Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:5]=1[C:6]([CH:8](C(=O)C)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])=[O:7])([O-:3])=[O:2].S(=O)(=O)(O)O.O>C(O)C>[N+:1]([C:4]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:5]=1[C:6](=[O:7])[CH2:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])([O-:3])=[O:2]
Reactant: CC(=O)C(C(=O)c1ccccc1)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: O=C(CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1ccccc1
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A solution of 2-(2-nitro-4-trifluoromethylbenzoyl)-1-phenylbutan-1,3-dione (28.5 g) in ethanol (300 ml) was added to a mixture of concentrated sulphuric acid (225 ml) and ethanol (225 ml). The resultant solution was stirred and heated at 100° C. for 1 hour. The cooled solution was poured onto a mixture of ice and water (21) and extracted with dichloromethane (3×250 ml). The combined organic layers were washed with water (2×100 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from petroleum spirit (bp 60°-80° C.) to give 1-(2-nitro-4-trifluoromethylphenyl)-3-phenylpropan-1,3-dione (19.6 g) as an off-white solid mp 101°-103° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: O=C(O)c1cccc(O)c1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(O)c1O
Yield: 100 %

Procedure:
To a solution of 2,3-dihydroxybenzoic acid (25 g) in ethanol (320 ml) was added concentrated sulfuric acid (1.8 ml), and the mixture was heated under reflux for one day. The reaction mixture was concentrated, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to normal phase chromatography (elution solvent ethyl acetate) to give the title compound (30 g, 100%).
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][O:26][CH3:27])[CH:21]=[CH:20][C:19]=1[CH:28]1[CH2:33][CH2:32]C(=O)[CH2:30][CH2:29]1.O1CCC[CH2:36]1>>[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][O:26][CH3:27])[CH:21]=[CH:20][C:19]=1[CH:28]1[CH2:33][CH2:32][C:5](=[CH:4][C:6]([O:8][CH3:36])=[O:7])[CH2:30][CH2:29]1
Reactant: COCOc1ccc(C2CCC(=O)CC2)c(OCOC)c1
Reactant: C1CCOC1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: COCOc1ccc(C2CCC(=CC(=O)OC)CC2)c(OCOC)c1
Temperature: 0 °C
Yield: 95 %

