Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]([CH3:40])[CH:32]1[CH:37]2[CH2:38][CH2:39][CH:33]1[CH2:34][NH:35][CH2:36]2>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:35]5[CH2:36][CH:37]6[CH:32]([N:31]([CH3:40])[CH3:30])[CH:33]([CH2:39][CH2:38]6)[CH2:34]5)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25]([N:26]([CH3:27])[CH3:28])=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C1C2CCC1CNC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)C5N(C)C)cn3)nc2n1C1CCCC1
Yield: 14 %

Procedure:
The 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with N,N-dimethyl-3-azabicyclo[3.2.1]octan-8-amine following amide formation method 3 which gave 7-cyclopentyl-2-(5-(8-(dimethylamino)-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (12 mg) 14% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.82 (s, 1H) 8.76 (s, 1H) 8.55 (d, J=9.60 Hz, 1H) 8.44 (d, J=2.02 Hz, 1H) 7.78 (dd, J=8.59, 2.02 Hz, 1H) 6.48 (s, 1H) 4.87-4.73 (m, 1H) 4.31 (br. s., 1H) 3.75 (br. s., 1H) 3.35 (m, 2H) 3.16 (s, 6H) 2.68-2.51 (m, 2H) 2.30 (s, 7H) 2.16-1.97 (m, 6H) 1.86-1.66 (m, 6H). HR-MS (m/z MH+) 531.32 RT 2.67 min
Reaction SMILES: Cl[Si](C)(C)C.[I-].[Na+].C[O:9][C:10]1[C:15]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[CH:18][CH:17]=2)=[N:14][N:13]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:12](=[O:37])[CH:11]=1.O>CC#N>[OH:37][C:12]1[N:13]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=2)[N:14]=[C:15]([C:16]2[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=[CH:18][CH:17]=2)[C:10](=[O:9])[CH:11]=1
Reactant: COc1cc(=O)n(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=c1cc(O)n(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Chlorotrimethylsilane (0.46 mL, 3.6 mmol) was added to a solution of sodium iodide (0.55 g, 0.73 mmol) in MeCN (20 mL) at room temperature. After stirring for 30 min, 5-methoxy-6-(1-phenyl-1H-pyrazol-5-yl)-2-[3-(trifluoromethyl)phenyl]pyridazin-3(2H)-one (0.30 g, 0.73 mmol) was added to the resulting suspension. The mixture was stirred at room temperature for 1 h, and then refluxed for 3 h. After cooling to room temperature, the mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with diisopropyl ether/hexane and recrystallized from AcOEt/hexane to give the title compound (0.21 g, 73% yield) as white crystals: mp 241-243° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 6.16 (1H, s), 6.88 (1H, d, J=1.9. Hz), 7.36-7.42 (3H, m), 7.45-7.54 (4H, m), 7.59 (1H, t, J=7.9 Hz), 7.70 (1H, d, J=7.9 Hz), 7.82 (1H, d, J=1.9 Hz), 12.23 (1H, brs). LC-MS (ESI) m/z 399 [M+H]+. Anal. Calcd for C20H13F3N4O2: C, 60.30; H, 3.29; N, 14.07. Found: C, 60.35; H, 3.37; N, 14.10.
