Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]CCCN1CCC(C2C=C(NC(=O)N(C)C)C=CC=2)CC1.NCCCN1CCC(C2C=C(NC(=O)OC(C)C)C=CC=2)CC1.NCCCN1CCC(C2C=C(NC(=O)OCC3C=CC=CC=3)C=CC=2)CC1.NC[CH2:75][CH2:76][N:77]1[CH2:82][CH2:81][CH:80]([C:83]2[CH:84]=[C:85]([NH:91][C:92](=[O:96])[CH:93]([CH3:95])[CH3:94])[CH:86]=[CH:87][C:88]=2OC)[CH2:79][CH2:78]1.NCCCN1CCC(C2C=C(NC(=O)CCC)C=CC=2OC)CC1.NCCCN1CCC(C2C=CC(O)=C(NC(=O)C(C)C)C=2)CC1>>[NH2:1][CH2:75][CH2:76][N:77]1[CH2:78][CH2:79][CH:80]([C:83]2[CH:84]=[C:85]([NH:91][C:92](=[O:96])[CH:93]([CH3:94])[CH3:95])[CH:86]=[CH:87][CH:88]=2)[CH2:81][CH2:82]1
Reactant: CN(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: COc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Agent: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1O
Agent: CC(C)OC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Agent: CCCC(=O)Nc1ccc(OC)c(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCN)CC2)c1

Procedure:
Using the methods described above, the following additional intermediates were synthesized. N′-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}-N,N-DIMETHYLUREA: 1H NMR (400 MHz, CD3OD) δ 7.36 (s, 1H), 7.32–7.25 (m, 1H), 7.21 (t, 1H, J=7.9 Hz), 6.92 (d, 1H, J=7 Hz), 3.33 (s, 6H), 3.17–3.07 (m, 2H), 2.75 (t, 2H, J=6,9), 2.58–2.44 (m, 3H), 2.14 (dt, 2H, J=11.8, 2.7 Hz), 1.93–1.67 (m, 8H). ISOPROPYL 3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYLCARBAMATE: 1H NMR (400 MHz, CDCl3) δ 7.20 (broad s, 1H), 7.16 (d, 1H, J=5.3 Hz), 7.08 (t, 1H, J=8.3 Hz), 6.80 (d, 1H, J=7.4 Hz), 4.89–4.79 (m, 1H), 3.21 (quintet, 1H, J=1.6 Hz), 3.03–2.95 (m, 2H), 2.61 (t, 2H, 6.8 Hz), 2.46–2.31 (m, 3H), 2.01 (dt, 2H, J=11.7, 2.8 Hz), 1.78–1.57 (m, 7H), 1.19 (d, 6H, J=6.2 Hz). BENZYL 3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYLCARBAMATE: 1H NMR (400 MHz, CDCl3) δ 7.60–7.30 (m, 9H), 7.08 (dt, 1H, J=7.5, 1.4 Hz), 5.34 (s, 2H), 4.09 (quintet, 1H, J=5.7 Hz), 3.30–3.10 (m, 4H), 2.65 (t, 2H, J=7.8 Hz), 2.28 (dt, 2H, J=12, 1.4 Hz), 2.07–1.85 (m, 7H). N-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-4-METHOXYPHENYL}-2-METHYLPROPANAMIDE: ESMS m/e: 334.6 (M+H)+. N-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-4-METHOXYPHENYL}BUTANAMIDE: 1H NMR (400 MHz, CD3OD) δ 7.46–7.57 (m, 1H), 6.97 (s, 1H), 6.77 (d, 1H, J=8.8 Hz), 3.88–3.80 (m, 2H), 3.78 (s, 3H), 3.12–2.74 (m, 4H), 2.46 (t, 2H, J=6.6 Hz), 2.39 (t, 2H, J=7.3 Hz), 2.07–1.94 (m, 2H), 1.87–1.44 (m, 9H), 1.02 (t, 3H, J=7.4 Hz). N-{5-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-2-HYDROXYPHENYL}-2-METHYLPROPANAMIDE: 1H NMR (400 MHz, CD3OD) δ 8.12–8.08 (m, 1H), 7.70–7.66 (m, 2H), 7.44 (d, 1H, J=2.2 Hz), 2.79–2.55 (m, 3H), 2.39–2.28 (m, 3H), 2.26 (d, 2H, J=11.6 Hz), 1.98 (dt, 2H, J=12, 2.5 Hz), 1.74–1.53 (m, 6H), 1.11 (d, 6H, J=6.8 Hz).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH3:9])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.[N:10]1([C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN(C=O)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>[CH3:1][CH:2]([CH2:8][CH3:9])/[CH:3]=[CH:4]/[C:5]([N:13]1[CH2:14][CH2:15][N:10]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([F:29])([F:27])[F:28])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:12]1)=[O:7]
Reactant: CCC(C)/C=C/C(=O)O
Reactant: FC(F)(F)c1ccc2c(N3CCNCC3)ccnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)/C=C/C(=O)N1CCN(c2ccnc3cc(C(F)(F)F)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4-Methylhex-2-enoic acid (26 mg, 0.2 mmol) was dissolved in DMF (0.5 ml) together with diisopropylethylamine (35 μl), HATU was added (76 mg, 0.2 mmol) and the mixture was stirred at room temperature for 15 minutes. 4-piperazin-1-yl-7-(trifluoromethyl)quinoline (56 mg, 0.2 mmol) was dissolved in DMF (0.5 ml) together with diisopropylethylamine (35 μl), the two solutions were combined and stirred at room temperature overnight. The mixture was evaporated to dryness under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 62.6 mg (0.16 mmol, 80%). MS (APCI) m/z=391.9 [M+1]+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH3:29][C:30](=[O:33])[C:31]#[CH:32]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:32]=[C:31]([C:30](=[O:33])[CH3:29])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C#CC(C)=O
