Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[NH2:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[C:23]([Cl:28])[N:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:25]2[CH:24]=[C:23]([Cl:28])[N:22]=[C:21]([NH2:20])[N:26]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccn(-c2cc(Br)ccc2[C@@H](O)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(Cl)nc(N)n2)C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of (R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (160 mg, 0.2 mmol, Intermediate 1) in dioxane (2 mL) was added 2-amino-4,6-dichloropyrimidine (100 mg, 0.16 mmol) and Cs2CO3 (48 μg, 0.16 mmol). The reaction was heated to 80° C. for 16 h, cooled to RT, and filtered. The solvent was removed in vacuo and the residue was dissolved in a mixture of CH2Cl2 and heptane, concentrated to half the volume, filtered, and concentrated again in vacuo. Purification via normal phase silica gel chromatography (CH2Cl2/Heptane) provided 4-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]-6-chloro-pyrimidin-2-amine as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][NH2:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(O)C>[Br:1][C:2]1[C:3]([NH:29][CH2:28][CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNc1nc(Cl)ncc1Br
Reaction time: 20 h

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine 3.2 g (0.0135 mole) in ethanol 80 mL was added Hunig's base 3.0 mL followed by the addition of a solution of N-(tert-butoxy carbonyl)-1,2-diaminoethane 2.5 g (0.0156 mole) in 20 mL ethanol. The contents were stirred overnight for 20 hrs. The solvent was evaporated under vacuum. Ethyl acetate (200 mL) and water (100 mL) was added and the layers separated. The organic layer was dried with magnesium sulfate and then concentrated under vacuum. Column chromatography on silica gel using hexane/ethyl acetate (0-60%) afforded tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. 1HNMR (d6-DMSO) 8.21 (s, 1H), 7.62 (brs, 1H), 7.27 (brs, 1H), 3.39 (m, 2H), 3.12 (m, 2H), 1.34 (s, 9H). LCMS (ESI) 351 (M+H)
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[OH:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])[C:9]([OH:11])=[O:10].[OH-].[Na+]>O>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:8](=[O:7])[C:9]([OH:11])=[O:10])([O-:20])=[O:19]
Reactant: O=C(O)C(O)c1ccccc1[N+](=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
KY-780-batch B KMnO4 (0.168 gr) was added to the cooled (ice water) solution of 2-hydroxy-2-(2-nitrophenyl)acetic acid (0.3 gr, 4.1 mmol), NaOH (70 mg) in water 6 ml. the mixture reaction was stirred for 2 h at 0° c. The mixture reaction was concentrated in vacuum and The residue was purified on C18-reversed phase flash chromatography column employing a linear gradient of 0-30% A in B (flow-rate 40 mL/min), where A is 0.1% formic acid in CH3CN and B is 0.1% of formic acid in water, yielding 80 mg (10%) of pure KY-780-batch B
Reaction SMILES: [CH:1]1([NH:4][C:5]2[S:6][CH:7]=[C:8]([C:10](OCC)=[O:11])[N:9]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1([NH:4][C:5]2[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1csc(NC2CC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1csc(NC2CC2)n1

Procedure:
The reaction described in Preparation 15 was repeated, but using 1.2 g of ethyl 2-cyclopropylaminothiazole- 4-carboxylate, 0.2 g of lithium aluminum hydride and 20 ml of tetrahydrofuran, giving the title compound as a pale yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N:7]1[C:14](Cl)=[N:13][C:11]([Cl:12])=[N:10][C:8]=1Cl.[CH2:16]([NH:19][CH2:20][CH:21]=[CH2:22])[CH:17]=[CH2:18].[OH-].[Na+]>O1CCOCC1>[CH2:16]([N:19]([CH2:20][CH:21]=[CH2:22])[C:14]1[N:7]=[C:8]([N:19]([CH2:20][CH:21]=[CH2:22])[CH2:16][CH:17]=[CH2:18])[N:10]=[C:11]([Cl:12])[N:13]=1)[CH:17]=[CH2:18]
Reactant: C=CCNCC=C
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCN(CC=C)c1nc(Cl)nc(N(CC=C)CC=C)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
After 21.2 g (0.20 mol) of sodium carbonate and 20.0 g (0.10 mol) of cyanuric chloride were added and dissolved into 140 g of 1,4-dioxane, 19.8 g (0.20 mol) of diallylamine was gradually added thereinto and further, 8.4 g (0.20 mol) of caustic soda was added thereinto. By generating the heat of reaction, the temperature of reaction solution was raised to about 60° C. and the reaction was continued at the temperature for 2 hours. Thereafter, the reaction mixture was cooled and filtered to remove the sodium chloride generated as the byproduct. The obtained filtrate was distilled under reduced pressure to recover the solvent. Therefore, 34 g (0.09 mol) of 4,6-bis(diallylamino)-2-chloro-1,3,5-triazine was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[C:27]1([NH2:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([NH:33][S:12]([N:9]2[CH2:10][CH2:11][C:6]3([C:2](=[O:1])[N:3]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)[CH2:4][CH2:5]3)[CH2:7][CH2:8]2)(=[O:14])=[O:13])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: Nc1ccccc1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Nc1ccccc1)CC2

