Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:11]([N:12]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:19])[O:3]1.Cl.CO>C1COCC1>[NH2:18][CH2:17][C:16]1[N:12]([CH:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:19])[O:3][C:2]2([CH3:20])[CH3:1])[CH:13]=[N:14][CH:15]=1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C#N
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1CN

Procedure:
The solution of 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbonitrile (0.130 g, 0.5 mmol) (Example 20) in THF (2 mL) is added borane dimethyl sulfide complex (0.055 mL, 0.55 mmol) dropwise, and the resulting mixture is stirred at reflux for 30 min. The reaction mixture is concentrated in vacuo and the residue is redissolved in THF (2 mL) and 0.5 M hydrogen chloride in methanol (1.1 mL, 0.55 mmol) is added dropwise. The reaction mixture is stirred at ambient temperature for 1.5 h. The mixture is concentrated in vacuo and the residue is purified by semi-preparative reverse phase HPLC to give 4-(5-aminomethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one as a yellowish solid; MS (ESI) m/z 271.9 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.28 (s, 3 H), 1.59 (s, 3 H), 4.55-4.74 (m, 2 H), 5.99 (s, 1 H), 7.67-7.76 (m, 3 H), 7.82 (td, J=7.6, 1.5 Hz, 1 H), 8.29 (dd, J=7.7, 1.4 Hz, 1H), 8.52 (br. s, 1 H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]([OH:21])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]([Cl:24])=[O:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C(=O)O
Solvent: Cc1ccccc1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (E22, 19 mg), thionyl chloride (2 mL) was added at room temperature, and the mixture was stirred for 2 hours under reflux by heating. The reaction mixture was cooled to room temperature, and then toluene was added to the mixture. The solvent was evaporated under reduced pressure to obtain 2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidine-5-carbonyl chloride (E23) as white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])[CH:14]=2)[C:9](=[O:23])[N:8]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:7]=1[CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])[CH:14]=2)[C:9](=[O:23])[N:8]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:7]=1[CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(/C=C/C(=O)OCC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(/C=C/C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of ethyl (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-2-propenate (1.00 g, 2 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N sodium hydroxide (4 mL). The obtained mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl)-2-propenic acid (0.89 g, 94.7%) as crystals.
Reaction SMILES: Cl.C(OC([NH:9][CH:10]([C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=1)[CH2:11][N:12]([C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH:14]([Cl:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)(C)(C)C>C(OCC)(=O)C>[NH2:9][CH:10]([C:25]1[CH:26]=[C:27]([F:33])[C:28]([F:32])=[C:29]([F:31])[CH:30]=1)[CH2:11][N:12]([C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH:14]([Cl:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(Cl)CN(CC(NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1)C(=O)OC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cl)CN(CC(N)c1cc(F)c(F)c(F)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 118.6 %

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (20 mL) was added to a solution of ethyl 3-{[2-tert-butoxycarbonylamino-2-(3,4,5-trifluorophenyl)ethyl]methoxycarbonylamino}-2-chloropropionate (2.16 g) in ethyl acetate (20 mL), and the reaction solution was stirred at room temperature for 15.5 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 2.03 g of a crude product of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].[Li]CCCC.[CH:15](=[O:18])[CH2:16][CH3:17]>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][CH:15]([OH:18])[CH2:16][CH3:17])[CH3:2]
Reactant: C#CC(OCC)OCC
Reactant: CCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(C#CC(O)CC)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3,3-Diethoxy-propyne (2.73 g, 21.3 mmol) in THF (40 ml) was cooled to −78 C under N2. A solution of n-BuLi (2.0M in cyclohexane, 14 mL, 28 mmol) was added. After 30 min., Propionaldehyde (1.61 g, 27.7 mmol) in THF (10 ml) was added. After 15 h, the reaction was quenched by dilution with 1N HCl, warmed to room temperature and extracted into EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to give product, 4.30 g (83%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:41][N:42]1[CH:46]=[C:45]([S:47](Cl)(=[O:49])=[O:48])[CH:44]=[N:43]1>O1CCCC1.C(=O)([O-])O.[Na+]>[F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][N:5]([S:47]([C:45]2[CH:44]=[N:43][N:42]([CH3:41])[CH:46]=2)(=[O:49])=[O:48])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cnn(C)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (324 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 121 mg) at room temperature and the mixture was stirred for 15 min. 15-Crown-5 (664 mg) was added dropwise and the mixture was stirred for 5 min. 1-Methyl-1H-pyrazole-4-sulfonyl chloride (362 mg) was added, and the mixture was further stirred for 30 min. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 460 mg, 98%).
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Si]([O:25][C:26]1[CH:31]=[C:30]([O:32][Si](C(C)(C)C)(C)C)[CH:29]=[CH:28][C:27]=1[C@H:40]1[CH2:45][CH2:44][C@H:43]([NH2:46])[CH2:42][CH2:41]1)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>CN(C)C1C=CN=CC=1.ClC(Cl)C.ClCCl.C1(C)C=CC=CC=1.O>[C:1]1([O:7][C:8](=[O:9])[NH:46][C@H:43]2[CH2:42][CH2:41][C@H:40]([C:27]3[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=3[OH:25])[CH2:45][CH2:44]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(N[C@H]1CC[C@H](c2ccc(O)cc2O)CC1)Oc1ccccc1

