Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([S:14][CH3:15])[NH:5][C:6](=O)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Cl)(Cl)([Cl:18])=O>C(OC(=O)C)C>[Cl:18][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([CH3:1])[N:3]=[C:4]([S:14][CH3:15])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)nc(SC)[nH]c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc(SC)nc1Cl

Procedure:
A solution of ethyl 4-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (60 g, 0.26 mole) and phosphorous oxychloride (POCl3, 320 mL) was heated under reflux for 4 to 5 h (monitor reaction by TLC using 30% ethylacetate and hexanes). After completion of reaction, phosphorous oxychloride was removed on a rotary evaporator. The residue was poured on to ice water and extracted with ethylacetate several times. The combined organic layers were evaporated, on a rotary evaporator, to give crude ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (65 g). This compound was used without purification.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][C:7]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:12]2[NH:18][S:19]([CH3:22])(=[O:21])=[O:20].C(=O)([O-])[O-].[Ca+2]>O1CCOCC1>[CH3:22][S:19]([NH:18][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[CH:15][C:16]([NH:17][C:3](=[O:4])[CH2:2][Cl:1])=[C:7]2[OH:6])(=[O:21])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: CS(=O)(=O)Nc1cccc2c(O)c(N)ccc12
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cccc2c(O)c(NC(=O)CCl)ccc12
Temperature: 85 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
0.32 ml of chloroacetyl chloride (4 mmol) was introduced into a suspension of 1 g of N-(5-hydroxy-6-aminonaphthalen-1-yl)methanesulphonamide (4 mmol, prepared according to the method described in Patent U.S. Pat. No. 4,956,456) and 0.4 g of calcium carbonate (4 mmol) in 50 ml of dioxane, with stirring and under an inert atmosphere. The reaction medium was stirred for 2 hours at 85° C. and then cooled to 30° C. The suspension was filtered on sintered glass and the inorganic salts were rinsed twice with a minimum of dioxane. The combined organic phases were poured over 100 ml of ice-cold water. The precipitate formed was drained, washed twice with water and dried under vacuum to constant weight to give 1.12 g of N-(5-methanesulphonylamino-1-hydroxynaphthalen-2-yl)-2-chloroacetamide in the form of a pink powder, with a yield of 84%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1.B.C(=O)([O-])[O-:23].[Na+].[Na+].OO>C1COCC1.C(OCC)(=O)C>[OH:23][CH2:10][CH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:16]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: C=Cc1ccc(-c2ccc(C(=O)OC)cc2)c(OC)c1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(CCO)cc2OC)cc1
Temperature: 60 °C

Procedure:
A solution of Example 445A (228 mg) and 1M borane in THF (1.2 mL) in THF (2 mL) at room temperature was stirred for 5 hours, and treated sequentially with 2M sodium carbonate (1 mL) and 33% hydrogen peroxide (1 mL). The mixture was heated to 60° C. for 1 hour, diluted with ethyl acetate (100 mL), washed with water (45 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20-40% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][CH3:28])=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>CN(C=O)C>[C:36]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][CH3:28])=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1)(=[O:38])[CH3:37]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4N)sc3c2)ccn1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4NC(C)=O)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.5 %

