Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: O=C(O)C1CCNC1
Reactant: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCc1c(CCN2CCC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.7 %

Procedure:
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]acetaldehyde (D15) (73 mg) and 3-pyrrolidinecarboxylic acid (72.4 mg) in dichloromethane (DCM) (10 mL) stirred at room temperature was added AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (66.6 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated, the residue was purified by Mass Directed AutoPrep to give 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]ethyl}-3-pyrrolidinecarboxylic acid (E12) (27 mg) as a TFA salt (off-white solid). δH (DMSO-d6, 400 MHz): 1.13 (3H, t), 1.35 (6H, d), 2.23 (1H, m), 2.86 (2H, m), 3.10 (2H, m), 3.22 (2H, m), 3.48 (4H, m), 3.72 (1H, m), 3.87 (1H, m), 4.84 (1H, m), 7.39 (2H, dd), 7.50 (2H, m), 7.96 (1H, dd), 8.10 (1H, d), 9.95 (1H, br s), 12.97 (1H, br s). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C26H30ClN3O3S requires 499. found 500.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11](Cl)=[O:12])[CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH2:28]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([NH:28][CH2:27][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])=[O:12])[CH2:7]1
Reactant: O=C(Cl)N1CCC(Oc2cccc(Cl)c2)C1
Reactant: CN(C)CCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)CCCNC(=O)N1CCC(Oc2cccc(Cl)c2)C1
Temperature: 0 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
A solution, 13 g (0.05 mole) of 3-(3-chlorophenoxy)-1-pyrrolidinecarbonyl chloride in 100 ml of chloroform was stirred at 0° C. for 5 min. Then, the following were added in order: 25 g of ice, 12.8 g of sodium carbonate; and 5.62 g (0.055 mole) of N,N-dimethyl-1,3-propanediamine. The resulting mixture was allowed to come to room temperature and stirred for 72 hours. At this time the reaction mixture was diluted with excess water and the organic phase separated. The chloroform solution was washed with water and extracted with 50 ml of 3N hydrochloric acid. The chloroform portion was washed with 2×25 ml of water. The hydrochloric acid portion was combined with the last 2 washes and the pH adjusted to neutral with 3N sodium hydroxide. The resulting solution was extracted with 3×30 ml of chloroform and the chloroform extracts were combined, dried over magnesium sulfate and concentrated to a dark oil, 13.2 g. All of the samples were converted to the free base, charcoaled, and chromatographed on 25 g of silica gel. Elution with chloroform gave after concentrating a dark orange oil. Trituration of this oil with ethyl ether and concentration of the triturates gave 7 g of a pale yellow viscous oil. This oil was pumped under high vacuum for 24 hours. The oil upon standing crystallized and was recrystallized from ethyl ether/30-60 petroleum ether to give 3.2 g of fine white crystals; m.p. 60°-61° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[S:8](=[O:30])(=[O:29])[CH2:9][C:10]3[C:14]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])=[N:13][N:12]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:11]=3[C:4]=2[CH:3]=1.[K+].[CH3:32][B-](F)(F)F.C([O-])([O-])=O.[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:32][C:2]1[CH:7]=[CH:6][C:5]2[S:8](=[O:29])(=[O:30])[CH2:9][C:10]3[C:14]([C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[O:16])=[N:13][N:12]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:11]=3[C:4]=2[CH:3]=1
Reactant: O=C(c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccc(Br)cc1-2)N1CCOCC1
Reactant: C[B-](F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)-c1c(c(C(=O)N3CCOCC3)nn1-c1ccccc1)CS2(=O)=O
Temperature: 120 °C

