Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:28]3[C:27]4[C@@H:26]([CH2:29]C=O)[CH2:25][CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CO[CH:34]([O:37][CH3:38])[O:35][CH3:36].CC1C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:38][O:37][CH:34]([O:35][CH3:36])[CH2:29][C@H:26]1[CH2:25][CH2:24][C:23]2[S:22][C:21]3[N:20]=[CH:19][N:18]=[C:17]([O:16][CH:13]4[CH2:12][CH2:11][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:6])[CH3:8])[CH2:15][CH2:14]4)[C:28]=3[C:27]1=2
Reactant: COC(OC)OC
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC=O)CC4)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
For the preparation of the starting material compound 43.1, see Example 43. Into a 50-mL round-bottom flask containing a solution of tert-butyl N-methyl-N-(4-[[(3R)-3-(2-oxoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (460 mg, 1.03 mmol, 1.00 equiv) in methanol (15 mL) was added trimethoxymethane (548 mg, 5.16 mmol, 5.00 equiv) and 4-methylbenzene-1-sulfonic acid (18 mg, 0.10 mmol, 0.10 equiv) at room temperature under nitrogen. The reaction mixture was stirred for 4 hr at ambient temperature. After completion, the reaction was quenched with saturated aqueous NaHCO3 and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:8) to afford the desired tert-butyl N-(4-[[(3R)-3-(2,2-dimethoxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (470 mg, 93%) as a colorless oil. LC-MS (ES): m/z 562 [M+H]+.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:10](=[O:20])[CH2:9]2)C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].O.CO>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:20]
Reactant: O=C1CN(Cc2ccccc2)CCN1c1ccccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: O=C1CNCCN1c1ccccn1
Yield: 46.1 %

Procedure:
A slurry of palladium on carbon (5%, 3.6 g) in water was added to a solution of 4-phenylmethyl-1-(2-pyridinyl)piperazin-2-one (Description 150, 3.6 g, 13.48 mmol) and ammonium formate (4.25 g, 67.5 mmol) in methanol (100 mL) and the mixture was heated under reflux for 4 hours, cooled and filtered through Hyflo™, washing with methanol. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with CH2Cl2/MeOH (90:10), to give the title compound as an orange oil (1.1 g, 46%). m/z (ES+) 178 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](S(C)(=O)=O)[N:8]([CH2:16][CH2:17][O:18][CH3:19])[C:7]2=[O:20].[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].[OH-].[Na+]>CS(C)=O>[C:21]([NH:25][C:9]1[N:8]([CH2:16][CH2:17][O:18][CH3:19])[C:7](=[O:20])[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: COCCn1c(S(C)(=O)=O)nc2c(I)cccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCCn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Temperature: 80 °C
Yield: 70 %

Procedure:
To a solution of 8-iodo-3-(2-methoxyethyl)-2-(methylthio)quinazolin-4(3H)-one (715a; 1.33 g, 3.54 mmol) in 100 mL of DCM at 0° C. was added 3-chloroperoxybenzoic acid (77% max., 1.47 g, 6.56 mmol) and the resulting mixture was stirred for 1 h at 0° C. It was diluted with 50 mL of DCM, washed with 2×15 mL of sat NaHCO3. The DCM layer was dried over Na2SO4 and concentrated to give a yellow solid as a mixture (715b) of 8-iodo-3-(2-methoxyethyl)-2-(methylsulfonyl)quinazolin-4(3H)-one and 8-iodo-3-(2-methoxyethyl)-2-(methylsulfinyl)quinazolin-4(3H)-one. To the crude mixture (715b) in a sealable glass vessel was added tert-butylamine (3.72 mL, 35.4 mmol) and 5 mL of DMSO. The glass vessel was sealed and heated in an oil bath at 80° C. for 3 h. It was treated with 10 mL of 0.5 N NaOH, and extracted with 2×35 mL of EtOAc. The organic extracts were dried over Na2SO4 and concentrated. The residue was stirred in 25 mL of ether. The insoluble solid was filtered and rinsed with 2×10 mL of ether. The filtrate was concentrated and the residue was purified on a silica gel column (30-80% EtOAc in hexanes) to afford 2-(tert-butylamino)-8-iodo-3-(2-methoxyethyl)quinazolin-4(3H)-one (715) (0.99 g, 2.467 mmol, 70% yield for 2 steps) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (1H, dd, J=7.5, 1.5 Hz), 7.94 (1H, dd, J=7.8, 1.4 Hz), 6.92 (1H, t, J=7.7 Hz), 6.46 (1H, s), 4.23 (2H, t, J=4.8 Hz), 3.66 (2H, t, J=4.7 Hz), 3.35 (3H, s), 1.58 (9H, s). m/z (ESI, +ve) 401.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: Nc1ccccn1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1ccccn1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to pyridin-2-amine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-2-yl)terephthalamide. MS (Q1) 463 (M)+.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCCCOc1ccccc1/C=C/c1nc2ccccc2s1
Reactant: CCCCNCCCC
Product: CCCCN(CCCC)CCCOc1ccccc1/C=C/c1nc2ccccc2s1
Yield: 34 %

