Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:11])=[C:8]([CH:10]=1)[NH2:9])[CH2:2][CH3:3].[F:12][C:13]([F:22])([F:21])[C:14](I)([F:19])[C:15]([F:18])([F:17])[F:16].C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC.COC(C)(C)C.O>[CH3:11][C:7]1[CH:6]=[C:5]([C:14]([F:19])([C:15]([F:18])([F:17])[F:16])[C:13]([F:22])([F:21])[F:12])[C:4]([CH2:1][CH2:2][CH3:3])=[CH:10][C:8]=1[NH2:9]
Reactant: CCCc1ccc(C)c(N)c1
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCCCCC
Product: CCCc1cc(N)c(C)cc1C(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
5-n-Propyl-2-methylaniline (14.9 g, 0.1 mol) was diluted in a mixed solvent (300 ml) of tert-butyl methyl ether-water (1:1), and heptafluoroisopropyl iodide (29.6 g, 0.1 mol), tetrabutylammonium hydrogen sulfate (3.4 g, 0.01 mol), sodium hydrogen carbonate (8.4 g, 0.1 mol) and sodium dithionite (17 g, 0.1 mol) were successively added. The mixture was stirred overnight at room temperature. The reaction mixture was diluted in hexane, washed twice with 3N hydrochloric acid, and washed with aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate 5:1) to give the desired compound (28.5 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C@H:15]([C:28]([OH:30])=[O:29])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH:26]=[O:27])[CH:18]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].IC>CN(C=O)C>[C:7]([O:11][C:12]([NH:14][C@H:15]([C:28]([O:30][CH3:1])=[O:29])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH:26]=[O:27])[CH:18]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1cn(C=O)c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To DMF (50 mL) suspension of potassium carbonate (6.2 g) was added dropwise DMF (70 mL) solution of Nα-tert-butoxycarbonyl-1-formyl-L-tryptophan (10.0 g) at 0° C., and the mixture was stirred for 1 hour at room temperature. Next, DMF (25 mL) solution of iodomethane (2.8 mL) was added dropwise at 0° C., and the mixture was stirred for 20 hours at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and thereafter the residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel column chromatography (BZ-127ZH, n-hexane:ethyl acetate=7:3), to give the captioned compound (9.0 g, 86%) as crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:40][CH3:41])=[C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:29][CH:28]5[CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH:27]5[CH2:26]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2].Cl>C(Cl)Cl.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:40][CH3:41])=[C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH:27]5[CH:28]([CH2:30][NH:31][CH2:32]5)[CH2:29]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2]
Reactant: C#Cc1cc(Nc2ncnc3cc(OC)c(OCCCN4CC5CN(C(=O)OC(C)(C)C)CC5C4)cc23)ccc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C#Cc1cc(Nc2ncnc3cc(OC)c(OCCCN4CC5CNCC5C4)cc23)ccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.2 %

