material was purified by chromatography over silica, using an eluent gradient of 10-30% ethyl acetate in hexanes, to afford the alcohol (1.16 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.O1CCOCC1.Cl>[Zn].O>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CCC(=O)CCc2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CCCCCc2ccc(OC)cc2)cc1
Yield: 111 %

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)pentan-3-one of Example 7 (57 g, 0.19 mole), amalgamated zinc (200 g), dioxane (250 ml), concentrated hydrocloric acid (250 ml) and 150 ml of water was refluxed overnight. A further 50 ml of concentrated hydrochloric acid was added after the first 6 hours. The organic layer was separated, diluted with ether, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 60 g of a thick oil. NMR and mass spectra confirmed the structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[H-].[Na+].Br[CH2:17][C:18]([CH3:27])=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.O>CN(C)C=O>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:17][C:18]([CH3:27])=[CH:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: CC(=Cc1ccc(C)cc1)CBr
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=Cc1ccc(C)cc1)COc1cc(C)c(NC=O)c(C)c1C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
To a solution of N-(4-hydroxy-2,3,6-trimethylphenyl)formamide (9.31 g, 52.0 mmol) in N,N-dimethylformamide (120 ml) was added at 0° C. under nitrogen atmosphere sodium hydride (a 60% dispersion in liquid paraffin, 2.11 g, 52.8 mmol) and the resulting mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added a solution of 1-(3-bromo-2-methyl-1-propenyl)-4-methylbenzene (12.48 g, 55.44 mmol) in N,N-dimethylformamide (20 ml) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate-isopropyl ether to obtain 7.34 g (44% yield) of the title compound. Melting point: 167-169° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[N:16][C:15]=2ON2C3C=CC=CC=3N=N2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[N:16][C:15]=2[NH:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)c1ccc(NC(=O)c2cc(Cl)nnc2On2nnc3ccccc32)cc1
Product: CC(C)(C)c1ccc(NC(=O)c2cc(Cl)nnc2NCc2ccc(F)cc2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(benzotriazol-1-yloxy)-6-chloro-pyridazine-4-carboxylic acid (4-tert-butyl-phenyl)-amide (0.348 g, 0.82 mmol) and 4-fluorobenzylamine (1.0 mL, 8.75 mmol) was stirred at 60° C. under N2 for 30 min, cooled to RT, and purified by flash column chromatography. The desired compound was obtained as a solid. MS (ES+) 413.0 (M+H)+. Calc'd for C22H22ClFN4O-412.89.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)[C:48](=[O:52])N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.COC1C=CC=CC=1N=C=S>>[CH3:48][O:52][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Agent: COc1ccccc1N=C=S
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4OC)cc3)ccc2C1=O

Procedure:
The compound of example 280 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 2-methoxyphenyl isothiocyanate. The compound of example 280 was used directly without isolation, for the preparation of compound of example 281.
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=O)C.Cl.[Cl:28][CH2:29][C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[ClH:28].[OH:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:29][C:30]3[N:31]=[C:32]([CH3:35])[S:33][CH:34]=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: Cc1nc(CCl)cs1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1csc(C)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A solution of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg, 1.06 mmol), (prepared as described for the starting material in Example 1), 4-chloromethyl-2-methylthiazole hydrochloride (390 mg, 2.12 mmol), potassium carbonate (438 mg) and potassium iodide (40 mg) in DMF (15 ml) was heated at 60° C. for 15 hours. After cooling to ambient temperature the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was diluted with methanol (10 ml) and 2M sodium hydroxide (2 ml) was added. After stirring for 1 hour, the reaction mixture was diluted with water (20 ml) and 2M hydrochloric acid (3 ml) was added. The resulting solid was filtered off, washed with water and dried under vacuum to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methylthiazol4-ylmethoxy)quinazoline hydrochloride (300 mg, 59%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[C:5]#[C:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[CH3:2]>[Pd].C1COCC1>[CH2:18]([O:17][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[CH3:19]
Reactant: CCOC(C#Cc1ccc2ncccc2c1)OCC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(CCc1ccc2ncccc2c1)OCC
Reaction time: 6 h
Yield: 98.1 %

