Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47](O)=[O:48]>CN(C)C=O>[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47]([NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:48]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[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: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Reaction time: 2 h

Procedure:
Diisopropylethylamine (1.34 ml, 7.69 mmol), 3-aminopyridine (0.43 g, 4.61 mmol) and HATU (2.19 g, 5.77 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 87; 1.25 g, 3.84 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred for 2 hours. The solid was then filtered and washed with ethyl acetate to yield the title compound as a white solid. 650 mg.
Reaction SMILES: NC1SC2C3C(CC=2C=1[C:14]([NH2:16])=[O:15])=CC=CC=3.FC(F)(F)C(O)=O.[NH2:24][C:25]1[S:29][C:28]2[C:30]3[C:35]([CH2:36][CH2:37][C:27]=2[C:26]=1[C:39]([NH2:41])=[O:40])=[CH:34][C:33]([Br:38])=[CH:32][CH:31]=3>>[Br:38][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[C:28]1[S:29][C:25]([NH:24][C:14]([NH2:16])=[O:15])=[C:26]([C:39]([NH2:41])=[O:40])[C:27]=1[CH2:37][CH2:36]2
Reactant: NC(=O)c1c(N)sc2c1CCc1cc(Br)ccc1-2
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Nc1sc2c(c1C(N)=O)CCc1cc(Br)ccc1-2

Procedure:
The title compound was prepared by the same procedure as Example 2 except 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide was replaced with 2-amino-7-bromo-4,5-dihydro-naphtho[1,2-b]thiophene-3-carboxylic acid amide trifluoroacetate to give the above title compound as brown solid. ESMS m/z: 367 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][N:7]=1.[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>O1CCCC1>[C:17]([NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][N:7]=1)(=[O:19])[CH3:18]
Reactant: NCCOc1cc(-c2ccccc2)on1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCOc1cc(-c2ccccc2)on1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
3-(2-Aminoethoxy)-5-phenylisoxazole hydrochloride (240 mg) was suspended in anhydrous tetrahydrofuran (5 ml), and the suspension was cooled to 5° C. Acetyl chloride (94 mg) and triethylamine (243 mg) were added thereto, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the reaction mixture was added to ice-cold water (40 ml) and extracted with ethyl acetate (40 ml×2). Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The crystals thus obtained were recrystallized from ethyl acetate to obtain the title compound (225 mg, 91%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[CH2:25][C:26](=[O:28])[CH3:27]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][N:11]([CH2:25][C:26](=[O:28])[CH3:27])[CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1
Reactant: CC(=O)CCl
Reactant: Cc1ccc2c3c(c(=O)oc2c1)CNCC3
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)ccc23)C1
Yield: 77.8 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.0 g, 0.009 moles), triethylamine (1.4 ml, 0.010 moles), and 1-chloro-2-propanone (0.8 g, 0.009 moles) in ethanol (50 ml) is stirred and heated to reflux. After 20 hours the mixture is cooled and the precipitate filtered off, rinsed with ethanol, and dried to give the product (1.9 g), mp 128°-129° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.Br[CH2:15][CH2:16][CH:17]=[CH2:18]>>[CH2:18]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCBr
Reactant: COc1ccc2c(c1)CCCC2=O
Product: C=CCCC1CCc2cc(OC)ccc2C1=O

Procedure:
The title compound 75 is prepared according to the procedure reported in step A of Example 17 with 6-methoxy-1-tetralone (0.88 g, 5.0 mmol) and 4-bromo-but-1-ene (5.0 mmol, 1 equiv) as reactants.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH2:15]O)=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl:3][CH2:15][CH2:14][CH2:13][NH:12][C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1
Reactant: OCCCNc1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1ccc(NCCCCl)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Thionyl chloride (5.3 mL) was added to a solution of 3-(4-fluorophenylamino)propan-1-ol (2.37 g) in toluene (30 mL) at room temperature, and the reaction solution was stirred at 60° C. for five hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ice and a saturated sodium bicarbonate solution were added to the residue, followed by extraction with ethyl acetate (100 mL). Heptane (100 mL) was added to the resulting extract, and the solution was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1) to obtain (3-chloropropyl)-(4-fluorophenyl)amine. Triethylamine (5.4 mL) and phenyl chlorocarbonate (1.9 mL) were added to a solution of (3-chloropropyl)-(4-fluorophenyl)amine (2.40 g) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (3.93 g). Hydrazine monohydrate (0.40 mL) was added to a solution of phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (500 mg) in ethanol (10 mL) at room temperature. The reaction solution was stirred at room temperature for one hour, stirred at 60° C. for one hour and heated under reflux for seven hours. Hydrazine monohydrate (0.40 mL) was added to the reaction solution, and the reaction solution was heated under reflux for 13 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 265 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:17]=[C:18]([C:25](O)=[O:26])[N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15][C:25]([C:18]1[N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]2=[N:16][CH:17]=1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Reactant: O=C(O)c1cnc2ccccn12
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)c1cnc2ccccn12

