Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.CS(C)=O.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>CO>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][CH:2]2[C:7]3=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]3[CH:5]([CH3:16])[CH2:4][CH2:3]2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC1CCC(Br)c2ncc(C(=O)O)c(=O)n21
Solvent: CS(C)=O
Solvent: CO
Product: CC1CCC(Nc2ccc(Br)cc2)c2ncc(C(=O)O)c(=O)n21
Reaction time: 72 h
Yield: 45.2 %

Procedure:
2.9 g. (0.01 mole) of (-)-9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ([α]D20 =-105°, c=2, methanol) are dissolved in 5 ml. of dimethyl-sulfoxide and 3.8 g. (0.022 mole) of p-bromo-aniline are added. The solution is allowed to stand for 3 days at room temperature in an open vessel. 20 ml. of methanol are then added to the reaction mixture. The precipitated crystals are then filtered and washed with methanol. 1.7 g. (45.2%) of (-)-9-(4-bromo-anilino)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is obtained. Melting point: 210°-211° C.
Reaction SMILES: [CH2:1]([C:3]1[NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[C:4]=1[CH2:26][CH3:27])[CH3:2].[H-].[Na+].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].Cl>CN(C=O)C.O>[CH2:1]([C:3]1[N:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[C:4]=1[CH2:26][CH3:27])[CH3:2]
Reactant: CCc1[nH]c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2c1CC
Reactant: CCOC(=O)CCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1c(CC)c(CC)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 6,7-diethyl-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazine (step 1) (14 mg, 0.039 mmol) in dry DMF (1 ml) under nitrogen was treated with NaH (1.733 mg, 0.043 mmol). The resulting mixture was stirred at RT for 20 minutes and treated with ethyl 7-bromoheptanoate (8.44 μl, 0.043 mmol). After stirring at RT for 3 hours, the mixture was added to water and the pH was adjusted to pH1 using 2M HCl. The aqueous was extracted with EtOAc (×3) and the combined organic extracts were sequentially washed with water (×1) and brine (×1), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound (with trace hydrolysis acid product present);
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.O>CN(C)C=O>[C:1]1([C:7]2[N:8]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cn(-c2ncccn2)c(-c2ccccc2)n1
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (700 mg) in dimethylformamide (30 mL) was added sodium hydride (60% in oil, 180 mg) at room temperature and the mixture was stirred for 30 min. 2-Chloropyrimidine (489 mg) was further added and the mixture was stirred for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3) to give the title compound as a yellow oil (yield 160 mg, yield 16%).
Reaction SMILES: C[O-].[Na+].[CH:4]([O:6][CH3:7])=[O:5].[Br:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24](OC)=[O:25])[CH:12]=[CH:11][CH:10]=1.O>C1(C)C=CC=CC=1>[Br:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[C:23](=[CH:24]\[OH:25])/[C:4]([O:6][CH3:7])=[O:5])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)Cc1ccccc1COc1cccc(Br)n1
Reactant: COC=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C(=C/O)c1ccccc1COc1cccc(Br)n1
Yield: 97.9 %

