Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[C:10]([NH2:24])=[N:11][C:12](=[O:23])[N:13]([CH:22]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)=[O:4].N1C=CN=C1.[CH3:32][C:33]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C=O)C>[Si:36]([O:20][CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[CH:22]=[C:9]([C:8]#[C:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:25])([F:1])[F:26])[C:10]([NH2:24])=[N:11][C:12]2=[O:23])[CH2:15][C@@H:16]1[OH:17])([C:33]([CH3:35])([CH3:34])[CH3:32])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C#CCNC(=O)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(N)nc2=O)C[C@@H]1O
Reaction time: 2 h

Procedure:
To a solution of the starting material (7) (1.0 g, 2.66 mmol) and imidazole (200 mg, 2.93 mmol) in DMF (3.0 ml) at 0° C., was slowly added TBDMSCl (442 mg, 2.93 mmol) in four portions over 1 h. After 2 h, the volatiles were evaporated under reduced pressure and the residue was adsorbed on silica gel and purified by flash chromatography (EtOAc, EtOAc:MeOH 9.5:0.5). The expected product (8) was isolated as a crystalline solid (826 mg, 64%). 1H NMR (d6 DMSO) δ 0.00 (s, 1H, CH3); 0.01 (s, 1H, CH3), 0.79 (s, 9H, tBu), 1.87-1.80 (m, 1H, H-2′), 2.12 (ddd, J=13.0, 5.8 and 3.0 Hz, 1H, H-2′), 3.65 (dd, J=11.5, 2.9 Hz, 1H, H-5′), 3.74 (dd, J=11.5, 2.5 Hz, 1H, H-5′), 3.81-3.80 (m, 1H, H-4′), 4.10-4.09 (m, 1H, H-3′), 4.17 (d, 2H, J=5.1 Hz, NCH2), 5.19 (d, 1H, J=4.0 Hz, 3′ —OH), 6.04 (t, J=6.6 Hz, 1H, H-1′), 6.83 (br s, 1H, NHH), 7.78 (br s, 1H, NHH), 7.90 (s, 1H, H-6), 9.86 (t, J=5.1 Hz, 1H, —H2CNH); MS (ES): m/z (%) (MH)+ 491 (40%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[N:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:8]=1)C.C(SC1N=NC(C2C=CC(OC)=CC=2)=C(C2C=CC(OC)=CC=2)N=1)C.C(SC1N=NC(C2C=CC(OC)=CC=2)=C(C2C=CC(OC)=CC=2)N=1)(C)C.COC1N=NC(C2C=CC(OC)=CC=2)=C(C2C=CC(OC)=CC=2)N=1.C(OC1N=NC(C2C=CC(OC)=CC=2)=C(C2C=CC(OC)=CC=2)N=1)C.CC1N=NC(C2C=CC(OCC)=CC=2)=C(C2C=CC(OCC)=CC=2)N=1.C(C1N=NC(C2C=CC(OC)=CC=2)=C(C2C=CC(OC)=CC=2)N=1)(C)C.C(OC1N=NC(C2C=CC(OC)=CC=2)=C(C2C=CC(OC)=CC=2)N=1)(C)C.C(SC1N=NC(C2C=CC(OC)=CC=2)=C(C2C=CC(OC)=CC=2)N=1)CC>>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[N:8]=[C:3]([CH3:1])[N:4]=[N:5][C:6]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: CCc1nnc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)n1
Agent: CCCSc1nnc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)n1
Agent: CCOc1ccc(-c2nnc(C)nc2-c2ccc(OCC)cc2)cc1
Agent: CCOc1nnc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)n1
Product: COc1ccc(-c2nnc(C)nc2-c2ccc(OC)cc2)cc1