Procedure:
A solution of phenylchloroformate (0.045 ml, 0.36 mmol), triethylamine (0.085 ml), 4-dimethylaminopyridine (catalytic) and trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexylamine (0.043 g) in dichloroethane (11 ml) was stirred at room temperature for 60 hr. The mixture was partitioned between saturated aqueous sodium carbonate (15 ml) and dichloromethane (15 ml). The aqueous phase was extracted with dichloromethane (2×15 ml) and the combined organic extracts washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether) afforded a colourless gum. This was dissolved in dichloromethane (15 ml) and warmed with a mixture of water (7.5 ml) and trifluoroacetic acid (7.5 ml) at 80° C. for 17 hr. On cooling, toluene (25 ml) was added and the solution concentrated in vacuo. Methanol (25 ml) was added and the solution again concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether) afforded the title compound (0.013 g, 13%) as a colourless solid. δH (CD3OD) 1.44-1.63 (4H, m), 1.96 (2H, m), 2.13 (2H, m), 2.86 (1H, m), 3.55 (1H, m), 6.30 (2H, m), 6.92 (1H, d), 7.12 (2H, m), 7.22 (1H, m) and 7.40 (2H, m); m/s(ES+) 328.26 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[S:20][C:21]([C:27]2[C:32]([F:33])=[CH:31][C:30]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:29][C:28]=2[F:38])=[CH:22][C:23]=1[C:24]([NH2:26])=[O:25]>>[F:38][C:28]1[CH:29]=[C:30]([C:34]([OH:37])([CH3:36])[CH3:35])[CH:31]=[C:32]([F:33])[C:27]=1[C:21]1[S:20][C:19]([NH:18][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][C:9]([NH:11][C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[O:10])[N:7]=2)=[C:23]([C:24]([NH2:26])=[O:25])[CH:22]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cn1cc(NC(=O)Cc2cccc(Br)n2)cn1
Product: Cn1cc(NC(=O)Cc2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-(6-bromopyridin-2-yl)-N-(1-methyl-1-H-pyrazol-4-yl)acetamide (217 mg, 0.74 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (230 mg, 0.74 mmol) as starting materials.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([NH:14][C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][NH:22]4)=[O:16])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29][O:30][CH2:31][CH2:32]Br>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([NH:14][C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:32][CH2:31][O:30][CH3:29])=[O:16])[CH2:7][C:8]([CH3:12])([CH3:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(NC(=O)Nc2cccc3[nH]ncc23)c2ccc(F)cc2O1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1ncc2c(NC(=O)NC3CC(C)(C)Oc4cc(F)ccc43)cccc21
Reaction time: 1 h

Procedure:
A solution of Example 65D (500 mg, 1.41 mmol) in DMF (7 mL) was treated with 60% sodium hydride (68 mg, 1.7 mmol) at room temperature, and the mixture was stirred at this temperature for 1 hour. Bromoethyl methyl ether (0.15 mL, 1.6 mmol) was then added, and the mixture was stirred overnight at room temperature. After this time, most of the DMF was evaporated in vacuo, then water (50 mL) was added. The resulting sticky residue was collected by filtration and was then chromatographed on silica gel (98:2 CH2Cl2—CH3OH) to afford the title compound, 131 mg (23%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.73 (s, 1H), 8.07 (s, 1H), 7.69 (d, J=6.44 Hz, 1H), 7.32 (dd, J=15.09, 7.63 Hz, 1H), 7.18-7.26 (m, 2H), 6.71-6.79 (m, 2H), 6.61 (dd, J=10.85, 2.71 Hz, 1H), 4.96 (m, 1H), 4.51 (t, J=5.43 Hz, 2H), 3.75 (t, J=5.43 Hz, 2H), 3.18 (s, 3H), 2.20 (dd, J=13.39, 6.27 Hz, 1H), 1.78 (dd, J=13.05, 11.02 Hz, 1H), 1.41 (s, 3H), 1.30 (s, 3H). MS (ESI+) m/z 413 (M+H), 435 (M+Na).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]3)=[O:15])[C:10]([CH3:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:27]1(/[CH:33]=[CH:34]/B(O)O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1(/[CH:33]=[CH:34]/[C:2]2[CH:3]=[C:4]([N:8]3[C:12]([CH3:13])=[C:11]([C:14]([N:16]4[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]4)=[O:15])[C:10]([CH3:26])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: OB(O)/C=C/C1CCCCC1
Reactant: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(Br)c3)c2C)C1
Product: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(/C=C/C4CCCCC4)c3)c2C)C1
Yield: 40 %