Product: CC(=O)c1cn(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.125 mmol) and but-3-yn-2-one (0.125 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 50:50 as the eluent to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.C(OC([N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[B-](F)(F)F)=O)(C)(C)C.[K+].C(#N)C.O.C(=O)([O-])[O-].[K+].[K+].ClCCCl.FC(F)(F)C(O)=O>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.C(OCC)(=O)C>[NH:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1cccc1[B-](F)(F)F
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Nc1cc2ccc(-c3ccc[nH]3)cc2cn1)C1CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 15.7 %

Procedure:
To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (116.6 mg, 0.4005 mmol) and potassium (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)trifluoroborate (215 mg, 0.787 mmol) was added acetonitrile (3 mL, 60 mmol) and water (0.3 mL, 20 mmol). Potassium carbonate (173.6 mg, 1.256 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (13.4 mg, 0.0189 mmol) were added and the reaction was stirred in a sealed vial at 90° C. for two hours. The reaction mixture was then poured into ethyl acetate, which was washed with two portions water, dried with brine and MgSO4, filtered, and evaporated in vacuo. The resulting residue was dissolved in 1,2-dichloroethane (3 mL, 40 mmol), and trifluoroacetic acid (0.30 mL, 3.9 mmol) was added. The mixture was stirred at room temperature for 15 hours, and then trifluoroacetic acid (1.0 mL) was added and the mixture was stirred at 40° C. for 4 hours. The reaction mixture was evaporated in vacuo, dissolved in dichloromethane and washed once with saturated aqueous NaHCO3. The organic portion was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 17.4 mg (16%) of N-(7-(1H-pyrrol-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (Min)=4.073, M+H=278.0, method=E; 1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 10.81 (s, 1H), 9.02 (s, 1H), 8.39 (s, 1H), 8.17 (s, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 6.93 (s, 1H), 6.67 (s, 1H), 6.17 (s, 1H), 2.15-1.99 (m, 1H), 0.84 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=O.[NH2:13]OS(O)(=O)=O>O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[C:4]#[N:13]
Reactant: NOS(=O)(=O)O
Reactant: COc1cc(F)cc(F)c1C=O
Solvent: O
Product: COc1cc(F)cc(F)c1C#N
Temperature: 110 °C
Yield: 95 %

Procedure:
2,4-Difluoro-6-methoxybenzaldehyde (for a preparation see Intermediate 47) (34.5 g, 0.20 mol) and hydroxylamine-o-sulfonic acid (24.95 g, 0.22 mol) were charged to a round-bottom flask. Water (500 mL) was added and the suspension was heated at 110° C. for 3 h. After TLC shows reaction to be complete, it was cooled in ice-water and extracted thrice with ethyl acetate. The organic solutions were dried (MgSO4) and evaporated, and the residue was purified by dry flash chromatography (DCM eluent) to give the title compound (32.05 g, 95%) as a pale pink solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][CH3:15])=[C:9]([CH2:11][CH:12]=O)[CH:10]=1.Cl.NO.C([N:22](CC)CC)C.C1(=O)OC(=O)C2=CC=CC=C12>C(#N)C.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][CH3:15])=[C:9]([CH2:11][C:12]#[N:22])[CH:10]=1
Reactant: CCN(CC)CC
Reactant: CCc1ncc(CC(=O)OC)cc1CC=O
Agent: Cl
Agent: NO
Agent: O=C1OC(=O)c2ccccc21
Solvent: CC#N
Solvent: O
Product: CCc1ncc(CC(=O)OC)cc1CC#N
Temperature: 90 °C
Yield: 79.5 %

Procedure:
A solution of 6-ethyl-5-(2-oxo-ethyl)-pyridin-3-yl-acetic acid methyl ester (0.77 g, 3.46 mmol), hydroxylamine hydrochloride (0.26 g, 3.80 mmol) and triethylamine (0.53 mL, 3.80 mmol) in acetonitrile (9 mL, 0.4 M) is stirred under nitrogen at room temperature for 2 h. Phthalic anhydride (0.55 g, 3.71 mmol) is added and the mixture is warmed to 90° C. for 16 h. After cooling to room temperature, water (50 mL) is added and the mixture is extracted with ethyl acetate (50 mL). The organic layer is washed with saturated NaHCO3 (50 mL) and dried over Na2SO4. The product is purified by flash chromatography (20-50% ethyl acetate in n-heptane) to provide 5-cyanomethyl-6-ethyl-pyridin-3-yl-acetic acid methyl ester as a clear oil (0.60 g, 80%): Rf 0.31 (50% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.44 (s, 1 H), 7.67 (s, 1 H), 3.74 (s, 2 H), 3.73 (s, 3 H), 3.65 (s, 2 H), 2.83 (q, J=7.5 Hz, 2 H), 1.33 (t, J=7.5 Hz, 3 H). ESI-LCMS m/z calcd for C12H14N2O2: 218.1; found 219.0 (M+1)+.