Procedure:
To a solution of tert-butyl 5-(3-((4-((3-ethynyl-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.03 g) in DCM (30 mL) was added a solution of HCl in EtOAc at room temperature. The reaction mixture was stirred for 6 h at room temperature and filtered to give crude product. The crude product was recrystallized from a mixture of MeOH and EA to give the title compound as a white solid (0.78 g, 92.60%), HPLC: 95.04%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 462.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.83-1.88 (m, 4H), 2.32-2.45 (m, 6H), 2.66-2.76 (m, 4H), 4.03 (s, 3H), 4.06 (s, 1H), 4.15 (t, J=7.2 Hz, 2H), 7.15 (s, 1H), 7.23 (s, 1H), 7.40 (s, 1H), 7.53-7.60 (m, 1H), 7.90-7.93 (m, 1H), 8.66 (s, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].CC1C=C(C)N=C(C)C=1.CC1C([IH+:40])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([I:40])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: Cc1cc(C)c([IH+])c(C)n1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)c1nc(I)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (150 mg, 0.48 mmol) and bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (1.24 g, 2.42 mmol) in 5 mL of CH2Cl2 was stirred for 16 h at r.t. The mixture was diluted with 30 mL of CH2Cl2 and washed with 5% sodium thiosulfate and 1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (20-100% CH2Cl2/hexanes+2% AcOH) to give 136 mg of the title compound as an off-white solid. MS: (+) m/z 436.82 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CN(C)CCN
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCN(C)C)sc2Br)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride obtained in Step III as describe above (586 mg; 1.41 mmol; 1 eq), is dissolved in anhydrous DCM (15 ml). The reaction is put under nitrogen. Triethylamine (1.9 ml; 14.1 mmol; 10 eq) and N,N-dimethyl-ethane-1,2-diamine (0.17 ml; 2.82 mmol; 2 eq) are added successively and the reaction mixture is stirred at room temperature for 30 minutes. The solvents are evaporated and the crude mixture is purified by preparative HPLC, affording the title compound (68 mg; 10%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>CS(C)=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:7]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Nc2ccc(C#N)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzonitrile (2.00 g, 12.04 mmol) and methyl 4-aminobenzoate (1.94 g, 12.83 mmol) in DMSO (40 mL) was cooled in an ice-bath and potassium tert-butoxide (2.96 g, 26.38 mmol) was added over 15 min. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was quenched with ice; the solid product was recovered by filtration, washed with water and dried under vacuum to afford 2.4 g (68%) of methyl 4-[(4-cyano-2-nitrophenyl)amino]benzoate. To a solution of methyl 4-[(4-cyano-2-nitrophenyl)amino]benzoate (0.2 g, 0.67 mmol) in ethanol (4 mL) was added palladium on carbon (10 wt. %, 0.06 g) and hydrazine hydrate (0.13 g, 2.60 mmol) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, filtered through celite, and the solvent evaporated. The residue was dissolved in ethyl acetate, washed with water, dried (Na2SO4) and evaporated under reduced pressure to afford a crude oil. To a solution of the oil in trimethyl orthoformate (10 mL) was added formic acid (0.31 g, 7.7 mmol, 3 eq) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate and the organic layer was dried (Na2SO4) and evaporated to afford a crude solid. Purification by flash column chromatography (silica, CHCl3/MeOH 98:2) afforded 0.12 g (63%) of methyl 4-(5-cyano-1H-benzimidazol-1-yl)benzoate. MS [M+H] 277.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:32]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)([O:15][CH3:32])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCC[C@@](OC)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C

Procedure:
To a mixture of (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-piperidine-1-carboxylate (0.1874 g, 0.45 mmol, 1.0 equiv) and 60% NaH in oil (0.345 g, 8.6 mmol, 19 equiv) in THF (15 mL) was added iodomethane (1.195 g, 8.4 mmol, 18.5 equiv). The resulting mixture was heated at 70° C. for 16 h and then quenched with water, extracted with EtOAc and dried over Na2SO4. After the solvent was removed, the crude (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1,5-dimethoxypentyl)piperidine-1-carboxylate (0.3175 g) was used in the next step without further purification. LC-MS (3 min) tR=2.44 min m/z 450, 448 (M+Na+), 426 (M+H+), 340, 338, 294.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([F:22])([F:21])C([O-])=O.[Na+]>CN(C)C=O.O.Cl.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH:17]([F:22])[F:21]
Reactant: Oc1c(F)cccc1Cl
Reactant: O=C([O-])C(F)(F)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Fc1cccc(Cl)c1OC(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
2-Chloro-6-fluorophenol (1.8 g, 12.33 mmol) was dissolved in dimethylformamide (DMF; 22 mL) and water (2.2 mL). Potassium carbonate (2.55 g, 18.5 mmol) and sodium chlorodifluoroacetate (4.7 g, 30.8 mmol) were then added and the solution was heated to 100° C. for 3 h. The cooled reaction mixture was then diluted with concentrated HCl (10 mL) and the resulting solution was stirred for 2 h. The reaction mixture was diluted with diethyl ether, washed with water, washed twice with 1M NaOH, washed once with brine, dried, filtered and concentrated under vacuum to yield the title compound (1 g, 41% yield) that was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16])=[O:6].[NH:18]1C=CN=[CH:19]1>>[N:2]1([CH2:3][CH2:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH3:16])=[O:6])[CH:1]=[CH:19][N:18]=[CH:17]1
Reactant: Cc1[nH]c2ccccc2c1C(=O)CCN(C)C
Reactant: c1c[nH]cn1
Product: Cc1[nH]c2ccccc2c1C(=O)CCn1ccnc1