Procedure:
In analogy to the procedure described in Example 14C], [1-(3-bromo-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone (Example 30A]) and trans-2-cyclohexylvinylboronic acid gave the title compound in 40% yield as brown gum. MS: 449.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH:11]=1)=[O:9])(C)([CH3:3])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.CC(C)=O>[N:16]1([C:12]2[CH:11]=[C:10]([C:8]3[O:9][C:1]([CH3:3])([CH3:2])[O:5][C:6](=[O:21])[CH:7]=3)[CH:15]=[CH:14][N:13]=2)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-n2ccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)C=C(c2ccnc(-n3ccnc3)c2)O1

Procedure:
Prepared from 3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H5) by stirring in TFA/acetone with TFAA according to general procedure J (method b). Obtained as a brown solid (10.8 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]3[N:22]4[CH2:23][CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C:21]4=[N:20][C:15]=3[CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClCCl.C(OCC)C>O1CCOCC1>[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]3[N:22]4[CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C:21]4=[N:20][C:15]=3[CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c(nc3cnc4cc(OCc5ccccc5)ccc4c32)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1ccc(COc2ccc3c(c2)ncc2nc4n(c23)CCCNC4)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (25 mL of a 4 N solution in 1,4-dioxane) was added to a solution of tert-butyl 3-benzyloxy-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate in a 1:1 mixture of dichloromethane and diethyl ether (50 mL). The reaction was stirred overnight at ambient temperature; a precipitate formed. The precipitate was harvested via filtration and dried under reduce pressure to provide 9.66 g of 3-benzyloxy-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.[C:24](N1C=CN=C1)([N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1)=O.CN(C)CCN>O1CCCC1>[CH3:24][N:26]([CH3:27])[CH2:30][CH2:29][NH:28][C:19](=[O:21])[CH2:18][N:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:23])[F:22])=[CH:4][CH:5]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
A suspension of 2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0156 mole), 1,1'-carbonyldiimidazole (3.0 g, 0.0185 mole) and dry tetrahydrofuran (125 ml) was stirred at room temperature for 2 hours with nitrogen bubbling through it. The reaction mixture was then heated at 50° C. under nitrogen for 2 hours. The solution was cooled and a solution of N,N-dimethylethylenediamine (4.2 g, 0.047 mole) in tetrahydrofuran (5 ml) was added. The reaction mixture was stirred at room temperature overnight under nitrogen and evaporated under reduced pressure. The residue was triturated in water, and the solid was collected by filtration, washed once with water, twice with 5% potassium hydroxide solution and then twice again with water to yield 3.0 g (49%) of product. A 0.7-g sample of the solid was dissolved in hot isopropyl ether with a little isopropyl alcohol added to aid solubility, filtered, and cooled to room temperature to yield 0.4 g of a white solid, mp 196°-197.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC[O-].[Na+].[Na].[CH3:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)=[CH:20][CH:19]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:26][CH2:25][CH2:24][CH2:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH3:17])=[CH:29][CH:28]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: Cc1ccc(OCCCCBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCOc1ccc(C)cc1)C(=O)OCC
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
176.2 g of malonic acid diethyl ester are added dropwise at 50° C. to a sodium ethylate solution freshly prepared from 23 g of sodium and 500 ml of ethanol. The mixture is kept at this temperature for 2 hours, and 243.2 g of 4-(4-methylphenoxy)butyl bromide are then added dropwise. When the addition is complete, the obtained mixture is stirred at 60° C. for 3 hours, and substantially concentrated; 1 l of ice-water is then added and the mixture is extracted 3 times with a total of 1 liter of methylene chloride. The combined organic phases are dried over sodium sulfate, and the solvent and the excess malonic acid diethyl ester is distilled off in vacuo. 303.9 g of 4-(4-methylphenoxy)butylmalonic acid diethyl ester are obtained as pale yellow, oily residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=O)[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C([O:36][CH2:37][CH2:38][O:39][NH2:40])(=O)C.CS(O)(=O)=O.C(=O)([O-])O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=[N:40][O:39][CH2:38][CH2:37][OH:36])[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC#CC(=O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: CC(=O)OCCON
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC#CC(=NOCCO)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
To a solution of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (IV) (10 g) in 1,4-dioxane (300 mL) was added 2-(acetoxy)ethoxyamine (1.5 equiv) and then 2 mol/L methane sulfonic acid aq. solution (28 mL) and stirred for 17 hr at 60° C. The reaction mixture was poured into saturated sodium hydrogen carbonate aq. solution and extracted with ethyl acetate. Organic layer was washed with water and dried over sodium sulfate. The filtrate was concentrated and the residue was recrystallized from hydrous ethanol-water, filtered and dried to give 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-hydroxyethoxyimino)-2-butyn-1-yl)quinazoline (VIII) (7.6 g) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18]C)=[O:17])[C:3]1=[O:24].[OH-].[Na+]>CO.O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([OH:18])=[O:17])[C:3]1=[O:24]
Reactant: COC(=O)c1ccc(C)c(-c2cc3cnc(C)cc3n(C)c2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2c(cn1)cc(-c1cc(C(=O)O)ccc1C)c(=O)n2C