Reaction SMILES: [CH2:1]([OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16]C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:18][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC/C=C\CCCCCCCCCCO
Solvent: c1ccncc1
Product: CCCC/C=C\CCCCCCCCCCOC(C)=O
Yield: 40 %

Procedure:
The obtained (Z)-11-hexadecenol (Formula II, R=H) is added to a mixture of 5 ml. of dry pyridine and 4 ml. of acetic anhydride, and the mixture is stirred at 0° C. for 3 hours. The solution is poured onto ice and extracted with methylene chloride. The extract is washed with water, 3% aqueous sulfuric acid and again with water, dried over magnesium sulfate, filtered, and the solvent is evaporated. The residue is distilled in fine vacuo. 2.2 g (40%) of (Z)-11-hexadecenyl acetate (Formula I, R=H) are obtained; the product is identical with the substance obtained according to step (A) above.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)=[CH:13][CH:12]=1.FC1C=CC(C(=O)C)=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:58][CH2:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:70]=[N:71][CH:72]=[C:73]([Cl:75])[CH:74]=2)[CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[Cl:75][C:73]1[CH:74]=[C:69]([O:68][CH:65]2[CH2:64][CH2:63][N:62]([C:60](=[O:61])[CH2:59][NH:58][C:22]([C:19]3[CH:18]=[C:17]([C:14]4[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=4)[O:21][N:20]=3)=[O:24])[CH2:67][CH2:66]2)[CH:70]=[N:71][CH:72]=1
Reactant: NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)on1
Agent: CC(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1)c1cc(-c2ccc(F)cc2)on1
Reaction time: 8 h
Yield: 17.9 %

Procedure:
DIPEA (253 mg, 1.96 mmol) was added to a stirred solution of 5-(4-fluoro-phenyl)-isoxazole-3-carboxylic acid (81 mg, 0.39 mmol) (prepared by the method used for the synthesis of Intermediate 25, starting from 4′-fluoroacetophenone) in DMF (2 mL), followed by HOBt (56 mg, 0.41 mmol) and EDCI.HCl (79 mg, 0.41 mmol). After 2 minutes 2-amino-1-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-ethanone hydrochloride (120 mg, 0.39 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by recrystallisation from 10% ethyl acetate in hexane afforded 32 mg (17.8% Yield) of 5-(4-fluoro-phenyl)-isoxazole-3-carboxylic acid {2-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 459, 92.84%. 1H NMR (300 MHz, CDCl3): δ8.2 (s, 2H), 7.86 (m, 1H), 7.76 (m, 2H), 7.14 (m, 3H), 6.9 (s, 1H), 4.7 (m, 1H), 4.3 (m, 2H), 3.7 (m, 3H), 3.5 (m, 1H), 1.9 (m, 4H).
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH:7]([NH:11][CH:12]1[CH2:14][CH2:13]1)[CH:8]([CH3:10])[CH3:9])C.II.[H][H]>C1COCC1.CO>[CH:12]1([NH:11][CH:7]([CH:8]([CH3:10])[CH3:9])[CH2:6][OH:5])[CH2:14][CH2:13]1
Reactant: CCOC(=O)C(NC1CC1)C(C)C
Reactant: [H][H]
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(CO)NC1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (167 mg) was added to dry THF (10 mL) under argon and cooled to 0° C. To this mixture was added 2-cyclopropylamino-3-methyl-butyric acid ethyl ester (341 mg, obtained in example 25, step A]) followed by a solution of iodine (467 mg) in THF (5 mL) that was added over a period of 30 minutes. A strong hydrogen evolution was observed. The mixture was stirred at 0° C. for 30 minutes and then heated to reflux for 12 hours. The mixture was cooled and methanol was carefully added until a clear solution was obtained. After 30 minutes, the mixture was evaporated. The residue was treated with 20% aqueous KOH solution for 4 hours. The mixture was extracted with DCM three times and the combined organic layers were dried over Na2SO4 and evaporated to give crude 2-cyclopropylamino-3-methyl-butan-1-ol as a light yellow liquid (195 mg) that was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][C:20]#[N:21]>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][CH2:18][CH2:19][C:20]#[N:21])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCOc1ccc(C=O)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 109.7 %

