Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[C@@H:16]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](=[O:35])([O-:34])[O-].[Cs+].[Cs+].[C:38]([O:42][C:43](=[O:53])[NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]Br)([CH3:41])([CH3:40])[CH3:39].O>CN(C)C=O.[Cl-].[Na+].O>[NH3:19].[C:2]([O:34][C:32]([N:44]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([C@@H:16]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][N:19]([CH:20]([CH3:22])[CH3:21])[CH:23]([CH3:24])[CH3:25])[CH:11]=1)[C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:53])=[O:35])([CH3:7])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)NCCCCCCCBr
Reactant: O=C([O-])[O-]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(O)ccc1OCc1ccccc1)C(C)C
Agent: [Cl-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(OCCCCCCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1OCc1ccccc1)C(C)C
Product: N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenol (Preparation 16, 150 mg, 0.36 mmol) was dissolved in dimethylformamide (2 ml), caesium carbonate (140 mg, 0.43 mmol) was added and stirred at room temperature for 30 minutes. tert-Butyl(7-bromoheptyl)carbamate (Prepared according to J. Med. Chem., 1994, 137, p2537-2551; 170 mg, 0.43 mmol), dissolved in dimethylformamide (1 ml), was added and heated to 70oC. After 2.5 hours caesium carbonate (70 mg, 0.22 mmol) was added and after a further 10 minutes tert-butyl(7-bromoheptyl)carbamate (70 mg, 0.18 mmol) was added. After 1 hour caesium carbonate (20 mg, 0.06 mmol) and tert-butyl(7-bromoheptyl)carbamate (35 mg, 0.09 mmol) were added and after 1 hour at 70° C. the mixture was cooled to room temperature and stirred for 3 days before the addition of water and brine were added, the mixture extracted with ethyl acetate, dried (magnesium sulphate), filtered and the solvents removed in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98/2/0.2 to 95/5/0.5 by volume) to furnish the title compound as a colourless gum, 220 mg.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17](=O)[NH2:18])=[CH:16][C:11]=2[N:10]=[C:9]1[CH3:20])[CH3:7]>N1C=CC=CC=1>[CH2:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[N:10]=[C:9]1[CH3:20])[CH3:7]
Reactant: CCn1c(C)nc2cc(C(N)=O)ccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCn1c(C)nc2cc(C#N)ccc21
Temperature: 60 °C

Procedure:
Phosphorus oxychloride (POCl3) (42.4 ml - 0.44 mole) was added to a stirred and ice-cooled solution of IV (81.2 g - 0.4 mole) in pyridine (160 ml). The temperature reached 45° C. After this addition, the mixture was heated to 60° C. The reddish-brown oil was poured immediately in 1 kg of ice/water with stirring. The precipitate was filtered, washed with ice-cold water, and dried. The crude product was crystallized from pyridine (1.5 ml/g) and water (9 ml/g).
Reaction SMILES: [CH2:1]([S:8](Cl)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>N1C=CC=CC=1>[C:2]1([CH2:1][S:8]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)Cc1ccccc1
Yield: 63.1 %

Procedure:
Prepared according to the procedure described for Example 121 using benzylsulfonyl chloride (1.90 g, 10 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (2.5 g); m.p. 216-216° C. after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][NH2:8])[C:4]([OH:6])=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=O)=O)=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[N:2][C:18]=2[C:20]2[CH:21]=[CH:22][C:23]([Br:26])=[CH:24][CH:25]=2)=[CH:14][CH:15]=1
Reactant: NCC(N)C(=O)O
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: Cl
Product: O=C(O)c1cnc(-c2ccc(Br)cc2)c(-c2ccc(Br)cc2)n1

