Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.I[C:70]1[C:75]([CH3:76])=[CH:74][CH:73]=[CH:72][C:71]=1[C:77]1[N:81]2[CH:82]=[CH:83][CH:84]=[CH:85][C:80]2=[CH:79][N:78]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:79]1[N:78]=[C:77]([C:71]2[CH:72]=[CH:73][CH:74]=[C:75]([CH3:76])[C:70]=2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH2:26])[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16]3)[N:81]2[CH:82]=[CH:83][CH:84]=[CH:85][C:80]=12
Reactant: Cc1cccc(-c2ncc3ccccn23)c1I
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cccc(-c2ncc3ccccn23)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.236 g, 0.664 mmol, prepared as in Example 2, Step 1-2), potassium phosphate (0.564 g, 2.66 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.063 g, 0.133 mmol), Pd2(dba)3 (0.030 g, 0.033 mmol), and 3-(2-iodo-3-methylphenyl)imidazo[1,5-a]pyridine (0.222 g, 0.664 mmol). The vessel was evacuated and flushed with nitrogen three times before dioxane (4.43 mL) and water (2.215 mL) (each degassed by bubbling nitrogen gas through the solution for 10 min prior to addition) were added. The reaction mixture was stirred and heated in a microwave reactor at 140° C. for 15 min. The reaction mixture was diluted with 10:1 saturated ammonium chloride/ammonium hydroxide and extracted with EtOAc. The combined organic extracts were washed with 10:1 saturated ammonium chloride/ammonium hydroxide, water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:20 2M NH3 in MeOH/DCM. The fractions containing the product (with some impurities) were combined and concentrated. The solid was dissolved in MeOH and filtered to remove some of the impurity. The remainder of the sample was purified by reverse-phase preparative HPLC with 0.1% TFA in CH3CN/H2O, gradient 5-70% over 20 min to provide 6-(2-(imidazo[1,5-a]pyridin-3-yl)-6-methylphenyl)-3-morpholinoquinolin-2-amine. The purified compound was partitioned between DCM and saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give 6-(2-(imidazo[1,5-a]pyridin-3-yl)-6-methylphenyl)-3-morpholinoquinolin-2-amine as a white solid. MS (ESI, pos. ion) m/z: 436 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)=O.[C:24]([O:31][CH3:32])(=[O:30])[CH2:25][CH2:26][C:27]([CH3:29])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:32][O:31][C:24](=[O:30])[CH2:25][C:26]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:27]=1[CH3:29]
Reactant: COC(=O)CCC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1ccc(OC(F)(F)F)cc1)CCCC2
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(OC(F)(F)F)cc1)CCCC3
Yield: 78.1 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-trifluoromethoxyphenyl)methanone (0.341 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.340 g (78%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:39]1([CH2:45][CH2:46][CH2:47][C:48](Cl)=[O:49])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CO>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:48](=[O:49])[CH2:47][CH2:46][CH2:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)CCCc1ccccc1)CC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (10 mg, 0.023 mmol) in CH2Cl2 (5 mL) was added Et3N (0.020 mL, 0.140 mmol) and the resulting mixture cooled to 0° C. Added to this was 4-phenylbutanoyl chloride (12.79 mg, 0.070 mmol) and the mixture stirred at room temperature (mixture became a clear colorless solution over time). After 1 h, 0.5 mL MeOH was added and the mixture was concentrated under a stream of air, taken up in MeOH and purified by preparative HPLC (10% AcCN/90% H2O/0.1% CF3CO2H, Sunfire 19×100 mm, C18, 5 μm). The product-containing fractions were combined, concentrated to remove the organic solvent and the resulting precipitate isolated by filtration to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(4-phenylbutanoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (7.7 mg, 55% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.41-7.57 (1H, m), 7.12-7.40 (7H, m), 7.02-7.12 (1H, m), 4.88 (1H, s), 4.29-4.42 (1H, m), 4.15-4.29 (0.5H, m), 3.80-4.06 (1H, m), 3.44-3.70 (2.5H, m), 2.67 (1H, t, J=7.53 Hz), 2.57 (0.5H, t, J=7.40 Hz), 2.34-2.53 (2H, m), 2.20 (0.5H, t, J=7.53 Hz), 1.74-1.98 (2H, m), 1.23-1.42 (9H, m), 1.16 (3H, dd, J=6.65, 4.39 Hz), 0.88-1.09 (9H, m). 19F NMR (400 MHz, CD3OD) δ ppm −114.74, −115.22. LCMS (M+H) calcd for C35H44FN2O4: 575.32. found: 575.02.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([O:17]CC)=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 1.5 h