Procedure:
To the solution of 4-(2-((1R,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (9 mg, 22 μmole) and triethylamine (11 μL, 80 μmole) in 300 μL of DMF was added acetic anhydride (5 μL, 50 μmole). The reaction solution was stirred at room temperature for 1.5 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give 4-(2-((1R,2R)-2-acetamidocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (5.1 mg, 12 μmole) as white powder. ES/MS m/z 440.2 (MH+).
Reaction SMILES: COCCOC[O:7][C:8]1[C:16]([CH2:17]/[CH:18]=[C:19](\[CH3:28])/[CH2:20][CH:21]([NH2:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]([O:29][CH3:30])[C:14]([CH3:31])=[C:13]2[C:9]=1[C:10](=[O:32])[O:11][CH2:12]2.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[OH:7][C:8]1[C:16]([CH2:17]/[CH:18]=[C:19](\[CH3:28])/[CH2:20][CH:21]([NH:27][S:41]([CH3:40])(=[O:43])=[O:42])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]([O:29][CH3:30])[C:14]([CH3:31])=[C:13]2[C:9]=1[C:10](=[O:32])[O:11][CH2:12]2
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(N)C/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Ethyl (E)-6-(4-methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-2-amino-4-methyl-4-hexenoate (373 mg) was dissolved in CH2Cl2 (10 ml), cooled to 0° C., and triethylamine (0.17 ml) and methylsulfonyl chloride (0.09 ml) were added. The mixture was stirred at 0° C. for 1 hour and at room temperature for 2 hours. The reaction mixture was diluted with CH2Cl2 (10 ml), washed with water (10 ml), dried over Na2SO4, and evaporated to dryness to give a residue which was passed through a column (silica gel, hexanes-EtOAc 1:1) giving 368 mg (82%) of ethyl (E)-6-(4-hydroxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5yl) -2-methylsulfonylamino-4-methyl-4-hexenoate as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([F:23])[C:21]=1[F:22]>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[C:18]2[CH:17]=[C:16]([F:15])[C:21]([F:22])=[C:20]([F:23])[CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Product: Nc1nnc(-c2cc(F)c(F)c(F)c2)c(-c2ccccc2)n1
Yield: 36.4 %

Procedure:
5-Phenyl-6-(3,4,5-trifluorophenyl)-1,2,4-triazin-3-amine (131 mg, 37%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3,4,5-trifluorophenylboronic acid (0.23 g, 1.30 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH2:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH:14][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c([C@@H]3C[C@H]3CNC(=O)c3ccccc3)cccn2n1
Yield: 67.3 %

Procedure:
To a solution of trans-1-[2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine (50.0 mg, 0.248 mmol) and triethylamine (41.6 μL, 0.298 mmol) in tetrahydrofuran (2.5 mL) was added benzoyl chloride (31.7 μL, 0.273 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 5 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) 15 and silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95) to give the title compound (51.0 mg, yield 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[CH:22][C:21]=2[C:34]#[N:35])[N:15]=[CH:14]3)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][C:21]=2[C:34]#[N:35])[N:15]=[CH:14]3)=[O:10])=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(-n2ncc3cc(C(=O)NCCc4ccc(Cl)cc4)ccc32)c(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(CC(=O)O)ccc1-n1ncc2cc(C(=O)NCCc3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 794 %

Procedure:
To a fitted solution of tert-butyl 2-(4-(5-((4-chlorophenethyl)carbamoyl)-1H-indazol-1-yl)-3-cyanophenyl)acetate (43.4 mg, 0.084 mmol) in DCM (2 mL) was added TFA (250 μL). The reaction was stirred at ambient temperature for 4 hours and then concentrated. The crude product was purified over silica gel on a Biotage Horizon high-performance FLASH chromatography system (12+M silica gel cartridge) eluting with a gradient of 0.5% MeOH/DCM containing 0.5% AcOH to 5% MeOH/DCM containing 0.5% AcOH to give 2-(4-(5-((4-chlorophenethyl)carbamoyl)-1H-indazol-1yl)-3-cyanophenyl)acetic acid (0.038 g, 0.667 mmol, 79%). 1H NMR (400 MHz, CDOD3) δ 8.68 (t, J=5.5 Hz, NH), 8.62 (s, 1H), 8.43 (s, 1H), 8.03 (s, 1H), 7.97 (d J=8.6 Hz, 1H), 7.84 (s, 2H), 7.65 (d, J=8.3 Hz, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 3.82 (s, 2H), 3.53 (q. J=6.5 Hz, 2H), 2.88 (t, J=7.3 Hz, 2H). MS(APCI)=459.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[CH2:11][O:12]C)=[O:4].B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[CH2:11][OH:12])=[O:4]
Reactant: COCc1nc(N)sc1C(=O)OC
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1sc(N)nc1CO
Yield: 72.3 %

