Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[C:5]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[N:9]=1.CCN(C(C)C)C(C)C.[Cl:37][C:38]1[CH:39]=[N:40][C:41](I)=[N:42][CH:43]=1.CCOC(C)=O>CN1C(=O)CCC1>[Cl:37][C:38]1[CH:39]=[N:40][C:41]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:5]3[C:4]([CH2:3][OH:2])=[N:9][N:8]([C:10]4[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][CH:15]=4)[C:7](=[O:20])[CH:6]=3)[CH2:23][CH2:24]2)=[N:42][CH:43]=1
Reactant: CS(=O)(=O)c1ccc(-n2nc(CO)c(OC3CCNCC3)cc2=O)cc1
Reactant: Clc1cnc(I)nc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(-n2nc(CO)c(OC3CCN(c4ncc(Cl)cn4)CC3)cc2=O)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
To a stirring solution of 6-(hydroxymethyl)-2-(4-(methylsulfonyl)phenyl)-5-(piperidin-4-yloxy)pyridazin-3(2H)-one HCl (18.97 mg, 0.05 mmol) in NMP (2 mL) at room temperature under argon was added DIPEA (19.4 mg, 0.150 mmol) and 5-chloro-2-iodopyrimidine (24 mg, 0.1.0 mmol). The resulting reaction mixture was heated at 100° C. under argon overnight. 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 24 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 16 mg (62%) of 5-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-6-(hydroxymethyl)-2-(4-(methylsulfonyl)phenyl)pyridazin-3(2H)-one was obtained as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.73-1.95 (m, 2H) 1.98-2.22 (m, 2H) 2.58 (s, 1H) 2.96-3.16 (m, 3H) 3.61-3.83 (m, 2H) 3.96-4.17 (m, 2H) 4.48-4.82 (m, 3H) 6.30 (s, 1H) 7.88 (d, J=8.79 Hz, 2H) 8.04 (d, J=8.35 Hz, 2H) 8.24 (s, 2H). MS (ESI) 492 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=2[O:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38]N1C(=O)CCC1=O>CCCCCC>[Br:38][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=2[O:6][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)COc1cccc2c(CCO)coc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Product: COC(=O)COc1cccc2c(CCBr)coc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Methyl (3-(2-hydroxyethyl)benzofuran-7-yloxy)acetate (1.30 g) was dissolved in THE (15 ml) and the solution was cooled to 0° C. To this solution, triphenylphosphine (2.05 g) and N-bromosuccinimide (NBS, 1.39 g) were added and the resulting solution was stirred for 1 hour. Hexane (10 ml) was added to the reaction solution and the reaction solution was filtered through Celite. The filtrate was poured into water layer (50 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (1.39 g, yield: 85%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11]O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.P(Br)(Br)[Br:30]>C1COCC1>[Br:30][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[C:7]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[N:6]=[C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])[N:4]=2
Reactant: BrP(Br)Br
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CO)n(C)c2n1
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1

Procedure:
To crude (9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methanol (6 g) in anhydrous THF (400 mL) was added phosphorus tribromide (2.7 mL). The reaction was monitored by LC/MS until complete. The heterogeneous reaction mixture was passed thru a Buchner funnel and the solid was collected and rinsed with thrice with water and twice with MeOH.to get 2 g of crude 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine of which 50 mg was reacted with bicyclo[2.2.2]octan-1-amine (1-adamantyl amine) via General Procedure E to give 5.7 mg of 270 following reverse phase purification. MS (Q1) 513.3 (M)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12.[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH3:16][C:15]([CH3:17])=[CH:14][CH2:13][NH:18][C:2]1[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]2=[N:10][CH:11]=[CH:12][C:3]=12
Reactant: CC(C)CCN
Reactant: CSc1nc(Cl)c2ccnc-2[nH]1
Product: CSc1nc(NCC=C(C)C)c2ccnc-2[nH]1

