Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:17]=[CH:16][C:8]([CH:9]=[CH:10][C:11]2[N:15]=[CH:14][NH:13][N:12]=2)=[CH:7][CH:6]=1)#[N:4].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]1([O:34][CH2:33]1)[CH2:27][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1>CN(C)C=O.O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[CH:10][C:11]2[N:15]=[CH:14][N:13]([CH2:33][C:26]([C:20]3[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=3[F:18])([CH2:27][N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)[OH:34])[N:12]=2)=[CH:16][CH:17]=1)#[N:4]
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Reactant: N#Cc1ccc(C=Cc2nc[nH]n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=Cc2ncn(CC(O)(Cn3cncn3)c3ccc(F)cc3F)n2)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
Sodium hydride (55% oil dispersion) (0.4 g.) was added to a solution of 3-(4-cyanostyryl)-1,2,4-triazole (1.6 g.) in dimethylformamide (20 ml.). After the effervescence had ceased, a solution of 2-(2,4-difluorophenyl)-2,3-epoxy-1-(1,2,4-triazol-1-yl)propane (1.9 g.) in dimethylformamide (10 ml.) was added, and the mixture was heated at 75° C. for 5 hours, then stirred at room temperature for 16 hours. The reaction mixture was diluted with water (150 ml.) and extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was crystallised from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.) to give 2-[3-(4-cyanostyryl)-1,2,4-triazol-1-yl]-1-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl methyl)ethanol, m.p. 189°-91° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:21])=[C:9]([O:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[CH:10]=2)[N:5]=[C:4]([N:22]2[CH:26]=[C:25]([C:27]([O:29]CC)=[O:28])[CH:24]=[N:23]2)[N:3]=1.[Li+].[OH-].Cl>C1COCC1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:21])=[C:9]([O:12][C:13]3[C:14]([CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=3[CH3:19])[CH:10]=2)[N:5]=[C:4]([N:22]2[CH:26]=[C:25]([C:27]([OH:29])=[O:28])[CH:24]=[N:23]2)[N:3]=1
Reactant: CCOC(=O)c1cnn(-c2nc(N)c3cc(Oc4c(C)cccc4C)c(F)cc3n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1Oc1cc2c(N)nc(-n3cc(C(=O)O)cn3)nc2cc1F
Temperature: 40 °C
Yield: 76.3 %

Procedure:
A mixture of 1-[4-amino-6-(2,6-dimethyl-phenoxy)-7-fluoro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, ethyl ester (65 mg, 0.15 mmol), 1M aqueous LiOH (1.5 mL, 1.5 mmol), and THF (3 mL) was heated to 40° C. for 16 h with rapid stirring. The mixture was then cooled in an ice bath, and 1M HCl (1.5 mL, 1.5 mmol) was added. The resulting precipitate was collected by filtration, washed with water, and dried to furnish the titled compound (45 mg, 74%). MS (ESI): mass calcd. for C20H16FN5O3, 393.1; m/z found, 394.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 12.72 (s, 1H), 8.91 (d, J=0.7 Hz, 1H), 8.42-7.98 (m, 3H), 7.70 (d, J=11.9 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.25-7.20 (m, 2H), 7.17 (dd, J=8.6, 6.2 Hz, 1H), 2.12 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH:17]([OH:30])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25](OCC)=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CC(C[AlH]CC(C)C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH:17]([OH:30])[C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][OH:26])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(C(O)c2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: OCCc1ccc(C(O)c2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 82.5 %

