Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:43]1[CH:44]=[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:48])=[CH:47][C:42]=1[O:41][C@H:40]2[O:58][CH3:59])C1C=CC=CC=1.ClC1C=CC=CC=1Cl.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:48][C:46]1[C:45]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[CH:44][C:43]2[C@@:10]3([C@H:40]([O:58][CH3:59])[O:41][C:42]=2[CH:47]=1)[C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)O[C@@H](OC)[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc3c(cc2Cl)O[C@@H](OC)[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 76.4 %

Procedure:
To a solution of 54 (22 mg, 27 μmol) in a mixture of MeOH (1.5 mL) and THF (0.5 mL) were added Pd(OH)2/C (15 mg) and 1,2-dichlorobenzene (20 μL). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LC/MS indicated that de-protection was complete. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by preparatory TLC (5% MeOH in DCM) to give 55 (9.3 mg, 76%). 1H NMR (300 MHz, CD3OD) δ 7.20 (s, 1H), 7.06 (s, 4H), 6.82 (s, 1H), 5.61 (s, 1H), 3.99 (s, 2H), 3.63-3.79 (m, 3H), 3.55 (s, 3H), 3.42-3.60 (m, 3H), 2.57 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H). LCMS m/z 451 (M+H), 473 (M+Na).
Reaction SMILES: C(CC[C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)#N.[OH-].[K+].C(O)(=[O:24])C.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>C(O)C.CCOCC>[OH2:24].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[C:29]([CH2:28][CH2:27][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([CH2:14][C:15]2[NH:19][CH:18]=[CH:17][N:16]=2)=[CH:5]1)([OH:31])=[O:30]
Reactant: N#CCCc1[nH]c2ccccc2c1Cc1ncc[nH]1
Reactant: CC(=O)O
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: O
Product: O=C(O)CCn1cc(Cc2ncc[nH]2)c2ccccc21

Procedure:
A mixture of 1-(2-cyanoethyl-3-(1-imidazolyl methyl)-indole (1.0 g) and 10% aqueous potassium hydroxide (10 ml) was heated under reflux for 2 hours to give a clear solution. The solution was just acidified with acetic acid and then evaporated. The residue was chromatographed on silica gel. Elution with a mixture of chloroform and methanol (1:1) gave first a small amount of impurity followed by pure product. Evaporation of the product-containing eluate gave an oil which was dissolved in the minimum volume of ethanol. A slight excess of a saturated ethanolic solution of fumaric acid was added and the mixture was diluted with ether. The precipitate was collected by filtration and crystallised from methanol to give 1-(2-carboxyethyl)-3-(1-imidazolylmethyl)indole fumarate monohydrate 0.45 g, m.p. 161°-163° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[O:13]=[C:14]([CH3:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].N1CCCCC1.CC(O)=O>C1C=CC=CC=1>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:15]([C:14](=[O:13])[CH3:20])[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc2c(c1)CCCO2
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)C(=Cc1ccc2c(c1)CCCO2)C(C)=O
Yield: 60.47 %

Procedure:
A solution of 6-iodochroman (13.8 g, 53.1 mmol) in tetrahydrofuran (THF) (143 mL) was cooled to −78° C. in a dry ice/acetone bath and then treated with n-BuLi, 2.5M solution in hexanes (23.35 mL, 58.4 mmol). The mixture was stirred for 10 minutes before being treated with N,N-dimethylformamide (6.16 mL, 80 mmol) and the resultant was warmed to ambient temperature and stirred for 10 minutes. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford the crude chroman-6-carbaldehyde as a yellow solid which was used without further purification. LC/MS (m/z) ES+=163.22 (M+1). A solution of the crude chroman-6-carbaldehyde, methyl 3-oxobutanoate, piperidine (0.263 mL, 2.66 mmol) and AcOH (0.152 mL, 2.66 mmol) in Benzene (113 mL) was refluxed (DS-trap) overnight. The mixture was concentrated and diluted with ethyl acetate. The dilution was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-30% hexanes/ethyl acetate) the afford methyl 2-(chroman-6-ylmethylene)-3-oxobutanoate (mixture of E and Z isomers, 8.352 g, 32.08 mmol, 60.47% yield) as a thick yellow oil. 1H NMR (400 MHz, CHLOROFORM-d, major isomer) δ ppm 7.48 (s, 1 H), 7.22-7.12 (m, 2 H), 6.78 (d, J=8.6 Hz, 1 H), 4.27-4.18 (m, 2 H), 3.92-3.81 (m, 3 H), 2.77 (t, J=6.3 Hz, 2 H), 2.39 (s, 3 H), 2.06-1.99 (m, 2 H); 1H NMR (400 MHz, CHLOROFORM-d, minor isomer) δ ppm 7.58 (s, 1 H), 7.16-7.08 (m, 2 H), 6.79-6.71 (m, 1 H), 4.23-4.18 (m, 2 H), 3.84-3.78 (m, 3 H), 2.76 (t, J=6.4 Hz, 2 H), 2.38 (s, 3 H), 2.03-1.96 (m, 2 H); LC/MS (m/z) ES+=261.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[C:22]([F:31])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:33][OH:34].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[C:22]([F:31])[CH:21]=1)[CH2:9]/[C:10](=[N:33]\[OH:34])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: NO
Reactant: CCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2Cl)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCNC(=O)c1ccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccccc2Cl)cc1F

