Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13]([Cl:38])=[CH:14][C:15]2[N:21]3[CH2:22][CH2:23][CH2:24][C@@H:25]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C@H:20]3[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[O:17][C:16]=2[CH:37]=1>C(Cl)Cl.C(N(CC)CC)C>[Cl:38][C:13]1[C:12]([N:11]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:37][C:16]2[O:17][C:18]3[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=3[C@@H:20]3[C@H:25]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23][CH2:22][N:21]3[C:15]=2[CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc2c(cc1Cl)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)c(N(S(=O)(=O)c4ccccc4)S(=O)(=O)c4ccccc4)cc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 40 °C
Reaction time: 4 h
Yield: 105.5 %

Procedure:
N-acylation of an amine of Structure 25 to an amide of Structure 26 Benzenesulfonyl chloride (5 μL, 0.04 mmol) was added under N2 to trans-N-(8-amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2,-trifluoroacetamide (5.0 mg, 0.01 mmol) in a mixture of 1 mL of CH2Cl2 and 25 μL of triethylamine. The resulting mixture was stirred at 40° C. for 4 h. After cooling the mixture was evaporated and the crude compound was purified by chromatography on silica. Elution with toluene/ethyl acetate 1:0→0:1 (gradient) gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-8-[bis(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (7.3 mg, 83%). Data: (m/z)=692 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=[C:11]3[C:10]4[C:14](=[CH:15][C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[CH:8][CH:9]=4)[NH:13][C:12]3=[O:16])[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 70.6 %

Procedure:
6-Pyridin-3-yl-1,3-dihydroindol-2-one (60 mg, 0.28 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (75 mg) to give 90 mg (71%) of the title compound as a light orange solid.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:8][N:7]=1>O.C(O)(=O)C>[Cl:5][C:6]1[CH:11]=[C:10]([C:12](=[N:1][OH:3])[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:8][N:7]=1
Reactant: O=C(Cc1ccnc(Cl)c1)c1ccc(F)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(C(=NO)c1ccnc(Cl)c1)c1ccc(F)cc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
With stirring and cooling in a water bath (about 10° C.), a solution of NaNO2 (0.85 g; 12.3 mmol) in H2O (10 ml) was added dropwise over a period of 2.5 min to a solution of 21a (3.0 g; 12 mmol) in glacial acetic acid. After the addition had ended, the reaction mixture was stirred at room temperature for 0.5 h, H2O (60 ml) was added and stirring at room temperature was continued for 3 h. The light-beige precipitate was filtered off, washed with water and dried under reduced pressure over CaCl2.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCCCC1.[Br:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([CH2:30]Br)[N:24]=1.Cl.[Cl-].[NH4+]>O1CCCC1>[Br:22][C:23]1[N:24]=[C:25]([CH2:30][C:11]2([C:14]#[N:15])[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Fc1ccc(CBr)nc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(Cc2ccc(F)c(Br)n2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
N-Boc-4-cyanopiperidine (5.35 g, 25.4 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to −78° C. Thereafter, to this, a cyclohexane solution (1.5 M, 16.5 mL, 24.8 mmol) of a lithium diisopropylamide/tetrahydrofuran complex was added while maintaining the inside temperature at −70° C. or less. The reaction mixture was stirred at −78° C. for 20 minutes. To the resultant reaction mixture, a THF solution (10 mL) of 2-bromo-6-(bromomethyl)-3-fluoropyridine (6.28 g, 23.4 mmol) was added while maintaining the inside temperature at −70° C. or less and then stirred at −78° C. for 20 minutes. To the reaction solution, a mixture of hydrochloric acid (5 M, 4.95 mL, 24.8 mmol) and a saturated aqueous ammonium chloride solution (95 mL) was added. After stirred at room temperature, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, then filtered and concentrated. A tar-like residue was dissolved in ethyl acetate (6 mL). To the mixture, heptane (50 mL) was added dropwise while stirring. A seed crystal was added and stirred at room temperature for one hour. To the resultant light yellow suspension solution, heptane (50 mL) was further added dropwise and stirred overnight. The resultant solid substance was collected by filtration, washed with a heptane solution of ethyl acetate and dried under reduced pressure to obtain the target product as an off-white solid substance (7.10 g, 17.8 mmol) (yield 76%). Note that the seed crystal was obtained from the tar-like residue by a purification method routinely used in silica gel column chromatography. Physical property values are shown below.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[CH:3]=1.[CH3:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][CH2:15][N:16]=[N+:17]=[N-:18])=[O:13].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.O>[CH3:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][CH2:15][N:16]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[N:18]=[N:17]1)=[O:13]
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Reactant: C#Cc1cccc(Br)c1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)C(=O)OCn1cc(-c2cccc(Br)c2)nn1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a mixture of 1-bromo-3-ethynylbenzene (0.430 g; 2.38 mmol; Note 1), and azidomethyl 2,2-dimethylpropanoate (0.391 g; 2.49 mmol; Note 2) in t-BuOH/water (3.5/3.0 mL respectively) at room temperature was added a solution of CuSO4.5H2O in water (0.030 g/0.5 mL), followed by sodium ascorbate (0.141 g; 0.71 mmol) in one portion. The mixture was stirred 25 h at room temperature, diluted with water and extracted with EtOAc (×3). Combined organics were washed (5% NH4OH, water, brine), dried over Na2SO4 and concentrated in vacuo affording the title compound as a tan solid which was used without further purification. LC/MS (method B) 2.77 min, m/z 338, 340 (M+H, Br isotopes).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:5][CH:4]=1)=[CH2:2].N1C=CC=CC=1C1C=CC=CN=1.Br[CH:34]([C:39]1[CH:40]=[C:41]([Cl:47])[C:42]([Cl:46])=[C:43]([Cl:45])[CH:44]=1)[C:35]([F:38])([F:37])[F:36]>ClC1C=CC=CC=1Cl.Cl[Cu]>[F:38][C:35]([F:36])([F:37])[CH:34]([C:39]1[CH:40]=[C:41]([Cl:47])[C:42]([Cl:46])=[C:43]([Cl:45])[CH:44]=1)/[CH:2]=[CH:1]/[C:3]1[CH:4]=[CH:5][C:6]([NH:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:7][CH:8]=1
Reactant: FC(F)(F)C(Br)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: C=Cc1ccc(NN2C(=O)c3ccccc3C2=O)cc1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)N1Nc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Temperature: 180 °C
Yield: 77.8 %