Procedure:
Following general procedure E1, ethyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)(hydroxy)methyl)phenyl)acetate (0.065 g, 0.15 mmol) was reacted with DIBAL (1.0 M, 0.46 mL, 0.46 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.047 g, 73%) as a white solid. MW=379.88. 1H NMR (DMSO-d6, 500 MHz) δ 8.10-8.07 (m, 1H), 8.03 (s, 1H), 8.00-7.97 (m, 1H), 7.59-7.52 (m, 2H), 7.31 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 5.78 (s, 1H), 3.56 (t, J=7.0 Hz, 2H), 3.03-2.90 (m, 3H), 2.71-2.60 (m, 3H), 2.09-2.00 (m, 2H); APCI MS m/z 380 [M+H]+.
Reaction SMILES: CS([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([Br:24])=[C:13]2[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:8][CH:7]=1)(=O)=O.CC(C)([O-])C.[K+].Cl>CS(C)=O.O>[Br:24][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][C:6]([OH:5])=[CH:7][CH:8]=2)[C:13]=1[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)Nc1c(Br)ccc2ccc(OS(C)(=O)=O)cc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1c(Br)ccc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-bromo-1-(tert-butoxycarbonylamino)naphth-7-yl methanesulfonate, as described above in Step E, (5.87 g, 14.09 mmol) in DMSO (70 mL) was added potassium tert-butoxide (5.17 g, 42.27 mmol) in one portion. The reaction mixture was stirred at ambient temperature for 1 hour, then neutralized with aqueous HCl, diluted with water and extracted with Et2O (2×). The combined organic extracts were washed with water (3×), dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [CH2:1]([N:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[CH2:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:2][CH:3]([CH3:5])[CH3:4].C1(=O)NC(=O)C2=CC=CC=C12>>[NH2:13][CH2:12][C@H:7]1[N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: CC(C)CCN1C(=O)CC[C@H]1CN1C(=O)c2ccccc2C1=O
Agent: O=C1NC(=O)c2ccccc21
Product: CC(C)CCN1C(=O)CC[C@H]1CN
Yield: 100 %

Procedure:
The (S)-2-((1-isopentyl-5-oxopyrrolidin-2-yl)methyl)isoindoline-1,3-dione was subjected to the phthalimide deprotection procedure described in example 5.6.123, Part B, to obtain 100% yield of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:13][C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:16]=2)[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7][CH2:6]1)=[O:4].[BH4-].[Na+].CO>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([NH:13][C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:16]=2)[CH2:11][CH2:10][CH2:9][CH:8]([OH:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CCCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CCCC(O)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
The compound of step 1 (67 mg, 0.148 mmol) was dissolved in THF (1 ml) and cooled in an ice bath. Sodium borohydride (5.7 mg, 0.148 mmol) was added. Subsequently methanol (0.3 ml) was added dropwise. The ice bath was removed and after stirring for 45 min at room temperature the mixture was partitioned between EA and 2 N hydrochloric acid. The aqueous phase was extracted with EA, and the combined organic phases were dried over sodium sulfate and evaporated to dryness to yield the title compound (65 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:17][CH2:18][CH3:19])[CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1)=[O:8])(=[NH:3])[NH2:2].[H][H]>CO.[Pd]>[C:1]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:17][CH2:18][CH3:19])[CH:11]=[C:12]([NH2:14])[CH:13]=1)=[O:8])(=[NH:2])[NH2:3]
Reactant: CCCn1cc([N+](=O)[O-])cc1C(=O)NCCC(=N)N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCn1cc(N)cc1C(=O)NCCC(=N)N
Reaction time: 0.5 h

