Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(=O)(O)(O)O.OO.Cl[CH2:9][CH2:10][S:11]([CH2:14][C:15]([CH2:25][S:26]([CH2:29][CH2:30]Cl)(=[O:28])=[O:27])([CH2:18][S:19]([CH2:22][CH2:23]Cl)(=[O:21])=[O:20])[CH2:16][CH3:17])(=[O:13])=[O:12]>>[CH:29]([S:26]([CH2:25][C:15]([CH2:18][S:19]([CH:22]=[CH2:23])(=[O:21])=[O:20])([CH2:14][S:11]([CH:10]=[CH2:9])(=[O:13])=[O:12])[CH2:16][CH3:17])(=[O:28])=[O:27])=[CH2:30]
Reactant: CCC(CS(=O)(=O)CCCl)(CS(=O)(=O)CCCl)CS(=O)(=O)CCCl
Agent: O=P(O)(O)O
Agent: OO
Product: C=CS(=O)(=O)CC(CC)(CS(=O)(=O)C=C)CS(=O)(=O)C=C
Temperature: 25 °C

Procedure:
To 300 parts of ethanol were successively added 6.9 parts of metallic sodium, 23.4 parts of 2-mercaptoethanol and 18.9 parts of 1,1,1-tris(chloromethyl)propane in this order, and the resulting mixture was heated under reflux. Thereafter, the deposited sodium chloride was removed, and the solution was concentrated to obtain 1,1,1-tris(2-hydroxyethyl-thiomethyl) propane. This compound was added to 50 parts of chloroform, and 45 parts of thionyl chloride was dropped into the resulting mixture. Subsequently, the mixture was heated under reflux, and then the solvent chloroform and unreacted thionyl chloride were removed by distillation under reduced pressure. The residual oily substance was poured into ice water and extracted with ether, and the ether extract was dehydrated over anhydrous sodium sulfate and then freed from the solvent by distillation to obtain 1,1,1-tris(2-chloroethylthiomethyl)propane. To this compound were successively added 0.3 part of phosphoric acid and 60 parts of 30% aqueous hydrogen peroxide, and the resulting medium mixture was heated under reflux and then cooled to deposit 1,1,1-tris(2-chloroethylsulfonylmethyl)propane. The deposited compound was recovered by filtration and dissolved in 200 parts of acetone, and the resulting acetone solution was incorporated with 30 parts of triethylamine and then stirred at room temperature to deposit triethylamine hydrochloride. This hydrochloride was removed, and the acetone solution was concentrated to deposit white solids. The solids were recrystallized from ethanol-acetone to obtain 1,1,1-tris(vinylsulfonylmethyl)propane.
Reaction SMILES: [O:1]([CH:8]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])[C:9]([Cl:12])([Cl:11])[Cl:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:31])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.O>CC(C)=O>[O:1]([CH:8]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:23]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:31])[C:9]([Cl:10])([Cl:11])[Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(NC(Oc1ccccc1)C(Cl)(Cl)Cl)c1ccccc1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: O=C(Oc1ccccc1)Oc1ccccc1C(=O)NC(Oc1ccccc1)C(Cl)(Cl)Cl
Reaction time: 3 h
Yield: 39 %

Procedure:
10 g of N-(1'-phenoxy-2',2',2'-trichloroethyl)-2-hydroxybenzamide and 5.2 g of phenyl chlorocarbonate were dissolved in 200 ml of acetone and the solution was kept at a temperature below 10° C. with an ice-water bath. 3.3 g of triethylamine were added dropwise thereto under stirring and the reaction was continued at room temperature for a further period of three hours. The reaction mixture was poured into water and the resulting crystals were recrystallized from methanol to obtain 5.2 g of N-(1'-phenoxy-2',2',2'-trichloroethyl)-2-phenoxycarbonyloxybenzamide as which crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.S(C)C>C1COCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:5][NH2:7])[CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)c1cccc(Br)c1F
Solvent: CSC
