Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].CC(O)C.Cl[C:7]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH3:32])[C:27](=[O:33])[CH:26]=[C:25]2[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)([C:16]1[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=1)[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.O>C1COCC1>[NH2:1][C:7]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH3:32])[C:27](=[O:33])[CH:26]=[C:25]2[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)([C:16]1[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=1)[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: Cn1cncc1C(Cl)(c1ccc(C#N)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: N
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cn1cncc1C(N)(c1ccc(C#N)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
NH3/iPrOH (6 ml) was added dropwise at 5° C. to a solution of 4-[chloro[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl](1-methyl-1H-imidazol-5-yl)methyl]-benzonitrile (0.00121 mol), (obtained in stage c), in THF (7 ml). The mixture was stirred at room temperature for 4 hours, poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: toluene/iPrOH/NH4OH; 90/10/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.3 g (52%) which were then purified by column chromatography over kromasil (eluent: CH3CN/NH4OAc; 40/60; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.18 g (31%) which were crystallized from CH3CN/diethyl ether. The precipitate was filtered off and dried, yielding 0.13 g (22%) of 4-[amino[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6quinolinyl](1-methyl-1H-imidazol-5-yl)methyl]-benzonitrile, melting point 245° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[N:11]3[N:12]=[C:13](Cl)[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[CH:5][N:4]=[C:3]1[N+:17]([O-:19])=[O:18].[CH3:20][NH:21][CH3:22]>CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7]2[N:11]3[N:12]=[C:13]([N:21]([CH3:22])[CH3:20])[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[CH:5][N:4]=[C:3]1[N+:17]([O-:19])=[O:18]
Reactant: CNC
Reactant: Cn1c(-c2nnc3ccc(Cl)nn23)cnc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)c1ccc2nnc(-c3cnc([N+](=O)[O-])n3C)n2n1

Procedure:
0.5 g. 3-(1-methyl-2-nitro-5-imidazolyl)-6-chloro-s-triazolo[4,3-b]pyridazine were dissolved, with heating, in 10 ml. dimethyl formamide and gaseous dimethylamine passed in at 60° C. over the course of 15 minutes. The resultant suspension was then diluted with 6 ml. water, filtered with suction, first washed with aqueous dimethyl formamide, then with water and finally with methanol. There was thus obtained 0.4 g. (78% of theory) of the desired 3-(1-methyl-2-nitro-5-imidazolyl)-6-dimethylamino-s-triazolo[4,3-b]-pyridazine in the form of yellow crystals which melt, with decomposition, at 261° - 263° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:4]([CH3:12])[C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F-].[K+].[CH:26]1([NH2:29])[CH2:28][CH2:27]1>CS(C)=O>[CH:26]1([NH:29][C:5]2[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([F:1])=[C:3]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:4]=2[CH3:12])[CH2:28][CH2:27]1
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2C)CC1
Reactant: NC1CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(NC3CC3)c2C)CC1
Temperature: 60 °C
Yield: 93.7 %

Procedure:
To 3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrotoluene (7.1 g) are added anhydrous dimethylsulfoxide (23 ml), potassium fluoride (2.0 g) and cyclopropylamine (1.5 g), and the mixture is heated at 60° C. for 6 hours. The reaction mixture is poured into ice water, and extracted with dichloromethane. The solvent is distilled off and the residue is recrystallized from ethanol to give N-cyclopropyl-2-methyl-3-(4-ethoxycarbonyl-1-piperazinyl)-4-fluoro-6-nitroaniline (7.4 g), as orange red prisms, m.p. 97°-98° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9].[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)#[N:9]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1cnccc1Br
Product: Cc1ccc(-c2ccncc2C#N)cc1

Procedure:
Synthetic Scheme XXVII shows the 5-step preparation of the alkylating reagent 4-(4-bromomethylphenyl)-3-cyanopyridine (69) from 4-bromopyridine (70) (Aldrich). In step 1, the ortho-bromo carbanion was generated with LDA in THF at -78° C. and reacted with anhydrous DMF to give the 4-bromo-3-carboxaldehyde 71. In step 2, the aldehyde 71 was reacted with hydroxylamine to give the oxime 72. In step 3, the oxime 72 was dehydrated with 1,1-carbonyldiimidazole in methylene chloride at reflux to give 4-bromo-3-cyanopyridine (73). In step 4, the nitrile 73 was coupled with 4-methylphenylboronic acid (52) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 3-cyano-4-(4-methylphenyl)pridine (74). In step 5, 74 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 69. ##STR81##
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[OH:10]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[N:4]=[O:10]
Reactant: OO
Reactant: Nc1c(Cl)cccc1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=Nc1c(Cl)cccc1Cl
Temperature: 5 °C