Procedure:
8-bromo-3-(morpholin-4-ylcarbonyl)-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (160 mg, 0.32 mmol) is dissolved in 1,4-Dioxane:water (4:2) to which is added methyltrifluoroborate potassium salt (80 mg, 0.65 mmol) and K2CO3 (90 mg, 0.65 mmol). The reaction mixture is degassed for 5 min and is added S-phos (6.5 mg, 0.016 mmol) followed by palladium acetate (3.6 mg, 0.016 mmol). The reaction mixture is heated under microwave for 2 h at 120° C. After this time, the reaction mass is concentrated and purified by silica gel flash chromatography to afford the title compound as an off white solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.90-7.88 (d, J=8.0 Hz, 1H), 7.64-7.62 (m, 3H), 7.54-7.52 (m, 2H), 7.43-6.55 (d, J=7.5 Hz, 1H), 6.55 (s, 1H), 4.85 (s, 2H), 3.94 (m, 2H), 3.66 (m, 4H), 3.62 (m, 2H), 2.11 (s, 3H). MS (ESI+): 424.0. HPLC (max plot) 91.94%; Rt 4.17 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][C:10]1[C:11]([NH:17][CH:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:19])=[N:12][C:13](Cl)=[N:14][CH:15]=1>>[Br:9][C:10]1[C:11]([NH:17][CH:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:19])=[N:12][C:13]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)=[N:14][CH:15]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(Nc1nc(Cl)ncc1Br)c1ccc(F)cc1
Product: CC(Nc1nc(Nc2cccc(O)c2)ncc1Br)c1ccc(F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 3-aminophenol and (±)-5-bromo-2-chloro-N4-[1-(4-fluorophenyl)ethyl]-4-pyrimidineamine were reacted to produce (±)-5-bromo-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.97 (s, 1H), 7.36-7.31 (m, 2H), 7.17 (s, 1H), 7.09-7.01 (m, 4H), 6.82 (dd, 1H, J=2.2 and 8.2 Hz), 6.46 (d, 1H, J=2.2 and 8.2 Hz), 5.50 (br d, 1H, J=7.0), 5.27 (overlapped dq, 1H, J=7.1 and 7.9 Hz), 1.58 (d, 3H, J=7.0 Hz); LCMS: ret. time: 22.64 min.; purity: 94%; MS (m/e): 404 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[C:33](=[O:35])[CH3:34])[CH2:23][CH2:24]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNc4nccs4)CC3)nc3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1nccs1
Yield: 66.3 %

Procedure:
A mixture of 6.76 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[2-thiazolylamino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine, 15 parts of acetic acid anhydride and 40 parts of acetic acid was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was taken up in water. The whole was alkalized with ammonium hydroxide and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The second fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 4.9 parts (66.3%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-amino]-1-piperidinyl]ethyl]-N-(2-thiazolyl)acetamide; mp. 185.5°-193.0° C. (compound 102).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:16][CH3:17])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[C:12][CH:13]2[CH2:15][CH2:14]2)[CH:7]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:13]1([C:12]#[C:11][C:10]2[CH:9]=[N:8][N:6]3[CH:7]=[C:2]([C:22]4[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=4)[CH:3]=[C:4]([O:16][CH3:17])[C:5]=23)[CH2:15][CH2:14]1
Reactant: COc1cc(Br)cn2ncc(C#CC3CC3)c12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#CC3CC3)c12
Temperature: 90 °C

Procedure:
6-bromo-3-(cyclopropylethynyl)-4-methoxypyrazolo[1,5-a]pyridine (10.0 mg, 0.034 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (21.4 mg, 0.103 mmol), tetrakis(triphenylphosphine)palladium (0) (4.0 mg, 3.4 mmol), sodium carbonate (10.9 mg, 0.103 mmol) was suspended in 1,4-dioxane (900 μl/Water (100 μl). The mixture was sparged with Ar for 10 minutes, then heated to 90° C. for 4 h. The reaction mixture was cooled to ambient temperature, diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 3-(cyclopropylethynyl)-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine. 1H NMR (600 MHz, CDCl3) δ 8.16 (s, 1H); 7.86 (s, 1H); 7.71 (s, 1H); 7.59 (s, 1H); 6.46 (s, 1H); 3.98 (s, 3H); 3.95 (s, 3H); 1.43-1.46 (m, 1H); 0.78-0.89 (m, 4H). LRMS (ESI) calculated for C17H17N4O [M+H]+, 293.1; found 293.1.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.[CH3:17][NH:18][CH3:19]>>[CH3:17][N:18]([CH3:19])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1
Reactant: CNC
Reactant: Nc1nc2ccccc2c2ccc(Cl)nc12
Product: CN(C)c1ccc2c(n1)c(N)nc1ccccc12
Temperature: 100 °C