Procedure:
In analogy to example 151, step 3, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N-ethyl-2-fluorobenzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 4% of the corresponding Z isomer as a colorless waxy solid, MS (ESI+): m/z=456.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[CH:17][N:16]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20][C:21]([O:23]CC)=[O:22])[C:15]=2[CH:32]=1)=[O:9])=[NH:3]>Cl>[NH2:3][C:2]([NH:4][C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[CH:17][N:16]([CH:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:20][C:21]([OH:23])=[O:22])[C:15]=2[CH:32]=1)=[O:9])=[NH:1]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3cccc(NC(=N)N)c3)cc21
Agent: Cl
Product: N=C(N)Nc1cccc(C(=O)Nc2ccc3ncn(C(CC(=O)O)c4ccccc4)c3c2)c1

Procedure:
A solution of ethyl 3-{6-[(3-{[amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (24 mg, 51 μmol) in hydrochloric acid (20 mL of a 5N solution) was stirred at room temperature for 72 hours. The solution was evaporated in vacuo, and the residue was purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=2.96 min, MH+ 443].
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-])=O)[C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C.CO.[Ni]>[CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25])[C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C(=O)CCCCCCC(=O)c1ccccc1)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C(=O)CCCCCCC(=O)c1ccccc1)c1ccccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a solution of amide 87 (420 mg, 1.14 mmol) in a mixture of ethyl acetate and methanol (5 mL, 9:1) was added catalytic amount of a suspension of Raney Nickel. The mixture was stirred at room temperature under hydrogen pressure for 2 hours and then without pressure for 10 hours. The reaction mixture was filtered through a short pad of Celite and the solvents were removed in vacuo. Purification by flash silica gel chromatography (2% methanol in dichloromethane) afforded the corresponding amide 88 (180 mg, 47% yield). 1H NMR (300 MHz, CDCl3): δ 7.96-7.90 (m, 2H), 7.58-7.41 (2 m, 4H), 7.17-7.10 (m, 1H), 6.98 (dd, J=1.5, 7.5 Hz, 1H), 6.80-672 (m, 2H), 3.18 (s, 3H), 2.91 (t, J=7.2 Hz, 2H), 2.15-1.95 (m, 2H), 1.73-1.51 (m, 4H), 1.35-1.20 (m, 4H).
Reaction SMILES: C(O[C:4]([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=2)[N:8]([CH2:23][CH3:24])[C:7]1=[O:25])=[O:5])C.[NH2:26][C:27]1[CH:28]=[C:29]([CH:40]=[CH:41][CH:42]=1)[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][CH:34]=1)=[O:31]>>[Br:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:30]([C:29]2[CH:28]=[C:27]([NH:26][C:4]([CH:6]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:15](=[O:22])[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:13]=4)[N:8]([CH2:23][CH3:24])[C:7]3=[O:25])=[O:5])[CH:42]=[CH:41][CH:40]=2)=[O:31])=[CH:34][CH:35]=1
Reactant: CCOC(=O)C1C(=O)N(CC)c2ccc(C(=O)c3ccccc3)cc21
Reactant: Nc1cccc(C(=O)Nc2ccc(Br)cc2)c1
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccc(Br)cc3)c2)c2cc(C(=O)c3ccccc3)ccc21

