Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[CH:3]1.N1C=CN=C1.[CH2:16]([Si:18](Cl)([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:17]>CN(C)C=O.CCOCC>[CH2:8]([C:4]1[C:5](=[O:7])[CH2:6][CH:2]([O:1][Si:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:16][CH3:17])[CH:3]=1)[C:9]#[CH:10]
Reactant: C#CCC1=CC(O)CC1=O
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCC1=CC(O[Si](CC)(CC)CC)CC1=O
Yield: 80.3 %

Procedure:
A solution of 250 mg (1.84 mmole) of the title compound of Example 2 in 4 ml of dimethylformamide was treated successively with 200 mg (3 mmole) of imidazole and 300 mg (2 mmole) of triethylsilyl chloride. After stirring for thirty minutes, the reaction mixture was diluted with ether, washed with water, dried over sodium sulfate, filtered, and concentrated to dryness. The crude material was chromatographed on silica gel to give 0.37 g of the title compound as an oil. Structure assignment was confirmed by the proton nmr spectrum: 2.13 (t, J=2 Hz, ≡C--H), 3.08 (mult, --CH2 --C≡), 4.90 (mult, C-11), ##STR7##
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:5]=1[NH2:6].[OH-].[K+]>C(Cl)(Cl)Cl>[Br:1][C:9]1[CH:10]=[C:4]([F:3])[C:5]([NH2:6])=[C:7]([F:11])[CH:8]=1
Reactant: BrBr
Reactant: Nc1c(F)cccc1F
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Nc1c(F)cc(Br)cc1F
Yield: 78.5 %

Procedure:
300 g of bromine was added drop-wise to 231 g of 2,6-difluoroaniline dissolved in 400 ml of chloroform. The mixture was refluxed for one hour and the reaction solution was poured into an aqueous 10% solution of potassium hydroxide. The potassium hydroxide was extracted with chloroform and the organic layer was washed with an aqueous 10% solution of potassium hydroxide and water. The chloroform was distilled off and the residue was distilled under reduced pressure (bp: 70°-80° C./4 mmHg) and recrystallized from hexane, to yield 292 g of 4-bromo-2,6-difluoroaniline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](Cl)(=[O:13])=[O:12])[N:7]([C:15](=[O:17])[CH3:16])[CH2:6][CH2:5]2.CN.[CH2:20]([N:22](CC)CC)C.C(Cl)(Cl)Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:13])(=[O:12])[NH:22][CH3:20])[N:7]([C:15](=[O:17])[CH3:16])[CH2:6][CH2:5]2
Reactant: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)Cl)cc21
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1cc2c(cc1Br)CCN2C(C)=O

Procedure:
To a suspension of 5-bromo-6-chlorosulfonyl-N-acetylindoline, 71.83 g (0.212 mol) in tetrahydrofuran was added a 40% aqueous solution of 2 equivalents of methylamine and 2 equivalents of triethylamine. The mixture was heated to reflux for 1.5 hours, then allowed to cool. Thin layer chromatography with chloroform showed that the reaction was complete. The cooled mixture was evaporated under reduced pressure, and the resulting white solid was suppended in hot methanol, filtered and washed with methanol and allowed to dry overnight. 65.12 g of 5-bromo-6-methylsulfamoyl-N-acetylindoline was obtained (92% by weight yield).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.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>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[OH:12])=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(F)cc2)c(O)c1

