Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:10](OC)(=[O:15])[CH2:11][C:12]([CH3:14])=O>C(O)(=O)C>[CH:2]1([N:8]2[C:10](=[O:15])[CH2:11][C:12]([CH3:14])=[N:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CC(C)=O
Reactant: NNC1CCCCC1
Agent: Cl
Solvent: CC(=O)O
Product: CC1=NN(C2CCCCC2)C(=O)C1
Temperature: 100 °C
Yield: 102.6 %

Procedure:
Cyclohexylhydrazine hydrochloride (2.00 g, 13.3 mmol) and methyl acetoacetate (2.37 g, 20.4 mmol) were combined in glacial acetic acid (55 mL). The reaction was heated to 100° C. for 18 h. After allowing the reaction to cool to RT, the solvent was removed under reduced pressure to give 2.46 g of the desired product as a pale orange solid. This material was used without further purification. MS (ES+) m/z 181.2 (M+H+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][N:30]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][N:30]([CH3:29])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: CN(CCCCCCCl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN(C)c2ccccc2)CC1
Yield: 70.3 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.3 g) as starting compound, potassium carbonate (2.0 g) and 6-(N-methyl-N-phenylamino)hexyl chloride (0.8 g) were reacted and treated in the same manner as in Example 168 to give 1.2 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(N-methyl-N-phenylamino)hexyl)piperidin-4-yl)-methyl)benzamide.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].F[C:11](F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:11][O:8][C:1](=[O:9])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(O)C[C@H](O)C(=O)O
Product: COC(=O)[C@@H](O)CC(=O)O
Yield: 100 %

Procedure:
L-malic acid (10 g., 74.6 mmole) was placed in a 100 ml. round-bottom flask and cooled in an ice bath. Trifluoroacetic anhydride, TFAA, (25 ml.) was added to the flask and the suspension was stirred in the cold. Within 15 minutes a homogeneous solution was obtained. After stirring for 2 hours at a temperature of about 0° C., the TFAA and trifluoroacetic acid were removed by vacuum distillation at 0° C. The solid residue of L-malic anhydride trifluoroacetate represented by the formula ##STR84## was dissolved in 50 ml. of anhydrous methyl alcohol and the solution stirred at room temperature for 3.5 hours. The solvent was removed by evaporation to provide in 100% yield L-malic acid monomethyl ester melting at about 75° to about 79° C. After recrystallization from ethyl acetate-hexane the product melted at about 79° to about 80° C. [α]D20 =5.8±1° (C=9.5, methanol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=2)=[N:4][O:5][N:6]=1.[H-].[Na+].Cl.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][Cl:30]>CN(C)C=O>[ClH:30].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:8]2[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=[C:7]2[C:3]2[C:2]([NH2:1])=[N:6][O:5][N:4]=2)=[CH:17][CH:18]=1
Reactant: Nc1nonc1-c1nc2cnccc2n1-c1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(-n2c(-c3nonc3N)nc3cnccc32)cc1
Temperature: 60 °C

Procedure:
To a solution of the product of Example 38 (30 mg, 0.102 mmol), in N,N-dimethylformamide (2 ml), was added sodium hydride (60% dispersion in mineral oil, 4 mg, 0.10 mmol). After 5 minutes at room temperature 2-(dimethylamino)ethyl chloride hydrochloride (15 mg, 0.102 mmol) and sodium hydride (60% dispersion in mineral oil, 4 mg, 0.102 mmol) were added and the reaction heated at 60° C. for 5 hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and 2M sodium hydroxide solution. The organic phase was separated then washed with water (×3), dried over anhydrous sodium sulphate and evaporated in vacuo. Purification of the residue by silica gel chromatography eluting with 10% methanol in dichloromethane gave the free base of the title compound. The product was dissolved in methanol (1 ml) and treated with a 1M solution hydrochloric acid (36 uL, 0.036 mmol) in diethyl ether and evaporated in vacuo to yield the title compound (14 mg, 32%); MS (ES+) m/e 366 (M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10]Cl.[C-:12]#[N:13].[Na+]>C(O)C.O>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:10][C:12]#[N:13]
Reactant: ClCc1c(Cl)cc(Cl)cc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1c(Cl)cc(Cl)cc1Cl
Yield: 69.4 %

