Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)#[N:2].[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH2:16][C:5]3[CH:6]=[CH:7][C:8]([C:9]4[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=4)=[C:3]([C:1]#[N:2])[CH:4]=3)=[N:26][CH:25]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: N#Cc1cc(CC(=O)O)ccc1-c1ccnc(F)c1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(F)c4)c(C#N)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 206-6 (50 mg, 0.20 mmol) was dissolved in DMF (2 mL). 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (52 mg, 0.23 mmol) and DIEA (170 uL, 0.98 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (111 mg, 0.29 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)acetamide 211. MS m/z 459.2 (M+1)); 1H NMR 400 MHz (DMSO-d6) δ 10.64 (s, 1H), 8.41 (d, 1H), 8.05 (d, 1H), 7.98 (d, 1H), 7.91 (d, 1H), 7.81 (dd, 1H), 7.71 (d, 1H), 7.62 (dt, 1H), 7.49 (s, 1H), 7.42 (dd, 1H), 3.85 (s, 2H), 3.59-3.54 (m, 4H), 3.15 (t, 2H), 3.08 (t, 2H), 2.04 (s, 3H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(OC(=O)c2ccccc2)cc1

Procedure:
The synthesis of this compound proceeded in the same fashion as in Example 1 using 21.63 g (0.20 mol) of p-cresol, 22.26 g (0.22 mol) of triethylamine and 28.11 g (0.20 mol) of benzoyl chloride. The product amounted to 39.95 g, m.p. 66°-69° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[N:11]=[C:10]([NH:17][CH:18]2[CH2:20][CH2:19]2)[C:9]=1[F:21]>ClCCl>[CH:18]1([NH:17][C:10]2[C:9]([F:21])=[C:8]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)[N:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]=2)[CH2:20][CH2:19]1
Reactant: Fc1c(Cl)nc(C2CC2)nc1NC1CC1
Reactant: C1CSCCN1
Solvent: ClCCl
Product: Fc1c(NC2CC2)nc(C2CC2)nc1N1CCSCC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
A mixture of thiomorpholine (2.27 g, 22 mmol) and 6-chioro-N,2-dicyclopropyl-5-fluoro-4-pyrimidinamine 31 (1 g, 4.4 mmol) is stirred at 110° C. for 18 hours. After cooling, the brown solution is diluted with dichloromethane, washed two times with a saturated sodium bicarbonate solution. The combined organic layers are dried over magnesium sulfate and concentrated under high vacuum to afford a brown oil. The crude oil is purified by column chromatography (hexane/ethyl acetate: 80/20) to give N,2-dicyclopropyl-5-fluoro-6-(4-thiomorpholinyl)-4-pyrimidinamine 120 (915 mg, 71%) as a yellowish solid.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[CH:9][C:8]=1[O:16][CH3:17])(=[O:5])[CH3:4].[CH3:18]I>CN(C)C=O>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([O:13][CH3:14])[C:7]=1[N:6]([CH3:18])[C:3](=[O:5])[CH3:4]
Reactant: COc1cc(C)cc(OC)c1NC(C)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)cc(OC)c1N(C)C(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 12.0 g. of sodium hydride (50% dispersion in oil) in 50 ml. of absolute dimethylformamide was treated with a solution of 46.0 g. of 4-acetamido-3,5-dimethoxy-toluene in 200 ml. of absolute dimethylformamide over a period of 30 minutes with stirring and exclusion of moisture. After stirring at room temperature for 4 hours, 31.2 ml. of methyl iodide were added dropwise over a period of 20 minutes with stirring and ice-cooling. The mixture was stirred at room temperature for 70 hours and subsequently evaporated to dryness under vacuum. The residue was treated with 300 ml. of water and the resulting suspension was extracted with two 500 ml. portions of ethyl acetate. The combined ethyl acetate extracts were washed with 300 ml. of water, dried over magnesium sulfate, filtered and evaporated under vacuum. Recrystallization of the residue from ethyl acetate gave 3,5-dimethoxy-4-(N-methyl-acetamido)-toluene having a melting point of 160°-161° C.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[F:1][CH:2]([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(C(F)F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-(difluoromethyl)benzoic acid (0.7 g, 4 mmol) dissolved in DCM (20 ml), cooled to 0° C. and added oxalyl chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(difluoromethyl)benzoyl chloride quantitatively. 2-Amino-5-bromophenol (0.64 g, 3.4 mmol) dissolved in DCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(difluoromethyl)benzoyl chloride (0.77 g, 4.1 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (0.5 g) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.27 (s, 1H), 9.62 (s, 1H), 8.07 (d, J 8.2, 2H), 7.71 (d, J 8.2, 2H), 7.61 (d, J 8.5, 1H), 7.12 (t, J 55.7, 1H), 7.07 (d, J 2.2, 1H), 7.03-6.94 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=[C:11]([C:21](O)=[O:22])[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:25][O:26][C:27]1[CH:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:20])([F:18])[F:19])=[CH:13][N:12]=[C:11]([C:21]([NH:33][CH2:32][C:30]3[O:29][N:28]=[C:27]([O:26][CH3:25])[CH:31]=3)=[O:22])[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)n1
Reactant: COc1cc(CN)on1
Agent: Cl
Product: COc1cc(CNC(=O)c2ncc(OCC(F)(F)F)c(-c3ccc(Cl)c(Cl)c3)n2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(3,4-dichloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic acid (example AA) and 3-methoxy-5-isoxazolemethanamine hydrochloride as starting materials, 477.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[NH:17][C:16]2=[O:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27](C)([O-])C.[K+].C(I)C.[Na+].[Cl-]>CN(C=O)C.O.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH2:26][CH3:27])[C:16]2=[O:25])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCI
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C)c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.2 %

