Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[CH2:24][CH2:23][CH2:22][C:21]4=[O:25])[CH2:16][CH2:15]3)[N:8]2[CH2:11][CH3:12])=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1.[Si]([N:39]1[C:47]2[C:42](=[C:43](B(O)O)[C:44]([F:48])=[CH:45][CH:46]=2)[CH:41]=[CH:40]1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([N:8]1[C:7]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH2:16][CH2:15]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:39]1[C:47]3[C:42](=[CH:43][C:44]([F:48])=[CH:45][CH:46]=3)[CH:41]=[CH:40]1)=[N:3][C:4]=2[N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)[CH3:12]
Reactant: CCn1c(CN2CCC(N3CCCC3=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(B(O)O)c(F)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1c(CN2CCC(N3CCCC3=O)CC2)nc2c(N3CCOCC3)nc(-n3ccc4cc(F)ccc43)nc21
Temperature: 140 °C
Yield: 9.1 %

Procedure:
A mixture of 1-[1-(2-chloro-9-ethyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-piperidin-4-yl]-pyrrolidin-2-one (115 mg, 0.26 mmol), [1-(tert-butyldimethylsilanyl)-5-fluoro-1H-indol-4-yl]boronic acid (105 mg, 0.36 mmol), Pd(PPh3)4 (30 mg, 10 mol %) and cesium carbonate (167 mg, 0.51 mmol) in dioxane/water (5:2 mL) was purged with nitrogen gas then heated at 140° C., for 30 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si-PPC, MeOH:DCM, gradient 0:100 to 07:93) to give 109 as a colourless oil (13 mg, 9%). LCMS (Method F) RT 8.15 min, [M+H]+ 547.3. 1H NMR (CDCl3, 400 MHz): δ 8.74 (dd, J=9.1, 4.8 Hz, 1H); 8.30 (d, J=3.6 Hz, 1H); 7.28-7.24 (m, 1H); 7.08-6.99 (m, 1H); 6.58 (d, J=3.6 Hz, 1H); 4.42-4.30 (m, 6H); 4.09-3.97 (m, 1H); 3.88 (t, J=4.75 Hz, 4H); 3.72 (s, 2H); 3.35 (t, J=7.0 Hz, 2H); 2.95 (d, J=11.3 Hz, 2H); 2.39 (t, J=8.1 Hz, 2H); 2.32-2.22 (m, 2H); 2.06-1.95 (m, 2H); 1.77-1.61 (m, 4H); 1.52 (t, J=7.15 Hz, 3H)
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]2[CH2:11][CH2:10]2)[C:6](=[O:12])[N:5]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:4](=[O:17])[C:3]=1[N:18]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.C(O)C>[NH2:18][C:3]1[C:4](=[O:17])[N:5]([CH2:13][CH:14]2[CH2:15][CH2:16]2)[C:6](=[O:12])[N:7]([CH2:8][CH:9]2[CH2:10][CH2:11]2)[C:2]=1[NH2:1]
Reactant: Nc1c(N=O)c(=O)n(CC2CC2)c(=O)n1CC1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1c(N)n(CC2CC2)c(=O)n(CC2CC2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.1 %

Procedure:
Compound c (3.0 g, 11.4 mmol) was suspended in a mixture of 25 ml of water and 40 ml of ethanol. Twenty milliliters of aqueous solution of 6.9 g (40 mmol) of sodium hydrosulfite was added, and the resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was extracted three times with 50 ml of chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: 3% methanol/chloroform) to give 2.40 g (yield: 84%) of Compound b as an amorphous substance.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[NH:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[CH3:6][C:7]1[N:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccccc2)c[nH]1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)n1cc(-c2ccccc2)cc1C
Reaction time: 0.33 h
Yield: 106.9 %