Solvent: C1CCOC1
Product: NCc1cccc(Br)c1F
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a solution of 3-bromo-2-fluorobenzamide (3.0 g, 13.76 mmol) in THF (50 mL) was added BH3.Me2S (1.57 mL, 20.6 mmol) and stirred at 50° C. for 2 h (monitored by TLC). The reaction was quenched by adding HCl (20 mL, 3 N) and the result mixture was stirred for 2 h before THF was removed under vacuum. The aqueous layer was extracted with AcOEt (30 mL), and then was adjusted to pH=9.0 with NaOH (1 N). The aqueous layer was extracted with AcOEt (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 1.30 g of the title compound, as a colorless oil (yield: 46%). 1H NMR (400 MHz, D2O): δ 4.30 (S, 2 H), 7.19-7.22 (m, 1 H), 7.47 (t, J=8.8 Hz, 1 H), 7.73-7.77 (m, 1 H); 13C NMR (100 MHz, D2O): δ 37.4, 108.9, 121.2, 126.2, 130.7, 135.1, 156.2, 158.6.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl.CN(C=O)C>[O:29]1[CH2:30][CH2:31][N:26]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:27][CH2:28]1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To stirred solution of 3-nitrobenzoic acid (5 g, 29.9 mmol) in DCM: DMF (30 ml, 29:1) was added oxalyl chloride (3.14 ml, 35.9 mmol) dropwise at RT. Resulting reaction mixture was stirred for 1 h. The mixture was concentrated and the residue was dissolved in DCM (25 ml), the reaction mixture was cooled to 0° C. and triethylamine (6.26 ml, 44.9 mmol) and morpholine (3.13 ml, 35.9 mmol) were added and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated under vacuum and the residue was diluted with cold water, the solid separated out was filtered and washed with n-hexanes and dried under vacuum to give the product (4.9 g).
Reaction SMILES: [C:1]([C@:3]1([OH:23])[CH:9]=[CH:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH2:5][CH3:6])[C@@H:18]1[C:13](=[CH:14][C:15](=[O:22])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3)#[CH:2].N1C(C)=CC(C)=CC=1C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([O:23][C@@:3]1([C:1]#[CH:2])[CH:9]=[CH:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH2:5][CH3:6])[C@@H:18]1[C:13](=[CH:14][C:15](=[O:22])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Solvent: Cc1cc(C)nc(C)c1
Product: C#C[C@]1(OC(C)=O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 2.0 g. of 17α-ethynyl-17β-hydroxy-18-methyl-4,15-estradien-3-one in 40 ml. of collidine and 13 ml. of acetic anhydride is heated to boiling for 5 hours under nitrogen. After cooling, the solution is poured into ice/water. The reaction product is extracted with methylene chloride, washed in succession with 2N hydrochloric acid, sodium bicarbonate solution, and water, and dried over sodium sulfate. The crude product is chromatographed on silica gel. With 25-30% ethyl acetate-hexane, 950 mg. of 17β-acetoxy-17β-ethynyl-18-methyl-4,15-estradien-3-one is eluted which melts, after recrystallization from acetone/methanol, at 163°-164°.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20])=[CH:13][CH:12]=3)[C:4]=2[CH2:3][O:2]1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([N:17]4[C:18](=[O:22])[C@@H:19]([CH3:21])[NH:20][C:24]4=[O:26])=[CH:15][CH:16]=3)[C:4]=2[CH2:3][O:2]1
Reactant: C[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2COC3)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1NC(=O)N(c2ccc(Oc3cccc4c3COC4)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 134.6 %

Procedure:
A solution of N1-[4-(1,3-dihydro-2-benzofuran-4-yloxy)phenyl]-D-alaninamide (Intermediate 7, 80 mg) and TEA (0.187 ml, 1.341 mmol) in dichloromethane (10 ml) was stirred under argon at 0° C. Triphosgene (39.8 mg, 0.134 mmol) in dichloromethane (4 ml) was added and the mixture was left under stirring at 0° C. for 45 minutes. An aqueous saturated solution of NaHCO3 was then added. The phases were separated and the aqueous one was extracted 3 times with dichloromethane. The gathered organic phases were dried over sodium sulphate and concentrated under vacuum. The crude was purified by flash chromatography (FlashMasterPersonal), using as eluents a gradient Cyclohexane/Ethyl acetate from 100:0 to 40:60. This afforded the title compound as a white solid (58.5 mg).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][N:12]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:17]=2[N:16]=[CH:15][C:14]2=[CH:23][CH:24]=[CH:25][N:13]12.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH3:11][N:12]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:17]=2[NH:16][CH:15]([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]2=[CH:23][CH:24]=[CH:25][N:13]12
Reactant: CN1c2ccncc2N=Cc2cccn21
Reactant: BrCCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1c2ccncc2NC(CCc2ccccc2)c2cccn21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2.8 g of magnesium turnings in 20 ml of diethyl ether and 20 ml of tetrahydrofuran was added 1 ml of 1,2-dibromoethanne followed by 13.94 ml of 2-bromoethylbenzene (dropwise). After initiating the reaction with external heat, the mixture was stirred at room temperature for one hour and then treated, dropwise, with a solution of 10.0 g of 5-methyl-5H-pyrido[3,4-f]-pyrrolo[1,2-b][1,2,5] triazepine in 100 ml of tetrahydrofuran. The reaction mixture was then stirred at room temperature for two hours, poured into an iced ammonium chloride solution, stirred for five minutes, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrate was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate). Flash chromatography of the resultant oil (silica gel; elution with 10% methanol/dichloromethane) afforded a solid which was recrystallized from diethyl ether/ethyl acetate (10:1) to yield 1.25 g of 10,11-dihydro-5-methyl-10-(2-phenylethyl)-5H-pyrido-[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, mp 92°-94° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CCCCOC[C:16]([C:18]1[CH:23]=[CH:22]C=CC=1)=[O:17].CC(C)([O-])C.[K+].[C:30](=O)([O:34]CC)[O:31][CH2:32][CH3:33]>O.C1(C)C=CC=CC=1>[CH2:16]([O:17][C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH2:2][C:30]([O:31][CH2:32][CH3:33])=[O:34])=[CH:5][CH:6]=1)[CH2:18][CH2:23][CH3:22]
Reactant: CCOC(=O)OCC
Reactant: CCCCOCC(=O)c1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccc(C(=O)CC(=O)OCC)cc1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
The acetophenone (9.6 g, 0.05 mole) from (d) was added to a suspension of potassium t-butoxide (9.0 g, 0.08 mole) in diethyl carbonate (24.0 g, 0.2 mole) at 75° C. over 10 minutes. Toluene (40 ml) was added to keep the suspension mobile and heating at 95° C. continued for 30 minutes. After cooling to 50° C., the suspension was poured into cold water (500 ml) and extracted with ethyl acetate (300 ml). The organic solution was dried and evaporated under reduced pressure to give the product (13.2 g, 95%) as a dark red liquid which was used in the next reaction without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC([O-])(C)C.[K+].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=3)[CH:21]=2)[C:16]([Cl:31])=[CH:15][N:14]=1>COCCOC.CN1C(=O)CCC1>[Cl:31][C:16]1[C:17]2[C:22](=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=3)=[CH:19][CH:18]=2)[C:13]([NH:4][C:3]([NH2:5])=[NH:2])=[N:14][CH:15]=1
Reactant: N=C(N)N