Procedure:
To a stirred solution of 1,3,5-trichloro-2-chloromethyl-benzene (12.85 g, 58.8 mmole) in ethanol (45 ml), NaCN (3.20, 67.0 mmole) solution in water (15 ml) was added at ambient temperature. The reaction mixture was refluxed for 4 hours to complete the reaction. Ethanol was evaporated and the reaction mixture was diluted with water (50 ml). The aqueous layer was extracted with EtOAc (3×100 ml). The combined organic layer was washed with brine (30 ml) and dried over sodium sulfate. Organic layer was concentrated under vacuum to give white solid. Crude product was purified by chromatography on silica-gel column to afford 9.0 g (75.0% of theory) of (2,4,6-trichloro-phenyl)-acetonitrile
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH3:8])=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N+:6]([O-:20])[C:5]([CH3:8])=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCCc1cc(Cl)nnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCc1cc(Cl)n[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-3-methyl-4-propyl-pyridazine (8.03 g, 47.06 mmol) in CH2Cl2 (200 ml) is added mCPBA (11.6 g, 77%, 51.77 mmol). The mixture is stirred at room temperature overnight. Saturated K2CO3 aqueous solution (50 ml) is added and the layers are separated. The organic layer is then washed with brine (100 ml) and dried (Na2SO4) and evaporated, which provides the title product as a light yellow oil.
Reaction SMILES: CO.[C:3]([C:6]1[CH:29]=[CH:28][C:9]([NH:10][C:11]2[CH:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)(=O)[CH3:4]>[C].[Pd].C(OCC)(=O)C>[CH2:3]([C:6]1[CH:29]=[CH:28][C:9]([NH:10][C:11]2[CH:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH3:4]
Reactant: CC(=O)c1ccc(Nc2cc(CCc3ccccc3)ccc2C(=O)O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1ccc(Nc2cc(CCc3ccccc3)ccc2C(=O)O)cc1
Temperature: 40 °C
Reaction time: 7 h
Yield: 100.9 %

Procedure:
To a mixed solution of methanol 1.0 mL and ethyl acetate 1.0 mL of 2-(4-acetylanilino)-4-phenethylbenzoic acid 10 mg was added 5% palladium-carbon 2.0 mg at room temperature, and it was stirred under hydrogen atmosphere at 40° C. for 7 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and the solvent was removed under reduced pressure to give 2-(4-ethylanilino)-4-phenethylbenzoic acid 9.7 mg of a white solid.
Reaction SMILES: [P:1]([O-:32])([O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:13])=[CH:6][C:5]=1[O:21][CH3:22])=[O:2].[Na+:33].[O-]CC.[Na+].Cl[CH2:39][C:40]([OH:42])=[O:41]>C(O)C>[P:1]([O-:32])([O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:39][C:40]([O-:42])=[O:41])[CH:15]=2)=[O:13])=[CH:6][C:5]=1[O:21][CH3:22])=[O:2].[Na+:33].[Na+:33]
Reactant: O=C(O)CCl
Reactant: COc1cc(CCC(=O)c2cccc(O)c2)ccc1OP(=O)([O-])Oc1cc(C)cc(C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CCC(=O)c2cccc(OCC(=O)[O-])c2)ccc1OP(=O)([O-])Oc1cc(C)cc(C)c1
Reaction time: 1 h

Procedure:
To a mixture of 22.5 g sodium 4-(3-(3-hydroxyphenyl)-3-oxopropyl)-2-methoxyphenyl 3,5-dimethylphenyl phosphate (see Example 6) and 1000 ml of 0.22 M sodium ethoxide kept under nitrogen, 5.7 g of chloroacetic acid in 50 ml anhydrous ethanol is added dropwise with stirring and the mixture being kept boiling. After all of the acid is added the refluxing is continued for one hour. The reaction mixture is cooled and sodium chloride is removed by filtration. The solvent is evaporated under vacuum, and the residue is dissolved in water, acidified with 2 M hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with saturated sodium sulphate solution. Water is added and pH adjusted to 7 with 2 M sodium hydroxide. The water layer is freeze-dried giving disodium 4-(3-(3-carboxylatomethoxyphenyl)-3-oxopropyl)-2-methoxyphenyl 3,5-dimethylphenyl phosphate.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[S:21](Cl)(=[O:23])=[O:22].Br[CH:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31]>O>[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[S:21]([CH:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31])(=[O:23])=[O:22]
Reactant: O=C1OCCC1Br
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1OCCC1S(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 150 °C
Yield: 17.7 %