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and phenylamine. MS (ESI): 440.4 (MH+).
Reaction SMILES: Br[C:2]1([C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([O:10][CH:11]([F:13])[F:12])[CH2:4]1)[NH2:3].[Cu][C:15]#[N:16].C(N)CN.Cl>CN(C=O)C.O>[C:15]([C:2]1([C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([O:10][CH:11]([F:13])[F:12])[CH2:4]1)[NH2:3])#[N:16]
Reactant: N#C[Cu]
Reactant: CC1=CC=C(OC(F)F)CC1(N)Br
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: NCCN
Product: CC1=CC=C(OC(F)F)CC1(N)C#N
Temperature: 150 °C
Reaction time: 8 h

Procedure:
1-Bromo-3-difluoromethoxy-6-methylaniline (1.70 g, 6.74 mmol) is initially charged in 7 ml of DMF, and copper(I) cyanide (0.79 g, 8.76 mmol) is added. The reaction is stirred at 150° C. overnight. After cooling to room temperature, the DMF is removed under reduced pressure and 15 ml of water and ethylenediamine (3.6 ml, 53.9 mmol) are added to the residue. The mixture is then stirred at room temperature for 1 hour. The reaction mixture is then acidified to pH=5 using hydrochloric acid, and the aqueous phase is extracted with ethyl acetate (6 times). The combined organic phases are dried over sodium sulphate and then purified chromatographically on silica gel. (logP: 1.90; MH+: 199, 1H-NMR (400 MHz, DMSO, ppm): 2.12 (s, 3H), 5.91, (s, 2H), 7.10 (t, 1H), 7.20 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=1.[CH3:28][C:29]1([CH3:46])[CH2:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([CH3:45])([CH3:44])[NH:30]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[CH:11]1([N:8]2[C:6]3[N:7]=[C:2]([C:33]4[CH2:32][C:31]([CH3:45])([CH3:44])[NH:30][C:29]([CH3:46])([CH3:28])[CH:34]=4)[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]4[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[O:16])[C:5]=3[CH:10]=[N:9]2)[CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCC2)c(=O)[nH]1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 6-bromo-1-cyclobutyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) solution was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (80% yield). LCMS: 489.30 (M+1)+; HPLC: 95.97% (@ 254 nm) (Rt; 5.425); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.89 (t, 1H), 8.31 (s, 1H), 7.79 (s, 1H), 6.81 (s, 1H), 5.89 (s, 1H), 5.52-5.44 (m, 1H), 4.37 (d, 2H, J=4.8 Hz), 2.73-2.63 (m, 2H), 2.43 (m, 4H), 2.22 (s, 3H), 2.12 (s, 3H), 1.94-1.88 (m, 2H), 1.24 (d, 6H, J=6 Hz), 1.15 (s, 6H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[N+:12]([C:15]1[CH:16]=[C:17](/[C:21](/[CH2:25][CH3:26])=[CH:22]/[CH2:23]O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>ClCCl>[Cl:1][CH2:23]/[CH:22]=[C:21](/[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)\[CH2:25][CH3:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC/C(=C\CO)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CSC
Product: CC/C(=C\CCl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-chlorosuccinimide (52.3 g, 0.39 mol) in dichloromethane (1.2 l) at 0° C. was added dropwise over 20 minutes dimethylsulfide (27.9 ml, 0.38 mol). To the mixture was added dropwise over 20 minutes at 0° C. a solution of (E)-3-(3-nitrophenyl)-2-penten-1-ol (Preparation 14, 80 g, 0.39 mol) in dichloromethane (300 ml). The mixture was warmed to room temperature over 1 h, stirred at room temperature for 16 h, then partitioned between water (2 l) and dichloromethane (1 l). The layers were separated and the organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica column chromatography (2 kg), eluting with 10:1 hexane/diethyl ether. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (54 g, 62%).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]I.[NH2:8][C:9]1[CH:10]=[C:11]([C:19]([O:21][CH3:22])=[O:20])[CH:12]=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15]>CN(C1C=CN=CC=1)C.O>[N:8]1([C:9]2[CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[C:11]([CH:10]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: ICCCCCI
Agent: CN(C)c1ccncc1
Solvent: O
Product: COC(=O)c1cc(C(=O)OC)cc(N2CCCCC2)c1
Temperature: 25 °C
Yield: 33 %