Procedure:
Under argon, 2.44 g (20 mmol; 1 eq.) of 4-hydroxybenzaldehyde are dissolved in 20 mL DMF, and 5.53 g (40 mmol; 2 eq.) of K2CO3 are added. After 1 hour's stirring at 70° C., the medium becomes pink. Using a dropping funnel, a solution of 2.4 mL (24 mmol; 1.2 eq.) of 4-bromobutyronitrile in 6 mL DMF are added slowly. The reaction medium is stirred 1 hour at 70° C. then 2 hours at 90° C. After cooling, the medium is filtered through a sintered glass filter. The filtrate is diluted with dichloromethane until precipitation, then filtered again through a sintered glass filter. The new filtrate is concentrated to dryness then re-dissolved in dichloromethane. The organic phase is washed twice in water then with a saturated NaCl solution, dried over Na2SO4 and concentrated to dryness. 4.15 g of compound (11) are obtained and used without any additional purification (quantitative yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[C:16]([F:28])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[NH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][O:72][C:73]1[CH:82]=[CH:81][CH:80]=[C:79]([OH:83])[C:74]=1[C:75]([O:77][CH3:78])=[O:76]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:25])(=[O:26])[NH:23][C:22](=[O:27])[CH2:21]2)=[C:16]([F:28])[CH:15]=1)[C:10]([NH:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][O:72][C:73]1[CH:82]=[CH:81][CH:80]=[C:79]([OH:83])[C:74]=1[C:75]([O:77][CH3:78])=[O:76])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1)C(=O)O
Reactant: COC(=O)c1c(O)cccc1OCCCCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)cccc1OCCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
(2S)-2-[(tert-Butoxycarbonyl)amino]-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-fluorophenyl]propanoic acid (16.7 mg, 0.0400 mmol) in DMF (2.00 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (19.5 mg, 0.044 mmol). After five minutes N,N-diisopropylethylamine (20.9 μL, 0.120 mmol) and methyl 2-[(5-aminopentyl)oxy]-6-hydroxybenzoate hydrochloride (14.5 mg, 0.050 mmol) were added and the solution stirred at rt for 1 h. The product was directly purified by preparative LCMS to afford product as a white solid (17.8 mg, 68%). 1H NMR (400 MHz, CD3OD): δ 7.45–7.42 (m, 1H), 7.24–7.21 (m, 1H), 7.16–7.10 (m, 2H), 6.50–6.45 (m, 2H), 5.37–5.34 (m, 1H), 4.27–4.24 (m, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.87 (s, 3H), 3.42–3.05 (m, 7H), 2.99–2.94 (m, 1H), 1.79–1.75 (m, 2H), 1.47–1.40 (m, 4H), 1.36 (s, 9H). LCMS found for C30H39FN3O10S (M+H)+: m/z=652.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[H-].[Na+].F[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([O:18][C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[CH2:16][CH2:17]2)=[O:10])=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: N#Cc1ccc(F)cc1
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(O[C@H]2CC[C@H](NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 07086 (1.35 g, 4 mmol) in DMF (40 mL) was added 60% sodium hydride in oil (0.24 g, 6 mmol) portionwise at 0° C. After 10 min, 4-fluorobenzonitrile (0.73 g, 6 mmol) was added. The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction was quenched by adding water and the resulting white precipitates were collected and washed with water. The collected solid was recrystallized from methanol to give the title compound, 1.5 g (86%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.83-8.78 (s, 1H), 8.08 (d, J=2 Hz, 1H), 7.75 (d, J=9 Hz, 2H), 7.57-7.47 (m, 2H), 7.13 (d, J=9 Hz, 2H), 6.37 (d, J=7 Hz, 1H), 4.55-4.41 (m, 1H), 3.62-3.43 (m, 1H), 2.15-1.83 (m, 4H), 1.60-1.30 (m, 4H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[O:18][C:19]=2[CH2:20][CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:29][C:30]([F:44])([F:43])[C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:42])[CH2:38][C:39](=O)[CH3:40])=[CH:33][CH:32]=1.C(N(CC)CC)C>CO.COC(OC)OC.C(Cl)Cl>[CH2:20]([C:19]1[O:18][C:17]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[N:16][C:15]=1[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:2]([NH:1]/[C:39](/[CH3:40])=[CH:38]\[C:37](=[O:42])[C:34]2[CH:35]=[CH:36][C:31]([C:30]([F:29])([F:43])[F:44])=[CH:32][CH:33]=2)[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1)[CH3:21]
Reactant: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCc1oc(-c2ccc(F)cc2)nc1COc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: COC(OC)OC
Product: CCc1oc(-c2ccc(F)cc2)nc1COc1ccc(C[C@H](N/C(C)=C\C(=O)c2ccc(C(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 176 mg (0.46 mmol) of Intermediate 63, 105 mg (0.46 mmol) of Intermediate 24, and 0.14 mL triethylamine in MeOH (3.0 mL) and trimethylorthoformate (0.75 mL) to yield 152 mg (56% yield) of Example 76 after silica gel chromatography (5%-15% MeOH in DCM): TLC (DCM/MeOH, 4/1): Rf=0.55; 1H NMR (DMSO-d6, 300 MHz) δ11.55 (d, 1H, J=9.0), 7.99-7.94 (m, 4H), 7.73 (d, 2H, J=8.4), 7.33 (t, 2H, J=8.7), 7.16 (d, 2H), J=8.4), 6.90 (d, 2H, J=8.7), 5.61 (s, 1H), 4.93 (s, 2H), 4.23-4.18 (m, 1H), 3.22-3.18 (m, 1H), 2.85-2.73 (m, 4H), 1.72 (s, 3H), 1.17 (t, 3H, J=7.5); low resolution MS (ES+)m/e 597.09 (MH+).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([C:19]1[CH:28]=[CH:27][C:26]3[C:21](=[N:22][C:23]([Cl:29])=[CH:24][CH:25]=3)[N:20]=1)[CH:12]2[OH:30].N1C=CC=CC=1>C(#N)C.C(N(CC)CC)C>[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([C:19]1[CH:28]=[CH:27][C:26]3[C:21](=[N:22][C:23]([Cl:29])=[CH:24][CH:25]=3)[N:20]=1)[CH:12]2[O:30][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7]
Reactant: CCCCN=C=O
Reactant: O=C1c2ccc(Cl)cc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCNC(=O)OC1c2cc(Cl)ccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reaction time: 0.67 h

Procedure:
n-Butyl isocyanate (11.2 cc.) is added over the course of 15 minutes to a suspension of 5-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (3.5 g.) in acetonitrile (350 cc.) and triethylamine (0.2 cc.) heated at the reflux temperature. Pyridine (10 cc.) and triethylamine (5 cc.) are added and refluxing is continued for a further 40 minutes. After filtering hot and then cooling, the precipitate formed is filtered off and recrystallised from acetonitrile (250 cc.) to give 5-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-3-n-butylaminocarbonyloxy-isoindolin-1-one (3.3 g.) melting at 228°-230° C.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([CH3:6])[CH2:4][OH:5].F[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)=[N:11][CH:12]=[N:13]2>>[CH3:26][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[CH:17][C:8]=3[O:5][CH2:4][C@H:3]([NH:2][CH3:1])[CH3:6])[N:13]=[CH:12][N:11]=2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: Cc1cc(Nc2ncnc3cccc(F)c23)ccc1O
Reactant: CN[C@H](C)CO