Procedure:
To a stirred solution of 2-(4-vinylphenylamino)isoindoline-1,3-dione (0.3 g, 1.1 mmol) in 1,2-dichlorobenzene (5 mL) were added CuCl (0.022 g, 0.273 mmol), 2,2-bipyridyl (0.07 g, 0.46 mmol) and 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.77 g, 2.27 mmol). The reaction mixture was degassed with argon for 30 min and was heated at 180° C. for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 0-30% EtOAc in petroleum ether) to afford the title compound as a solid (450 mg, 75%): mp 187-189° C.; 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.96 (m, 4H), 7.82 (s, 2H), 7.37 (d, J=8.8 Hz, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.61 (m, 2H), 6.58 (m, 1H), 4.59 (m, 1H); ESIMS m/z 523.05 ([M−H]−).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([O:17]C)[C:11]=3[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:9]2)[CH2:4][O:3]1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][NH:13][C:12](=[O:17])[C:11]=2[C:10]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)=[CH:9]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2CC1COC(C)(C)O1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-c2cn(CC(O)CO)c3cc[nH]c(=O)c23)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
To a solution of 4-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)benzenesulfonamide (32.0 mg) in acetonitrile (3 mL) were added sodium iodide (28.7 mg) and chloro(trimethyl)silane (0.097 mL), and the mixture was stirred overnight at 50° C. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (Example 90)(4.5 mg) and the title compound (Example 91) (5.7 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[C:16]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH3:16]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(Cl)cc(S(F)(F)(F)(F)F)cc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(S(F)(F)(F)(F)F)cc1Br
Yield: 78.6 %

Procedure:
4.20 g of 2-bromo-6-chloro-4-pentafluorosulfanylphenol were stirred together with 3.48 g of K2CO3 and 2.68 g of CH3I in 50 ml of anhydrous DMF at RT for 24 hours. The solvent was then removed under reduced pressure and subsequently taken up with 100 ml each of water and EA. The phases were left to separate and extraction was then effected twice more with 100 ml each time of EA. Drying was effected over Na2SO4 and the solvent was removed under reduced pressure. Chromatography on silica gel using 1:1 DIP/HEP afforded 3.44 g of a colorless viscous liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[CH:27][CH2:28]O)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.S(Cl)([Cl:32])=O>C(Cl)Cl.C(Cl)CCl>[Cl:32][CH2:28][CH:27]=[CH:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[NH:15][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(Nc2ncnc3ccc(C=CCO)cc23)ccc1Oc1cccnc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(Nc2ncnc3ccc(C=CCCl)cc23)ccc1Oc1cccnc1
Temperature: 100 °C

