Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:11]
Reactant: O=C(COCc1ccccc1)Nc1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(CO)Nc1ccc(O)cc1
Reaction time: 8 h
Yield: 34.2 %

Procedure:
2-Benzyloxy-N-(4-hydroxy-phenyl)-acetamide 26 (18 g, 70 mmol) was dissolved in methanol (100 ml) in a pressure vessel, palladium on carbon (5%, 8 g) was added and the mixture stirred under an atmosphere of hydrogen (4 Kg) for 8 hours. The catalyst was removed by filtration and the methanol was distilled off. The crude 27 was recrystallized from a mixture of chloroform:methanol (1:5) to get pure 27 (4 grams, 34.2%) as a white shining powder.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:28]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CSc1nc(-c2cccc(OC(=O)Oc3ccccc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 100 mg) with phenyl chloroformate (324 μl) was performed according to the methods described in example 1g. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([O:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[CH3:7].[N+:22]([O-])([OH:24])=[O:23]>>[C:6]([O:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[C:19]=1[O:20][CH3:21])[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[CH3:7]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OC)c(OC(C)=O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC(C)=O)c(OC)c([N+](=O)[O-])c1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
A mixture of 90% nitric acid (40 mL) and concentrated sulfuric acid (8 mL) were cooled to −5° C. followed by portionwise addition of solid methyl 3-(acetyloxy)-4-(methyloxy)benzoate (25.9 g, 115 mmol.) over 25 minutes. After stirring for 5 minutes the solution was poured onto ice and the aqueous mixture was extracted once with dichloromethane. The organic solution was then washed with dilute aqueous sodium hydrogencarbonate (3×) then once with water and dried over anhydrous magnesium sulfate. Filtration and concentration followed by suspension of the solid residue in hexanes and filtration gave methyl 3-(acetyloxy)-4-(methyloxy)-5-nitrobenzoate (27.2 g, 88% yield) as a white solid on drying. 1H NMR (400 MHz, CDCl3): 8.38 (d, 1H), 7.99 (d, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:23])[CH:8]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.[OH-].[Na+]>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:23][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(N)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc3nc(C)cc(N4CCC(c5ccccc5)C4)c3c2)cc1
Yield: 9 %

Procedure:
2-Methyl-6-amino-4-(3-phenylpyrrolidin-1-yl)quinoline (0.08 g; see Example 45 below), 4-methoxybenzaldehyde (0.071 g), sodium triacetoxyborohydride (0.165 g) and acetic acid (0.05 mL) in 1,2-dichloroethane (5 mL) was refluxed for 4 hours. The reaction mixture was diluted with 1 N sodium hydroxide and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with a mixture of dichloromethane, and methanol. The desired fractions were concentrated and the sample evaporated to dryness. Trituration from ether gave the title compound as a white powder (0.01 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]([F:12])([CH3:11])[CH3:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]1([CH2:25][CH2:26][CH2:27][CH:28]([NH2:32])[CH:29]2[CH2:31][CH2:30]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([C:9]([F:12])([CH3:11])[CH3:10])[N:5]=[C:6]([NH:32][CH:28]([CH:29]2[CH2:31][CH2:30]2)[CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1
Reactant: NC(CCCc1ccccc1)C1CC1
Reactant: CC(C)(F)c1nc(N)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(F)c1nc(N)nc(NC(CCCc2ccccc2)C2CC2)n1

Procedure:
1.52 g (0.008 mol) of 2-amino-4-chloro-6-(1-fluoro-1-methylethyl)-1,3,5-triazine and 1.64 g (0.012 mol) of potassium carbonate are introduced into 30 ml of acetonitrile. 1.50 g (0.008 mol) of 4-phenyl-1-cyclopropyl-1-butylamine, dissolved in 10 ml of acetonitrile, are added dropwise to this solution. The mixture is refluxed for three hours. The solid components are then filtered off with suction and the filtrate is evaporated on a rotary evaporator. The residue is purified by column chromatography (eluant: methyl acetate). This gives 2.36 g (86% of theory) of 2-amino-4-(1-fluoro-1-methylethyl)-6-(1-phenyl-4-cyclopropyl-4-butylamino)-1,3,5-triazine.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:16])[C:9]=1[NH:10]2.[OH-].[K+].[C:19]1([CH:25]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH:25](=[C:7]1[CH2:6][CH2:5][C:4]2[C:3]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:15])[C:2]=3[Cl:1])[NH:10][C:9]=2[C:8]1=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCc2c1[nH]c1ccc(Cl)c(Cl)c21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2ccccc2)CCc2c1[nH]c1ccc(Cl)c(Cl)c21
Temperature: 80 °C
Yield: 103.8 %