Procedure:
The title compound was prepared essentially as described in Preparation A step (a), using monohydrochloride of 2,3-diaminopropionic acid (600 mg, 4.26 mmol) and 4,4′-dibromobenzil (1.745 g, 4.26 mmol, 90%) as starting materials. The reaction mixture was refluxed for 2 hours and air was bubbled through for 1 hour. Hydrochloric acid (aq, 2 M) was added until pH 2. The mixture was evaporated under reduced pressure and the residue was dissolved in water. The solution was extracted with diethyl ether, the combined diethyl ether phases were dried (MgSO4), filtered and evaporated under reduced pressure. The crude product (500 mg, 27%) was used in steps described below without further purification. MS m/z 435, 437, 439 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:31]([C:30]3[CH:29]=[CH:28][C:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:34][CH:33]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc(N5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 74.9 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (40.0 mg, 0.118 mmol) and 4-morpholin-4-yl-benzaldehyde (24.9 mg, 0.130 mmol) were reacted to produce 45 mg (75%) of the title compound. mp: 283-284° C., 1H NMR (300 MHz, DMSO-d6): 12.97 (s, 1H), 8.22 (s, 1H), 8.00 (d, J=8 Hz, 2H), 7.93 (s, 1H), 7.65 (s, 1H), 7.11 (s, 1H), 7.03 (d, J=8 Hz, 2H), 6.98 (d, J=8 Hz, 1H), 6.36 (br s, 1H), 6.33 (br s, 1H), 5.27 (t, J=8 Hz, 1H), 3.77 (br s, 4H), 2.88 (s, 1H), 2.77 (s, 1H), 2.62 (d, J=7 Hz, 1H), 2.26 (br s, 4H), 1.39 (d, J=8 Hz, 1H). MS: 509, 511 (M+H), HPLC: 2.31 min (G method).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([NH:28][C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.C1COCC1.O.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([NH:28][C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH:16]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-n2nc(NC(=O)N(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1ccc(-n2nc(NC(=O)N(C)C)cc2-c2ccc(O)cc2)cc1
Yield: 58.6 %

Procedure:
To a solution of N′-[5-[4-(benzyloxy)phenyl]-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea (1.19 g) in EtOH (10 ml) and THF (10 ml) were added a solution of ammonium formate (509 mg) in H2O (2 ml) and 10% Pd-C 50% wet (150 mg). The mixture was refluxed for 1 hour. The catalyst was filtered off through a celite pad and the pad was washed with EtOH. The filtrate and combined washings were concentrated in vacuo. To the residue were added AcOEt and H2O. White precipitates were appeared and collected and washed with H2O and IPE successively to give N′-[5-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea (555 mg) as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:6]=1)C.CO.[OH-].[Na+].Cl>C(OCC)(=O)C.C1COCC1>[CH:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:20])=[O:3])=[CH:6][N:7]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: CCOC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1ccc(Oc2ccc(C(=O)O)cn2)cc1
Yield: 84.8 %

Procedure:
Combine 6-(4-Formyl-phenoxy)-nicotinic acid ethyl ester (1.5 g, 5.53 mmol), MeOH (5 mL), THF (5 mL), and 5N NaOH (aq) (2 mL). Reflux the reaction 18 hours and then add 1N HCl (aq) (2 mL). After concentrating the reaction on the rotovap, add Ethyl acetate to precipitate out the desired product. Filter and concentrate the ethyl acetate filtrate to afford 1.14 g (85% yield) of the title compound: TLC 1:1 Hexanes:Ethyl acetate Rf:=0.01.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.Cl.[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH2:25])[CH3:21].CN(C=O)C.C(N(CC)CC)C>O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:25][CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:26])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Temperature: 85 °C
Reaction time: 5.5 h
Yield: 73.6 %

Procedure:
To 550 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3) and 419 mg of glycine ethyl ester hydrochloride were added 3 ml of DMF and 607 mg of triethylamine, followed by stirring at 85° C. for 5.5 hours. The resulting reaction solution was poured into 100 ml of water and extracted with ethyl acetate. The extract was concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1 to 3:1 to obtain 503 mg of the titled compound. Mp.146.1° C. 1H NMR (CDCl3): 1.30 (3H, t, J=7.2 Hz), 4.25 (2H, q, J=7.2 Hz), 4.31 (2H, d, J=5.2 Hz), 5.97 (1H, br. s), 7.54-7.63 (5H, m), 7.67-7.70 (2H, m), 7.79 (1H, s).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]([CH2:35][CH3:36])[CH2:33][CH3:34]>O>[CH2:35]([N:32]([CH2:33][CH3:34])[C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:29])[F:31])=[CH:27][C:22]=1[NH:21][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:36]
Reactant: CCN(CC)c1ccc(C(F)(F)F)cc1N
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCN(CC)c1ccc(C(F)(F)F)cc1NC(=O)c1ccncc1
Temperature: 25 °C
Yield: 34.1 %