Procedure:
To 400 mg of 4-chloro-2-methylthiopyrrolo[2,3-d] -pyrimidine was added 2 ml of isopentylamine. The solution was heated at reflux under nitrogen for 2 hours. The resulting dark oil was purified by chromatography on 30 g of Sephadex LH-20, elution with H2O and then with increasing concentrations of EtOH up to 40% EtOH. The appropriate fractions were combined and evaporated to dryness and the solid residue was crystallized from EtOH/H2O to afford white crystals of product, yield 131 mg (26%), m.p. 155.0° - 155.5°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[NH2:19][C:18]1[C:12]2[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]=2[N:15]=[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=12
Reactant: N#Cc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2nc3ccccc3c(N)c2C1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
1-t-Butoxycarbonyl-4-piperidone (1.69 g, 8.46 mmol), zinc chloride (1.50 g, 11.0 mmol) and 2-aminobenzonitrile (1.0 g, 8.46 mmol) were mixed and then reacted at 90° C. for 1 hour. The reaction mixture was cooled to room temperature to obtain a solid, which was ground together with toluene and filtered. The thus treated solid was suspended in chloroform and concentrated aqueous ammonia was added thereto and stirred. The chloroform layer was separated, dried over anhydrous sodium sulfate and then concentrated to obtain the desired compound (0.54 g, 1.8 mmol, 21%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)[N:15]=2)[CH:5]=1.C(C1C=CC(C2N=C(CC3C=C(C=CC=3)C(N)=O)NC=2)=CC=1)#N.[OH-].[Na+]>C1COCC1.CO>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:24])=[O:2])[NH:12][CH:13]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)c1cccc(Cc2nc(-c3ccc(C#N)cc3)c[nH]2)c1
Agent: N#Cc1ccc(-c2c[nH]c(Cc3cccc(C(N)=O)c3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(-c2c[nH]c(Cc3cccc(C(=O)O)c3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve the mixture of crude 3-[4-(4-cyano-phenyl)-1H-imidazol-2-ylmethyl]-benzoic acid methyl ester and 3-[4-(4-cyano-phenyl)-1H-imidazol-2-ylmethyl]-benzamide (0.13 g) into 5 mL of 1:1 THF/MeOH. To this add 0.5 mL of 15% NaOH. Stir the mixture at room temperature for 2 h. Add 1 mL of 15% NaOH and stir an additional 2 h. Concentrate to dryness. Dissolve the residue into 5 mL of H2O and make acidic by the addition of 5% HCl. Extract with 3×10 mL of CH2Cl2 and dry with MgSO4. Concentrate to give 0.13 g of crude 3-[4-(4-cyano-phenyl)-1H-imidazol-2-ylmethyl]-benzoic acid and 3-[4-(4-cyano-phenyl)-1H-imidazol-2-ylmethyl]-benzamide as a purple residue.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.C(OC(=O)[NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[ClH:45].C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:45].[ClH:45].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:30]3[CH2:31][CH2:32][CH:28]([NH2:27])[CH2:29]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CO
Product: NC1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)C1
Temperature: 60 °C
Yield: 52.8 %

Procedure:
The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (800 mg, 2.66 mmol) obtained in Step 6 of Example 1, (pyrrolidin-3-yl)carbamic acid tert-butyl ester (1.00 g, 5.32 mmol), 1-hydroxybenzotriazole monohydrate (470 mg, 3.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (720 mg, 3.72 mmol) and N-methylmorpholine (0.58 mL, 5.32 mmol) in a similar manner to Example 5, was dissolved in methanol (5.00 mL), and the solution was added with 4 mol/L hydrogen chloride-methanol solution (2.00 mL), followed by heating under reflux at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 122 (398 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH2:47]([O:49][C:50]([C:52]1[N:53]=[C:54]([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[S:55][CH:56]=1)=[O:51])[CH3:48]>CN(C=O)C>[CH2:47]([O:49][C:50]([C:52]1[N:53]=[C:54]([CH:57]2[CH2:62][CH2:61][N:60]([C:8](=[O:10])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]3)[CH2:59][CH2:58]2)[S:55][CH:56]=1)=[O:51])[CH3:48]
Reactant: CCOC(=O)c1csc(C2CCNCC2)n1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.5 %