Procedure:
To a solution of 5,6-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (intermediate 5a) (0.8 g, 1.97 mmol) in MeOH (10 mL), KOH (0.055 g, 0.98 mmol) followed by PhCHO (1.0 g, 9.42 mmol) were added. The reaction mixture was heated to 80° C. for 12 h cooled to room temperature during which a solid precipitated out which was filtered and dried in vacuo to give the title compound as a light yellow solid (0.7 g, 70%). 1H NMR (500 MHz, CDCl3, δ in ppm) 9.25 (bs, 1H), 7.80 (s, 1H), 7.45-7.42 (m, 4H), 7.39-7.35 (m, 2H), 7.31 (d, J=9.0 Hz, 1H), 3.44 (t, J=6.0 Hz, 2H), 3.28 (t, J=6.0 Hz, 2H).
Reaction SMILES: F[C:2](F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.Br[CH2:15]C(=O)CC.C(O)C>[Pt](=O)=O.CO>[CH2:2]([C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1)[CH3:15]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: CCC(=O)CBr
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCO
Product: CCc1cn2c(n1)CNCC2

Procedure:
2-Ethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was prepared in an analogous manner to that described above for 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Intermediate 4) but starting from 1-bromo-2-butanone instead of 3-bromo-1,1,1-trifluoro-2-propanone and using platinum (IV) oxide and ethanol in the place of 10% palladium on carbon paste and methanol for the hydrogenation step.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH3:14].[Na].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.[I-].[K+]>CN(C)C=O>[NH2:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]2[C:9]([C:10]=1[C:11]([OH:13])=[O:12])=[N:8][N:7]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)[CH:6]=2
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Reactant: COc1ccc(CCl)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc3cc(C)c(N)c(C(=O)O)c3n2)cc1
Reaction time: 18 h

Procedure:
To a suspension of 6-amino-5-methyl-1H-indazole-7-carboxylic acid (0.956 g, 5 mmol) in dimethylformamide (4 ml) was added sodium hydrogenocarbonate (0.462 g, 5.5 mmol) and the resulting mixture was stirred at 40° C. for 15 minutes before 4-methoxybenzyl chloride (0.861 g, 5.5 mmol) was introduced. A catalytic amount of potassium iodide was added and the mixture was stirred for 18 hours at that temperature. After cooling down, the crude mixture was placed on top of a silica gel column and the product was purified by flash chromatography using a gradient starting from 50% ethyl acetate-50% cyclohexane to 100% ethyl acetate, then 1% acetic acid in ethyl acetate. The fractions containing the desired compound were evaporated and the residue was triturated with diethyl ether and filtered to yield light orange crystals.
Reaction SMILES: C(NC(=NC(C)C)O[C:7]([CH3:10])([CH3:9])[CH3:8])(C)C.[CH:15]1([C:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(Cl)Cl>[CH:15]1([C:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30]([O:32][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:31])=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Yield: 58 %

Procedure:
2 eq of tert-butyl N,N′-diisopropylimidocarbamate (prepared according to literature precedent: Synthesis 1979, 561) were added to a solution of 3-cyclohexyl-1H-indole-6-carboxylic acid (prepared as described in published International patent application WO2004087714) in CH2Cl2 (0.4 M) and the mixture heated at reflux under N2 for 16 h. A further 2.5 eq of tert-butyl N,N′-diisopropylimidocarbamate were then added portionwise over 3 h, with heating being resumed after each addition. The reaction mixture was then filtered whilst hot through a pad of CELITE and the filtrate concentrated in vacuo. The residue was purified by flash chromatography (5% EtOAc/PE) to afford the title compound (58%); MS (ES−) m/z 298 (M−H)−.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21]>>[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: COCCOCCO
Agent: [Na]
Product: COCCOCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of sodium (210 mg, 9 mmol) in 2-(2-methoxyethoxy)ethanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol). The mixture was stirred at 50° C. for 4 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[O:8].C(=O)([O-])[O-].[K+].[K+].[C@H:27]12[CH2:33][C@H:30]([NH:31][CH2:32]1)[CH2:29][N:28]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>C(#N)C>[CH:14]([NH:13][C:11](=[O:12])[CH2:10][NH:9][C:7]([C:6]1[CH:17]=[C:2]([N:31]2[CH2:32][C@@H:27]3[CH2:33][C@H:30]2[CH2:29][N:28]3[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:3]=[CH:4][C:5]=1[N+:18]([O-:20])=[O:19])=[O:8])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NC(=O)CNC(=O)c1cc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 92.1 %