Procedure:
Prepared as in Example 1, Step A, from 5-benzoyl-1-ethyl-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid ethyl ester (U.S. Pat. No. 4,686,224) and 3-amino-N-(4-bromo-phenyl)-benzamide. Purified by flash-chromatography (hexanes/acetone, 1:1) followed by trituration in ethyl acetate/hexanes. mp 139-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH:10]=[C:9]2[CH:20]=[O:21].[CH2:27]([Mg]Br)[CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH:10]=[C:9]2[C:20](=[O:21])[CH2:27][CH3:28]
Reactant: N#CCCCn1cc(C=O)c2cc(OCc3c(Cl)cccc3Cl)ccc21
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1cn(CCCC#N)c2ccc(OCc3c(Cl)cccc3Cl)cc12
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a flame dried flask was added a solution of 4-[5-(2,6-dichlorobenzyloxy)-3-formyl-indol-1-yl]butyronitrile (0.23 g, 0.59 mmol) in THF (10 mL) and cooled to −78° C. To this solution ethyl magnesium bromide (1.0M in THF, 0.65 mL, 0.65 mmol) was added via dropwise addition. The reaction was stirred at −78° C. for 3 h then warmed to room temperature slowly. After stirring at room temperature for 18 h, the reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over Na2SO4. Purification by flash column chromatography (silica gel, ethyl acetate/hexane) afforded three products, one of which was identified by NMR, IR and LC-MS as the ketone 4-[5-( 2,6-dichlorobenzyloxy)-3-propionyl-indol-1-yl]butyronitrile (0.034 g, 14%). MS(ES) m/e 415.0 [M+H]+. None of the expected secondary alcohol was recovered.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([O-:3])=[O:2].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:33][S:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:23])(=[O:31])=[O:32])=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)CCN2Cc1cccc([N+](=O)[O-])c1
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(c1)CCN2Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the carboxylic acid (Example 33) (0.5 g), 2-methylbenzene sulphonamide (0.28 g), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.37 g) and 4-dimethylaminopyridine (0.05 g) in dichloromethane (6 ml) was stirred at room temperature for 72 hours. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Purification by flash chromatography on silica, eluting with 0-2% ethyl acetate in dichloromethane, gave a yellow oil which, on crystallisation from methanol, afforded N-[1-(3-nitrobenzyl)indolin-5-ylcarbonyl]-2-methylbenzene sulphonamide, m.p. 159°-163° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](=O)[NH:9][N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]1=[O:18].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:8]1[C:7]2[N:2]([CH3:1])[C:3](=[O:18])[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][C:6]=2[CH:11]=[N:10][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc2cn[nH]c(=O)c2n(C)c1=O
Product: CCOC(=O)c1cc2cnnc(Cl)c2n(C)c1=O
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
In a RBF equipped with reflux condenser, ethyl 1-methyl-2,8-dioxo-1,2,7,8-tetrahydropyrido[2,3-d]pyridazine-3-carboxylate (1.65 g, 6.63 mmol) was treated with phosphorus oxychloride (8.00 mL, 85.8 mmol). The reaction mixture was stirred in an oil bath at 110° C. for 90 min, and then cooled to RT. The volatiles were removed in vacuo and the residue was treated with CH2Cl2 then concentrated in vacuo. The residue was treated with CH2Cl2/Et2O and the resulting suspended solid was collected by suction filtration and dried in vacuo to give ethyl 8-chloro-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylate as a green solid. MS (ESI, pos. ion) m/z: 268 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CS(=O)(=O)Cl
Reactant: O=c1[nH]c2cc(Br)cc3c2n(c1=O)C(CO)CC3
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a solution of 9-bromo-5-hydroxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (3 g, 9.65 mmol) and triethylamine (1,28 g, 12.67 mmol) in THF (200 mL) was added methanesulfonyl chloride (1.44 g, 12.57 mmol) at -20° C. The mixture was stirred for 1.5 h at the same temperature and triethylamine (0.6 mL) and methanesulfonylchloride (0.4 mL) were added. The mixture was further stirred for 1 h at -20° C. and for 30 min at 0° C. and poured into water (500 mL). The mixture was acidified with 3N hydrochloric acid and extracted with ethyl acetate (500 mL×3). The organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 1 to 5% acetic acid/ethyl acetate to give 2.42 g of the title compound (64%): mp 125°~130° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.05 (bs, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 4.97~5.06 (m, 1H), 4.28 (d, 2H, J=7.5 Hz), 3.20 (s, 3H), 2.97 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.27 (dm, 1H, J=13.5 Hz), 1.81~1.97 (m, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[C:10]([N:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)=[C:11]2[CH:17]=[N:16][N:15](CC3C=CC(OC)=CC=3)[C:12]2=[N:13][CH:14]=1.C(Cl)[Cl:41]>>[ClH:41].[ClH:41].[Br:8][C:9]1[C:10]([N:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]2)=[C:11]2[CH:17]=[N:16][NH:15][C:12]2=[N:13][CH:14]=1
Reactant: ClCCl
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Brc1cnc2[nH]ncc2c1N1CCNCC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
TFA (0.5 mL) was added to a solution of tert-butyl 4-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.10 g, 0.20 mmol, see Example 1) in DCM (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was then concentrated to dryness. The resulting residue was dissolved in TFA (3.067 mL, 39.81 mmol) and heated at 60° C. for 3 hours. The reaction was concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (2 mL, 2N) was added. The resulting solid was collected by filtration to give 5-bromo-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.050 g, 70%). MS APCI (+) m/z 282.0 detected.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[CH:11]=2)[N:4]=1.[CH2:27]([O:34][CH2:35][CH:36]1[CH:40]([CH2:41][N:42]2[CH:46]=[C:45](Br)[CH:44]=[N:43]2)[O:39][C:38](=[O:48])[NH:37]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH2:27]([O:34][CH2:35][CH:36]1[CH:40]([CH2:41][N:42]2[CH:46]=[C:45]([C:14]3[CH:13]=[C:12]([CH3:25])[CH:11]=[C:10]([NH:9][C:5]4[N:4]=[C:3]([CH:2]([F:1])[F:26])[CH:8]=[CH:7][N:6]=4)[CH:15]=3)[CH:44]=[N:43]2)[O:39][C:38](=[O:48])[NH:37]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1NC(COCc2ccccc2)C(Cn2cc(Br)cn2)O1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC3OC(=O)NC3COCc3ccccc3)c2)c1
Temperature: 110 °C

