Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1OC([S:7](=[O:10])(=[O:9])[NH2:8])=C(C(O)=O)C=1.[CH3:14][C:15]1[O:16][CH:17]=[CH:18][C:19]=1[CH3:20].[Na+].[CH3:22][C:23]1[CH:24]=C(S([O-])(=O)=O)O[C:27]=1C.P(Cl)(Cl)(Cl)(Cl)Cl.C(N)(C)(C)C>>[C:23]([NH:8][S:7]([C:18]1[C:19]([CH3:20])=[C:15]([CH3:14])[O:16][CH:17]=1)(=[O:9])=[O:10])([CH3:24])([CH3:27])[CH3:22]
Reactant: Cc1ccoc1C
Reactant: Cc1cc(C(=O)O)c(S(N)(=O)=O)o1
Reactant: Cc1cc(S(=O)(=O)[O-])oc1C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC(C)(C)N
Product: Cc1occ(S(=O)(=O)NC(C)(C)C)c1C
Yield: 34 %

Procedure:
Analogous to the preparation of the 5-methyl-2-sulfamoyl-furan-3-carboxylic acid (see starting compound of Example 1), 2,3-dimethyl-furan [K. C. Rice and J. R. Dyer, J. Heterocycl. Chem. 12, 1325 (1975)] was converted with sulfur trioxide-pyridine complex into the 4,5-dimethyl-furan-2-sulfonic acid sodium salt and treated with phosphorus pentachloride and tert. butylamine. N-tert. butyl-4-,5-dimethylfuran-3-sulfonamide was obtained with a yield of 34% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:26]=[CH:25][C:19]2[N:20]=[C:21]([CH2:23]Cl)[NH:22][C:18]=2[CH:17]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:15][C:16]1[CH:26]=[CH:25][C:19]2[N:20]=[C:21]([CH2:23][N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:22][C:18]=2[CH:17]=1
Reactant: ClCc1nc2ccc(Cl)cc2[nH]1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(Cl)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
The mixture of ethyl N-(4-chlorophenyl)glycinate (0.43 g), 5-chloro-2-chloromethylbenzimidazole (0.4 g), and sodium bicarbonate (0.17 g) in N,N-dimethylformamide (2 ml) was stirred at 150° C. for 0.5 h. After cooling to rt the mixture was poured into saturated sodium bicarbonate solution (50 ml) and extracted twice with EtOAc (40 ml). The combined organic layers were washed with 10% sodium carbonate solution (40 ml) and water (40 ml) and dried (sodium sulfate). After concentration the crude (0.66 g) was purified by flash chromatography (dichloromethane/1% methanol) on silica gel to provide an orange solid. The solid was further purified by trituration with diethyl ether to give ethyl N-[(5-chloro-2-benzimidazolyl)methyl]-N-(4-chlorophenyl)glycinate (0.17 g) as a light orange crystals.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]=[C:20]([Br:22])[CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:14]=3[NH:15][C:16]=2[CH:17]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O.CCOC(C)=O.CCCCCC>[Br:22][C:20]1[CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:14]2[NH:15][C:16]3[CH:17]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=3[C:13]=2[N:21]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(OCc3ccccc3)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(O)ccc12
Yield: 50.8 %