Procedure:
Sodium methoxide (0.34 g, 6.0 mmol) and methyl formate (1 ml, 16 mmol) were added portionwise to a stirred solution of methyl 2-(6-bromopyrid-2-yloxymethyl)phenylacetate (0.8 g, 2.3 mmol) in dry toluene (10 ml) under a nitrogen atmosphere at room temperature. After 8 hours at room temperature the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried and the ethyl acetate removed to give (E)-methyl 2-[2-(6-bromopyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (0.82 g, 80%) as a brown gum which was used in the final stage without further purification; 1H NMR (270 MHz)δ: 3.74(3H,s), 5.28(2H,s), 6.66(1H,d), 7.06(1H,d), 7.15-7.55(6H,m), 11.95(1H,d) ppm.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[C:8]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[N:9][O:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O>[C:13]([C:8]1[C:7]([NH:6][C:3](=[O:4])[CH2:2][Br:1])=[C:11]([CH3:12])[O:10][N:9]=1)(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Br)CBr
Reactant: Cc1onc(C(=O)c2ccccc2)c1N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1onc(C(=O)c2ccccc2)c1NC(=O)CBr
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Bromoacetylbromide (40 g, 0.2 mole) was added slowly to a mixture of 20 g (0.1 mole) (4-amino-5-methylisoxazol-3-yl)-phenylmethanone of Example Ib in 500 ml dichloromethane with 200 ml of 2N sodium carbonate and 500 ml saturated sodium bicarbonate at 5° C. After stirring for 30 minutes the mixture was diluted with 400 ml dichloromethane and 400 ml water. The organics were washed with water and brine and dried (magnesium sulfate). Concentration gave 32 g of an oil which was chromatographed on high pressure liquid chromatograph (HPLC) using dichloromethane as an eluent to yield 23 g (71%) of a solid, melting point 89°-92° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[C:9]1=[N:10][NH:11][C:12]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[C:8]1[CH2:7]2.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].C(N(C(C)C)CC)(C)C>C1COCC1>[C:30]1([O:29][C:27]([N:10]2[C:9]3[C:21]4[C:6]([CH2:7][C:8]=3[C:12]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[N:11]2)=[CH:5][C:4]([O:3][CH3:2])=[C:23]([O:24][CH3:25])[CH:22]=4)=[O:28])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1cc2c(cc1OC)-c1n[nH]c(Nc3cccc(F)c3)c1C2
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)-c1c(c(Nc3cccc(F)c3)nn1C(=O)Oc1ccccc1)C2

Procedure:
To a mixture of (6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine (Compound 14) (1.5 g g, 4.2 mmol), phenyl chloroformate (Compound 55a) (0.76 mL, 6.3 mmole) and THF (10 mL) was added Diisopropylethylamine (DIPEA) (1.4 mL, 8.4 mmole) at room temperature with stirring. The reaction was stirred at room temperature over night. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The solvent was dried over sodium sulfate and removed via rotovap to give a crude material (Compound 433). MS m/z 446.1 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](S(C)=O)[N:8]([CH3:15])[C:7]2=[O:16].IC1C=CC=C2C=1N=C(S(C)(=O)=[O:29])N(C)C2=O.O[Li].O>C1COCC1.O>[OH:29][C:9]1[N:8]([CH3:15])[C:7](=[O:16])[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cn1c(S(C)(=O)=O)nc2c(I)cccc2c1=O
Reactant: Cn1c(S(C)=O)nc2c(I)cccc2c1=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(O)nc2c(I)cccc2c1=O
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
A suspension of 8-iodo-3-methyl-2-(methylthio)quinazolin-4(3H)-one (700a; 15 g, 45.2 mmol) in 400 mL of DCM was set stirring at 0° C. before adding 3-chlorobenzoperoxoic acid (15.59 g of 77% max. Aldrich, 70 mmol) portion wise over 10 min. The ice bath was removed; and the reaction mixture was stirred at RT for 30 min. It was diluted with 200 mL of DCM, washed sequentially with ice cold 2×50 mL of saturated Na2CO3 followed by sat. Na2SO3 solution and 15 mL of brine. The organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to give yellow crystalline solid (700b) containing a mixture of 8-iodo-3-methyl-2-(methylsulfinyl)quinazolin-4(3H)-one and 8-iodo-3-methyl-2-(methylsulfonyl)quinazolin-4(3H)-on. The crude material of yellow crystalline solid (700b) in 40 mL of THF and 40 mL of water at RT was treated with LiOH—H2O (6.60 g, 275 mmol). The reaction mixture was stirred in an oil bath at 75° C. for 2.5 h. It was concentrated to half of its volume under reduced pressure. The precipitated solid was filtered, rinsed with 2×5 mL of water followed by 2×5 mL of ether. The off-white crystalline solid was dried in a vacuum oven at 45° C. for 48 h to give 2-hydroxy-8-iodo-3-methylquinazolin-4(3H)-one (700c; 12.79 g, 42.3 mmol, 94% yield). The crude material was used in the next step. m/z (ES, +ve) 302.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:7]2[C:6]([CH2:16][CH2:17][C:18](=O)[C:19]([OH:21])=O)=[CH:5][CH:4]=1.C(O)(=O)C.[NH2:27][NH2:28]>C(O)C>[CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:7]2[C:6]([C:16]2[CH2:17][CH2:18][C:19](=[O:21])[NH:27][N:28]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(CCC(=O)C(=O)O)c2cc(C(F)(F)F)nn12
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C2=NNC(=O)CC2)c2cc(C(F)(F)F)nn12
Reaction time: 8 h
Yield: 20.2 %