Procedure:
To a solution of 2,6-dichloroaniline (42.3 g, 0.26 mole) in glacial acetic acid (520 ml) in a 1 litre conical flask at room temperature, was added 100 vol hydrogen peroxide (157 ml, 1.38 mole). The flask was plugged with absorbant cotton, and set aside on a thermostatically controlled water bath at a temperature of 25°-30° C. for 70 hours. The flask was then cooled to 5° C., and the crystalline solid collected on a sintered glass funnel, washed with ethanol-pet. ether (40°-60°) (200 ml, 1:1, v/v), and dried in an oven at 90° C. The buff leaflets weighed 40.25 g (87.6%) m.p. 171°-172° C.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)[CH2:11][CH:12]([CH3:14])[CH3:13].[C:26](OC(=N)C(Cl)(Cl)Cl)([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[CH2:10]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=1)[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CCOc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CCOc1ccc(CC(=O)OC(C)(C)C)cc1
Reaction time: 16 h
Yield: 41.7 %

Procedure:
Boron trifluoride etherate (0.65 mL) was added in one portion to a stirred solution of [4-(isopentyloxy)phenyl]acetic acid (crude from preparation of intermediate 11; 7.31 g, 32.9 mmol) and t-butyltrichloroacetimidate (14.4 g, 11.8 mL, 65.8 mmol) in THF (70 mL) at room temperature under nitrogen. The resulting solution was stirred for 16 h then quenched with saturated aqueous sodium hydrogen carbonate solution (50 mL). The resulting suspension was extracted with ethyl acetate (3×50 mL) then the organic_extracts combined, dried_(magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (5-10% diethyl ether: cyclohexane) to give the title compound as a colourless oil (3.82 g, 42% over 2 steps). LC/MS: 3.94 min; z/e 296, calcd (M+18) 296. 1H NMR (400 MHz: CDCl3): 7.25 (2H), 6.90 (2H), 4.05 (2H), 3.55 (2H), 1.90 (1H), 1.75 (2H), 1.50 (9H), 1.05 (6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([NH:22][C:23]([CH2:25]Br)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:16]1([NH:22][C:23]([CH2:25][O:11][C:10](=[O:12])[C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CBr)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In 15 ml of DMF were dissolved 2.8 g of N-t-butoxycarbonyl-(S)-proline and 2.8 g of phenylcarbamoyl methyl bromide. To the solution was added 1.1 g of sodium hydrogencarbonate. The mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (using chloroform as an eluent), giving the title compound as a colorless oil. Yield 3.5 g.
Reaction SMILES: [N:1]1C=C[CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[Na+].[C:29]([OH:38])(=[O:37])[CH:30]([CH:32]([C:34](O)=O)[OH:33])O>C1COCC1.C(O)C.CO>[C:7]([NH:1][C:2]1[CH:34]=[C:32]([OH:33])[C:30](=[CH:4][CH:3]=1)[C:29]([OH:38])=[O:37])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: c1ccncc1
Reactant: CCCCCCCC/C=C/CCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: CCCCCCCC/C=C/CCCCCCCC(=O)Nc1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To a solution of PAS (2.6 g, 17 mmol) in 100 ml anhydrous THF and 4 ml pyridine was added dropwise a solution of elaidic acid chloride (5.11 g, 17 mmol) in 20 ml THF at 0° C. The reaction mixture was stirred at ambient temperature for 24 hours. More elaidic acid chloride (1.0 g) was added, and after 4 hours, a small amount methanol was added. The solvents were evaporated at high, vacuum, and the residue was partitioned between ether and water. The organic phasewas washed with tartaric acid (aq) and water. The solvent was evaporated off, and the residue was dissolved in 100 ml methanol to which was added 5 ml water. The solid deposit was filtered off and recrystallised from ethanol to give 3.9 g crude material 1.5 g of this material was dissolved in 100 ml ethanol to which was added 11 ml 1M NaOH(aq). The mixture was stirred at ambient temperature for 2 hours and acidified with 30 ml 0.5M tartaric acid(aq). The solid deposit was washed with water, dissolved in ether, and the organic phase washed with tartaric acid(aq). The solvent was evaporated off, and the residue was evaporated from anhydrous chloroform×2, to give 1.3 g(87%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][NH:30][CH3:31]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:13])[N:30]([CH2:29][CH2:28][N:27]([CH3:32])[CH3:26])[CH3:31])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: CNCCN(C)C
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Product: CN(C)CCN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with N,N,N′-trimethylethylenediamine gives “A90”; method 2: HPLC/MS: 1.55 min, [M+H]419;
Reaction SMILES: BrBr.[OH-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]([CH3:18])([CH3:17])[C:14]([NH2:16])=O)[CH:9]=[CH:10][C:11]=1[Cl:12]>>[ClH:5].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]([CH3:18])([CH3:17])[CH2:14][NH2:16])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: CC(C)(C(N)=O)c1ccc(Cl)c(Cl)c1
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(CN)c1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 95 °C
Reaction time: 18 h