Procedure:
prepared by reaction of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester with Imidazo[1,2-a]pyridine-3-carboxylic acid.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]([N:12]2[CH2:13][C:14](=[O:16])[CH2:15][NH:11]2)=[O:26])=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: O=C1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: O=C1CNN(C(=O)Cc2ccc(F)cc2)C1
Reaction time: 3 h

Procedure:
To a solution of 2-[2-(4-fluorophenyl)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid benzyl ester, 4, (1 g, 4.5 mmol) in methanol (30 mL) is added Pd/C (100 mg). A balloon filled with hydrogen gas is placed over the flask and the mixture stirred for 3 hours. The solution is filtered to remove the catalyst and concentrated in vacuo to afford 0.8 g of the desired product as a yellow oil which is used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:26])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:8][CH:9]=1)=[O:4].[OH-].[K+]>CO.O>[C:22]([O:21][C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:10]([C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)=[O:26])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
To a suspension of 18.5 g (50 mmol) 5-(2-tert-Butoxycarbonylamino-phenyl-carbamoyl)-thiophene-2-carboxylic acid methyl ester in 500 ml MeOH was added within 20 minutes a solution of 5.6 g (100 mmol) potassium hydroxide in 100 ml water. The reaction mixture was stirred at room temperature for 2 d. The MeOH was evaporated and the remaining aqueous solution was extracted three times with ethylacetate and acidified with a 3N aqueous HCl solution. The precipitation was filtered off, washed with water and dried at 45° C. in high vacuum to yield 14.5 g (40 mmol) 5-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-thiophene-2-carboxylic acid., 1H-NMR (D6-DMSO) δ=1.45 (s, 9H), 7.14 (m, 1H), 7.22 (m, 1H), 7.46 (m, 1H), 7.59 (m, 1H), 7.90 (m, 2H), 8.72 (s, 1H), 9.99 (s, 1H), 13.54 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].S([O-])(O[CH3:22])(=O)=O>[OH-].[Na+]>[CH3:22][N:13]([CH2:12][CH2:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: COS(=O)(=O)[O-]
Reactant: CS(=O)(=O)NCCNc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Product: CN(CCNc1ccc([N+](=O)[O-])cc1)S(C)(=O)=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
25.9 g (0.1 mol) of N-[2-(4-nitrophenylamino)ethyl]methanesulfonamide (22) were dissolved in 200 mL of 1N sodium hydroxide at 50° C. The insoluble matter was filtered off, the filtrate was cooled to 30° C. and 11.4 mL (0.12 mol) of methyl sulfate were added dropwise. The mixture was stirred for 1 hour at room temperature and then heated to 40° C. and the yellow precipitate was filtered off. The product was reslurried in 0.5N sodium hydroxide and in water. The wet crude product was recrystallized from 50 mL of 96% ethanol with carbon black. 13.3 g of product with a melting point of 109° C. were isolated.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[OH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[CH:12]=[CH:11]2.[Cl:17][CH2:18][C:19](Cl)=[O:20]>>[Cl:17][CH2:18][C:19]([O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[CH:12]=[CH:11]2)=[O:20]
Reactant: O=c1ccc2cccc(O)c2[nH]1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCl)Oc1cccc2ccc(=O)[nH]c12

Procedure:
20 g of aluminum chloride was added to 5.0 g of 8-hydroxycarbostyril (VII) and the resulting mixture was thoroughly mixed. 10 g of chloroacetyl chloride was gradually added to the mixture while ice-cooling. The mixture was allowed to react by heating at 40° to 45° C. for 2 hours to form 8-chloroacetoxycarbostyril (V) followed by stirring at 70° C. for 3 hours. After cooling, the precipitated crystals were collected by filtration, and the crystals were washed with 300 ml of water followed by recrystallization from methanol to obtain 2.6 g of 5-chloroacetyl-8-hydroxycarbostyril (IV) having a melting point of 285°-287° C. (with decomposition) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:21])[CH:3]=1.[Si]([C:26]#[N:27])(C)(C)C.O>CCN(CC)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:4]1[CH:3]=[C:2]([CH:20]=[CH:19][C:5]=1[CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8]1=[O:18])[C:26]#[N:27]
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCCCC1
Reactant: C[Si](C)(C)C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Yield: 98.2 %