Procedure:
The compound of Example 207 (616 mg, crude) was dissolved in ethanol (15.0 mL). To this solution, hydrazine monoacetate (428 mg) was added and the mixture was stirred for 8 hours under reflux. Subsequently, the solvent was evaporated and the residue was purified by amino-silica gel column chromatography (ethyl acetate) to afford the title compound as a yellow powder (123 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][NH2:19])[O:15][N:14]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:26](=[O:28])[CH3:27])[O:15][N:14]=3)=[CH:11][CH:12]=2)=[CH:5][CH:6]=1
Reactant: NCc1cc(-c2ccc(-c3ccncc3)cc2)no1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CC(c2ccc(-c3ccncc3)cc2)=NO1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a flame drived flask containing (R)-4,5-Dihydro[3-[4-(4-pyrdinyl)phenyl]-5-(hydroxymethyl)]isoxazole (440 mg, 1.73 mmol) in methylene chloride (20 mL) at 0° C. under an inert atmosphere is added triethylamine (0.36 mL, 2.60 mmol) and methanesulfonyl chloride (0.14 mL, 1.82 mmol). The reaction is slowly warmed to ambient temperature, stirred 3 hours, and quenched with water (25 mL). The organic phase is separated, washed with saturated NaHCO3 (25 mL) and saline (25 mL), dried over sodium sulfate and concentrated in vacuo to give crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-[[(methylsulfonyl)oxy]methyl]isoxazole. The crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-[[(methylsulfonyl)oxy]-methyl]isoxazole (580 mg, 1.73 mmol) is dissolved in tetrahydrofuran (4 mL), isopropanol (4 mL), and concentrated ammonium hydroxide (4 mL) in a thick wall resealable vessel and heated to 100-110° C. for 15 hours. The reaction is cooled to ambient temperature, diluted with ethyl acetate (50 mL), washed with saline (20 mL), dried over sodium sulfate and concentrated in vacuo to give crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-(aminomethyl)isoxazole. The crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-(aminomethyl)isoxazole (320 mg. 1.57 mmol) is dissolved in methylene chloride (15 mL) and cooled to 0° C. under an inert atmosphere. Pyridine (0.31 mL, 3.78 mmol) and acetic anhydride (0.15 mL, 1.57 mmol) are added to the cooled solution and stirred 20 hours at ambient temperature. The reaction is concentrated in vacuo, diluted with methylene chloride (50 mL), washed with saline (25 mL), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-240 mesh, 200 mL), eluting with chloroform/methanol (97/3). The appropriate fractions are combined (Rf =0.14, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 244-245° C.
Reaction SMILES: [CH:1]([N:4]([CH3:17])[C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:3])[CH3:2].[H][H]>[Pd].CCO.C1COCC1>[CH:1]([N:4]([CH3:17])[C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(C)c1nc2ccc([N+](=O)[O-])cc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)N(C)c1nc2ccc(N)cc2s1
Yield: 89.5 %

Procedure:
Combine isopropyl-methyl-(6-nitro-benzothiazol-2-yl)-amine (1.32 g, 5.25 mmol) and 5% palladium on carbon (3.00 g) in EtOH (50 mL) and THF (25 mL). Shake on a Parr shaker at 60 psi hydrogen at room temperature for 7 h. Filter with filter paper, washing with EtOH (20 mL), and concentrate in vacuo to afford the title compound (1.04 g, 90%). 1H NMR (400 MHz, CDCl3): δ 7.36 (d, 1H, J=8.4 Hz), 6.93 (d, 1H, J=2.2 Hz), 6.67 (dd, 1H, J=8.6, 2.4 Hz), 4.31 (m, 1H), 3.62 (s, 2H), 2.99 (s, 3H), 1.25 (d, 6H, J=6.6 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:35])[N:17]([C:21]3[CH:22]=[C:23]([CH:30]=[C:31]([F:34])[C:32]=3[CH3:33])[C:24]([NH:26][CH:27]3[CH2:29][CH2:28]3)=[O:25])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[CH3:36][NH2:37]>O.O1CCOCC1>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:22]=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:37][CH3:36])[CH2:13][CH2:12]4)[C:16]3=[O:35])[C:32]([CH3:33])=[C:31]([F:34])[CH:30]=2)[CH2:29][CH2:28]1
Reactant: CN
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Solvent: C1COCCO1
Solvent: O
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)cc(F)c3C)c2=O)CC1

