Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[N:49](C)[N:48]=[C:47]([CH3:51])[CH:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:49]([CH3:45])[N:48]=[C:47]([CH3:51])[CH:46]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Cc1cc(CCl)n(C)n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1cc(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)n(C)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole and isolated as light yellow gum. MS (m/e): 391.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:22][CH2:21][CH2:20][O:19][CH3:18])[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cccs2)c1C#N
Reactant: COCCN
Solvent: C1COCCO1
Product: COCCNc1nc(N)nc(-c2cccs2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-thiophen-2-yl-pyrimidine-5-carbonitrile and 2-methoxyethylamine in dioxane. ES-MS m/e (%): 276 (M+H+, 100).
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.[CH:31](OCC)=[O:32].Cl>C1COCC1>[Br:16][C:17]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[C:18]=1[CH:31]=[O:32]
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CCOC=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(Br)cc(C(F)(F)F)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A 2.59 M hexanes solution of n-BuLi (1.13 mL, 2.92 mmol) was added dropwise to a, 0° C., THF solution (4 mL) of 2,2,6,6-tetramethylpiperidine (0.50 mL, 2.92 mmol). After 5 min at 0° C., the solution was cooled to −78° C. and 1-bromo-3,5-bis(trifluoromethyl)benzene was added dropwise over 2 min. The resulting brown amber colored solution was stirred at −78° C. for an additional 20 min. Ethyl formate (0.587 mL, 7.30 mmol) was then added dropwise at −78° C. over 1 min. After 30 min at −78° C., 1 M aqueous HCl was added, the layers were separated and the organic layer was washed with 0.1 M aqueous HCl and 1 M aqueous. The organic layer was dried (Na2SO4), concentrated, and short path vacuum distilled to provide the title compound.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([Cl:32])[C:16]=2[N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19]2)[NH:11][CH:10]=1.[CH3:33][CH:34]([CH3:39])[CH2:35][C:36](Cl)=[O:37].CC#N.O>CN1C(=O)CCC1.C(Cl)Cl.O[Li].O>[Cl:32][C:15]1[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:19]2)=[C:17]2[C:9]([NH:8][C:36](=[O:37])[CH2:35][CH:34]([CH3:39])[CH3:33])=[CH:10][NH:11][C:12]2=[N:13][CH:14]=1
Reactant: CC(C)CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Agent: [Li]O
Solvent: O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C)CC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Triethylamine (522 μL, 3.83 mmol) was added to an aliquot of (R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (200 mg, 0.547 mmol) in NMP (3 mL) at 0° C. under N2 atmosphere. The mixture was then treated dropwise with 3-methylbutanoyl chloride (231 mg, 1.91 mmol) and stirred at 0° C. After 1 hour, the reaction mixture was diluted with CH2Cl2 (4 mL), and 2M LiOH.H2O (3 mL) was added. The resulting mixture was stirred at room temperature for 18 hours. The mixture was then diluted with additional CH2Cl2 (50 mL) and washed with water (3×10 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 40M+, 15-85% CH3CN/water, 40 CV) to provide (R)-tert-butyl 1-(5-chloro-3-(3-methylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (130 mg, 53% yield) as a solid.
Reaction SMILES: [N+:1]([C:4]1[C:12]([N+:13]([O-])=O)=[CH:11][C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>CCO.[Pd]>[NH2:13][C:12]1[C:4]([NH2:1])=[CH:5][C:6]2[NH:10][CH:9]=[N:8][C:7]=2[CH:11]=1
Reactant: O=[N+]([O-])c1cc2nc[nH]c2cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2nc[nH]c2cc1N
Yield: 67.5 %

