Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:22][OH:23])[N:12]=[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])[C:8]2=[C:7]([NH:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[N:6]=1.[C:36]([NH:43][C@H:44]([C:48](O)=[O:49])[CH:45]([CH3:47])[CH3:46])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.ClC(OC(C)=C)=O>C(Cl)Cl>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:22][O:23][C:48](=[O:49])[CH:44]([NH:43][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH:45]([CH3:47])[CH3:46])[N:12]=[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])[C:8]2=[C:7]([NH:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[N:6]=1
Reactant: CS(=O)(=O)CCNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1cc(F)ccc1F)nn2CO
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C=C(C)OC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCn1nc(-c2cc(F)ccc2F)c2c(NCCS(C)(=O)=O)nc(Oc3ccc(F)cc3F)nc21
Temperature: 0 °C
Yield: 51.2 %

Procedure:
[6-(2,4-Difluoro-phenoxy)-3-(2,5-difluoro-phenyl)-4-(2-methanesulfonyl-ethylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-methanol (170 mg, 0.33 mmol) was dissolved in methylene chloride, and Boc-(L)-Valine (216 mg, 0.99 mmol), dimethylamino pyridine (81 mg, 0.66 mmol), and triethylamine (0.23 mL, 1.6 mmol) were added. The reaction mixture was cooled to 0° C. and stirred under nitrogen, and isopropenyl chloroformate (54 uL, 0.49 mmol) was added. The reaction mixture was stirred for 10 minutes and then partitioned between water and methylene chloride. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography through silica (1:1 hexanes/EtOAc) to give 120 mg of 2-tert-butoxycarbonylamino-3-methyl-butyric acid 6-(2,4-difluoro-phenoxy)-3-(2,5-difluoro-phenyl)-4-(2-methanesulfonyl-ethylamino)-pyrazolo[3,4-d]pyrimidin-1-ylmethyl ester as an oil.
Reaction SMILES: O[N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2N=N1.[CH:11]1([N:17]=C=NC2CCCCC2)CCCC[CH2:12]1.CS(NC1C=CC(C(=O)CCC(O)=O)=CC=1)(=O)=O>CN(C)C=O>[CH3:12][C:11]1[N:17]=[C:8]([CH2:7][CH2:6][NH2:2])[CH:9]=[CH:10][CH:5]=1
Reactant: On1nnc2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Solvent: CN(C)C=O
Product: Cc1cccc(CCN)n1
Reaction time: 1 h
Yield: 100 %

Procedure:
4.76 g (35.3 mmol) of 1-hydroxybenzotriazole and 7.27 g (35.3 mmol) of dicyclohexylcarbodiimide were added to a solution of 7.02 g (29.4 mmol) of 4-(4-methylsulfonylaminophenyl)-4-oxobutyric acid in 60 ml of dimethylformamide at 0° C. and the mixture was stirred at that temperature for 1 h. 4.80 g (35.3 mmol) of 2-(6-methyl-2-pyridyl)ethylamine obtained in the above step (2) was added thereto. The mixture was stirred at room temperature for 12 h and then filtered. The filtrate was concentrated. The solid residue thus obtained was washed with a solvent mixture of chloroform/acetic acid/ethanol to give 9.39 g (yield: 89%) of the intended compound in the form of white crystals.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[Cl:10][CH2:11][S:12]([NH:15][C:16]1[CH:21]=[C:20]([N:22]=[C:23]=[O:24])[C:19]([F:25])=[CH:18][C:17]=1[Cl:26])(=[O:14])=[O:13].Cl>[OH-].[Na+].C(C(C)=O)C(C)C>[Cl:26][C:17]1[C:16]([NH:15][S:12]([CH2:11][Cl:10])(=[O:14])=[O:13])=[CH:21][C:20]([NH:22][C:23]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@@H:4]2[C:7]([OH:9])=[O:8])=[O:24])=[C:19]([F:25])[CH:18]=1
Reactant: O=C=Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Yield: 90 %