Procedure:
3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide (Example 259d 0.5 g) and 40% methylamine in water (0.697 mL) were heated at 100° C. in dioxane (8 mL) in a sealed tube for 24 h. Purification of the cooled solution by preparative HPLC (Xbridge column—acetonitrile/0.2% ammonia mobile phase) gave the title compound (270 mg).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:20][C:21]#[N:22])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: C1COCCO1
Product: N#CCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A suspension of 4,4-diphenylpiperidine (4.00 g, 16.9 mmol, 1.00 equiv), chloroacetonitrile (1.40 mL, 21.9 mmol, 1.30 equiv, Aldrich), potassium carbonate (4.67 g, 33.8 mmol, 2.00 equiv), and potassium iodide (561 mg, 3.38 mmol, 0.20 equiv) in n-butanol (20 mL) and 1,4-dioxane (20 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc) to afford 4.01 g (86%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][C:11]1=[O:16].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:13]2[CH2:14][CH2:15][NH:10][C:11](=[O:16])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C1CNCCN1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C1CN(Cc2ccc(Cl)nc2)CCN1
Temperature: 25 °C
Reaction time: 84 h
Yield: 34.3 %

Procedure:
A mixture of 2-chloro-5-(chloromethyl)pyridine (1.4 g, 8.4 mmol), piperazinone (0.84 g, 8.4 mmol), and potassium carbonate (1.0 mL, 17 mmol) in a mixed solvent consisting of acetonitrile (40 mL) and THF (20 mL) was stirred at room temperature for 3.5 days. Upon workup, the mixture was filtered through a layer of celite and the cake was washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was subjected to combi-flash column chromatography (methanol/DCM) to give compound 356 (0.65 g, 34% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.35 (1 H, d, J=2.0 Hz), 7.81 (1 H, dd, J=8.1, 2.4 Hz), 7.76 (1 H, br. s.), 7.49 (1 H, d, J=8.3 Hz), 3.57 (2 H, s), 3.10-3.16 (2 H, m), 2.93 (2 H, s), 2.52-2.56 (2H, m). LCMS-ESI (POS), M/Z, M+1: Found 226.0.
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][C:16]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:17]=3[O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:12][C:11]=2[F:32])=[S:8])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.Cl[C:34](OC(Cl)(Cl)Cl)=[O:35].C(N(CC)CC)C>O1CCOCC1>[N:1]12[CH:7]([N:9]=[C:10]3[CH:31]=[CH:30][C:13]([O:14][CH2:15][C:16]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:17]=4[O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:12][CH:11]3[F:32])[S:8][C:34](=[O:35])[N:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2
Reactant: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(NC(=S)N2CCCCN2)c(F)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)Oc1cc(C)ccc1COC1=CC(F)C(=NC2SC(=O)N3CCCCN23)C=C1
Yield: 31.4 %

