Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([CH2:8][C:9](O)=O)(C(O)=O)O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]([C:26](=[O:41])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:29][CH:28]=1)[C:21](=O)[CH2:20][CH2:19]2.[CH2:43](C(C)=O)C>CC(C)=O>[C:1]1([C:21]2[CH2:20][CH2:19][C:18]3[C:23]([C:22]=2[C:26](=[O:41])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:29][CH:28]=2)=[CH:24][CH:25]=[C:16]([O:15][CH3:14])[CH:17]=3)[CH:2]=[CH:3][CH:8]=[CH:9][CH:43]=1
Reactant: COc1ccc2c(c1)CCC(=O)C2C(=O)c1ccc(OCCN2CCCC2)cc1
Reactant: CCC(C)=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CCC(c1ccccc1)=C2C(=O)c1ccc(OCCN2CCCC2)cc1
Temperature: 0 °C

Procedure:
The aqueous mixture was rendered alkaline by addition of base, and the alkaline mixture was extracted with ethyl acetate. The extract was dried and concentrated to obtain 8.7 grams of product which was dissolved in acetone, and one equivalent of citric acid was added to the mixture. The acetone was stripped off, and methyl ethyl ketone was added to the residue. The mixture was maintained at 0° C. overnight, and the crystals which formed were collected by filtration and washed with cold methyl ethyl ketone and vacuum dried. The solid was recrystallized from acetone to obtain the title compound in the form of its citrate salt. mp 98-100° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1.[BH4-].[Na+]>C(O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[NH:3][CH2:4][C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(c1C)CNC(Cl)=N2
Yield: 51.1 %

Procedure:
To a solution of 4.66 g of 2,4-dichloro-5,6-dimethylthieno[2,3-d]pyrimidine in 150 ml of ethanol-chloroform (1:1 by volume) was slowly added 2.32 g of sodium borohydride with stirring. The mixture was stirred at room temperature for 6 hours and the solvent removed in vacuo. To the solid residue was added 50 ml of water and the insoluble material was filtered, washed with water, dried, and recrystallized from benzene to give 2.05 g of 2-chloro-5,6-dimethyl-3,4-dihydrothieno[2,3-d]pyrimidine, mp 170°-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[NH:43]1[C:51]2[CH2:50][CH2:49][NH:48][CH2:47][C:46]=2[N:45]=[CH:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:48]1[CH2:49][CH2:50][C:51]2[NH:43][CH:44]=[N:45][C:46]=2[CH2:47]1)=[O:24]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)N1CCc2[nH]cnc2C1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][NH2:7].[Cl:8][C:9]1[C:10](=O)[O:11][CH:12](O)[C:13]=1[Cl:14].C([O-])(=O)C.[Na+]>O>[Cl:8][C:9]1[C:10](=[O:11])[NH:6][N:7]=[CH:12][C:13]=1[Cl:14]
Reactant: O=C1OC(O)C(Cl)=C1Cl
Reactant: NN
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ncc(Cl)c1Cl
Yield: 55.7 %

Procedure:
Hydrazine sulfate (305.7 g, 2.35 mol) was added to a solution of 3,4-dichloro-5-hydroxy-5H-furan-2-one (419 g, 2.48 mol) and sodium acetate (212 g, 2.58 mol) in water (600 mL). The mixture was stirred at reflux for 4 h. After filtration and evaporation, the residual solid was recrystallized from ethanol to afford 4,5-dichloropyridazin-3(2H)-one (216 g, 67%) as an off-white solid. LC-MS 165 [M+H+].
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[CH:37]([NH:38][CH2:39][CH2:40][NH2:41])[CH2:36][C:35]([CH3:43])([CH3:42])[O:34][C:23]3=[N:24][C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:16][CH:15]=1.CCN(CC)CC>C(Cl)(Cl)Cl.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[C:22]3[CH:37]([N:38]4[CH2:39][CH2:40][NH:41][C:1]4=[O:2])[CH2:36][C:35]([CH3:43])([CH3:42])[O:34][C:23]3=[N:24][C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:18][CH:19]=1
Reactant: CC1(C)CC(NCCN)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(N2CCNC2=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1′-carbonyldiimidazole (18.1 mg, 0.11 mmol) in 5.0 mL of CHCl3 was added the product of Step B (0.07 mmol) and NEt3 (51.8 μL, 0.37 mmol) in 5.0 mL of CHCl3. The mixture was allowed to stir at rt for 2 h and then refluxed for 16 h. After cooling to rt, the reaction mixture was diluted with EtOAc (50 mL) and washed with brine (2×50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridge using EtOAc as the eluant afforded the title compound: 1H NMR δ 1.48 (s, 3H), 1.58 (s, 3H), 2.00-2.09 (m, 2H), 3.18-3.50 (m, 4H), 4.70 (br. s, 1H), 5.44 (m, 1H), 7.00 (d, J=8.5, 2H), 7.18-7.27 (m, 4H), 7.50 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(OP([CH2:35][C:36]#[N:37])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)=[CH:35][C:36]#[N:37])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(C(=O)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Yield: 209.2 %

