Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([CH:12]=[O:13])=[CH:10][N:11]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([Si](C)(C)C)([F:23])[F:22]>CN(C)C=O>[F:20][C:21]([F:23])([F:22])[CH:12]([C:9]1[S:8][C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:11][CH:10]=1)[OH:13]
Reactant: O=Cc1cnc(N2CCOCC2)s1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1cnc(N2CCOCC2)s1)C(F)(F)F
Yield: 65.1 %

Procedure:
According to Reference Example 8-2, by use of 2-morpholinothiazole-5-carbaldehyde (177 mg, 0.893 mmol) dissolved in N,N-dimethylformamide (5.3 mL), potassium carbonate (25 mg, 0.18 mmol) and (trifluoromethyl)trimethylsilane (0.198 mL, 1.34 mmol), the mixture was stirred and reacted at room temperature for 2.3 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give 2,2,2-trifluoro-1-(2-morpholinothiazol-5-yl)ethanol (Compound DY) (156 mg, yield: 65%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]#[N:16])=[CH:7][N:8]2[CH:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(OB(OC(C)C)OC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[C:38]([O:42][C:43](=[O:52])[NH:44][C:45]1[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=1)([CH3:41])([CH3:40])[CH3:39].C([O-])([O-])=O.[K+].[K+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[C:38]([O:42][C:43](=[O:52])[NH:44][C:45]1[CH:46]=[CH:47][C:48]([C:7]2[N:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[C:9]3[C:5]([C:6]=2[C:15]#[N:16])=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=3)=[CH:49][CH:50]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: N#Cc1cn(C2CCC2)c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(Br)cc3n2C2CCC2)cc1
Temperature: -78 °C
Yield: 52.7 %

Procedure:
To a solution of 6-bromo-1-cyclobutyl-1H-indole-3-carbonitrile (1.38 g, 5.0 mmol), and triisopropylborate (1.37 mL, 6.0 mmol) in THF (15.0 mL) at −78° C. was added LDA (1.5M mono THF in cyclohexane, 3.83 mL, 5.75 mmol) with stirring. The mixture was stirred at −78° C. for 10 min and at room temperature for 30 min followed by addition of (4-iodophenyl)-carbamic acid tert-butyl ester (1.75 g, 5.5 mmol) and PdCl2(dppf) (0.37 g, 0.5 mmol). The reaction mixture was cooled to −78° C., flushed with nitrogen and DMF (30 mL) and aq. K2CO3 (2.0M, 7.5 mL, 15.0 mmol) added. The mixture was stirred at −78° C. for 20 min, room temperature overnight and poured into ice water (200 mL). The precipitate was filtered, washed with water and purified on silica gel (hexanes/EtOAc, 9:1 to 8:2) to give [4-(6-bromo-3-cyano-1-cyclobutyl-1H-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester as a solid (1.23 g, 53%).
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:7]#[N:8])=[CH:5][CH:6]=1.[CH3:9][C:10]1([CH3:24])[C:15]2[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:14]=2[NH:13][C:12](=[O:23])[O:11]1>>[CH3:9][C:10]1([CH3:24])[O:11][C:12](=[O:23])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:2]3[O:3][C:4]([C:7]#[N:8])=[CH:5][CH:6]=3)=[CH:16][C:15]1=2
Reactant: N#Cc1ccc(Br)o1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)o3)cc21

Procedure:
The title compound was prepared according to the procedure B from 2-bromo-5-cyanofuran (1.0 g, 5.6 mmol) (J. Med. Chem. (1997), 40(23), 3804-3819) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (1.8 g, 8.18 mmol) as a white solid (0.39 g, 1.45 mmol, 17%): mp. 257-260° C.; 1H-NMR (DMSO-d6) □10.48 (s, 1H), 7.73-7.70 (m, 3H), 7.19 (d, 1H, J=3.8 Hz), 6.98 (d, 1H, J=8.9 Hz), 1.66 (s, 6H); MS ((+)−APCI) m/z=269 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([O:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Li+]>CO.O>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][C:24]([O:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:25][CH:26]=2)=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(NC/C=C/c2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(Cc1ccc(NC/C=C/c2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O