Procedure:
A solution of sodium sulfite (153 mg, 1.21 mmol) and sodium bicarbonate (306 mg, 3.63 mmol) in water (3 mL) was treated with 2,4,5-trifluorobenzenesulfonyl chloride (280 mg, 1.21 mmol) and heated in a microwave reactor at 150° C. for 400 seconds. The resulting mixture was treated with 3-bromodihydrofuran-2(3H)-one (299 mg, 1.82 mmol) and then heated in a microwave reactor at 150° C. for 500 seconds. The mixture was cooled to 10° C. and the resulting solid filtered off and dried in vacuo to give the title compound (60 mg).
Reaction SMILES: [CH2:1]=O.[Cl:3][C:4]1[C:5]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([NH2:30])=[O:29])[C:21]=3[CH:20]=2)=[N:6][C:7]([NH:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[N:8][CH:9]=1.[BH4-].[Na+].[ClH:33]>CO.ClCCl>[ClH:3].[ClH:33].[Cl:3][C:4]1[C:5]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([NH2:30])=[O:29])[C:21]=3[CH:20]=2)=[N:6][C:7]([NH:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:1])[CH2:15][CH2:14]2)=[N:8][CH:9]=1
Reactant: C=O
Reactant: NC(=O)c1cccc2sc(-c3nc(NCCC4CCNCC4)ncc3Cl)cc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Aqueous formaldehyde (37.4% or 13.5 M, 0.134 mL, 1.80 mmol) is added to a stirred solution of 2-[5-chloro-2-(2-piperidin-4-ylethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid amide (150 mg, 0.361 mmol) in CH3OH (15 mL) and dichloromethane (15 mL) at room temperature to form a light suspension. The mixture is allowed to stir for 90 minutes. The mixture is cooled to 0° C. before it is treated with powdered sodium borohydride (68.1 mg, 1.80 mmol). The mixture is stirred at 0° C. for 1 hour, then allowed to slowly warm up to room temperature to form a clear solution. After concentration, the crude product is subject to chromatographic purification on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane 4-12%, to give the desired methylated product as a yellowish solid. The free base is dissolved in CH3OH (20 mL) and dichloromethane (20 mL) then treated with 12 N HCl (0.30 mL) to form a yellow solution. After concentration and vacuum drying at 60° C., the title compound is obtained as a yellow solid (174 mg, 95% yield). ES+(m/z) 430 (35Cl) and 432 (37Cl) [M(free base)+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:25])=[CH:11][C:12]([NH:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:37])[C:27]1[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[C:29]([O:30][CH3:31])[CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([F:25])=[CH:11][C:12]([NH:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:13]([CH:17]=1)[C:14]([NH:37][CH2:26][C:27]1[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[C:29]([O:30][CH3:31])[CH:28]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(O)c1cc(OCc2ccccc2)c(F)cc1NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2cc(OCc3ccccc3)c(F)cc2NC2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A mixture of 14 g of the compound obtained in Step 4.4, 7.46 g of veratrylamine, 19.99 g of HBTU and 13.1 g of DIEA in 300 ml of DMF is stirred for 2 hours at room temperature. The solvent is evaporated off under reduced pressure and the residue is taken up in DCM. The resulting solution is washed twice with saturated aqueous NaHCO3 solution. The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/EtOAc mixture from (90/10, v/v) to (40/60, v/v) to give 16 g of the expected product.
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][OH:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[Li]CCCC.[CH2:18]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[C:24]1=[O:33])[CH2:19][CH2:20][CH2:21][CH3:22]>C1COCC1>[OH:32][C:25]1([C:2]2[C:3]([CH2:11][OH:12])=[CH:4][C:5]3[O:9][CH2:8][O:7][C:6]=3[CH:10]=2)[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:24]1=[O:33]
Reactant: CCCCCN1C(=O)C(=O)c2ccccc21
Reactant: OCc1cc2c(cc1Br)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2CO)OCO3)c2ccccc21
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 17.1 %