Product: CN[C@H](C)COc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Yield: 80 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using (2R)-2-(methylamino)propan-1-ol (obtained as described in Becker et al., J. Chem. Soc. 1957, 858) and 4-[(5-fluoroquinazolin-4-yl)amino]-2-methylphenol (obtained as described in Example 3, preparation of starting materials) to give 2-methyl-4-[(5-{[(2R)-2-(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol as a brown solid in 80% yield; NMR spectrum (DMSO-d6) 1.16 (d, 3H), 2.14 (s, 3H), 2.34 (s, 3H), 3.04 (m, 1H), 3.24 (bs, 1H), 4.08 (dd, 1H), 4.25 (dd, 1H), 6.76 (d, 1H), 7.06 (d, 1H), 7.26 (d, 1H), 7.47 (d, 1H), 7.53 (dd, 1H), 7.65 (t, 1H), 8.39 (s, 1H), 9.17 (s, 1H), 10.37 (s, 1H); Mass spectrum MH+ 339.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:26](=[O:28])[CH3:27])[CH2:20][C:19]2[C:18]([OH:21])=[C:17]3[C:8]([C:9](=[O:23])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]3=[O:22])=[C:7]([OH:24])[C:6]=2[CH:5]([OH:25])[CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)(Cl)Cl.O1CCCC1>[C:26]([C:3]1([NH:2][C:40]([CH3:41])=[O:42])[CH2:20][C:19]2[C:18]([OH:21])=[C:17]3[C:8]([C:9](=[O:23])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]3=[O:22])=[C:7]([OH:24])[C:6]=2[CH:5]([OH:25])[CH2:4]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(=O)C1(N)Cc2c(O)c3c(c(O)c2C(O)C1)C(=O)c1ccccc1C3=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)NC1(C(C)=O)Cc2c(O)c3c(c(O)c2C(O)C1)C(=O)c1ccccc1C3=O
Reaction time: 0.5 h

Procedure:
A mixture of 9-amino-9-acetyl-6,7,11-trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione hydrochloride (130 mg), sodium carbonate (400 mg), a saturated sodium bicarbonate solution (20 ml), chloroform (10 ml) and tetrahydrofuran (10 ml) was stirred vigorously, and acetyl chloride (200 mg) was dropwise added thereto at room temperature. After the dropwise addition was completed, stirring was continued for 30 minutes. The reaction mixture was shaken with chloroform (50 ml). The chloroform layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from diethyl ether to give 9-acetyl-9-acetamino-6,7,11-trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione. M.P., 240°-248° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][OH:12])=[CH:9][CH:10]=1.C1OCCOCCOCCOCCOC1.[Cl:28][C:29]1[CH:38]=[C:37](Cl)[C:36]2[C:31](=[C:32]([Cl:42])[C:33]([O:40][CH3:41])=[CH:34][CH:35]=2)[N:30]=1.[NH4+].[Cl-]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:37]2[C:36]3[C:31](=[C:32]([Cl:42])[C:33]([O:40][CH3:41])=[CH:34][CH:35]=3)[N:30]=[C:29]([Cl:28])[CH:38]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CO)cc1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Sodium hydride (2.74 g, 1.2 eq.) was added portionwise to a solution of p-methoxybenzyl alcohol (8.55 mL, 1.2 eq.) and 15-crown-5 (13.6 mL, 1.2 eq.) in 35 mL of DMF. The mixture was allowed to stir at room temperature for 30 min, and then added to a solution of 2,4,8-trichloro-7-methoxyquinoline (15 g, 1 eq.) in DMF (75 mL) via canula. After 18 hrs of stirring at room temperature, the mixture was poured on 500 mL of water and NH4Cl aqueous. Ethyl acetate (200 mL) was added and the precipitate was filtered. The filtrate was purified by chromatography on silica gel to yield compound 274 in 56% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 3.85 (s, 3H), 4.05 (s, 3H), 5.19 (s, 2H), 6.77 (s, 1H), 6.97 (d, J=8.64 Hz, 2H), 7.23 (d, J=9.25 Hz, 1H), 7.41 (d, J=8.64 Hz, 2H), 8.08 (d, J=9.25 Hz, 1H); MS (ESI, EI+): m/z=386.1 (MNa+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.[Mg].II.BrC1C=CC(C2C=CC=CC=2)=CC=1F.[CH2:32]([CH:35]1[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]1)[CH2:33][CH3:34].Cl>C(OCC)C>[F:14][C:4]1[CH:3]=[C:2]([C:38]2([OH:41])[CH2:39][CH2:40][CH:35]([CH2:32][CH2:33][CH3:34])[CH2:36][CH2:37]2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: CCCC1CCC(=O)CC1
Agent: Cl
Agent: Fc1cc(-c2ccccc2)ccc1Br
Agent: II
Solvent: CCOCC
Product: CCCC1CCC(O)(c2ccc(-c3ccccc3)c(F)c2)CC1
Reaction time: 1 h

Procedure:
A few ml of a solution of 4-bromo-2-fluorobiphenyl (50 gram) in diethyl ether (150 ml) was added to magnesium turnings (5.3 gram) and diethyl ether (25 ml) under nitrogen. A crystal of iodine was added and reaction was initiated by warming. The remainder of the solution of 4-bromo-3-fluorobiphenyl was then added at a rate fast enough to sustain vigorous refluxing. After boiling for 1 hour, the solution of the Grignard reagent was cooled to 20° C. and then a solution of 4-n-propylcyclohexanone (27.9 gram) in diethyl ether (75 ml) was added over 30 minutes. After stirring for 1 hour, the mixture was poured onto 15% hydrochloric acid (2 liter) and the product extracted with ether (2×300 ml). The combined extracts were washed with water, dried and evaporated. The residue was crystallised from petroleum ether (b.p. 60°-80°, 120 ml) to give 1-(2-fluoro-4-biphenylyl)-4-propyl cyclohexane-1-ol as pale yellow crystals, m.p. 45°-72° (37.2 gram: 61.2% theory) (isomer ratio by glc 60.6: 39.4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[Li]CCCC.[B:19](OC)([O:22]C)[O:20]C.C(OCC)(=O)C>C1COCC1.CCCCCC>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([B:19]([OH:22])[OH:20])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: COB(OC)OC
Reactant: COCOc1ccc(Br)cc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1ccc(B(O)O)cc1OC
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 76.6 %

Procedure:
3-Methoxy-4-(methoxymethoxy)benzeneboronic acid was prepared as follows: In a 100 mL flask a mixture of 50% KOH in water (20 g KOH, 7 equiv, 20 g ice) was prepared under argon. To this rapidly stirring mixture at 0° C. (maintained with an ice bath) was added dichloromethane (50 mL) followed by 4-bromo-2-methoxyphenol (10.1 g, 50 mmol, 1.00 equiv), methoxymethylchloride (MOMCl) (4.00 mL, 42.5 mmol, 1.05 equiv) and tetrabutylammonium bromide (322 mg, 1 mmol, 0.02 equiv). The bath was removed and the mixture was slowly allowed to warm to 23° C. with rapid stirring for 2 h. The mixture is transferred to a separatory funnel and diluted with dichloromethane (350 mL) and water (300 mL) which are used to aid the transfer. The organic material (now the bottom layer) are separated, dried over sodium sulfate, decanted and concentrated under reduced pressure to give 4-bromo-2-methoxy-1-(methoxymethoxy)benzene as a yellow liquid which is pure by 1H NMR (11.9 g, 97%): 1H NMR (CDCl3) δ 7.0 (s, 3H), 5.13 (s, 2H), 3.84 (s, 3H), 3.47 (s, 3H). MS (EI) [m+H]/z Calc'd 235, found 235. In a 50 mL round-bottom flask, 4-bromo-2-methoxy-1-(methoxymethoxy)benzene (4.80 g, 19.4 mmol, 1.00 equiv) was taken up in THF (35 mL) and was cooled to −78° C. (20 min for this volume). To this was added n-BuLi (12.75 mL, 1.6 M in hexane, 20.4 mmol. 1.05 equiv) and the mixture was allowed to stir at −78° C. for 40 min. This was then added via cannula to a second flask containing B(OMe)3 (22 mL, 194 mmol, 10 equiv) in THF (50 mL) at −78° C. After 20 min, the cold bath was removed. After 15 min of warming (−0° C., ice on the side of the flask begins to melt) water (50 mL) was added to the reaction mixture which was stirred for 45 min. The mixture was concentrated under reduced pressure to remove most THF and was then partitioned between ethyl acetate (300 mL) and water (150 mL) which was made acidic by addition of a small amount of 20% citric acid (−10 mL). The organic material was dried over sodium sulfate and concentrated under reduced pressure to give a solid. Trituration with ethyl acetate (10 mL) and hexane (5 mL) followed by filtering gave 3-methoxy-4-(methoxymethoxy)benzene-boronic acid as a white solid (3.15 g, 77%): Rf sm 0.59, p 0.18 (ethyl acetate-hexane 1:1); 1H NMR (CDCl3) δ 7.85 (d, 1H, J=8 Hz), 7.72 (s, 1H), 7.22 (d, 1H, J=8 Hz), 5.30 (s, 2H), 4.00 (s, 3H), 3.55 (s, 3H).