Procedure:
A mixture of 6-(3,3-diethoxyprop-1-yn-1-yl)quinoline (22, 56 mg, 0.22 mmol) and 10% palladium on carbon (5 mg) in THF (5 mL) was hydrogenated under H2 at 1 atm for 6 h. The reaction mixture was filtered through a celite bed and the celite bed was washed with THF (2×2 mL). The combined filtrates were concentrated under the reduced pressure to afford 6-(3,3-diethoxypropyl)quinoline (23, 56 mg, 57 mg theoretical, 98% yield) as a clear oil, which was found to be sufficiently pure to be used in the subsequent reaction without further purification and was identical to the material made from Method A in every comparable aspect.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]([CH2:10][CH:11]2[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.Cl>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]([CH2:10][CH:11]2[CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccc(CC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(Cc2ccc(OCCCCl)cc2)CC1
Yield: 100.3 %

Procedure:
A solution of 8-[4-(3-chloropropoxy)benzyl]-1,4-dioxaspiro[4.5]decane (630 mg) in a mixture of tetrahydrofuran (9.7 mL) and a 2N aqueous solution of hydrochloric acid (4.85 mL) is stirred for 20 h at room temperature, then concentrated under reduced pressure and diluted with ethyl acetate (10 mL) and alkalinized with an aqueous solution of sodium hydroxide. The organic phase is separated by decantation, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give 546 mg of 4-[4-(3-chloropropoxy)benzyl]cyclohexanone used without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=O.P([Cl:31])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]=[C:3]([Cl:31])[C:2]([F:14])([F:13])[F:1])=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccc(Cl)cc1)C(F)(F)F
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: FC(F)(F)C(Cl)=Nc1ccc(Cl)cc1
Temperature: 82 °C
Yield: 78.5 %

Procedure:
Four grams (17.9 mmol) of 2,2,2-trifluoro-N-(4-chlorophenyl)acetamide, 9.61 g (35.8 mmol) of diphenyl chlorophosphate, 3.62 g (35.8 mmol) of triethylamine, and 20 ml of acetonitrile were introduced into a 50 ml flask and reacted for 16 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 16 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 3.40 g of N-(4-chlorophenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 78.6%).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([CH:18]2O[CH:21]=[N:20][C:19]2([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])S(C2C=CC(C)=CC=2)(=O)=O)[N:9]=[N:8]1.C[NH2:51].CO>C1(C)C(C)=CC=CC=1>[F:47][C:44]([F:46])([F:45])[C:42]1[CH:41]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:49])[F:48])[CH:43]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[N:51]=[CH:21][NH:20][C:19]=2[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[N:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)C2(Cc3ccccc3Cl)N=COC2c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)cc1
Reactant: CN
Solvent: Cc1ccccc1C
Solvent: CO
Product: FC(F)(F)c1cc(Cn2nnc(-c3nc[nH]c3Cc3ccccc3Cl)c2-c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Combine 1-(3,5-bis-trifluoromethyl-benzyl)-4-[4-(2-chloro-benzyl)-4-(toluene-4-sulfonyl)-4,5-dihydro-oxazol-5-yl]-5-phenyl-1H-[1,2,3]triazole (0.100 mmol), 2.5 mL of xylene, and 2N solution of methylamine in methanol (0.2 mL, 0.40 mmol) and heat in a sealed pyrex tube to 135° C. After 19 hours, cool to RT. Concentrate the mixture to 1.0 mL and apply to a 2 mm chromatotron plate with CH2Cl2 and EtOAc and elute with a 100 mL of Hexanes, and 200 mL each of 20:80 EtOAc/Hexanes, 30:70 EtOAc/Hexanes, 50:50 Hexanes/EtOAc, 85:15 EtOAc/Hexanes to provide the title compound: Exact Mass 561.1: mass spectrum (IS): m/z=563.1 (M+1), 561.1 (M−1); 1H NMR (250 MHz, CDCl3) 7.74 (s, 1H), 7.62 (s, 1H), 7.48-7.32 (m, 6H), 7.30-7.00 (m, 6H), 5.52 (s, 2H), 4.20 (s, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:8][S:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>>[NH2:13][S:10]([C:9]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1cscc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1cscc1C(=O)O
Reaction time: 72 h