Procedure:
By the method of Example 1, Step D, of U.S. Pat. No. 4,906,281, 1.50 g (0.00325 mole) of methyl 2-[2-[4-(perhydropyridazin-1-ylthiocarbonylamino)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate and 0.36 g (0.09017 mole) of trichloromethyl chloroformate were reacted in the presence of 0.36 g (0.0035 mole) of triethylamine in 35 mL of dioxane, yielding 0.50 g of methyl 2-[2-[4-(8-thia-1,6-diazabicyclo[4.3.0]nonane-7-on-9-ylimino)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate as a syrup. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH =8.0 Hz); 1.78-1.96 (m, 4H); 2.30 (s, 3H); 3.64-3.80 (m, 4H); 3.70 (s, 3H); 4.80 (q, 1H, JHH =8.0 Hz); 5.10 (dd, 2H); 6.58-7.30 (m, 6H) .
Reaction SMILES: [CH3:1][N:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[Cl:18][C:19]1[C:20]([C:25](Cl)=[O:26])=[N:21][CH:22]=[CH:23][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:10])/[CH:3]=[C:4](/[C:25](=[O:26])[C:20]1[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][N:21]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C/N(C)C
Reactant: O=C(Cl)c1ncccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(=C\N(C)C)C(=O)c1ncccc1Cl
Temperature: 83 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
To a light yellow solution of (E)-ethyl 3-(dimethylamino)acrylate (1.72 g, 12.0 mmol) in toluene (20 mL) was added triethylamine (1.21 g, 1.67 mL, 12.0 mmol) at room temperature. To this, a solution of 3-chloropicolinoyl chloride (34) (1.76 g, 10 mmol) in toluene (5 mL, heated to dissolve) was added. Then, the resulting dark brown solution was heated to 83° C. and stirred for 12 h at this temperature. During this period, it turned to a dark brown solution. Then, the heating was stopped and the dark brown mixture was filtered off and the solids were washed with ethyl acetate. The brown ethyl acetate solution was washed with water which was diluted with 1.0N HCl. The acidic aqueous layer was extracted one more time with ethyl acetate and the combined organic layer was washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave only 1.6 g of crude brown mixture. Then, the acidic aqueous layer was extracted with dichloromethane (2×100 mL) and then the aqueous layer was neutralized with a saturated sodium bicarbonate solution and then extracted one more time with dichloromethane. The combined dichloromethane extracts were washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave another 1.2 g of dark drown oil which was combined with the first brown residue and the mixture was purified using an ISCO (120 g) column, eluting with ethyl acetate in hexanes (0 to 100%) and then 10% methanol in dichloromethane. The pure fractions were combined and the solvent was removed under vacuum to obtain (Z)-ethyl 3-(dimethylamino)-2-(3-chloropicolinoyl)acrylate (35) (1.16 g, 41% yield) as a dark brown oil.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].S(Cl)([Cl:14])(=O)=O>>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([Cl:14])[CH:7]=[CH:8][C:1]=1[O:9][CH3:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccccc1OC
Product: COc1ccc(Cl)cc1OC
Reaction time: 1 h

Procedure:
Into a triple-necked flask of a liter, provided with a magnetic stirring system, with a thermometer, with a calcium chloride trap and with a dropping funnel, were introduced in the cold at about 0° C. and successively 138 g (1 mole) of veratrol then drop by drop 135 g (1 mole) of sulfuryl chloride. When the addition was terminated, the reaction medium was brought to room temperature, then after standing one hour was distilled under reduced pressure.
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH2:10][CH2:11][S:12](=[O:15])(=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[CH3:32][CH2:33][C:34](Cl)=[S:35].[OH-].[Na+]>CC(C)=O>[CH3:32][CH2:33][C:34]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:18][N:19]=[N:20][N:21]=3)[CH2:10][CH2:11][S:12](=[O:14])(=[O:15])[NH2:13])[CH2:7][S:8][C@H:3]12)=[S:35]
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@H]12
Reactant: CCC(=S)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(C(CCS(N)(=O)=O)Sc3nnn[nH]3)CS[C@H]12
Reaction time: 0.33 h

Procedure:
To a stirred, cooled (-20° ) solution of 10.8 g. (0.026 mol.) of 7-amino-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 220 ml. of 3% sodium bicarbonate and 220 ml. of acetone is dropwise added a solution of 3.66 g. (0.029 mol.) of methylthioacetyl chloride in 52 ml. of acetone, during which time the pH of the reaction mixture is maintained at 8.0 by addition of 10% sodium hydroxide. After addition the reaction mixture is stirred an additional 20 minutes at -15°, then is warmed to 25° and extracted with ether. The remaining aqueous phase is cooled, 250 ml. of ethyl acetate is added and the slurry is acidified with 3N hydrochloric acid. The layers are separated and the aqueous phase is extracted twice more with ethyl acetate. The combined extracts are dried (MgSO4) and evaporated to dryness to yield the title compound.