Procedure:
The product obtained in Step 1 (2.5 g, 12 mmol) and Pd/C (0.5 g) were dissolved in EtOH (50 mL), reacted in a Parr hydrogenation apparatus at room temperature and hydrogen gas pressure until the reaction is completed. The catalyst was removed by filtration, the filtrate was concentrated under vacuum, diluted with ethyl acetate, washed with water, dried, and concentrated under vacuum to obtain a product (1.2 g, 66.7%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:24][CH:23]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: COc1ccc(S)cc1
Product: COc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-methoxy-thiophenol.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:10][CH3:11])([CH2:8][CH3:9])[C:5]([OH:7])=[O:6])[CH3:2].[Si:12]([O:19][C@H:20]1[CH2:29][C@H:28](O)[C@H:27]2[C:22]([CH:23]=[CH:24][C@H:25]([CH3:48])[C@@H:26]2[CH2:31][CH2:32][C@H:33]2[O:38][C:37](=[O:39])[CH2:36][C@H:35]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:34]2)=[CH:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Si:12]([O:19][C@H:20]1[CH2:29][C@H:28]([O:6][C:5](=[O:7])[C:4]([O:3][CH2:1][CH3:2])([CH2:8][CH3:9])[CH2:10][CH3:11])[C@H:27]2[C:22]([CH:23]=[CH:24][C@H:25]([CH3:48])[C@@H:26]2[CH2:31][CH2:32][C@H:33]2[O:38][C:37](=[O:39])[CH2:36][C@H:35]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])[CH2:34]2)=[CH:21]1)([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:14])[CH3:13]
Reactant: CCOC(CC)(CC)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCOC(CC)(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 21.5 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 875 mg of 2-ethoxy-2-ethylbutyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 271 mg of the title compound as a colorless foam.
Reaction SMILES: [C:1]([NH:22][C@@H:23]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:43])/[CH:37]=[CH:38]/[C:39]([O:41][CH3:42])=[O:40])[C:24]([O:26]C(C)(C)C)=[O:25])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].Cl>O1CCOCC1>[C:1]([NH:22][C@@H:23]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:43])/[CH:37]=[CH:38]/[C:39]([O:41][CH3:42])=[O:40])[C:24]([OH:26])=[O:25])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CCCCNC(=O)/C=C/C(=O)OC)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CCCCNC(=O)/C=C/C(=O)OC)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-tert-Butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-6--((E)-4-methoxy-4-oxobut-2-enamido)hexanoate (200 mg, 0.334 mmol) was taken up in 3 mL of a 4 N HCl solution in dioxane and stirred at room temperature under an inert atmosphere of argon for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was portioned between 30 mL of EtOAc and 30 mL of water. The organic layer was further washed with brine until the pH of the water layer was close to neutral, dried over Na2SO4 and concentrated under reduced pressure. Purification by preparative HPLC using a mixture of aqueous acetonitrile that has been buffered with 0.1% TFA afforded (S) -2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-6-((E)-4--methoxy-4-oxobut-2-enamido)hexanoic acid, (90 mg; 50%). MS (EI) called for C31H46N2O6: 542.34; found 543 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][NH:11][C:10](Cl)([NH2:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[N:22][N:21]=[N:20]1.C(N(CC)CC)C>C(#N)C.[OH-].[Na+]>[CH2:1]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][NH:11][C:10]([N:19]2[CH:23]=[N:22][N:21]=[N:20]2)([NH2:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1(Cl)N=C(Cc2ccccc2)C([N+](=O)[O-])=CN1
Reactant: c1nnn[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC1(n2cnnn2)N=C(Cc2ccccc2)C([N+](=O)[O-])=CN1
Reaction time: 8 h

Procedure:
4.0 g of 4N-benzyl-2-chloro-5-nitropyrimidineamine (Reference Example 2) was added to a solution of 3.0 g of 1H-tetrazole in 120 ml of acetonitrile. A mixture of 2.5 ml of triethylamine and 45 ml of acetonitrile was added dropwise to the solution. The reaction solution was stirred overnight and was cencentrated under reduced pressure to obtain solid. The resulting solid was suspended in 3N sodium hydroxide solution for 1 hour, filtered and dried to obtain 3.80 g of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[N:7][CH:8]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].CN(C)C=O.[H-].[Na+]>O>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]=1[CH2:10][O:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Reactant: COC(=O)Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.8 %

Procedure:
To a mixture of 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolyl)methoxypyridine (0.91 g), methyl 2-(2-hydroxyphenyl)acetate (0.44 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.12 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetate as an oil (0.81 g, 70%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[CH3:18])=[CH:8][C:7]=2[CH:19]=1.N1C(=O)CC[C@H]1C(O)=O.Cl>>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:19][C:7]=3[CH:8]=2)=[C:12]([CH3:18])[CH:13]=1
Reactant: COc1ccc2oc(-c3ccc(O)cc3C)cc2c1
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Product: Cc1cc(O)ccc1-c1cc2cc(O)ccc2o1
Temperature: 180 °C