Procedure:
The title compound was synthesized by hydrolyzing ethyl 2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino]-phenyl}propionate obtained in example 11 (140 mg, 0.313 mmol) in methanol-water (2:1, 6 mL) using lithium hydroxide (17 mg, 0.407 mmol) following the same procedure as described in the Example 14 (40 mg, 30.5%).
Reaction SMILES: [CH2:1]([CH2:15][C:16]([NH:18][CH2:19][CH:20](O)[CH2:21][O:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[S:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:67]I.S(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[I:67][CH:20]([CH2:19][NH:18][C:16](=[S:17])[CH2:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:21][O:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: II
Reactant: CCCCCCCCCCCCCCCC(=S)NCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCC(=S)NCC(I)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 21 %

Procedure:
3-tetradecylthioacetylamino-1-triphenylmethyloxypropan-2-ol (example 20a) (2 g, 3.31 mmol) was dissolved in toluene (100 ml). Imidazole (0.564 g, 8.28 mmol), triphenylphosphine (2.171 g, 8.28 mmol) and iodine (1.681 g, 6.62 mmol) were then added in that order. The reaction medium was stirred at room temperature for 20 hours. A saturated sodium bisulfite solution was added until complete blanching of the reaction medium. The phases were separated and the aqueous phase was extracted with toluene. The organic phases were combined, washed with saturated sodium chloride solution, dried on magnesium sulfate and filtered. The residue obtained after evaporation of the solvent (4.65 g) was purified by chromatography on silica gel (eluent: dichiromethane) to give the desired compound in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[OH:22])=[N:12][NH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][C@H:31]1[C:36](O)=[O:37])=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N=C=NC(C)C)(C)C.O[Li].O.C(O)(=O)C>ClCCl.O.C(OCC)(=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][C@H:31]1[C:36](=[O:37])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[OH:22])=[N:12][NH:13][CH:14]=2)=[CH:4][CH:3]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)O
Reactant: Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1
Agent: CC(C)N=C=NC(C)C
Agent: [Li]O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of compound 24A (930 mg, 3.0 mmol) and (S)-morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (19A, 2.09 g, 9.0 mmol) in anhydrous dichloromethane (20 mL) was added N,N′-diisopropylcarbodiimide (DIPC, 1.4 mL, 9.0 mmol). The reaction mixture was stirred at rt overnight. Solvent was removed. To the residua were added THF (20 mL) and methanol (20 mL) and a solution of LiOH.H2O (1.0 g, 23.84 mmol) in water (10 mL). The mixture was stirred at rt for 2 h. It was then neutralized with acetic acid (1.36 mL, 23.84 mmol). The mixture was diluted with ethyl acetate (˜100 mL), washed with brine, and dried over sodium sulfate. It was filtered, concentrated and filtered again to remove diisopropylurea. The filtrate was purified with silica column chromatography eluting with dichloromethane/ethyl acetate (v/v 5/1, 3/1, 2/1, 1/1) to provide the title compound (28A, 1.12 g) as a yellowish solid in 71.3% yield. LCMS (ESI) m/z 587.15 (MNa+), 521.05 (MH+), 421.06; HPLC: tR=5.32 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1)(=[O:4])=[O:3].[H][H]>CO.[Pd]>[F:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][C:7]=1[NH2:12]
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(F)c(N)c1
Yield: 80.4 %

Procedure:
A mixture of 4-fluoro-3-nitrophenyl methyl sulfone (ABCR; 1.50 g; 6.84 mmol) and 10% Pd/C (100 mg) in MeOH (30 ml) was placed in a PARR reactor and treated with a pressure of 15 atm of hydrogen for 2 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated to dryness affording the title compound (1.04 g, 80%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:15]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][N:12]3S(C)(=O)=O)=[CH:8][C:7]=2[CH2:6]1)[CH3:3].N.[Na]>O1CCCC1>[CH3:3][N:2]([CH2:4][C:5]1([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:15]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][NH:12]3)=[CH:8][C:7]=2[CH2:6]1)[CH3:1]
Reactant: CN(C)CC1(C2(O)CCCCC2)Cc2cc3c(cc21)N(S(C)(=O)=O)CC3
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: CN(C)CC1(C2(O)CCCCC2)Cc2cc3c(cc21)NCC3
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
3.75 g of the product obtained in Step 4 in 100 ml of tetrahydrofuran are added dropwise to 400 ml of liquid ammonia cooled to −50° C. 0.56 g of sodium are added in portions, and stirring is carried out for 15 minutes. The reaction is terminated by the addition of 2.65 g of ammonium chloride. The whole is allowed to return to ambient temperature to evaporate the ammonia, and is then taken up in water and extracted with ether. Drying, evaporation and recrystallisation from acetonitrile are carried out to yield the expected product.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:36][C:37]1[CH:38]=[CH:39][C:40]([Cl:44])=[C:41]([Pb+3])[CH:42]=1>ClCCl.Cl>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:44])=[C:39]([CH:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]2=[O:9])[CH:38]=1
Reactant: Clc1ccc(Br)cc1[Pb+3]
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(Br)ccc2Cl)C1=O
Temperature: 80 °C
Yield: 7.5 %