Procedure:
A mixture of 4-(difluoromethyl)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (111 mg, 0.307 mmol), 4-[(benzyloxy)methyl]-5-[(4-bromo-1H-pyrazol-1-yl)methyl]-1,3-oxazolidin-2-one (109 mg, 0.298 mmol), potassium phosphate tribasic (239 mg, 1.13 mmol), and Pd(dbpf)Cl2 (4 mg, 0.006 mmol) in dioxane (2 mL) was stirred and heated to 110° C. in a microwave reactor for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by prep-TLC (ethyl acetate/petroleum ether) to give 4-[(benzyloxy)methyl]-5-{[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]methyl}-1,3-oxazolidin-2-one. MS ESI calc'd. for C27H27F2N6O3 [M+H]+ 521. found 521. 1H NMR (400 MHz, CD3OD) δ 8.60 (d, J=4.8 Hz, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.40 (s, 1H), 7.38-7.26 (m, 5H), 7.15 (s, 1H), 7.05 (d, J=4.8 Hz, 1H), 6.56 (t, J=54.4 Hz, 1H), 4.88-4.76 (m, 1H), 4.54 (s, 2H), 4.48-4.46 (m, 2H), 3.94-3.92 (m, 1H), 3.48-3.46 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]([S:10]([NH:13][C:14]1[CH:19]=[C:18]([C:20](O)=[O:21])[CH:17]=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][CH:31]=[CH:32][C:33]=2[NH:34][S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:25][CH:24]=1)(=[O:12])=[O:11])[CH3:9].[CH3:41][N:42](C=O)C.CN>ClCCl>[CH3:41][NH:42][C:20]([C:18]1[CH:17]=[CH:16][C:15]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[S:30][CH:31]=[CH:32][C:33]=3[NH:34][S:35]([CH:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])=[CH:25][CH:24]=2)=[C:14]([NH:13][S:10]([CH:8]([CH3:7])[CH3:9])(=[O:12])=[O:11])[CH:19]=1)=[O:21]
Reactant: CC(C)S(=O)(=O)Nc1cc(C(=O)O)ccc1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Reactant: CN(C)C=O
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2ccc(-c3sccc3NS(=O)(=O)C(C)C)cc2)c(NS(=O)(=O)C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add oxalyl chloride (0.12 mmol) to a suspension of 2-(Propane-2-sulfonylamino)-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-4-carboxylic acid (0.1 mmol) and DMF (0.05 mmol) in dichloromethane at 0° C. Stir 1 h at RT. Concentrate to dryness under reduced pressure. Dissolve resultant residue in 3 ml CH2Cl2 and add (2.8 mmol) of MeNH2 (2M in THF). Concentrate the reaction to dryness and purify by flash chromatography (Silica gel- eluting with 5%MeOH/CH2Cl2). Concentrate the desired fractions to provide the title compound. MS (ES−): 534(M−1).
Reaction SMILES: [OH:1][C:2]1([CH3:19])[CH:8](Br)[CH:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[O:6][C:4](=[O:5])[CH2:3]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[OH:1][C:2]1([CH3:19])[CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(O)CC(=O)OC(CCc2ccc(Cl)cc2)C1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CC1(O)CC(=O)OC(CCc2ccc(Cl)cc2)C1
Yield: 57.6 %