Procedure:
The compound (4.68 g) obtained in Step 2 was suspended in dichloromethane (160 ml), and boron tribromide (1.0M dichloromethane solution, 35 ml) was added dropwise with stirring under ice-cooling. The reaction mixture was stirred under ice-cooling for 90 min, 4N aqueous sodium hydroxide solution (26 ml) was added dropwise with stirring under ice-cooling, and the mixture was stirred at room temperature for 30 min. The precipitated solid was collected by filtration, washed with water and acetone, and dried to give the title compound (3.15 g).
Reaction SMILES: [CH2:1]([C:4]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10]CC)=[O:9])[CH:2]=[CH2:3].[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([C:4]1[C:16]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OCC(=O)OCC)cccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCc1c(OCC(=O)O)cccc1C(F)(F)F
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
8.1 g of the product of Step C in 50 ml of ethanol was stirred for one hour at ambient temperature in the presence of 14 ml of 2N sodium hydroxide and 14 ml of 2N hydrochloric acid were then added with stirring for 15 minutes, followed by concentration to obtain 10.19 g of crude product which was taken up in water. After extracting with methylene chloride and drying, the solvent was evaporated to obtain 7.26 g of the expected product.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12][C:13]3[C:14]([C:26]([NH:28][C:29]4[S:33][N:32]=[C:31]([CH3:34])[N:30]=4)=[O:27])=[N:15][C:16]([S:19][C:20]4[N:24]([CH3:25])[CH:23]=[N:22][N:21]=4)=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH2:2]1.[CH:35](=O)[CH3:36]>>[CH2:35]([N:1]1[CH2:2][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12][C:13]3[C:14]([C:26]([NH:28][C:29]4[S:33][N:32]=[C:31]([CH3:34])[N:30]=4)=[O:27])=[N:15][C:16]([S:19][C:20]4[N:24]([CH3:25])[CH:23]=[N:22][N:21]=4)=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)[CH2:4]1)[CH3:36]
Reactant: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(OC3CNC3)cc2)n1
Reactant: CC=O
Product: CCN1CC(Oc2ccc(Sc3ccc(Sc4nncn4C)nc3C(=O)Nc3nc(C)ns3)cc2)C1

Procedure:
Starting from 3-{[4-(azetidin-3-yloxy)phenyl]thio}-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide obtained in Example 2 (step 2) and using acetaldehyde, the entitled compound was obtained as a yellow solid in the same method as in Example 2 (step 3) or in accordance with the method or by combining it with an ordinary method.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10](CC3C=CC=CC=3)[CH2:9][CH:8]2[CH2:19][NH2:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:19][NH2:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: NCC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCC1CNCC1c1ccccc1
Yield: 86.4 %

Procedure:
A mixture of 4.79 g (0.018 mole) of 4-phenyl-1-(phenylmethyl)-3-pyrrolidinemethanamine, 0.7 g of 20% palladium on carbon, and 250 ml of methanol was shaken in an atmosphere of hydrogen at about 50 psi and at room temperature for 24 hours. The catalyst was filtered and the filtrate evaporated under reduced pressure to give 2.74 g of 4-phenyl-3-pyrrolidinemethanamine.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:17]([C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH3:2]
Reactant: CCC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A stirred and cooled solution of 6-ethyl-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (38 mg, 100 μmol) in dichloromethane (2 mL) was treated drop-wise under nitrogen at −30° C. with a solution of 1.0 M boron tribromide in dichloromethane (500 μL, 500 μmol). After the addition was completed, the reaction mixture was allowed to warm to room temperature and was stirred for four hours. The reaction mixture was cooled to −30° C. and quenched with methanol (600 μL). The solvent was removed in vacuo to yield the title compound (36.5 mg, 100 μmol, 100%), which was confirmed by LCMS (ES−, FA, CV=20 or 5);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([CH2:8][O:9][CH2:10][CH2:11]Cl)=[O:7])[CH3:2].CC(C)=O.[I-:18].[Na+]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([CH2:8][O:9][CH2:10][CH2:11][I:18])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)COCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CC(=O)COCCI
Reaction time: 13 h
Yield: 67 %

