Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)[C:3]([O:5][CH3:6])=[O:4].Cl[CH2:33][CH2:34][N:35]([CH2:46][CH2:47]Cl)[S:36]([C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=1)(=[O:38])=[O:37]>C(N(C(C)C)CC)(C)C.C(#N)C>[CH3:45][C:42]1[CH:43]=[CH:44][C:39]([S:36]([N:35]2[CH2:34][CH2:33][N:1]([C@@H:2]([CH2:7][C:8]3[N:9]=[CH:10][N:11]([C:13]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:12]=3)[C:3]([O:5][CH3:6])=[O:4])[CH2:47][CH2:46]2)(=[O:38])=[O:37])=[CH:40][CH:41]=1
Reactant: COC(=O)[C@@H](N)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N1CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19 %

Procedure:
A suspension of methyl (2S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanoate (1 g, 2.4 mmol) in diisopropylethylamine (5 ml), was stirred at room temperature for 20 minutes. N,N-Bis(2-chloroethyl)-4-methylbenzenesulfonamide (720 mg, 2.4 mmol) was added and the mixture was stirred at reflux for 3 hours. The mixture was allowed to cool and diluted with acetonitrile. The resultant solution was concentrated under reduced pressure and the residue was suspended in aqueous sodium carbonate solution and extracted with dichloromethane (3×20 ml). The combined organic extracts were washed with brine (3×20 ml), dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of dichloromethane:methanol (99:1). The isolated material was dissolved in ether and the resultant solution concentrated under reduced pressure to afford the title compound as a colorless foam, 300 mg, 19% yield.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH2:6][C:5]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:4]2)[O:2]1.Cl.C(=O)(O)[O-].[Na+].ClCCl>CC(C)=O>[F:25][C:24]([F:26])([F:27])[C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:21]=1)[CH2:17][O:16][CH2:15][C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7][CH2:8][C:3](=[O:2])[CH2:4]1
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCC3(C2)OCCO3)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Yield: 92.3 %

Procedure:
To a solution of 1-(((3,3-ethylenedioxy-1-phenylcyclohexyl)methoxy)methyl)-3,5-bis(trifluoromethyl)benzene (990 mg, 2.09 mmol) in acetone (4 mL) at room temperature were added 1N HCl solution (3.13 mL) and the resulting mixture was stirred at reflux for 2 hr. After cooling down, saturated sodium bicarbonate and dichloromethane were added and the organic layer was separated. The aqueous layer was extracted with dichloromethane 2 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to give the title compound as clear pale yellow sticky oil (830 mg, 92% yield). 1H NMR (400 MHz, CDCl3) δ 1.60 (1H, m), 1.88 (1H, m), 2.19-2.24 (2H, m), 2.29-2.32 (2H, m), 2.85 (2H, dd, J=12, 68 Hz), 3.51 (2H, dd, J=12, 56 Hz), 4.52 (2H, dd, J=16, 18 Hz), 7.22-7.25 (1H, m), 7.32 (4H, d, J=4 Hz), 7.63 (2H, s), 7.77 (1H, s). HPLC purity (retention time): 90% (2.32 min, method C). MS: 453.37 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[CH:7][NH2:8])=[CH:4][C:3]=1[CH3:11].CO.S([CH2:24][N+:25]#[C-:26])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[N:25]([CH3:26])[CH:24]=[N:8][CH:7]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cc(C=CN)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: Cc1cc(-c2cncn2C)ccc1Br
Yield: 59.9 %

Procedure:
(4-Bromo-3-methylbenzylidene)methylamine (D91, 2.15 g, 10.1 mmol) was dissolved in dry DME (30 ml) and methanol (70 ml) containing tosylmethylisocyanide (3.0 g; 15.4 mmol) and this solution was treated with potassium carbonate (2.8 g, 20.3 mmol). The whole was heated at reflux for 48 hours, cooled and evaporated in vacuo. The residue was partitioned between brine and chloroform (3 times), and the organics combined and dried over Na2SO4. The organics were filtered and evaporated in vacuo then the residue purified by flash silica gel chromatography (with chloroform as eluant) to yield the title compound as an orange gum (1.52 g, 60%).
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([NH:13][C:14](=O)[CH2:15][C:16](O)([CH3:18])[CH3:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([C:3]2[N:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH3:17])[S:31][C:2]=2[NH2:1])[CH:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(Cl)cc1C(NC(=O)CC(C)(C)O)C(N)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1nc(C=C(C)C)sc1N
Temperature: 100 °C
Yield: 22.8 %