Procedure:
To a solution of 5-fluoro-N-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (1.0 g, 3.53 mmol) (Intermediate 2A) in acetonitrile (20 mL) was added potassium carbonate (1.46 g, 10.9 mmol) followed by (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.70 g, 3.53 mmol). The resulting suspension was heated to reflux at 90° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, then filtered and concentrated. The resultant crude material was purified by a 25 g silica column in neat ethylacetate (Biotage Snap cartridge). Fractions of the product were combined and reduced to dryness under reduced pressure to afford (1S,4S)-tert-butyl 5-(3-(2-(isopropylamino)-2-oxoethylcarbamoyl)-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.5 g, 3.25 mmol).
Reaction SMILES: IC.[CH3:3][C:4]1([CH3:18])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)[O:5]1.[C:19](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:19][N:15]1[CH:16]=[C:11]([B:6]2[O:5][C:4]([CH3:18])([CH3:3])[C:8]([CH3:9])([CH3:10])[O:7]2)[CH:12]=[CH:13][C:14]1=[O:17]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
Iodomethane (0.283 mL, 4.52 mmol) was added to a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (0.500 g, 2.262 mmol) and potassium carbonate (1.563 g, 11.31 mmol) in acetonitrile (10 mL). The reaction vial was sealed and stirred at 50° C. for 16 h. The resulting mixture was filtered to remove the inorganic salt and the filter cake rinsed with ethyl acetate. The filtrate was concentrated, treated with ethyl acetate (20 mL) and dichloromethane (20 mL), and filtered to remove the residual inorganic salt. The filtrate was concentrated and dried under vacuum to give crude 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one as white solid (399.4 mg). This material was used in subsequent Suzuki coupling reactions without further purification. 1H NMR (400 MHz, chloroform-d) δ ppm 7.76 (d, J=2.0 Hz, 1H), 7.60 (dd, J=9.2, 2.0 Hz, 1H), 6.52 (d, J=9.0 Hz, 1H), 3.55 (s, 3H), 1.31 (s, 12H).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[C:7](=[O:11])[CH:6]=[CH:5][C:4](=[O:12])[C:3]=2[O:2]1.[CH2:13]=[CH:14][C:15]([Cl:17])=[CH2:16].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>C(O)(=O)C.O>[Cl:17][C:15]1[CH:16]=[C:5]2[C:6](=[CH:13][CH:14]=1)[C:7](=[O:11])[C:8]1[O:9][CH2:10][CH2:1][O:2][C:3]=1[C:4]2=[O:12]
Reactant: C=CC(=C)Cl
Reactant: O=C1C=CC(=O)C2=C1OCCO2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C2=C(OCCO2)C(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 90 h
Yield: 71.2 %

Procedure:
A mixture of 2,3-ethylenedioxy-1,4-benzoquinone (17 g) and freshly distilled chloroprene (13 g) in glacial acetic acid (100 mL) was stirred at ambient temperature for 90 hours. The mixture was then diluted with additional acetic acid (500 mL) followed by the addition of a solution of sodium dichromate (40 g) and sulfuric acid (2 mL) in water (25 mL). The mixture was heated at 60° -70°C. for 2 hours, then cooled and diluted with water (500 mL). The resulting bright orange precipitate was collected and dried to yield 18.25 g of 6-chloro-2,3-ethylenedioxy-1,4-naphthoquinone, mp 279°-80° C.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@@H:12]3[CH2:14][C@H:13]3[CH2:15][NH2:16])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1.C(O)C>O1CCCC1>[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@@H:12]3[CH2:14][C@H:13]3[CH2:15][NH:16][C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc2c([C@@H]3C[C@H]3CNC(=O)C3CC3)cccn2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a suspension of 1-[(1R,2R)-2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine dihydrochloride (750 mg, 2.74 mmol) and triethylamine (1.52 mL, 10.9 mmol) in tetrahydrofuran (27 mL) was added cyclopropanecarbonyl chloride (372 μL, 4.10 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Ethanol was added to the reaction 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) to give the title compound (647 mg, yield 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.[OH:19]CC1C=CC2C=CC3C=CC=CC=3SC=2C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:19])[C:10]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: OCc1ccc2c(c1)Sc1ccc(F)cc1C=C2
Reactant: OCc1ccc2c(c1)Sc1ccccc1C=C2
Product: O=S1c2ccc(F)cc2C=Cc2ccc(CO)cc21