Procedure:
A solution of methyl 7-(benzyloxy)-2-bromo-5H-pyrido[3,2-b]indole-4-carboxylate (25 mg, 0.061 mmol) in TFA (0.5 mL) was heated at 80° C. for 20 min. The solvent was removed to leave a solid. This was suspended in a mixture of EtOAc and hexane and the solid was collected by filtration to give methyl 2-bromo-7-hydroxy-5H-pyrido[3,2-b]indole-4-carboxylate (10 mg, 0.031 mmol, 51% yield). MS (ESI) m/z 320.9 (M+H). 1H NMR (400 MHz, MeOD) δ ppm 8.03 (1H, d, J=8.56 Hz), 7.79 (1H, s), 6.99 (1H, d, J=1.76 Hz), 6.79 (1H, dd, J=8.56, 2.27 Hz), 4.00-4.07 (3H, m).
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][C:17]([OH:19])=[O:18].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:23][CH2:22][CH2:21][CH2:20][CH:2]([OH:1])/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCCC(O)CCCCCCC=CC=CC=CC=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CCCCC(O)/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Temperature: 0 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
An equimolar mixture of 16-hydroxyeicosatetraenoic acid (16 HETE) and N-hydroxysuccinimide in anhydrous tetrahydrofuran (THF) was cooled to 0° C. To this was added 1 equivalent of dicyclohexylcarbodiimide (DCC) with stirring. After 12 h at room temperature, the solvent was removed in vacuo and the residue was purified by SiO2 chromatography to afford the corresponding 16-HETE N-hydroxysuccimide ester in 75% yield as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:25][C@@H:26]2[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[N:3]=1
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (320 mg, 0.862 mmol), tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (280 mg, 1.293 mmol) and DIPEA (0.226 mL, 1.293 mmol) in ACN (5 mL) was stirred at 85° C. overnight. UPLC indicated the presence of starting material, so the mixture was stirred at 85° C. overnight. UPLC showed about 50% conversion. Additional stirring at 85° C. for 3 d and at 100° C. overnight did not appreciably increase the conversion, so the reaction was stopped and the solvent was removed. The resulting crude material was reconstituted in MeOH/DMF (10 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (50%, 0.035% TFA). The collected fractions were combined and the ACN was removed via rotary evaporation. The resulting aqueous solution was neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to give the title compound (51 mg, 11%). [M+H] calc'd for C26H32ClFN4O6, 552; found, 552.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][C:11]#N)=[C:8]([Cl:13])[N:7]=[C:6]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].[OH-:20].[Na+].S(=O)(=O)(O)[OH:23]>>[CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:23])=[O:20])=[C:8]([Cl:13])[N:7]=[C:6]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: O=S(=O)(O)O
Reactant: CCCCn1c(-c2ccccc2)nc(Cl)c1CC#N
Agent: [Na+]
Product: CCCCn1c(-c2ccccc2)nc(Cl)c1CC(=O)O

Procedure:
3.2 g of 1-n-butyl-4-chloro-2-phenyl-5-cyanomethylimidazole was heated in 18 ml of 60% sulfuric acid at 145° C. for 15 hours. The reaction solution, under cooling with ice, was made to pH 4 with 20% aqueous sodium hydroxide solution, and the deposited precipitate was recrystallized twice from 50 ml of 60% ethanol, thus yielding 2.4 g of 1-n-butyl-4-chloro-2-phenylimidazole-5-acetic acid as colorless needles, m.p. 189°-190° C.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]1[C:13]([O:15]C)=O.[Cl-].[NH2:18][C:19]([NH2:21])=[NH:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:21][C:19]1[N:18]=[C:13]([OH:15])[C:3]2[CH2:4][CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2]=2[N:20]=1
Reactant: COC(=O)C1CCCc2ccccc2C1=O
Reactant: N=C(N)N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(O)c2c(n1)-c1ccccc1CCC2
Yield: 68.4 %

Procedure:
A solution of the product from Example 4A (4.2 g, est. 18 mmol), guanidine chloride (7.1 g, 72.8 mmol), and K2CO3 (10.8 g, 78 mmol) in DMF (30 mL) was heated to 125° C. for 3 hours. The mixture was cooled and the solids were removed by filtration. The solids were washed with EtOAc. The combined filtrates were concentrated under reduced pressure and the residue was passed through silica gel pad eluting with EtOAc:hexanes (8:2) and then with MeOH:EtOAc:CH2Cl2 (10:45:45) to provide the title compound as a white solid (2.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:24]1([N:34]=[C:35]=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:34][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[O:36]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C=Nc1cccc2ccccc12
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc5ccccc45)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (122 mg) was dissolved in chloroform (10 ml), and 1-naphthyl isocyanate (75 mg) was added to the solution. The mixture was stirred at room temperature overnight. Methanol was added to the reaction solution, and the solvent was removed by distillation under the reduced pressure. The residue was dissolved in a minor amount of chloroform, and a large amount of ether was added to the solution to precipitate a crystal. The crystal was collected by filtration to give 105 mg (yield 57%) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])C>C(=O)([O-])[O-].[K+].[K+].C(#N)C.Cl>[CH2:17]([O:16][C:13]([NH:1][C@H:2]([C:10]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:11])[CH3:3])=[O:15])[C:18]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 39 %