Procedure:
Bromine (139 g) was added dropwise with stirring to a solution of 3 molar sodium hydroxide (1712 ml) at 0° C. with stirring. When all the bromine had dissolved, 2-(3,4-dichlorophenyl)-2-methylpropionamide (201 g) was added in portions of 0° C. The mixture was stirred at 0° C. for 5 hours and then left to stand at 0° C. for 18 hours. The mixture was heated at 95° C. for 1 hour, then cooled and extracted with ether. The combined ether extracts were washed with 5M hydrochloric acid whereupon a solid precipitated. The solid was collected by filtration to give 2-(3,4-dichlorophenyl)-2-methylpropylamine hydrochloride, m.p. 238°-239° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC=CC=1>CCOCC>[O:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[O:1][CH2:13][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 135 °C
Yield: 99 %

Procedure:
A mixture of ethyl 4-oxocyclohexanecarboxylate (25 g), 10-campharsulfonic acid, ethylene glycol (40 mL), and toluene (400 mL) was heated under reflux with a Dean-Stark apparatus for 2.5 h (bath temp. 135° C.). The mixture was cooled down, and then was diluted with ether (200 mL). After the ethylene glycol layer was separated, the organic layer was washed with saturated aqueous sodium bicarbonate solution (2×) and brine (1×), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give 2 as an oil (31.29 g, 99%): 1H NMR (CDCl3) δ 4.13 (2H, q, J=7.1 Hz), 3.95 (4H, s), 2.33 (1H, m), 1.93 (2H, m), 1.79 (4H, m), 1.56 (2H, m) 1.25 (3H, t, J=7.1 Hz); 13C NMR (CDCl3) δ 175.4, 108.3, 64.5, 60.5, 41.8, 33.9, 26.5, 14.4.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:43]=[N:42][N:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCCC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCCC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (1.01 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.55 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9→1:4), and was recrystallized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 143) (794.5 mg) as yellow crystals.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[C:30]([O:34][C:35]([NH:37][CH:38]([CH3:42])[C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31].C1(N=C=NC2CCCCC2)CCCCC1.O>O1CCCC1.C(OCC)(=O)C>[C:30]([O:34][C:35]([NH:37][CH:38]([CH3:42])[C:39]([NH:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C(N)Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)C(C)NC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 23 %