Procedure:
3-(Dimethylamino)-1-(2-methyl-1H-indol-3-yl)-1-propanone was converted to the methiodide (1.50 g) which was then reacted with imidazole (2.67 g) to give a solid which was crystallised from methanol to give the title compound (0.65 g), m.p. 196°-197°; λmax (EtOH) 244 (ε12,920), λmax 268.5 nm (ε10,460), λmax 302.5 (ε11,400).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 105.8 %

Procedure:
To a solution of CH2Cl2 (60 mL) and 3,5-dichlorophenol (5.0 g, 30 mmol) was added tert-butyldimethylsilyl chloride (5.54 g, 36 mmol), N,N-diisopropylethylamine (8.0 mL, 46 mmol) and a catalytic amount of 4-dimethylaminopyridine. The initially exothermic solution was stirred at ambient temperature for 6 h then diluted with CH2Cl2 (40 mL). The mixture was washed consecutively with 10% aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide 13 as a pale yellow liquid (8.8 g, 100%). 1H NMR (300 MHz, CDCl3) d 6.98 (s, 1H), 6.72 (s, 2H), 0.98 (s, 9H), 0.22 (s, 6H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][OH:20])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:18][CH2:19][O:20][C:28]2[CH:29]=[CH:30][C:25]([NH:24][C:21](=[O:23])[CH3:22])=[CH:26][CH:27]=2)=[CH:7][C:8]=1[C:14]([F:16])([F:17])[F:15])#[N:11]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC2CC2)cc1C(F)(F)F
Product: CC(=O)Nc1ccc(OCCN(CC2CC2)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(cyclopropylmethyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-acetamidophenol: MS (APCI) m/z 418 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29](O)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][C@H:43]([CH3:45])[C@H:42]([N:46]2[CH:50]=[CH:49][N:48]=[N:47]2)[C@H:41]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C1COCC1.CO.O>[C:54]([O:53][C:52]([NH:51][C@H:41]1[C@@H:42]([N:46]2[CH:50]=[CH:49][N:48]=[N:47]2)[C@@H:43]([CH3:45])[CH2:44][N:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH:32][C:29]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:40]1)=[O:58])([CH3:57])([CH3:56])[CH3:55]
Reactant: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CC1
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxylic acid (9.9 mg, 0.024 mmol), tert-butyl [(3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-3-yl]carbamate (8.0 mg, 0.021 mmol), and HATU (26 mg, 0.069 mmol), in DMF (0.23 mL) and THF (0.5 mL), DIPEA (0.014 mL, 0.083 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with MeOH and H2O, filtered and purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as bright yellow powder (8.0 mg, 48%). LCMS calc. for C41H50N11O5 (M+H)+: m/z=776.4. Found: 776.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN1CCN(c2cccc3ccc(O)cc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(c2cccc3ccc(OC(=O)c4ccc(Cl)cc4)cc23)CC1
Temperature: 25 °C

Procedure:
The title product was obtained following the procedure of example 30 from 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.065 g, 0.268 mmol) and 4-chlorobenzoyl chloride (0.035 mL, 0.275 mmol) in methylene chloride (1 mL) and saturated sodium bicarbonate (1 mL) with a second equivalent of 4-chlorobenzoyl chloride added after several hours of stirring at room temperature. The title product was obtained in a yield of 0.058 g (57%) after recrystallization from ether/hexane: mp 110°-111 ° C. Analysis calculated for C22H21ClN2O2 : C, 69.38; H, 5.56; N, 7.36. Found: C, 69.31; H, 5.61; N, 7.35.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[Cl:5][C:6]1[C:7]([C:17]([O:19][CH3:20])=[O:18])=[N:8][C:9]([C:13]([F:16])([F:15])[CH3:14])=[CH:10][C:11]=1Cl.CO.[BH4-].[Na+]>CN(C)C=O.O>[NH2:1][C:11]1[CH:10]=[C:9]([C:13]([F:16])([F:15])[CH3:14])[N:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:6]=1[Cl:5]
Reactant: COC(=O)c1nc(C(C)(F)F)cc(Cl)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(C(C)(F)F)cc(N)c1Cl
Temperature: 50 °C
Reaction time: 5 h
Yield: 56.8 %