Procedure:
To a solution of (6-bromo-1,3-benzodioxol-5-yl)methanol (Mann, J., et al, J. Chem. Soc. Perkin Trans. 1 (1984):2081-8) (1.27 g, 5.50 mmol) in THF (45.0 mL) was added n-BuLi (5.00 mL, 2.0 M, 10.0 mmol) dropwise at −75° C. The reaction mixture was stirred at −75° C. for 45 min followed by the addition of a solution of 1-pentyl-1H-indole-2,3-dione (1.00 g, 4.60 mmol) in THF (20.0 mL) at −75° C. The resulting mixture was stirred at ambient temperature for 12 hrs and quenched with ammonium chloride solution (5.00 mL). More ethyl acetate and water were added and separated. The organic layer was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with 50% EtOAc:Hexanes to yield the title compound (0.29 g, 25%) as a solid: 1H NMR (300 MHz, CDCl3) δ 7.38-7.24 (m, 2H), 7.11 (t, 1H), 6.91 (d, 1H), 6.81 (s, 1H), 6.43 (s, 1H), 5.90-5.87 (m, 2H), 4.77 (dd, 2H), 3.75-3.56 (m, 2H), 1.75-1.58 (m, 2H), 1.26-1.35 (m, 2H), 0.89-0.83 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 177.8, 147.4, 147.2, 142.8, 133.5, 132.2, 131.1, 130.1, 125.3, 123.8, 111.4, 109.2, 108.1, 101.5, 79.5, 64.7, 40.4, 29.0, 26.8, 22.3, 13.9; MS (ES+) m/z 352.1 (M−17).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[CH2:26]1[CH2:33][O:32][S:29](=[O:31])(=[O:30])[CH2:28][CH2:27]1.C(N(CC)CC)C>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:29]([CH2:28][CH2:27][CH2:26][CH2:33][OH:32])(=[O:31])=[O:30])[CH2:24][CH2:25]2)[N:3]=1
Reactant: O=S1(=O)CCCCO1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCO)CC2)nc1N
Temperature: 150 °C
Yield: 85.9 %

Procedure:
The mixture of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (100 mg, 0.290 mmol, Example 59), 1,4-butane sultone (81 uL, 0.870 mmol, Aldrich) and triethylamine (41 uL, 0.290 mmol) in tetrahydrofuran (3 mL) was heated at 150° C. for 1 hour using the Smith Creator microwave synthesizer. Upon cooling to room temperature, the reaction mixture was concentrated. Purification of the crude residue by reverse phase HPLC (C18, eluting with water and acetonitrile) gave [4-amino-2-[1-(4-hydroxy-butane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as white solids (120 mg, 86%). HR-MS (ES, m/z) calculated for C21H29N5O5SF [(M+H)+] 482.Example 221, observed 482.1874.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].O.[C:6]1(C)[CH:11]=[CH:10][C:9](S(O)(=O)=O)=[CH:8][CH:7]=1.C1C=CC=CC=1>O>[CH2:2]1[CH2:1][O:4][CH2:9][CH:10]([CH2:11][CH2:6][CH:7]=[CH2:8])[O:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Solvent: c1ccccc1
Solvent: O
Product: C=CCCC1COCCO1
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 5-oxy-1-hexene (9.8 g.), ethylene glycol (18.6 g.), p-toluene sulfonic acid monohydrate (1.56 g.) and benzene (250 ml.) is heated at reflux under a Dean-Stark water separator. After 2 hrs., the reaction mixture is washed with water and the organic layer is separated, dried with magnesium, and evaporated in vacuo. Distillation of the residue gives 5-ethylenedioxy-1-hexene (90% yield) b.p. 34°-37°/1.5 mm. nmr (CDCl3) δ: 1.27 (s, CH3), 1.5-2.4 (m, CH2 --CH2); 2.83 (s, --O--CH2 --CH2 --O); 4.80-6.1 (m, CH2 =CH--). IR (film) μ: 6.06 (CH2 =CH--).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH2:17])=[C:11]([Cl:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:21]([CH3:20])(=[O:23])=[O:22])=[C:11]([Cl:18])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(Cl)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(Cl)c1NS(C)(=O)=O
Reaction time: 5 h
Yield: 60.8 %