Procedure:
To a solution of 4-nitro-1-propyl-1H-pyrrole-2-carboxylic acid (2-carbamimidoyl-ethyl)-amide (52 mg, 0.2 mmol) in 15 ml of MeOH was added 20 mg of 5% Pd/C under argon. The reaction mixture was flashed with hydrogen and shaken under hydrogen at 30 psi for 30 min. The catalyst was removed by filtration through celite and washed with methanol. The filtrate was evaporated to dryness to give 4-amino-1-propyl-1H-pyrrole-2-carboxylic acid (2-carbamimidoyl-ethyl)-amide 34. This product was immediately used in next step reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH:16]([OH:21])[CH2:17][N:18]([CH3:20])[CH3:19])[CH:13]=[CH:12][N:11]3[C:22]=2[C:23]2[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=2)=[CH:4][CH:3]=1.[NH3:33]>O1CCCC1>[NH2:33][C:25]1[N:24]=[C:23]([C:22]2[N:11]3[CH:12]=[CH:13][C:14]([CH:16]([OH:21])[CH2:17][N:18]([CH3:20])[CH3:19])=[CH:15][C:10]3=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CN(C)CC(O)c1ccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc2c1
Reactant: N
Solvent: C1CCOC1
Product: CN(C)CC(O)c1ccn2c(-c3ccnc(N)n3)c(-c3ccc(F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A pressure bottle containing sulfone 43 (320 mg, 0.703 mmol) was charged with tetrahydrofuran (40 mL), then chilled to <−40° C. in a dry ice/isopropanol bath. Ammonia gas (5.3 g, 0.31 mol) was then bubbled into the reaction. The pressure bottle was then sealed, and the reaction was allowed to warm to room temperature while stirring for 12 hours. The pressure was then released, and the reaction was concentrated under reduced pressure, dissolved in a minimum volume of CH2Cl2, then loaded onto a 40 g Isco RediSep normal phase silica cartridge, and purified on an Isco OptiX10 CombiFlash instrument using a gradient that started at 100% methylene chloride and ended at 90% methylene chloride, 9% methanol, 1% concentrated ammonium hydroxide. Fractions containing desired product were pooled and concentrated under reduced pressure. Yield of 44: 158 mg (57%). 1H NMR (400 MHz, DMSO-d6) δ 2.21 (s, 6H), 2.49 (m, 2H), 4.77 (m, 1H), 5.38 (m, 1H), 6.31 (d, J=5.4 Hz, 1H), 6.83 (bs, 2H), 7.04 (dd, J=7.2, 1.6 Hz, 1H), 7.28 (t, J=8.8 Hz, 2H), 7.60 (s, 1), 7.65 (m, 2H), 8.10 (d, J=5.4 Hz, 1H), 9.48 (d, J=7.2 Hz, 1H). MS (ESI+) 393.2.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][CH2:32][CH:33]([OH:38])[C:34]([F:37])([F:36])[F:35].N.FC(F)(F)C1CO1>CCCCO.CS(C)=O>[F:35][C:34]([F:37])([F:36])[CH:33]([OH:38])[CH2:32][NH:31][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Reactant: NCC(O)C(F)(F)F
Agent: FC(F)(F)C1CO1
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Product: CC(C)n1cnc2c(NCc3cccnc3)nc(NCC(O)C(F)(F)F)nc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 14.9 %

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (300 mg, 1.05 mmol) in n-BuOH/DMSO (5 ml, 4:1) at room temperature under an argon atmosphere was added DIEA (1.4 ml, 10 eq, 8 mmol) followed by 3-amino-1,1,1-trifluoropropan-2-ol (1 g, 7.8 mmol) [prepared from the reaction of ammonia with 2-(trifluoromethyl)oxirane]. The flask was fitted with a condenser and the reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 ml) and water (50 ml), the aqueous phase was extracted with more EtOAc (2×25 ml), and the combined organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient flash column chromatography on silica gel eluted with CHCl3:MeOH (100:0→95:5), to afford the title compound as a colorless oil (62 mg, 15%). δH (CDCl3, 500 MHz) 1.53 (6 H, d, J 7.5, CH[CH3]2), 3.64-3.6 (1 H, m, NHCHHCOH[CF3][CH3), 3.76-3.73 (1 H, m, NHCHHCOH[CF3][CH3), 4.18-4.16 (1 H, m, CHMe2), 4.62-4.56 (1 H, m, CHOHCF3), 4.72 (3 H, s, br, NHCH2Ar and NHCH2Ar), 7.22-7.2 (1 H, m, ArH), 7.52 (1 H, s, ArH), 7.66 (1 H, d, J 10, ArH), 8.47 (1 H, d, J 5, ArH), 8.58 (1 H, s, ArH); δC (CDCl3, 500 MHz) 159.77 (C), 154.68 (C), 149.04 (CH), 148.45 (CH), 135.44 (CH), 135.03 (CH), 134.44 (C), 125.91 (C), 123.49 (CH), 114.78 (C), 71.57 (CH), 46.76 (CH), 42.94 (CH2), 32.2 (CH2), 22.47 (2×CH3) 19FNMR δ −78.48; m/z 396.2 (M+H)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([OH:17])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Oc1cc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCOCC5)n4c3)c3ccccc32)ccc1Cl)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCOCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(O)c2)n1
Yield: 29.8 %