Procedure:
To a stirred solution of cis-4-hydroxy-D-proline (262 g, 2 mol) in 2 L of 1 N NaOH at 0° C. was added dropwise 1950 mL of a solution of 1-chloro-N-(2-chloro-4-fluoro-5-isocyanatophenyl)methanesulfonamide in methyl isobutyl ketone over 90 minutes. The temperature was kept between −3° C. and 5° C. The pH wag maintained at 8-9 by the addition of 550 mL of 10% NaOH. Stirring was continued at this temperature for another hour at pH 8 and then the two-phase mixture was allowed to come to room temperature. 70 mL of concentrated HCl was added in order to lower the pH to 6.5. After stirring for 20 minutes, the phases were separated. Methyl isobutyl ketone was added to the aqueous phase and the solution was acidified with concentrated hydrochloric acid to pH 2. After addition of solid sodium chloride and vigorous stirring the organic layer was separated. The solvent was removed to yield 775 g (90%) of the title compound (purity: 95-97% by HPLC). 1H NMR (Me2SO-d6) δ 12.4 (br s, 1H), 10.1 (br s, 1H), 8.2 (s, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 5.1-5.0 (br s, 1H), 5.0-4.9 (s, 2H), 4.4 (m, 1H), 4.3 (m, 1H), 3.7-3.6 (m, 1H); 3.4-3.3 (m, 2H), 2.4-2.3 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([C:15]1[CH:20]=[CH:19]C(F)=CC=1)[CH:7]=[C:6]([C:22]([O:24]CC)=[O:23])[C:5]2=[O:27].O>B(F)(F)F.F>[CH:15]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[C:10]=3[O:13][CH3:14])[C:5](=[O:27])[C:6]([C:22]([OH:24])=[O:23])=[CH:7]2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(OC)c(F)c(F)cc2c1=O
Agent: F
Agent: FB(F)F
Solvent: O
Product: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 3 h

Procedure:
A suspension of 1.0 g (0.0027 mole) of ethyl 6,7-difluoro-1-(4-fluorophenyl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XXXII, R11 =4-fluorophenyl) (prepared as described in Preparation 4) in 15 ml of 42% aqueous hydrofluoroboric acid was stirred at 90°-100° C. for 3 hours, after which it was poured into water. The precipitated crystals were collected by filtration to give 1 g of a chelate (IV) as a colorless powder. The whole of this was dissolved in 3 ml of dimethyl sulfoxide, and the solution was mixed with 0.43 g (0.005 mole) of anhydrous piperazine. The mixture was then stirred at 60°-70° C. for 3 hours. At the end of this time, the reaction mixture was allowed to cool to room temperature. On adding water, a chelate (V) separated out as yellow crystals, which were collected by filtration. The crystals were dissolved in a mixture of 150 ml of 80% aqueous methanol and 5 ml of triethylamine, and the solution was heated under reflux for 4 hours. It was then allowed to cool to room temperature, and insoluble materials were removed by filtration. The filtrate was then concentrated by evaporation under reduced pressure to give crystals. These were washed with ethanol to give 0.73 g of 6-fluoro-1-(4-fluorophenyl)-8-methoxy-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as a colorless powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7]I.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15]([CH3:19])=[N:16]2)=[C:12]([Cl:20])[N:11]=1.O>C1COCC1>[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[C:15]([CH3:19])[N:16]2[CH3:7])=[C:12]([Cl:20])[N:11]=1
Reactant: Cc1nc2nc(Cl)nc(Cl)c2[nH]1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(Cl)nc(Cl)nc2n1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Potassium carbonate (442 mg) and methyl iodide (0.17 mL) were added to a solution of 2,6-dichloro-8-methyl-7H-purine (500 mg) in THF (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. After the reaction mixture was ice-cooled, water was added thereto, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=9:1 to 8:2), whereby 2,6-dichloro-8,9-dimethyl-9H-purine (310 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:13])[C:8](=[O:9])[C:7](=[O:10])[C:6]([CH3:12])([CH3:11])[O:5]1.[N+](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-]>COC(C)(C)C.[Cl-].[Zn+2].[Cl-]>[CH2:20]([O:19][C:17]([CH:16]1[C:7](=[O:10])[C:6]([CH3:11])([CH3:12])[O:5][C:4]([CH2:3][O:2][CH3:1])([CH3:13])[C:8]1=[O:9])=[O:18])[CH3:21]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: COCC1(C)OC(C)(C)C(=O)C1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: COC(C)(C)C
Product: CCOC(=O)C1C(=O)C(C)(C)OC(C)(COC)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of zinc chloride (11.80 ml, 11.80 mmol, 1M solution in diethyl ether) at 8° C. is carefully added a second solution of 2-methoxymethyl-2,5,5-trimethylfuran-3,4-dione (2.15 g, 11.56 mmol) in tert-butyl methyl ether (8 ml). This mixture is allowed to warm to 15° C. at which stage a solution of ethyl diazoacetate (1.35 g, 11.84 mmol) in tert-butyl methyl ether (6 ml) is added dropwise over 1 hour, maintaining an internal temperature below 21° C. with further stirring at room temperature overnight. The mixture is diluted with tert-butyl methyl ether (15 ml), washed with 1M hydrochloric acid (3×20 ml) and extracted with 1M sodium hydroxide (2×100 ml). To this aqueous phase is added solid sodium chloride, followed by acidification with concentrated hydrochloric acid then the mixture is extracted with dichloromethane. The organic extract is dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated in vacuo to afford 2-methoxymethyl-2,6,6-trimethyl-3,5-dioxo-tetrahydropyran-4-carboxylic acid ethyl ester (2.11 g) as a pink oil.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:20][CH3:21])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=NO)C1C(=CC=CC=1)O.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.[Cu-]=O.C(OCC)(=O)C>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:20][CH3:21])[C:14]([N:33]3[CH:37]=[CH:36][N:35]=[CH:34]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1c(Br)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Reactant: c1c[nH]cn1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1c(-n2ccnc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 160 °C