Procedure:
Isonicotinoyl chloride hydrochloride (88.2 mg, 0.495 mmol, commercially available product) and triethylamine (140 μL, 1.00 mmol) were sequentially added at 0° C. to a dichloromethane (3 ml) solution of 2-amino-1-diethylamino-4-(trifluoromethyl)benzene (103 mg, 0.443 mmol), obtained as described in Referential Example 6-2. The resulting mixture was warmed to room temperature and stirred for one and a half hours. Water was added to the mixture, and the resulting mixture was extracted three times with dichloromethane. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=2/1). Thus, N-[2-diethylamino-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0347) (51.0 mg, 34.1%) was yielded as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=O)[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#CC1CCCN1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Carbamoyl-pyrrolidine-1-carboxylic acid benzyl ester (25.0 g, 101 mmol) was dissolved in pyridine (125 mL) under an N2 atmosphere and cooled to −10° C. The phosphorus oxychloride (12.6 mL, 135 mmol) was dissolved in DCM (25 mL) and added dropwise over 40 mins to the pyridine solution. The reaction mixture's temperature was maintained at −10° C. and the solution was allowed to stir for 2 hours. The reaction was quenched by addition of water/ice (100 g) and transferred into a separatory funnel. The solution was extracted with diethyl ether (3×200 mL). The organic layers were combined and washed with saturated cupric sulfate (200 mL). The organic layer was dried over MgSO4 and concentrated under vacuo to afford 20.0 g (82%) of 2-cyano-pyrrolidine-1-carboxylic acid benzyl ester as a green oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:15](F)=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.O.[NH2:18][NH2:19].O>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[NH:19][N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C(c1cccc(F)c1)c1ncccc1F
Solvent: O
Solvent: CO
Product: Fc1cccc(-c2n[nH]c3cccnc23)c1
Temperature: 80 °C

Procedure:
1.5 g of (3-fluorophenyl)-(3-fluoropyridin-2-yl)-methanone was dissolved in 5 mL of methanol, added with 1.0 mL of hydrazine monohydrate, and heated at 80° C. for 4 hours. The reaction solution was added with water, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:4), to afford 240 mg of the title compound as a colorless powder.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[NH:19]1[CH2:24][CH2:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:35][C@H:34]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[O:33][C:32]3=[O:41])=[CH:27][CH:26]=2)=[CH:21][CH2:20]1>ClCCl>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([N:19]2[CH2:24][CH2:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:35][C@H:34]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[O:33][C:32]4=[O:41])=[CH:27][CH:26]=3)=[CH:21][CH2:20]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(S(=O)(=O)c4ccc(C)cc4)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (202 mg), followed by p-toluenesulfonyl chloride (171 mg) were added to a stirred suspension of the TFA salt of Example 2 (322 mg) in dichloromethane (10 ml). After stirring for 30 minutes at ambient temperature, the reaction mixture had become a solution and the reaction was complete. The solution was washed with 2N HCl, water, saturated NaHCO3 and saturated NaCl. The organic phase was dried over anhydrous Na2SO4 and evaporated to give a crystalline solid which was triturated with ether to give the title compound. Yield=306 mg, 87%.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:50]([OH:52])=[O:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:58]O>>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:50]([O:52][CH3:58])=[O:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(=O)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(=O)OC)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 41.4 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid 2a (0.38 g, 0.53 mmol) in methanol (8 mL) was added concentrated sulphuric acid (56.9 mg, 0.58 mmol) at room temperature. The mixture was stirred at 40° C. for 12 hours and quenched with 0.5 mL of saturated aqueous sodium hydrogen carbonate. Most of the solvent of the mixture was removed in vacuo. To the residue was added water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 2b as colorless oil (155 mg, 41.4%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.48 (m, 1H), 7.39 (m, 2H), 7.38-7.29 (m, 7H), 7.28-7.23 (m, 3H), 7.19 (m, 3H), 7.08 (m, 2H), 6.91-6.86 (m, 2H), 6.80-6.73 (m, 2H), 4.82 (m, 3H), 4.63 (d, 1H), 4.53 (d, 1H), 4.26 (d, 1H), 4.24-4.16 (m, 2H), 4.09 (d, 1H), 4.05-3.94 (m, 4H), 3.87 (d, 1H), 3.75 (d, 1H), 3.71 (s, 3H), 1.41 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:24]3[CH:45]=[CH:44][C:27]([C:28]([NH:30][C@H:31]([C:39]([O:41]CC)=[O:40])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:29])=[CH:26][CH:25]=3)[CH2:15][C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[CH:8]=2)[N:3]=1.[OH-].[Na+]>O.C(O)C>[NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:30][C@H:31]([C:39]([OH:41])=[O:40])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:29])=[CH:44][CH:45]=3)[CH2:15][C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N(Cc2ccc3nc(N)nc(O)c3c2)Cc2c[nH]c(=O)[nH]c2=O)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(O)c2cc(CN(Cc3c[nH]c(=O)[nH]c3=O)c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)ccc2n1
Reaction time: 1.5 h