Procedure:
The preparation of the following compounds coming within the scope of formula II above can be found in U.S. Pat. 4,190,725: 3-ethyl-5,6-bis(4-methoxyphenyl)-1,2,4-triazine; 3-ethylthio-5,6-bis(4-methoxyphenyl)-1,2,4-triazine; 3-isopropylthio-5,6-bis(4-methoxyphenyl)-1,2,4-triazine; 3-methoxy-5,6-bis-(4-methoxyphenyl)-1,2,4-triazine, and 3-ethoxy-5,6-bis-(4-methoxyphenyl)-1,2,4-triazine. Other compounds of particular interest preparable by one or more of the above procedures include 3-methyl-5,6-bis(4-ethoxyphenyl)-1,2,4-triazine, m.p.=104°-106° C.; 3-isopropyl-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, m.p.=87°-89° C.; 3-n-propyl-5,6-(4-methoxyphenyl)-1,2,4-triazine, m.p.=74°-78° C.; 3-ethoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, m.p.=120°-122° C.; 3-isopropoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, m.p.=106°-108° C.; and 3-n-propylthio-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, m.p.=88°-90° C.
Reaction SMILES: C([O:4][CH:5]([C:7]1[N:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[I:14])[CH3:6])(=O)C.[OH-].[Na+]>C(O)C>[Cl:13][C:9]1[C:8]([I:14])=[C:7]([CH:5]([OH:4])[CH3:6])[N:12]=[CH:11][N:10]=1
Reactant: CC(=O)OC(C)c1ncnc(Cl)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(O)c1ncnc(Cl)c1I

Procedure:
In ethanol (20 ml) was dissolved 6-(1-acetoxyethyl)-4-chloro-5-iodopyrimidine (1.0 g), and 1N sodium hydroxide aqueous solution (20 ml) was added dropwise to the solution while stirring. After the dropping addition, the mixture was stirred for additional one hour at room temperature to complete the reaction. Then, the solvent was distilled off under reduced pressure, and the desired compound was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[C:4]([F:16])[CH:3]=1.[Br-].[Cl-].[NH4+].O.[CH2:21]1[CH2:25]OC[CH2:22]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:9][S@:10]([C:12]([CH3:13])([CH3:15])[CH3:14])=[O:11])[CH:22]2[CH2:21][CH2:25]2)=[C:4]([F:16])[CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccc(Cl)cc1F
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(Cl)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step 1 To a solution of (S)-2-methyl-propane-2-sulfinic acid 1-(4-chloro-2-fluoro-phenyl)-meth-(E)-ylideneamide (26.2 g, 0.1 mol, 1.0 eq) in anhydrous THF (700 ml) at −75° C. was added 0.5M cyclopropylmagensium bromide in THF (400 ml, 0.2 mol, 2.0 eq) dropwise at <−65° C. over 30 min. The reaction was stirred for 2 hours at <−65° C. then allowed to warm to room temperature and stirred for 4 hours. Saturated ammonium chloride solution (300 ml), was added, followed by water (150 ml). The layers were separated and the aqueous extracted with EtOAc (3×200 ml). The combined organic layers were washed with sat. brine (300 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by column chromatography on silica (500 g), eluting with 10% EtOAc/heptanesup to 80% EtOAc. (S)-2-Methyl-propane-2-sulfinic acid [(R)-(4-chloro-2-fluoro-phenyl)cyclopropyl-methyl]-amide was isolated in two batches (combined yield 26.4 g, 86.9 mmol, 87%): 1st batch; 18.4 g 1H NMR 4:1 mixture of diastereomers in favour of desired isomer, 2nd batch; 8 g 1H NMR 19:1 mixture of diastereomers in favour of desired isomer. The 2nd batch was repurified by column chromatography on silica (500 g), eluting with 10% EtOAc/heptanesup to 80% EtOAc, to give 6.6 g of pure (S)-2-methyl-propane-2-sulfinic acid [(R)-(4-chloro-2-fluoro-phenyl)-cyclopropyl-methyl]-amide. 1H NMR (270 MHz, CDCl3): 7.33 (1H, t), 7.11 (1H, dd), 7.08 (1H, dd), 3.86 (1H, dd), 3.56 (1H, d), 1.28-1.22 (1H, m), 1.18 (9H, s), 0.90-0.80 (1H, m), 0.74-0.64 (1H, m), 0.56-0.35 (2H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]2[CH2:11][CH2:12][C:13]3[C:18]([C:9]=2[N:8]([CH3:20])[C:7]=1[I:21])=[N:17][C:16]([NH2:19])=[N:15][CH:14]=3)=[O:5])C>CCO>[NH2:19][C:16]1[N:17]=[C:18]2[C:13]([CH2:12][CH2:11][C:10]3[C:6]([C:4]([OH:5])=[O:3])=[C:7]([I:21])[N:8]([CH3:20])[C:9]=32)=[CH:14][N:15]=1
Reactant: CCOC(=O)c1c2c(n(C)c1I)-c1nc(N)ncc1CC2
Solvent: CCO
Product: Cn1c(I)c(C(=O)O)c2c1-c1nc(N)ncc1CC2
Yield: 95 %