Procedure:
A mixture of 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoic acid (Intermediate 133, 0.20 g), copper (I) oxide (0.008 g), salicylaldoxime (0.032 g), imidazole (0.08 g), cesium carbonate (0.5 g) in acetonitrile (4 ml) was sealed under nitrogen in a microwave vial and heated at 160° C. for 1 hour. After cooling, ethyl acetate was added and the solid was filtered off. The filtrate was evaporated to dryness and the residue was purified by HPLC, eluting with a mixture of methanol and water containing 0.1% formic acid with a gradient of 20-98% to give 6-benzenesulphonylmethyl-3-(imidazol-1-yl)-2-methoxybenzoic acid as a white solid.
Reaction SMILES: NN.[F:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[S:22]([CH3:27])(=[N:24][C:25]#[N:26])=[O:23])[CH2:7][N:8]1C(=O)C2C(=CC=CC=2)C1=O.ClCCl>CO>[F:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[S:22]([CH3:27])(=[N:24][C:25]#[N:26])=[O:23])[CH2:7][NH2:8]
Reactant: CS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1F
Agent: NN
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=NC#N)c1ccc(CN)cc1F

Procedure:
Hydrazine (85% in water, 2.0 g, 53 mmol) is added to a solution of 2-(3-fluoro-4-(N-cyano-S-methylsulfonimidoyl)-benzyl)-isoindole-1,3-dione (preparation 15c, 3.5 g, 8.8 mmol) in a 1:1 mixture of dichloromethane and methanol (140 mL). The mixture is stirred over night and concentrated under reduced pressure. The residue is purified by preparative reversed phase HPLC (Luna C18(2), gradient of acetonitrile in water, 0.01 M NH3). Yield: 1.2 g (58% of theory); ESI mass spectrum: [M+H]+=228; r.t. HPLC: 0.26 min (X011_S03).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)=[O:4].[OH-].[K+].I[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CS(C)=O.O>[F:1][C:2]([F:20])([F:21])[C:3]([N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:16])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)=[O:4]
Reactant: CCCCCI
Reactant: CC1(C)CCC(C)(C)c2cc(NC(=O)C(F)(F)F)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCN(C(=O)C(F)(F)F)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 2,2,2-trifluoro-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (29) (15.05 g, 40.7 mmole) in 105 mL dimethylsulfoxide (DMSO) was treated with potassium hydroxide (3.38 g) and then cooled to 0° C. Iodopentane (7.9 mL) in 15 mL DMSO was added dropwise to the reaction mixture and the temperature was allowed to rise to 23° C. The reaction mixture was stirred at room temperature for 24 hours, diluted with 200 mL of water and extracted with two 200 mL portions of ether. The combined organic extracts were washed with four 200 mL portions of cold water, dried over MgSO4, filtered and concentrated in vacuo to give a brown oil. The product was purified by flash chromatography (SiO2, 1:15 ethyl acetate/hexanes) to afford 14.36 g of 2,2,2-trifluoro-N-pentyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (31) as a pale yellow oil.
Reaction SMILES: Cl.C[C:3]1[C:8]2[C:9](Cl)=[N:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[S:13](=[O:15])(=[O:14])[C:7]=2[CH:6]=[C:5]([C:21]([O-:23])=[O:22])[CH:4]=1.[CH3:24]COCC>>[CH:3]1[C:8]2[CH:9]=[N:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[S:13](=[O:14])(=[O:15])[C:7]=2[CH:6]=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:4]=1
Reactant: Cc1cc(C(=O)[O-])cc2c1C(Cl)=Nc1ccccc1S2(=O)=O
Reactant: CCOCC
Agent: Cl
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2