Procedure:
Diethyl N-(4-(N-(2-amino-4-hydroxy-6-quinazolinyl)methyl-N-(5-uracilyl)methyl-amino)benzoyl)-L-glutamate (0.327 g) was suspended in a mixture of water (7 ml) and ethanol (2 ml) and treated with 1N NaOH aq. (6 mol. eq.) Vigorous shaking gave a solution within 30 min. After a further 1.5 hr. the solution was clarified by filtration and the pH brought to 4.0 using 1N HCl aq. A particulate precipitate of the product resulted. It was freed from inorganic ions by three cycles of suspension-centrifugation-decantation. The amorphous white solid was dried at 40° C. in vacuo, to yield the pure diacid, N-(4-(N-(2-amino-4-hydroxy-6-quinazolinyl)methyl-N-(5-uracilyl)methyl-amino)benzoyl)-L-glutamic acid (CB 3743), as its dihydrate (68%), m.p. 250°-255° C. The structure was confirmed by elemental analysis (C,H,N) and by uv spectroscopy (spectrum determined in 0.1N NaOH aq.). λ(nm) (ε) maxima: 310 (29,200), 276.5(22,000), 230 (50,700); minima: 282.5 (21,500), 251.5 (11.600).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])=[CH:4][C:3]=1[C:19]1[C:20](=[O:46])[N:21]([CH2:44][CH3:45])[C:22]2[C:27]([CH:28]=1)=[CH:26][N:25]=[C:24]([NH:29][C:30]([C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1C(OC(C)(C)C)=O)=[O:31])[CH:23]=2.Cl.CO>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])=[CH:4][C:3]=1[C:19]1[C:20](=[O:46])[N:21]([CH2:44][CH3:45])[C:22]2[C:27]([CH:28]=1)=[CH:26][N:25]=[C:24]([NH:29][C:30]([C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)=[O:31])[CH:23]=2
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC(=O)[C@@H]3CCCN3C(=O)OC(C)(C)C)cc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC(=O)[C@@H]3CCCN3)cc21
Temperature: 50 °C
Yield: 27.8 %

Procedure:
A mixture of (S)-tert-butyl 2-((3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamoyl)pyrrolidine-1-carboxylate (115 mg, 0.177 mmol) in dioxane (3 mL) was treated with 1.25 N HCl in MeOH (2.8 mL, 3.5 mmol) and heated at 50° C. for 2 h. The mixture was concentrated to dryness, treated with satd. NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure and the aqueous residue treated with satd. NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford (S)—N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)pyrrolidine-2-carboxamide (27 mg, 30% yield). MS (ESI) m/z: 549.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3]C(=O)CC1C=CC(N)=CC=1)C.C1(C#N)CCCC1.[CH2:21]([O:23][C:24](=[O:40])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])[CH:27]=1)[CH3:22].[NH2:41][C:42]1[S:43][CH:44]=[CH:45][N:46]=1>>[CH2:21]([O:23][C:24](=[O:40])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])[CH:27]=1)[CH3:22].[CH2:21]([O:23][C:24](=[O:40])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:1]([NH:41][C:42]2[S:43][CH:44]=[CH:45][N:46]=2)=[O:3])=[C:28]([C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])[CH:27]=1)[CH3:22]
Reactant: Nc1nccs1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CCOC(=O)Cc1ccc(N)c(C(=O)C2CCCC2)c1
Agent: N#CC1CCCC1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2nccs2)c(C(=O)C2CCCC2)c1

Procedure:
(4-Amino-3-cyclopentanecarbonylphenyl)acetic acid ethyl ester (2.7 g) is prepared from (4-aminophenyl)acetic acid ethyl ester (18.0 g, 0.1 mol) and cyclopentanecarbonitrile (9.5 g, 0.1 mol) following the general procedure I. [3-Cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)phenyl]acetic acid ethyl ester (140 mg) is prepared from (4-amino-3-cyclopentanecarbonylphenyl)acetic acid ethyl ester (138 mg, 0.5 mmol) and 2-aminothiazole (0.060 g, 0.6 mmol) following the general procedure D.