Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][C:33]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-:41].[Ca+2].[Cl-]>C(O)(C(F)(F)F)=O>[ClH:41].[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][C:33]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[C:20]([OH:22])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccccc1-c1ncncc1C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Reactant: [Cl-]
Agent: [Ca+2]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1ncncc1C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
A solution of 290 mg (0.54 mmol) of (2R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-o-tolylpyrimidin-5-yl)propanoate in TFA (2.7 mL), protected from the atmosphere by a calcium chloride-filled drying tube was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo at less than 40° C. and the resulting orange oil was redissolved in toluene twice and evaporated to give the title compound as a white powder, 255 mg, 98% yield.
Reaction SMILES: C([CH:3](Br)[C:4](=O)[C:5]([O-:7])=[O:6])C.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1.Cl[CH2:19][CH2:20]Cl.C(O)C>C(O)C>[CH2:19]([O:7][C:5]([C:4]1[N:17]=[C:14]2[CH:13]=[CH:12][C:11]([Br:10])=[CH:16][N:15]2[CH:3]=1)=[O:6])[CH3:20]
Reactant: CCC(Br)C(=O)C(=O)[O-]
Reactant: Nc1ccc(Br)cn1
Reactant: ClCCCl
Solvent: CCO
Product: CCOC(=O)c1cn2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethylbromopyruvate (62.0 g; 318 mmol; 40.0 ml) was added to a solution of 5-bromo-2-aminopyridine (50.0 g; 289 mmol) in ethanol (500 ml) through a dropping funnel. The reaction batch was first stirred for 30 min at room temperature and then refluxed for 8 hours while stirring (DC control: DCE-ethanol 5:1). The solvent was removed under vacuum and the residue taken up in DCM. It was washed first with saturated common salt solution and then with saturated sodium hydrogen carbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness. The residue was recrystallized from dry diethyl ether. Yield: 41 g (53%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1I.[S:30]1[CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32][CH2:31]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1[C:33]1[CH2:34][CH2:35][S:30][CH2:31][CH:32]=1
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(C3=CCSCC3)c(Cl)cc21
Temperature: 85 °C

Procedure:
Palladium tetrakistriphenylphosphine (41.7 mg, 0.036 mmol) was added to a stirred suspension of (3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-hexahydrofuro[3,2-b]furan-3-ol (Intermediate 3, 100.0 mg, 0.181 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 45, 61.2 mg, 0.270 mmol), and potassium phosphate tribasic (115.0 mg, 0.542 mmol) in degassed 20% water in dioxane (1.85 mL). The reaction mixture placed under N2 and heated at 85° C. for 10 h. The reaction mixture was cooled to room temperature. The lower aqueous layer drawn off and discarded. The remaining reaction mixture was evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 12 g silica RediSep Rf® Gold column and employing a 0-100% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C23H32ClN3O5SSi 525.15 observed m/e: 526.17 (M+H)+ (Rt 1.64/2.0 min)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Cl[CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH2:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: O=C(CCCl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1CCC(=O)c1ccccc1
Temperature: 100 °C
Yield: 61.5 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 330 mg, 1.08 mmol), tetrabutylammonium iodide (400 mg, 1.08 mmol) and 3-chloropropiophenone (Acros; 820 mg, 4.86 mmol) in dimethylformamide (6 mL) was heated at 100° C. for 3.5 h. The reaction mixture was cooled to room temperature. Dichloromethane (100 mL) was added and the solution was washed with water (4×25 mL), aqueous sodium thiosulfate (25 mL), and brine (25 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 g column, eluting with 50-100% ethyl acetate/hexane. The resulting material was dried under high vacuum at 70° C. for 3 h to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(3-oxo-3-phenyl-propyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (290 mg, 61%) as a tan solid. APCI(+)-MS (M+H) 437.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][C:45]1[CH:46]=[C:47]([NH2:51])[CH:48]=[CH:49][CH:50]=1.O>CN(C=O)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:26]([NH:51][C:47]4[CH:48]=[CH:49][CH:50]=[C:45]([O:44][C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=5)[CH:46]=4)=[O:27])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc(Oc2ccccn2)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cccc(Oc5ccccn5)c4)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (1.11 g, 3.0 mmol) and 1,1′-Carbonyldiimidazole (535 mg, 3.3 mmol) were suspended in dry DMF (20 mL) and the mixture was stirred at rt for 24 h. While stirring, a portion of the reaction mixture (6.7 mL, ˜1 mmol) was transferred to a vial containing 3-(Pyridin-2-yloxy)-phenylamine (205 mg, 1.1 mmol). The resulting mixture was stirred at rt overnight and the reaction progress was monitored by LCMS. After 48 h, additional 3-(Pyridin-2-yloxy)-phenylamine (37 mg, 0.2 mmol) was transferred to the reaction mixture and stirring continued for another 24 h. The reaction mixture was acidified with acidic acid and water. The volatiles were removed in vacuo and the residue was dissolved in DMF and purified using C-18 preparatory HPLC to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-[3-(pyridin-2-yloxy)-phenyl]-urea as a white solid (310 mg, 64% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.81 min (98.6%); mp: 298-300° C.: 1H NMR (DMSO-d6) δ 1.84-2.06 (m, 1H, CHH), 2.19-2.44 (m, 1H, CHH), 2.54-2.68 (m, 1H, CHH), 2.79-3.05 (m, 1H, CHH), 4.08-4.60 (m, 4H, CH2, CH2), 5.10 (dd, J=5.1, 13.2 Hz, 1H, CH), 6.64 (dd, J=1.4, 8.0 Hz, 1H, Ar), 6.81 (t, J=5.9 Hz, 1H, NH), 6.99 (d, J=8.3 Hz, 1H, Ar), 7.07-7.18 (m, 2H, Ar), 7.24 (t, J=8.1 Hz, 1H, Ar), 7.33 (t, J=2.1 Hz, 1H, Ar), 7.43 (d, J=7.7 Hz, 1H, Ar), 7.50 (s, 1H, Ar), 7.68 (d, J=7.7 Hz, 1H, Ar), 7.78-7.97 (m, 1H, Ar), 8.16 (dd, J=1.5, 4.9 Hz, 1H, Ar), 8.82 (s, 1H, NH), 10.97 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.18, 42.73, 47.12, 51.56, 110.23, 111.51, 113.54, 113.68, 118.99, 121.85, 122.93, 126.86, 129.56, 130.29, 140.10, 141.79, 142.39, 144.77, 147.52, 154.37, 155.09, 163.03, 167.93, 170.99, 172.85; LCMS: MH=486; Anal Calcd for C26H23N5O5+0.3H2O: C, 63.61; H, 4.85; N, 14.27. Found: C, 63.62; H, 4.62; N, 14.18.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:15]#[N:16])[C:11]=1N(C)C)[N:8]=[C:7](CO[Si](C(C)(C)C)(C)C)[CH:6]=[CH:5]2.C(NCC)C.C[Si](C#C)(C)C>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>[N:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][C:10]=2[C:15]#[N:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1c(Br)cc2ccc(CO[Si](C)(C)C(C)(C)C)nc2c1C#N
Agent: I[Cu]I
Agent: C#C[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: N#Cc1cccc2cccnc12
Temperature: 110 °C
Yield: 201.8 %

