Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.FC(F)(F)S(O[C:32]1[CH:33]=[N:34][CH:35]=[C:36]([CH3:38])[CH:37]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:38][C:36]1[CH:37]=[C:32]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)[CH:33]=[N:34][CH:35]=1
Reactant: Cc1cncc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cncc(-c2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)c1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (250 mg, 0.68 mmol) in dry 1,4 dioxane (5 ml), polymer supported Pd(PPh3)4 (70 mg, 0.11 mmol/g, 0.0068 mmol) was added along with 5-methyl-3-pyridinyl trifluoromethanesulfonate (241 mg, 1.026 mmol) and 680 μl of a 2M Na2CO3 solution in water and the resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with DCM, washed with water and loaded on a 25M+ silica cartridge eluating with a cyclohexane/AcOEt 75/25 mixture. 95 mg of title compound were recovered as whitish solid (42%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-[(2S)-5-(5-methyl-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C)P(=O)(N(C)C)N(C)C.C1OC1C>C(N(CC)CC)C>[CH2:18]([O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCBr
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Agent: CC1CO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCCCCCCOc1c(OC)cc([N+](=O)[O-])c2nccc(C)c12
Yield: 52 %

Procedure:
A stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline [from Example 7B]--14.0 g, 0.06 mole - n-heptyl bromide (7.5 g, 0.045 mole) and hexamethylphosphoric triamide (12 ml) was heated at 120°, under N2, while a mixture of triethylamine (1 ml) and propylene oxide (6 ml) was added in small portions during 6 hr. Additional propylene oxide (4 ml) was added during 4 hr and the mixture was cooled and filtered and the dull red solid was washed with acetone to return 7.5 g of starting material. The combined filtrate and washings were diluted with water and the resulting solid was extracted with diethyl ether. The extract was washed with 5% sodium hydroxide and water, treated with carbon, dried (sodium sulfate) and evaporated to dryness. Trituration of the dark brown residual oil with petroleum ether (20°-40°) produced a tan solid which was extracted with additional petroleum ether (700 ml). Concentration of the extract to 300 ml and cooling in a Dry-Ice bath gave 7 g (52%) of 5-heptoxy-6-methoxy-4-methyl-8-nitroquinoline as a pale yellow solid, mp 52°-55°. Recrystallization from petroleum ether (20°-40°) provided the analytical sample as glistening pale yellow crystals, mp 56°-57°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:44])C(=O)C1>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Br:44])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CCCCCc1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCCCCc1cccc(CBr)c1
Temperature: 0 °C
Yield: 91.9 %

Procedure:
To a solution of 6-(3-hydroxymethyl-phenyl)-hexanoic acid methyl ester (587 mg, 2.48 mmol) in THF (10 mL) is added triphenylphosphine (716 mg, 2.73 mmol), stirred until homogeneous then cooled to 0° C. NBS (486 mg, 2.73 mmol) is added portionwise and the reaction mixture stirred for 45 min. The mixture is concentrated and the residue is purified by flash chromatography (eluting with 10% ethyl acetate/hexanes) to give 682 mg of title compound. 1H NMR (300 MHz, CDCl3) δ 7.23 (m, 3H), 7.10 (m, 1H), 4.48 (s, 2H), 3.66 (s, 3H), 2.60 (t, 2H), 2.31 (t, 2H), 1.63 (m, 4H), 1.37 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1.[C:18](=[O:21])([O-])[OH:19].[K+]>CC(=O)CC>[C:16]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:6][CH:3]1[CH2:4][CH2:5][N:1]([CH2:3][CH2:2][NH:1][C:18](=[O:21])[O:19][C:7]([CH3:15])([CH3:8])[CH3:6])[CH2:2]1)#[N:17]
Reactant: N#Cc1ccc2[nH]cc(CC3CCNC3)c2c1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)NCCN1CCC(Cc2c[nH]c3ccc(C#N)cc23)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Under an inert atmosphere, 47.3 mmol (10 g) of 3-[(3-pyrrolidinyl)methyl]-1H-indole-5-carbonitrile, 47.3 mmol (9.95 g) of the product described in Preparation B and 1.55 ml of 2-butanone are mixed together and then 47.3 mmol (4.45 g) of potassium hydrogen carbonate are added. The mixture is stirred at 80° C. for 2 hours. After hydrolysis and separating off, the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. Purification is carried out by chromatography on silica, using a mixture of dichloromethane/methanol/ammonia 97/3/0.3 as eluant, to yield the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([NH:17][NH2:18])=[O:16])[N:9]=2)[CH:5]=[C:4]([O:19][CH:20]([CH3:22])[CH3:21])[N:3]=1.[CH3:23]OC(OC)OC.CS(O)(=O)=O.CO.ClCCl>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]3[O:16][CH:23]=[N:18][N:17]=3)[N:9]=2)[CH:5]=[C:4]([O:19][CH:20]([CH3:22])[CH3:21])[N:3]=1
Reactant: COC(OC)OC
Reactant: CC(C)Oc1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(Cl)n1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1cc(-c2ncn(/C=C\c3nnco3)n2)cc(Cl)n1
Temperature: 70 °C
Yield: 2.3 %

