Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10]C(=O)C2C=CC=CC=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4].[OH-].[K+]>CO>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4]
Reactant: COC(=O)[C@@H]1[C@H](OC(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of 7B (18 g, 51.5 mmol) in anhydrous MeOH (360 mL) at RT was slowly added a freshly prepared 1N solution of KOH in anhydrous MeOH (77 mL, 77 mmol) in portions. The mixture was stirred at RT until the reaction was completed (about 1 hour). The reaction was cooled at 0° C., then quenched by slow addition of 1N aqueous HCl (77 mL). The mixture was concentrated under reduced pressure to remove most of the MeOH solvent, and the remaining mixture partitioned between water and EtOAc. The separated EtOAc phase was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was chromatographed eluting with 30% EtOAc/hexane to give 12.4 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([Br:4])[CH2:2][OH:3].N1C=CN=C1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C1C=CC=CC=1>CN(C)C=O>[Si:10]([O:3][CH2:2][CH2:1][Br:4])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCBr
Agent: c1c[nH]cn1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCBr
Yield: 94 %

Procedure:
2 g of ethylene bromohydrin and 2.4 g of imidazole were dissolved in 40 ml of N,N-dimethylformamide, to which 2.65 g of t-butyldimethylsilyl chloride were added at room temperature. After completion of the reaction, benzene was added, followed by washing with water and a sodium hydrogencarbonate aqueous solution and drying with anhydrous magnesium sulfate. This was filtered and the solvent was distilled off, thereby obtaining 3.60 g of the captioned compound (yield 94%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[N:18]([CH3:19])[CH:17]=[N:16][C:15]=2[Cl:20])(=[O:13])=[O:12])[CH2:3][CH2:2]1>C(O)C.[Pd]>[ClH:20].[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=2)(=[O:13])=[O:12])[CH2:5][CH2:6]1
Reactant: Cn1cnc(Cl)c1S(=O)(=O)NCCCN1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: Cl
Product: Cn1cncc1S(=O)(=O)NCCCN1CCOCC1

Procedure:
1 g (2.8 mmol) of N-(3-morpholinopropyl)-4-chloro-1-methyl-5-imidazolesulfonamide from Example 31 is dissolved in 130 ml of 25% strength aqueous ethanol, 0.3 g of Pd/C catalyst is added and the mixture is hydrogenated with shaking at an initial pressure of 3.45 bar until absorption of hydrogen is complete. The catalyst is filtered off. The filtrate is concentrated in vacuo and the residue is recrystallized from ethanol. The title compound of melting point 205°-206° C. is obtained in a yield of 0.8 g (88% of theory).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:47]=[CH:46][C:36]([O:37][C:38]3[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=3[C:40]#[N:41])=[CH:35][CH:34]=2)O1.COCCOC.O.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:33]3[CH:47]=[CH:46][C:36]([O:37][C:38]4[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=4[C:40]#[N:41])=[CH:35][CH:34]=3)[C:10]=12
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3C#N)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5C#N)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 85 °C
Yield: 67.8 %

Procedure:
A mixture of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.29 g, 5.19 mmol, 1 equiv), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]benzonitrile (2.0 g, 6.2 mmol, 1.2 equiv), tetrakis(triphenylphosphine)palladium (0.329 g, 0.311 mmol, 0.06 equiv), DME (21 mL), and sodium carbonate monohydrate (1.54 g, 12.5 mmol, 2.4 equiv) in water (16 mL) was heated at 85° C. for 60 h. Additional tetrakis(triphenylphosphine)palladium (0.100 g, 0.02 equiv) was added and the reaction mixture was heated at 85° C. for 6.5 h. The reaction mixture was allowed to cool to ambient temperature and was partitioned between saturated aqueous sodium bicarbonate