Procedure:
In a sealed tube were introduced the 6-bromo-2-((tert-butyldimethylsilyloxy)methyl)-7-(dimethylamino)quinoline-8-carbonitrile (946 mg, 2.25 mmol, 1.0 eq), PdCl2(PPh3)3 (79 mg, 0.11 mmol, 5% mol), copper iodide (21 mg, 0.11 mmol, 5% mol), and triphenylphosphine (106 mg, 0.39 mmol, 20% mol). Then, DMF (5 mL) was added followed by diethylamine (3.5 mL, 34 mmol, 15 eq) and trimethylsilylacetylene (350 μL, 2.5 mmol, 1.1 eq). The mixture was heated at 110° C. overnight. After cooling down the solvent was evaporated and the crude product was purified by column chromatography (Florisil, Cyclohexane-EtOAc 95:5) to afford 2-((tert-butyldimethylsilyloxy)methyl)-7-(dimethylamino)-6-(trimethylsilyl)ethynyl)quinoline-8-carbonitrile as a white solid (700 mg, 71%).
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([CH:9]=[CH:10][CH:11]=[CH:12][C:13]([O:15]CC)=[O:14])=[CH:7][N:8]=1)[CH2:2][CH3:3].[H][H]>>[CH2:1]([C:4]1[S:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1ncc(C=CC=CC(=O)OCC)s1
Reactant: [H][H]
Product: CCCc1ncc(CCCCC(=O)O)s1

Procedure:
Using the procedure of Example 10, ethyl 5-(2-propyl-5-thiazolyl)2,4-pentadienoate was reacted with hydrogen in the presence of activated carbon containing 10% palladium and the resulting product was saponified to obtain 2-propyl-5-thiazole-pentanoic acid. The latter product was reacted with α,β-ethanedisulfonic acid to obtain the hemi-α,β-ethane disulfonate of 2-propyl-5-thiazole-pentanoic acid melting at 124°C.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:5][CH:4]=1)=O.[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.CO.[O:26]1[CH2:31][CH2:30][O:29][CH2:28]C1>>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH2:15][NH:14][C:31](=[O:26])[CH:30]([C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH:13]=[CH:12][N:11]=[CH:10]3)=[CH:5][CH:4]=2)[O:29][CH3:28])=[CH:17][CH:18]=1)#[N:21]
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: N#Cc1ccc(CN)cc1
Reactant: C1COCCO1
Solvent: CO
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(-n2ccnc2)cc1

