Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:34]=3[N:33]=[C:32]2[CH:42]([F:44])[F:43])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:44][CH:42]([F:43])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:24]=[C:19]([NH:1][C:2]3[N:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:34]=2[N:33]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1cccnn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Nc2cccnn2)nc(N2CCOCC2)n1
Reaction time: 0.17 h
Yield: 30.2 %

Procedure:
To 0.215 g (2.26 mmol) of 3-aminopyridazine (Example 23) in THF (4 mL) was added 1.30 mL of NaHMDS (2 M solution in THF), and the mixture was stirred for 10 min. A solution of 0.297 g (0.75 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) in THF (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hr. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water and aqueous NH3, and dried. Removal of the solvent, followed by chromatography on silica eluting with CH2Cl2/EtOAc (1:1) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.103 g (30% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridazinyl)-1,3,5-triazin-2-amine: mp 261-263° C.; 1H NMR (DMSO-d6) δ11.13 (s, 1H), 8.97 (dd, J=4.7, 1.4 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.05 (t, JHF=52.9 Hz, 1H), 7.73 (dd, J=9.1, 4.7 Hz, 1H), 7.41 (t, J=8.3 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 3.98 (s, 3H), 3.85 (s, 4H), 3.75 (s, 4H); Anal. Calcd. for C20H19F2N9O2: C, 52.75; H, 4.2; N, 27.7. Found: C, 52.7; H, 4.25; N, 27.7%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20](B2OC(C)(C)C(C)(C)O2)=[C:19]([CH3:33])[CH:18]=1.C(O)CCC.[OH-].[Li+]>O.C(O[Pd]OC(=O)C)(=O)C.C1(P(C2CCCCC2)C2C=C(C3C(C(C)C)=CC(C(C)C)=CC=3C(C)C)C=CC=2)CCCCC1>[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=3[F:15])=[N:6][CH:7]=2)=[C:19]([CH3:33])[CH:18]=1
Reactant: Cc1cc(Cl)cc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(-c2ccc(Br)cn2)c(F)c1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: [Li+]
Solvent: CCCCO
Solvent: O
Product: Cc1cc(Cl)cc(C)c1-c1ccc(-c2ccc(F)cc2F)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
One 100 mL round-bottomed flask was charged with 5-bromo-2-(2,4-difluorophenyl)pyridine (0.5 g, 1.851 mmol), 2-(4-chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.730 g, 2.74 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-3-yl)phosphine (0.021 g, 0.044 mmol), diacetoxypalladium (8.31 mg, 0.037 mmol), and butanol (Volume: 6 ml) to give a yellow suspension. The reaction mixture was then stirred for 15 minutes at room temperature. Lithium hydroxide (0.075 g, 3.15 mmol) was added into reaction mixture and then heated to 80° C. for 1 hour. The reaction mixture was then diluted with deionized water and extracted by ethyl acetate. The organic portion was combined and subjected to column chromatography (SiO2 gel, 5% EtOAc in heptane) to yield the desired compound, 5-(4-chloro-2,6-dimethylphenyl)-2-(2,4-difluorophenyl)pyridine (0.525 g, 86%).
Reaction SMILES: [CH2:1]([C:8]1[C:17]([OH:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12](Br)=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([C:8]1[C:17]([OH:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([C:20]#[N:21])=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cc2ccc(Br)cc2nc1Cc1ccccc1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2cc(O)c(Cc3ccccc3)nc2c1
Reaction time: 7 h

Procedure:
A mixture of 370 mg of 2-benzyl-7-bromo-3-hydroxyquinoline (including n-hexadecyl-tri-n-butylphosphonium bromide), 208 mg of zinc cyanide, 272 mg of tetrakis(triphenylphosphine) palladium(0) and 10 ml of N,N-dimethylformamide was heated under stirring for 7 hours in an oil bath kept at 90° C. After cooling as it was, insoluble matters were filtered through Celite and an aqueous potassium carbonate solution was added to the filtrate. The mixture was extracted with ethyl acetate, and the organic phase was washed with brine and the solvent was removed. The residue was subjected to silica gel column chromatography and eluted with hexane/ethyl acetate (3:1) and then with hexane/ethyl acetate (2:1), to give 203 mg of the target compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:39](=[O:41])[CH3:40])[CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 290 mg), Et3N (0.23 mL; 1.65 mmol) in DCM (20 mL) was added acetyl chloride (87 mg; 1.1 mmol) dropwise under nitrogen. The reaction mixture was stirred for 1 h and concentrated to afford 256 mg (100%) of the title compound as a white solid, which was used directly without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12]C)=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+]>O>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)Oc1ccc(C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(OC(C)C(=O)O)cc1
Yield: 76.2 %