solution (25 mL) and EtOAc (25 mL). The organic extract was dried over MgSO4, filtered, and concentrated. The residue was triturated from Et2O and purified by column chromatography on silica gel (elution with 1 L of 5% MeOH/CH2Cl2, 1 L of 10% MeOH/CH2Cl2, 1 L of 20% MeOH/CH2Cl2, and 1 L of 25% MeOH/CH2Cl2) to give cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile as a pale yellow solid (1.79 g, 3.52 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 8.24 (1H, s), 7.94 (1H, d, J=7.7 Hz), 7.68-7.73 (3H, m), 7.31-7.34 (3H, m), 7.18 (1H, d, J=8.5 Hz), 4.78-4.83 (1H, m), 2.21-2.51 (11H, m), 2.19 (3H, s), 2.05-2.08 (2H, m), 1.56-1.71 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.16 min. MS: MH+ 509.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:31]([O:35][N:36]1N=NC2C=CC=C[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CN(C)O>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:13]([N:36]([O:35][CH3:31])[CH3:37])=[O:15])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H](CCCCCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (S)-2-(((benzyloxy)carbonyl)amino)-8-(tert-butoxy)-8-oxooctanoic acid (prepared as described in WO2006/061638), HBTU (1.1 eq.) and DIPEA (2 eq.) in DMF (0.7 M) was stirred at room temperature for 10 min. Then, dimethylhydroxylamine hydrochloride (1.1 eq.) was added. The reaction mixture was stirred at room temperature for a further 16 h then diluted with EtOAc. Organic phase was washed with sat. aq. NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure to give a residue that was purified by column chromatography (eluent: petroleum ether/EtOAc from 85:15 to 1:4) to give the title compound as a pale yellow oil. MS (ES+) C22H34N2O6: 423 (M+H)+.
Reaction SMILES: FC1C=C([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([OH:19])[CH:13]=3)C=CC=1O.[CH3:22]OC1C=C2C(CCCC2=O)=CC=1>C1(C)C=CC=CC=1>[CH3:22][O:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[CH:9][CH:10]=[C:11]2[C:20]#[N:21])=[CH:16][CH:15]=1
Reactant: N#Cc1cc(-c2ccc(O)c(F)c2)cc2ccc(O)cc12
Reactant: COc1ccc2c(c1)C(=O)CCC2
Solvent: Cc1ccccc1
Product: COc1ccc2cccc(C#N)c2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In a highly preferred aspect of this invention illustrated in Scheme 1, there is provided a new and improved process for the large-scale production of 3-(3-fluoro-4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile (1). Commercial material 3,4-dihydro-7-methoxy-1(2H)-naphthalenone (7-methoxy-1-tetralone) may be transformed into an unsaturated nitrile (3) as shown on Scheme 1. The reaction is performed in toluene solution. Upon the completion of the reaction, it is quenched by caustic solution. The reaction mixture is extracted with toluene. After washing the toluene solution, the crude unsaturated nitrile (3) is aromatized directly in this toluene solution by stirring with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) at 60° C. for 2 h. The solid is removed by filtration and the filtrate is washed with sodium hydroxide solution and brine and respectively. Most of the solvent is removed by distillation and heptane is added to precipitate the product. 7-methoxy-1-naphthonitrile (4) is isolated. The expected yield over these two steps is at least 70-75%. By performing two reactions in the same solvent, isolation of the low melting point intermediate (3) can be avoided, improving efficiency and yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([Cl:24])[CH:5]=[CH:4][C:3]=1[OH:25].