Procedure:
Reaction of this product (3.0 g, 9.1 mmol) with dibutylamine produced 1.5 g (34% yield) of the title compound as the HCl salt, mp 182°-184° C. IR(KBr): 3400, 1600 cm-1. MS: 422(M+). 1H NMR (CDCl3): δ 8.28-6.87 (m 10H), 4.19 (t, J=5.3 Hz, 2H), 3.74-2.93 (m, 6H), 2.51-0.82 (m, 16H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14]>C(Cl)Cl.Cl>[CH:13]([NH:16][C:17]([NH:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])=[O:18])([CH3:15])[CH3:14]
Reactant: CC(C)N=C=O
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)NC(=O)N[C@@H](CC(=O)O)c1ccccc1
Reaction time: 3 h

Procedure:
To a stirred suspension of (S)-3-amino-3-phenylpropionic acid (1.22 g, 7.3 mmol) and TEA (1.24 mL, 8.86 mmol) in CH2Cl2 (30 mL) at ambient temperature was added isopropyl isocyanate (0.798 mL, 8.12 mmol). The reaction mixture was stirred for 3 h, diluted with 1M HCl (25 mL), and extracted with CH2Cl2 (3×25 mL). The combined CH2Cl2 extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=251 (M+1).
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[CH:18][C:17]=2[NH:29][C:30]([C:32]2[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=2)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:31])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:52][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[CH:18][C:17]=2[NH:29][C:30]([C:32]2[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=2)[CH2:35][S:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:31])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(OC3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(OC3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-carbamoyl)benzylthio)propanoate (190 mg, 0.20 mmol, 1.00 equiv, 80%) in dichloromethane (5 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 82.4 mg (57%) of as a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.94 (d, J=3 Hz, 1H), 8.30 (s, 1H), 8.22 (d, J=9 Hz, 1H), 7.89-7.85 (m, 2H), 7.77 (d, J=9 Hz, 1H), 7.70 (s, 1H), 7.66-7.52 (m, 4H), 7.48-7.43 (m, 2H), 7.19-7.15 (q, J=9 Hz, 1H), 4.69 (s, 3H), 4.01-3.95 (m, 2H), 3.86 (s, 2H), 3.66-3.58 (m, 2H), 2.73-2.68 (m, 2H), 2.59-2.54 (m, 2H), 2.06 (m, 2H), 1.80-1.76 (m, 2H). MS (ES, m/z): 694 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:31][CH2:32]2)[N:10]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and ethanesulfonyl chloride (Aldrich), to give [4-amino-2-( 1-ethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone. MS (M+H)+, 438.
Reaction SMILES: [CH2:1]([CH2:3][CH:4]([NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=1)[CH2:5][OH:6])C.[OH-:18].[Na+].[CH3:20][OH:21]>>[CH2:3]([C:4]([NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=1)([CH2:5][OH:6])[C:20]([OH:21])=[O:18])[CH3:1]
Reactant: CCCC(CO)NC(=O)c1cccc(C=O)c1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: CCC(CO)(NC(=O)c1cccc(C=O)c1)C(=O)O
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of compound 39 (200 mg, 0.75 mmol) in MeOH (2 ml) was added NaOH (120 mg, 3.01 mmol). The reaction mixture was stirred at r.t ° C. for 4 h. checked TLC, starting material consumed, adjust the pH up to 6 using 50% HCl and concentrated under vacuum to obtain 178 mg (100%) a white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[C:13]([OH:20])(=[O:19])[CH2:14][CH2:15][C:16]([CH3:18])=O.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:18][C:16]1([CH2:15][CH2:14][C:13]([OH:20])=[O:19])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1
Reactant: OCCC1=CCc2ccccc21
Reactant: CC(=O)CCC(=O)O
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1(CCC(=O)O)OCCC2=C1Cc1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of indene-3-ethanol (15 g), dry benzene (300 ml), levulinic acid (22.6 g), boron trifluoride etherate (3 ml) and hydrated alkali-aluminum silicate (Molecular Sieves No. 4) is stirred at ambient temperature for 2 hr.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]([CH2:8][CH2:9][C@H:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:7])[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]([CH2:8][CH2:9][C@H:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:17][C:26]1[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=1)[CH3:7])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CCOC(=O)CN(C)CC[C@H](O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(C)CC[C@@H](Oc1ccc(C(C)(C)C)cc1)c1ccccc1
Yield: 41 %