Procedure:
A solution of Intermediate 64a (243 mg, 0.29 mmol) and TBAF (1M in THF, 1.3 mL, 1.33 mmol) in THF (3 mL) was stirred at RT for 1 h, then diluted with water and extracted with DCM (3×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the product. This was further purified by HPLC (XBridge C18 column, 25-98% MeCN in H2O, 0.1% NH4OH) to give the title compound (58 mg, 29%). LCMS (Method 5): Rt 4.10 min, m/z 671 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.84-2.13 (6H, m), 3.46-3.50 (4H, m), 3.81-3.92 (4H, m), 4.81-4.85 (1H, m), 5.52 (1H, t, J=4.4 Hz), 6.33 (1H, s), 6.94 (1H, dd, J=8.5, 2.4 Hz), 7.08 (1H, d, J=8.4 Hz), 7.12-7.19 (2H, m), 7.31-7.43 (4H, m), 7.43 (1H, d, J=8.5 Hz), 7.60-7.62 (2H, m), 8.12 (1H, s).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:48](OC(=O)C)(=[O:50])[CH3:49]>CN(C=O)C>[C:48]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)(=[O:50])[CH3:49]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)N5CCCCC5)C4)nnc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (70 mg, 0.13 mmol) was dissolved in 4 mL DMF. To it were added DIEA (230 μL, 1.30 mmol) and then acetic anhydride (37 μL, 0.39 mmol). The mixture was stirred at RT for 1 hour, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-5-(4-(1-acetylpiperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (497), as HCl salt (47 mg). LC-MS (ESI): m/z (M+1) 550.3. UV: λ=261, 329, 337 nm.
Reaction SMILES: I[C:2]1[CH:19]=[N:18][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[C:12]1([C:10]([N:9]2[CH2:8][CH2:7][NH:6][C:5]3[N:18]=[CH:19][C:2]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)=[CH:3][C:4]2=3)=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C(c1ccccc1)N1CCNc2ncc(I)cc21
Product: O=C(c1ccccc1)N1CCNc2ncc(-c3cccnc3)cc21
Yield: 25 %

Procedure:
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenylmethanone (50 mg) was reacted with pyridine 3-boronic acid as in General Procedure 4A to give the title compound as a yellow solid (25% yield). M.p. 219-220° C., LCMS: m/z=317.40 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.45-3.50 (m, 2H), 4.02 (t, J=4.8 Hz, 2H), 5.39 (s, 1H), 7.20-7.22 (m, 2H), 7.40-7.44 (m, 3H), 7.47-7.51 (m, 3H), 8.03 (s, 1H), 8.30 (s, 1H), 8.47 (d, J=4.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH:20]=O>C(O)C.[Pd]>[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20][NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)[CH:5]=1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(NCC(OC)OC)cc1N1CCN(C)CC1
Yield: 93.3 %