Procedure:
Dissolve 3-(4-bromo-2-chlorobenzyl)-1-cyclohexylpyrrolidin-2-one (Example 55) (0.50 g, 1.35 mmol) in Et3N (20 mL) under N2. Add Pd(PPh3)4 (0.32 g, 0.27 mmol), TMSCN (0.40 g, 4.05 mmol) with stirring. Heat the reaction mixture for 24 hours until LC-MS shows the starting material has gone. Cool the reaction to room temperature and add water (20 mL). Extract the aqueous with EtOAc (3×50 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 30-60% of EtOAc-Hexane) to give 0.42 g (98%) of the title compound as white solid: MS (APCI-pos mode) m/z (rel intensity) 317.2 (100), 319.2 (30).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.[C:9](=O)([O:15]C(C)(C)C)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]>O1CCCC1.CN(C)C1C=CN=CC=1>[O:8]=[C:3]1[C@@H:4]2[CH2:7][C@@H:1]([CH:6]=[CH:5]2)[N:2]1[C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15]
Reactant: O=C1NC2C=CC1C2
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(=O)[C@H]2C=C[C@@H]1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
(+)-2-Azabicyclo[2.2.1]hept-5-en-3-one (Chiroscience, Cambridge, England; 54.565 g, 0.500 mole) was dissolved in dry tetrahydrofuran (350 ml). Di-tert-butyl carbonate (Aldrich, 114.87 g, 0.510 mole as 97%) and 4-dimethylaminopyridine (Aldrich, 600 mg) were added to the stirred mixture. The resulting solution was stirred at ambient temperature for 2 hours. Solvent was evaporated under reduced pressure and the residual orange solid was crystallized from toluene-hexanes to give title compound as white crystals (95.72 g, 91%), m.p. 85–86° C.; 1H-NMR (CDCl3) δ 1.50 (s, 9H), 2.24 (app AB q, J=8.4 Hz, 2H), 3.39 (br s, 1H), 4.96 (m, 1H), 6.66 (m, 1H), 6.89 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Br:24])[C:15]2[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Br:24])[C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:22])[N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)O)cc2)CC1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of compound 51 (1.0 g, 2.5 mmol) in dry dichloromethane (10 mL) at −20° C. was added iso-butylchloroformate (450 mg, 3.3 mmol). After 20 min at −20° C. diethylamine (4 mL) was added and the reaction was allowed to warm to room temperature. After 1.5 hrs the solvent was evaporated and the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate was washed with water and brine and dried over MgSO4 and removed by evaporation. The crude product was purified by silica gel chromatography (0-60% ethyl acetate in heptanes) to give the product (compound 52) as white needles (800 mg, 73%).
Reaction SMILES: [CH3:1][C:2]1[NH:16][CH2:15][CH2:14][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[CH:6]3.C(N(CC)CC)C.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>ClCCl>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=3)[C:4]=2[CH2:14][CH2:15][N:16]1[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)=C1CCNC(C)=C1N=2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C1c2[nH]c3ccc(OC)cc3c2CCN1S(C)(=O)=O
Temperature: 25 °C