Procedure:
A round bottomed flask equipped with magnetic stirrer was loaded with sodium hydride (0.20 g, 5.10 mmol, 60% dispersion in mineral oil) which was washed with petroleum ether (4×20 ml). The excess petroleum ether was removed under reduced pressure. Anhydrous tetrahydrofuran (120 ml) was added and the stirred solution was cooled to 0° C. Trimethylphosphonoacetate (756 μl, 5.10 mmol) was added dropwise via syringe and the stirred mixture was allowed to warm to room temperature over 1 hr. The mixture was cooled to 0° C. prior to the addition of 4-[2,4-bis(methoxymethoxy)phenyl]cyclohexanone (1.00 g, 3.40 mmol) as a solution in tetrahydrofuran (30 ml). The pale yellow mixture was heated to reflux temperature for 0.75 hr, then cooled to room temperature and partitioned between ethyl acetate (100 ml) and saturated aqueous ammonium chloride solution (30 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated in vacuo, affording a yellow oil. Purification via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:2, v/v) furnished the title compound as a yellow oil (1.13 g, 95%). δH(CD3OD) 1.53-1.70 (2H, m), 2.00-2.13 (4H, m), 2.45 (2H, m), 3.26 (1H, m), 3.48 (3H, s), 3.53 (3H, s), 3.71 (3H, s), 5.17 (2H, s), 5.24 (2H, s), 5.73 (1H, s), 6.67 and 6.68 (1H, d), 6.83 (1H, d), 7.08 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:29][CH2:30][CH:31]=[C:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[N:42][C:37]=2[CH2:36][O:35][C:34]2[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:29][CH2:30][CH:31]=[C:32]3[C:38]4[CH:39]=[CH:40][CH:41]=[N:42][C:37]=4[CH2:36][O:35][C:34]4[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]3=4)[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: O=C(Cc1ccc(Cl)cc1)NC1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(NC(=O)Cc3ccc(Cl)cc3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(4-chloro-phenyl)-N-piperidin-4-yl-acetamide (0.2 g, 0.8 mmol) in isopropanol (6.0 mL) was added 2,6-lutidine (0.095 mL, 0.8 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/20% methanol) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].S(Cl)(Cl)=O.C[N:20](C=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([NH2:20])=[O:9]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc([N+](=O)[O-])c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 5-methoxy-2-nitrobenzoic acid (7.5 g, 38.0 mmol) in anhydrous benzene (50 mL), was added thionyl chloride (3.8 mL, 52.05 mmol) followed by the addition of anhydrous DMF (0.4 mL). The resulting reaction mixture was refluxed for 5 h, upon which the volatiles were removed in vacuo. The residue was dissolved in anhydrous THF (60 mL) and added to an ice-cold saturated solution of ammonia in THF (60 mL). The resulting heterogeneous reaction mixture was allowed to warm room temperature and stirring was continued at RT for 48 h. The s volatiles were removed in vacuo and the residue was used without further purification for next step. HPLC retention time 3.29 mins.
Reaction SMILES: [CH:1]([N:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][C:5]1=[O:13])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:36][CH2:37][C:38]1[C:39]([OH:46])=[N:40][C:41]([CH3:45])=[CH:42][C:43]=1[CH3:44]>ClCCl.C(N(CC)CC)C>[OH:46][C:39]1[C:38]([CH2:37][NH:36][C:10]([C:7]2[CH:8]=[CH:9][N:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:13])[CH:6]=2)=[O:12])=[C:43]([CH3:44])[CH:42]=[C:41]([CH3:45])[N:40]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(C)n1ccc(C(=O)O)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccn(C(C)C)c(=O)c2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (50 mg, 0.28 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95 mg, 0.5 mmol), 1-Hydroxybenzotriazole (67 mg, 0.5 mmol), triethylamine (0.1 mL) in dichloromethane (5 mL) were stirred at 25° C. for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (50 mg, 0.33 mmol) was added to the above mixture. The mixture was stirred at 25° C. overnight and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxamide (31 mg, 35%) as a white solid. LRMS (M+H+) m/z: 315.16. found 315. HPLC Purity (214 nm): 100%. 1H NMR (300 MHz, DMSO): δ 11.48 (d, J=4.2 Hz, 1H), 8.53 (t, J=5.1 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 6.56-6.53 (m, 1H), 5.85 (s, 1H), 5.03-4.98 (m, 1H), 4.24 (d, J=5.1 Hz, 2H), 2.14-2.09 (m, 6H), 1.28-1.22 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][N:8]([C:14](=[O:39])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([O:22][CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH:16]=1)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:2].[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][N:8]([C:14](=[O:39])[C:15]1[CH:16]=[C:17]([O:22][CH2:23][CH2:24][NH:25][C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCC1
Reaction time: 2 h

Procedure:
A solution of crude 4-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)ethoxy]-5-chloro-benzoyl}-cyclopentyl-amino)-butyric acid ethyl ester (0.020 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.005 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[H][H].CCOCC>C(O)(=O)C.[Pd]>[Br:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CBr)C2
Yield: 78.2 %

Procedure:
2-Bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (4.0 g, 13.6 mmol) was dissolved in acetic acid (100 ml). To the resultant solution, 10% palladium-on-carbon (4 g) was added, followed by stirring at 70° C. for 7 hours in the stream of hydrogen. The palladium-on-carbon was filtered off, and the filtrate was condensed under reduced pressure. Ether was added to the residue, obtaining 3.15 g of the title compound as a colorless solid (78.2%).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH:17](=[C:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH:17](=[C:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)CN1C(=O)CCc2ccccc21
Reactant: CCCC=C1CCNCC1
Solvent: CC#N
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)CCc3ccccc32)CC1
Reaction time: 20 h
Yield: 66.8 %

Procedure:
A 4 mL vial was charged with (S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.169 g, 0.51 mmol) and 4-butylidenepiperidine (0.200 g, 1.4 mmol) in MeCN (2 mL) and shaken at 40° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; n-heptane/EtOAc 4:1) to give the title compound (107LH53) (0.116 g, 67%). 1H NMR (CD3OD) d 7.23-7.18 (m, 3H), 7.02-6.98 (m, 1H), 5.11 (t, J=7.4 Hz, 1H), 3.98 (d, J=6.8 Hz, 2H), 2.89-2.85 (m, 2H), 2.61-2.56 (m, 2H), 2.40-2.35 (m, 2H), 3.32-2.04 (m, 11H), 1.98-1.92 (m, 2H), 1.36-1.29 (m, 2H), 0.90-0.85 (m, 2 CH3); 13C NMR (CD3OD) d 173.0, 140.3, 137.1, 129.1, 128.4, 128.4, 124.3, 123.7, 116.9, 64.6, 57.4, 56.6, 46.5, 37.0, 32.9, 30.2, 30.1, 29.1, 26.3, 24.2, 17.2, 14.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:21][CH2:22][CH3:23])[CH:6]=1)=[O:4]
Reactant: CCCBr
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cc(C(=O)OC)c2ccccc21