Procedure:
A suspension of 4-methoxy-3-(4-methyl-1-piperazinyl) benzenamine (5 g, 0.023 mol) in ethanol (150 ml) and dimethoxyethanal (9.5 g, 1.2 eq) was hydrogenated over 10% Palladium on charcoal (3 g) at standard temperature and pressure for 3 h. The suspension was filtered through kieselguhr, washed with methanol and evaporated to give a pale yellow oil. Purification by Fcc, eluting with 2% methanol/dichloromethane afforded the title compound (6.64 g, 95%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:20])[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1)=O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:20][N:8]([CH2:9][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1)[CH3:7]
Reactant: CN(C)C(=O)c1n[nH]c2ccccc12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
Lithium aluminum hydride (13.7 g, 36.1 mmol) was suspended in THF (500 mL), and the suspension was added with a solution of N,N-dimethyl-1H-indazole-3-carboxamide obtained in Step 1 (34.2 g, 181 mmol) in THF (250 mL), followed by stirring at room temperature under the flow of nitrogen gas for 30 minutes. The reaction mixture was mixed with sodium sulfate decahydrate, was stirred for further 1 hour and was filtered through Celite. The solvent was evaporated under reduced pressure to obtain 3-dimethylaminomethyl-1H-indazole (24.2 g, 76%).
Reaction SMILES: [OH-:1].[Na+].OO.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:32]#[N:33])([NH:18][C:19]([C:21]2[C:29]3[O:28][C:27]([F:31])([F:30])[O:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)=O)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C1COCC1.CCO>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2([N:18]=[C:19]([C:21]3[C:29]4[O:28][C:27]([F:31])([F:30])[O:26][C:25]=4[CH:24]=[CH:23][CH:22]=3)[NH:33][C:32]2=[O:1])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2cccc3c2OC(F)(F)O3)CC1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(c1cccc3c1OC(F)(F)O3)NC2=O
Temperature: 25 °C
Reaction time: 43 h
Yield: 91.3 %

Procedure:
A 1 N aqueous NaOH solution (0.274 ml, 0.274 mmol) and a 35% aqueous H2O2 solution (0.051 ml, 0.52 mmol) were added to a solution of 4-cyano-4-[(2,2-difluoro-benzo[1,3]dioxole-4-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (56.0 mg, 0.137 mmol) in THF (0.23 ml) at room temperature. The reaction mixture was stirred at room temperature for 43 hours, and a 35% aqueous H2O2 solution (0.030 ml, 0.31 mmol) was then further added at room temperature. After stirring at room temperature for 48 hours, the mixture was quenched with a 1 N aqueous HCl solution (0.2 ml) and concentrated under reduced pressure. A 6 N aqueous NaOH solution (0.33 ml, 2.0 mmol) was added to a suspension of the resulting residue in EtOH (1.2 ml) at room temperature, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with a saturated aqueous NH4Cl solution (0.4 ml) and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with water, and then dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to give 2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (51.2 mg, 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.CC1(C)COB([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][CH3:36])=[N:32][CH:33]=2)OC1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][CH3:36])=[N:32][CH:33]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: CCCc1ccc(B2OCC(C)(C)CO2)cn1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
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: O
Solvent: CCO
Product: CCCc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)oxazoline (0.8 g, 2.4 mmol) was refluxed for 8 hours with dimethyl-2-(2-n-propylpyridin-5-yl)-1,3,2-dioxaborinane (0.72 g, 3.1 mmol), Pd(PPh3)4 (0.14 g, 0.12 mmol) and sodium carbonate (0.5 g) in tolune/ethanol/water 8:2:1 (11 ml). After extraction and chromatography, 2-(2,6-difluorophenyl)-4-[4-(2-n-propylpyridin-5-yl)phenyl]oxazoline was obtained, 0.20 g, pale solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH:30](O)([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][CH2:21][C:22]([O:24][CH:30]([CH3:32])[CH3:31])=[O:23])=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: O=C(O)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
0.155 g (0.478 mmol) of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl) methoxy)acetic acid were solubilized with magnetic stirring in 5 ml of isopropanol and a drop of sulfuric acid was added. The mixture was stirred at 60° C. for 3 h. The reaction medium was washed with 2×10 ml of water, and then extracted with 2×30 ml of ethyl acetate. The combined organic phases were washed with 30 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. 0.162 mg (yield=91%) of isopropyl 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)-methoxy)acetate were obtained as a brown oil. LC-MS: m/z=367 (MH+); UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) δ 8.62 (d, J=6.8 Hz, 1H), 7.74 (dd, J=8.7, 5.5 Hz, 2H), 7.67 (d, J=9.0 Hz, 1H), 7.45 (d, J=7.0 Hz, 1H), 7.33 (t, J=8.9 Hz, 2H), 7.12 (t, J=6.5 Hz, 1H), 4.93 (dt, J=12.5, 6.3 Hz, 1H), 4.78 (s, 2H), 4.19 (s, 2H), 1.15 (d, J=6.3 Hz, 6H).