Procedure:
A mixture of the monomethyl ether 79 (0.27 g, 1.1 mmol) and Pyr-HCl was heated at 180° C. for 30-45 minutes. The reaction mixture was allowed to cool and partitioned between EtOAc and 2 N HCl aq and the EtOAc was washed with brine and dried over MgSO4. The solution was filtered, concentrated and chromatographed on silica gel (EtOAc/hexanes 1:3): Mp=167-169° C.; 1H NMR (DMSO-d6) δ 8.61 (s, 1 H), 8.11 (s, 1H), 7.67 (d, 1 H, J=8.9 Hz), 7.33 (d, 1 H, J=8.7 Hz), 7.02 (d, 1 H, J=2.4 Hz), 6.82-6.78 (m, 4H (overlapping protons)), 2.50 (s, 3 H); MS 239 (M−H)−.
Reaction SMILES: [CH3:1][Mg]Br.[OH:4][C@H:5]1[CH2:15][C@@:14]2([CH3:17])[O:16][C@@:6]31[C@@H:18]1[C@@H:10]([N:11]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=4)[C:12](=[O:19])[C@H:13]21)[O:9][CH2:8][CH2:7]3>C1COCC1>[OH:4][C@:5]1([CH3:1])[CH2:15][C@@:14]2([CH3:17])[O:16][C@@:6]31[C@@H:18]1[C@@H:10]([N:11]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:29])([F:30])[F:31])[CH:21]=4)[C:12](=[O:19])[C@H:13]21)[O:9][CH2:8][CH2:7]3
Reactant: C[Mg]Br
Reactant: C[C@@]12C[C@H](O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Solvent: C1CCOC1
Product: C[C@@]12C[C@@](C)(O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Reaction time: 1 h
Yield: 21.9 %

Procedure:
Methylmagnesium bromide (3M in ether, 0.476 mL, 1.427 mmol) was added drop wise to a solution of Example 3 (280 mg, 0.714 mmol) in THF (10 mL) at −30° C. The resulting reaction mixture was stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 10-100% EtOAc/hexane, Flow rate: 40 mL/min) to give Example 37 (64 mg, 22% yield) as a white solid along with 204 mg of recovered starting material.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(NC1C=C(C2C3N(C4C=CC=CC=4)C=NC=3C=C(C#N)C=2)C=CC=1)(=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:17]=[C:16]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1cccc(B(O)O)c1
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)Nc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Yield: 31.3 %

Procedure:
This was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 3-methoxyphenylboronic acid (76 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) in a similar manner to 7-(3-acetamidophenyl)-5-cyano-1-phenylbenzimidazole. Purification by a similar procedure afforded the title compound (51 mg, 31%) m/z, 326.5 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.Cl[CH2:12][C@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C(#N)C.O>[CH3:18][C:15]1([CH3:19])[O:14][C@@H:13]([CH2:12][N:9]2[CH:8]=[C:4]3[N:5]=[CH:6][CH:7]=[C:2]([I:1])[C:3]3=[N:10]2)[CH2:17][O:16]1
Reactant: Ic1ccnc2c[nH]nc12
Reactant: CC1(C)OC[C@H](CCl)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@H](Cn2cc3nccc(I)c3n2)O1
Temperature: 120 °C
Yield: 34.8 %

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (100 mg, 0.408 mmol), (R)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (0.056 ml, 0.408 mmol) and cesium carbonate (266 mg, 0.816 mmol) were combined in DMF (5 mL) at room temperature. The mixture was heated at 120° C. for 1 hour, then cooled and purified by preparative HPLC using a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column eluting with a gradient of 20-70% 10 mmol NH4HCO3 in 20/80 (v/v) water/acetonitrile in 10 mmol NH4HCO3 in water to give (S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-7-iodo-2H-pyrazolo[4,3-b]pyridine (51 mg, 34.8% yield). MP 85-87° C. MS [M+H] found 360.1.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>C1COCC1.O>[CH3:13][O:14][C:15]1[C:20]([B:21]([OH:26])[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: COc1ccccn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ncccc1B(O)O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 32.7 %

Procedure:
To a solution of diisopropylamine (1.42 mL, 10 mmol) in THF (10 mL) at 0° C. was added nBuLi (2.5 M, 4.25 mL, 10.6 mmol) dropwise. After stirring at 0° C. for 45 min, a solution of 2-methoxypyridine (0.96 mL, 9.2 mmol) in THF (5 mL) was added, and the mixture was stirred for an additional 1 h before B(OiPr)3 (2.54 mL, 11 mmol) was added. 30 min later, H2O was added to quench the reaction, the THF was removed in vacuo and the aqueous layer was extracted with ether. The aqueous layer was separated, acidified with 48% HBr to pH=4, the resulting precipitates were collected by filtration to yield 2-methoxypyridine-3-ylboronic acid (0.46 g, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([O:14]CC)=O)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[OH-].[K+].[C:29]1(=[O:35])[O:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[OH:14][C:12]1[C:11]2[C:10](=[N:20][CH:19]=[CH:18][CH:17]=2)[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:33](=[O:34])[C:32]=1[CH2:31][CH2:30][CH2:29][OH:35]
Reactant: O=C1CCCCO1
Reactant: CCOC(=O)c1cccnc1Nc1ccc(OC)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(-n2c(=O)c(CCCO)c(O)c3cccnc32)cc1
Temperature: 100 °C