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (9.1 g, 36.1 mmol) in DMF (100 mL) is added diisopropylethylamine (45 mL, 216 mmol), followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (15.5 g, 39.7 mmol). After stirring 15 min at RT, 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester hydrochloride (10 g, 36.1 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (300 mL), washed with saturated aqueous sodium bicarbonate solution (300 mL), 1M HCl solution (300 mL), and brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture is purified by column chromatography on silica gel (dichloromethane/methanol 10:1) to give 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (13.6 g, 88%). 1H-NMR (400 MHz, CDCl3): δ=1.40 (t, 3H), 1.70-1.85 (m, 2H), 2.16-2.30 (m, 2H), 2.32 (s, 3H), 2.79-2.89 (m, 1H), 3.22-3.43 (m, 1H), 4.03-4.12 (m, 1H), 4.42 (q, 3H), 4.54-4.69 (m, 1H), 4.93-5.08 (2 d, 2H (diastereotopic)), 6.35 (s, 1H), 8.10 (br, 1H). MS: m/z=209 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[SH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=1.C(N(CC)CC)C.Cl>O.CN(C)C=O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][S:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:29]=2)=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: O=C(O)CCc1ccc(S)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CSc2ccc(CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.73 g), 3-(4-mercaptophenyl)propionic acid (1.00 g), triethylamine (1.22 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give crystals of 3-[4-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl]sulfanyl]phenyl]propionic acid. Recrystallization from ethyl acetate gave colorless prism crystals (1.85 g, 73%). melting point: 157-158° C.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH3:15])[C:9]=1[F:16].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CC(N(C)C)=O>[Cl:17][C:18]1[CH:23]=[C:22]([O:14][C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([F:16])[C:10]=2[CH3:15])[CH:21]=[CH:20][N:19]=1
Reactant: Cc1c(O)ccc(N)c1F
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1c(Oc2ccnc(Cl)c2)ccc(N)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
Potassium tert-butoxide (3.5 g, 31 mmol) was added to a solution of 4-amino-3-fluoro-2-methyl-phenol (4.2 g, 30 mmol) in dimethylacetamide. The mixture was stirred at RT for 30 min. A solution of 2,4-dichloropyridine (4.38 g, 30 mmol) in dimethylacetamide was added and the mixture was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL) and filtered through silica gel. The filter cake was washed with ethyl acetate and the combined filtrates were concentrated in vacuo and purified by silica gel chromatography to give 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (3.2 g, 42% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J=6.4 Hz, 1 H), 6.84 (d, J=2.0 Hz, 1 H), 6.81 (dd, J=5.6, 2.4 Hz, 1 H), 6.67-6.65 (m, 2 H), 5.13 (s, 2H), 1.91 (s, 3 H); MS (ESI): m/z 253.2 [M+H]+.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:31](=[N:34]O)([NH2:33])[CH3:32]>CN(C=O)C.C(OCC)(=O)C>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]1[O:5][N:34]=[C:31]([CH3:32])[N:33]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(N)=NO
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc([C@@H]2CCCN2C(=O)OCc2ccccc2)n1
Temperature: 115 °C
Reaction time: 5 h

Procedure:
To a solution of 122 mg Z-Pro-OH in 4 ml DMF was added a solution of 325 mg 1,1′-carbonyldiimidazole in 5 ml DMF and the solution was stirred for 30 minutes at RT before a solution of 148 mg acetamide oxime in 3 ml DMF was added. The reaction mixture was stirred for 12 h before 325 mg 1,1′-carbonyldiimidazole were added and the mixture stirred at 115° C. for 5 h. Then, the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4% w/w), saturated aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was used in the next reaction step without further purification. Yield: 337 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[Cl:1][C:2]1[C:7]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: CCOC(=O)Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Temperature: -78 °C
Reaction time: 1.33 h
Yield: 97 %

Procedure:
To a solution of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.856 g, 2.77 mmol, Preparation #1, Step A) in THF (20 mL) at about −78° C. was added sec-BuLi (4.35 mL1, 6.10 mmol) dropwise. The reaction was stirred at −78° C. for about 80 min. To the mixture was added ethyl chloroformate (0.665 mL, 6.93 mmol. The flask was removed from the cooling bath and stirred for about 70 min at rt. The mixture was quenched by the addition of a saturated aqueous NH4Cl (5 mL). EtOAc (20 mL) and water (20 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×15 mL), and the combined organic layers were washed with brine (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The material was purified by flash chromatography (40 g Redi-Sep™ silica column) eluting with 0-10% EtOAc in heptane to give ethyl 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.02 g, 97%): 1H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 7.69 (d, J=3.6, 1H), 6.72 (dd, J=68.4, 3.5, 1H), 4.34 (q, J=7.0, 2H), 1.86 (dt, J=15.0, 7.5, 3H), 1.34 (t, J=7.1, 3H), 1.05 (d, J=7.5, 18H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[C:24]([N:36]3[CH2:41][CH2:40][CH:39]([N:42]([CH3:50])[C:43](=[O:49])[C@@H:44]4[CH2:48][CH2:47][CH2:46][NH:45]4)[CH2:38][CH2:37]3)[N:23]=2)=[C:17]([F:51])[CH:16]=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:8]([N:45]1[CH2:46][CH2:47][CH2:48][C@H:44]1[C:43]([N:42]([CH:39]1[CH2:38][CH2:37][N:36]([C:24]2[N:23]=[C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][C:17]=3[F:51])[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=2)[CH2:41][CH2:40]1)[CH3:50])=[O:49])(=[O:10])[CH3:9]
Reactant: COc1cc2nc(N3CCC(N(C)C(=O)[C@@H]4CCCN4)CC3)nc(Nc3ccc(Cl)cc3F)c2cc1OC
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nc(N3CCC(N(C)C(=O)[C@@H]4CCCN4C(C)=O)CC3)nc(Nc3ccc(Cl)cc3F)c2cc1OC
Temperature: 25 °C