Procedure:
A mixture of N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-hydroxy-3-methylbutanamide (240 mg, 0.762 mmol), Lawesson's reagent (308 mg, 0.76 mmol) and pyridine (2.5 mL) was heated to 100° C. for 18 hours. After cooling, DCM was added and the mixture washed with water, sodium hydrogen carbamate (sat. aq.) and brine, and concentrated to dryness. 4-(5-chloro-2-methoxyphenyl)-2-(2-methylprop-1-enyl)thiazol-5-amine (51.0 mg) was isolated as a pale yellow solid. LCMS (ESI) m+H=295.3; NMR (400 MHz, DMSO-d6): δ 7.38 (d, 1H); 7.31 (dd, 1H); 7.09 (d, 1H); 6.24 (t, 1H); 5.50 (s, br, 2H); 3.83 (s, 3H); 2.02 (d, 3H); 1.89 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Sn](CCCC)(CCCC)CCCC)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[CH2:23]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45](Br)[CH:46]=2)[NH:41][CH:40]=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:23]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH2:2])=[CH:9][CH:8]=3)[CH:46]=2)[NH:41][CH:40]=1)=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(N)=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(-c2ccc3[nH]cc(C[C@H]4CCCN4C(=O)OCc4ccccc4)c3c2)cc1
Yield: 29.5 %

Procedure:
4-carbamoylphenyltri-n-butylstannane (1.833 g, 4,469 mmol) (see Preparation 8) and 3-(1-benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-bromo-1H-indole (1.67 g, 4.05 mmol) (see Preparation 35B) were reacted together in the presence of tri-o-tolylphosphine, triethylamine and palladium (II) acetate using a procedure similar to that described in Example 1. This yielded the title compound as an off-white foam (541 mg). Found: C,71.64; H,6.02; N,8.57; C28H27N3O3. 1/4CH2Cl2 requires: C,71.84; H,5.84; N,8.85%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])=[N:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH2:21][CH2:22][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:28]([F:31])([F:29])[F:30])([C:32]([F:33])([F:35])[F:34])[OH:27])=[N:10]1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(C3=CCNCC3)nc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CC=C(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.4 %

Procedure:
1-(2-chloro-phenyl)-5-[6-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-3-yl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 356, cyclopropanesulfonyl chloride (8.0 uL, 0.08 mmol), and triethylamine (38.0 uL, 0.28 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [OH-].[Na+].C(O)(=O)C.[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:39])[CH:25]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=[NH:38])[NH2:37])[CH:31]=2)[CH2:26][CH2:27][CH3:28])=[CH:19][CH:18]=1)(=[O:10])=[O:9].Cl[C:41]([O:43][CH3:44])=[O:42]>ClCCl>[CH3:44][O:43][C:41](=[O:42])[NH:38][C:36](=[NH:37])[C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH:25]([C:24](=[O:39])[NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:8]([CH3:7])(=[O:9])=[O:10])=[CH:22][CH:21]=2)[CH2:26][CH2:27][CH3:28])[CH:31]=1
Reactant: CCCC(Oc1cccc(C(=N)N)c1)C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCC(Oc1cccc(C(=N)NC(=O)OC)c1)C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1

