Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f8) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CON(C)[C:17]([C@@H:19]1[CH2:21][C@H:20]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18]>C1COCC1>[O:18]=[C:17]([C@@H:19]1[CH2:21][C@H:20]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:1][C:2]#[N:3]
Reactant: CC#N
Reactant: CON(C)C(=O)[C@@H]1C[C@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: -60 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a stirred solution of MeCN (208.3 mL) and THF (200 mL) at −60° C. under N2 was added dropwise 1M LHMDS in THF (1040 mL). The reaction mixture was stirred at −60° C. for 3 h, and 37 (62.5 g, 304.5 mmol, 1.00 equiv) was then added dropwise. The resulting solution was stirred at −60° C. for 10 min and then quenched with sat'd. aq. NH4Cl solution (400 mL). The reaction mixture was extracted with EtOAc (3×1 L), and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with EtOAc/petroleum ether (10 to 25% EtOAc) to afford 28.5 g (51%) of trans-3-oxo-3-(2-phenylcyclopropyl)propanenitrile (39) as a light yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[N:9][C:10]=1[CH3:11])([CH3:3])[CH3:2].[Li+].[OH-].O.CCOC(C)=O>C1COCC1.O>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[N:9][C:10]=1[CH3:11])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC(C)C)c(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C(=O)O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
Methyl 5-isopropoxy-6-methylpicolinate (1.3 g, 6.22 mmol) was dissolved in THF/water 2:1 (9 mL). LiOH*H2O (0.26 g, 6.22 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was poured into a mixture of water and EtOAc and the layers were separated. The aqueous layer was acidified to pH 4 with 2 N HCl and was extracted with EtOAc (2×). The combined organics were dried (Na2SO4) and concentrated to give 5-isopropoxy-6-methylpicolinic acid (860 mg, 74%) as a beige solid. 1H-NMR (300 MHz, DMSO) 1.31 (d, 6H), 4.73 (m, 1H), 7.44 (d, 1H), 7.86 (d, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:21])/[C:9](/[S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:27]\[C:26]2[CH:29]=[CH:30][C:23]([Br:22])=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C(CS(=O)(=O)Cc1ccc(I)cc1)c1ccc(I)cc1
Product: O=C(/C(=C\c1ccc(Br)cc1)S(=O)(=O)Cc1ccc(I)cc1)c1ccc(I)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 10. A solution of 1-(4-iodophenyl)-2-(4-iodobenzylsulfonyl)ethanone (10 mmol) and 4-bromobenzaldehyde (10 mmol) was subjected to the procedure described as Method A in in part C of Synthesis Example 10 and the product obtained was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:22])[S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[N:23]1([CH2:28][CH2:29][O:30][C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35]([CH:40]=O)=[CH:34]3)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:22])[S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[C:15]3=[CH:40][C:35]2[NH:36][C:37]3[C:33]([CH:34]=2)=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:39][CH:38]=3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: CN(c1cccc(Cl)c1)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CN(c1cccc(Cl)c1)S(=O)(=O)c1ccc2c(c1)C(=Cc1cc3cc(OCCN4CCCC4)ccc3[nH]1)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)-methyl-amide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12](O)[CH:11]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:40]2[C:36](=[O:46])[C:37]3[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:39]2=[O:41])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1C1=CC(O)CCC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of 3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 equiv.), triphenylphosphine (1.5 equiv.) and phthalimide (1.5 equiv.) in THF (0.3 M) at 0° C. was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (1.5 equiv.) dropwise. The reaction was stirred at 0° C. for 2 hours. Concentrated to dryness under vacuo, then purified the crude via silica gel column chromatography eluting with EtOAc and hexanes (1:1 with 5% methanol) to afford the 2-(3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (63% yield). LC/MS=350.3 (M+H), LC=3.936 min.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36](Cl)=[O:37])[CH2:32][CH2:31]1.O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3[C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]1)=[O:37])=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: CC(C)(C)c1ccc2c(c1)CC[C@H]2NC(=O)Nc1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)n2ncc3c(NC(=O)N[C@@H]4CCc5cc(C(C)(C)C)ccc54)cccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of the product from Example 56J (240 mg, 0.69 mmol) in N,N-dimethylformamide (5 mL) was treated with 60% NaH (45 mg, 1.13 mmol) and stirred at room temperature for 15 min. 4-methylpiperazine carbonyl chloride (1.64 mmol) was then added, and the reaction mixture was stirred overnight at 80° C. It was then cooled to room temperature and poured into H2O, and the resulting precipitate was collected by filtration. Chromatography on silica gel (eluted with 97:3 CH2Cl2-methanol) afforded the desired product. 1H NMR (d6-DMSO) 67 8.59 (s, 1H), 8.07 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.28 (m, 3H), 7.17 (d, J=7.5 Hz, 1H), 6.66 (d, J=7.5 Hz, 1H), 5.17 (m, 1H), 4.44 (m, 2H), 3.48 (m, 2H), 3.02 (m, 1H), 2.90 (m, 1H), 2.81 (m, 1H), 2.53 (s, 3H), 2.42 (m, 1H), 1.80 (m, 1H), 1.27 (s, 9H). MS (DCI) m/z 475 (M+H). C27H34N6O2.0.5H2O: C, 67.06; H, 7.29; N, 17.38. Found: C, 66.87; H, 7.22; N, 17.04.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])=[CH:10][C:11]([C:13]4[CH:14]=[CH:15][C:16]5[O:17][CH2:18][CH2:19][NH:20][C:21]=5N=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:33]1C=CC2OCCNC=2C=1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])=[CH:10][C:11]([C:13]4[CH:14]=[CH:15][C:16]5[O:17][CH2:18][CH2:19][NH:20][C:21]=5[CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Brc1ccc2c(c1)NCCO2
Reactant: C[C@@H](Oc1cc(-c2ccc3c(n2)NCCO3)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Product: C[C@@H](Oc1cc(-c2ccc3c(c2)NCCO3)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 18 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((1-cyclopropyl-5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:, using instead 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine as a starting material to afford 27.9 mg (18%) of (R)-4-((R)-1-((1-cyclopropyl-5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.06 (s, 1H), 7.59 (s, 1H), 7.24 (m, 1H), 6.78 (m, 4H), 5.80 (s, 1H), 4.79 (m, 1H), 4.13 (m, 2H), 3.69 (m, 1H), 3.39 (m, 1H), 3.31 (m, 1H), 3.25 (m, 2H), 2.82 (m, 1H), 2.32 (m, 2H), 1.37 (d, J=6.4 Hz, 3H), 1.11 (m, 4H). MS (ESI+) m/z 419.2 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]([N:8]1[C@H:11]([S:12]SC2SC3C=CC=CC=3N=2)[C@@H:10]([O:23][CH3:24])[C:9]1=[O:25])=[C:5]([CH3:7])[CH3:6].[BH4-].[Na+].[C:29](Br)(=[O:31])[CH3:30].C1C=CC=CC=1>CN(C)C=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[C:4]([N:8]1[C@H:11]([S:12][C:29](=[O:31])[CH3:30])[C@@H:10]([O:23][CH3:24])[C:9]1=[O:25])=[C:5]([CH3:6])[CH3:7]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC)[C@H]1SSc1nc2ccccc2s1
Reactant: CC(=O)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC)[C@H]1SC(C)=O
Reaction time: 0.5 h