Procedure:
prepared by Mitzunobu reaction (analogously to Example 8C, Step 1) of [S]-(−)-N-(3-hydroxy-3-phenylpropyl)sarcosine ethyl ester (from step 1) with 4-tert-butylphenol (Aldrich)—yield 41%; [α]D25+18.6° (c 7.84, CHCl3). See Reaction 24, FIG. 3.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8].C(N(CC)CC)C.[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:7]([C:6]1[N:5]([CH3:9])[N:4]=[C:3]([CH3:10])[C:2]=1[NH:1][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])#[N:8]
Reactant: Cc1nn(C)c(C#N)c1N
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(C#N)c1NC(=O)C(C)C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A solution of 24 g (0.176 mol) of 4-amino-5-cyano-1,3-dimethylpyrazole and 28 ml of triethylamine in 200 ml of chloroform is treated dropwise with 19.3 g (0.18 mol) of isobutyryl chloride and stirred overnight. The mixture is stirred with 100 ml of saturated sodium bicarbonate solution, the organic layer is separated and evaporated in vacuo. The residue is crystallized from ethyl acetate to give 30 g (83%) of N-(5-cyano-1,3-dimethylpyrazol-4-yl)isobutyramide. This amide (30 g, 0.0146, mol) is added in portions to a solution of 7.1 g (0.017 mol) sodium hydroxide in 250 ml of water containing 36 ml of 30% hydrogen peroxide at 80° C. After stirring at 80° C. overnight, the solution is cooled and acidified with glacial acetic acid to give 23 g (74%) of 1,3-dimethyl-5-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol, mp 264°-266° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCC(c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCN1CCC(c2ccccc2)CC1

Procedure:
20 g (61.2 mmol) 2-[4-(4-phenyl-piperidin-1-yl)-butyl]-isoin-dolin-1,3-dione and 6.1 g (122.5 mmol) hydrazine hydrate are heated under reflux in 250 ml ethanol for 3 hours. The cooled solution is concentrated under vacuum and the residue is taken up in chloroform. The suspension is filtered and the residue is distributed between chloroform and 10% sodium hydroxide solution. The combined organic phases are dried over sodium sulfate and steam evaporated under vacuum until dry. The resin is further processed without further purification: Yield 11.7 g (82%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:7]2.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1>CCOC(C)=O>[Cl:18][C:17]1[C:12]([C:6]2[N:7]=[C:8]3[C:3]([C:2]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][N:21]=4)=[CH:11][CH:10]=[N:9]3)=[CH:4][CH:5]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccnc1-c1ccc2c(Cl)ccnc2n1
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(Nc2ccnc3nc(-c4ncccc4Cl)ccc23)nc1