Procedure:
A solution of 5-[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzyl]thiazolidin-2,4-dione hydrochloride (2.3 g, 5.27 mmol) and 2-t-butoxycarbonylaminopropionic acid (0.997 g, 5.27 mmol) in tetrahydrofuran (20 ml) was stirred for 1 h at 0° C. N,N′-Dicyclohexylcarbodiimide (1.086 g, 5.27 mmol) was added to this solution and stirring was continued for 1.5 h at ambient temperature. Water (200 ml) was added to the reaction mixture, stirred for 15 minutes, ethyl acetate (250 ml) was added and stirring was continued for another 15 minutes. The organic layer was separated and washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated to give the title compound, which was purified by column chromatography (0.7 g, yield 23%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][N:25]1[C:29](=[O:30])[CH2:28][NH:27][C:26]1=[O:31]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:28][C:29](=[O:30])[N:25]([CH3:24])[C:26]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1C(=O)CNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(=O)N(C)C4=O)nc3)CC2)c(C)c1
Yield: 40.4 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 3-methylimidazolidine-2,4-dione (46 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (66 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]([CH3:24])[CH:16]2[CH2:23][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.C1C=NC2N([OH:34])N=NC=2C=1.CCN=C=[N:39][CH2:40][CH2:41][CH2:42]N(C)C.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:15]([CH3:24])[CH:16]2[CH2:23][CH:19]3[CH2:20][N:21]([C:42](=[O:34])[CH2:41][C:40]#[N:39])[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CC2CNCC2C1
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CC2CN(C(=O)CC#N)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a suspension of 5-chloro-N4-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (43.3 mg, 0.51 mmol) in DCM (15 mL) were added HOAT (71.6 mg, 0.53 mmol), EDCI (103.3 mg, 0.53 mmol) and Et3N (111.1 mg, 1.10 mmol). The reaction mixture was stirred at rt for 1 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/30) to give the title compound as a beige solid (93.1 mg, 91.1%).
Reaction SMILES: S(Cl)(C)(=O)=O.Cl.[CH3:7][O:8]/[N:9]=[C:10](/[C:14]1[N:15]=[C:16]([NH:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17][CH:18]=1)\[C:11](O)=[O:12].C(N(CC)C(C)C)(C)C.[NH2:48][C@@H:49]1[C:69](=[O:70])[N:51]2[C:52]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[C:53]([CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][O:57]3)[CH2:54][S:55][C@H:50]12>CN(C=O)C.N1C=CC=CC=1>[CH3:7][O:8]/[N:9]=[C:10](/[C:14]1[N:15]=[C:16]([NH:19][C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[S:17][CH:18]=1)\[C:11]([NH:48][C@@H:49]1[C:69](=[O:70])[N:51]2[C:52]([C:62]([O:64][C:65]([CH3:66])([CH3:68])[CH3:67])=[O:63])=[C:53]([CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][O:57]3)[CH2:54][S:55][C@H:50]12)=[O:12]
Reactant: CC(C)(C)OC(=O)C1=C(C2CCCCO2)CS[C@@H]2[C@H](N)C(=O)N12
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(C3CCCCO3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -50 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
Mesyl chloride (121mg, 82μl) was added to 2-(Z)-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid hydrochloride (466mg) and N,N-diisopropylethylamine (252mg, 340μl) in dry DMF (10ml) at -50° C. under argon and stirred at -50° C. for 1h. Then t-butyl (6R,7R)-7amino-3-(tetrahydropyran-2-yl)-ceph-3-em-4-carboxylate (Isomer A, 300mg) in dry DMF (5ml) followed by pyridine (70mg, 72μl) were added and reaction mixture left for a further 1h whilst warming to ambient temperature. The reaction mixture was partitioned between ethyl acetate and water, reextracted with ethyl acetate, organic extracts washed with water (x3) and brine, dried, concentrated and flash chromatography (eluting with 30,40,50,60% ethyl acetate in hexane) to afford the title compound as a pale yellow foam (420mg, 62%); vmax (CH2Cl2) 3420, 1784, 1732 (shoulder), 1717, 1685cm-1 ; δH (CDCl3), 1.53 (9H, s) overlapping 1.4-1.7 (4H, m), 1.73-1.94 (2H, m), 3.38-3.58 (3H, m), 3.95-4.00 (1H, m), 4.07 (3H, s), 4.54-4.59 (1H, m), 5.02 (1H, d, J4.8Hz), 5.90 (1H, dd, J4.5, 9.1Hz) 6.74 (1H, s), 6.86 (1H, d, J8.8Hz), 7.04 (1H, s) and 7.30 (15H, s). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (788)].
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2.N1C=CC=CC=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl.CCOC(C)=O>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCc2cc(OCCO)ccc2N1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)CCC(=O)N3)cc1
Reaction time: 4 h
Yield: 26.8 %

Procedure:
To a solution of 6-(2-hydroxyethoxy)-3,4-dihydroquinolin-2(1H)-one (0.15 g, 0.724 mmol) in DCM (2 mL) was added pyridine (0.117 mL, 1.448 mmol) and 4-methylbenzene-1-sulfonyl chloride (0.152 g, 0.796 mmol) and the reaction was stirred for 4 h. The reaction was diluted with EtOAc (25 mL), washed with 0.1 N HCl (10 mL), brine (10 mL), and sat. NaHCO3 solution (10 mL). The organic layer was dried over sodium sulfate, evaporated to dryness, and purified by flash chromatography on silica gel (4 g, 50% EtOAC in hexanes) to yield 2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)ethyl 4-methylbenzenesulfonate (0.07 g, 27%).