Procedure:
Sodium azide (26.5 mg, 0.41 mmol) was added to a solution of methyl 3,4-dichloro-6-(1,1-difluroethyl)pyridine-2-carboxylate (100 mg, 0.37 mmol) in dimethylformamide (2 mL) and water (0.2 mL). After the reaction mixture was stirred at 50° C. for 5 hours, it was quenched with water and extracted with ethyl ether. The orgainc phase was dried and concentrated to provide the crude 4-azide compound. It was immediately taken up into methanol (2 mL) and sodium borohydride (21 mg, 0.55 mmol) was carefully added. After stirring for 10 minutes, water was added and the mixture concentrated. Ethyl acetate was added and the mixture washed with brine. The organic layer was dried (MgSO4), filtered and concentrated to dryness. The crude product was purified by column chromatography (20% ethyl acetate in hexane) to give methyl 4-amino-3-chloro-6-(1,1-difluroethyl)pyridine-2-carboxylate (53 mg, 0.21 mmol) as an oil; 1H NMR (CDCl3): δ 7.04 (s, 1H), 4.92 (b.s, 2H), 3.98 (s, 3H), 1.97 (t, d=18.7 Hz, 3H).
Reaction SMILES: Cl.Cl[C:3]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[N:14]=[N:15][N:16]=[C:9]1[N:8]=[C:7]2[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1.[NH3:37].CC(O)C>C1COCC1>[Cl:23][C:19]1[CH:18]=[C:17]([C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:3]([C:31]4[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=4)([C:24]4[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=4)[NH2:37])[CH:5]=3)[N:10]3[N:14]=[N:15][N:16]=[C:9]3[N:8]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(Cl)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Reactant: N
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1ccc(C(N)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of intermediate 26 (0.0083 mol) in THF (80 ml) was cooled to 5° C. under N2 flow. NH3/iPrOH (80 ml ) was added dropwise. The mixture was stirred at 5° C. for 1 hours, then brought to room temperature. The mixture was stirred at room temperature overnight, poured out into ice water and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-40 μm) (eluent: DCM/MeOH/NH4OH 96/4/0.2). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 1.37 g (33%) of 5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(4—methylphenyl)-tetrazolo[1,5-a]quinazoline-7-methanamine .hydrate (1:1) (intermediate 27), mp. 150° C.
Reaction SMILES: I[C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1>C(#N)C.C(N(CC)CC)C.C(O)C#C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:8][C:7]1[C:2]([C:2]#[C:7][CH2:6][OH:9])=[N:3][CH:4]=[N:5][C:6]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1c(I)ncnc1Oc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(C#CCO)ncnc1Oc1ccccc1
Yield: 174.8 %

Procedure:
4-Iodo-6-phenoxypyrimidin-5-amine (3.0 g) was dissolved in a mixed solvent of acetonitrile (159 mL)/triethylamine (117 mL), and 2-propyn-1-ol (0.669 mL), trans-dichlorobis(triphenylphosphine)palladium(II) (336 mg) and copper(I) iodide (109.5 mg) were sequentially added. The title compound (2.02 g) was obtained as crystals by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:19]=[CH:18][C:17]2[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[C:14](=[O:24])[NH:13][CH2:12][C:11]=2[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C.O>[CH2:2]([N:9]1[CH2:19][CH2:18][C:17]2[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[C:14](=[O:24])[NH:13][CH2:12][C:11]=2[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1NCc2c[n+](Cc3ccccc3)ccc2-c2ccccc21
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1NCC2=C(CCN(Cc3ccccc3)C2)c2ccccc21
Reaction time: 0.5 h

Procedure:
To a suspension of Example 180E (17.7 g, 46.4 mmol) in 200 mL of ethanol/water (4:1) at 0° C. was added NaBH4 (8.9 g, 0.232 mol) portion-wise. After stirring for 0.5 hour, the mixture was quenched with 1 N HCl to pH 4-5 and concentrated under reduced pressure. The residue was dissolved in 100 mL of saturated aqueous K2CO3 and extracted with dichloromethane. The organic phase was washed with brine, dried and purified by column chromatography on silica gel eluting with dichloromethane/methanol (30:1) to obtain the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=1
Reactant: COC(=O)c1cc(CN=[N+]=[N-])ccn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(CN)ccn1
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of methyl 4-(azidomethyl)picolinate (280 mg, 1.36 mmol) in methanol (20 mL) was added 10% Pd/C (50 mg). The mixture was stirred under 35 psi H2 for 2 hours. The reaction mixture was filtered through Celite, concentrated, and purified via column chromatography to provide methyl 4-(aminomethyl)picolinate (150 mg).