Procedure:
A solution of 372 mg of 2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonic acid methyl ester in 10 ml of dimethylformamide is cooled to -20°, 10 ml of a solution of 2 g of sodium borohydride in 200 ml of dimethylformamide are added and the mixture is stirrcd at the same temperature for 30 minutes. 5 ml of freshly distilled acetyl bromide are added to the reaction mixture and the mixture is further stirred for 110 minutes at 0°. After adding 150 ml of benzene, the reaction mixture is washed in succession with sodium bicarbonate solution and water, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue yields, after chromatography over silica gel with toluene/ethyl acetate (9:1), the title compound in the form of a slightly yellowish oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([C:6]1[C:11](Cl)=[N:10][N:9]2[C:13]([NH2:16])=[N:14][N:15]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].[O-:19][CH2:20][CH3:21].[Na+]>C(O)C>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([C:6]1[C:11]([O:19][CH2:20][CH3:21])=[N:10][N:9]2[C:13]([NH2:16])=[N:14][N:15]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)c1cc2nnc(N)n2nc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2cc1C(=O)N(CC)CC
Reaction time: 8 h
Yield: 98.5 %

Procedure:
N,N-Diethyl-3-amino-6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-7-carboxamide (W2.019, 50 mg) was initially charged in ethanol (5 ml) and admixed with sodium ethoxide (28 mg) while stirring. After stirring at RT for 7 h and leaving to stand overnight, the solvent was drawn off and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 51 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[N:12][O:13][C:14]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:4][C:3]=1[NH:26][C:27]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=1)=[O:28].[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:18]3[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=3[Cl:24])=[N:12][O:13][C:14]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:4][C:3]=1[NH:26][C:27]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=1)=[O:28]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)cc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(NC(=O)c2ccc(C(=O)O)cc2)c(Cl)c1