Procedure:
To a solution of 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (86.1 g) in DMF (860 mL) was added potassium tert-butoxide (87.5 g) with cooling in water bath. To the mixture was added ethyl iodide (122 g), and the mixture was stirred at room temperature for 6 h. The mixture was poured into EtOAc (1.2 L) and 5% aq. NaCl (1 L). The organic layer was separated. The aqueous layer was extracted with EtOAc (500 mL). The combined organic phase was washed with brine, dried over MgSO4, passed through a silica gel pad, and evaporated to give 3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (88 g) as a black solid. This product was subjected to the next reaction without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.FC1C=C(C2C3C(=CC=C(OC)C=3)C(=O)C=2C2C=NC=CC=2)C=C(F)C=1>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=C(c1ccncc1)C2=O
Agent: COc1ccc2c(c1)C(c1cc(F)cc(F)c1)=C(c1cccnc1)C2=O
Product: O=C1C(c2ccncc2)=C(c2ccccc2)c2cc(O)ccc21
Yield: 88 %

Procedure:
The procedure of Step 5 of Example 128 was repeated except for using 5-methoxy-3-phenyl-2-(pyridin-4-yl)-1H-inden-1-one obtained in Step 1 as a starting material instead of 3-(3,5-difluorophenyl)-5-methoxy-2-(pyridin-3-yl)-1H-inden-1-one to obtain the title compound (88%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:11](N)(=O)[CH3:12]>C(O)C>[CH3:11][C:12]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: CC(N)=O
Reactant: NC(=O)c1ccccc1N
Solvent: CCO
Product: Cc1nc2ccccc2c(=O)[nH]1
Temperature: 180 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
A mixture of 2-amino benzamide (20 g, 0.147 mol) and acetamide (43 g, 0.735 mol) was heated to 180° C. for 20 h. The dark brown reaction mixture was cooled and suspended in ethanol (200 ml). After stirring for 2 h, it was filtered and dried under suction to afford 11 g (47%) of the titled compound as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:9]1[CH:13]=[C:12](I)[S:11][C:10]=1[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[O:48][C:47]4[C:42](=[N:43][CH:44]=[CH:45][CH:46]=4)[CH:41]=3)=[CH:36][CH:35]=2)O1>>[C:1]([O:5][C:6]([N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:9]1[CH:13]=[C:12]([C:34]2[CH:35]=[CH:36][C:37]([C:40]3[O:48][C:47]4[C:42](=[N:43][CH:44]=[CH:45][CH:46]=4)[CH:41]=3)=[CH:38][CH:39]=2)[S:11][C:10]=1[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(I)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2ccc(-c3cc4ncccc4o3)cc2)OC1(C)C
Product: COC(=O)c1sc(-c2ccc(-c3cc4ncccc4o3)cc2)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