Procedure:
A mixture of delta-valerolactone (120 ml.), ethyl 2-(4-methoxyphenylamino)nicotinate (12 g.) and potassium t-butoxide (24 g.) was stirred and heated in an atmosphere of nitrogen to 100° C. for 2 hrs. After cooling, the mixture was poured into 1000 ml. of 5% KOH solution and stirred overnight. The aqueous solution was extracted with ether (2×250 ml.) which was discarded. The aqueous solution was then acidified to pH 4.5 with conc. HCl. The product was filtered off, washed with water, dried in air and recrystallized from CHCl3 /isopropanol to yield the desired product, m.p. 229°-231° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=1)[CH2:8][CH2:9]O)=[O:5].FC1C=CC=C(F)C=1C(NC(C1C=CC(Cl)=CC=1)CCO)=O>>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[C:4]1[O:5][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=2)[N:6]=1
Reactant: CCCCCCCc1cccc(C(CCO)NC(=O)c2c(F)cccc2F)c1
Agent: O=C(NC(CCO)c1ccc(Cl)cc1)c1c(F)cccc1F
Product: CCCCCCCc1cccc(C2CCOC(c3c(F)cccc3F)=N2)c1

Procedure:
The procedure is as for Example 85, but 4.0 g (10.3 mmol) of N-(2,6-difluorobenzoyl)-3-amino-3- (3-n-heptylphenyl)-1-propanol are employed instead of N-(2,6-difluorobenzoyl)-3-amino-3-(4-chlorophenyl)-1-propanol. 2.7 g (70.8%) of 2-(2,6-difluorophenyl-4-(3-n-heptylphenyl)-5,6-dihydro(4H)1,3-oxazine are obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]=[N+]=[N-])=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCN=[N+]=[N-])cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(CCCN)cc1

Procedure:
Amine 13 was prepared as described in procedure A from azide 12 (5.2 g, 0.027 mol) and LAH (26 ml of 1 M solution in THF).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>O.[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>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: Brc1ccccn1
Reactant: C=Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(-c2ccccn2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
4-Vinyl-phenylboronic acid (10 g, 0.0676 mol), 2-bromopyridine (12.64 g, 0.08 mol), tetrahydrofuran (100 ml), 2M potassium carbonate aqueous solution (26 ml), and tetrakis(triphenylphosphine) palladium (Pd(Ph3)4, 0.06 g, 1 mol %) were placed into 250 ml of 2-necked round-bottomed flask under N2. The reaction mixture was refluxed at 80° C. for 24 hr and then poured in 200 ml of water in beaker. The reaction mixture was extracted with ether (3×150 ml) and the ether layer was then dried over magnesium sulfate (10 g) by stirring for 30 min. The dried ether layer was evaporated in vacuo to dryness and purified further by column chromatography on silica gel with eluting hexane/ethylacetate (1/9) to yield 2-(4-vinyl-phenyl)pyridine (90%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:12]2[N:11]=[N:10][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:14][CH:13]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazine-1-carboxylic acid t-butyl ester, the title compound was obtained as a white solid (47% yield). 1H NMR (400 MHz, CDCl3) δ 8.04-7.95, 6.97, 3.62-3.54, 1.59-1.44, 1.34-1.23, 0.72-0.62, 0.45-0.36, 0.06-0.04. MS (ES+) m/z 376.3 (M+1).
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:13])(=[NH:12])[CH2:8][CH2:9][CH2:10][CH3:11].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25])([O-:16])=[O:15]>C1C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:12][C:7](=[NH:13])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:25])([O-:16])=[O:15]
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCC(=N)NC(=O)Nc1ccccc1[N+](=O)[O-]

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 150 ml. dry acetone, 13.6 g. valeramidine hydrochloride, and 16.4 g. 2-nitrophenyl isocyanate in 300 ml. benzene, there was obtained after recrystallization from ethyl alcohol 9.1 g. of the hydrochloride of 1-(2-nitrophenyl)-3-(pentanimidoyl)urea; m.p. 130°-132°C.