Procedure:
In a 100 mL, 3-neck round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (Z)-3-(3-(2-chloro-6-isopropoxypyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (1.11 gm, 1.0 eq.) was dissolved in THF (17 mL, 15V). Trimethylorthoformate (0.364 g, 1.1 eq.) was added followed by methane sulphonic acid (0.178 g, 0.5 eq.). The Reaction mixture was refluxed at 70° C. for 2 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% MeOH-dichloromethane as mobile phase. Reaction mixture was poured in to ice water (500 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine solution (3×15 mL), dried over NaSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 1 g of Crude compound. The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column (5×10 cm) was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (25 mL fraction each) from 35-40% ethyl acetate in hexane. Compound started eluting with 35% ethylacetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound (26 mg), Yield: 0.026 g (2.6%), 1H NMR: (400 MHz, DMSO) δ =10.25 (s, 1H), 8.50 (s, 1H), 7.608-7.610 (d, 1H), 7.524-7.496 (s, J=11.2, 1H), 6.359-6.360 (d, 1H), 6.316-7.288 (s, J=11.2, 1H), 5.385-5.323 (m, 1H), 1.42-1.38 (s, 6H). LC-MS: Calculated for C15H14ClN5O2(M+H)+332.75 Found: 332.8 at 3.354 min (93.31%).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[Cl-].C[O:28][C:29](=[O:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>C1COCC1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:34]([C:33]2[CH:37]=[CH:38][C:30]([C:29]([OH:39])=[O:28])=[CH:31][CH:32]=2)=[O:35])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 1 (2 tert-butylphenyl)piperazine dihydrochloride (29 mg, 0.1 mmol) and triethylamine (0.021 mL, 0.3 mmol) in THF (1.0 mL) was added terephthalic acid monomethyl ester chloride (59 mg, 0.3 mmol) at room temperature. After stirring for 2 h at room temperature, saturated sodium hydrogen carbonate solution (1.5 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (2 mL). The organic layer was separated by phase separation filter kit and the filtrate was evaporated in vacuo. The resulting residue was dissolved in DMSO (1 mL) and the solution was purified by preparative HPLC. The eluted fraction was evaporated by air blowing at 60° C. to give a methyl ester of title compound. The obtained ester was dissolved in MeOH (0.5 mL) and THF (0.5 mL), and 1 M NaOH (0.5 mL) was added to the mixture. After stirring for 2 h at 60 deg C., the mixture was neutralized with 1 M hydrochloric acid solution, extracted with ethyl acetate. The organic layer was separated by phase separation filter kit and the filtrate was evaporated under reduced pressure to give a title compound (17.1 mg, 47%). LC/MS (ESI+) m/z 367 [M+H], purity 100%.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7]>[OH-].[Na+]>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:23])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccc(OCc2ccc(Cl)cc2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(OCc2ccc(Cl)cc2)c1C(=O)O
Yield: 98.3 %

Procedure:
A solution of 3-(4-chloro-benzyloxy)-phthalic acid dimethyl ester (2.2 g, 6.3 mmol) in reagent alcohol (100 mL) and 3 N sodium hydroxide (60 mL) was refluxed for two hours. The solution was evaporated and the residue was dissolved in water (100 mL) and washed with methylene chloride (3×100 mL) then acidified to pH around 4. The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers was washed with water (2×100 mL), dried and concentrated to give 3-(4-chloro-benzyloxy)-phthalic acid as an off-white solid (1.9 g, 98% yield). The product was used in the next step without further purification.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]([F:26])([F:25])[C:5]1[CH:6]=[C:7]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][C:21]([O:23]C)=[O:22])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1>O.O1CCCC1>[F:26][C:4]([F:3])([F:25])[C:5]1[CH:6]=[C:7]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][C:21]([OH:23])=[O:22])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 90 %