Procedure:
Methyl 4-bromo-3-hydroxybenzoate (2.1 g, 9.0 mmol), 4-fluorophenyl-boronic acid (2.52 g, 18 mmol), tetrakis(triphenylphosphine)palladium (0.52 g, 0.45 mmol), and 2M aqueous sodium carbonate solution (11 ml) in ethanol/toluene (1:5, 30 ml) were heated at reflux overnight. After cooling the solvent was removed in vacuo and the residue dissolved in EtOAc then washed with sat. aq. sodium bicarbonate and dried over MgSO4. The crude product was purified by column chromatography eluting with 1% MeOH/DCM giving the title compound as a solid (1.9 g). MS(ES): MH+ 247, M-H+ 245.
Reaction SMILES: [CH2:1]1[O:4][C@H:2]1[CH3:3].[Si:5]([O:22][C@H:23]([CH3:35])[C@H:24]([NH2:34])[C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl([O-])(=O)(=O)=O.[Li+].C(Cl)Cl>C(OCC)C>[Si:5]([O:22][C@H:23]([CH3:35])[C@H:24]([NH:34][CH2:1][C@@H:2]([OH:4])[CH3:3])[C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=1)([C:18]([CH3:19])([CH3:20])[CH3:21])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@H]1CO1
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](N)c1cc(F)c(F)c(F)c1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](O)CN[C@H](c1cc(F)c(F)c(F)c1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (S)-(−)-propylene oxide (0.1 ml) and (1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamine (212 mg) in diethyl ether (1 ml) was added to a suspension of lithium perchlorate (750 mg) in diethyl ether (1 ml), and the reaction solution was stirred in a nitrogen atmosphere at room temperature overnight. Methylene chloride and ice water were added to the reaction solution. After stirring the reaction solution, the organic layer was separated. The aqueous layer was subjected to extraction with methylene chloride again. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:heptane=9:1 to 4:1) to obtain 172 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=3)=[CH:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: NC(=O)c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2oc(-c3ccc(C(N)=O)nc3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
5-methoxybenzofuran boronic acid (1.2 mmol), 5-bromopyridine-2-carboxamide (1.0 mmol), Pd(PPh3)2Cl2 (0.024 mmol) and NEt3 (317 μL) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140° C. for 10 min in a microwave reactor, filtered, and the precipitate was washed with water and EtOAc and dried under vacuum to afford the title compound (75 mg). 1H NMR δ ppm 9.10 (d, 1 H) 8.34 (dd, 1 H) 8.21 (br. s., 1 H) 8.00 (d, 1 H) 7.52-7.72 (m, 3 H) 7.25 (d, 1 H) 7.00 (dd, 1 H) 3.82 (s, 3H); MS m/z 269 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH2:14][O:15][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Oc2cccc(CO)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2cccc(COS(C)(=O)=O)c2)cc1
Reaction time: 19 h
Yield: 89 %

Procedure:
To a solution of the obtained (3-(4-methoxy-phenoxy)-phenyl)-metanol (2.0 g, 8.73 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.81 mL, 10.5 mmol) and triethylamine (1.46 mL, 10.5 mmol) on an ice bath, and the solution was stirred for 19 hours. The reaction solution was diluted with dichloromethane, washed with an aqueous solution of 5% sodium bicarbonate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain methanesulfonic acid 3-(4-methoxy-phenoxy)benzyl ester (2.49, 89%) as a pale brown oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[C:8]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[NH:4][N:3]=1.[Cu](C#N)[C:32]#[N:33].C(N)CN>CN1CCCC1=O>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[C:8]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[N:6]=[C:5]3[NH:4][N:3]=[C:2]([C:32]#[N:33])[C:10]=23)=[CH:16][CH:15]=1
Reactant: Fc1ccc(-c2nc3[nH]nc(Br)c3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Solvent: NCCN
Product: N#Cc1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)c12

Procedure:
In a volumetric flask, 3-bromo-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.20 g, 0.4 mmol, obtained in example 64), copper cyanide (I) (0.05 g, 0.6 mmol) and anhydrous 1-methyl-2-pyrrolidone (1 mL) were introduced under argon atmosphere and heated to reflux for 2 h. This was poured into a 10% aqueous solution of ethylendiamine (4 mL) and extracted with CHCl3. Brine was added to the aqueous phase and it was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford the title compound in a solid form (yield: quantitative).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:37][O:38][CH3:39])[C:8]([NH:10][CH:11]2[C:35](=[O:36])[N:13]3[C:14]([C:18]([O:20][CH2:21][C:22]([O:24]CC4C=CC([N+]([O-])=O)=CC=4)=[O:23])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[H][H]>[Pd].O1CCCC1.CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:37][O:38][CH3:39])[C:8]([NH:10][CH:11]2[C:35](=[O:36])[N:13]3[C:14]([C:18]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: [H][H]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 34.1 %

Procedure:
A suspension of 4-nitrobenzyloxycarbonylmethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.34 g) and 10% palladium on carbon (0.7 g) in tetrahydrofuran (50 ml) and methanol (15 ml) was subjected to catalytic reduction under hydrogen atmosphere at 1 atm., until the uptake of hydrogen ceased. After removing the insoluble substance by filtration, the filtrate was concentrated in vacuo. The residue was triturated with ethyl acetate to give powder (0.35 g) of carboxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer), mp>250° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[OH:9])[CH2:4][CH2:3]1.BrCC1C=C[C:26]([C:29]2[N:30]=[N:31][N:32]([CH3:34])[N:33]=2)=CC=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:34][N:32]1[N:31]=[N:30][C:29]([CH2:26][N:2]2[CH2:7][CH2:6][CH:5]([CH:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:12][CH:11]=3)[OH:9])[CH2:4][CH2:3]2)=[N:33]1
Reactant: Cn1nnc(-c2ccc(CBr)cc2)n1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(CN2CCC(C(O)c3ccc(OC(F)(F)F)cc3)CC2)n1