Procedure:
1-(4-Formylphenyl)-1H-imidazole was reacted according to general procedure A using methanol/dioxane as a solvent. The product of this reaction was subsequently coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(4-imidazol-1-yl-phenyl)-2-methoxy-acetamide. Colorless foam. MS 347.2 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][OH:16])[CH2:12][CH2:13][C:7]=2[C:6]([O:17][CH3:18])=[C:5]([O:19][CH3:20])[C:4]=1[O:21][CH3:22].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:30][S:31]([O:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][C:7]2[C:6]([O:17][CH3:18])=[C:5]([O:19][CH3:20])[C:4]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[C:8]=2[CH2:9][CH2:10]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCO)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOS(C)(=O)=O)CC2
Reaction time: 0.25 h

Procedure:
To a solution of 2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethanol (2.50 g) and triethylamine (1.68 ml) in acetonitrile (50 ml) was dropwise added methanesufonyl chloride (0.750 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, saturated aqueous sodium bicarbonate was added to the solution with cooling with ice, which was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (3.12 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[OH:13].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1.O>CN(C=O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1
Reactant: O=c1cc(CO)occ1OCCCCCBr
Reactant: Oc1ccnc2c(C(F)(F)F)cccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(CO)occ1OCCCCCOc1ccnc2c(C(F)(F)F)cccc12
Reaction time: 0.17 h
Yield: 35 %

Procedure:
8-Trifluoromethyl-quinolin-4-ol (0.84 g, 2.88 mmol) was dissolved in DMF (5 mL). Cs2CO3 (0.98 g, 3.02 mmol) was added at room temperature and the mixture was stirred for 10 min. A solution of 5-(5-bromo-pentyloxy)-2-hydroxymethyl-pyran-4-one 10 (0.86 g, 3.02 mmol) in DMF (5 mL) was added via syringe. This mixture was stirred at 50° C. for 18 h. Water (10 mL) was added and the mixture extracted with EtOAc (2×50 mL), washed with water (3×50 mL), brine (3×50 mL) dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent (CH2Cl2:MeOH)=90:10. 5-(5-(8-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 14 was obtained (0.53 g, 35% yield) as a pale yellow foam.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][NH:11][CH3:12])[CH:8]=[CH:9][C:2]1=2.Cl.[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[CH:21][C:20]([CH:25]=[CH:26][C:27]([OH:29])=O)=[CH:19][C:18]=2[CH2:17][CH2:16]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][N:11]([CH3:12])[C:27](=[O:29])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[N:22][C:23]4[NH:24][C:15](=[O:14])[CH2:16][CH2:17][C:18]=4[CH:19]=3)[CH:8]=[CH:9][C:2]1=2
Reactant: CNCc1ccc2sccc2c1
Reactant: O=C(O)C=Cc1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccc2sccc2c1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Temperature: 40 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of benzo[b]thiophen-5-yl-N-methylmethanamine (260 mg, 1.47 mmol), 3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-acrylic acid hydrochloride (377 mg, 1.48 mmol), HOBt (200 mg, 1.48 mmol) and DIPEA (1.05 mL, 6.03 mmol) in anhydrous DMF (24 mL) was added EDC hydrochloride (284 mg, 1.48 mmol). The mixture was stirred overnight at 40° C. Water (50 mL) was added and the solution was stirred for 1 h. The reaction mixture was extracted with ethyl acetate (3×80 mL). Combined organic layers were washed with water (50 mL) and brine (50 mL) and concentrated to give an orange solid which was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to afford (E)-N-(benzo[b]thiophen-5-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide (430 mg, 78%) as a pink solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.67-10.64 (m, 1H), 8.37-8.33 (m, 1H), 8.08-8.05 (m, 1H), 8.00-7.95 (m, 1H), 7.75-7.71 (m, 2H), 7.56-7.52 (m, 1H), 7.45-7.43 (m, 1H), 7.37-7.22 (m, 2H), 4.93-4.73 (m, 2H), 3.12-2.86 (m, 5H), 2.54-2.51 (m, 2H); ESI MS m/z 378 [C21H19N3O2S+H]+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:22][C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[CH:24]=1>C1COCC1>[S:27]1[C:23]([CH2:22][CH:9]2[CH2:10][CH2:11][N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]2=[O:12])=[CH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]1=2
Reactant: O=C1CCCN1C1CCCCC1
Reactant: BrCc1cc2ccccc2s1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2cc3ccccc3s2)CCN1C1CCCCC1
Yield: 71.5 %