Procedure:
A solution of 3-chlorobenzo[f][1,7]naphthyridin-5-amine (Example 20) (1.0 eq.) was dissolved in 40% aqueous dimethylamine (0.26 M) and heated in a microwave reactor at 100° C. for 30 minutes. The reaction mixture was concentrated en vacuo, and the residue was purified by a COMBIFLASH® system (ISCO) using 0-90% ethyl acetate in hexane to give N3,N3-dimethylbenzo[f][1,7]naphthyridine-3,5-diamine. 1H NMR (methanol d-4): δ 8.63 (d, 1H), 8.20 (d, 1H), 7.55 (d, 1H), 7.41-7.45 (dd, 1H), 7.29-7.33 (dd, 1H), 7.27 (d, 1H), 3.26 (s, 6H). LRMS [M+H]=239.1
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:19]1[N:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].ClCCl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.CCCCCC>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]2[N:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][CH:20]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=Cc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1cccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Yield: 48.8 %

Procedure:
In a 35 mL, microwave vial, 3,5-bis(trifluoromethyl)phenylboronic acid (2.0 g, 7.7 mmol) and 6-bromopicolinaldehyde (1a) (1.44 g, 7.7 mmol) dissolved in 1,2-dimethoxyethane (20 mL) was treated with a solution of K2CO3 (3.22 g, 23.3 mmol) in water at room temperature. Pd(dppf)Cl2.dichloromethane was added to reaction mass and charged in microwave for 30 min at 90° C. The progress of the reaction was monitored by TLC analysis on silica gel with ethyl acetate:hexane (3:7) as mobile phase. Reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation to afford 2.5 g of Crude compound which was purified by chromatography. Product elute at 4% ethyl acetate in hexane to give 1.2 g of pure product. (Yield 48.38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH2:22][NH2:23])=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH2:22][NH:23][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])=[CH:18][CH:17]=1
Reactant: COc1ccc(OCCN)cc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: COc1ccc(OCCNC(=O)c2cc3cc(Cl)ncc3[nH]2)cc1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(4-methoxyphenoxy)ethylamine. The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (3:97) to give the title compound as a yellow solid. δH (CD3OD): 3.71 (3H, s), 3.77 (2H, t), 4.12 (2H, t), 6.81–6.91 (4H, m), 7.09 (1H, s), 7.67 (1H, s), 8.58 (1H, s); m/z (ES+)=346 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[K+].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>CS(C)=O>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:13][CH:15]3[O:17][CH2:16]3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: ClCC1CO1
Reactant: Oc1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: c1cc(OCC2CO2)c2cc[nH]c2c1
Temperature: 45 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
The solvents used in reactions were dried prior to use. All other reagents were used as received without purification. All moisture-sensitive reactions were performed in flame-dried and/or oven-dried glassware under a positive pressure of nitrogen unless otherwise noted. Thin-layer chromatography was carried out with glass TLC plates precoated with silica gel 60 F254. Flash column chromatography was accomplished with silica gel BW820MH. Proton nuclear magnetic resonance spectra were recorded in deuterated solvents at 270 or 600 MHz. To a solution of 4-hydroxy indole (1) (0.50 g, 3.8 mmol) in dimethylsulfoxide (10 mL) at 45° C. was added potassium hydroxide (0.4 g, 7.6 mmol) followed by epichlorohydrin (1.4 g, 15.2 mmol). The reaction mixture was stirred at 45° C. for 4 h. The reaction was quenched with a saturated solution of NH4Cl, extracted with diethyl ether (3×50 mL). The combined organics were dried with MgSO4, and concentrated. The product was purified by elution from silica gel column with benzene/acetone mixtures to give the glycidyl 4-indolyl ether (2) (0.75 g, 3.8 mmol, 99%) as a clear oil. To a solution of glycidyl 4-indolyl ether (2) (215 mg, 1.14 mmol) in methanol (2 mL) was added isobutyl amine (160 mg, 2.28 mmol). The solution was heated to 100° C. and stirred for 32 h. The product was purified by elution from silica gel column with benzene/acetone mixtures to give the corresponding amine (3) (120 mg, 0.46 mmol, 40%) as a clear oil. To a solution of 4,4′-bipiperidine (420 mg, 5.0 mmol) and triethylamine (2 mL) in 150 mL of CHCl3 was added a solution of 1-adamantanecarbonyl chloride (4) (500 mg, 2.5 mmol) in 50 mL of CHCl3. The resulting mixture was refluxed for 0.5 h, diluted with brine, and dried over MgSO4. The solution was then concentrated in vacuum and purified by elution from silica gel column with CHCl3/methanol mixtures to give the corresponding amide (5) (750 mg, 2.3 mmol, 90%) as a clear oil. See FIG. 11 and FIG. 13.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([NH:16]C(OC(C)(C)C)=O)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl>CCOC(C)=O>[C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
The product of Step A, (3S)-1-Cbz-3-(N-BOC-amino)pyrrolidine, (5.26 g, 16.4 mmol) was dissolved in EtOAc (50 mL) and treated with a saturated HCl in EtOAc (15 mL). After the reaction mixture was stirred at rt for 30 min., the volatiles were removed to provide the title compound (4.11 g, 98.1%) as a colorless solid. The crude product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17](I)[C:10]=12.[CH3:45][N:46]([CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1)[C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17]([N:57]3[CH2:56][CH2:55][CH:54]([N:46]([CH3:45])[C:47](=[O:53])[O:48][C:49]([CH3:50])([CH3:51])[CH3:52])[CH2:59][CH2:58]3)[C:10]=12
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(N3CCC(N(C)C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (100 mg, 0.142 mmol, prepared in Example 63, step A), tert-butyl methyl(piperidin-4-yl)carbamate (152 mg, 0.708 mmol), copper(I)iodide (5.39 mg, 0.0283 mmol), (S)-pyrrolidine-2-carboxylic acid (6.52 mg, 0.0566 mmol), K2CO3 (97.8 mg, 0.708 mmol) and DMSO (10 mL). The reaction mixture was stirred at 100° C. overnight. The reaction was cooled to ambient temperature and partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (98.5 mg, 87.8%). LRMS (APCI pos): m/e 693 (M−99).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:38])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH2:33][C:34](=[NH:37])[NH:35][OH:36])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:45](Cl)(Cl)=[O:46].O>C1COCC1.CC(O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:38])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH2:33][C:34]5[NH:37][S:45](=[O:46])[O:36][N:35]=5)[C:19]=4[CH2:18]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: N=C(COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2)NO
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=S1NC(COc2cccc3c2CC(=CCCN2CCC(O)(c4ccc(Cl)cc4)CC2)c2cccnc2O3)=NO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Example 407 (700 mg) in THF (20 ml) were added pyridine (0.21 ml) and thionyl chloride (0.1 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hour and the mixture was stirred at room temperature for 30 minutes. Water, chloroform and 2-propanol were added to the reaction mixture. The organic layer was extracted and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with chloroform-methanol (5:1) to give the titled compound (170 mg).
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:9]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:7][C:8]1[CH:9]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(OC3CCCCO3)c2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(O)c2)CC1
Yield: 93.1 %