Reaction SMILES: [ClH:1].FC1C=CC=C(F)C=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4C=NC=CC=4)=[CH:23][C:16]=23)=[C:10]([F:30])[CH:9]=1)=[O:6].Cl.FC1C=C([CH:64]([C:68]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=2)=[O:69])C(N)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:1].[F:30][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:64][C:68]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=2)=[O:69])[CH:13]=[CH:12][C:11]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:21][C:22]([CH3:24])=[CH:23][C:16]=12
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1)c1c(F)cccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)ccnc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a mixture of 3-fluoro-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzenamine (20 mg, 0.078 mmol, Compound E of Example 292), 3-(4-fluorophenylamino)-3-oxopropanoic acid (20 mg, 1 mmol, Compound A of Example 25), and HATU (44 mg, 0.12 mmol) in DMF (0.5 mL) was added DIPEA (0.1 mL). The reaction mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was purified by preparative HPLC to give the desired product (HCl salt, 12.5 mg, 34%) as a white solid. 1H NMR (CD3OD) δ 8.05 (d, 1H, J=7.2 Hz), 7.79 (dd, 1H, J=12.7, 2.8 Hz), 7.50–7.53 (m, 2H), 7.27–7.36 (m, 2H), 6.97 (m, 2H), 6.70 (d, 1H, J=6.6 Hz), 6.20 (s, 1H), 3.47 (s, 2H), 2.40 (s, 3H); LC/MS(ESI+) m/z 437 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:14]([Br:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)=[O:5].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)Cl>[Br:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:3]2[C:2]=1[NH:1][C:17](=[O:19])[N:6]([CH:7]1[CH2:8][CH2:9][CH2:10]1)[C:4]2=[O:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(Br)cccc1C(=O)NC1CCC1
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CCC1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 326.4 %

Procedure:
A mixture of 2-amino-3-bromo-N-cyclobutylbenzamide (2.127 g, 7.90 mmol) and triphosgene (0.797 g, 2.69 mmol) in DCM (80 mL) was heated at reflux (using a water-cooled reflux condenser) for 17 h. The reaction mixture was then concentrated in vacuo, and the residue was taken up in toluene (80 mL) and heated at 110° C. for 1.5 h. Additional triphosgene (0.040 g, 014 mmol) was added, and the resulting solution was stirred at 110° C. for 45 min. The reaction mixture was then cooled to RT and concentrated in vacuo to give crude 8-bromo-3-cyclobutylquinazoline-2,4(1H,3H)-dione (2.59 g, 8.78 mmol) as a light-yellow solid. m/z (ESI, +ve) 295.0/297.0 (M+H)+. This material was used directly in the subsequent transformation.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Se]Cl)C=CC=CC=1.O>C(OCC)(=O)C>[CH2:1]([CH:8]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCC(Cc2ccccc2)CCC1
Agent: Cl[Se]c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C=CCC(Cc2ccccc2)CCC1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
1.2 g of 5-benzyl-1-cyclooctanone prepared in Example 1 was dissolved in 50 ml of ethyl acetate. To the solution was added 1.25 g of phenylselenenylchloride. The reaction solution was stirred at room temperature for forty minutes. To the reaction solution was added 10 ml of water, followed by stirring for three minutes. The organic layer was separated. To the organic layer were added 20 ml of tetrahydrofliran and 1.4 ml of 30% hydrogen peroxide. The reaction solution was stirred at room temperature for two and a half hours. Then, the organic layer was washed with water and a saturated sodium bicarbonate aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated. The crude product was subject to column chromatography on silica gel, and the eluate with ethyl acetate-hexane (1:10) was collected, to afford 0.71 g of the titled compound as colorless liquid.