Procedure:
Place 1-cyclohexyl-pyrrolidin-2-one (500 mg) in THF (30 mL) and cool to −78° C. Slowly add lithium diisopropylamide (LDA) (2M, 1.5 eq) and stir for 15 minutes. Add 2-bromomethyl-benzo[b]thiophene [J. Med. Chem. (1992) 1176-1183] (815 mg, 3.59 mmol) and stir for 3 hours. Quench with ammonium chloride and extract with dichloromethane. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (20-50% ethyl acetate in hexanes) to give 670 mg, 71% of the title compound as a white powder. MS (APCI-pos mode) m/z (rel intensity) 314 (100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[C:16]#N)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[O:30]1CCCC1>CCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:30])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)(C#N)c1cccc(OCc2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a 15° C. solution of 325 g. (1.25 mole) of 2-(3-benzyloxyphenyl)-2-methylpropionitrile in 1.85 liters of tetrahydrofuran is added 1.6 moles of diisobutylaluminum hydride as a 1.3 M solution in hexane (reaction temperature is maintained at 15°-18° C.). The reaction mixture is allowed to warm to room temperature and is stirred 2 hours longer. It is then quenched by addition to a solution of 170 ml. of concentrated sulfuric acid in 670 ml. of water (temperature ≤30° C.). The resultant mixture is allowed to warm to room temperature and is then stirred an additional 2 hours. The organic layer is separated and the aqueous phase extracted once with one liter of ether. The combined organic phase is washed with 500 ml. of water and 500 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 315 g. (99%) of the title product.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:29])=[CH:23]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.[H][H]>C(Cl)Cl.CN(C=O)C.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:29])=[CH:23]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31]
Reactant: [H][H]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Yield: 87.1 %

Procedure:
A solution of 7-benzyloxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (0.2 g, 0.5 mmol), (prepared as described in Example 48), in a mixture of methylene chloride (5 ml) and DMF (2 ml) containing 10% palladium-on-charcoal (50 mg) was treated with hydrogen at 1.8 atmospheres pressure for 2 hours. The suspension was filtered and the catalyst was washed with methanol followed by methylene chloride. The volatiles were removed from the filtrate by evaporation. The residue was triturated with water. The resulting solid was washed with water and dried under vacuum over phosphorus pentoxide at 60° C. to give 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (140 mg, 89%).
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].Cl>C1(C)C=CC=CC=1.C1CCCCC1.CS(C)=O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])[CH:19]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 65.8 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a distillation device and a dropping funnel and having an inner volume of 200 ml were charged 3.40 g (62.9 mmol) of sodium methoxide and 30 ml dimethyl sulfoxide under argon atmosphere, and then, while stirring at room temperature, 8.48 g (62.9 mmol) of dimethyl malonate with a purity of 98% was gradually added dropwise over 5 minutes. Moreover, 10 ml of cyclohexane was added to the mixture, and after raising the temperature to 100 to 105° C., the formed methanol was subjected to azeotropic distillation (removed by distillation) with cyclohexane. After this operation (removal of methanol by distillation) was repeated twice, the reaction mixture was cooled to 70° C., and 5.10 g (31.4 mmol) of 2,4-difluoro-nitrobenzene with a purity of 98% was gradually added dropwise over 10 minutes, and the resulting mixture was reacted at 70 to 80° C. for one hour. After completion of the reaction, the mixture was cooled to room temperature, 100 ml of toluene was added to the mixture and 5.25 ml (31.4 mmol) of 6 mol/l hydrochloric acid was gradually added dropwise while stirring. Then, the organic layer was separated, and the resulting mixture was washed successively with 50 ml of water and 50 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent: hexane:ethyl acetate=9:1 (volume ratio)) to obtain 5.60 g of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate (isolation yield: 64%) as white crystals with a purity of 98% (areal percentage by high performance liquid chromatography)
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1.II.C([O:15][CH2:16][CH3:17])=O>CCOCC>[F:2][C:3]1[CH:4]=[C:5]([CH:16]([C:17]2[CH:4]=[C:3]([F:2])[CH:8]=[C:7]([F:9])[CH:6]=2)[OH:15])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CCOC=O
Reactant: Fc1cc(F)cc(Br)c1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: OC(c1cc(F)cc(F)c1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 486 mg magnesium, 8 mL dry ether, a small amount of 3,5-difluoro-bromobenzene and some iodine was warmed to start the Grignard reaction. 2.38 mL 3,5-difluoro-bromobenzene in 40 mL dry ether were added dropwise and the mixture refluxed for one hour. 0.81 mL ethyl formate was added and the mixture stirred for 21 hours at room temperature. The reaction was quenched with 7 mL 1N hydrochloric acid, diluted with ethyl acetate and washed with water and brine. Evaporation of the solvents and chromatography of the residue afforded 1.56 g of a light yellow solid, m.p.: 62° C.; MS: 315 ([M+AcO]−).