Procedure:
A mixture of tert-butyl 4-[3-(tetrahydropyran-2-yloxy)phenyl]piperazine-1-carboxylate (5.20 g, 14.4 mmol) prepared in Reference Example 199 and a catalytic amount of pyridinium p-toluene sulfonate in ethanol (100 ml) was stirred at 70° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and a saturated sodium hydrogencarbonate aqueous solution were added to the residue, which was stirred for a while. The resulting precipitates were collected by filtrasion, and then dried in vacuo to afford tert-butyl 4-(3-hydroxyphenyl)piperazine-1-carboxylate (3.73 g, yield 93%) as a a pale brown powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[OH:8].[C:15]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([N+:28]([O-])=O)=[CH:23][CH:22]=2)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[N:20]([CH2:3][C@@H:2]([OH:1])[CH2:7][OH:8])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH:28][C:12]([C:9]1([C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=3)[CH2:10][CH2:11]1)=[O:14])=[CH:23][CH:22]=2)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=C(O)C1(c2ccc(O)c(O)c2)CC1
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc(O)c(O)c4)CC3)ccc2n1C[C@@H](O)CO

Procedure:
(R)—N-(2-tert-butyl-1-(2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(3,4-dihydroxyphenyl)cyclopropanecarboxamide was prepared using an experimental procedure similar to Example 72 from 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid and 2-tert-butyl-5-nitro-1H-indole.