Intermediate VII.5 was prepared starting from methyl 3-(bis[ter-butoxycarbonyl]amino)-5-iodo-2-thiophenecarboxylate and 2-[4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]furo[3,2-b]pyridine (according to the general procedure in WO 2008/017688) as described for Intermediate VII.1. Intermediate VII.5 was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[C:10]1(=O)[O:15][C:13](=[O:14])[CH2:12][CH2:11]1>>[C:13]([CH2:12][CH:11]=[C:10]1[C:7]2[CH:8]=[C:2]([CH3:1])[C:3]([OH:9])=[CH:4][C:5]=2[O:6][C:5]2[C:7]1=[CH:8][C:2]([CH3:1])=[C:3]([OH:9])[CH:4]=2)([OH:15])=[O:14]
Reactant: Cc1ccc(O)cc1O
Reactant: O=C1CCC(=O)O1
Product: Cc1cc2c(cc1O)Oc1cc(O)c(C)cc1C2=CCC(=O)O
Temperature: 65 °C
Yield: 74.2 %

Procedure:
4-Methylresorcinol (25.8 g, 0.208 mol) and succinic anhydride (20.8 g, 0.208 g) were placed in a round bottom flask and the flask was purged with nitrogen. Methanesulfonic acid (150 mL) was added and the solution heated under nitrogen to 65° C. for 2 hours. The solution was added dropwise to 1 L of rapidly stirred, ice-cooled water with the simultaneous addition of 50% ag sodium hydroxide to maintain the pH at 2.25+/-0.25. The product was collected by centrifugation and washed with water (3×) and acetone (2×). The solid was air-dried, then vacuum-dried at 110° C. to afford a brick-red powder (24.1 g, 74%).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7].C(N(CC)CC)C.ClC(OCC)=O>C(Cl)(Cl)Cl>[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:7])[C:5]1[CH:13]=[CH:14][CH:15]=[CH:3][CH:4]=1
Reactant: O=C(O)CCC(=O)c1cccc(C(F)(F)F)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)CCC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a mixture of 24.5 g. 3-(m-trifluoromethylbenzoyl) propionic acid (0.10 mole) and 10.1 g. triethylamine (0.10 mole) in 250 ml. of chloroform cooled to 0°C., there is added dropwise 10.8 g. (0.10 mole) of ethyl chloroformate at such a rate that the critical temperature does not exceed 10°C. The reaction is stirred for 2 1/2 hours to obtain the mixed anhydride of 3-benzoylpropionic acid which is then treated with 3.1 g. of methylamine (0.10 mole) in 100 ml. of chloroform. The cooling apparatus is removed and the reaction is stirred for about 20 hours. The chloroform layer is then washed with 50 ml. of water, 100 ml. 1N hydrochloric acid, 100 ml. saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue is crystallized from methylene chloride/hexane to give 5-hydroxy-1-methyl-5-(m-trifluoromethylphenyl)pyrrolidone; m.p. 137°-139°C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[C:17]([C:23]([NH:25][C:26]2[S:30][N:29]=[C:28]([CH3:31])[N:27]=2)=[O:24])=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1.Cl>O.C(Cl)(Cl)Cl.CN(C)C=O>[Cl:22][C:19]1[N:18]=[C:17]([C:23]([NH:25][C:26]2[S:30][N:29]=[C:28]([CH3:31])[N:27]=2)=[O:24])[C:16]([S:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:21][CH:20]=1
Reactant: Cc1nsc(NC(=O)c2nc(Cl)ccc2Cl)n1
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)c2nc(Cl)ccc2Sc2ccc(O)cc2)n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 71.7 %