Procedure:
1 N NaOH is added up to a pH of 9 to a solution of 500 mg (1.07 mmol) of 2-(3-carbamimidoylphenoxy) pentanoic acid (2′-methanesulfonylbiphenyl-4-yl)amide acetate (3) in 40 ml of dichloromethane kept at 5° C. 0.108 ml (1.40 mmol) of methyl chloroformate is then added. During the following hour, the pH is kept at a value of 9 by addition of further 1 N NaOH. The organic phase is then separated off, washed with water, dried over sodium sulfate and evaporated. A colourless solid is obtained; FAB 524
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=S)=[CH:25][CH:24]=1.C(N=C=NC(C)C)(C)C>C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[NH:15][C:11]3=[N:10][C:9]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[F:1])[CH:13]=[C:12]3[N:14]=2)=[CH:25][CH:24]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CCO
Product: Fc1cnccc1-c1cc2nc(Nc3ccc(Cl)cc3)[nH]c2nc1-c1cccnc1
Temperature: 50 °C
Yield: 46.9 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.050 g, 0.179 mmol) and 1-chloro-4-isothiocyanatobenzene (0.045 g, 0.267 mmol) in ethanol (1 mL), 1,3-diisopropylcarbodiimide (0.042 mL, 0.267 mmol) was added. The mixture was heated at 50° C. for 2 h. After cooling at room temperature, the solid precipitated was filtered off to give the title compound (0.035 g, 47% of yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[C:25](=O)[C:24]([CH3:28])([CH3:27])[C:23]([CH3:29])=[N:22]4)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[C:25](=[S:39])[C:24]([CH3:28])([CH3:27])[C:23]([CH3:29])=[N:22]4)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1=NN(c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)C(=O)C1(C)C
Solvent: Cc1ccccc1
Product: CC1=NN(c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)C(=S)C1(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 2-{4-[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-4,4,5-trimethyl-2,4-dihydro-pyrazol-3-one (0.21 g, 0.0005 mol) and Lawesson reagent (0.22 g 0.0005 mol) in toluene (3 ml) is stirred at 100° C. for one hour. After cooling the resulting solution is directly purified by silicagel column chromatography to the title compounds (IVb) (0.19 g, 88.1%) m.p. 167–168° C.,
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][N:6]1[CH:14]([C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:24])[CH3:2].S(=O)(=O)(O)O.[C:32](=O)([O-])O.[Na+]>CO>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH:14]([C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([O:19][CH3:32])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:24])[CH3:26]
Reactant: CCN(CC)CCN1C(=O)c2ccccc2C1c1ccccc1C(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCN1C(=O)c2ccccc2C1c1ccccc1C(=O)OC