Procedure:
Repeat the process of Example 2, substituting an equivalent quantity of 8-fluoro-3-hydroxymethyldibenzo[b,f]thiepin for the 3-hydroxymethyldibenzo[b,f]thiepin to obtain the title product (m.p., 161°-163° C.).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@H:14]([OH:22])[CH2:15][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.Cl[CH2:31][C:32]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[O:34][N:33]=1>C(O)(C)(C)C>[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@H:14]([OH:22])[CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH2:31][C:32]4[CH:36]=[C:35]([C:37]5[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:41][CH:42]=5)[O:34][N:33]=4)[CH2:20][CH2:21]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(Cc4cc(-c5ccc(C(F)(F)F)cc5)on4)CC3)ccc2s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol hydrochloride (50 mg) in t-butanol at room temperature was added triethylamine (60 μl), and the mixture was stirred at room temperature for 5 minutes. To this mixture was added 3-(chloromethyl)-5-[4-(trifluoromethyl)phenyl]isoxazole (26 mg), and the mixture was stirred at 100° C. overnight. The solvent was removed under reduced pressure, and the residue was dissolved in 1 ml of methanol, and purified by preparative thin layer chromatography, eluting with 5% methanol/dichloromethane, to afford (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methyl)piperazinyl]propan-2-ol, a compound of Formula I.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:9]2[C:10]([F:27])=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:26])=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.[OH-].[Na+].C1COCC1.Cl>O.CO>[F:27][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[C:17]([CH3:26])=[N:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2cc(OCc3ccc(C(F)(F)F)nc3C)cc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1COc1cc(F)c2c(CC(=O)O)csc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
A mixture of methyl(4-fluoro-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (240 mg), 1N NaOH (2 mL), THF (2 mL) and MeOH (2 mL) was stirred at room temperature for 1.5 h. To the mixture were added 1N HCl (2 mL) and water. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residual solid was washed with hexane to give the title compound (210 mg). The crystals were crystallized from acetone-hexane.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([CH2:12][O:13][N:14]=[C:15]([C:43]2[N:44]=[C:45]([NH:48][C:49](=[O:54])[C:50]([F:53])([F:52])[F:51])[S:46][CH:47]=2)[C:16]([NH:18][CH:19]2[C:41](=[O:42])[N:21]3[C:22]([C:28]([O:30]CC4C=CC([N+]([O-])=O)=CC=4)=[S:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]23)=[O:17])=[O:11])=CC=1)([O-])=O.C(O)C.P([O-])([O-])([O-])=O.[H][H]>[Pd].O1CCCC1>[C:10]([CH2:12][O:13][N:14]=[C:15]([C:43]1[N:44]=[C:45]([NH:48][C:49](=[O:54])[C:50]([F:51])([F:52])[F:53])[S:46][CH:47]=1)[C:16]([NH:18][CH:19]1[C:41](=[O:42])[N:21]2[C:22]([C:28]([OH:30])=[S:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]12)=[O:17])([OH:11])=[O:9]
Reactant: C=CC1=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCc3ccc([N+](=O)[O-])cc3)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CC1=C(C(O)=S)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Yield: 67.5 %

Procedure:
p-Nitrobenzyl 7-[2-(p-nitrobenzyloxycarbonylmethoxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthio-3-cephem-4-carboxylate (syn isomer) (2.3 g) was hydrogenated in the presence of 5% palladium on carbon in a mixture of tetrahydrofuran (100 ml), ethanol (11.5 ml) and 0.025M phosphate buffer solution (pH 6.85) (125 ml) at ambient temperature for 5 hours under 1 atmospheric pressure of hydrogen. The catalyst was filtered off and washed with ethyl acetate and a saturated aqueous solution of sodium bicarbonate successively. The filtrate and washings were combined and adjusted to pH 8 with dilute hydrochloric acid. The aqueous layer was separated, adjusted to pH 6 with dilute hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo and triturated with diisopropyl ether to give 7-[2-carboxymethoxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthio-3-cephem-4-carboxylic acid (syn isomer) (1.05 g).
Reaction SMILES: O=P(Cl)(Cl)Cl.[I:6][C:7]1[CH:8]=[C:9]([CH:13]([NH:24][CH:25]=O)[S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.CCN(CC)CC.CCOC(C)=O>C1COCC1.C(Cl)Cl.O>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([CH:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([I:6])[CH:8]=2)[N+:24]#[C-:25])(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(I)c2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: [C-]#[N+]C(c1cccc(I)c1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
POCl3 (3.05 mL) was added to a stirred solution of {(3-iodophenyl)[(4-methylphenyl)sulfonyl]methyl}formamide (Intermediate 52) (6.23 g) in dry THF (35 mL) at 25° C. and stirred for 5 minutes. The reaction mixture was cooled to 0° C. and Et3N (13.7 mL) was added dropwise over 45 minutes, keeping the internal temperature below 10° C. The reaction mixture was allowed to stir at 5-10° C. for a further 45 minutes. EtOAc (140 mL) and water (140 mL) was added and then stirred for 5 minutes. The organic phase was washed with water (2×140 mL), NaHCO3 (sat. aq., 140 mL) and then brine (140 mL). The organic phase was concentrated in vacuo to afford a dark brown gum. This was then passed through a pad of silica washing with DCM and concentrated in vacuo to afford a dark brown gum (ca. 70% pure 3.5 g, 58%);