Procedure:
To a solution of 19 g (91 millimoles) of ethyl-4-(2-chloroethoxy)-acetoacetate (IV) and 380 ml of acetone 134.4 g (910 millimoles) of sodium iodide are added. The reaction mixture is heated to boiling for 13 hours. The inorganic substance is filtered off and the filtrate is evaporated in vacuo. The residual oil is dissolved in dichloro methane, the solution is washed with water, dried and evaporated. The crude product is subjected to fractionated distillation in vacuo. Bp.: 170° C./0.1 Hgmm. Thus 18.3 g of the desired product are obtained, yield 67%.
Reaction SMILES: [F:1][C:2]([F:18])([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[C:3](OCC)=[O:4].[NH2:19][NH2:20].Cl>C(O)C>[F:1][C:2]([F:18])([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[C:3]([NH:19][NH2:20])=[O:4]
Reactant: NN
Reactant: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Agent: Cl
Solvent: CCO
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
As shown in step 3-ii in Scheme 3, Compound 1009 (10.0 g, 39.80 mmol) was dissolved in ethanol (100 mL), hydrazine (7.65 g, 7.50 mL, 239 mmol) was added, and the reaction mixture was stirred at room temperature for 10 minutes. After pouring the mixture into 2N HCl solution, the aqueous mixture was washed twice with DCM and the pH was adjusted to 8 while bubbling nitrogen gas through the solution. The resulting aqueous solution was exhaustively extracted with DCM (10×) and the combined organics dried over MgSO4, filtered, and the volatiles removed under reduced pressure to provide 2,2-difluoro-2-(quinolin-6-yl)acetohydrazide as a yellow solid (Compound 1010, 91% yield). This compound that was used directly without further purification.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:24][CH:25]([CH3:29])[CH2:26][C:27]#[CH:28]>>[OH:23][C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:2]([CH3:1])[S:3]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:5])=[O:4])=[CH:13][CH:14]=1)([C:19]([F:21])([F:22])[F:20])[C:28]#[C:27][CH2:26][CH:25]([CH3:29])[CH3:24]
Reactant: CN(c1ccc(C(=O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Reactant: C#CCC(C)C
Product: CC(C)CC#CC(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F

Procedure:
The compound was prepared from N-methyl-N-(4-trifluoroacetyl-phenyl)-benzenesulfonamide (Example 22, Step A) and 4-methyl-pent-1-yne following the procedure described in Example 29. 1H NMR (CDCl3) δ 1.01 (d, J=6.6 Hz, 6H), 1.90 (sept, J=6.6 Hz, 1H), 2.21 (d, J=7.7 Hz, 2H), 3.17 (s, 3H), 3.24 (br s, 1H), 7.12–7.68 (m, 9H). Mass Spectrum (CI+) m/e=426 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH3:8][C:9](=O)[CH2:10][C:11](=O)[CH3:12].N1CCCCC1>C(O)C>[CH3:1][N:2]1[C:9]([CH3:8])=[CH:10][C:11]([CH3:12])=[C:4]([C:5]#[N:6])[C:3]1=[O:7]
Reactant: CC(=O)CC(C)=O
Reactant: CNC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)n(C)c(=O)c1C#N
Reaction time: 3 h
Yield: 77.4 %

Procedure:
N-methyl cyanoacetamide (113 g., 1.15 mole), 2,4-pentanedione (115 g., 1.15 mole), piperidine (11.5 ml.) and anhydrous ethanol (250 ml.) are refluxed with stirring for 3 hours. The mixture is allowed to stand overnight at room temperature and the white crystalline precipitate is collected by filtration to give 1-methyl-3-cyano-4,6-dimethylpyrid-2-one, 144 g. (77.4% yield), mp. 202°-205° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH2:11])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1[N:3]([NH:11][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1ccncc1
Reactant: Cc1cc2ccccc2n1N
Agent: Cl
Product: Cc1cc2ccccc2n1Nc1ccncc1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-1-amine and 4-chloropyridine hydrochloride at 120° C. for 30 minutes in substantially the same manner as in Example 1, m.p. 75°-78° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([F:12])=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1)[CH3:2].[OH-].[Na+].[Br:15]N1C(=O)CCC1=O>CN(C=O)C>[Br:15][C:5]1[C:6]2[C:7](=[N:8][C:9]([F:12])=[CH:10][CH:11]=2)[N:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1ccc2ccc(F)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCn1cc(Br)c2ccc(F)nc21
Yield: 96.6 %