Procedure:
12 g of 4-hydroxythiophenol and 16 g of potassium carbonate were added to a dimethylformamide (150 ml) solution of 15 g of 3,6-dichloro-N-(3-methyl-1,2,4-thiadiazol-5-yl)pyridine-2-carboxamide, and stirred at 50° C. for 1.5 hours. At room temperature, chloroform and water were added to it, and its pH was controlled to 3 with aqueous 2 N hydrochloric acid solution added thereto. This was extracted with chloroform, the organic layer was washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, 300 ml of t-butyl methyl ether was added to the residue, and the resulting solid was taken out through filtration to obtain 14.1 g of the entitled compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([C:11]2[N:15]=[CH:14][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:12]=2)=[CH:7][C:8]=1[CH:9]=O)([O-:3])=[O:2].[NH2:24][OH:25].Cl.CC([O-])=O.[Na+]>CCO.C([O-])(O)=O.[Na+]>[N+:1]([C:4]1[S:5][C:6]([C:11]2[N:15]=[CH:14][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:12]=2)=[CH:7][C:8]=1[CH:9]=[N:24][OH:25])([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc(C=O)c([N+](=O)[O-])s2)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cnc(-c2cc(C=NO)c([N+](=O)[O-])s2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Nitro-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)thiophene-3-carbaldehyde (1.85 g, 5.22 mmol), NH2OH.HCl (381 mg, 5.48 mmol), and NaOAc (450 mg, 5.48 mmol) were combined in EtOH (30 mL) and stirred at room temperature for 2 h. The reaction was diluted with saturated NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to afford the title compound as an orange solid (mixture of oxime E/Z isomers).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+]>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:6][C:5]2[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Yield: 175.7 %

Procedure:
The title compound (26.6 g, 110%) was prepared from methyl 4-hydroxybenzoate (15.2 g, 125 mmol) utilising sodium hydride as base, in a similar manner to Intermediate 76. 1H NMR (CDCl3) δ 8.00 (2H, d, J 8.9 Hz), 7.82-7.73 (5H, br m), 6.99 (2H, d, J 8.9 Hz), 5.12 (2H, s) and 3.89 (3H, s). MS (ES) m/e 243 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:29])[CH:26]=[N+]=[N-])[N:17]=[CH:16]2)[C@H:6]1[F:30])(=[O:3])[CH3:2].F[C@@H]1[C@H](O)[C@@H](CO)O[C@@H]1OC.[ClH:42]>ClCCl.C(OCC)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:29])[CH2:26][Cl:42])[N:17]=[CH:16]2)[C@H:6]1[F:30])(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)C=[N+]=[N-])c2N=CN(C)C)[C@@H](F)[C@@H]1OC(C)=O
Agent: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N=CN(C)C)[C@@H](F)[C@@H]1OC(C)=O
Yield: 75 %