Procedure:
To a solution of L-phenylalanine (0.33 g, 2.0 mmol) in 0.20M potassium carbonate (20 mL) and acetonitrile (30 mL) was added dropwise a solution of N-benzyloxycarbonyl-L-alanine N-carboxyanhydride (0.45 g, 1.8 mmol) in acetonitrile (5 mL) at 0° C. The mixture was stirred 40 min at 0° C. and diluted with ethyl acetate (50 mL) and 1M hydrochloric acid (10 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (2×35 mL). The combined organic fractions were washed with brine (30 mL), 0.5M hydrochloric acid (2×50 mL) and water (2×50 mL), dried (MgSO4) and concentrated. The residue was recrystallized from chloroform/hexane to give 0.26 g (39%) of N-benzyloxycarbonyl-L-alanyl-L-phenylalanine: mp 121°-122° C.; NMR (DMSO-d6) δ 12.71 (s, 1H), 8.06 (m, 1H), 7.30 (m, 5H), 5.01 (s, 2H), 4.43 (m, 1H), 4.06 (m, 1H), 2.99 (m, 2H), 11.19 (d, 2H, J=7 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:16](#[N:20])[CH2:17][C:18]#[N:19].N1CCCCC1>C(O)C>[C:18]([C:17]1[C:16](=[NH:20])[O:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)#[N:19]
Reactant: O=C(c1ccccc1)c1ccccc1O
Reactant: N#CCC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1c(-c2ccccc2)c2ccccc2oc1=N
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To a mixture of 2-hydroxybenzophenone (2.0 g, 10 mmol) and malononitrile (661 mg, 10 mmol) in ethanol (15 mL) was added piperidine (0.5 mL, 5.0 mmol). The mixture was stirred under 0-5° C. for 2 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate and hexane (1:2) as eluant, yielding 1.2 g (48%) of the title compound. 1H NMR (CDCl3): 7.74-7.29 (m, 7H), 7.20-7.13 (m, 2H).
Reaction SMILES: [NH+:1]1([O-])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.CS([Cl:15])(=O)=O.[OH-].[Na+]>CN(C=O)C>[Cl:15][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: CS(=O)(=O)Cl
Reactant: [O-][NH+]1C=Cc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1ccnc2[nH]ccc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A solution of 2a (1.926 kg) in DMF (9.705 kg) was heated to about 50° C. Methanesulfonyl chloride (4.399 kg) was added to the heated solution at such a rate as to maintain the reaction temperature at 65 to 75° C. The resulting mixture was heated at about 68 to 77° C. until the reaction was judged complete by reversed phase HPLC analysis. The reaction mixture was cooled to about 30° C., and then quenched with water (31.024 kg). Upon cooling the quenched reaction mixture to 5° C., sufficient 10 N NaOH solution was added to raise the pH of the solution to about 7. The resulting slurry was warmed to 25° C., agitated for approximately 1 h, and then filtered to collect the product. The product was washed with additional water, and dried under high vacuum at 45 to 50° C. to afford 1.904 kg of 3a.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH3:21][O:22][C:23](=[O:33])[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C[O:35][C:36](=O)[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>O1CCCC1>[CH3:21][O:22][C:23](=[O:33])/[C:24](/[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:36](\[OH:35])/[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]
Reactant: COC(=O)C(=O)OC(C)(C)C
Reactant: COC(=O)COCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
Lithium diisopropylamide was generated by addition of n-butyl lithium (17 mL, 1.9M in hexane, 33.33 mmol), di-isopropyl amine (4.66 mL, 33.33 mmol) in tetrahydrofuran (15 mL) at 0° C. and stirred for 10 min. In a separate flask, a mixture of benzyloxy-acetic acid methyl ester (3) (4 g, 22.22 mmol) and oxalic acid tert-butyl ester methyl ester (2) (5.33 g, 33.33 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C. and then lithium diisopropylamide was added at −78° C. The mixture was stirred at −78° C. for 1 h. After 1 h, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for another 1 h. After completion of the reaction, the reaction was quenched with 1N HCl, and extracted with ethyl acetate. The separated organic part was dried over sodium sulfate and concentrated under reduced pressure, passed over a normal silica column using 25% ethyl acetate in hexane to get (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (2.4 g, 35%) as ketoenol tautomers and ketone hydrate as a thick light yellow coloured oil. These were immediately used for next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:21]#[N:22])=[CH:4][C:3]=1[NH:23][C:24]1[N:29]=[C:28]([N:30]([CH:40]2[CH2:42][CH2:41]2)CC2C=CC(OC)=CC=2)[C:27]2=[N:43][CH:44]=[C:45]([C:46]#[N:47])[N:26]2[N:25]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:16][C:17]([F:20])([F:19])[CH2:18]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:21]#[N:22])=[CH:4][C:3]=1[NH:23][C:24]1[N:29]=[C:28]([NH:30][CH:40]2[CH2:41][CH2:42]2)[C:27]2=[N:43][CH:44]=[C:45]([C:46]#[N:47])[N:26]2[N:25]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(NC5CC(F)(F)C5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCC(NC3CC(F)(F)C3)CC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11.9 %