Reactant: N#Cc1cccc(-c2ccc3c(Cl)cnc(Cl)c3c2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(-c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A stirred suspension of guanidine hydrochloride (3.8 kg, 39.8 mol) and KOtBu (4.28 kg, 38.1 mol) in DME (17.6 L) was heated to reflux under N2 for 1 hour. The gum containing solution was cooled to room temperature, diluted with NMP (8.8 L) and 1,4-dichloro-7-(3-cyanophenyl)isoquinoline (4.4 kg, 14.7 mol) was added as a solid. The mixture was heated at reflux overnight, cooled to room temperature, filtered through a pad of celite and the pad washed with DME (4.4 L). Water (35.2 L) was added to the filtrate. The resultant slurry was stirred for 2 hour and the solid collected by filtration. The solid was washed with water (4.4 L) and dried in vacuo at 50° C. to give (4-chloro-7-(3-cyanophenyl)isoquinolin-1-yl)guanidine (4.55 kg, 14.1 mol, 96%) as a green solid.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[C:38]2[CH:45]=[C:44]([C:46]#[N:47])[CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)(=[O:36])[CH3:35]>O1CCCC1>[Br:1][CH2:35][C:34]([C:37]1[C:38]2[CH:45]=[C:44]([C:46]#[N:47])[CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)=[O:36]
Reactant: [Br-]
Reactant: CC(=O)c1csc2ccc(C#N)cc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc2scc(C(=O)CBr)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A solution of phenyltrimethylammonium tribromide (2.8 g) in tetrahydrofuran (5 ml) was added dropwise under nitrogen over 30 minutes to a stirred solution of 3-acetylbenzo[b]thiophen-5-carbonitrile (1.5 g) in tetrahydrofuran (50 ml), then the mixture was stirred at ambient temperature for 2 hours. The resulting solid was collected by filtration and triturated with a hot mixture of ethanol (21 ml) and acetic acid (14 ml). The product was collected by filtration and dried in vacuo to give 3-(bromoacetyl)benzo[b]thiophen-5-carbonitrile as a white solid (1.05 g).
Reaction SMILES: OC[C@@H](N[C:11](=[O:26])[C@:12]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.S(=O)(=O)(O)[OH:28]>O1CCOCC1>[CH3:25][C@@:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:13][CH2:14][C:15]([CH3:16])([CH3:17])[CH3:18])[C:11]([OH:26])=[O:28]
Reactant: CC(C)(C)CC[C@](C)(C(=O)N[C@H](CO)c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@](C)(C(=O)O)c1ccccc1
Yield: 90 %

Procedure:
To a solution of Example 48A (4.48 g, 12.7 mmol) in 1,4-dioxane (60 mL) was added 4 M sulfuric acid (60 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo, dissolved in 1 N NaOH (250 mL), and washed with hexane (200 mL). The aqueous layer was acidified to pH 1 with 6 N HCl and extracted with ethyl acetate (3×200 mL). The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a clear oil (2.66 g, 90%). 1H NMR (300 MHz, CDCl3): δ ppm 0.86 (s, 9H) 1.09 (m, 2H) 1.56 (s, 3H) 1.99 (m, 2H) 7.33 (m, 5H).
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>CN(C)C=O>[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][CH:3]=[C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[NH:6][C:5]2=[O:15])=[CH:19][CH:18]=1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Reactant: NCc1ccc(N)cc1
Solvent: CN(C)C=O
Product: Nc1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