Procedure:
To a solution of 0.53 g of Compound 27 in 5 ml of methyl alcohol was added 0.2 ml of conc. sulfuric acid. After heating at reflux for 2 hours, pH was adjusted to 7 with sodium hydrogencarbonate. The mixture was concentrated under reduced pressure. After 30 ml of water and 30 ml of methylene chloride were added to the residue, pH was adjusted to 12 with 10N-sodium hydroxide solution. After shaking, the aqueous layer was discarded and the organic layer was washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure to give 0.14 g of methyl 2-[2-(2-diethylaminoethyl)isoindolin-1-on-3-yl]benzoate (Compound 28).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([CH3:38])=[CH:32]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([CH3:38])=[CH:32]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
A solution of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline (155 mg, 0.3 mmol), (prepared as described in Example 69), in methylene chloride (5 ml) containing TFA (1 ml) was stirred at ambient temperature for 30 minutes. The volatiles were removed under vacuum and the residue was treated with water and adjusted to pH12 with 2M sodium hydroxide. The mixture was extracted with methylene chloride. The organic layer was dried (MgSO4), and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate/methanol (5/4/1) followed by methylene chloride/methanol (9/1) and by 3M ammonia in methanol/methanol/methylene chloride (5/15/80). After removal of the solvent by evaporation, the residue was dissolved in the minimum of methylene chloride, ether was added followed by petroleum ether. The precipitate was collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (120 mg, 96%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:25])[C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:25])[C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:29][CH:26]4[CH2:28][CH2:27]4)=[O:21])=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CN(c1ccc(C(=O)O)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc(C(=O)NC2CC2)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)nicotinic acid (33.8 mg, 0.1 mmol) in DMF (2 mL) were added cyclopropylamine (5.71 mg, 0.2 mmol), DIPEA (26 mg, 0.2 mmol) and HATU (38.0 mg, 0.1 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography to give the title compound. MS (m/z): 378 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([CH2:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([CH2:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[CH2:2][CH2:3]1
Reactant: CCc1nn2c(-c3c(C)cc(C)cc3OC)cccc2c1NCC1CC1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nn2c(-c3c(C)cc(C)cc3OC)cccc2c1N(CC1CCOCC1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
After dissolving N-cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine (255 mg) in tetrahydrofuran (2 mL), tetrahydro-2H-4-pyrancarbaldehyde (173 mg) [CAS No. 50675-18-8] and sodium triacetoxyborohydride (241 mg) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (134 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a yellow oil.
Reaction SMILES: [C:1](=O)([O:17]N1C(=O)CCC1=O)[O:2][CH2:3][CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[NH2:26][C:27]1([C:31]([OH:33])=[O:32])[CH2:30][O:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH:15]1[C:16]2[CH:4]([CH2:3][O:2][C:1]([NH:26][C:27]3([C:31]([OH:33])=[O:32])[CH2:30][O:29][CH2:28]3)=[O:17])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: NC1(C(=O)O)COC1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC1(C(=O)O)COC1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-yl carbonate (3.2 g, 9.5 mmol) in dioxane (30 ml) was added to a solution of 3-amino-oxetane-3-carboxylic acid (1.17 g, mmol) and potassium carbonate (2.76 g, 20.0 mmol) in water (30 ml). The light yellow opaque solution was stirred at room temperature for 75 minutes. During that time, a white solid precipitated. The mixture was diluted with water and extracted two times with diethyl ether. The white solid did not dissolve and was kept therefore in the aqueous layer, which was acidified to pH 2 by addition of 1N HCl and extracted three times with EtOAc. The combined EtOAc layers were washed with brine, dried with Na2SO4 and evaporated. The crude title compound was obtained as white solid and was used without further purification.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:3]=1[F:22].[C:23]1([CH3:54])[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([Sn](CCCC)(CCCC)CCCC)[CH:38]=3)[CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.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>[CH:13]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:22])=[C:2]([C:36]4[CH:35]=[C:34]5[C:39](=[CH:38][CH:37]=4)[CH2:40][N:32]([S:29]([C:26]4[CH:27]=[CH:28][C:23]([CH3:54])=[CH:24][CH:25]=4)(=[O:31])=[O:30])[CH2:33]5)[C:11]=3[CH3:12])[C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8]2)[CH2:15][CH2:14]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CN(S(=O)(=O)c1ccc(C)cc1)C2
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(Br)c(F)cc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(-c3ccc4c(c3)CN(S(=O)(=O)c3ccc(C)cc3)C4)c(F)cc2c1=O

Procedure:
In 1 ml of toluene was suspended 47 mg of ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, and to this suspension were added 74 mg of 2-(p-toluenesulfonyl)-5-tributylstannylisoindoline and 1.5 mg of tetrakis(triphenylphosphine)palladium (0), after which the resulting mixture was heated under reflux for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by a column chromatography (eluent: n-hexane:ethyl acetate=1:1), and diethyl ether was then added thereto, after which the crystals formed were collected by filtration, to obtain 27 mg of colorless, crystalline ethyl 1-cyclopropyl-6-fluoro-8-methyl-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]1[CH:19]([CH3:21])[S:20][C:7]1=[C:6]([C:22]([O:24]CC)=[O:23])[C:5]2=[O:27].[OH-].[K+].C(O)(C)(C)C>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:18])[C:11]=1[N:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[N:8]1[CH:19]([CH3:21])[S:20][C:7]1=[C:6]([C:22]([OH:24])=[O:23])[C:5]2=[O:27]
Reactant: CCOC(=O)c1c2n(c3c(F)c(N4CCNCC4)c(F)cc3c1=O)C(C)S2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC1Sc2c(C(=O)O)c(=O)c3cc(F)c(N4CCNCC4)c(F)c3n21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To 0.5 g of ethyl 6,8-difluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate was added 10 ml of 5% solution of potassium hydroxide in a 3:1 mixture of tert-butanol and water and the mixture was stirred at 60° C. for 30 minutes. tert-Butanol was evaporated therefrom in vacuo and the residue was neutralized with acetic acid. After cooling, the crystals separated out therefrom were collected by filtration, washed with water and then washed with acetone and ether to give 0.43 g of the title product, m.p. 260° C. (decompn.).