Procedure:
(4-Amino-3-chloro-5-vinylbenzyl)carbamic acid tert-butyl ester (40.2 mg, 0.14 mmol), methanesulfonyl chloride (5 eq, 0.71 mmol, 55.15 μl), and triethylamine (3 eq, 0.42 mmol, 58.34 μl) were added in methylene chloride. The reaction mixture was stirred for 5 hr. The reaction mixture was purified with similar procedure to step 5 of Example 8 to obtain a title compound (30.7 mg, 59.83%).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:51])/[C:16](/[N:24]2[CH:27]([S:28]S(C3C=CC(C)=CC=3)(=O)=O)[CH:26]([NH:39][C:40](=[O:49])[CH2:41][O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:25]2=[O:50])=[C:17](\N2CCCC2)/[CH3:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(OCC)(=[O:61])C>C(#N)C>[C:1]1([CH:7]([O:14][C:15]([C@@H:16]2[N:24]3[C:25](=[O:50])[C@@H:26]([NH:39][C:40](=[O:49])[CH2:41][O:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C@H:27]3[S:28][CH2:18][CH:17]2[OH:61])=[O:51])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C/C(=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1)N1CCCC1
Reactant: CCOC(C)=O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1SCC(O)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 139.32 g (160 mmol) of a mixture consisting of the 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-(1-pyrrolidinyl)-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 1350 ml of dry acetonitrile is heated at 80° for approximately 6 hours under nitrogen until it is no longer possible to detect any starting material by thin layer-chromatography (silica gel; toluene/ethyl acetate 1:1). The heating bath is removed, the reaction mixture containing the 7β-phenoxyacetamido-3-(1-pyrrolidinyl)-3-cephem-4-carboxylic acid diphenylmethyl ester is left to cool for a further 11/2 hours, 550 ml of 0.1 N hydrochloric acid are added and the mixture is further stirred for 81/2 hours at room temperature. The reaction mixture is diluted with ethyl acetate, the water is separated off, the organic phase is washed twice with 2 N hydrochloric acid and three times with water, dried over sodium sulphate, concentrated by evaporation in vacuo and dried under a high vacuum. The residue, containing the 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, is used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[C:25]2[CH:40]=[CH:39][C:28]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[C:27]([N+:41]([O-])=O)[CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.C1COCC1.[Pt](=O)=O>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]2[N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)[CH:12]([C:25]3[CH:26]=[C:27]([NH2:41])[C:28]([NH:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[CH:39][CH:40]=3)[CH2:13][CH2:14]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CNc2ccc(C3CCC(c4ccc([N+](=O)[O-])cc4)N3c3ccc(C(C)(C)C)cc3)cc2[N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CNc2ccc(C3CCC(c4ccc(N)cc4)N3c3ccc(C(C)(C)C)cc3)cc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of the product from Example 179D (2.74 g, 4.72 mmol) in EtOH (25 mL) and THF (25 mL) was added platinum(IV) oxide (0.5 g, 2.2 mmol). The resulting mixture was stirred at rt under 1 atm H2 overnight. The mixture was filtered through celite, washed with methanol, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-45% EtOAc in hexane to give the title compound (1.74 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:28])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[F:27])=[C:10]([CH2:17][CH3:18])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:42](OC(=O)C)([F:44])[F:43]>O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:28][CH:42]([F:44])[F:43])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[F:27])[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Cl)cc1F
Temperature: 80 °C
Reaction time: 96 h

Procedure:
A mixture of [3-(4-chloro-2-fluorobenzyl)-2-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.20 g), N,N-dimethylformamide (3.0 mL), potassium carbonate (0.20 g) and acetic acid chlorodifluoromethyl ester (0.15 mL) was stirred at 80° C. for 4 days. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:4 by volume) gave title compound, 0.071 g.