Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=O)C1C=CC=CC=1.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([O:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][C:34]=2[C:40]([F:43])([F:42])[F:41])=[CH:28][CH:27]=1.CN1CCCC1=O>C(OCC)(=O)C>[CH3:25][C:26]1[N:31]=[CH:30][C:29]([O:32][C:33]2[CH:39]=[CH:38][C:36]([NH:37][C:22]3[C:23]4[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH:16]=[CH:17][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:35][C:34]=2[C:40]([F:43])([F:41])[F:42])=[CH:28][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2C(F)(F)F)cn1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccn(CCOCCO)c34)cc2C(F)(F)F)cn1
Temperature: 140 °C
Yield: 57.5 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (150 mg), 4-[(6-methylpyridin-3-yl)oxy]-3-(trifluoromethyl)aniline (175 mg) and 1-methyl-2-pyrrolidone (0.863 mL) was stirred with heating at 140° C. for 2.5 hrs. The reaction mixture was diluted with ethyl acetate (80 mL) and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10). The object fraction was concentrated under reduced pressure. The obtained residue was dissolved in methanol (1.9 mL), 1N sodium hydroxide (0.433 mL) was added, and the mixture was stirred at room temperature for 1.5 hrs. 1N hydrochloric acid (0.433 mL) was added, and the mixture was diluted with ethyl acetate (80 mL) and washed with saturated brine (30 mL). The organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) and crystallized from diisopropyl ether to give the title compound (118 mg).
Reaction SMILES: [CH:1]([N:4]1[C:10]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:9]=2[C:8](=[O:18])[NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)C.C(Cl)Cl>[Pd].CO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]2[C:8](=[O:18])[NH:7][CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:10]=2[CH:11]=1
Reactant: CC(C)N1CCNC(=O)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCNC(=O)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 61.3 %

Procedure:
To a 500 ml round bottom flask, 1-isopropyl-8-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (4.10 g, 16 mmoles), ethanol (300 ml), and palladium (320 mg) were added. The mixture was evacuated and charged with hydrogen (3 times). The reaction was stirred at room temperature under hydrogen balloon for the weekend (64 hrs). The solid was filtered through celite and washed with methanol. The solvent was then removed under vacuum to afford a brown oil. The desired product (2.15 g, 60% yield) was isolated via column chromatography with DCM and methanol as eluant (0 to 25% methanol). NMR 1H-(DMSO)-δ-7.32-7.52 (m, 1H), 7.00 (bs, 1H), 6.80 (bs, 1H), 4.80 (p, 1H), 3.40 (bs, 4H), 1.10 (d, 6H, J=6.58 Hz)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)[CH:17]=2)[C:12]([Cl:33])=[CH:11][N:10]=1.O>CO.C(O)(=O)C.[Fe]>[NH2:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([NH:15][C:13]2[C:12]([Cl:33])=[CH:11][N:10]=[C:9]([Cl:8])[N:14]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1cccc(CNc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: [Fe]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(CNc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(2,5-dichloropyrimidin-4-yl)-N′-(3-nitrobenzyl)benzene-1,3-diamine trifluoroacetate (67 mg, 0.13 mmol) in methanol (0.51 mL), acetic acid (0.20 mL), and water (0.10 mL) was treated with iron (30 mg, 0.53 mmol) and stirred at 25° C. for 1 h. The reaction mixture was treated with additional iron (25 mg, 0.45 mmol) and stirred at 25° C. for 16 h. The reaction mixture was diluted with methanol (2 mL) and celite was added. The resulting suspension was filtered through a pad of celite and rinsed with methanol. The filtrate was concentrated to give the desired product as a crude residue that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([NH2:11])=[O:10])=[CH:4][N:3]=1.Cl.[C:13]12([NH2:18])[CH2:17][CH:15]([CH2:16]1)[CH2:14]2.C(=O)(O)[O-].[Na+].CN1C(=O)CCC1>O>[C:13]12([NH:18][C:6]3[C:5]([C:9]([NH2:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH2:17][CH:15]([CH2:16]1)[CH2:14]2
Reactant: NC12CC(C1)C2
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)c1cnc(Cl)nc1NC12CC(C1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.7 %