Procedure:
To a solution of 8-amino-2-iodo-1-methyl-4,5-dihydro-1H-1,7,9-triaza-cyclopenta[a]naphthalene-3-carboxylic acid ethyl ester N1 (1.28 mmol) in 95% EtOH (30 mL) 4M NaOH (1.2 mL) was added. The mixture was heated to reflux for 10 h then cooled and evaporated to dryness. The residue was dissolved in 30 mL of water, acidified with glacial AcOH and the precipitate was filtered and washed with water. The product was dried affording the title compound (95% yield). ESI (+) MS: m/z 371 (MH+). 1H NMR: 2.63 (t, J=7.80, 2H), 2.90 (t, J=7.80, 2H), 4.18 (s, 3H), 6.33 (bs, 2H), 8.00 (s, 1H), 12.26 (bs, 1H).
Reaction SMILES: C(OC([C:6]1[CH:38]=[CH:37]C=C[C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[CH3:39][N:40]1C=CC=C(O)[C:41]1=[O:47]>>[CH3:39][N:40]1[CH:37]=[CH:38][CH:6]=[C:7]([O:8][C:9]2[C:23]([O:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=3)=[CH:22][C:12]3[NH:13][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[N:15][C:11]=3[CH:10]=2)[C:41]1=[O:47]
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: Cn1cccc(O)c1=O
Product: Cn1cccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2Oc2ccc(S(C)(=O)=O)cc2)c1=O

Procedure:
The entitled compound was obtained as a brown solid in the same method as in Example 14 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14 and 1-methyl-2-oxo-1,2-dihydro-pyridin-3-ol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.C[N:21](C=O)C>C1COCC1>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([NH2:21])=[O:8]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc(N)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 5-methyl-2-nitrobenzoic acid (25.4 g) in THF (150 ml) was added oxalyl chloride (13.5 ml) and DMF (0.1 ml) dropwise and the mixture was stirred at room temperature for 14 hours and concentrated to dryness. To an ice-cooled, stirred 25% aqueous solution of ammonia (150 ml) was added the resulting acid chloride dropwise and the mixture was stirred at the same temperature for 1 hour. The white precipitates were collected by filtration, washed with water, and dried in vacuo. A suspension of the white precipitates and 10% Pd/C (2.4 g) in a mixture of THF (200 ml) and methanol (150 ml) was stirred under hydrogen atmosphere at room temperature for 4 hours. After removal of insoluble materials by filtration, the filtrate was concentrated to dryness. Recrystallization of the resultant crystalline residue from ethyl acetate-hexane afforded colorless crystals (18.7 g, 89%), m.p. 178°-180° C.
Reaction SMILES: [Sn](Cl)Cl.[CH2:4]([NH:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1)[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-])=O)[CH2:17][CH2:16]1)=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH2:4]([NH:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1)[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])[CH2:17][CH2:16]1)=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C([C@H](COCc1ccc(Cl)c(Cl)c1)NCc1ccccc1)N1CCN(c2ccccc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccccc1N1CCN(C(=O)[C@H](COCc2ccc(Cl)c(Cl)c2)NCc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Tin (II) chloride (1.79 g, 9.45 mmol) was added to a solution of (S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-nitrophenyl)piperazine (1.03 g, 1.89 mmol) in ethanol (15 mL) and the mixture was stirred at 70° C. for 1 h. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate and washed with aqueous sodium hydroxide (2M, 3 x). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (Aq.) (99:1:0.1) to give (S)-1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-aminophenyl)piperazine was a yellow oil (678 mg, 70%). A sample (70 mg) was dissolved in methanolic hydrogen chloride and the solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile/water (1:1) and freeze-dried to give the title compound as a colorless solid (70 mg); Found: C, 54.06; H, 5.42; N, 9.20. C27H30Cl2N4O2.2HCl.0.5H2O requires: C, 54.47; H, 5.59; N, 9.41%. m/e (ES+) 513 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[N:3][CH:2]=1.NC1N=C(N)[C:19]2[C:14](=NC=C(C=C)N=2)N=1.ClCC(=O)C=NO.NC1C=CC=CN=1>>[CH:14]([C:2]1[N:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][N:6]=2)[N:1]=1)=[CH2:19]
Reactant: C=Cc1cnc2nc(N)nc(N)c2n1
Reactant: c1cnc2ncncc2n1
Agent: Nc1ccccn1
Agent: O=C(C=NO)CCl
Product: C=Cc1ncc2nccnc2n1
Yield: 15 %