Procedure:
A solution of 0.16 g (1.00 mmol) of indole-3-carboxylic acid methyl ester, 0.5 g (4 mmol) of K2CO3 and 0.5 g (5 mmol) of 1-bromopropane in 10 ml of DMF was stirred at 50° C. overnight. The mixture was partitioned between EtOAc and water. The aqueous phase was extracted with additional EtOAc. The combined organic phases were washed with water, brine and finally dried over Na2SO4 to give crude 1-propylindole-3-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]2[S:8][C:9]3[CH2:18][C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:10]=3[N:11]=2)[CH2:3]1.[CH3:19][I:20]>>[I-:20].[CH3:1][N+:2]1([CH3:19])[CH2:6][CH2:5][CH:4]([C:7]2[S:8][C:9]3[CH2:18][C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:10]=3[N:11]=2)[CH2:3]1
Reactant: CI
Reactant: CN1CCC(c2nc3c(s2)Cc2ccccc2-3)C1
Product: C[N+]1(C)CCC(c2nc3c(s2)Cc2ccccc2-3)C1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In 2 ml of methyl iodide, 30 mg of 2-(1-methyl-3-pyrrolidinyl)-8H-indeno[1,2-d]thiazole was dissolved, followed by stirring at room temperature for 18 hours. The solvent was evaporated under reduced pressure. The resulting oily substance was crystallized from diethyl ether-chloroform-methanol, whereby 43 mg of 1,1-dimethyl-3-(8H-indeno[1,2-d]thiazol-2-yl)pyrrolidinium iodide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=O)[CH2:6][CH2:5]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:19].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[CH:7]([NH2:19])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)c(Cl)cc21
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: NC1CCc2cc(Cl)c(Cl)cc21

Procedure:
Following the procedure of Example 1, 5,6-dichloro-1-indanone was reacted with ammonium acetate and sodium cyanoborohydride to yield 5,6-dichloro-1-aminoindane; yield = 670 mg. The crystalline compound was treated with 360 mg. of maleic acid in 25 ml. of isopropanol. The maleate salt crystallized and was separated by filtration. Recrystallization of the salt from a 1:3 isopropanol/ethyl acetate solvent mixture yielded 650 mg. of 5,6-dichloro-1-aminoindane maleate melting at 167°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([C:18]#[N:19])[CH:5]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:18]#[N:19])[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:8][CH:9]=1)=[O:20]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccccc2)c(C#N)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
3-Cyano-4-(trifluoromethanesulfonyloxy)-benzoic acid methyl ester from step 1 (2.5 g, 8.1 mmol) and phenylboronic acid (2 g, 16.2 mmol) were dissolved in DMF (33 ml) and treated with Et3N (3.1 ml, 17.8 mmol). Argon was bubbled into the solution for 20 min. and then a catalytic amount of PdCl2 (PPh3)2 (285 mg, 0.405 mmol) was added. The reaction mixture was warmed to 90° C. and stirred for 3 hours under argon atmosphere. The reaction was quenched with satd. NaHCO3 (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (10% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18](=[O:40])[C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([N:26](S(CCC)(=O)=O)[S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[C:20]=3[F:39])[CH:15]=2)[N:10](S(C2C=CC(C)=CC=2)(=O)=O)[N:9]=1>CO.O>[Br:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18](=[O:40])[C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[C:20]=3[F:39])[CH:15]=2)[NH:10][N:9]=1
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)Nc2cnc3c(c2)c(Br)nn3S(=O)(=O)c2ccc(C)cc2)c1F)S(=O)(=O)CCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(Br)c3c2)c1F
Temperature: 60 °C
Yield: 37.2 %