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 3, using 7.0 grams (0.026 mole) of 4-piperidyl[4-(trifluoromethoxy)phenyl]methanol, hydrochloride, 6.8 grams (0.026 mole) of 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetraazole (prepared in a manner analogous to that of Steps A-C of Example 4), and 9.9 grams (0.077 mole) of N,N-diisopropylethylamine in about 40 mL of DMSO. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:14])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)O.O>C(O)C>[CH3:2][C:1]([O:4][C:12]1[CH:11]=[CH:10][CH:9]=[CH:7][C:6]=1[C:5]([OH:14])=[O:13])=[O:3]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccccc1O
Solvent: CCO
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)O

Procedure:
A dosage form of salicylic acid acetate for topical or oral use was prepared as follows: Desalted egg phosphatides (Hepar) were dissolved in absolute ethanol at a concentration of 250 mg/ml in a 1000 ml flask. To 400 mg of salicylic acid acetate, 1.6 ml of the above solution containing 400 mg of phosphatides was added and the solution adjusted with absolute ethanol to 4 ml. The final concentration of both ingredients in this pharmacological agent-lipid solution was 100 mg/ml. This procedure was performed at about 22.5° C.+/- about 2.5° C. and atmospheric pressure. Next, the topical/oral administration dosage form was prepared by adding the pharmacological agent-lipid solution, to water at about 22.5° C.+/- about 2.5° C. and briefly agitating the mixture. A cloudy suspension promptly formed. This salicylic acid acetate formulation may then be ingested or used topically.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CN(C=O)C>[CH3:4][C:3]([CH3:6])([CH3:5])[CH:2]([S:15][C:13](=[O:16])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)C(Br)c1ccccc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC(c1ccccc1)C(C)(C)C
Temperature: 50 °C
Yield: 99.1 %

Procedure:
(1-Bromo-2,2-dimethyl-propyl)-benzene (1.00 g, 4.40 mmol) was dissolved in dry DMF (5 mL) under an argon atmosphere. Potassium thioacetate (2.51 g, 22.0 mmol) was added and the reaction was heated to 50° C. for 7 days. The solution was then concentrated and the product purified by column chromatography to obtain the desired thioester (970 mg, 99%). TLC (Hexane:CH2Cl2, 7:3 v/v): Rf=0.40. 1H NMR (400 MHz, CDCl3): δ 7.33-7.22 (m, 5H), 4.52 (s, 1H), 2.32 (s, 3H), 1.00 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 193.9 (q), 140.4 (q), 129.0, 127.2, 126.4, 58.7, 34.9 (q), 30.2, 27.6. HRMS (m/z): [M+Na]+ calcd. for C13H18ONaS 245.0976; found, 245.0972.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:19]=[C:20]([CH3:25])[C:21]([OH:24])=[CH:22][CH:23]=1>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Cc1cc(N)ccc1O
Product: Cc1cc(NC(=O)c2cc(NC3CCCCC3)ncn2)ccc1O

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-o-cresol (Aldrich), the title compound was obtained as a brown solid.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:20]#[N:21])[C:10]([CH3:19])=[C:11]([C:14]([O:16]CC)=[CH2:15])[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1.O.[Br:23]N1C(=O)CCC1=O>O1CCCC1>[Br:23][CH2:16][C:14]([C:11]1[C:12]([F:13])=[C:6]2[O:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:8][C:7]2=[C:9]([C:20]#[N:21])[C:10]=1[CH3:19])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)CBr)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.9 %