Procedure:
An interesting extension of the above systems is the preparation and use of a pteridine-based monomer. Such an example is 2,4-diamino-6-vinylpteridine (XIII). This molecule is synthesised in five synthetic steps, from -chloropyruvaldoxime, in 15% yield following the method of Taylor & Kobayashi (J. Org. Chem., 38, 2187-2821 (1973)). 6. Aminopyridine Based Monomers
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[NH:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[NH:3][C:4]=3[CH:10]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: O=C(O)c1ccc2[nH]c(=O)[nH]c2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]c(=O)[nH]c2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 11 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 11% of theory; LC (method 4): tR=1.86 min; Mass spectrum (ESI+): m/z=334 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[C:16](=[O:31])[CH:15]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:15]1[C:16](=[O:31])[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:29])([F:28])[F:30])[C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][C:11]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:10]=1[F:9]
Reactant: Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1ccccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-bromosuccinimide (0.24 g, 1.36 mmol) was added into 4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-[2-(trifluoromethyl)phenyl]pyridin-2(1H)-one (0.54 g, 1.36 mmol) in 20 ml of dichloromethane. The mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (150 ml) was added into the reaction mixture and the combine solution was transferred to a separatory funnel. The product was extracted with ethyl acetate (250 ml). The ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=7.25 Hz, 1H), 7.7 (app t, J=7.66 Hz, 1H), 7.60 (m, 2H), 7.26 (s, 1H), 6.97 (m, 1H), 6.87 (m, 1H), 6.09 (s, 1H), 5.25 (app d, J=3.35 Hz, 2H), 1.94 (s, 3H); LC/MS, tr=2.84 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-HRMS m/z 474.0113 (M+H calcd for C20H14BrF5NO2 requires 474.0123).
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].[CH3:12][C:13]1[N:18]=[C:17]2[C:19]([O:21][C:22](=O)[C:16]2=[CH:15][CH:14]=1)=[O:20].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[Cl:10][C:9]1[C:2]([N:1]2[C:22](=[O:21])[C:16]3[C:17](=[N:18][C:13]([CH3:12])=[CH:14][CH:15]=3)[C:19]2=[O:20])=[C:3]([C:4]#[N:5])[C:6]([CH3:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc2c(n1)C(=O)OC2=O
Reactant: Cc1ccc(Cl)c(N)c1C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: Cc1ccc2c(n1)C(=O)N(c1c(Cl)ccc(C)c1C#N)C2=O
Temperature: 170 °C
Reaction time: 8 h

Procedure:
3.1 g (18.61 mmol) of the compound from example 4 were added to 2.9 g (17.7 mmol) of 6-methylpyridine-2,3-dicarboxylic anhydride and, with warming to 170° C., the mixture was stirred for a total of 8 h as a melt. After cooling, the residue was taken up in methylene chloride, and the solution was treated with active carbon and magnesium sulfate. After filtering off with suction, the filtrate was chromatographed on silica gel, 1.3 g (24.4% of theory) of the title compound being obtained after concentration as beige crystals of m.p. 173-176° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:27])[N:17]([CH3:26])[C:18]([NH:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)=[N:19][CH:20]=2)=[CH:11][C:10]=1[F:28])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH:23]1([CH2:22][NH:21][C:18]2[N:17]([CH3:26])[C:16](=[O:27])[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:28])[CH:11]=3)=[CH:20][N:19]=2)[CH2:25][CH2:24]1
Reactant: Cn1c(NCC2CC2)ncc(-c2ccc(OCc3ccccc3)c(F)c2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(NCC2CC2)ncc(-c2ccc(O)c(F)c2)c1=O
Yield: 82.1 %