Procedure:
Stir a suspension of 12.766 gm (67.33 mmole) of anhydrous stannous chloride in 350 ml of dry ether while passing dry hydrogen chloride through the suspension at a rate sufficient to cause brisk reflut. When the suspension is saturated, add 5.63 gm 16,83 mmole) of methyl-11-chlorodibenzo[b,f][1,4]thiazepin-3-carboxylate 5,5-dioxide in portions over 15 minutes. Continue introduction of hydrogen chloride for 1 hour. Decant the ether layer and pour the residue into a mixture of 200 ml of ether and 100 ml of water. Separate the ether layer and wash with 25 ml of 5 N aqueous sodium hydroxide and then with 50 ml of saturated sodium chloride solution. Dry the ether layer over magnesium sulfate and evaporate to 20 ml. Separate the precipitate by filtration. Chromatograph over silica gel eluting with 1:4 ethyl acetate in toluene. Disolve the product in boiling methanol, filter and evaporate to 10 ml. Separate the solid by filtration to obtain the title product (m.p. 181°-181.5° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][NH:7][CH2:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>C(#N)C>[CH2:28]([N:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH2:8][CH:9]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCNCC(C(=O)OCC)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCN(Cc1ccccc1)CC(C(=O)OCC)c1ccccc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of ethyl 3-[(3-ethoxy-3-oxopropyl)amino]-2-phenylpropanoate (1.0 g) and sodium carbonate (0.72 g) in acetonitrile (2 ml), benzyl bromide (0.64 g) was added, and the reaction mixture was stirred at 75° C. for 2 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then the solvent was evaporated under reduced pressure to obtain ethyl 3-[benzyl(3-ethoxy-3-oxopropyl)amino]-2-phenylpropanoate as colorless oil (1.20 g).
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14]CC)=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][CH:19]([CH3:21])[CH3:20])[CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][CH:19]([CH3:21])[CH3:20])[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC(C)C)cc(F)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cc(F)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 17.9 %

Procedure:
To a solution of ethyl 2-(4-fluoro-1-hydroxy-6-isopropoxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (148 mg, 0.50 mmol) in THF (2 mL) was added dropwise an solution of lithium hydroxide (102 mg, 2.5 mmol) in 3 mL of water at 0° C. The reaction mixture was stirred at room temperature for 1.5 h and then acidified to pH=2 using diluted hydrochloride acid. The reaction mixture was extracted with ethyl acetate (15 mL×2) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by HPLC to give the title compound as a white solid (24 mg, Yield: 18%). 1H NMR (400 MHz, DMSO-d) δ 12.40 (s, 1H), 9.39 (s, 1H), 7.06-7.07 (d, J=2.0 Hz, 1H), 6.87-6.91 (m, 1H), 5.51-5.54 (m, 1H), 4.62-4.64 (m, 2H), 2.90-2.95 (m, 1H), 2.31-2.33 (m, 1H), 1.28 (s, 1H). MS (ESI) m/z=536 [2M]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:10]([CH:12]([CH3:14])[CH3:13])[NH2:11])=[O:9])[C:5]([NH:15][C:16]([C:18]2[N:19]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:20]=[C:21]([Br:23])[CH:22]=2)=[O:17])=[C:4]([CH3:31])[CH:3]=1.Cl[C:33]([O:35][CH3:36])=[O:34]>N1C=CC=CC=1>[CH3:36][O:35][C:33]([NH:11][N:10]([C:8]([C:6]1[C:5]([NH:15][C:16]([C:18]2[N:19]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:20]=[C:21]([Br:23])[CH:22]=2)=[O:17])=[C:4]([CH3:31])[CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:9])[CH:12]([CH3:13])[CH3:14])=[O:34]
Reactant: Cc1cc(Cl)nc(C(=O)N(N)C(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)NN(C(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [6-chloro-2-(N-isopropyl-hydrazinocarbonyl)-4-methyl-pyridin-3-yl]-amide (13-a) (121 mg) was dissolved in pyridine (2 mL), methyl chloroformate (70 μL) was added and the reaction mixture was stirred at 50° C. After 1 h, methyl chloroformate (each 40 μL) was added 8× in a time interval of 30 min at 50° C. After 10 h stirring at room temperature, the reaction mixture was quenched with water and 3× co-evaporated with toluene. The residue was dissolved in water and ethyl acetate, the layers were separated and the aqueous layer was extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, chloroform/ethyl acetate=3:1, Rf=0.15) to afford 67 mg of the title compound (13) of the present invention of the formula
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-])=O)[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C>CCO.[Fe]>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(N)c1