Procedure:
A solution of lithium hydroxide (1 g, 22 mmol) in water (44 ml) was added dropwise to a solution of methyl 2-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)acetate (4.38 g, 12 mmol) in tetrahydrofuran (176 ml) while stirring at 0° C. The mixture was stirred for 16 h at 25° C. The solvent was removed under vacuum, the residue dissolved in water and washed with diethyl ether. The aqueous phase was carefully acidified with citric acid solution (10%) and extracted with ethyl acetate. This organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to small volume under vacuum. The crude product was used in the next stage with no further purification. Yield: 90%
Reaction SMILES: C1(O[C:8](=[O:28])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[F:24])[C:11]=2[C:25](=[O:27])[NH2:26])C=CC=CC=1.[CH:29]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])([CH3:31])[CH3:30]>>[F:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:25]([NH2:26])=[O:27])=[C:10]([NH:9][C:8]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][NH:32][CH:29]([CH3:31])[CH3:30])=[O:28])[S:14][N:13]=1
Reactant: Cc1ccc(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: CC(C)NCCCCCN
Product: Cc1ccc(COc2nsc(NC(=O)NCCCCCNC(C)C)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2-fluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N-isopropyl-pentane-1,5-diamine by the procedure analogous to Example 1. MS (APCl, m/z): 452 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:4](N)[N:3]=1.CS(C)=[O:41].[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH2:14]([O:13][C@@H:12]1[C@H:32]([OH:33])[C@@H:34]([CH2:36][OH:37])[O:35][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:41])[C:5]=2[N:6]=[CH:7]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CS(C)=O
Reactant: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Reaction time: 216 h

Procedure:
2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl) purine (10 g) in 0.1 M sodium phosphate buffer (50 mL, pH 7.4), 0.1 M tris buffer (1000 mL, pH 7.4) and DMSO (1000 mL) was treated with adenosine deaminase (1.5 g) at RT. At day 3, day 5 and day 7 an additional aliquot (500 mg, 880 mg and 200 mg, respectively) of adenosine deaminase was added. The reaction was stirred for a total of 9 day and purification by silica gel chromatography yielded the product (2 g). An analytical sample was recrystallized from MeOH 1H NMR (DMSO-d6) δ 0.84 (t, 3, CH3), 1.22 [s, 32, O—CH2—CH2—(CH2)16], 5.07 (m, 2, 3′-OH and 5′-OH); 5.78 (d, 1, 1′-H); 6.43 (s, 2, NH2), 7.97 (s, 1, 8-H) and 10.64 (s, 1, NH2). Anal. Calcd. for C28H49N5O5: C, 62.80; H, 9.16; N, 12.95. Found: C, 62.54; H, 9.18; N, 12.95.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[O:14])[CH:7]=[CH:6]2.[C-:15]#[N:16].[Na+].C(O)(=O)C.O>C(O)C>[C:15]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH2:13][OH:14])#[N:16]
Reactant: COc1ccc2cc(C=O)ccc2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(C#N)c(CO)ccc2c1

Procedure:
6.5 g of 6-methoxy-2-naphthaldehyde are treated with a solution of 4.28 g of sodium cyanide in 115 ml of 95% ethanol. 11.5 ml of acetic acid are then added dropwise at 0° C. over a period of 1 hour. The mixture is left to react overnight and then 400 ml of water are needed. The mixture is extracted three times with ether, the ether extracts are washed with 10% potassium bicarbonate solution and semisaturated and saturated sodium chloride solution. The extracts are dried over sodium sulfate and evaporated to yield α-cyano-(6-methoxy-2-naphthyl)methanol which, without further purification, is reacted with cyclopropane carboxylic acid chloride in the process of Example 2. The resulting product is cyclopropane carboxylic acid α-cyano-(6-methoxy-2-naphthyl)methyl ester; nD20 =1.5765.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>O1CCOCC1.O>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: NCc1ccccn1
Solvent: O
Solvent: C1COCCO1
Product: FC(F)c1nc2ccccc2n1-c1nc(NCc2ccccn2)nc(N2CCOCC2)n1
Yield: 50.2 %