Procedure:
Preparation is according to the method disclosed in U.S. Pat. No. 4,028,373. A solution of 0.5 g. of 4-(aminosulfonyl)-3-thiophenecarboxylic acid methyl ester in 20 ml. of 10% aqueous sodium hydroxide is allowed to sit at room temperature for 3 days. The solution is acidified with concentrated hydrochloric acid. The precipitate which forms is collected to give 0.35 g. of product. A small amount is recrystallized twice from ethyl acetate (petroleum ether is added to the cloudy point to initiate precipitation) to give the analytical sample, m.p. 222°-224° C.
Reaction SMILES: [Na+].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:26])[CH:11]2[NH:15][C:16](=[O:25])[CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[CH:23]=[O:24])[C:8]=1[C:27]([O-:29])=[O:28])(=[O:4])[CH3:3].Cl[CH2:31][O:32][C:33](=[O:46])[C@H:34]([CH:43]([CH3:45])[CH3:44])[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C)C=O.C(OCC)(=O)C>[C:39]([O:38][C:36]([NH:35][CH:34]([CH:43]([CH3:45])[CH3:44])[C:33]([O:32][CH2:31][O:28][C:27]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH:15][C:16](=[O:25])[CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=[O:24])[C:10]2=[O:26])=[O:29])=[O:46])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cn3cccc3C=O)C2SC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OCOC(=O)C(NC(=O)OC(C)(C)C)C(C)C)N2C(=O)C(NC(=O)Cn3cccc3C=O)C2SC1
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 3-[(acetyloxy)methyl]-7-[[(2-formyl-1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, prepared according to the general procedure described in W. German Offen. No. 2,236,620, are mixed in 100 ml of dimethylformamide (DMF) and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water and aqueous sodium bicarbonate and again with water. The ethyl acetate portion is dried over magnesium sulfate, filtered and evaporated to dryness to give 3-[(acetyloxy)methyl]-7-[[(2-formyl-1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the protecting group can be removed by standard procedures to give the title compound.
Reaction SMILES: C1(C[O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])C=CC=CC=1.[H][H]>CO.[Pd]>[F:20][C:16]([F:21])([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8])[CH:17]([F:18])[F:19]
Reactant: FC(F)C(F)(F)Oc1ccccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Oc1ccccc1OC(F)(F)C(F)F

Procedure:
A solution of 58.6 g of 1-(phenylmethoxy)-2-(1,1,2,2-tetrafluoroethoxy)benzene in 200 ml methanol was blanketed with nitrogen and 1.0 g of 10% palladium on charcoal added. The mixture was hydrogenated at 50 psi hydrogen for 3 hours. The reaction mixture was filtered to remove catalyst and the filtrate concentrated under reduced pressure to give an oil, which darkened on standing. The oil was distilled, bp 25°-32° (0.2 mm), to give the phenol as a colorless oil, which solidified on standing. The infrared spectrum showed OH absorption at 3570 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31]C)[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.N[C:48]1[CH:53]=CC=[CH:50][CH:49]=1>>[NH:22]([C:20](=[O:21])[C@H:19]([NH:18][C:16]([N:13]1[C:14](=[O:15])[CH:8]([CH2:7][C:6]2[CH:34]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:35][CH3:36])[CH2:9][NH:10][C:11](=[O:33])[CH2:12]1)=[O:17])[CH3:31])[C:23]1[CH:24]=[CH:50][CH:49]=[CH:48][CH:53]=1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: Nc1ccccc1
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: COc1ccc(Cl)cc1CC1CNC(=O)CN(C(=O)N[C@H](C)C(=O)Nc2ccccc2)C1=O