Procedure:
A mixture of 2,4-dichloro-pyrimidine-5-carboxamide (2 g), bicyclo[1.1.1]pentan-1-amine hydrochloride (1.18 g), sodium bicarbonate (1.75 g), and NMP (10 mL) was stirred at 25° C. for 24 h. Water (10 mL) was charged maintaining the reaction temperature less than 30° C., and the mixture was stirred at 25° C. for 2 h. The suspension was filtered, and washed with NMP:water (1:1 10 mL), then water (2×10 mL), and dried in a vacuum oven at 40° C. with nitrogen sweep to give 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-chloropyrimidine-5-carboxamide as a white solid (1.97 g, 83% yield). 1H NMR (DMSO-d6) δ 2.14 (s, 6H), 2.51-2.53 (m, 1H), 7.76 (br. s., 1H), 8.23 (br. s., 1H), 8.60 (s, 1H), 9.57 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[N:5][C:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[N:3]1.CCO>CN>[CH3:1][N:2]1[C:6]([CH2:7][CH2:8][NH2:9])=[N:5][C:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[N:3]1
Reactant: Cn1nc(-c2ccncc2)nc1CCN1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CCO
Product: Cn1nc(-c2ccncc2)nc1CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
2-(2-(1-Methyl-3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)ethyl)isoindoline-1,3-dione (114.9 mg, 345 μmol) was dissolved in methylamine solution in EtOH (3.07 mL, 22.5 mmol) and stirred at RT for 1 h. The reaction mixture was evaporated to give light brown solid. The solid was again dissolved in methylamine solution in EtOH (3.07 mL, 22.5 mmol) and the mixture was heated to 50° C. and stirred for 3 h. All volatiles were removed in vacuo and the residue was suspended in dichloromethane (1.5 mL) and filtered. The filtrate was evaporated to give the product as light yellow solid (81.3 mg (80% purity), 256 μmol, 74.2%) which was used without purification for the next step. MS: M=204.2 (M+H)+
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:26][NH2:27]>C1COCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([NH:27][CH3:26])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C(=O)O)cc1OCC2
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Following the same procedure as for 133, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (100 mg, 0.3 mmol) was reacted with 2M methylamine (0.59 mL) in THF to provide 159. LC/MS (ESI+): m/z 353 (M+H). 1H NMR (400 MHz, DMSO) δ 8.54-8.39 (m, 1H), 7.93 (dd, J=18.0, 11.2, 1H), 7.67-7.46 (m, −1H), 6.47 (d, J=33.7, −2H), 5.94-5.78 (m, −2H), 4.68-4.47 (m, −4H), 3.52-3.55 (s, −3H), 2.90-2.68 (m, 1H), 1.47 (t, J=13.6, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:34][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CN(C)CCN
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CCNCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 109.5 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (40.0 mg, 0.0974 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with N,N-dimethylethylenediamine (0.043 mL, 0.39 mmol), acetic acid (0.112 mL, 1.96 mmol) and sodium triacetoxyborohydride (103 mg, 0.486 mmol). The reaction mixture was added with water and sodium carbonate to adjust the pH to 9, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[(2-dimethylaminoethyl)aminomethyl]indol-2-yl)isoindolinone (51.5 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][N:8]1[C:14](=[O:15])[CH:13]2[CH2:16][CH2:17][CH2:18][C:12]2=[N:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)([O-:3])=[O:2]>C(OCC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)([O-:3])=[O:2]
Reactant: O=C1C2CCCC2=Nc2ccccc2N1Cc1cccc([N+](=O)[O-])c1
Solvent: CCOCC
Product: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1cccc([N+](=O)[O-])c1
Yield: 86 %

Procedure:
Using 9-(3-nitrobenzyl)-2,3,9,10a-tetrahydrobenzo-[b]cyclopenta[e][1,4]diazepin-10(1H)-one, the title compound was synthesized in otherwise the same manner as Reference Example 4. Yield 86%, m.p. 169°-171° C. (diethyl ether).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:16][CH3:17])[C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9].Cl[CH:19]([F:21])[F:20]>O1CCCC1>[CH3:17][O:16][C:13]1[CH:12]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[C:14]=1[O:15][CH:19]([F:21])[F:20])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Reactant: FC(F)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c(OC(F)F)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium hydride (0.144 g, 6 mmol) was added portionwise to a solution of methyl 3,5-dimethoxy-4-hydroxy-benzoate (0.21 g, 1 mmol) in tetrahydrofuran (20 mL) cooled to 0° C. After 2 hours, chlorodifluoromethane (gas) was introduced by sparge for 10 minutes every 2 hours (5 times). After 18 hours, an additional portion of sodium hydride (0.048 g, 2 mmol) was added followed by chlorodifluoromethane (gas) sparge for 10 minutes. The reaction mixture was sealed and stirred for 3 weeks. The reaction mixture was cooled to -78° C. and methanol (5 mL) was added. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4, filtered, and evaporated in vacuo to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC#N>[F:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:30][CH:29]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(F)cn2)c1
Temperature: 100 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1H-pyrazol-1-yl)phenyl)methanone (30 mg, 96 μmol), 2-chloro-5-fluoropyrimidine (18 μl, 144 μmol) and anhydrous DIPEA (50 g, 288 μmol) in CH3CN (2 mL) was heated at 100° C. for 3 days. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. aq. NaHCO3, brine, and dried (MgSO4). The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 409 (M+H).
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:11][C:10]1[C:2]([C:16]2[CH:17]=[CH:18][C:13]([NH2:12])=[N:14][CH:15]=2)=[CH:3][C:4]2[O:8][CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: Cc1cc2ncoc2cc1Br
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: Cc1cc2ncoc2cc1-c1ccc(N)nc1
Temperature: 85 °C
Yield: 82.5 %