Procedure:
To a suspension of 0.035 g (0.091 mmol) of 3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-en-1-ol in 0.5 mL of methylene chloride and 1 mL of ethylene dichloride was added 1 mL of thionyl chloride. The reaction was heated at 100° C. for 1 hour and the solvents were evaporated to provide [6-(3-chloro-propenyl)-quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine [MS: M+ 403.1] which was dissolved in THF and used directly in the next reaction. To the solution of [6-(3-chloro-propenyl)-quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine was added 0.10 mL of morpholine and 0.044 mL of triethylamine. The mixture was heated at 85° C. for 16 hours, cooled to room temperature, and partitioned between 10% aqueous potassium carbonate and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organics were dried and evaporated to yield 57 mg of material. The product was purified on a silica gel prep plate, eluting with 96:4:0.1 chloroform/methanol/concentrated ammonium hydroxide to afford 26 mg of the title compound; 1H NMR (CDCl3): δ 8.71 (s, 1), 8.33 (m, 2), 7.94 (s, 1), 7.80 (m, 2), 7.69 (s, 1), 7.58 (m, 1), 7.20 (m, 1), 6.94 (d, J8.7 Hz, 1), 6.68 (d, J=15.8 Hz, 1), 6.46 (m, 1), 3.79 (m, 4), 3.26(m, 2), 2.63 (m, 4), 2.25 (s, 3).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:38]=[CH:39][C:34]([C:32]#[N:33])=[CH:35][CH:36]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 30 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a off-white foam (30%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3cccnc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3cccnc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 45.1 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.086 mmol), 3-tributylstannanyl-pyridine (0.040 mL, 0.13 mmol) and PdCl2(PPh3)2 (12 mg, 0.017 mmol) in 3 mL of DMF was heated at 120° C. for 3 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (0-10% MeOH/EtOAc) to give 18 mg of the title compound. MS: (+) m/z 465.35 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]1[C:18](=[O:19])[CH:17]2[CH:12]([CH:13]3[O:20][CH:16]2[CH:15]=[CH:14]3)[C:11]1=[O:21].[CH:22](I)=[CH2:23].C([O-])=O.[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]1[C:11](=[O:21])[CH:12]2[CH:17]([CH:16]3[O:20][CH:13]2[CH:14]([CH:22]=[CH2:23])[CH2:15]3)[C:18]1=[O:19]
Reactant: Cc1cc(C)c(C2C(=O)C3C4C=CC(O4)C3C2=O)c(C)c1
Reactant: C=CI
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=CC1CC2OC1C1C(=O)C(c3c(C)cc(C)cc3C)C(=O)C21
Temperature: 150 °C

Procedure:
A mixture of (1RS,2SR,6RS,7SR)-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione (510 mg, 1.8 mmol), vinyl iodide (280 mg, 1.8 mmol), palladium acetate (20 mg, 0.09 mmol), sodium formate (454 mg, 5.4 mmol) and tetrabuylammonium chloride (500 mg, 1.8 mmol) in dry N,N-dimethylformamide (15 ml) are heated at 150° C. for 20 minutes under microwave irradiation. The mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR,8RS)-4-(2,4,6-trimethylphenyl)-8-vinyl-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: O=[C:2]1[N:21]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2=[N:6][C:7]([C:10]3[CH:11]=[N:12][N:13]4[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=34)=[CH:8][CH:9]=[C:4]2[NH:3]1.[C:28](OCC)(OCC)(OCC)C.C(Cl)Cl.CO>CCO>[CH3:28][C:2]1[N:21]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2=[N:6][C:7]([C:10]3[CH:11]=[N:12][N:13]4[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=34)=[CH:8][CH:9]=[C:4]2[N:3]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: N#Cc1ccn2ncc(-c3ccc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: Cc1nc2ccc(-c3cnn4ccc(C#N)cc34)nc2n1C1CCOCC1
Temperature: 145 °C
Reaction time: 2.5 h
Yield: 15 %