Procedure:
n-Butyllithium (0.87 mL, 1.6M solution, 1.40 mmol) was added to a cold (below 0° C.) solution of 2-methyl-4-phenyl-1H-pyrrole (200 mg, 1.27 mmol) in tetrahydrofuran (6 mL) and stirred at below 0° C. for 20 min. Ethyl chloroformate (0.1 mL, 1.02 mmol) was added slowly to the reaction mixture and stirred at 0 to 10° C. for 90 min. The reaction mixture was quenched into saturated ammonium chloride solution and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford ethyl 2-methyl-4-phenyl-pyrrole-1-carboxylate (250 mg, 86%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=O)[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:5][C:4]=2[N:3]=1.NC1N=CC2C(=[N:36][OH:37])CC(C3C=CC(F)=CC=3C3C=NC=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[N:36][OH:37])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=NO
Reactant: Nc1ncc2c(n1)CC(c1ccccc1-c1ccncc1)CC2=O
Product: Nc1ncc2c(n1)CC(c1ccccc1-c1ccncc1)CC2=NO

Procedure:
The title compound was prepared from 2-amino-7-(2-pyridin-4-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one from stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one oxime (example 4/a stage 2).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:22]=2)[CH2:14][C@H:13]1[C:27]([OH:29])=O)=[O:10].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:22]=2)[CH2:14][C@H:13]1[C:27]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])=[O:10]
Reactant: C1COCCN1
Reactant: COC(=O)c1cnc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](C(=O)O)C2)s1
Product: COC(=O)c1cnc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](C(=O)N3CCOCC3)C2)s1

Procedure:
The title compound was prepared in a manner analogous to (Intermediate 37) starting from cis(±)4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-[5-(methoxycarbonyl)-1,3-thiazol-2-yl]piperidine-3-carboxylic acid (Example 77) and morpholine. MS (ES+): 530, 532 for C21H25Cl2N5O5S.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[CH:10]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])=O>C(O)C>[OH:8][C:7]1[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=1[N:1]=[CH:10][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: Cc1ccc(O)c(N)c1
Reactant: COC(=O)c1ccccc1C=O
Solvent: CCO
Product: COC(=O)c1ccccc1C=Nc1cc(C)ccc1O
Yield: 76.5 %

Procedure:
A solution of 2-amino-p-cresol (7.4 g) and methyl 2-formylbenzoate (obtained as described in J. Chem. Soc. (C), 1969, 1818) (9.8 g) in ethanol (120 ml) was heated under reflux for 2 hours. The solvent was removed by evaporation and the residue recrystallised from hexane to give 2-hydroxy-5-methyl-N-(2-methoxycarbonylbenzylidene)aniline (B) (12.3 g), m.p. 82°-83° C; NMR: 2.35 (s, 3H), 4.0(s, 3H), 6.9(d, 1H), 7.0(d, 1H), 7.05(br s, 1H), 7.15(d, 1H), 7.5-7.7(m, 2H), 7.95(dd, 1H), 8.2(dd, 1H), 9.45(s, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.CC(C)(OC([N:14](C(OC(C)(C)C)=O)[C:15]1[C:20]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[C:19]([O:27][C:28]2[C:33]([F:34])=[CH:32][C:31]([NH:35][C:36]([C:38]3[C:39](=[O:54])[N:40]([C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)[CH:41]=[CH:42][C:43]=3[O:44][CH2:45][CH3:46])=[O:37])=[C:30]([F:55])[CH:29]=2)[CH:18]=[CH:17][N:16]=1)=O)C>C(Cl)Cl>[NH2:14][C:15]1[C:20]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[C:19]([O:27][C:28]2[C:33]([F:34])=[CH:32][C:31]([NH:35][C:36]([C:38]3[C:39](=[O:54])[N:40]([C:47]4[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=4)[CH:41]=[CH:42][C:43]=3[O:44][CH2:45][CH3:46])=[O:37])=[C:30]([F:55])[CH:29]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2-c2cnn(C)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(N)c2-c2cnn(C)c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
TFA (1 mL) was added to a solution of N-(4-(2-[bis[(1,1-dimethylethoxy)carbonyl]amino]-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.17 g, 0.22 mmol) in CH2Cl2 (3 mL) and the mixture was stirred at RT for 1 h. The solvent was removed and the residue was partitioned between satd NaHCO3 solution (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (25 mL) and the combined organics were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford N-(4-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (120 mg, 95% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.24 (t, J=9.8 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.87 (s, 1H), 7.74 (d, J=5.8 Hz, 1H), 7.58 (s, 1H), 7.47 (m, 2H), 7.36 (t, J=8.7 Hz, 3H), 6.54 (d, J=7.9 Hz, 1H), 5.98 (d, J=5.8 Hz, 1H), 5.69 (s, 2H), 4.27 (q, J=7.0 Hz, 2H), 3.85 (s, 3H), 1.32 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 577.2 (M+H+).
Reaction SMILES: CO[S:3]([O-])(=O)=O.[CH3:7][N+:8]1[S:9][C:10]([Cl:15])=[C:11]([Cl:14])[C:12]=1Cl>C(O)C>[Cl:14][C:11]1[C:12](=[S:3])[N:8]([CH3:7])[S:9][C:10]=1[Cl:15]
Reactant: C[n+]1sc(Cl)c(Cl)c1Cl
Reactant: COS(=O)(=O)[O-]
Solvent: CCO
Product: Cn1sc(Cl)c(Cl)c1=S
Reaction time: 8 h
Yield: 77.9 %