Procedure:
10-Methoxyharmalan (646 mg, 3 mmol) is dissolved in dry dichloromethane (40 ml). Triethylamine (1 ml, 7.2 mmol) and then, dropwise, mesyl chloride (0.25 ml, 3.2 mmol) are successively added with stirring at room temperature under a nitrogen atmosphere. The mixture is stirred for 4 hours at room temperature. Subsequently, after removal of the dichloromethane, the residue is subjected to flash chromatography on a silica column (AcOEt/PE, 50/50). 1-Methylene-2-mesyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline is thus obtained (350 mg, Y=40%).
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:55][O:56][CH2:57][C:58]1N=C(N)[S:60][N:59]=1>ClCCl>[CH3:55][O:56][CH2:57][C:58]1[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])[S:60][N:59]=1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: COCc1nsc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCc1nsc(NC(=O)[C@H](CC(C)C)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 94 mg, 0.29 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol) and 1-hydroxybenzotriazole (42 mg, 0.31 mmol). The resulting solution was stirred for 5 min before 3-methoxymethyl-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.34 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (3-methoxymethyl-[1,2,4]thiadiazol-5-yl)-amide (62 mg, 47%) as a light yellow solid: HR-ES-MS m/z calculated for C20H23ClN4O4S [M+H]+ 451.1202, observed 451.1202; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.48 (br. s., 1H), 1.60-1.76 (m, 1H), 1.79-1.95 (m, 1H), 3.33 (s, 3H), 4.30 (d, J=18.1 Hz, 1H), 4.51 (d, J=18.1 Hz, 1H), 4.52 (s, 2H), 4.84 (s, 1H), 5.02 (dd, J=10.9, 4.5 Hz, 1H), 7.37 (td, J=7.5, 0.9 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 13.40 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[N:28]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:26][C:27]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])[N:28]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(F)c2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc(F)c3)cc2=O)n1
Yield: 53 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(3-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 42) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(3-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.74 g, 53%); ES+-HRMS m/e calcd for C25H30N5O4F [M+H+] 484.2355 found 484.2356. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.10 (m, 1H), 1.27-1.75 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.48 (dd, J=4.3, J=10.9 Hz, 1H), 5.88 (d, J=2.9 Hz, 1H), 6.40 (d, J=2.3 Hz, 1H), 7.17 (dd, Jm=2.3 Hz, Jo=8.3 Hz, 1H), 7.22 (td, Jm=2.3 Hz, Jo=8.3 Hz, 3JF=8.3 Hz, 1H), 7.31 (dt, Jm=2.3 Hz, 3JF=9.9 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 7.57 (dt, Jo=8.3 Hz, 4JF=6.9 Hz, 1H), 8.13 (d, J=2.9 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([C:6]1([CH2:15][CH:16]=C)[C:13](=[O:14])[N-:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])[CH3:5].[Na+].[O:19]=[O+][O-]>CO>[CH3:5][CH:4]([C:6]1([CH2:15][CH:16]=[O:19])[C:7](=[O:8])[NH:9][C:10](=[O:11])[NH:12][C:13]1=[O:14])[CH2:3][CH2:2][CH3:1]
Reactant: C=CCC1(C(C)CCC)C(=O)[N-]C(=O)NC1=O
Reactant: O=[O+][O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(C)C1(CC=O)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sodium secobarbital (5.30 g, 22.2 mmol) in methanol was passed a stream of ozone until the solution turned a blue color. After excess ozone was removed by passing nitrogen through the reaction dimethyl sulfide (14 mL) was added. The reaction was stirred at room temperature overnight before solvents were removed on a rotovap. The aldehyde was then purified on silica prep plates using ethyl acetate:hexanes (1:1).
Reaction SMILES: ClCCl.C[C:5]([O:7][CH2:8][C:9]1[CH2:18][S:17][C@@H:12]2[C@H:13]([NH2:16])[C:14](=[O:15])[N:11]2[C:10]=1[C:19]([OH:21])=[O:20])=O.S(=O)(=O)(O)O>CO>[NH2:16][CH:13]1[C:14](=[O:15])[N:11]2[C:10]([C:19]([OH:21])=[O:20])=[C:9]([CH2:8][O:7][CH3:5])[CH2:18][S:17][C@H:12]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 1.75 h

Procedure:
To 10 ml of dichloromethane were added 1.41 g of 7-ACA, 2.1 ml of concentrated sulfuric acid and 1.05 ml of methanol. The reaction was conducted at 0° C. for 1.75 hours. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.27 g. The yield of the desired product was 21%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH3:16])=[O:14].C([O-])(=O)C.[NH4+:22]>CO>[NH2:22]/[C:11](/[CH2:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1])=[CH:12]\[C:13]([O:15][CH3:16])=[O:14]
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Cc1cc(F)c(F)cc1F
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)/C=C(\N)Cc1cc(F)c(F)cc1F

Procedure:
Methyl 4-(2,4,5-trifluorophenyl)acetoacetate (21) was treated with anhydrous ammonium acetate in an alcoholic solvent, preferably methanol, and preferably at higher temperature, preferably at 60-65° C. The methyl(Z)-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate (28) formed was preferably isolated by complete removal of the solvent under reduced pressure, separation of excess of ammonium acetate by using a polar organic solvent such as ethyl acetate, distillation of the polar organic solvent and triturating the product with non-polar solvents like hexane.