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C=O)C>[Cl:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([Cl:24])[CH:5]=[CH:4][C:3]=1[O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 2,4-dichloro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenol (150 mg, 0.4 mmol, 1.0 eq) in DMF (50 mL), was added K2CO3 (220 mg, 0.6 mmol, 1.5 eq) and the solution was stirred at room temperature for 30 min. BrCH2CO2Et (100 mg, 1.6 mmol, 4.0 eq) was added dropwise and the reaction was stirred overnight. The reaction was quenched by addition of water (200 mL) and extracted with EtOAc. The combined organic extracts were dried (Mg2SO4), filtered and evaporated under reduced pressure and the residue obtained purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound (130 mg, 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[CH:40]1([CH2:46][NH2:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.O>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])([C:17]([NH:47][CH2:46][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:19])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NCC2CCCCC2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyloxycarbonyl-4-(t-butoxycarbonylamino)piperidin-4-carboxylic acid (297 mg) in dimethylformamide (2.5 mL) were added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (226 mg), 4-N,N-dimethylaminopiperidine (144 mg) and cyclohexylmethylamine (0.15 mL) and the solution was stirred at room temperature overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:methanol=40:1-10:1) to give the title compound having the following physical data.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[C:14]([CH:18]=[CH2:19])[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:20])[C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].C12BC(CCC1)CCC2.[OH:30]O.[OH-].[Na+]>O.O1CCCC1>[NH2:20][C:9]1[C:8]2[N:7]=[CH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]=2[C:16]2[CH:15]=[C:14]([CH2:18][CH2:19][OH:30])[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: OO
Reactant: C=Cc1ccc2nc(N)c3ncn(CC(C)C)c3c2c1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cn1cnc2c(N)nc3ccc(CCO)cc3c21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 500 mL round bottom flask was charged with 1-isobutyl-8-vinyl-1H-imidazo[4,5-c]quinolin-4-amine (850 mg, 3.2 mmol) and 200 mL of tetrahydrofuran. The flask was purged with nitrogen. A solution of 9-borabicyclo[3.3.1]nonane (0.5M in tetrahydrofuran, 8.5 mL, 4.25 mmol) was added in one portion and the reaction was stirred overnight. Additional 9-borabicyclo[3.3.1]nonane (0.5M in tetrahydrofuran, 12.5 mL, 6.25 mmol) was added and the mixture was stirred for approximately 24 hours. The reaction was cooled to 0° C. with an ice/water bath and 30% H2O2 (2 mL) was added dropwise. After 5 minutes, 10% NaOH (5 mL) was added dropwise. The reaction was stirred for 30 minutes, diluted with water (100 mL) and then extracted with chloroform (3×100 mL). The combined organic fractions were concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-30% CMA in chloroform) followed by recrystallization from acetonitrile to provide 580 mg of 2-(4-amino-1-isobutyl-1H-imidazo[4,5-c]quinolin-8-yl)ethanol as an off-white solid, mp 214-216° C.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.Br[CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH:24]([CH3:32])[CH:25]2[O:30][CH3:31].O>CCOCC>[CH3:31][O:30][CH:25]1[C:26]2[C:22](=[C:21]([CH2:20][CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[CH:29]=[CH:28][CH:27]=2)[CH2:23][CH:24]1[CH3:32]
Reactant: COC1c2cccc(CBr)c2CC1C
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COC1c2cccc(CC3c4ccccc4-c4ccccc43)c2CC1C
Temperature: -80 °C
Reaction time: 12 h

Procedure:
To a solution of 3.32 g (0.20 mol) of 9H-fluorene in 500 ml of ether 80 ml of 2.5 M (0.20 mol) n-BuLi in hexanes was added at 0° C. This mixture was stirred for 12 h, cooled to −80° C., and then a solution of 5.10 g (0.20 mol) of 4-(bromomethyl)-1-methoxy-2-methylindane in 150 ml of ether was added dropwise by vigorous stirring for 30 min at this temperature. The resulting mixture was stirred for 24 h at room temperature, and then 500 ml of water was added. The organic layer was separated, and the aqueous layer was extracted with 3×200 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The product was isolated by flash chromatography on Silica Gel 60 (40-63 um, d 60 mm, l 150 mm; eluent: hexanes/ether=20/1). Yield 5.31 g (78%) of a mixture of the diastereomers A and B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](N2C3N=C(N4CCOCC4)N=C(C4C=NC(N(CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=NC=4)C=3CC2)[CH:5]=[CH:4][N:3]=1.[CH3:48][O:49][C:50]1[CH:106]=[CH:105][C:53]([CH2:54][N:55]([CH2:96][C:97]2[CH:102]=[CH:101][C:100]([O:103][CH3:104])=[CH:99][CH:98]=2)[C:56]2[N:61]=[CH:60][C:59]([C:62]3[C:63]4[CH2:76][CH2:75][N:74](C5C=CN=C([N:83]6[CH2:88][CH2:87][CH:86]([O:89][CH:90]7[CH2:95][CH2:94][CH2:93][CH2:92][O:91]7)[CH2:85][CH2:84]6)C=5)[C:64]=4[N:65]=[C:66]([N:68]4[CH2:73][CH2:72][O:71][CH2:70][CH2:69]4)[N:67]=3)=[CH:58][N:57]=2)=[CH:52][CH:51]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([N:74]2[C:64]3[N:65]=[C:66]([N:68]4[CH2:69][CH2:70][O:71][CH2:72][CH2:73]4)[N:67]=[C:62]([C:59]4[CH:58]=[N:57][C:56]([N:55]([CH2:54][C:53]5[CH:105]=[CH:106][C:50]([O:49][CH3:48])=[CH:51][CH:52]=5)[CH2:96][C:97]5[CH:102]=[CH:101][C:100]([O:103][CH3:104])=[CH:99][CH:98]=5)=[N:61][CH:60]=4)[C:63]=3[CH2:76][CH2:75]2)=[CH:6][CH:7]=1.[O:91]1[CH2:92][CH2:93][CH2:94][CH2:95][CH:90]1[O:89][CH:86]1[CH2:87][CH2:88][NH:83][CH2:84][CH2:85]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(N4CCC(OC5CCCCO5)CC4)c3)cn2)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(Cl)c3)cn2)cc1
Product: C1CCC(OC2CCNCC2)OC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1

Procedure:
Using {5-[7-(2-chloro-pyridin-4-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.307 mmol) obtained in Step A in Example 1-D-69 instead of {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine, and 4-[(tetrahydro-2-H-pyran-2-yl)oxy]piperidine (86 mg, 0.46 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Example 1-D-48, a crude product of bis-(4-methoxy-benzyl)-(5-{2-morpholin-4-yl-7-[4-(tetrahydro-pyran-2-yloxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine was obtained as a yellow amorphous (180 mg), and then the PMB groups and THP group were removed according to the above Deprotection method 2, to obtain the desired compound (D-75) as a pale yellow powder (35 mg, 33%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]2=[C:4]([C:13](N[C@@H](CC(C)C)C(NC)=O)=[O:14])[N:3]=1.[NH2:25][C@H:26]([C:31]([OH:33])=O)[C:27]([CH3:30])([CH3:29])[CH3:28].[CH3:34][NH:35][CH3:36]>C1COCC1>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]2=[C:4]([C:13]([NH:25][C@@H:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:31]([N:35]([CH3:36])[CH3:34])=[O:33])=[O:14])[N:3]=1
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)c1nc(Br)n2c1CN(C)CCC2
Reactant: CNC
Solvent: C1CCOC1
Product: CN1CCCn2c(Br)nc(C(=O)N[C@H](C(=O)N(C)C)C(C)(C)C)c2C1

Procedure:
This intermediate was prepared following the synthesis of ((S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-3-bromo-8-methyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamide (Intermediate 55B) by replacing Z-Leu-OH with tert-Leu-OH, and replacing methylamine hydrochloride with dimethylamine solution in THF. LCMS (+ESI) m/z 417.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[S:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[S:12])=[N:6][CH:7]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: COC(=S)Cc1ccc(N)cn1
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: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)Nc2ccc(CC(O)=S)nc2)cc1

Procedure:
A mixture of 5-amino-(pyrid-2-yl)-thioacetic acid methyl ester [930 mg, Reference Example 1(a)], 4-[3-(2-methylphenyl)ureido]phenylacetic acid (1.26 g, prepared as described in Example 21 of International Patent Application Publication No. WO 96/22966), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.69 g) and diisopropylethylamine (1.2 g) in dimethylformamide (50 ml) was stirred at ambient temperature for 1 hour. The mixture was evaporated then poured into water (500 ml). The resultant solid was washed with water (50 ml) and then washed twice with diethyl ether (50 ml). The solid was suspended in methanol (100 ml), then treated with sodium hydroxide solution (10 ml, 1M). The mixture was heated at reflux for 5 hours, then cooled, then evaporated. The residue was treated with hydrochloric acid (200 ml, 1M). The resultant solid was filtered, washed with water (20 ml), then washed twice with diethyl ether (20 ml), then recrystallised from ethanol to give the title compound (220 mg) as a yellow solid, m.p. >235° C. (with decomposition). MS: MH+ 451.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[CH2:20]([O:27][CH2:28][CH2:29][C:30]([CH3:44])([CH3:43])[CH2:31][C@H:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:33]=[O:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.O1CCCC1>[CH2:20]([O:27][CH2:28][CH2:29][C:30]([CH3:44])([CH3:43])[CH2:31][C@H:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:33]([OH:34])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C#CC(=O)OCC
Reactant: CC(C)(CCOCc1ccccc1)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C#CC(O)[C@H](CC(C)(C)CCOCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
22.2 ml of a 1.6M n-butyllithium solution in hexane are added to a solution of 5.1 ml of diisopropylamine in 40 ml of tetrahydrofuran at -78° C. under argon, while stirring. After 30 min, a solution, cooled to -78° C., of 2.5 ml of ethyl propiolate in 20 ml of tetrahydrofuran is added dropwise via a cannula. The yellow reaction solution is stirred at -78° C. for a further 1 h and 5.0 g of 6-benzyloxy-2(S)-tert-butoxycarbonylamino-4,4-dimethyl-hexanal (Example 390) in 30 ml of tetrahydrofuran are then added dropwise. After the mixture has been stirred for 4.5 h, the reaction is quenched by addition of saturated aqueous ammonium chloride solution and the reaction mixture is allowed to warm to room temperature and is worked up in the customary manner. The crude product is purified by FC over silica gel (eluting agent C). The title compound is obtained as a mixture of the 4(S) and 4(R) diastereomers in a ratio of about (5.4:1): Rf (C)=0.28; FAB-MS: (M+H)+ =448.
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=[CH:10][C:9]=1[C:23]1[C:24](=[O:43])[O:25][C:26]2[C:31]([C:32]=1[CH3:33])=[CH:30][CH:29]=[C:28]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:27]=2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:56][CH2:57][C:58](Cl)=[O:59]>C1COCC1.C(OCC)C>[CH3:45][Si:2]([CH3:44])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[CH:11]=[CH:10][C:9]=1[C:23]1[C:24](=[O:43])[O:25][C:26]2[C:31]([C:32]=1[CH2:33][C:58](=[O:59])[CH2:57][Cl:56])=[CH:30][CH:29]=[C:28]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:27]=2
Reactant: Cc1c(-c2ccc(OCOCC[Si](C)(C)C)cc2OCOCC[Si](C)(C)C)c(=O)oc2cc(OCOCC[Si](C)(C)C)ccc12
Reactant: O=C(Cl)CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)CCOCOc1ccc(-c2c(CC(=O)CCl)c3ccc(OCOCC[Si](C)(C)C)cc3oc2=O)c(OCOCC[Si](C)(C)C)c1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
At room temperature, 3-[2,4-Bis-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-chromen-2-one (1.6 g, 2.37 mmol) in THF (10 mL) was added LiHMDS (2.9 mL, 2.84 mmol) slowly. The reaction mixture was stirred for 10 min and then added into chloroacetyl chloride (0.28 mL, 1.5 equiv.) in THF (20 mL) at −20° C. The reaction mixture was maintained at −20° C. for 1 hour, then diluted with diethyl ether (200 mL), washed with aqueous NH4Cl (100 ml), brine and organic layer was dried over anhydrous MgSO4. The resulting product was then concentration by vacuum to dryness and purified by silica gel column chromatography to yield the title compound as a colorless oil.