Reaction SMILES: [O-]S([O-])(=O)=O.[Ca+2].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:14]([O-])([OH:16])=[O:15].[N+](C1C=CC=CC=1)([O-])=O>C(Cl)(Cl)Cl>[N+:14]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH3:13])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A 100g portion of soluble anhydrite was added to a solution of 32.9g toluene in 100 ml chloroform. Then a 22.6g portion of anhydrous nitric acid was added to the dispersion over a 30-minute period. Stirring at 25°C was continued for an additional 2 1/2 hour period. Nitrobenzene was added before the last half hour period and was used as the internal standard. Gas chromatographic analysis showed a 93.2% yield of nitrotoluene with the proportion being 49.1% ortho, 2.1% meta, and 48.8% para.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:4]=1.[BH4-].[Na+].CCOC(C)=O.C1CCCCC1>CO.C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[N:4]=1
Reactant: COc1ccc(CCNc2cc(-c3ccc(C=O)s3)nc(OC)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCCCC1
Product: COc1ccc(CCNc2cc(-c3ccc(CO)s3)nc(OC)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
A mixture of 5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carbaldehyde [200 mg, 0.54 mmol, Example 8(b)] in MeOH (5 mL) and THF (5 mL) at 0° C. is treated with sodium borohydride (41 mg, 1.08 mmol). The mixture is stirred at ambient temperature for 1 hour and concentrated by rotary evaporator to remove the solvent. The residual solid is dissolved in water and the solution is extracted with ethyl acetate. The organic extract is dried over magnesium sulfate, filtered and concentrated to afford a solid which is subjected to flash column chromatography on silica gel eluting with a mixture of EtOAc and cyclohexane) to afford (5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-methanol [75 mg, 37%, Example 9(a)] as a solid. LCMS: RT=6.09 minutes; MS: 372 (M+H). IC50=0.55 nM
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[O:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:24]([CH3:28])[N:25]=[C:26]([CH3:27])[C:3]=12.[NH:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]1>O1CCCC1>[CH3:28][N:24]1[C:4]2=[N:5][CH:6]=[C:7]([C:8](=[O:9])[NH:10][C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[CH:15]=3)=[O:12])[C:2]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]3)=[C:3]2[C:26]([CH3:27])=[N:25]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1nn(C)c2ncc(C(=O)NC(=O)Nc3cccc(OC(C)C)c3)c(Cl)c12
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2c(C(=O)NC(=O)Nc3cccc(OC(C)C)c3)cnc3c2c(C)nn3C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(4-Chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl )-N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carboxamide (40 mg) was dissolved in tetrahydrofuran (5.0 mL), ethyl piperidine-4-carboxylate (160 mg) was added, and the mixture was stirred at room temperature for 5 hrs. The solvent was evaporated under reduced pressure, the residue was suspended in water (10 mL), the resulting solid was filtered, washed with water, and dried under high vacuum to give ethyl 1-{1,3-dimethyl-5-[N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carbamoyl]pyrazolo[5,4-b]pyridin-4-yl}piperidine-4-carboxylate as a white powder.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH:12]([OH:46])[CH2:13][N:14]1[C:22](=[O:23])[C:21]2[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:19]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]([F:43])([F:42])[F:41])[CH:34]=3)=[N:18][C:17]=2[N:16]([CH3:44])[C:15]1=[O:45])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].I[CH3:48]>C1COCC1>[Si:3]([O:10][CH2:11][CH:12]([O:46][CH3:48])[CH2:13][N:14]1[C:22](=[O:23])[C:21]2[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[C:19]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]([F:41])([F:43])[F:42])[CH:34]=3)=[N:18][C:17]=2[N:16]([CH3:44])[C:15]1=[O:45])([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: CI
Reactant: Cn1c(=O)n(CC(O)CO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CO[Si](C)(C)C(C)(C)C)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 118 %