Procedure:
Heat a mixture of 5-chloro-2-(3-chloropyridin-2-yl)-[1,8]naphthyridine (82.5 mg, 0.3 mmol) and 2-amino-5-trifluoromethylpyridine (97.2 mg, 0.6 mmol) at 180° C. for 2.0 hours. Cool the mixture, dilute with EtOAc/1.0 N aq. NaOH (5.0 mL each), and separate the organic layer, extract the aq. layer with EtOAc (2×5 mL) and dry the combined organic layers with MgSO4. Filter the dried extract and concentrate under vacuum to afford crude product. Purify by column chromatography using EtOAc to 2% MeOH/EtOAc as eluents to afford title compound as a yellow solid. 1H NMR (400 MHZ, DMSO-D6) δ 10.2 (s, 1H), 9.07 (d, 1H, J=1.9 Hz), 8.93 (d, 1H, J=1.2 Hz), 8.68 (m, 2H), 8.47 (s, 1H), 8.08 (m, 2H), 7.96 (d, 1H, J=2.2 Hz), 7.56 (dd, 1H), 7.46 (d, 1H, J=2.2 Hz). MS=402.22 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][CH2:47][CH3:48].O>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][N:36]([CH2:46][CH2:47][CH3:48])[CH2:35][CH2:34]5)=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCBr
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCN1CCC(COc2cc3nccc(Oc4ccc(Nc5ccc(C(C)(C)C)cc5)cc4)c3cc2OC)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 7 %

Procedure:
(4-Tert-butylphenyl)-{4-[6-methoxy-7-(4-piperidinylmethoxy)-4-quinolyloxy]phenyl}amine (150 mg) was dissolved in N,N-dimethylformamide (3 ml) to prepare a solution. Potassium carbonate (300 mg) and 1-bromopropane (0.15 ml) were then added to the solution, and the mixture was stirred at room temperature for 4 hr. Water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and was dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure, and the residue was purified by thin-layer chromatography on silica gel using chloroform/acetone for development to give the title compound (12 mg, yield 7%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[CH2:10].[OH2:14]>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CC(=O)CC>[C:8]([O-:13])(=[O:12])[C:9]([CH3:11])=[CH2:10].[C:4]([O-:6])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O-:7])=[O:14]
Reactant: O
Reactant: C=C(C)C(=O)O
Reactant: O=C1C=CC(=O)O1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCC(C)=O
Product: C=C(C)C(=O)[O-]
Product: O=C([O-])/C=C\C(=O)[O-]
Reaction time: 0.17 h

Procedure:
The preparation of Example 1 is repeated with the exception that 54 g (0.55 mole) maleic anhydride is copolymerized with 39 g (0.45 mole) methacrylic acid in the presence of 23 g benzoyl peroxide initiator and 95 g 2-butanone (boiling point 80° C.) as solvent, the methacrylic acid is added continuously over a 5-hour period, the refluxing is continued for 10 minutes following the methacrylic acid addition and the copolymer is hydrolyzed by the addition of 210 g water at reflux temperature. A substantially homogeneous methacrylate/maleate copolymer similar to the product of Example 1 is obtained.
Reaction SMILES: C([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([S:27]([O-:30])(=[O:29])=[O:28])[C:24]1=[O:31])=[O:21])(OCC1C=CC=CC=1)=O.[Na+:32].[C:33]([OH:36])(=[O:35])[CH3:34]>CO.[H][H].[Pd]>[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([S:27]([O-:30])(=[O:28])=[O:29])[C:24]1=[O:31])=[O:21].[Na+:32].[C:33]([O-:36])(=[O:35])[CH3:34]
Reactant: [H][H]
Reactant: CC(=O)O
Reactant: O=C(Cc1ccccc1CNC(=O)OCc1ccccc1)NC1CN(S(=O)(=O)[O-])C1=O
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Product: CC(=O)[O-]
Product: NCc1ccccc1CC(=O)NC1CN(S(=O)(=O)[O-])C1=O