Procedure:
To a solution of the compound obtained in example 2 section d (56.4 mg, 0.169 mmol) in EtOH (1.5 mL), PTSA monohydrate (3.21 mg, 0.017 mmol) and triethyl orthoacetate (547 mg, 3.37 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 145° C. and 270 W for 2.5 hours. The crude residue was cromategraphed on a silica gel flash system (ISCO Rf) using CH2Cl2/MeOH mixtures of increasing polarity, a eluent to afford the desired product (15% yield).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].SC(O)C.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.[C:61]([OH:92])(=[O:91])[CH2:62][CH2:63][C@H:64]([NH:68][C:69]([C:71]1[CH:90]=[CH:89][C:74]([NH:75][CH2:76][C:77]2[CH2:78][NH:79][C:80]3[N:81]=[C:82]([NH:84][C:85]([C:87]=3[N:88]=2)=[O:86])[NH2:83])=[CH:73][CH:72]=1)=[O:70])[C:65]([OH:67])=[O:66]>>[C:61]([OH:92])(=[O:91])[CH2:62][CH2:63][C@H:64]([NH:68][C:69]([C:71]1[CH:72]=[CH:73][C:74]([NH:75][CH2:76][CH:77]2[NH:88][C:87]3[C:85](=[O:86])[NH:84][C:82]([NH2:83])=[N:81][C:80]=3[NH:79][CH2:78]2)=[CH:89][CH:90]=1)=[O:70])[C:65]([OH:67])=[O:66]
Reactant: Nc1nc2c(c(=O)[nH]1)N=C(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Agent: CC(O)S
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Product: Nc1nc2c(c(=O)[nH]1)NC(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Temperature: 37 °C
Reaction time: 0.08 h

Procedure:
A solution of purified DHFR was added to a solution comprising a potassium phosphate buffer solution (pH: 7.5, 75 mM), mercaptoethanol (7.5 mM) and NADPH (0.25 mM) to make up to a total amount of 0.57 ml. Each of the serial dilutions of the compound according to the present invention in an amount of 0.015 ml was added to the mixture prepared above. The mixtures thus prepared were preliminarily heated at 37° C. for 5 minutes, followed by the addition of 0.015 ml of a 25 μM solution of dihydrofolic acid. The obtained mixtures were kept at 37° C. for 5 minutes to conduct a reaction. The resulting mixtures were each examined for the decrease in the absorbency at 339 nm per minute. The amount of tetrahydrofolic acid formed was determined on the basis of the decrease and compared with that of a control solution (containing none of the compounds according to the present invention) to calculate the 50% DHFR-inhibitory concentration (IC50). The results are given in Tables 1-A and 1-B.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[C:24](Cl)(=[O:26])[CH3:25].N1C=CC=CC=1>ClCCl>[C:24]([O:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1)(=[O:26])[CH3:25]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(O)c1cnoc1C1CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
A mixture of 4-[hydroxy-(2-nitro4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (0.69 g), acetyl chloride (0.27 g) and pyridine (0.10 g) in dichloromethane (40 ml) was stirred at 0° C. for 4 hours. The mixture was quenched with water and extracted with dichloromethane. The organic extracts were dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was triturated with ether/petroleum ether to give 4-[acetoxy-(2-nitro4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 297, 0.46 g) as a yellow solid: m.p. 82° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9](S(C)(=O)=O)[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1)(=[O:4])=[O:3].C(O)C.CN.FC1C=C(C=CC=1F)CO[C:41]1N=C(NC)C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2Cl)[N:42]=1>C(#N)C>[CH3:1][S:2]([C:5]1[N:10]=[C:9]([CH2:41][NH2:42])[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1)(=[O:3])=[O:4]
Reactant: CNc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Agent: CN
Solvent: CCO
Solvent: CC#N
Product: CS(=O)(=O)c1nc(CN)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reaction time: 1 h

Procedure:
To a round bottom flask fitted with a magnetic stirrer bar and rubber septum was added 2,4-bis(methylsulfonyl)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]-pyrimidine (Reference Example 5, Step A, 50 mg, 0.1 mmol), and 1 mL each of ethanol and acetonitrile. The mixture was cooled to 0° and methylamine (2 eq., 400 μL, 1M in THF) was added via syringe. The mixture was stirred for 1 h, the solvents removed under reduced pressure and the product chromatographed (77/23 hexanes/ethyl acetate) to give two products: a higher Rf product (unidentified) and 2-(3,4-difluorobenzyloxy)-4-(N-methylamino)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine as the lower Rf product. HPLC/MS: m/e=442 (M+−1); Rt=3.58 min. 1H-NMR 500 MHz (CDCl3): δ 3.13 (d, J=5 Hz, 3H), 3.37 (s, 3H), 7.07 (d, J=8 Hz 1H), 7.10 (d, J=8 Hz, 2H), 7.18 (d, J=8 Hz, 1H), 7.38-7.40 (m, 3H).