Procedure:
1,5-diiodopentane (0.85 ml, 1.8 g, 5.74 mmol, 3 eq) was added to a stirred solution of dimethyl 5-aminoisophthalate (0.40 g, 1.91 mmol, 1 eq) and DMAP (0.467 g, 3.82 mmol, 2.1 eq) at 100° C. under Ar. After heating overnight the reaction was cooled to room temperature and poured in water. The mixture was extracted with EtOAc (×2). The combined organic extracts were washed with water (×4), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.1736 g, 0.626 mmol, 33% yield) of the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Solvent: c1ccccc1
Product: CCCCNc1c(C(=O)OCC)cnc2c1cnn2CC
Reaction time: 5 h

Procedure:
To a solution of 50.8 g. of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.2 mol.) in 200 ml. of benzene, 29.2 g. of n-butylamine (0.4 mol.) are added. The mixture is kept at 50° for 5 hours. Then the separated butylamine hydrochloride is filtered under suction and the filtrate is evaporated in vacuo to dryness. The residual 4-butylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is recrystallized from hexane, m.p. 82°-83°, yield 53 g. (91.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[F:21][C:22]([F:30])([F:29])[CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:28][CH:23]([C:24]([F:27])([F:26])[F:25])[C:22]([F:30])([F:29])[F:21]
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCCBr)c(Cl)c1
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)C(OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.2 %

Procedure:
A reaction vessel was charged with 0.42 g of 3,5-dichloro-4-(4-bromobutyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.25 g of 1,1,1,3,3,3-hexafluoro-2-propanol, 0.17 g of potassium carbonate and 10 ml of N,N-dimethylformamide. After stirring at room temperature for 48 hours, the reaction mixture was poured into water and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then concentrated. The residue was subjected to silica gel chromatography, which afforded 0.077 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(1,1,1,3,3,3-hexafluoro-2-propyloxy)butyloxy)benzene (yield, 15%), nD24.0 1.4805.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[C:15]([Br:16])=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:17])C)(C)(C)C.Cl.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(O)C>[Br:16][C:15]1[C:10]([CH2:9][NH:7][CH3:6])=[C:11]([NH2:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c(N)cccc1Br)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1c(N)cccc1Br
Temperature: 100 °C
Yield: 765.5 %

Procedure:
(2-Amino-6-bromo-benzyl)-methyl-carbamic acid tert-butyl ester (371 mg) was dissolved in 50 ml ethanol. To this solution was added 2M ethanolic hydrochloride acid solution (10 ml). The reaction mixture was heated at 100° C. for 30 minutes, at which time the deprotection was completed. The solution was allowed to cool to room temperature and poured into the mixture of saturated NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with EtOAc three times and the organic fractions were concentrated to give 3-bromo-2-methylaminomethyl-phenylamine as a brown oil (1.938 g, 76%). MS: (M+H)+217.1.
Reaction SMILES: S([O-])(OC(C)(C)S(OC1C=CC(O)=CC=1)(=O)=O)(=O)=O.[C:20]([OH:39])(=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:55][C@@H:56]([C:59]([OH:61])=[O:60])[CH2:57][OH:58].C(N(CC)CC)C>C(#N)C.O>[C:20]([NH:55][C@@H:56]([C:59]([OH:61])=[O:60])[CH2:57][OH:58])(=[O:39])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: N[C@H](CO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(OS(=O)(=O)[O-])S(=O)(=O)Oc1ccc(O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@H](CO)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
4-hydroxyphenyldimethylsulfomethyl sulfate 2.66 g (0.01 mol) was heated and dissolved in 40 ml of acetonitrile. Oleic acid 2.82 g (0.01 mol) was added to the solution obtained, and the mixture was stirred at 0° C. To the mixture solution, dicyclohexyl carbodiimide 2.06 g (0.01 mol) was added little by little, and the solution was stirred for 2 hours at 0° C. and then for 2 hours at room temperature. The solution reacted was filtered to remove dicyclohexyl urea, and the filtrate was distilled in vacuo to obtain oily residue. D-serine 1.05 g (0.01 mol) and triethyl amine 1.4 ml (0.01 mol) were added to 10 ml of water. An acetonitrile solution of the above oily residue was added to the mixture with stirring, and stirred for 10 hours at room temperature. After reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was adjusted to pH 2 or 3 with 6N-HCl, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium acetate, and freed of solvent in vacuo. The oily residue obtained was purified by column chromatography (column: 2.5×15 cm) on 50 g of silica gel and N-oleoyl-D-serine 1.5 g was obtained.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[CH3:20][C:21]([CH3:23])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[CH3:20][CH:21]([N:8]1[CH2:9][CH2:10][C:4]2=[CH:3][N:2]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=3)[N:1]=[C:5]2[CH2:6][CH2:7]1)[CH3:23]
Reactant: NC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCc2cn(-c3ccc(C(N)=O)cc3)nc2CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide (may be prepared as described in Description 37) (31 mg, 0.12 mmol) in dichloromethane (3 ml) was added acetone (14 mg, 0.24 mmol) and acetic acid (2 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added and stirring continued for 2 hours. A further 6 eq. of acetone was added and stirring continued over the weekend. Methanol was added and the crude mixture was purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. The crude product was triturated with ether and filtered to afford the title compound (E17). MS (ES+) m/e 299 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])(O)=O.[Na+].[CH3:14][CH2:15]O>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:14]=[CH:15][N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ccn2ccnc2c1