Procedure:
To a slurry of sodium hydride (240 mg, 9.6 mmol) in anhydrous THF (10 ml) was added dropwise a solution of 1-(3-(tert-butyldimethylsilyloxy)-2-hydroxypropyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (124 mg, 0.19 mmol) in THF (3 mL) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 10 minutes. Then iodomethane (1.2 ml, 19.4 mmol) was added dropwise and the resulting mixture was allowed to warm from 0° C. to room temperature over 2 h. The mixture was quenched with ice-water (5 mL). The mixture was concentrated, diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was dried over sodium sulfate, filtered and concentrated to give crude product (150 mg, 100% yield) as yellow oil. LCMS MH+ 669.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH:8]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[C:9]#[N:10]>C1COCC1>[NH2:10][CH2:9][CH:8]([CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:15][CH2:16]1)[OH:7]
Reactant: N#CC(O)C1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)C1CCN(Cc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of LiAlH4 (1.1 g, 28.7 mmol) in THF (25 mL) at 0° C. was added dropwise via addition funnel a solution of hydroxy[1-(phenylmethyl)-4-piperidinyl]acetonitrile (2.2 g, 9.56 mmol) in THF (25 mL). After 12 h at 25° C., the solution was carefully quenched by dropwise additional of sodium potassium tartrate and extracted several times with DCM. The combined organic fractions were dried (Na2SO4) and concentrated yielding the title compound as a yellow oil which was used without further purification: LCMS (ES) m/e 235 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=2)[CH:7]=1.[N:19]1([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[F:18][C:5]1[CH:4]=[CH:3][C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:25]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[O:26])[CH2:24][CH2:23]2)=[CH:7][C:6]=1[C:8]1[N:12]([CH3:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]=1
Reactant: O=C(N1CCCC1)N1CCNCC1
Reactant: Cn1c(-c2cc(Br)ccc2F)nc2ccccc21
Product: Cn1c(-c2cc(N3CCN(C(=O)N4CCCC4)CC3)ccc2F)nc2ccccc21
Yield: 44 %

Procedure:
The same procedure described in step c method J was followed but starting from 2-(5-bromo-2-fluoro-phenyl)-1-methyl-1H-benzoimidazole and piperazin-1-yl-pyrrolidin-1-yl-methanone. The crude reaction mixture was purified by preparative HPLC to afford 0.06 g of the title compound (44%).
Reaction SMILES: [Li+].[Cl-:2].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2([CH3:16])[O:15][CH:10]2[C:11]([O:13][CH3:14])=[O:12])[CH:4]=1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:2][C:9]([C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)([CH3:16])[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C1OC1(C)c1cccnc1
Reactant: [Cl-]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(O)C(C)(Cl)c1cccnc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
0.8 g (20 mmol) of LiCl is dissolved in 100 ml of absolute tetrahydrofuran (THF), the solution is cooled to -20° C., and 20 ml of titanium tetrachloride (1M in dichloromethane) are added dropwise. After the mixture has been stirred for 30 minutes at -20° C., it is cooled to -78° C., and 3.8 g (20 mmol) of methyl 3-(3-pyridyl)-2,3-epoxybutyrate in 50 ml of THF are added dropwise. After the mixture has warmed to room temperature, stirring is continued for 6 hours, the solvent is distilled off, and the residue partitioned between ethyl acetate and water.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]4)[CH2:10][CH2:9][O:8][C:5]3=[CH:6][CH:7]=2)[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: NC1=N[C@@]2(CCOc3ccc(Br)cc32)C(F)(F)COC1
Product: NC1=N[C@@]2(CCOc3ccc(-c4cc(Cl)cc(Cl)c4)cc32)C(F)(F)COC1
Yield: 40 %

Procedure:
The cross coupling reaction of (R)-6-bromo-6′,6′-difluoro-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepin]-3′-amine (intermediate C3.2) with 3,5-dichlorophenylboronic acid yielded the title compound (40% yield) as a light brown foam. MS (ISP): m/z=413.2 [M+H]+ and 415.2 [M+2+H]+.