Procedure:
2-Methyl-3,4,5-trichloroisothiazolium methylsulfate (10.7 g) thiourea (2.6 g) were added to 100 ml of ethanol at room temperature. After stirring overnight the product which had precipitated from solution was collected by filtration and recrystallized from ethanol to yield 5.3 g (78%) of 4,5-dichloro-2-methyl-4-isothiazolin-3-thione, mp 143-144. Analysis: Calculated for C4H3ClNS2 : C, 24.00; H, 1.50; N, 7.00; Cl, 35.45; S, 32.05. Found: C, 24.07; H, 1.45; N, 7.00; Cl, 35.67; S, 31.78.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]=[CH:7][N:8]([C@H]3C[C@@H](CO)[C@H](O)[C@@H]3O)[C:9]=2[N:10]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>CS(C)=O.CO>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
A mixture of 2-amino-9-[(1S,2R,3S,4S)-2,3-dihydroxy-4-(hydroxymethyl)-cyclopentyl]-1,9-dihydro-6H-purin-6-one (60.0 g, 0.213 mol) and benzyl bromide (60.9 mL, 0.512 mol) in DMSO (300 mL) was stirred at room temperature for 18 h. Concentrated HCl aqueous solution (150 mL) was added to the reaction mixture and stirring was continued for 45 min. The resulting mixture was poured into MeOH (1800 ml). The solution was neutralized with 2 M NaOH solution. The resulting white precipitate was collected by filtration, washed with water, and dried under vacuum to afford the product (48 g, 93.3%). LCMS calculated for C12H12N5O (M+H): 242.1; found: 242.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:8](=[O:9])[O:7][CH2:6]2.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8](=[O:9])[O:7]1
Reactant: COc1cc2c(cc1OC)C(=O)OC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)C(Br)OC2=O

Procedure:
5,6-Dimethoxyphthalide (5.82 g; 0.03 mole.), N-bromosuccinimide (5.34 g; 0.03 mole.) and α-azo-isobutyronitrile (0.1 g.) were gently refluxed in dry carbon tetrachloride (150 ml.) for 2 hours.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[N+:5](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-:6]>ClC(Cl)Cl>[CH2:11]([O:10][C:8]([C:7]1[NH:5][N:6]=[C:2]([CH2:1][OH:4])[CH:3]=1)=[O:9])[CH3:12]
Reactant: C#CCO
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(CO)n[nH]1