Procedure:
To a round bottom flask charged with 2-((2-chloro-5-cyano-3-(4-((3,3-difluorocyclobutyl)amino)piperidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (34.9 mg, 0.053 mmol) in dichloromethane (530 μl) was added anisole (116 μl, 1.060 mmol), followed by the slow addition of trifluoroacetic acid (408 μl, 5.30 mmol). The reaction mixture was stirred at rt 2 d. Excess TFA was removed in vacuo. The crude residue was taken up in MeOH and free based using a Phenomenex Strata 1 g SCX column. The crude solid was purified via preparative LC/MS and provided 2-((2-chloro-5-cyano-3-(4-((3,3-difluorocyclobutyl)amino)piperidin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.4 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[C:13](N[C@@H](C2C=CC=CC=2)C)=[CH:12][C@H:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=2)[N:10]1[C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1.O=C1C(=O)C[C@H](C2C=CC=C(OC(F)(F)F)C=2)N1C1C=CC(C#N)=CC=1.[CH3:68][C:69]([NH2:81])([C:71]1[CH:76]=[CH:75][CH:74]=[C:73]([C:77]([F:80])([F:79])[F:78])[N:72]=1)[CH3:70]>ClCCl.O>[CH3:70][C:69]([NH:81][C:13]1[C:9](=[O:8])[N:10]([C:34]2[CH:35]=[CH:36][C:37]([C:38]#[N:39])=[CH:40][CH:41]=2)[C@@H:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:31])([F:33])[F:32])[CH:24]=2)[CH:12]=1)([C:71]1[CH:76]=[CH:75][CH:74]=[C:73]([C:77]([F:79])([F:80])[F:78])[N:72]=1)[CH3:68]
Reactant: CC(C)(N)c1cccc(C(F)(F)F)n1
Reactant: C[C@@H](NC1=C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C#N)cc2)C1=O)c1ccccc1
Agent: N#Cc1ccc(N2C(=O)C(=O)C[C@@H]2c2cccc(OC(F)(F)F)c2)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(NC1=C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C#N)cc2)C1=O)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
Add trifluoroacetic acid (2.00 mL, 26.43 mmol) to a biphasic mixture of 4-[(R)-2-oxo-3-((R)-1-phenyl-ethylamino)-5-(3-trifluoromethoxy-phenyl)-2,5-dihydro-pyrrol-1-yl]-benzonitrile) in dichloromethane (12 mL) and water (4.9 mL). Stir at ambient temperature for 2 hours. Observe significant formation of 4-[(R)-2,3-dioxo-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-1-yl]-benzonitrile (LC-MS ESI m/z: 361 (M+H)+, Tr=2.34 min., method 2. Wash the reaction mixture with water. Filter the organic phase through sodium sulfate and add 1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamine (1.30 g, 6.35 mmol). Heat to reflux temperature for 18 hours. Partially concentrate reaction mixture and place on a silica gel chromatography column. Purify by silica gel chromatography (25% ethyl acetate-hexane) to obtain 4-[(R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-2-oxo-5-(3-trifluoromethoxy-phenyl)-2,5-dihydro-pyrrol-1-yl]-benzonitrile (1.06 g, 37%). 1H NMR (400 MHz, CDCl3) δ 7.71 (t, J=7.9 Hz, 1H), 7.64-7.61 (m, 2H), 7.59 (d, J=7.9 Hz, 1H), 7.53-7.44 (m, 4H), 7.26-7.24 (m, 1H), 7.04-6.96 (m, 2H), 6.80 (s, 1H), 5.38 (d, J=2.6 Hz, 1H), 4.99-4.97 (m, 1H), 4.69 (d, J=2.6 Hz, 1H), 1.65 (d, J=7.5 Hz, 6H).
Reaction SMILES: [CH2:1]([C:3]1[S:19][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][N:9]3[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1.Cl[Si](C)(C)C.C(N(CC)CC)C.[N-]1C=CN=C1>CN(C)C=O>[CH2:1]([C:3]1[S:19][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13]([C:16]([NH:33][C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[O:18])=[CH:12][N:9]3[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CCc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1
Yield: 73.9 %