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (2.78 g, 16.3 mmol) and N,N-dimethylaminopyridine (9.97 g, 81.6 mmol) is added anhydrous chloroform (120 ml). To this solution is added anhydrous toluene (30 ml), followed by 5-bromo-2-chlorophenyllead triacetate (10.32 g, 18 mmol) in one portion and the reaction mixture is heated at 80° C. overnight. The mixture is allowed to cool to room temperature, then diluted with dichloromethane (120 ml) and 2M aqueous hydrochloric acid (250 ml), followed by filtration through diatomaceous earth to remove inorganic residues. The filter cake is washed with dichloromethane, and all organic fractions are combined, washed with 2M hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate then concentrated in vacuo. This material is finally purified by flash column chromatography on silica gel to afford 4-(5-bromo-2-chlorophenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.44 g) of sufficient purity to use directly in the next step.
Reaction SMILES: [OH-].[Na+].O[CH2:4][C:5]1[C:6]([CH2:11][OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=1>>[CH2:11]1[O:12][CH2:4][C:5]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: OCc1ccccc1CO
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(c1)COC2
Yield: 96 %

Procedure:
The procedure of Example 15 was performed except that the pH of the reaction mixture was regulated to 12 by use of sodium hydroxide. The reaction mixture was sampled for analysis. Formation of α,α′-dihydroxy-o-xylene was not observed. Instead, phthalan was formed at a yield of 96% based on α,α′-dichloro-o-xylene.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11]C3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=[CH:4][C:3]=2[O:2]1.Cl[C:28]1[N:33]=[C:32]([NH:34][CH:35]([C:42]([O:44][CH3:45])=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:31]([C:46]#[N:47])=[CH:30][N:29]=1.C1COC2C=CC(N)=CC=2O1>>[C:46]([C:31]1[C:32]([NH:34][CH:35]([C:42]([O:44][CH3:45])=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][C:28]([NH:11][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][CH2:1][O:2][C:3]=3[CH:4]=2)=[N:29][CH:30]=1)#[N:47]
Reactant: COC(=O)C(Nc1nc(Cl)ncc1C#N)c1ccccc1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Nc1ccc2c(c1)OCCO2
Product: COC(=O)C(Nc1nc(Nc2ccc3c(c2)OCCO3)ncc1C#N)c1ccccc1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-cyano-N4-(methoxycarbonylbenzyl)-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield 5-cyano-N2-(3,4-ethylenedioxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.23 (s, 1H), 7.41-7.32 (m, 5H), 7.01 (d, 1H, J=3.0 Hz), 6.86-6.71 (m, 3H), 6.54 (bs, 1H), 5.48 (d, 1H, J=6.3 Hz), 4.31 (bs, 4H), 3.68 (s, 3H); LCMS: ret. time: 25.53 min.; purity: 97%; MS (m/e): 418 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]>C1(C)C=CC=CC=1>[CH2:1]([C@H:3]1[CH2:12][NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)[CH3:2]
Reactant: CCc1cnc2ccccc2n1
Solvent: Cc1ccccc1
Product: CC[C@H]1CNc2ccccc2N1
Temperature: 40 °C
Reaction time: 25 h
Yield: 95.8 %