Procedure:
2-Cyclopropyl-6-[1-(ethoxy)ethenyl]-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-78) (9.34 g, 30.1 mmol) was dissolved in tetrahydrofuran (450 ml), then water (27 ml) and N-bromosuccinimide (5.73 g, 31.58 mmol) were added all at a time, followed by stirring at room temperature for 45 minutes. After the reaction, the solvent was evaporated away under reduced pressure, followed by dilution with ethyl acetate and by washing with aqueous sodium thiosulfate solution and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography and eluted with a mixed solvent of n-hexane/ethyl acetate (4:1, v/v) to obtain the intended product (9.63 g, 95%) as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:9]=1[OH:17])([CH3:7])[CH3:6].C(OCC)(=O)C>C(O)(=O)C>[CH:14]([C:10]1[CH:11]=[C:12]([N+:1]([O-:4])=[O:2])[CH:13]=[C:8]([CH:5]([CH3:7])[CH3:6])[C:9]=1[OH:17])([CH3:16])[CH3:15]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)c1cc([N+](=O)[O-])cc(C(C)C)c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
78.3 mmol (4.93 g) of fuming nitric acid are added dropwise to a solution, cooled to 0° C., of 53.9 mmol (9.62 g) of 2,6-diisopropylphenol in 350 ml of acetic acid. The reaction mixture is stirred at 0° C. for 1 hour 30 minutes and is then poured into a mixture of ethyl acetate and ice. The organic phase is isolated and then washed with water. After drying and evaporating off the solvent, an oily residue is recovered which is purified by chromatography on silica gel using a petroleum ether: ethyl acetate mixture 9:1 as eluant.
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH2:3][CH3:4].C(Cl)CCl.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>O>[CH2:2]([O:5][NH:6][C:18](=[O:19])[O:20][CH2:21][CH3:22])[CH2:3][CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CCCON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCCl
Product: CCCONC(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
22 g (197 mmol) of n-propoxyamine hydrochloride was dissolved in 100 ml of water, and 200 ml of ethylene dichloride was added thereto. Then, 27.2 g (197 mmol) of potassium carbonate was added in several times under cooling, and then 21.3 g (196 mmol) of ethyl chloroformate was dropwise added thereto at a temperature of not higher than 10° C. After raising the temperature to room temperature, the mixture was further stirred at the same temperature for 4 hours. The ethylene dichloride layer was separated, and then the aqueous layer was extracted twice with 100 ml of chloroform. The ethylene dichloride layer and the chloroform layer were put together, and washed with a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. 27 g of ethyl N-n-propoxycarbamate was obtained by distillation under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[CH2:20][C:21](=O)[CH3:22]>CCCCCCC.C(OCC)(=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:21]([CH3:22])[C:20]([C:19](=[O:24])[C:18]([F:26])([F:25])[F:17])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Yield: 50 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that heptane/ethyl acetate (10:1) was used. Yield: 50%; MS: m/z=392/394 (M).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[S:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:20].[C:30]([NH:33][C@@H:34]([CH3:46])[CH2:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)(=[O:32])[CH3:31]>>[C:30]([NH:33][C@@H:34]([CH3:46])[CH2:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([C:41]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][C:3]=2[S:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])=[O:42])=[CH:44][CH:45]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)N[C@@H](C)COc1ccc(C(=O)O)cc1
Reactant: CCCCC(CC)COC(=O)CCSc1cc(OCc2ccccc2)ccc1N
Product: CCCCC(CC)COC(=O)CCSc1cc(OCc2ccccc2)ccc1NC(=O)c1ccc(OC[C@H](C)NC(C)=O)cc1
Yield: 66.8 %

Procedure:
Using 2-ethylhexyl 3-{[2-amino-5-(benzyloxy)phenyl]sulfanyl}propanoate (1.00 g) and 4-{[(2S)-2-(acetylamino)propyl]oxy}benzoic acid (628 mg), and in the same manner as in Example 2, step C, the title compound (1.02 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11](=O)[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH2:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH2:28][CH2:29][CH3:30].[O-]CC.[Na+]>>[CH2:27]([NH:31][C:32]1[N:34]=[C:11]([C:10]2[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:8][N:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=23)[CH:12]=[CH:13][N:33]=1)[CH2:28][CH2:29][CH3:30]
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Reactant: CCCCNC(=N)N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Yield: 59 %

Procedure:
In a similar manner as described in Example 34 from 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (0.50 g, 1.7 mmol), N-butylguanidine sulfate and sodium ethoxide (0.81 mL, 21 wt % in ethanol, 2.2 mmol) at room temperature was obtained N-butyl-4-[7-chloro-2-(4-fluorophenyl)-pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (0.39 g, 59% o) as a fluffy pale yellow solid. 1H NMR (CDCl3): δ 8.40 (d, 1H), 8.07 (d, 1H), 7.65 (m, 2H), 7.29 (m, 1H), 7.15 (t, 2H), 7.06 (d, 1H), 6.32 (d, 1H), 5.16 (bs, 1H), 3.49 (q, 2H), 1.71–1.41 (m, 4H), 0.99 (t, 3H); 19F NMR (CDCl3) δ−112.77; MS m/z 396 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18].[C:23]([O:27][C:28]([NH:30][C:31]1([C@H:34]2[CH2:38][NH:37][CH2:36][C@H:35]2[F:39])[CH2:33][CH2:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CN1CCCCC1>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:37]2[CH2:38][C@H:34]([C:31]3([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH2:32][CH2:33]3)[C@H:35]([F:39])[CH2:36]2)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18]
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CNC[C@H]2F)CC1
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Solvent: CN1CCCCC1
Solvent: CS(C)=O
Product: Cc1c(N2C[C@@H](F)[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture consisting of 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (45 mg, 0.144 mmol), (3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidine (52.8 mg, 0.216 mmol), 1-methylpiperidine (18.5 mg, 0.186 mmol) and dimethyl sulfoxide (1.8 ml) was stirred at an outer temperature of 80° C. for 7 hours. When analysis was carried out by a high performance liquid chromatography after completion of the reaction, formed ratio of the compound of interest 5-amino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid was 4%. Also, residual ratio of the starting material was 90%.