Procedure:
A solution of 2 g Prop-2-yn-1-ol and 3 g Ethyl diazoacetate in 16 ml trichloromethane was stirred at 70° C. for 24 h. Then the solvent was removed under reduced pressure and the residue was purified on silica gel eluting with a gradient n-heptane/ethyl acetate 1:1->1:2. The fractions containing the product were collected and evaporated under reduced pressure. Yield: 1.9 g.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].C([Sn](CCCC)(CCCC)[C:39]1[O:40][CH:41]=[CH:42][N:43]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[CH3:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][NH:22][C:20]([C:4]2[C:5](=[O:19])[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=3)[C:7]([CH3:8])=[C:2]([C:39]3[O:40][CH:41]=[CH:42][N:43]=3)[CH:3]=2)=[O:21])=[CH:29][CH:28]=1)(=[O:31])=[O:32]
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1c(-c2ncco2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide (0.10 g, 0.169 mmol), 2-tributylstannyl-oxazole (0.12 g, 0.33 mmol, prepared according to literature procedures), Pd(PPh3)4 (0.015 g, 0.012 mmol) and dimethoxyethane (DME, 2.5 ml) and a magnetic stirrer bar were placed in a vial. The suspension was degassed and the vial sealed, and subsequently heated (100° C.) with stirring for 4 h. LC-MS confirmed the conversion of the iodide to the desired product, and the solvents were removed in vacuo. Purification on preparative HPLC afforded the title compound (0.06 g, 67%) as a white solid after freeze-drying the pure fractions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:22])[N:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:12]([CH2:14][OH:15])[CH:13]=1.[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N(C)C)=O)=NC(N(C)C)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:22])[N:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=[C:12]([CH2:14][O:15][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1
Reactant: Oc1ccccc1
Reactant: O=c1c(-c2ccccc2Cl)cc(CO)cn1-c1ccccc1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1c(-c2ccccc2Cl)cc(COc2ccccc2)cn1-c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
24 mg of 3-(2-Chlorophenyl)-5-hydroxymethyl-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of tetrahydrofuran. 9.4 mg of phenol, 33 mg of triphenylphosphine polymer (3 mmol/g resin) and 17 mg of 1,1′-azobis(N,N-dimethylformamide) were added thereto, followed by stirring at 60° C. overnight. Further, 50 mg of triphenylphosphine polymer (3 mmol/g resin) and 30 mg of 1,1′-azobis(N,N-dimethylformamide) were added, followed by stirring at 60° C. overnight. After cooling to room temperature, ethyl acetate was added thereto and the triphenylphosphine polymer was removed by filtration through Celite. The filtrate was washed with water and 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 12 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9](O)[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.C(N(S(F)(F)[F:28])CC)C>C(Cl)Cl>[F:28][CH:9]1[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:6]2[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1F
Temperature: 0 °C
Yield: 74 %