Procedure:
Bis-(3,4,5-trimethoxy-phenyl)-methanone (0.32 g, 0.88 mmol), cyanomethylphosphonic acid diethyl ester (0.28 ml, 0.31 mmol) in anhydrous THF (20 ml), and potassium bis(trimethylsilyl)amide (0.35 g, 1.8 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography to give 3,3-Bis-(3,4,5-trimethoxy-phenyl)-acrylonitrile as a solid (0.25 g, 74%): mp, 146-148° C.; 1HNMR (DMSO-d6) δ 6.69 (d, J=5 Hz, 4H, Ar), 6.32 (s, 1H, CH), 3.77-3.72 (m, 18H, 6OCH3); 13C NMR (DMSO-d6) δ 161.27, 152.69, 152.61, 139.60, 138.66, 133.06, 131.94, 118.43, 107.09, 106.23, 100.40, 95.21, 60.13, 60.10, 56.08, 56.07; Anal. Calcd. For C21H24NO6: C, 65.44; H, 6.02; N, 3.63. Found: C, 65.08; H, 5.99; N, 3.45.
Reaction SMILES: [Cl:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[OH-:18].[Na+].[CH:20]([N:23]([CH2:27][CH2:28][NH2:29])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21].O>C(Cl)Cl>[ClH:1].[CH:20]([N:23]([CH:24]([CH3:26])[CH3:25])[CH2:27][CH2:28][NH:29][C:3](=[O:4])[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:18])([CH3:22])[CH3:21]
Reactant: [OH-]
Reactant: CC(C)N(CCN)C(C)C
Reactant: O=C(Cl)C(Cl)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)N(CCNC(=O)C(O)(c1ccccc1)c1ccccc1)C(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g (38 mmole) of 2-chloro-2,2-diphenylacetyl chloride were slowly added to a chilled solution of 7.6 ml 5M sodium hydroxide (38 mmole) and 5.3 g (38 mmole) of diisopropylaminoethylamine in 50 ml of methylene chloride. The temperature was kept at 0° C. with good agitation. The mixture was stirred for 1 h. The water solution was discarded and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solution was evaporated to dryness and the remaining oil solidified. The product was dissolved in 2M hydrochloric acid and heated for 10 min on a steambath to hydrolyze the 2-chloro to a hydroxyl group. The solution was chilled to room temperature and was extracted with methylene chloride. The methylene chloride solution was evaporated and the product was crystallised from warm acetone.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.[Cl:34][C:35]1[CH:43]=[C:42]([C:44]#[C:45][CH2:46][O:47][CH3:48])[C:38]2[O:39][CH2:40][O:41][C:37]=2[C:36]=1[NH2:49]>CC(N(C)C)=O>[Cl:34][C:35]1[CH:43]=[C:42]([C:44]#[C:45][CH2:46][O:47][CH3:48])[C:38]2[O:39][CH2:40][O:41][C:37]=2[C:36]=1[NH:49][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CC(=O)N(C)C
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Temperature: 0 °C
Yield: 72.2 %