Procedure:
K2CO3 (0.151 g, 1.09 mmol) was added to a solution of N-(3-bromo-1-tosyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzamide (0.100 g, 0.136 mmol) in MeOH/H2O (4:1, 10 mL), and the reaction mixture was heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was taken up in ethyl acetate (100 mL) and washed with water (50 mL). The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1), hexanes/ethyl acetate (1:1) to give N-(3-bromo-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.024 g, 37%, 2 steps) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.7 (s, 1H), 8.5 (s, 1H), 7.7 (m, 1H), 7.1 (m, 1H), 3.1 (m, 2H), 1.9 (m, 2H), 1.1 (t, J=7.6 Hz, 3H); m/z (APCI-neg) M−1=472.2, 474.2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[CH3:19][O:20][CH2:21][CH2:22][NH2:23].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13]
Reactant: COCCN
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCNc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F

Procedure:
4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (1.536 g, 5 mmol), 2-methoxyethanamine (0.376 g, 5 mmol), and triethylamine (1.939 g, 15 mmol) in anhydrous tetrahydrofuran (30 mL) solution was heated at 55° C. for 3 hours. The solution was diluted with ethyl acetate, washed with water and brine, and dried (Na2SO4), filtered and the filtrate was concentrated. The crude material was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:18][C:17]=1[F:37])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:20]1[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:18][C:17]([F:37])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2cncnc2)cc1F
Reactant: OB(O)c1cccc(F)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: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cncnc2)cc1F
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
20 mg (0.03 mmol) of tert-butyl((5-chloro-4-((6-chloro-4-(pyrimidin-5-yl)pyridin-3-yl)oxy)-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 7 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.8 mg (10 mol %) of Pd(PPh3)4, 10.6 mg (0.10 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:31])[C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:19](=[O:30])[C@H:20]([OH:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][NH:14]2)[CH:2]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])[CH2:41][CH:40]1[C:55](O)=[O:56])=[O:38])([CH3:35])([CH3:34])[CH3:33].N1C2C(=CC=CC=2)C=C(NC(=O)[C@@H]2C[C@@H](NC(=O)[C@H](O)CCC3C=CC=CC=3)CN2C(=O)[C@@H]2C[C@@H](NC(OC(C)(C)C)=O)CN2C(OC(C)(C)C)=O)C=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:31])[C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:19](=[O:30])[C@H:20]([OH:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][N:14]2[C:55]([CH:40]2[CH2:41][N:42]([C:45]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[O:46])[CH2:43][CH2:44][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[O:56])[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1C(=O)O
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1C(=O)N1C[C@H](NC(=O)[C@H](O)CCc2ccccc2)C[C@H]1C(=O)Nc1cnc2ccccc2c1

Procedure:
trans-4-((R)-2-hydroxy-4-phenybutyrylamino)-L-proline 3-quinolylamide (Compound D101 (H), 272 mg) and 1-tert-butoxycarbonyl-4-benzyloxycarbonylpiperazine-2-ylcarboxylic acid (A, 237 mg) were coupled using the same procedure of Compound D101 (P) to afford the title compound (171 mg) as a colorless glassy solid: mass spectrum (FAB+) m/e 765 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:10][OH:11].Cl.[OH-].[K+].O>CO.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:10][OH:11]
Reactant: NO
Reactant: O=Cc1cccc(I)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: ONCc1cccc(I)c1

Procedure:
3-Iodobenzaldehyde prepared above (8.1 g, 34.9 mmol) was dissolved in 50 mL MeOH and 20 mL THF. After addition of H2NOH.HCl (10 mL H2O) and 6N KOH, an additional 20 mL H2O, 10 mL THF, and 10 mL MeOH were added. The product was recovered as a white solid (7.96 g, 91.6%, 92% desired product). mp: 63.0–70.0° C. IR (film): 3256, 3056, 2857, 1591, 1564, 1470, 1420, 1063, 995, 777. 1H-NMR (400 MHz, CDCl3): δ 7.73 (t, 1H, J=1.6, C6-H), 7.63 (dt, 1H, J=7.9, 1.3, C5-H), 7.31 (dt, 1H, J=7.6, C7-H), 7.09 (t, 1H, J=7.8, C6-H), 5.5 (br s, 1H, C1-NHOH), 5.1 (br s, 1H, C1-NHOH), 3.98 (s, 2H, C1-H2). 13C-NMR (100 MHz, CDCl3): δ 139.9, 137.9, 136.6, 130.2, 128.2, 94.4, 57.4. EI-MS m/z (rel int): 249 (M+, 65), 217 ([M−NHOH]+, 100). CI-MS (NH3) m/z (rel int): 284 ([M+2NH3+H]+, 28), 267 ([M+NH4]+, 100), 250 ([M+H]+, 45).