Procedure:
A mixture of 6-bromo-5-methybenzoxazole (43) (91 mg, 0.43 mmol), 2-aminopyridine-5-boronic acid pinacol ester (11) (220 mg, 1 mmol), Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (A-Phos) (30 mg) and K3PO4 (127 mg, 0.6 mmol) in 1.5 ml ACN, 1.5 ml dioxane, 0.5 ml H2O was bubbled with argon before heated at 85° C. for 2 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine, dried over Na2SO4, concentrated to dryness. The resulting red solid was dissolved in DCM and subjected to silica gel column purification using 0-100% B (A: hexane; B: EA) to furnish 79.9 mg 5-(5-methylbenzoxazol-6-yl)-2-pyridylamine (44) as orange solid (yield: 82.5%, purity>90%)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17](F)[CH:16]=1>CN(C=O)C.[NH4+].[Cl-]>[CH3:3][O:4][C:5](=[O:13])[CH:6]([C:19]1[CH:20]=[C:15]([Br:14])[CH:16]=[CH:17][C:18]=1[N+:21]([O-:23])=[O:22])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: COC(=O)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaH (1.6 g, 63 mmol) is added portion wise to a solution of phenyl-acetic acid methyl ester (9.0 g, 60 mmol) in DMF (150 mL) at −15° C. and stirred at this temperature for 3 hours. 4-Bromo-2-fluoro-1-nitro-benzene (6.57 g, 30.0 mmol) is added to the above mixture at −15° C. The mixture is warmed to room temperature slowly and stirred for 24 hours. The mixture is diluted with saturated aqueous NH4Cl solution and extracted with ethyl acetate (3×100 mL). The combined organic phase is washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue is purified by chromatography (ethyl acetate:petroleum ether=1:20) to give the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12].[Li]CCCC.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CCOCC>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:10][O:11][CH3:12])=[C:2]([C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COCOc1ccc(Br)cc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1cc(Br)ccc1OCOC
Reaction time: 0.75 h
Yield: 112.8 %

Procedure:
A solution of 2,4-dibromo-1-(methoxymethoxy)benzene (40.5 g, 137 mmol) in Et2O (140 mL) was cooled to −78° C. and treated with n-BuLi (2.5M in hexanes; 60.2 mL, 151 mmol) under nitrogen atmosphere. After 30 minutes a solution of diethyl oxalate (27.9 mL, 205 mmol) in Et2O (20 mL) was added dropwise. The reaction mixture was stirred for 45 minutes at that temperature then quenched cold with saturated ammonium chloride solution. The mixture was partitioned between Et2O and water. The organic phase was separated, washed with water, brine, then dried over MgSO4. The solvent was removed under reduced pressure to afford 49 g of ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate, which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])([O-])=O.C1(C)C=CC=CC=1>CN(C)C=O.[Pd].[H][H]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: [H][H]
Reactant: CCOC(=O)C(=CNc1ncnc2ccc([N+](=O)[O-])cc12)C(=O)OCC
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ncnc2ccc(N)cc12)C(=O)OCC
Yield: 97.4 %

Procedure:
A suspension of diethyl [(6-nitro-4-quinazolinylamino)methylene]propanedioate (2.8 g) in N,N-dimethylformamide (152 ml) was shaken with 10% palladium on carbon (0.93 g) in hydrogen atmosphere at ambient temperature for an hour. After the reaction was completed, the catalyst was removed by filtration and washed with chloroform. The combined filtrate and washing was concentrated under reduced pressure to give a residue, to which was added toluene and concentrated under reduced pressure. This operation was repeated to give crystalline diethyl [(6-amino-4-quinazolinylamino)methylene]propanedioate (2.50 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](OCC)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:27]#[N:28])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.[OH-].[Li+].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:44][O:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][NH2:51])=[CH:48][CH:47]=1>CO.O1CCCC1.ClCCl.O.CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH:51][CH2:50][C:49]1[CH:52]=[CH:53][C:46]([O:45][CH3:44])=[CH:47][CH:48]=1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([C:27]#[N:28])([CH3:25])[CH3:26])=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(C(C)(C)C#N)cc1
Reactant: COc1ccc(CN)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cnc3ccc(Cl)nc3c2Nc2ccc(C(C)(C)C#N)cc2)cc1
Temperature: 25 °C
Yield: 47 %