Procedure:
A stirred mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (0.183 g, 0.5 mmol) and 2-aminomethylpyridine (0.135 g, 1.25 mmol) in 10 mL dioxane was heated gently until a clear solution was obtained. After cooling, the mixture was diluted with water to give an oily solid, which was recrystallized from aqueous MeOH to give 0.11 g (50% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(2-pyridinylmethyl)-1,3,5-triazin-2-amine: mp 192-193° C.; 1H NMR (CDCl3) (rotamers) δ8.65 (d, J=1.8 Hz, 1H), 8.57 (dd, J=4.7, 1.0 Hz, 1H), 8.40 and 8.25 (2d, J=7.5 and 5.5 Hz, 1H), 7.88 (m, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.62 (t, JHF=54.5 Hz, 1H), 7.43-7.37 (m, 2H), 7.30 (ddd, J=7.9, 4.8, 0.7 Hz, 1H), 5.75 and 5.64 (2 m, exchangeable with D2O, 1H), 4.76 and 4.69 (2 d, J=5.7 and 5.8 Hz, 2H), 3.87 (m, 4H), 3.78 (m, 4H); Anal. Calcd. for C21H20F2N8O: C, 57.5; H, 4.6; N, 25.6. Found: C, 57.5; H, 4.5; N, 25.6%.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:6]=2[N:7]=1)[CH3:2].[CH2:26]([O:28][C:29]([C:31]1[N:32]=[C:33]([CH2:36]Br)[O:34][CH:35]=1)=[O:30])[CH3:27]>>[CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[N:22]([CH2:36][C:33]4[O:34][CH:35]=[C:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[N:32]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1coc(CBr)n1
Reactant: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Product: CCOC(=O)c1coc(Cn2cc(C3c4ccc(C)cc4C=Cc4oc(CC)nc43)c(=O)[nH]c2=O)n1

Procedure:
The subtitle compound was prepared from the product from example 1 step (vii) (6.5 g) and 2-[bromomethyl]-4-oxazolecarboxylic acid ethyl ester (Coll. Czech Chem. Comm., 1967, 32, 2155) (1.69 g) by the method of example 1 step (viii). Purification was by chromatography eluting with 60-66% ethyl acetate in toluene.
Reaction SMILES: CC(C)(OC([N:7]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=1)[CH2:8][C@H:9]([OH:19])[C:10]1[CH:11]=[CH:12][C:13]2[N:14](N=N[N:18]=2)[CH:15]=1)=O)C.O.O.[Sn](Cl)Cl.Cl>CO>[OH:19][C@H:9]([C:10]1[CH:15]=[N:14][C:13]([NH2:18])=[CH:12][CH:11]=1)[CH2:8][NH:7][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=1
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(CCN(C[C@H](O)c3ccc4nnnn4c3)C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(CCNC[C@H](O)c3ccc(N)nc3)cc2)cc1
Yield: 131.1 %

Procedure:
A mixture of 0.302 g (0.44 mmol) of the tetrazine from Example 4, 0.20 g (0.88 mol) of tin(II) chloride dihydrate and 0.3 ml of concentrated aqueous hydrochloric acid in 2 mL of methanol was heated at reflux for 5 h. The reaction mixture was concentrated and the residue purified by reverse-phase MPLC (C8, 47%methanol/53 0.1% trifluoroacetic acid buffer) to give 0.32 g (78%) of the title compound as its bistrifluoroacetate salt: 1H NMR (400 MHz, CD3OD) δ7.96 (dd, 1H, J=2.0, 9.2 Hz), 7.86 (d, 1H, J=2.0 Hz), 7.59 (d, 2H, J=8.8 Hz), 7.43 (d, 2H, J=8.8 Hz), 7.14 (d, 2H, J=8.4 Hz), 7.07 (d, 2H, J=8.4 Hz), 7.03 (d, 1H, J=9.2 Hz), 4.92 (m, 1H), 3.23 (m, 2H), 3.15 (m, 2H), 2.93 (m, 2H, 4.0 Hz), 1.49 (t, 2H, J=6.0 Hz), 1.32 (m, 8H), 0.91 (t, 3H, J=6.0 Hz); CI MS m/z 555(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:23][CH3:24])[CH2:32][CH2:33]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCc1ccccc1N1CCNCC1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Product: CCc1ccccc1N1CCN(C(=S)Nc2nc3ccccc3nc2OC)CC1
Yield: 60.7 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(2-ethylphenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7](Cl)[C:8]3[N:9]2[C:12]([O:15][CH3:16])=[N:13][N:14]=3)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH:23]([NH2:26])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([NH:26][CH:23]([CH3:25])[CH3:24])[C:8]3[N:9]2[C:12]([O:15][CH3:16])=[N:13][N:14]=3)=[CH:4][CH:3]=1
Reactant: COc1nnc2c(Cl)nc3ccc(Br)cc3n12
Reactant: CC(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nnc2c(NC(C)C)nc3ccc(Br)cc3n12
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a solution of 8-bromo-4-chloro-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline (2.0 g) in DMF (50 mL) was added solid sodium bicarbonate (1.1 g) and isopropylamine (0.82 mL). The resulting mixture was stirred at 23° C. for 18 hrs. and then diluted with EtOAc. The mixture was washed sequentially with water and brine, and then dried over sodium sulfate. Concentration afforded (8-bromo-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)-isopropyl-amine as a light yellow solid. MS (M+H)+=337.3.