Procedure:
To a solution of the potassium salt of 4-hydroxyacetophenone (8.8 g, 0.05 mol) in dimethylformamide (25 mL) is added methyl 2-bromopropanoate (10.2 g, 0.06 mol) over 30 minutes and stirred at 80°-90° C. for 4 hours under nitrogen. The reaction is cooled to room temperature and methylene chloride (75 mL) and water (75 mL) are added. The organic phase is separated, washed with water (100 mL), dried and concentrated to give methyl 2-(4-acetylphenoxy)propanoate (8.5 g) (yield 76%). Methyl 2-(4-acetylphenoxy)propanoate (7.0 g, 31.5 mmol) is combined with 2N NaOH (20 mL) and refluxed overnight. Water (30 mL) is added to the reaction which is then washed with methylene chloride (50 mL). It is then acidified to pH=1 with concentrated hydrochloric acid and extracted with ethyl acetate (3×100 mL). The organic phase is dried and concentrated to provide 2-(4 -acetylphenoxy)propanoic acid (5.0 g) (yield 92%): m.p. 104.3° C., IR (KBr) 3000 (br, vs), 2940 (br,s), 1754 (vs), 1650 (vs); 1H NMR (CDCl3) delta 1.69 (d, J=6.8 Hz, 3H), 2.55 (s,3H), 4.8 (q, J=6.8 Hz, 1H), 6.92 and 7.93 (dd, J=9.0 Hz, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)O)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH:39]=[N:38][CH:37]=[N:36]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)[N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(C(O)c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(c2ccc(OC)c(OCc3ccccc3)c2)n2cncn2)cc1OCc1ccccc1
Yield: 85 %

Procedure:
Bis-(3-benzyloxy-4-methoxyphenyl)methanol (1.60 g, 3.50 mmol), 1,2,4-triazole (0.48 g, 6.95 mmol) and p-TSA (160 mg) dissolved/suspended in toluene (230 mL) were heated at reflux with a Dean-Stark separator for 24 h. The reaction mixture was allowed to cool, and the solvent was removed in vacuo. The resulting residue was dissolved in EtOAc (100 mL) and the organic layer was washed with H2O (3×100 mL), dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified using Flashmaster II (EtOAc/Hexane) to give the title compound (1.51 g, 84%, mp 96-99° C.) as a yellow oil which solidified after standing for a prolonged period; δH (400 MHz, CDCl3) 7.95 (1H, s, NCHN), 7.67 (1H, s, NCHN), 7.34-7.24 (10H, m, ArH), 6.81 (2H, d, J=8.4, ArH), 6.58-6.48 (5H, m, ArH), 5.00 (4H, s, 2×CH2), 3.84 (6H, s, 2×CH3); δC (100 MHz, CDCl3) 152.3 (CH), 149.9 (2×C), 148.2 (2×C), 143.4 (CH), 136.7 (2×C), 130.5 (2×C), 128.7 (4×CH), 128.1 (2×CH), 127.5 (4×CH), 121.1 (2×CH), 114.1 (2×CH), 118.8 (2×CH), 71.2 (2×CH2), 67.4 (CH), 56.4 (2×CH3); LRMS (FAB+) 507.2 (M+, 20%), 439.2 (100), 349.2 (15), 257.2 (15), 91.1 (35); HRMS (FAB+) Found 507.2159, C31H29N3O4 requires 507.2158; Found: C, 73.00%; H, 5.73%; N, 8.31%, C31H29N3O4 requires: C, 73.35%; H, 5.76%; N, 8.28%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:16][CH:14]([CH2:15]2)[C:13](=[O:17])[N:12]([CH2:18][C:19]#[CH:20])[C:11]3=[O:21])=[CH:6][CH:5]=1)([O-])=O.[Sn]>O.Cl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:15][CH:14]([CH2:16]2)[C:13](=[O:17])[N:12]([CH2:18][C:19]#[CH:20])[C:11]3=[O:21])=[CH:8][CH:9]=1
Reactant: C#CCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: Cl
Agent: [Sn]
Solvent: O
Product: C#CCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.6 g of 1-(4-nitrophenyl)-3-propargyl-3-azabicyclo[3.1.1]heptane-2,4-dione and 4.2 g of tin powder in 12 ml of water and 12 ml of concentrated hydrochloric acid is stirred at 100° for 1 hour. After cooling to room temperature, the reaction mixture is diluted with a little water, filtered and rendered alkaline by the addition of sodium hydroxide solution. The reaction mixture is extracted with ethyl acetate, and the organic phase is washed neutral with dilute sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. After purification by chromatography over silica gel in the system ethyl acetate/hexane 1:1, the title compound is obtained. Rf (ethyl acetate/hexane 1:1)=0.15.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.[CH:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](OC2C=CC=CC=2)=[N:27][C:28]#[N:29])=[CH:21][CH:20]=1>CN(C=O)C>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:26](=[N:27][C:28]#[N:29])[O:25][C:22]4[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=4)=[CH:7][CH:6]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CN(C)C=O
Product: Cc1sc2ncnc(N)c2c1-c1ccc(NC(=NC#N)Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 24 %