Procedure:
Methyl 3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylbenzoate 28 (3 g, 9 mmol) is suspended in a mixture of MeOH/water (1:1, mL) and treated with NaOH (2.2 g, 55 mmol) at 80° C. for 2 h. MeOH is removed in vacuo. The resultant mixture is acidified to pH=7, and the solid product is filtered and washed with water and dried overnight to yield 29. 1H NMR (400 MHz, DMSO-d6) δ 8.8 (s, 1H), 8.02 (s, 1H), 7.88 (dd, J=7.9, 1.8 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.44 (s, 1H), 7.42 (d, J=8 Hz, 1H), 3.65 (s, 3H), 2.62 (s, 3H), 2.23 (s, 3H). LC/MS (M+1, m/z): 309.1.
Reaction SMILES: [NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:2]([C:23]([OH:25])=[O:24])[CH2:3][CH2:4][NH:5]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>CN(C=O)C>[NH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H](CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCN)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boc-D-Dab(Fmoc)-OH (206 mg, 0.5 mmol, Oakwood Products) and piperidine (0.3 mL, 3.03 mmol) were dissolved in DMF (1.6 mL). The resulting mixture was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and the residue was used directly in the subsequent step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:26]3[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32]C(=O)OC(C)(C)C)[CH2:27]3)=[N:6][C:7]([N:10]3[C:18]4[CH:17]=[C:16]([C:19]5[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=5)[N:15]=[CH:14][C:13]=4[CH:12]=[N:11]3)=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.Cl>CO.O1CCOCC1>[CH:1]1([C:4]2[C:5]([N:26]3[CH2:31][CH2:30][CH2:29][C@H:28]([NH2:32])[CH2:27]3)=[N:6][C:7]([N:10]3[C:18]4[CH:17]=[C:16]([C:19]5[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=5)[N:15]=[CH:14][C:13]=4[CH:12]=[N:11]3)=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C3CC3)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C3CC3)c(N3CCC[C@H](N)C3)n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of tert-butyl N-[(3S)-1-[3-cyclopropyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.2224 mmol; 117.1 mg) in Methanol (5 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 181 as an off-white solid (46.0 mg, 49%). 1H NMR (400 MHz, DMSO) δ 9.75-9.71 (s, 1H), 9.47-9.44 (s, 1H), 9.33-9.29 (s, 1H), 8.67-8.61 (d, J=9.6 Hz, 2H), 7.55-7.51 (d, J=8.2 Hz, 1H), 7.49-7.43 (d, J=8.2 Hz, 1H), 3.86-3.78 (d, J=10.8 Hz, 1H), 3.65-3.58 (s, 1H), 3.16-3.09 (s, 1H), 2.89-2.81 (m, 1H), 2.68-2.65 (s, 3H), 2.12-2.04 (m, 1H), 2.02-1.93 (d, J=8.9 Hz, 2H), 1.81-1.69 (m, 1H), 1.48-1.37 (d, J=8.7 Hz, 1H), 1.20-1.11 (m, 1H), 1.09-0.99 (m, 1H), 0.91-0.84 (m, 1H), 0.75-0.67 (s, 1H); MS (ESI) m/z: 427.2 [M+H]+