Procedure:
To a solution of 1,3-diethyl 2-{[(tert-butoxy)carbonyl]amino}propanedioate XCVI (2.22 g, 8 mmol) in a mixture of ethanol/water (45 mL/5 mL) was added KOH (0.45 g, 8 mmol) in water (3 mL) dropwise. The reaction mixture was stirred for 1.5 hours. The ethanol was evaporated and the residue was acidified to pH=2 by 2 M HCl and washed by DCM. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated to give 2-{[(tert-butoxy)carbonyl]amino}-3-ethoxy-3-oxopropanoic acid XCVII as crystals (1.68 g, 6.8 mmol, 85% yield). 1H NMR (CDCl3) 1.31 (t, J=7 Hz, 3H), 1.41-1.45 (m, 9H), 4.23-4.31 9 m, 2H), 4.76 (d, J=4 Hz, 1H), 7.77 (d, J=4 Hz, 1H), 10.84 (brs, 1H); ESIMS found for C10H17NO6 m/z 248 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[CH:3]=1.[Cl:23]N1C(C)(C)C(=O)N(Cl)C1=O>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23]
Reactant: COC(=O)c1cc(N)c(F)c(-c2ccc(Cl)c(OC)c2F)n1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of methyl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-picolinate (0.5 g, 1.52 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.30 g, 1.52 mmol) in acetonitrile (10 mL) was heated to reflux for 1.5 h. Upon cooling to room temperature, the reaction mixture was concentrated under vacuum and then purified by silica gel chromatography (100% hexane to 100% EtOAc gradient) to give a light brown solid (0.53 g, 100%): mp 169-170.5° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=8.4 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.15 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.8 (s), 153.1 (d, J=253 Hz), 146.3 (s), 144.5 (d, J=4 Hz), 143.7 (s), 142.8 (dd, J=227, 14 Hz), 136.4 (d, J=13 Hz), 128.6 (d, J=3 Hz), 125.9 (s), 125.5 (d, J=4 Hz), 122.9 (dd, J=14, 4 Hz), 113.0 (d, J=3 Hz), 61.6 (d, J=4 Hz), 52.7 (s). Anal. Calcd for C14H10Cl2F2N2O3: C, 46.30; H, 2.78; N, 7.71. Found: C, 46.60; H, 2.68; N, 7.51.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[C:8]([CH3:11])[C:9]=1[Br:10].S(O[CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([CH3:11])[C:9]=1[Br:10])[O:12][CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CCOP(=O)(COS(=O)(=O)c1ccc(C)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(COc1cc(C)c(Br)c(C)c1)OCC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred suspension of NaH (0.5 g, 22.0 mmol) in anhydrous DMF (20 mL) at 0° C. was added 3,5-dimethyl-4-bromophenol (2.2 g, 11.0 mmol) in DMF (5 mL) followed by diethyl tosyloxymethylphosphonate (3.9 g, 24.2 mmol) in DMF (5.0 mL) 30 min later. The reaction mixture was stirred for 14 h at room temperature and poured into water (30 mL). The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (2:3) to afford diethyl (3,5-dimethyl-4-bromophenoxy)methylphosphonate as a syrup. (1.85 g, 48%): 1H NMR (300 MHz, CDCl3): δ 6.88 (s, 2H), 4.15-4.25 (m, 6H), 2.41 (s, 2H), 1.40 (t, J=6.0 Hz, 6H); LC-MS m/z=351[α]3H20BrO4P+H]+; TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (2:3); Rf=0.3.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:26]1[CH2:27][CH2:28][CH:23]([C:19]2[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1cc2ccccc2s1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cc4ccccc4s3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 1-benzothiophene-2-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 393.2 (M+H)+.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.C(O)(=O)C.[CH2:23]([NH2:25])[CH3:24]>C1(C)C=CC=CC=1>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:25][CH2:23][CH3:24])=[O:4]
Reactant: COC(=O)CC[C@H](N)C(=O)O
Reactant: CCN
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)CC(C)=O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Yield: 3.7 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 45 g of toluene. To this, 15 g (233 mmol) of acetylacetone and 5.6 g (93 mmol) of acetic acid were added. The mixture was heated for 2 hours while removing water generated by use of an ester tube at 100° C. to 110° C. The solvent was removed to obtain 7.9 g of a yellow oily substance. To the oily substance, 13.5 g (210 mmol) of 70% ethylamine was added and allowed to react for 23 hours. The same procedure as in Example 1 was performed to obtain 0.2 g of theanine (yield: 5.5%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][N:10]=2)[NH:5][C:4](=[O:13])[N:3]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:14]([NH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][N:10]=2)[NH:5][C:4](=[O:13])[N:3]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cnc2c(N)nc(=O)[nH]c2n1
Solvent: c1ccncc1
Product: Cc1cnc2c(NC(=O)c3ccccc3)nc(=O)[nH]c2n1
Temperature: 80 °C