Procedure:
A solution of Example 1E (0.4 g, 1.56 mmol) and diphenyl cyanocarbonimidate (0.372 g, 1.56 mmol) in DMF (10 mL) was heated to 90° C. for 2 days, cooled to room temperature, quenched with water, and filtered. The filter cake was suspended in ethanol and filtered. The filtrate was concentrated and purified by flash column chromatography on silica gel with 5 to 8% methanol/dichloromethane to provide the desired product (150 mg). MS(ESI(+)) m/e 401(M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 11.06 (s, 1H); 8.27 (s, 1H); 7.67 (d, J=8.4 Hz, 2H); 7.50-7.43 (m, 4H); 7.36-7.29 (m, 3H); 2.29 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[CH3:20][O:21][C:22]1[C:27](B(O)O)=[CH:26][CH:25]=[CH:24][N:23]=1>>[CH3:20][O:21][C:22]1[C:27]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: COc1ncccc1B(O)O
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: COc1ncccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Example 20 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and (2-methoxypyridin-3-yl)boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:16]([O:19][CH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([I:30])[CH:27]=2)[NH:22]1)(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:20][CH:21]1[N:22]2[C:23]3[C:24]([C:11](=[O:13])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)=[CH:25][C:26]([I:30])=[CH:27][C:28]=3[CH2:29]1)(=[O:18])[CH3:17]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(=O)OCC1Cc2cc(I)ccc2N1
Product: CCOC(=O)c1cn2c3c(cc(I)cc3c1=O)CC2COC(C)=O
Temperature: 120 °C
Yield: 88 %

Procedure:
A mixture of diethyl ethoxymethylenemalonate (2.73 mL) and (5-iodo-2,3-dihydro-1H-indol-2-yl)methyl acetate (Preparation 8, 3.90 g) is heated to 120° C. under a stream of nitrogen. After starting material is consumed, the mixture is cooled and diluted with EtOAc. The crude product is chromatographed eluting with 20, 40, and 60% EtOAc in heptane (500 mL each) to give 5.28 g (88%) of the corresponding enamine as a brown oil. A portion of this material (4.61 g) is dissolved in Eaton's Reagent (10 mL) and heated to 80° C. for 1 h. Upon cooling, the crude mixture is poured into a cold beaker and a 50% NaOH solution is slowly added until pH=7. The cloudy solution is then poured into CH2Cl2. The organic layer is separated and washed with brine, dried (Na2SO4), filtered, and concentrated to give a brown solid. The crude product is chromatographed eluting with 0-4% methanol in CH2Cl2 to give 880 mg (21%) of the title compound as a brown solid. Physical characteristics: MS (ESI+) m/z 442 (M+H)+, 464 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([O:43][CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:38][C:37]=1[CH3:53].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:51][C:45]([CH3:52])([CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH2:44][O:43][C:39]1[CH:40]=[C:41]([CH3:42])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:37]([CH3:53])[CH:38]=1
Reactant: Cc1cc(OCC(C)(C)CS(C)(=O)=O)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC(C)(C)CS(C)(=O)=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-bromo-5-(2,2-dimethyl-3-(methylsulfonyl)propoxy)-1,3-dimethylbenzene following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.81 min; Mass spectrum (ESI+): m/z=611 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)=[CH:3][C:2]=1[C:29]1[CH:30]=[N:25][CH:26]=[N:27][CH:28]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2ccccc21
Product: NC1=NC(c2ccncc2)(c2ccc(F)c(-c3cncnc3)c2)c2ccccc21
Yield: 41 %