To a suspension of 4-Methoxymethylene-4H-isoquinoline-1,3-dione (406 mg, 2.0 mmol) in N,N-dimethylformamide (250 μL) is added 4-aminobenzylamine (244 mg, 2.0 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours, then concentrated. Ethyl acetate is added to the solid residue that remained and the solid is recovered by filtration, rinsing with diethyl ether, and drying to yield 555.5 mg of 4-[(4-Amino-benzylamino)-methylene]-4H-isoquinoline-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([N:8]2[N:12]=[N:11][C:10]([CH:13](OS(C)(=O)=O)[CH3:14])=[N:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])[CH3:28]>C(#N)C>[CH2:27]([O:29][C:30]([N:32]1[CH2:33][CH2:34][N:35]([CH:13]([C:10]2[N:11]=[N:12][N:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[F:20])[N:9]=2)[CH3:14])[CH2:36][CH2:37]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(OS(C)(=O)=O)c1nnn(-c2cc(Cl)ccc2F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(C(C)c2nnn(-c3cc(Cl)ccc3F)n2)CC1
Yield: 73.1 %

Procedure:
The title compound (25.2 mg, 72%, yellow oil, ˜90% pure) was prepared from methanesulfonic acid 1-[2-(5-chloro-2-fluoro-phenyl)-2H-tetrazol-5-yl]-ethyl ester (˜29.5 mg, 0.09 mmol) using potassium carbonate (38 mg, 0.27 mmol) and 1-ethoxycarbonyl piperazine (20 uL, 0.14 mmol) in acetonitrile (1.5 mL) at 80° C. overnight. The product was purified by chromatography using a silica SPE tube (25-35% ethyl acetate in hexane). 1H NMR (CDCl3) δ (ppm): 7.91 (dd, 1H), 7.51 (ddd, 1H), 7.33 (t, 1H), 4.32 (q, 1H), 4.11 (q, 2H), 3.52 (m, 4H), 2.61 (m, 2H), 2.51 (m, 2H), 1.65 (d, 3H), 1.24 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([SH:8])=[CH:6][C:5]([N:9]=[C:10]=[S:11])=[C:4]([F:12])[CH:3]=1.[O:13]1C=C[CH2:16][CH2:15][CH2:14]1.[Cl:19]CCl>>[Cl:19][C:6]1[C:5]([N:9]=[C:10]=[S:11])=[C:4]([F:12])[S:8][C:7]=1[CH:2]1[CH2:3][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: ClCCl
Reactant: C1=COCCC1
Reactant: Fc1cc(Cl)c(S)cc1N=C=S
Product: Fc1sc(C2CCCCO2)c(Cl)c1N=C=S

Procedure:
2.00 g of 4-chloro-2-fluoro-5-mercaptophenylisothiocyanate was dissolved in 20 ml of dichloromethane, and 0.77 g of dihydropyran was added thereto. Two hours later dichloromethane was distilled off to obtain 2.77 g of the above-identified compound as yellow oil.
Reaction SMILES: [Cl:1][CH:2]([CH2:10][CH3:11])[CH2:3][O:4][C:5](=[O:9])[CH2:6][CH2:7][CH3:8].C(OC([NH:19][CH2:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=O)(C)(C)C>>[ClH:1].[C:5]([O:4][CH:3]([O:26][C:24](=[O:25])[CH2:23][CH2:22][C:21](=[O:27])[CH2:20][NH2:19])[CH2:2][CH2:10][CH3:11])(=[O:9])[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(=O)OCC(Cl)CC
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Product: CCCC(=O)OC(CCC)OC(=O)CCC(=O)CN
Product: Cl

Procedure:
The compound was prepared as described in Procedures A and B above from 2-chlorobutylbutyrate and 5-(tert-butoxycarbonylamino)-4-oxopentanoic acid. 1H-NMR (300 MHz, CD3OD) ppm δ 0.95+0.96 (two t, J=6.6 Hz, 6H, two Me), 1.65 (m, 6H, CH3CH2CH2CO2+CH3CH2CH2CH), 2.27 (t, J=10.8 Hz, 2H, CH2CH2CH2CO2), 2.70 (“t”, 2H, COCH2CH2CO2), 2.87 (“t”, 2H, COCH2CH2CO2), 4.02 (s, 2H, CH2NH2), 6.72 (t, J=8.4 Hz, 1H, OCHO).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([OH:12])C.ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>O>[NH2:1][C:2]1[N+:7]([O-:12])=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CCO
Reactant: Nc1cc(Cl)nc(N)n1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Cl)nc(N)[n+]1[O-]
Temperature: -10 °C
Reaction time: 7 h

Procedure:
75 G. of 2,4-diamino-6-chloropyrimidine are dissolved at 35° C. in 1500 ml. of ethanol. The solution is cooled to -10° C. and a solution of 100 g. of 3-chloroperbenzoic acid in 500 ml. of ethanol is slowly added dropwise within 1 hour. The suspension is subsequently stirred at -10° C. for 7 hours and left to stand at 5° C. overnight. The suspension is neutralized with 24 g. of sodium hydroxide in 100 ml. of water. The solid material is filtered off and recrystallized from ethanol, there being obtained pure 2,4-diamino-6-chloropyrimidine-3-oxide.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:44]/[O:45][C:46](=[O:48])[CH3:47])/[C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:27])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]>ClCCl>[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:44]/[O:45][C:46](=[O:48])[CH3:47])/[C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cccnc3)CS[C@H]12)c1csc(N)n1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3cccnc3)CS[C@H]12)c1csc(N)n1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a solution of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetamido]-3-[(3-pyridyl)methylthio]-3-cephem-4-carboxylate (3.32 g, 4.83 m mol) and anisole (3.3 ml) in dichloromethane (16.6 ml) was added trifluoroacetic acid (6.6 ml) at 5° C. The mixture was stirred at 5° C. for 1.5 hours. The reaction mixture was poured into IPE. The resulting precipitates were collected by filtration, washed with IPE, and dried in vacuo to give 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetamido]-3-[(3-pyridyl)methylthio]-3-cephem-4-carboxylic acid bis(trifluoroacetic acid) salt (3.88 g, 5.08 m mol).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([N+:19]([O-])=O)[CH:13]=1)=[O:10])([CH3:5])([CH3:4])[CH3:3].O1CCCC1>[Fe].O>[C:2]([C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([NH2:19])[CH:13]=1)=[O:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)Oc2ccc(Cl)c([N+](=O)[O-])c2)cc(C(C)(C)C)c1O
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(C(=O)Oc2ccc(Cl)c(N)c2)cc(C(C)(C)C)c1O

Procedure:
Iron metal powder (50.2 g; 0.897 mole) and 10M-hydrochloric acid (92 ml; 0.92 mole) were added alternatively over 11/2 hr. to a mixture, of the nitro compound (60.6 g; 0.149 mole) from (a), tetrahydrofuran (520 ml) and water (52 ml), heated under reflux. Heating was continued for a further 31/2 hr. after which the mixture was filtered. The filtrate was evaporated to dryness and the residue partitioned between toluene (500 ml) and water (400 ml). The layers were separated and the toluene solution filtered through kieselguhr, dried and evaporated to give a solid. This material was crystallized from methanol (100 ml) to give the product (41 g; 75%) as a white solid, m.p. 64°-66° C.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[CH2:6]([NH:13][C:14]([C:16]1[S:20][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23](Br)[C:22]2=[O:28])=[N:18][C:17]=1[CH3:29])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH:13][C:14]([C:16]1[S:20][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:22]2=[O:28])=[N:18][C:17]=1[CH3:29])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1nc(N2CCCC(Br)C2=O)sc1C(=O)NCc1ccccc1
Reactant: NCC1CC1
Product: Cc1nc(N2CCCC(NCC3CC3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 69 %

Procedure:
Following the procedure as described in Example 5, making variation as required to use cyclopropylmethanamine in place of 2-cyclopropylethanamine to react with N-benzyl-2-(3-bromo-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide in place of 2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 69% yield: mp 125-126° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.38-7.29 (m, 5H), 5.95 (t, J=5.5 Hz, 1H), 4.56 (d, J=5.5 Hz, 2H), 4.37-4.26 (m, 1H), 4.04-3.91 (m, 1H), 3.54-3.45 (m, 1H), 2.63 (s, 3H), 2.59-2.44 (m, 2H), 2.31-1.82 (m, 4H), 1.81-1.68 (m, 1H), 1.01-0.89 (m, 1H), 0.57-0.41 (m, 2H), 0.23-0.08 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 171.5, 162.5, 156.7, 152.2, 137.9, 128.8, 127.9, 127.7, 119.6, 58.5, 52.5, 47.6, 44.1, 26.4, 20.5, 17.4, 11.2, 3.6, 3.3; MS (ES+) m/z 399.3 (M+1).