Procedure:
In 20 mL of pyridine is dissolved 1.63 g (0.01 mole) of 4-amino-7-methyl-pteridine-2-one (20). Then 3.12 g (0.02 mole) of benzoyl chloride is added dropwise while stirring the mixture. The mixture is heated to 80° C. for 30 minutes and then poured on ice. The resulting precipitate is collected, washed with ethanol and ether and then recrystallized from DMF to give 21.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:6][C:7]=1[C:13]([F:16])([F:14])[F:15])#[N:10]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A mixture of 4-(2,2,2-trifluoro-ethylamino)-2-trifluoromethyl-benzonitrile (5.00 g, 18.7 mmol), methyl bromoacetate (3.25 mL, 37.5 mmol), and Cs2CO3 (12.2 g, 37.3 mmol) in acetonitrile (50 mL) was held at reflux, under N2, for 2 h and cooled to rt, and solids were removed by filtration. The filtrate was adsorbed onto a minimal amount of silica gel, filtered through a short pad of silica gel (EtOAc/hexanes) and concentrated to dryness. Recrystallization from EtOAc/hexanes afforded 4.72 g of the title compound as fine needles, mp 144-145° C.: 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.9 Hz, 1H), 7.01 (d, J=2.3 Hz, 1H), 6.88 (dd, J=2.6 Hz, 1H), 4.24 (s, 2H), 4.06 (q, J=8.5 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]#[N:15])[CH2:10][CH2:9][CH2:8]2)(=O)[CH3:2].[OH:16]O.[OH-].[Na+].O>C(O)C>[CH3:2][C:1]1[NH:15][C:14](=[O:16])[C:13]2[C:5](=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][C:11]=3[CH:12]=2)[N:4]=1
Reactant: OO
Reactant: CC(=O)Nc1cc2c(cc1C#N)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)CCC3
Temperature: 50 °C

Procedure:
A mixture of 5-acetamido-6-cyanoindan (104 g), hydrogen peroxide (30% solution in water, 400 ml), sodium hydroxide (35 g), water (200 ml) and ethanol (1 L) was stirred and heated to 50° C. for 1 hour. The mixture was cooled to ambient temperature and evaporated. The residue was dissolved in water (2 L) and the solution was acidified to pH 5 by the addition of 2N aqueous hydrochloric acid. The precipitate was isolated, washed with water and dried under vacuum. There was thus obtained 2-methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (100 g), m.p. 284° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.N1C=CC=CC=1.[Cl:22][CH2:23][CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.C1COCC1.C(Cl)(Cl)Cl>[Cl:22][CH2:23][CH2:24][CH2:25][S:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2)(=[O:28])=[O:27]
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2cc(NS(=O)(=O)CCCCl)ccc2[nH]1
Reaction time: 16 h