Procedure:
A solution of 1-ethyl-6-fluoro-1H-pyrrolo[2,3-b]pyridine (16.38 g, 99.77 mmol) in DMF (300 mL) is cooled to 15° C. with stirring. To this is added sodium hydroxide (4.39 g, 109.7 mmol), followed by N-bromosuccinimide (19.53 g, 109.7 mmol) portionwise over 5 minutes, and then the reaction is allowed to stir at room temperature overnight. The reaction is poured onto brine (ca. 500 mL) and the product extracted with CHCl3 (ca. 2×300 mL). The combined organic phase is dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown oil. This is purified by column chromatography on silica, eluting with 0 to 60% DCM in hexane, to give the title compound as a light yellow oil (23.4 g, 96.4 mmol). MS (m/z): 243/245 (M+1).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:23]([O-:25])=[O:24])=[CH:20][CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1.[Na+].C(O)(=O)C>O>[CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:23]([OH:25])=[O:24])=[CH:20][CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 91.8 %

Procedure:
A solution of 5.40 mmol of ceftizoxime sodium salt (equivalent to 2 g of ceftizoxime) in 20 ml of water was acidified with 5.40 ml of 1N acetic acid. The resulting solid was collected and washed with ice water to give 1.90 g of ceftizoxime. A suspension of 1.85 g of ceftizoxime (dried at 80° C./0.1 mm) in 60 ml of methylene chloride was stirred overnight under argon with 2.03 g of N,O-bis(trimethylsilyl) acetamide and 1.73 g of diethyl chlorophosphate, whereupon the solid had dissolved. After a month the reaction mixture was evaporated to dryness and the residue was washed with water. The aqueous washes were extracted with chloroform, back-washing the chloroform extracts with water. Evaporation of the dried (MgSO4) chloroform extracts left 0.049 g of a colorless gum; NMR (CDCl3, 80 MHz) δ 1.37 (t, CH3) δ 1.41 (t, CH3), 4.17 (OCH2, NOCH3); IR (KBr) 1032 (P=O), 1787 (β-lactam).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][C:3]=1[O:36][CH3:37].[ClH:38]>O1CCOCC1.CCOCC>[ClH:38].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: COc1cc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)ccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1cc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
The tert-butyl (3R)-3-({4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate (0.785 g, 1.50 mmol) was dissolved in 15 ml of dioxane and treated with 7.5 ml of anhydrous 4N HCl in dioxane at room temperature. The reaction mixture was stirred at room temperature for two hours. The mixture was then diluted with 25 ml of ether and stirred until product separated as a solid. Solid product was filtered and washed with ether. The solid was dissolved in MeOH (20 ml) and concentrated to dryness twice. The product was dried at high vacuum to yield 0.709 g of yellow solid (bis HCl salt) (95%). 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 11.65 (br. s, 2H), 9.60 (br. s, 1H), 8.90 (br. s, 1H), 8.14 (d, J=6.3 Hz, 1H), 7.61 (m, 1H), 7.40 (dd, J=8.6, 2.0 Hz, 1H), 7.33 (dd, J=11.7, 8.6 Hz, 1H), 7.20 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 6.55 (d, J=6.3 Hz, 1H), 4.50-4.40 (m, 1H), 3.86 (s, 3H), 3.48-3.38 (m, 1H), 3.22-3.10 (m, 1H), 3.06-2.88 (m, 2H), 2.12-2.02 (m, 1H), 2.00-1.84 (m, 2H), 1.78-1.64 (m, 1H). LCMS: 425 [M+H].