Procedure:
The mixture of 4-(tert-butyldimethylsilyloxy)-2-nitrobenzenamine (0.5 g, 1.9 mmol), Fe powder (1.1 g, 19 mmol) and acetic acid (1.0 mL, 18 mmol) in EtOH (10 mL) was stirred at reflux for 4 hrs. The mixture was filtered through celite pad and the filtrate was concentrated.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](O)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C(OC(C1N=C(O)C2C(C)=NSC=2C=1O)=O)CCC.P(Br)(Br)([Br:41])=O>ClC(Cl)C>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([Br:41])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(O)c2snc(C)c2c1O
Reactant: O=P(Br)(Br)Br
Agent: CCCCOC(=O)c1nc(O)c2c(C)nsc2c1O
Solvent: CC(Cl)Cl
Product: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Temperature: 120 °C
Reaction time: 0.58 h

Procedure:
To a solution of the mixture of 4,7-dihydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and 4,7-dihydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester (6.67 mmol) obtained as described above in dichloroethane (33.3 mL) was added POBr3 (8.0 mmol). The reaction mixture was stirred at 120° C. in a microwave oven for 35 min. After cooling to r.t., the mixture was partitioned between CH2Cl2 and sat. NaHCO3, then filtered and the organic layer of the filtrate was washed with brine before it was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Eluting with 0-20% EtOAc/CH2Cl2, gave 7-bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester (850 mg) as a white solid: MS (m/z) 342.9 (M−1), 345.0 (M−1), and 4-Bromo-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester (473 mg) as a white solid: MS (m/z) 342.9 (M−1), 345.0 (M−1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=O)[CH2:15][O:14][CH-]2)=[CH:8][C:7]=1[N+:18]([O-:20])=[O:19].[OH-].[Na+]>>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:16][CH2:15][OH:14])=[CH:8][C:7]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C1CO[CH-]N1c1ccc(NCCCO)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(NCCO)ccc1NCCCO
Temperature: 80 °C

Procedure:
0.02 mole (5.1 g) of N-[4-(γ-hydroxypropyl)amino-3-nitrophenyl]oxazolidone, prepared according to Example 6 or 8, is added to 22 moles of 2N sodium hydroxide, After 30 minutes' heating at 80° C., the expected product crystallizes from the reaction medium.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH:18]([F:20])[F:19])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([N:26]1[CH:30]=[C:29](C2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1)([CH3:25])([CH3:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.CCOC(C)=O.[Cl-].[Na+].O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH:18]([F:20])[F:19])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([C:29]2[CH:28]=[N:27][N:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:30]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)n1cnc2cc(Cl)nc(OCc3ccccc3)c21
Reactant: CC(C)(C)n1cc(C2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)n1cc(-c2cc3ncn(C(F)F)c3c(OCc3ccccc3)n2)cn1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
4-(benzyloxy)-6-chloro-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridine 2.28 (109 mg, 0.352 mmol), 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole (177 mg, 0.708 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (17 mg, 0.024 mmol) and K3PO4 (235 mg, 1.11 mmol) were taken up in dioxane (3 mL) under Ar. Water (0.45 mL) was added and the stirred mixture was heated to 100° C. After 1.25 h, the reaction mixture was cooled to r.t. and was diluted with EtOAc (20 mL) and half-saturated brine (20 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (15% to 50% EtOAc in hexanes) provided 4-(benzyloxy)-6-(1-tert-butyl-1H-pyrazol-4-yl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridine 2.31.