Procedure:
Ethyl 5-aminoindole-2-carboxylate (2.0 g) and pyridine (0.82 ml) are dissolved in 15 ml of methylene chloride and 10 ml of THF. Then the reaction is cooled to 0° and 3-chloropropanesulfonyl chloride (1.25 ml) is added and the reaction is allowed to slowly warm to 20°-25° and stir for 16 hr. Then the reaction is diluted with chloroform, washed with saturated aqueous sodium bicarbonate and saline. The organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product is dissolved in ethyl acetate and filtered through a plug of silica gel and crystallized from methanol, mp 195°-196°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][CH2:10][C:11]=1OS(C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[Cl:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([F:35])[C:29]=1[C:36]1[CH:40]=[C:39]([CH2:41][O:42][C:43]2[CH:48]=[CH:47][C:46](B3OC(C)(C)C(C)(C)O3)=[CH:45][N:44]=2)[O:38][N:37]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:9][CH2:10][C:11]=1[C:46]1[CH:45]=[N:44][C:43]([O:42][CH2:41][C:39]2[O:38][N:37]=[C:36]([C:29]3[C:30]([F:35])=[CH:31][CH:32]=[C:33]([F:34])[C:28]=3[Cl:27])[CH:40]=2)=[CH:48][CH:47]=1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)OC1(C)C
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)nc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
Compound A2 (9.52 g, 23.6 mmol) and 2-[3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (13.2 g, 29.5 mmol) were dissolved in DME (164 mL), and aq. 2M Na2CO3 (118 mL) was added. The mixture was degassed with N2 (5 min), and Pd(PPh3)4 (1.36 g, 1.18 mmol) was added. The mixture was heated rapidly to 80° C., and was stirred at this temperature for 1 h. The mixture was allowed to cool to rt, and was diluted with EtOAc (200 mL). The mixture was washed with water (200 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane→EtOAc/heptane 30:70) yielded the title compound (8.45 g, 62%). LC-MS: tR=1.13 min, ES+: 576.41.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][CH3:16])[CH2:9]1)C1C=CC=CC=1.C(O)C.[ClH:20]>>[ClH:20].[CH3:16][O:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COCC1CN(Cc2ccccc2)CCO1
Agent: Cl
Solvent: CCO
Product: COCC1CNCCO1

Procedure:
N-Benzyl-2-methoxymethylmorpholine is subjected to hydrogenolysis in hydrogen chloride-containing ethanol in the same manner as described in Reference Example 15 to give 2-methoxymethylmorpholine hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:46]C)=[C:6]([S:8][C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11](COCC[Si](C)(C)C)[CH:10]=2)[CH:7]=1.B(Br)(Br)Br.N>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:46])=[C:6]([S:8][C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1Sc1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(Sc5cc(F)ccc5O)c34)n(-c3ccccc3)c(=O)c12
Yield: 69.5 %

Procedure:
(S)-2-(1-((5-((5-Fluoro-2-methoxyphenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (63 mg, 0.09 mmol) was treated with boron tribromide (1M in dichloromethane, 938 μl, 0.94 mmol) in dichloromethane (1.30 ml) and then with a solution of ammonia (7N in methanol, 1.30 ml, 9.10 mmol) according to the method described in Example 41. The residue was purified using SP1® Purification System (0% to 10% dichloromethane-2-propanol) to obtain 33 mg (64% yield) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:17]([O:16][C:14](=[O:15])[NH:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCNC1)OCc1ccccc1

Procedure:
To a solution of 3.21 g 3-Benzyloxycarbonylamino-pyrrolidine-1-carboxylic acid tert-butyl ester in 40 ml dichloromethane were added 11 ml TFA. After 16 h the solution was evaporated to give the crude hydrotrifluoroacetate. Yield: 3.20 g.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.F[C:23]1[C:28]([C:29]2[C:30]3[NH:37][CH:36]=[CH:35][C:31]=3[N:32]=[CH:33][N:34]=2)=[CH:27][CH:26]=[CH:25][N:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[N:32]1[C:31]2[CH:35]=[CH:36][NH:37][C:30]=2[C:29]([C:28]2[C:23]([NH:1][C:2]3[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][N:6]=[C:7]4[NH:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[N:24][CH:25]=[CH:26][CH:27]=2)=[N:34][CH:33]=1
Reactant: Fc1ncccc1-c1ncnc2cc[nH]c12
Reactant: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1Nc1ncccc1-c1ncnc2cc[nH]c12
Temperature: 25 °C

Procedure:
A mixture of 4-(5-amino-6-methylisoquinolin-1-ylamino)benzonitrile (0.150 g, 0.55 mmol) and 4-(2-fluoropyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine (0.13 g, 0.60 mmol) in anhydrous THF (10 mL) was stirred at RT and treated dropwise with lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 1.7 mL, 1.7 mmol) to give a dark suspension. After 1 h stirring, the mixture was treated with 1 N aq HCl (10 mL) and stirred at RT for 10 min. The reaction mixture was added to satd NaHCO3 (70 mL) and extracted with 3:1 CHCl3IPA (3×70 mL). The combined organic layers were washed with satd NaCl (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 70% to 90% EtOAc in CH2Cl2 to provide 50 mg. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 13 min. Fractions containing product were combined, concentrated in vacuo, and lyophilized to give 4-(5-(3-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile as a bright yellow solid. MS (ESI, pos. ion) m/z: 469.2 [M+H]+