Procedure:
4-Chloro-pyridin-2-ylamine (1 eq, 38.9 mmol, 5 g) is added to a solution of chloroacetic aldehyde (3 eq, 117 mmol, 15.1 ml) in EtOH (60 ml). NaHCO3 (2 eq, 77.8 mmol, 6.53 g) is added and the reaction mixture is heated at reflux for 17 h. The solvent is removed in vacuo and the product is purified by flash column chromatography eluting with 8:2 DCM/MeOH to afford 7-chloro-imidazo-[1,2-a]-pyridine as a red solid; [M+H]+=153
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br.Br.[CH2:19]([C:21]1[C:22]([C:29]2[CH:37]=[C:36]3[C:32]([C:33]([C:38]4[NH:39][C:40]5[CH2:45][CH2:44][NH:43][CH2:42][C:41]=5[N:46]=4)=[N:34][NH:35]3)=[CH:31][CH:30]=2)=[CH:23][C:24]([F:28])=[C:25]([OH:27])[CH:26]=1)[CH3:20]>>[CH2:19]([C:21]1[C:22]([C:29]2[CH:37]=[C:36]3[C:32]([C:33]([C:38]4[NH:39][C:40]5[CH2:45][CH2:44][N:43]([CH2:14][C:11]6[CH:12]=[N:13][C:8]([O:1][C:2]7[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=7)=[CH:9][CH:10]=6)[CH2:42][C:41]=5[N:46]=4)=[N:34][NH:35]3)=[CH:31][CH:30]=2)=[CH:23][C:24]([F:28])=[C:25]([OH:27])[CH:26]=1)[CH3:20]
Reactant: O=Cc1ccc(Oc2ccccc2)nc1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccc(Oc5ccccc5)nc3)C4)n[nH]c2c1
Yield: 33.4 %

Procedure:
The title compound was prepared from 6-phenoxy-pyridine-3-carbaldehyde (39 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 22. The crude material was purified by HPLC Method A to afford 24.7 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4].[CH3:22][Sn](C)(C)C>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([CH3:22])[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4]
Reactant: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C)c2nc(-c3ccccc3)oc2c1O
Temperature: 130 °C
Yield: 61.1 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4-bromo-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (200 mg, 0.573 mmol), tetramethyltin (0.32 mL, 2.29 mmol), and dichlorobis(triphenylphosphine)palladium(II) (40.2 mg, 0.057 mmol) was suspended in 4.8 mL of anhydrous N,N-dimethylformamide. The reaction mixture was heated at 130° C. for 1 hour, cooled to room temperature, and diluted with ethyl acetate. The organic mixture was successively washed with saturated sodium bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography eluting from silica gel with a gradient of 0-100% ethyl acetate in hexanes to give 99.6 mg of the title compound as a white solid. MS: (+) m/z 285.0 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][NH:17][CH2:16][CH2:15][C:14]=3[N:13]=2)[C:6](=[O:10])[N:7]([CH3:9])[CH:8]=1.[O:22]1[CH2:25][C:24](=O)[CH2:23]1.[BH3-]C#N.[Na+].O>CO.[Cl-].[Zn+2].[Cl-]>[Br:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][N:17]([CH:24]4[CH2:25][O:22][CH2:23]4)[CH2:16][CH2:15][C:14]=3[N:13]=2)[C:6](=[O:10])[N:7]([CH3:9])[CH:8]=1
Reactant: Cn1cc(Br)cc(Nc2ccc3c(n2)CCNC3)c1=O
Reactant: O=C1COC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Cn1cc(Br)cc(Nc2ccc3c(n2)CCN(C2COC2)C3)c1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
A mixture of 5-bromo-1-methyl-3-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridine-2(1H)-one hydrochloride 205a (800 mg, 2.16 mmol), oxetan-3-one (778 mg, 10.8 mmol), NaBH3CN (681 mg, 10.8 mmol), and zinc chloride (1.47 g, 10.8 mmol) in methanol (30 mL) was stirred for 4 hours at 50° C. The mixture was added to H2O (30 mL) and extracted with DCM (50 mL×3). The organic layers were concentrated under reduced pressure. The residue was purified by column chromatography eluting with 10:1 ethyl acetate/methanol to give 219a as a yellow solid (750 mg, 89%). MS: [M+H]+ 391.