Procedure:
Instead of the starting material of Example 220, that is, the compound 119, the compound 100 was used, while instead of the glycine tert-butyl ester hydrochloride, aniline was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br)#[N:23]>>[C:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20])#[N:23]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: N#Cc1cccc(CBr)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cccc(C#N)c2)c1
Yield: 55.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (222 mg, yield: 55.3%).
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.[Cl:41][C:42]1[N:43]=[N:44][CH:45]=[C:46](Cl)[CH:47]=1>>[Cl:41][C:42]1[N:43]=[N:44][CH:45]=[C:46]([N:26]2[C@@H:19]3[C@@H:24]([CH2:23][CH2:22][N:21]([C:27]([C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[N:36]4[N:40]=[CH:39][CH:38]=[N:37]4)=[O:28])[CH2:20]3)[CH2:25]2)[CH:47]=1
Reactant: Clc1cnnc(Cl)c1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN(c3cnnc(Cl)c3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 3,5-dichloropyridazine. MS (ESI) mass calcd. for C19H17ClFN7O, 413.9; m/z found, 414.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:11]([N+:26]([O-])=O)[CH:10]=2)=[CH:4][CH:3]=1.C(O)(=O)C>O1CCCC1>[NH2:26][C:11]1[CH:10]=[C:9]([NH:8][CH2:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][C:12]=1[NH:15][C:16](=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1
Reactant: O=C(Cc1ccc(F)cc1)Nc1ccc(NCc2ccc(Cl)s2)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1cc(NCc2ccc(Cl)s2)ccc1NC(=O)Cc1ccc(F)cc1
Reaction time: 0.08 h
Yield: 94.2 %

Procedure:
To a stirred red solution of N-{4-[(5-chlorothiophen-2-ylmethyl)amino]-2-nitrophenyl}-2-(4-fluorophenyl)acetamide (320 mg, 0.762 mmol) in tetrahydrofuran (25 ml) and acetic acid (8 mL) zinc powder (particle size <10 micron, 10 g) was periodically added by portions during 30 minutes. The solution turned colorless after 5 minutes. The obtained colorless suspension was filtered via plug of SiO2 (10 g) with ethyl acetate as an eluent and the obtained solution was evaporated in vacuo. The obtained solid was dissolved in a mixture of ethyl acetate/acetone/trifluoroacetic (3 mL/3 mL/0.2 mL), treated with saturated aq. NaHCO3 (50 mL) and heptane (30 mL) and the product was separated by filtration to furnish 280 mg of a pale grey solid. Yield 94.2%. LC/MS (m/z) 390.4 ([M+H]+); RT=2.26 (UV, ELSD) 99%, 100%. 1H NMR (DMSO-d6): 3.56 (s, 2H); 4.28 (d, 2H); 4.57 (s, 2H, NH2); 5.87 (dd, 1H); 5.98 (m, 2H, NH and arom. H); 6.74 (d, 1H); 6.86 (d, 1H); 6.93 (d, 1H); 7.13 (t, 2H); 7.35 (dd, 2H); 9.10 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][CH3:14].Cl[CH2:24][C:25](Cl)=[O:26]>C(OCC)(=O)C>[C:19]([O:18][C:16]([N:15]1[C@@H:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:25](=[O:26])[CH2:24]1)=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: O=C(Cl)CCl
Reactant: CCCC[C@@H](CNc1ccccc1C)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CCCC[C@H]1CN(c2ccccc2C)C(=O)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared essentially according to the procedure described in Example 39. Step D, except using N-(2-methylphenyl)-2(S)-(tert-butoxycarbonylamino)hexanamine (0.506 g, 1.65 mmol), chloroacetyl chloride (0.158 mL, 1.98 mmol) in ethyl acetate-saturated sodium bicarbonate at 0° C. The crude product thus obtained was dissolved in DMF (15 mL), cooled to 0° C. under nitrogen, and treated with cesium carbonate (1.61 g, 4.95 mmol). The reaction was stirred at 0° C. for 2 h, and at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride, and extracted with ethyl acetate. The extracts were dried and evaporated to give the title compound.