Procedure:
ethyl 6-chloro-4-((4-(2-cyanopropan-2-yl)phenyl)amino)-1,5-naphthyridine-3-carboxylate (6.9 g, 17.5 mmol) was dissolved in 50 mL methanol and 50 mL tetrahydrofuran. To the resulting mixture was added dropwise 50 mL of an aqueous lithium hydroxide (2.2 g, 52.4 mmol) solution at room temperature. After the completion of the dropwise addition, the resulting mixture was reacted at room temperature for 4 hrs. The reaction was concentrated. 200 mL water was added. The resulting mixture was adjusted with hydrochloric acid to pH=2-3. The solid was separated, and dried in vacuum to obtain a yellow solid, which was then dispersed in 100 mL dichloromethane. 0.05 mL DMF was added. To the resulting mixture was added dropwise oxalyl chloride (4.2 g, 33.3 mmol) under an ice bath. After the completion of the dropwise addition, the reaction mixture was warmed up to room temperature and reacted for 4 hrs. The reaction was evaporated under a reduced pressure to remove the solvent, then dissolved in 100 mL dichloromethane. To the resulting mixture was added dropwise a mixture of triethylamine (5.0 g, 49.8 mmol) and para-methoxybenzylamine (2.7 g, 19.9 mmol) under an ice bath. After the completion of the dropwise addition, the reaction mixture was reacted at room temperature for 15 hrs. 50 mL water and 100 mL DCM were added. The phases were separated. The aqueous phase was extracted with 100 mL DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was separated by silicagel column chromatography (EtOAc/PE=1/10-3/2) to obtain a pale yellow solid (4.0 g).
Reaction SMILES: B(O)(O)O.[OH:5]O.S(=O)(=O)(O)O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]1[CH:26]=[CH:25][C:22](C=O)=[CH:21][CH:20]=1>O1CCCC1>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]1[CH:26]=[CH:25][C:22]([OH:5])=[CH:21][CH:20]=1
Reactant: OO
Reactant: O=Cc1ccc(Oc2ccccn2)cc1
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: C1CCOC1
Product: Oc1ccc(Oc2ccccn2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 9.6 %

Procedure:
Following Scheme I: To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 3.1 g (50.2 mmol) boric acid, 10 mL tetrahydrofuran, 2.3 mL (20 mmol) 30% hydrogen peroxide, and 1 mL concentrated sulfuric acid. To the reaction was added a solution of 2.0 g (10 mmol) 4-(pyridin-2-yloxy)-benzaldehyde in 10 mL tetrahydrofuran dropwise over 5 minutes. The reaction was stirred 3 hr at 60° C., cooled, filtered, and the filtrate neutralized with saturated aqueous sodium bicarbonate solution. The mixture was extracted into 2× ethyl acetate, and the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to afford 180 mg (9.6%) of the product as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([N:23]3[CH:24]=[C:20]([I:19])[N:21]=[CH:22]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: Ic1c[nH]cn1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (1.76 g, 6.0 mmol) and commercially available 4-iodo-imidazole (1.28 g, 6.6 mmol) according to the general procedure IVa. Obtained as an off-white (2.59 g, 96%). MS (ISP) 451.0 [(M+H)+]; mp 258° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH3:2].[H-].[Na+].[CH3:19]I>CN(C=O)C>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][N:6]([CH3:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH3:2]
Reactant: CI
Reactant: CCOC(CNc1ccccc1F)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CN(C)c1ccccc1F)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To a stirred solution of N-(2,2-diethoxyethyl)-2-fluoroaniline (1.00 g, 4.40 mmol) in anhydrous DMF (10 mL) at 0° C. was added NaH (0.16 g, 6.60 mmol) portionwise. After 30 min, MeI (0.5 mL, 8.80 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc (2×100 mL), and the EtOAc solution was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure to give N-(2,2-diethoxyethyl)-2-fluoro-N-methylaniline (0.41 g, 38%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.05-6.96 (m, 3 H), 6.83-6.81 (m, 1H), 4.69 (t, 1H, J=5.2 Hz), 3.72-3.64 (m, 2H), 3.55-3.49 (m, 2H), 3.33 (dd, 2H, J=5.2, 1.2 Hz), 2.97 (s, 3H), 1.19-1.53 (m, 6H).