Procedure:
A solution of methyl 4-{[(2-chloro-4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}phenyl)amino]carbonyl}benzoate (10 mg, 17 μmol) in tetrahydrofuran (150 μL) was stirred vigorously with aqueous lithium hydroxide (104 μL, 0.5M) at ambient temperature for 24 h. The reaction was partitioned with ethyl acetate and then dried over anhydrous sodium sulfate, filtered, and was condensed to a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:5][CH:4]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:41])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:41])[NH:13]3)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cccc3[nH]ccc23)cc1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Temperature: 27 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To the suspension of 4-(4-methoxy-phenyl)-1H-indole (1.84 g, 8.24 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (99 mL) was added pyridinium tribromide (90% purity from Aldrich, 8.78 g, 24.72 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (40 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (1.66 g, 84%) as a tan solid.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=O.C(OC(N1CCC(O[C:22]2[CH:23]=[CH:24][C:25]3[C:37](=[O:38])[C:36]4[C:35]5[C:30](=[CH:31][C:32]([C:39]#[N:40])=[CH:33][CH:34]=5)[NH:29][C:28]=4[C:27]([CH3:42])([CH3:41])[C:26]=3[CH:43]=2)CC1)=O)(C)(C)C>C1COCC1>[CH3:41][C:27]1([CH3:42])[C:28]2[NH:29][C:30]3[C:35](=[CH:34][CH:33]=[C:32]([C:39]#[N:40])[CH:31]=3)[C:36]=2[C:37](=[O:38])[C:25]2[CH:24]=[CH:23][C:22]([CH:3]3[CH2:1][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:43][C:26]1=2
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Solvent: C1CCOC1
Product: CC1(C)c2cc(C3CCNCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C

Procedure:
With the same condition as the method for synthesizing the Compound A8-1 (THF (0.5 mL) and TFA (0.5 mL) were added to 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Compound A7-1, 35 mg, 0.072 mmol), and the mixture was stirred at room temperature until Compound A7-1 disappears. The reaction solution was concentrated under reduced pressure and the residue was desalinated by using anionic exchange resin PL StratoSpheres (trademark) PL-HCO3 MP to obtain the Compound A8-1 (37 mg, 76%)), the title compound was synthesized from the Compound B3-13-1.
Reaction SMILES: C([N:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2OCCC)=[CH:8][C:7]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25](C(=O)C)[N:24]=[CH:23]3)=[N:6][C:5]1=[O:32])(=O)C.Cl>CO.O1CCOCC1>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([C:7]3[CH:8]=[C:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[NH:4][C:5](=[O:32])[N:6]=3)=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: CCCOc1ccccc1-c1cc(-c2ccc3c(cnn3C(C)=O)c2)nc(=O)n1C(C)=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=c1nc(-c2ccc3[nH]ncc3c2)cc(-c2ccccc2)[nH]1
Yield: 117 %

Procedure:
To a solution of 1-acetyl-4-(1-acetyl-1H-indazol-5-yl)-6-[2-(propyloxy)phenyl]pyrimidin-2(1H)-one (1.06 g, 2.46 mmol) in methanol (100 mL) was added hydrogen chloride in dioxane 4.0 N (1.0 mL) and then refluxed for 30 min. The solution was evaporated in vacuo to afford the title compound (0.83 g, 98%) as the di-hydrochloride salt. 1H NMR (400 MHz, d6-DMSO): 8.74 (s, 1H), 8.37 (s, 1H), 8.05 (d, 1H), 7.78 (t, 2H), 7.64 (t, 1H), 7.58 (s, 1H), 7.28 (d, 1H), 7.19 (t, 1H), 4.08 (t, 2H), 1.78 (m, 2H), 0.98 (t, 3H); MS (EI) for C20H18N4O2: 347 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][CH2:5]2.[C:15]([O:19][C:20](=[O:38])[NH:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:28]=1)([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O>[C:15]([O:19][C:20](=[O:38])[NH:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:2]2[CH:11]=[N:10][C:9]3[N:8]([C:12](=[O:13])[NH2:14])[CH2:7][CH2:6][CH2:5][C:4]=3[CH:3]=2)[CH:28]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: NC(=O)N1CCCc2cc(Br)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Temperature: 100 °C
Yield: 94.2 %