Procedure:
In 35 ml of 30% methanol is dissolved 0,30 g of the above sodium 3-[2-(2-carbobenzoxyaminomethylphenyl)acetamido]-2-oxoazetidine-1-sulfonate, followed by addition of 0.68 ml of 6% acetic acid and 76 mg of palladium black. The mixture is stirred in hydrogen gas streams at room temprature for 90 minutes. The catalyst is filtered off and the filtrate is purified on an Amberlite XAD-II column. The above procedure provides 0.167 g of sodium 3-[2-(2-aminomethylphenyl)acetamido]-2-oxoazetidine-1-sulfonate·acetate.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[C:20]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:21]3[CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:36](=[O:37])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]3=[O:38])=[CH:17][CH:16]=2)=[O:14])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[O-]S(C(F)(F)[F:50])(=O)=O.F[N+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[S:3][C:4]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([F:50])=[C:20]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[N:21]3[CH2:24][CH2:25][CH2:26][CH2:27][N:28]3[C:36](=[O:37])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]3=[O:38])=[CH:17][CH:16]=2)=[O:14])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3c(F)c(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Temperature: 25 °C
Yield: 18.8 %

Procedure:
To a solution of 5 (209 mg, 0.31 mmol) in 3 mL CH2Cl2 was added 1-fluoropyridinium triflate (81 mg, 0.33 mmol), and then the mixture stirred at room temperature until no 5 was detected by NMR. The resulting mixture was diluted with 40 mL Et2O, washed with brine (2×10 mL), dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex/EtOAc 9:1) gave 6 (40 mg, 19%) as a yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.77-7.63 (m, 6H), 7.57 (s, 1H), 7.48-7.40 (m, 5H), 4.25 (t, J=7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 3.72 (s, 2H), 3.48 (t, J=6.8 Hz, 2H), 1.65-1.61 (m, 2H), 1.50-1.44 (m, 2H), and 1.26 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 187.16, 169.94, 168.50, 143.96, 143.10, 140.65, 135.88, 135.17, 134.22, 134.17, 132.37, 132.31, 132.11, 131.68, 129.96, 129.51, 129.17, 129.13, 128.96, 128.45, 127.58, 127.38, 123.46, 121.80, 121.19, 120.18, 120.03, 116.97, 112.58, 61.52, 43.64, 37.21, 35.33, 27.32, 25.76, and 14.44; 19F NMR (376 MHZ, CDCl3) δ −174.33.
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[C:6](=[O:17])[CH:7]2[CH:12]([C:13](=[O:15])[CH:14]=1)[CH:11]1[CH2:16][CH:8]2[CH:9]=[CH:10]1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[CH:11]3[CH2:16][CH:8]([CH:9]=[CH:10]3)[C:7]=2[C:6]=1[OH:17]
Reactant: COC1=CC(=O)C2C3C=CC(C3)C2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(O)c2c(c1O)C1C=CC2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
To stirred MeOH (65 mL), which had been purged with N2 for 5 min, there was added 1,4,4a,8a-tetrahydro-6-methoxy-1,4-methanonaphthalene-5,8-dione (47, 1.50 g, 7.30 mmol) to give a solution. Solid Na2CO3 (2.02 g, 14.6 mmol) was then added under N2. The resulting light green suspension was allowed to stir under N2 for 15 min at rt. TLC analysis (10% MeOH, 90% CHCl3) indicated total consumption of the organic starting material. While still under N2, the reaction was diluted with H2O (20 mL). The pH was adjusted to slightly acidic by the slow and careful addition of concd HCl, after which the solution was light pink. The methanol was then removed in vacuo (vacuum relieved with N2) to give a light green solution. The pH was approximately 8. The pH was then adjusted to 2 with 10% HCl at which point the product crystallized. The crystals were collected, washed with 10% HCl (4×3 mL) and dried in vacuo to yield 48 as a near colorless crystalline solid (1.32 g, 88%, pure by TLC and 1H NMR); mp 151°-153° C.; 1H NMR (vide infra).