Procedure:
The title compound was synthesized from 1-(3-bromo-4-fluorophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine (Scheme #11, G) as described in Example 67 (Scheme #10, D) in 41% yield using pyrimidin-5-ylboronic acid. 1H NMR (DMSO-d6) δ 9.02 (s, 1 H), 8.78-8.72 (m, 2 H), 8.30-8.23 (m, 2 H), 7.78-7.70 (m, 1 H), 7.66-7.58 (m, 1 H), 7.41-7.26 (m, 4 H), 7.20-7.08 (m, 3 H), 6.76 (br s, 2 H), 1.72 (s, 1.9 H); MS (ESI) m/z 382 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:7](=[O:16])[C:6]2[CH:17]=[CH:18][CH:19]=[N:20][C:5]=2[O:4]1.[CH3:21][NH:22][CH3:23].[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)(C)C>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH:10]1([N:8]2[C:7](=[O:16])[C:6]3[CH:17]=[CH:18][CH:19]=[N:20][C:5]=3[O:4][CH:3]([CH2:2][N:22]([CH3:23])[CH3:21])[CH2:9]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C1c2cccnc2OC(CCl)CN1C1CCCCC1
Reactant: CNC
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Product: CN(C)CC1CN(C2CCCCC2)C(=O)c2cccnc2O1