Procedure:
6-Bromo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (79 mg, 0.31 mmol), [5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester (205 mg, 0.61 mmol) and 2.0 M Na2CO3 aqueous solution (0.31 mL, 0.61 mmol) are dissolved in 2.0 mL of 1,4-dioxane. Argon gas is bubbled through the solution for 5 min. Then PdCl2dppf (16 mg, 0.021 mmol) is added. The mixture is heated at 100° C. for 2 hrs and the mixture is cooled down to room temperature. Then 30 mL of EtOAc and 20 mL of water are added and the organic layer is separated. The aqueous layer is extracted with EtOAc (2×20 mL). The organic layers are combined, dried and concentrated to give the crude product. Purification by flash column chromatography affords 112 mg of [5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[C@@H:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[O:19]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][N:13]1[C@H:11]1[CH2:12][NH:8][CH2:9][C@@H:10]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(Cc2ccccc2)C[C@@H]1N1CCCCC1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CNC[C@@H]1N1CCCCC1=O
Yield: 4705.3 %

Procedure:
To a solution of the product of Step 8 (2 g, 0.06 mmol) in MeOH was added excess ammonium formate and 10% Pd/C. The reaction mixture was heated under reflux overnight. After filtering, the solution was evaporated and residue was purified on silica gel (10% MeOH/chloroform) to obtain the title product (800 mg). 1H NMR (300 MHz, CDCl3) δ 5.25 (1H,s), 4.7 (1H, m), 3.45 (1H, m), 3.25 (1H, m), 3.04 (m) 2.9 (1H, m), 2.5 (6H, m), 1.80 (4H, m), 1.45 (9H, s). MS m/z 284 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH:31]3[CH2:33][CH2:32]3)=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH2:34]([OH:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[OH-].[K+].O>CS(C)=O>[CH2:34]([O:41][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH:31]3[CH2:33][CH2:32]3)=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: OCc1ccccc1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(Cl)ccn45)cccc32)n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCc6ccccc6)ccn45)cccc32)n1
Temperature: 90 °C
Yield: 94.6 %

Procedure:
A mixture of 7-chloro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (1.0 g, 2.2 mmol; prepared as in Example 65, step C), benzyl alcohol (1.2 g, 11 mmol) and potassium hydroxide (0.61 g, 11 mmol) was dissolved in DMSO (7 mL). The reaction mixture was heated at 90° C. for 20 hours. The mixture was cooled to ambient temperature, transferred into water (100 mL) with stirring, and the resulting solid was collected by vacuum filtration and dried under vacuum to give the product (1.1 g). MS (ES+APCI) m/z=529.7 (M+H).
Reaction SMILES: [CH3:1][CH:2]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([NH2:19])[CH:15]=[CH:14]2)[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].C([BH3-])#N.[CH:23](=O)[CH2:24][CH3:25]>CO.C(Cl)CCl>[CH2:23]([NH:19][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[C:9]([O:8][CH:2]([CH3:1])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:10]=[CH:11][CH:12]=2)[N:17]=1)[CH2:24][CH3:25]
Reactant: CC(CC(C)(C)C)Oc1cccc2ccc(N)nc12
Reactant: CCC=O
Agent: [BH3-]C#N
Solvent: ClCCCl
Solvent: CO
Product: CCCNc1ccc2cccc(OC(C)CC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 4 mL scintillation vial was added a stir bar and the title compound from Example 16 (15.0 mg, 0.058 mmol). To this was added 0.42 mL of a 1:1 MeOH/ClCH2CH2Cl mixture followed by MP-cyanoborohydride resin (84 mg, 3.7 equiv Argonaut Technologies, Inc.) and 40 μL (10 equiv) of propionaldehyde. The reaction vessel was placed in an oil bath that had been preheated to 80° C. and the contents were allowed to stir overnight. Upon cooling to room temperature, the suspension was filtered and the filtrate was evaporated in vacuo. The crude material was purified by reverse phase HPLC to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.06 (d, 1H), 7.30 (m, 1H), 7.17 (m, 2H), 6.90 (d, 1H), 4.54–4.81 (m, 1H), 3.38 (m, 2H), 2.38 (m, 1H), 1.80 (m, 1H), 1.50 (m, 2H), 1.39 (d, 3H), 1.03 (t, 3H), 0.96 (s, 9H); MS (DCI/NH3) m/z 301 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:10][OH:11])[CH2:13][CH:14]1[CH2:15][CH2:16]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclopropylpropanoic acid (2.5 g, 11 mmol) in tetrahydrofuran (30 mL) at 0° C. was added 1.0 M borane-THF complex in THF (32.4 mL). After addition, the reaction mixture was stirred at room temperature for 3 hours, then cooled down with an ice-bath, quenched by the slow addition of AcOH:MeOH (1:5, 20 mL) and the mixture was then warmed to room temperature for 2 hours. The THF volume was reduced by ½ and the product was partitioned between saturated aqueous NaHCO3 and DCM. The combined organic fractions were dried over Na2SO4 and concentrated under reduced pressure to give an oil residue, which was used directly in the next reaction without further purification. LC-MS found: 216.1 (M+H)+.