Procedure:
Sodium hexamethyldisilazane (1M solution in THF; 1.0 ml) was added to a mixture of 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (0.16 g) and 5-chloro-7-(3-methoxyprop-1-ynyl)-1,3-benzodioxol-4-amine (0.12 g) in DMA (5 ml) that was cooled to 0° C. The resultant mixture was stirred and allowed to warm to ambient temperature for 2 hours. The reaction mixture was reduced in vacuo and partitioned between ethylacetate and water. The organic layers were washed with water and brine and the product was purified column chromatography on silica using a gradient of 0-10% methanol/methylene chloride as eluent. The resultant yellow gum was dissolved in minimal methylene chloride, diluted with diethyl ether and precipitated as an HCl salt by the addition of 1.0M ethereal HCl. The resultant solid was centrifuged and washed with diethyl ether (3 times) and dried to give the title compound as a yellow solid (185 mg); NMR Spectrum: (DMSOd6+CD3CO2D at 100° C.) 2.33-2.40 (m, 2H), 3.30-3.40 (m, 9H), 3.93-3.98 (m, 4H), 4.03 (s, 3H), 4.38-4.41 (m, 4H), 6.19 (s, 2H), 7.15 (s, 1H), 7.41 (s, 1H), 8.16 (s, 1H), 8.66 (s, 1H); Mass Spectrum: M+H+ 541.5.
Reaction SMILES: [ClH:1].O[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[S:9][CH2:10][C:11]([OH:13])=[O:12].O>[Cl-].[Na+].O>[Cl:1][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[S:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: Cl
Reactant: O=C(O)CS[C@@H]1CCCC[C@H]1O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CSC1CCCCC1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Concentrated hydrochloric acid (200 ml) was added to the compound of Example 10 (27.1 g, 0.13 mole) and the reaction mixture was stirred at room temperature for 20 hours. Water (100 ml) and brine (50 ml) were added to the reaction mixture. The reaction mixture was extracted three times with 175 ml of diethyl ether. The combined diethyl ether extracts were washed three times with 30 ml of water and dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product was purified by silica gel chromatography. The structure was supported by NMR.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O.Cl.[C:37]([NH2:45])(=[NH:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C([O-])(=O)C.[Na+]>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]2[C:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:14])=[C:11]([CH2:10][O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[NH:45][C:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:44]2)[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccccc1
Reactant: N=C(N)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCCc1ccccc1)C1=C(COCCN2CCCCC2)NC(c2ccccc2)=NC1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 2.3 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (1.50 g, 4.32 mmol), 3,4-dichlorobenzaldehyde (0.907 g, 5.18 mmol), benzamidine hydrochloride (0.811 g, 5.18 mmol) and sodium acetate (0.425 g, 5.18 mmol) was stirred in N,N-dimethylformamide (10 mL) for 14 days at room temperature and then heated to 60° C. for 3 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (60 mg) as an oil. Electrospray MS m/z 606/608 [M+H]+.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.COC1C=CC=CC=1[Li].[Cl:23][C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1>CCOCC.O1CCCC1>[Cl:23][C:24]1[N:25]=[C:26]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[O:7][CH3:8])[CH:27]=[C:28]([CH3:30])[N:29]=1
Reactant: COc1ccccc1
Reactant: Cc1ccnc(Cl)n1
Agent: [Li]CCCC
Agent: [Li]c1ccccc1OC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1-c1cc(C)nc(Cl)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Part A: Anisole (2.16 g), n-butyllithium (2.5 M in hexanes, 4.0 mL), and dry ether (4.0 mL) were stirred 18 h at room temperature. Ether (5 mL) and tetrahydrofuran (SmL) were added to make a 0.47 M solution of 2-methoxyphenyllithium (21.12 mL), of which 0.47 mL was added to 2-chloro-4-methylpyrimidine (0.71 g, prepared as described by Strekowski et al (J. Heterocylic Chem. 27, 1393 (1990)) dissolved in dry ether (37 mL) and stirred 30 minutes at -30° C. and 2 hours at 0° C. The reaction was quenched with acetic acid (515 μL), water (36 μL) and tetrahydrofuran (5 mL). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.31 g) dissolved in tetrahydrofuran (5 mL) was added to the reaction which was then stirred 20 minutes. 1N Sodium hydroxide (aq.) (10 mL) was added at 0° C. and the reaction was washed with iN sodium hydroxide (3×10 mL). The organic layer was filtered through silica gel and concentrated to dryness to give 2-chloro-6-methyl-4-(2-methoxyphenyl)pyrimidine (0.72 g).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].Br[CH:9]([CH2:15][CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][CH2:15][CH2:16][N:4]1[C:5](=[O:6])[CH2:7][NH:1][C:2]1=[S:3])[CH3:14]
Reactant: O=C1CNC(=S)N1
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1C(=O)CNC1=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.9 %

Procedure:
As depicted in Scheme 40 below, 2-thiohydantoin (1.4 grams, 12 mmol) was dissolved in DMF (50 ml) and ethyl bromobutyrate (0.48 ml, 3.4 mmol, 0.28 molequivalents) and K2CO3 (2.07 grams, 15 mmol, 1.5 molequivalents) were added thereto. The mixture was stirred at room temperature for 2 hours and then additional ethyl bromobutyrate (0.48 ml, 3.4 mmol, 0.28 molequivalents) was added and the reaction mixture was stirred for 16 hours until all starting material was consumed, as indicated by TLC. Thereafter methylene chloride was added followed by addition of water, the organic phase was extracted, the aqueous layer was washed 5 times with methylene chloride and the combined organic phase was washed 10 times in order to remove residual DMF, dried over Na2SO4 and the solvent was evaporated under reduced pressure to afford a black oil. The crude product was purified by liquid chromatography using silica gel 60 (230-400 mesh) and a 6:4 hexane:methylene chloride mixture, a 5.8:4:0.2 hexane:methylene chloride:ethyl acetate mixture, a 5.5:4:0.5 hexane:methylene chloride:ethyl acetate mixture, a 5:4:1 hexane:methylene chloride:ethyl acetate mixture, a 4:4:2 hexane:methylene chloride:ethyl acetate mixture and a 3:4:3 hexane:methylene chloride:ethyl acetate mixture, sequentially, as eluents. Pure 4-(5-oxo-2-thioxo-imidazolidin-1-yl)-butyric acid ethyl ester (884 mg, 32% yield) was obtained as a yellowish oil.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.O1CCCC1.C([O-])(=O)C.[Na+].C(OCC)(=O)C>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: O=C(O)C1=CCS[C@@H]2C(NC(=O)C(=NOCc3ccc(Cl)cc3Cl)c3csc(NC(=O)C(F)(F)F)n3)C(=O)N12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCc2ccc(Cl)cc2Cl)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 120 h
Yield: 17.7 %