Procedure:
A solution of 5-(4-(benzyloxy)-3-fluorophenyl)-2-(cyclopropylmethylamino)-3-methylpyrimidin-4(3H)-one (0.128 g, 0.337 mmol) in TFA (2 mL) was stirred at 40° C. for 2 hours and 45 minutes. The reaction mixture was concentrated to dryness and then purified by flash column chromatography, eluting with 20:1 dichloromethane/MeOH. The desired product (0.080 g, 82%) was obtained as a colorless glassy solid. 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.87 (s, 1H), 7.46 (dd, J=2.3, 13.7 Hz, 1H), 7.35 (t, J=5.3 Hz, 1H), 7.24 (dd, J=2.3, 8.4 Hz, 1H), 6.90 (dd, J=8.4, 9.6 Hz, 1H), 3.34 (s, 3H), 3.24 (t, J=6.2 Hz, 2H), 1.16 (m, 1H), 0.44 (m, 2H), 0.26 (m, 2H). LRMS (ESI pos) m/e 290 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:12]2[CH2:13][CH2:14][N:15]([C:16]([C@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:17])[C@H:11]2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4]1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>O1CCCC1>[C:33]([NH:1][CH2:2][C@H:3]1[C@H:12]2[CH2:13][CH2:14][N:15]([C:16]([C@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[NH:24][C:25](=[O:32])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:17])[C@H:11]2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)NC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.4 %

Procedure:
To a solution of the compound (163 mg, 0.377 mmol) synthesized in Example 73 in tetrahydrofuran (3 ml) was added acetic anhydride (0.179 ml, 1.88 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography using basic silica gel and eluted with hexane-ethyl acetate (8:2-0:1, v/v) to give the title compound (117 mg, 60%) as an amorphous form.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22](/[CH:29]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:21]1
Reactant: CN1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CN1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A solution of 6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.100 g, 0.381 mmol) obtained in Example A31, Step 1 in methanol (1.5 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.0557 g, 0.381 mmol) and piperidine (0.00324 g, 0.0381 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated solid was collected by filtration to obtain (Z)-2-((1H-pyrrolo[2,3-b]pyridin-3-yl)methylene)-6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.109 g, 73%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[O-].[Na+].CO.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CO.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[O-]
Agent: [I-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a solution of N-Boc-tyrosine (281 mg, 1.0 mmol) in methanol (0.5 mL) were added 28% sodium methoxide-methanol solution (0.42 mL, 2.1 mmol), benzyl chloride (115 μL, 1.4 mmol) and tetrabutylammonium iodide (28 mg) and the mixture was stirred at 40° C. for 24 hr. Then, water (2 mL) was added to make the system homogeneous, which system was then analyzed by HPLC (conversion yield 89%). The aqueous solution was washed with toluene (0.5 mL), neutralized with hydrochloric acid to allow precipitation of a solid, and the solid was filtered and dried to give the objective N-Boc-(O-benzyl)tyrosine (312 mg, yield 84%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[C:25]1([S:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:37]3[CH2:38][CH2:39][N:34]([S:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:33])=[O:32])[CH2:35][CH2:36]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCN(S(=O)(=O)c4ccccc4)CC3)n2n1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and 1-(phenylsulfonyl)piperazine (170 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (40-65% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (103.0 mg, 77%). 1H NMR (DMSO-d6) δ: 10.88 (s, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.81-7.85 (m, 2H), 7.75-7.80 (m, 1H), 7.68-7.74 (m, 2H), 7.59 (d, 2H), 7.30 (s, 1H), 6.16 (s, 1H), 3.76-3.81 (m, 4H), 3.09-3.18 (m, 4H), 2.34 (s, 3H), 1.45 (s, 6H); ESI-MS: m/z 535.0 (M+H)+.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:20]=[C:19]([Cl:31])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>CO.O1CCOCC1>[Cl:31][C:19]1[NH:20][C:21]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[C:22]([F:23])[C:17](=[N:9][NH2:8])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NC2CCOCC2)c1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NN=c1nc(Cl)[nH]c(NC2CCOCC2)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
To a solution of tris(1,1-dimethylethyl)2-[2-chloro-5-fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-4-pyrimidinyl]-1,1,2-hydrazinetricarboxylate (0.602 g, 1.071 mmol) in MeOH (20 mL) was added 4M HCl in 1,4-dioxane (20 mL). After stirring at room temperature for 2 days, the solvent was evaporated and saturated NaHCO3 was added. The aqueous layer was extracted, and the organics were dried (Na2SO4) and concentrated in vacuo to provide 2-chloro-5-fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-4(1H)-pyrimidinone hydrazone as a red solid (0.199 g). LCMS: (M+H)+=261.8.