Procedure:
Triethylamine (175 μl) and acetyl chloride (32 μl) were added under ice-cooling to a dichloromethane (5 mL) solution of N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N-methyl-L-prolinamide dihydrochloride (250 mg), followed by stirring under ice-cooling for 2 hours and under room temperature for 20 hours. A saturated sodium bicarbonate aqueous solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated. By purifying the resulting residue by a silica gel column chromatography (chloroform-MeOH), 1-acetyl-N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N-methyl-L-prolinamide was obtained. This compound was dissolved in MeOH (3 mL), 4 M HCl/ethyl acetate solution (203 μl) was added thereto, and the solvent was evaporated. By crystallizing the resulting crude crystals from isopropanol-diisopropyl ether, 1-acetyl-N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N-methyl-L-prolinamide hydrochloride (167 mg) was obtained as pale yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][NH:21][CH2:22]3)[CH2:18]2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].Br[C:29]1[C:36](C)=[CH:35][CH:34]=[CH:33][C:30]=1[C:31]#[N:32].[C:38](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:31]([C:30]1[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=1[CH2:38][N:21]1[CH2:22][CH:23]2[O:25][CH:19]([CH2:18][N:17]([CH2:16][CH2:15][N:10]([CH2:9][CH2:8][O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=3)[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:24]2)[CH2:20]1)#[N:32]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(C#N)c1Br
Reactant: CS(=O)(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CNCC(C1)O2
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CN(Cc3ccccc3C#N)CC(C1)O2
Temperature: 160 °C
Yield: 55.9 %

Procedure:
To N-[2-(4-cyano-phenoxy)-ethyl]-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]-non-3-yl)-ethyl]-methanesulfonamide (0.079 g, 0.20 mmol), 2-bromo-methyl-benzonitrile (0.041 g, 0.21 mmol) and anhydrous potassium carbonate (0.042 g, 0.30 mmol) was added dry acetonitrile (4 mL). The mixture was heated by microwave irradiation (15 minutes, 160° C.) and was then filtered. The filtrate was loaded onto a cation exchange column (SCX-2, Isolute™, 2 g). The column was washed with dichloromethane, acetonitrile and dichloromethane/methanol 80:20 before eluting the crude product with 20% methanol saturated with ammonia in dichloromethane. The filtrate was concentrated in vacuo and the crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 57 mg (55.9%) of the title compound.
Reaction SMILES: N[C:2]1C(=O)C2[C:9]([C:10](=[O:13])[C:11]=1N)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:15]1([C:21](=O)[C:22](=[O:24])[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C.O>[CH3:2][C:11]1[C:10](=[O:13])[C:9]2[C:23]([C:22](=[O:24])[C:21]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC(=O)C(=O)c1ccccc1
Reactant: NC1=C(N)C(=O)c2ccccc2C1=O
Solvent: CC(=O)O
Solvent: O
Product: CC1=C(c2ccccc2)C(=O)c2ccccc2C1=O
Reaction time: 0.08 h
Yield: 94.5 %

Procedure:
In a 200 ml Erlenmeyer flask were placed 5.0 g (26.5 mmols) of 2,3-diaminonaphthoquinone and 75 ml of acetic acid/water (1/1), then a solution composed of 5.9 g (39.8 mmols) of 1-phenyl-1,2-propanedione and 25 ml of acetic acid/water (1/1) was added dropwise to the mixture under ice-cooling over a period of about 10 minutes, and after stirring the mixture for 5 minutes, yellow precipitates formed were collected by filtration and washed with water. The precipitates were dissolved in methylene chloride; and, after purifying the solution by silica gel short column (eluted by methylene chloride), the product obtained was recrystallized from methylene chloride-methanol to provide 6.22 g (yield 78%) of 2-methyl-3-phenylnaphthoquinone as a yellow powder. Melting point 235°-236° C.
Reaction SMILES: ClCCl.[OH:4][C:5]1[C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:9][C:8]([CH3:25])=[CH:7][N:6]=1.N1C(C)=CC=CC=1C.Br[C:35]([CH3:40])([CH3:39])[C:36](Br)=[O:37]>CN(C)C=O>[CH3:39][C:35]1([CH3:40])[O:4][C:5]2[N:6]=[CH:7][C:8]([CH3:25])=[CH:9][C:10]=2[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]2)[C:36]1=[O:37]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cc1cnc(O)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)N(C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
At room temperature, to a dichloromethane solution (15 ml) of tert-butyl 4-[(2-hydroxy-5-methylpyridin-3-yl)amino]piperidine-1-carboxylate (3.08 g) were added 2,6-lutidine (2.25 ml) and 2-bromoisobutyryl bromide (1.74 ml). After stirring at room temperature for 18 hours, N,N-dimethylformamide (15 ml) was added, and stirred at 70° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford tert-butyl 4-(3,3,7-trimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (1.04 g).