Procedure:
7-[2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-(2,4-dichlorobenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.0 g.) and tetrahydrofuran (30 ml.) were added to a solution of sodium acetate (4.6 g.) in water (100 ml.), and then the mixture was stirred at room temperature for 5 days. Ethyl acetate and water were added to the reaction mixture, and the aqueous layer was separated. Ethyl acetate and tetrahydrofuran were added to the aqueous solution and adjusted to pH 6.2 with 10% hydrochloric acid. The aqueous layer was separated and adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-(2,4-dichlorobenzyloxyimino)-acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.3 g.). m.p. 167° to 193° C. (dec.).
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.C(N(CC)CC)C.[C:25]([O:29][C:30](=[O:48])[NH:31][CH2:32][CH2:33][NH:34][C:35](=[O:47])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[CH:38][CH:37]=1)([CH3:28])([CH3:27])[CH3:26]>CO>[C:25]([O:29][C:30](=[O:48])[NH:31][CH2:32][CH2:33][NH:34][C:35](=[O:47])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:14]([NH2:17])=[N:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[CH:38][CH:37]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(CCCCN)cc1
Agent: I
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Reaction time: 2 h
Yield: 86.8 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl)-2-methylisothiourea hydriodide (0.32 g, 0.82 mmol) and triethylamine (0.27 mL, 1.64 mmol) were sequentially added into a solution of 33 (0.39 g, 0.82 mmol) in 5 mL of methanol. The reaction mixture was stirred in the boiling solvent for 2 h. The solvent was evaporated and the residue was separated by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, 6:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) to provide 34 (0.39 g, 62%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.07 (t, 2H), 1.38 (s, 9H), 1.52 (m, 2H), 1.65 (m, 2H), 2.66 (m, 2H), 3.10 (m, 2H), 3.28 (m, 2H), 4.39 (m, 1H), 6.65 (br s, 1H), 6.94 (m, 1H), 7.28 (m, 2H), 7.75 (d, 2H), 8.49 (m, 1H). m/z (APCI)=548 [C24H34ClN9O4+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[CH2:24]([N:26]([CH2:27][CH3:28])[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ncccc1C
Reactant: CCNCC
Product: CCN(CC)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with diethylamine
Reaction SMILES: Cl[Si:2]([Cl:12])([Cl:11])[CH2:3][CH:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][CH3:8].[CH2:13]([Mg]Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O1CCCC1.C(OCC)C>[Cl:12][Si:2]([Cl:11])([CH2:3][CH:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][CH3:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCC[Mg]Br
Reactant: CCCCC(CC)C[Si](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCC[Si](Cl)(Cl)CC(CC)CCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Trichloro(2-ethylhexyl)silane (synthesized in accordance with J. Am. Chem. Soc. 2008, 130, 16144-16145, 24.8 g) was placed in a 300 mL four-necked flask in a nitrogen atmosphere, and dissolved in tetrahydrofuran (100 mL). The resulting solution was cooled to 0° C., and a solution of n-octyl magnesium bromide in diethyl ether (Sigma-Aldrich Co. LLC., 2.00 M, 50.0 mL) was added dropwise. The reaction solution was agitated for about 30 minutes at 7° C., and then agitated for about 3 hours at room temperature. The solvent was then distilled off with an evaporator. Hexane was added to the resulting crude product, which was then filtered, after which the solvent was again distilled off. Finally, distillation purification (111° C., 0.61 torr) was performed to obtain the target dichloro(2-ethylhexyl)n-octylsilane (Compound G6, 15.9 g, yield 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N:10]=[C:11]=[O:12].C[Si]([N:17]=[N+:18]=[N-:19])(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N:10]1[C:11](=[O:12])[NH:19][N:18]=[N:17]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1cc(N=C=O)c(Cl)cc1Cl
Product: Cc1cc(-n2nn[nH]c2=O)c(Cl)cc1Cl
Yield: 27.3 %

Procedure:
In the manner of Example 1, Step A, the reaction of 3.4 g (0.016 mole) of 2,4-dichloro-5-methylphenyl isocyanate and 3.6 g (0.031 mole) of trimethylsilyl azide produced 1.07 g of 1-(2,4-dichloro-5-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one as a solid, mp 135°-137° C.