Procedure:
Utilizing the procedure of Example 10, 2-(chloromethyl)-4-cyclohexyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5(4H)-one (Intermediate 35) is reacted with 40% aqueous dimethylamine and reacted with oxalic acid in isopropyl alcohol.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33](F)[N:32]=3)[C:19](=[O:29])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[C:14](=[O:38])[CH2:13][N:12]1[CH2:39][CH:40]=[CH2:41])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH:48]1[CH2:51][CH:50]([N:52]2[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][C@@H:53]2[CH3:59])[CH2:49]1.C(C1C=CC=CC=1)C1C=CC=CC=1>CCCCCCC.C(OCC)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([N:48]4[CH2:51][CH:50]([N:52]5[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][C@@H:53]5[CH3:59])[CH2:49]4)[N:32]=3)[C:19](=[O:29])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[C:14](=[O:38])[CH2:13][N:12]1[CH2:39][CH:40]=[CH2:41])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Reactant: C[C@H]1CN(C)CCN1C1CNC1
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: c1ccc(Cc2ccccc2)cc1
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3)C(=O)N(Cc3cccc(N4CC(N5CCN(C)C[C@@H]5C)C4)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
To a mixed solution of (6S,9aS)-N-benzyl-8-((6-fluoropyridin-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (3.68 g, 6.59 mmol) described in Production Example 2-4 and pyridine (20 mL) was added a mixture (4.45 g) of (2S)-1-(azetidin-3-yl)-2,4-dimethylpiperazine and benzylbenzene described in Production Example 6-3 at room temperature. The resultant mixture was stirred under reflux for 5 hours and 45 minutes. The reaction mixture was cooled to room temperature, and was then concentrated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1 and subsequently methanol) and then further purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to give a solid material. Ethyl acetate, diethyl ether and heptane were added to the solid material, and a precipitate was collected by filtration to give the title compound (3.44 g, yield: 74%).
Reaction SMILES: [CH:1]#[C:2][CH2:3]C(C1C=CC(C(N[C@H](C(O)=O)CCC(O)=O)=O)=CC=1)CC1N=C2C(N)=NC(N)=NC2=NC=1.[H-].[Na+].[CH3:38][O:39][C:40](=[O:52])[CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1.C(Br)C#C>C1COCC1.O.C(O)(=O)C>[CH3:38][O:39][C:40](=[O:52])[CH:41]([CH2:3][C:2]#[CH:1])[C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1
Reactant: C#CCC(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C#CCC(C(=O)OC)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
FIG. 1 shows a synthetic scheme useful in preparing 10-propargyl-10-deazaaminopterin. A mixture of 60% NaH in oil dispersion (1.06 g, 26.5 mmol) in 18 mL of sieve-dried THF was cooled to 0° C. The cold mixture was treated with a solution of homoterephthalic acid dimethyl ester (5.0 g, 24 mmol. compound 1 in FIG. 1) in dry THF (7 mL), and the mixture was stirred for 1 hour at 0° C. Propargyl bromide (26.4 mmol) was added, and the mixture was stirred at 0° C. for an additional 1 hour, and then at room temperature for 16 hours. The resulting mixture was treated with 2.4 mL of 50% acetic acid and then poured into 240 mL of water. The mixture was extracted with ether (2×150 mL). The ether extracts were combined, dried over Na2SO4, and concentrated to an orange-yellow oil. Chromatography on silica gel (600 mL of 230-400 mesh) with elution by cyclohexane-EtOAc (8:1) gave the product α-propargylhomoterephthalic acid dimethyl ester (compound 2) as a white solid (4.66) which appeared by TLC (cyclohexane-EtOAc, 3:1) to be homogeneous. Mass spectral data on this product, however, showed it to be a mixture of the desired product 2, and the di-propargylated compound. No starting material 1 was detected. HPLC shows the ratio of mono- to di-propargylated products to be about 3:1. Since the dipropargylated product, unlike compound 1, cannot produce an unwanted coproduct in the next step of the reaction, this material was suitable for conversion to compound 3. Absence of starting compound 1 in the product used to proceed in the synthesis is very important in order to avoid the sequential formation of 10-dAM during the transformations lading to the final product, because complete removal from 10-dAM from 10-propargyl-10-deazaaminopterin is very difficult.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(N(CC)CC)C.[Br:13][C:14]1[CH:15]=[N:16][C:17]([Cl:23])=[C:18]([CH:22]=1)[C:19](Cl)=[O:20].O>ClCCl>[Br:13][C:14]1[CH:15]=[N:16][C:17]([Cl:23])=[C:18]([CH:22]=1)[C:19]([N:4]([O:3][CH3:2])[CH3:5])=[O:20]
Reactant: CNOC
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cc(Br)cnc1Cl
Reaction time: 8 h
Yield: 71.4 %

Procedure:
5-Bromo-2-chloro-N-methoxy-N-methylnicotinamide. To a mixture of 5-bromo-2-chloronicotinic acid (6 g, 25.5 mmol) in thionyl chloride (30 mL) was added a drop of N,N-dimethylformamide, and the reaction mixture was heated at 80° C. for 2 h. The mixture was cooled to room temperature, and concentrated to give crude 5-bromo-2-chloronicotinoyl chloride. A solution of O,N-dimethyl-hydroxylamine hydrochloride salt (3.45 g, 35.6 mmol) and triethylamine (7.48 g, 74.1 mmol) in dichloromethane (80 mL), and a solution of the above 5-bromo-2-chloronicotinoyl chloride in dichloromethane (20 mL) were added, and the reaction mixture was stirred overnight. The mixture was poured into water, and extracted with dichloromethane (50 mL×3). The combined organic layer was concentrated under reduced pressure, and purified on silica gel column (eluting with 5-10% ethyl acetate in petroleum ether) to give 5-bromo-2-chloro-N-methoxy-N-methylnicotinamide as a solid (6.2 g, 71.4% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.65 (s, 1H), 8.39 (s, 1H), 3.49 (s, 3H), 3.30 (s, 3H).