Procedure:
0.64 g (0.0023 mol) of 2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid (Example 2) and 0.75 g (0.0046 mol) of 1,1'carbonyldiimidazole (Aldrich Chemical Company) in 70 ml of dimethylformamide are stirred at 70° C. for two and one-half hours. To 0.31 g (0.003 mol) of 5-amino-tetrazole monohydrate (Aldrich Chemical Company) in 40 ml of dimethyl/formamide cooled to 0°-5° C. is added 1.5 ml (0.012 mol) of chlorotrimethylsilane (Aldrich Chemical Company) and 2.5 ml (0.018 mol) of triethylamine. The mixture is stirred and allowed to reach room temperature. After two hours the mixture is combined with the previous imidazolide mixture and stirred for fourteen hours at room temperature. The resulting precipitate is collected, slurried in boiling glacial acetic acid, the mixture is cooled and filtered to give 0.58 g of 2-ethyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d] pyrimidine-7-carboxamide; mp 310°-312° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.Cl.[F:10][C:11]1[CH:21]=[CH:20][C:14]([O:15][CH:16]2[CH2:19][NH:18][CH2:17]2)=[CH:13][CH:12]=1.C(N(C(C)C)C(C)C)C>CC(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:18]2[CH2:19][CH:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:21][CH:20]=3)[CH2:17]2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: Fc1ccc(OC2CNC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1ccc(OC2CN(c3ccnc(Cl)c3)C2)cc1
Temperature: 84 °C
Yield: 90.3 %

Procedure:
To 2-chloro-4-fluoropyridine (160.0 mg, 1.216 mmol) and 3-(4-fluoro-phenoxy)-azetidine hydrochloride (248 mg, 1.216 mmol) in 2-propanol (3.0 mL) in a disposable sealed tube at RT was added N-ethyl-N-isopropylpropan-2-amine (0.530 mL, 3.04 mmol). The resulting reaction mixture was heated at 84° C. for 18 h, cooled to RT, concentrated, purified using MPLC (5 g cartridge, 12 g column, 0 to 60% EtOAc-hexanes) giving 2-chloro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyridine (306.1 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:17])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[CH3:20][O:21][C:22](=[O:28])[C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:28])[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:8](=[O:17])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)C=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Triethylamine (25.26 ml) and cinnamoyl chloride (16.60 g) were successively added to a methylene chloride solution (300 ml) of L-proline methylester hydrochloride (15.0 g) under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. After stirring at room temperature for 1.5 hours, the mixture was poured into ice water and successively washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate, and saturated salt water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 23.09 g of N-cinnamoyl-L-proline methyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=O)[NH:11][N:12]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].O>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=[S:15])[NH:11][N:12]=1
Reactant: O=c1ccc(-c2ccccn2)n[nH]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Product: S=c1ccc(-c2ccccn2)n[nH]1
Temperature: 25 °C
Yield: 92 %

Procedure:
500 mg (2.9 mmol) of pyridazinone 7 and 772 mg (3.5 mmol) of phosphorus pentasulfide are dissolved in 20 ml of anhydrous pyridine. The reaction mixture is brought to reflux for 18 h, and then cooled to ambient temperature. It is then poured into 200 ml of water, and the precipitate thus formed is filtered off and then washed with ice-cold water. The pyridazinethione 10 is obtained with a yield of 92%.