Procedure:
The product obtained by reducing 200 mg of 3-hydroxy-3-methyl-4-bromo-7-(p-chlorophenyl)-5-heptanolide with 680 mg of tri-n-butyltin hydride in 5 ml of anhydrous tetrahydrofuran according to the method described in Example 2 (a), was recrystallized from a mixture of n-hexane and benzene (5:1) to give 89 mg of the desired compound melting at 61°-64° C.
Reaction SMILES: CN(C)P(=O)(N(C)C)[S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12].C([O-])(O)=O.[Na+]>C(O)=O>[CH3:11][C:7]1[C:6]2[CH:12]=[C:12]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:5]=3)[S:4][C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(SP(=O)(N(C)C)N(C)C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: Cc1cccc2sc(-c3ccccc3)cc12

Procedure:
11 g (29.2 mmol) of the compound from Example XII are boiled under reflux in 50 ml of formic acid for 1 hour. The residue is neutralized with NaHCO3 solution and extracted with ethyl acetate and the extract is chromatographed over silica gel. The by-product from Example XIII can be removed particularly easily at this stage by distillation under a high vacuum, the title compound remaining as a solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:11][O:10][C:9]1[C:2]([O:1][CH2:13][CH2:14][CH3:15])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: CCCBr
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(C=O)cccc1OC
Temperature: 25 °C
Yield: 101.2 %

Procedure:
A suspension of 2-hydroxy-3-methoxy-benzaldehyde (10.0 g, 65.6 mmol), 1-bromopropane (60 mL, 657 mmol) and K2CO3 (11.3 g, 82.1 mmol) in MeCN (250 mL) was heated to reflux for 12 h. The mixture was cooled to ambient temperature and the solution filtered. The filtrate was concentrated to give the title compound (12.9 g, quantitative) as light yellow oil: MS (ESI) m/e 195 (M+H)+.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:24])[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][N:14]2[CH2:17][CH3:18])=[CH:9][CH:8]=1)=[O:6].Cl.NO>>[CH2:17]([N:14]1[C:15]2[C:10](=[CH:9][CH:8]=[C:7]([C:5]3[O:6][N:2]=[CH:3][CH:4]=3)[CH:16]=2)[C:11](=[O:24])[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13]1)[CH3:18]
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)C=CN(C)C)ccc2c1=O
Agent: Cl
Agent: NO
Product: CCOC(=O)c1cn(CC)c2cc(-c3ccno3)ccc2c1=O

Procedure:
Ethyl 1-ethyl-1,4-dihydro-7-(5-isoxazolyl)-4-oxo-3-quinolinecarboxylate was prepared from 30.8 g ethyl 7-[3-(dimethylamino)-1-oxo-2-propenyl]-1-ethyl-1,4-dihydro-4oxo-3-quinolinecarboxylate and 6.95 g hydroxylamine hydrochloride according to the procedure of Example 23, part (b), and was obtained (28.1 g) in the form of a light-tan solid, m.p. 180-183° C. when recrystallized from ethanol.