Procedure:
Compound (37) (80 mg) obtained in item (4) above was dissolved in dichloromethane (4 ml), to which was added at 5° C. a 1.25M hydrogen chloride solution (0.2 ml) in diethylether and the mixture obtained was allowed to undergo the reaction at that temperature overnight. The resulting reaction solution was washed with water, and the organic layer was dried over anhydrous sodium sulfate and then concentrated to give the titled compound (38) (61 mg) as a syrup. Yield: 75%.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:35]=[C:36]([C:38]1[CH:39]=[CH:40][C:41]([CH3:44])=[N:42][CH:43]=1)[CH3:37]>CN(C=O)C.O.[Cu](I)I>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11](/[CH:35]=[C:36](/[C:38]3[CH:43]=[N:42][C:41]([CH3:44])=[CH:40][CH:39]=3)\[CH3:37])[C:10]3[CH2:9][CH2:8][N:7]4[CH:6]([C:5]=3[C:4]=2[CH:3]=1)[CH2:17][CH2:16][CH2:15]4
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: CC(=CBr)c1ccc(C)nc1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)C1CCCN1CC2)c1ccc(C)nc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a degassed solution of 9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (50 mg, 0.22 mmol), potassium phosphate (100 mg, 0.462 mmol), L-proline (5 mg, 0.022 mmol) and copper iodide (5 mg, 0.044 mmol) in DMF (1 mL) was added 5-(2-bromo-1-methyl-vinyl)-2-methyl-pyridine (80 mg, 0.375 mmol). The reaction mixture was stirred at 120° C. for 20 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The organic layer was washed with water (3×10 mL), followed by brine (15 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by reverse phase HPLC;
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])=[O:18])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-:45].[Ca+2].[OH-:47]>C(Cl)Cl>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])=[O:18])=[CH:15][CH:14]=2)(=[O:47])=[O:45])=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)NCC(=O)OCC)cc2)ccc(C(C)=O)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)NCC(=O)OCC)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound of Example 1 (400 mg, 0.845 mmoles) was taken up in methylene chloride (30 ml) to which was added m-chloroperbenzoic acid (343 mg, 2 eqts). The reaction mixture was stirred at room temperature under nitrogen for one hour. An additional 20 mg of m-CPBA was added and stirring was continued for one hour. Calcium hydroxide (400 mg) was added to the reaction mixture and stirring was continued for ten minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with ether to afford the title compound, m.p. 138°-140°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.ClCCl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:14]=3)[O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(-c2nc(-c3cccc(Cl)c3)co2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2nc(-c3cccc(Cl)c3)co2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 63.7 %

Procedure:
under an N2 atmosphere, 4-(4-(3-chlorophenyl)oxazol-2-yl)benzenamine (0.127 g, 0.469 mmol) was dissolved in dichloromethane (4.00 ml, 62.2 mmol). Benzoyl chloride (0.0572 ml, 0.493 mmol) was added followed by pyridine (0.200 ml, 2.47 mmol), and the reaction was allowed to stir at room temperature for 2.5 hours. The reaction was diluted with ethyl acetate and washed with 0.1N N HCl, and 5% NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude solid was triturated with ethyl acetate/hexanes and the resulting solid was collected by filtration to afford N-(4-(4-(3-chlorophenyl)oxazol-2-yl)phenyl)benzamide (0.112 g, 63.7% yield). ESI m/z=375.1 (M+H+).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:13]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[CH:28])[C:20]=2[CH:29]=1)=[C:14]=[O:15]>>[CH2:7]([O:6][C:4]([CH:3]=[C:2]([NH:1][C:14](=[O:15])[NH:13][C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[CH:28])[C:20]=2[CH:29]=1)[C:9]([F:10])([F:11])[F:12])=[O:5])[CH3:8]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: C#CCN1C(=O)COc2ccc(N=C=O)cc21
Product: C#CCN1C(=O)COc2ccc(NC(=O)NC(=CC(=O)OCC)C(F)(F)F)cc21

Procedure:
Analogously to the procedure described in Example 1, starting from ethyl 3-amino-4,4,4-trifluorocrotonate and 3,4-dihydro-6-isocyanato-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine there is obtained 6-{3-[2-(ethoxycarbonyl)-1-trifluoromethyl-vinyl]ureido}-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine (not isolated) and, after cyclization of this benzoxazine, there is obtained 3-[3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, m.p. >250° C.