Procedure:
A stirred suspension of 4.2 g (0.012 mole) of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one in 200 ml methylene chloride was cooled to -70°, and 5 ml (0.04 mole) of diethylaminosulfur trifluoride was added dropwise. The reaction mixture was allowed to warm to -10°, and held at this temperature until most of the solid had dissolved. The reaction mixture was poured into ice-water and stirred vigorously. The organic layer was separated, washed with water, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was recrystallized from benzene-hexane to give 3.12 g of 3-fluoro-7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one as light yellow crystals: mp 195°-197° (dec.); 19F nmr (DMSO-d6) δ -113.0 ppm (m, 1F) and -162.1 ppm (d, J=56 Hz, 1F), 1H nmr (DMSO-d6) δ 5.88 ppm (d, J=56 Hz, 1H), 7.2-7.9 ppm (m, 7H), 11.2 ppm (NH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][Si:15]([CH3:18])([CH3:17])Cl.O>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Si:15]([CH3:18])([CH3:17])[CH3:14])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(C)c1ccc(Br)nc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a reaction container equipped with a dropping funnel, 8 g of 2,5-dibromopyridine and 90 ml of diethyl ether were added. The obtained solution was cooled at −70° C. and then, 21.37 mL of butyl lithium (1.58 M/hexane solution) was added dropwise thereto. The obtained mixture was stirred for 1 hour and 30 minutes and then, a solution obtained by dissolving 4.32 mL of trimethylchlorosilane in 6.2 mL of diethyl ether was added dropwise thereto. The obtained mixture was stirred for 2 hours and 40 minutes and then, 60 mL of water was added dropwise thereto at 0° C. The obtained mixture was stirred at room temperature overnight and then, 30 mL of diethyl ether was added thereto. The obtained solution was extracted three times with 30 mL of diethyl ether. The obtained organic layers were mixed and dried with magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated to obtain a crude product. The crude product was purified with silica gel column chromatography to obtain 5.96 g of 2-bromo-5-trimethylsilylpyridine. Purity: 90% (area percentage value obtained by gas chromatography analysis).
Reaction SMILES: [OH:1][CH:2]([C@H:4]1[CH2:8][CH2:7][N:6]([C:9](OC(C)(C)C)=O)[CH2:5]1)[CH3:3].Cl.CCN(C(C)C)C(C)C.ClC1[C:36]2[C:31](=[N:32][CH:33]=[CH:34][N:35]=2)[CH:30]=[C:29]([Cl:37])[N:28]=1>C1COCC1>[Cl:37][C:29]1[N:28]=[C:9]([N:6]2[CH2:7][CH2:8][CH:4]([C@@H:2]([OH:1])[CH3:3])[CH2:5]2)[C:36]2[C:31](=[N:32][CH:33]=[CH:34][N:35]=2)[CH:30]=1
Reactant: Clc1cc2nccnc2c(Cl)n1
Reactant: CC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](O)C1CCN(c2nc(Cl)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-butyl 3-(1-hydroxyethyl)pyrrolidine-1-carboxylate was treated with HCl solution (in EtOAc, 5 mL) at room temperature for 2 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in anhydrous THF (10 mL). To the resulted THF solution, DIPEA (570 mg, 4.4 mmol) and 5,7-dichloropyrido[4,3-b]pyrazine (400 mg, 2.0 mmol) were added, and the reaction was stirred at room temperature overnight. The volatiles were removed under reduced pressure, and the residue was dissolved in ethyl acetate, washed with brine and dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to afford the title compound. MS (m/z): 279 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[C:9](=[O:21])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1>NC1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([N:10]2[CH:11]([CH3:12])[C:5]3[C:6](=[N:7][C:2]([NH:10][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:3][CH:4]=3)[N:8]([C@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[C:9]2=[O:21])=[CH:18][CH:17]=1
Reactant: COc1ccc(N2C(=O)N([C@@H](C)c3ccccc3)c3nc(Cl)ncc3C2C)cc1
Solvent: Cc1ccccc1
Solvent: Nc1ccccc1
Product: COc1ccc(N2C(=O)N([C@@H](C)c3ccccc3)c3nc(Nc4ccccc4)ncc3C2C)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of crude 7-chloro-3-(4-methoxy-phenyl)-4-methyl-1-[1-(S)-phenyl-ethyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (308 mg, from 0.56 mmol) (from Example 17 supra) in aniline (0.195 mL) (Aldrich) was stirred at 100° C. for 3 hours. Reaction mixture was then cooled to room temperature, diluted with toluene (3 mL) and purified by column chromatography (silica gel) eluting with hexanes-ethyl acetate (1:1) to give 3-(4-methoxy-phenyl)-4-methyl-7-phenylamino-1-[1-(S)-phenyl-ethyl]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 140 mg, 53.7%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccc(Cl)c(Cl)c4)c3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 78.9 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol), 3,4-dichlorophenyl isocyanate (0.29 g, 1.6 mmol), and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at the same temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed using a methylene chloride-methanol gradient, eluting with 97:3 methylene chloride-methanol, to provide 0.60 g of the product in 82% yield: mp 241-243° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.54-2.64 (m, 2H), 2.84-2.97 (m, 1H), 4.71 (d, J=6.0 Hz, 2H), 5.17 (dd, J=12.5 Hz, d=5.4 Hz, 1H), 6.92 (t, J=6.0 Hz, 1H), 7.25 (dd, J=8.8 Hz, J=2.5 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.75-7.88 (m, 4H), 9.15 (s, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.8, 48.9, 117.8, 118.8, 121.9, 122.4, 127.2, 130.4, 130.9, 131.6, 133.7, 134.8, 139.9, 140.5, 154.9, 167.0, 167.6, 169.8, 172.8; Anal. calcd. for C21H16Cl2N4O5.0.25H2O: C, 52.57; H, 3.47; N, 11.68. Found: C, 52.78; H, 3.41; N, 11.37.