Procedure:
To an argon-purged pressure-resistant glass vessel (100 mL) equipped with a magnetic stir bar, RuCl[(R)-daipena][(R)-dm-segphos] (2.0 mg, 1.7 μmol) and KO(t-Bu) (9.2 mg, 0.082 mmol) were added, and the vessel was purged with argon again. To this vessel, a toluene (1.7 mL) solution containing 2-ethylquinoxaline (269.4 mg, 1.70 mmol) and being degassed by the freeze-pump-thaw technique in advance was added by pressure transfer using a cannula. An operation in which hydrogen was introduced into the pressure-resistant vessel up to 0.8 MPa and then released was repeated 10 times to completely substitute the inside with hydrogen. Then, hydrogen was introduced up to 2.0 MPa, and the vessel was stirred in a water bath at 40° C. for 25 hours. After hydrogen was released, the solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1 to 3:1 to 1:1) to obtain (S)-2-ethyl-1,2,3,4-tetrahydroquinoxaline (264.3 mg, 96%). A result of an analysis conducted by high performance liquid chromatography (column: CHIRALCEL OD-H, mobile phase: hexane:IPA=90:10, 1 mL/min) showed that the optical purity of this product was 99% ee or higher.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH3:19])[CH2:10]1)C1C=CC=CC=1>CCO>[NH2:8][CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH3:19])[CH2:10]1
Reactant: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C
Solvent: CCO
Product: CCOC(=O)C1CC(N)CC1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a vessel containing a slurry of 20% wet Pd(OH)2—C (5.00 g, 35.6 mmol) in EtOH (355 mL) was added ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (50.0 g, 142 mmol). The reaction was shaken for about 60 min at about 50° C. under about 30 psi of H2. The resulting mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure to give ethyl 4-amino-2-methylcyclopentanecarboxylate (23.5 g, 96%) as a yellow oil: 1H NMR (CDCl3) δ 4.24-4.02 (m, 2H), 3.41-3.27 (m, 1H), 2.81 (dd, J=7.6, 15.4 Hz, 1H), 2.36-2.20 (m, 1H), 2.21-2.02 (m, 4H), 1.81-1.69 (m, 1H), 1.33-1.15 (m, 4H), 0.98 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[N:16][C:17]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25](C3CCCCO3)[N:24]=[CH:23]4)=[CH:18][C:4]=2[N:3]1[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38].Cl.ClCCl>O1CCOCC1>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([NH:19][C:17]3[N:16]=[CH:15][C:5]4[N:6]([C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=5)[C:7](=[O:8])[CH:2]([CH3:1])[N:3]([CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])[C:4]=4[CH:18]=3)=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: CC(C)CCN1c2cc(Nc3ccc4c(cnn4C4CCCCO4)c3)ncc2N(c2ccccc2)C(=O)C1C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)CCN1c2cc(Nc3ccc4[nH]ncc4c3)ncc2N(c2ccccc2)C(=O)C1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a stirred solution of 2-methyl-1-(3-methylbutyl)-4-phenyl-7-{[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]amino}-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one (15 mg) in dioxane (2 mL) was added 2N aq. HCl (2 mL) at rt. The resulting mixture was stirred at rt for 2 h. LC-MS indicated completion of reaction. Dichloromethane (30 mL) was added to the reaction mixture, the organic phase was washed with aq. NaHCO3, dried over anhydrous sodium sulfate, and evaporated to give a residue, which was purified by preparative Thin-Layer Chromatography (developing solvent: 2% methanol in dichloromethane) to give the desired product (yield: 60%) 1H NMR (400 MHz, CD3OD) b 0.88 (d, J=6.4 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H), 1.41 (d, J=6.82 Hz, 3H), 1.55-1.65 (m, 3H), 3.18-3.28 (m, 1H), 3.39-3.49 (m, 1H), 4.26 (q, J=6.74 Hz, 1H), 6.10 (s, 1H), 6.79 (s, 1H), 7.27-7.34 (m, 3H), 7.49-7.55 (m, 2H), 7.56-7.62 (m, 2H), 7.75 (d, J=1.52 Hz, 1H), 7.97 (s, 1H). MS(ES+): m/z 441.19 [MH+]. HPLC: tR=2.55 (ZQ3, Polar_5 min).
Reaction SMILES: O[CH:2]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[O:27][C@H:26]([CH3:33])[CH2:25]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C@H:5]1[CH2:20]O.S(Cl)(Cl)=O.[CH2:38]([NH2:41])[CH:39]=[CH2:40].[I-].[Na+]>C(OCC)(=O)C>[CH2:38]([N:41]1[CH:2]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[O:27][C@H:26]([CH3:33])[CH2:25]3)[CH2:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][C@H:5]2[CH2:20]1)[CH:39]=[CH2:40]
Reactant: C=CCN
Reactant: C[C@@H]1Cc2cc(C(O)CN3CCN(C(=O)OCc4ccccc4)C[C@H]3CO)ccc2C(=O)O1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: C=CCN1C[C@@H]2CN(C(=O)OCc3ccccc3)CCN2CC1c1ccc2c(c1)C[C@@H](C)OC2=O
Temperature: 90 °C

Procedure:
A solution of (3S)-benzyl 4-(2-hydroxy-2-((R)-3-methyl-1-oxoisochroman-6-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (2.07 g, 4.55 mmol) in thionyl chloride (30.0 mL, 411 mmol) was heated at reflux for 1 h. After removing the volatiles, the residue was dissolved in N,N-dimethylformamide (20 mL) and treated with allylamine (1.879 mL, 25.05 mmol) at 0° C. The resulting solution was treated with sodium iodide (0.0680 g, 0.455 mmol) and heated at 90° C. for 1 h. The solution was diluted in ethyl acetate (300 mL) and was washed with saturated sodium bicarbonate three times, dried over sodium sulphate concentrated and the residue was purified on Biotage using 40-100% ethyl acetate/hexane to give the title compound: LC/MS: (M+1)+: 476.14.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:15]2[CH:16](O)[CH2:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH2:20][C:14]=2[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl-].[Li+].C1CCN2C(=NCCC2)CC1>C(#N)C.O>[C:4]([Si:1]([O:8][CH2:9][C:10]1[C:15]2[CH:16]=[CH:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH2:20][C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:3])[CH3:2])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC1(C)CCC(O)c2c(CO[Si](C)(C)C(C)(C)C)cccc2C1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CC=Cc2c(CO[Si](C)(C)C(C)(C)C)cccc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[[[tert-butyl(dimethyl)silyl]oxy]methyl]-8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol (28.90 g, 86.38 mmol), triethylamine (24.1 ml, 173 mmol) and 4-N,N-dimethylaminopyridine (1.06 g, 8.64 mmol) in acetonitrile (100 ml) was dropwise added a solution of methanesulfonyl chloride (14.8 g, 130 mmol) in acetonitrile (10 ml) under ice-cooling. Lithium chloride (5.49 g, 130 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hrs. The reaction solution was poured into water and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (100 ml), and 1,8-diazabicyclo[5.4.0]-7-undecene (25.8 ml, 173 mmol) was added. The mixture was stirred at 80° C. overnight. The reaction solution was-poured into water and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give the objective substance.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[H-].[Na+].I[CH3:17]>CN(C=O)C>[Br:1][C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:17]
Reactant: CC(C)c1ccc2[nH]ncc2c1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc2c(cnn2C)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A solution of 4-bromo-5-isopropylindazole (27) (488 mg, 2.04 mmol) in 5 ml of anhydrous DMF is added to a suspension of sodium hydride (122 mg, 60% in mineral oil, 3.06 mmol, 1.5 eq.) in 5 ml of DMF under nitrogen at 0° C. The resulting mixture is stirred at 0° C. for 30 minutes, then warmed to room temperature. After stirring at room temperature for an additional 2 hours, the reaction mixture is cooled to 0° C., and iodomethane (318 mg, 2.24 mmol, 1.1 eq.) is added dropwise, the mixture is stirred at 0° C. for 2 hours, then warmed to room temperature, and stirred overnight. The reaction mixture is poured into 30 ml of ice-water, extracted with ethyl acetate (30 ml×3), washed with water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated and the product is purified via flash chromatography to give 340 mg of 4-bromo-5-isopropyl-1-methylindazole 1H NMR (400 MHz, CDCl3) 7.95 (1H, s), 7.31 (2H, S), 4.05 (3H, S), 3.55 (1H, m), 1.27 (6H, d, J=6.8 Hz). MS (+VE) m/z 253 (M+). 165 mg of 4-bromo-5-isopropyl-2-methylindazole (28). 1H NMR (400 MHz, CDCl3) δ 7.82 (1H, s), 7.59 (1H, d, J=9.2 Hz), 7.21 (1H, d, J=8.8 Hz), 4.16 (3H, s), 3.50 (1H, m), 1.21 (6H, d, J=6.8 Hz). MS (+VE) m/z 253 (M+).