Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH3:17]O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)[C:7]([O:9][CH3:17])=[O:8])([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
3-Nitro-5-(trifluoromethyl)benzoic acid (25.0 g, 106.3 mmol) was dissolved in methanol (60 mL) which was bubbled with hydrochloric acid gas for 1 h. The reaction was allowed to stir at room temperature overnight and concentrated. The crude product was dissolved in ethyl acetate, washed with water (2×), brine (2×) dried over sodium sulfate and concentrated. Flash chromatography on silica gel afforded 23.4 g (88%) of the desired compound. 1H-NMR (CDCl3, 500 MHz) δ 9.02 (s, H), 8.66 (s, 1H), 8.61 (s, 1H), 4.03 (s, 3H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH2:13][NH:14][C:15]3[C:20]([F:21])=[C:19]([O:22][CH3:23])[CH:18]=[C:17]([O:24][CH3:25])[C:16]=3[F:26])=[CH:11][N:10]=[C:9]([S:27][CH3:28])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32]>O1CCCC1>[CH:1]1([N:6]2[C:7]3=[N:8][C:9]([S:27][CH3:28])=[N:10][CH:11]=[C:12]3[CH2:13][N:14]([C:15]3[C:16]([F:26])=[C:17]([O:24][CH3:25])[CH:18]=[C:19]([O:22][CH3:23])[C:20]=3[F:21])[C:31]2=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(OC)c(F)c(NCc2cnc(SC)nc2NC2CCCC2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(N2Cc3cnc(SC)nc3N(C3CCCC3)C2=O)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 16.33 g (0.0398 mol) of cyclopentyl-(5-[(2,6-difluoro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-amine in 288 mL of anhydrous tetrahydrofuran was cooled to 0° C. using an ice/acetone bath. The reaction mixture was treated with 3.98 g (0.0995 mol) of sodium hydride and continued stirring at 0° C. for 30 minutes. After 30 minutes, 19.35 g (0.019 mol) 1,1′-carbonyldiimidazole was added and continued to stir at 0° C. for an additional 30 minutes. After 1 hour, the ice bath was removed and the reaction mixture was allowed to warm up to room temperature. The reaction mixture heated at reflux overnight under nitrogen atmosphere. Evaporated the tetrahydrofuran and partitioned the residue between dichloromethane and water. The aqueous layer was extracted one time with 500 mL dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate, filtered and evaporated. There was a portion of the crude material that did not dissolve in the eluent. Filtered the solid and dried in the housevac oven overnight to give the title compound, 6.80 g of crop 1. The remaining crude material was purified using medium pressure-chromatography, eluting with a gradient of 2:1 hexanes/ethyl acetate to 1:1 hexanes/ethyl acetate to give the title compound as a white solid, 8.74 g of crop 2. Combined the crops to give a total of 15.54 g (90%) of the title compound. MS (APCI) (m+1)/z 437.1.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][C:16]1([C:19]2[O:20][C:21]([CH:24]3[CH2:30][CH2:29][C@@H:28]4[CH2:31][N:25]3[C:26](=[O:40])[N:27]4[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:22][N:23]=2)[CH2:18][CH2:17]1)(C)(C)C>C(Cl)Cl>[NH2:14][CH2:15][C:16]1([C:19]2[O:20][C:21]([CH:24]3[CH2:30][CH2:29][C@@H:28]4[CH2:31][N:25]3[C:26](=[O:40])[N:27]4[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:22][N:23]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NCC1(c2nnc(C3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1(c2nnc(C3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.5 %

Procedure:
TFA (30 mL) was added to a 0° C. solution of tert-butyl(1-(5-((5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)cyclopropyl)methylcarbamate (8 g, 0.017 mol) in DCM (100 mL). The mixture was allowed to warm to rt and was stirred at rt for 1 h. The mixture was concentrated and the residue was washed with Et2O (50 mL), and then filtrated to afford (5R)-2-(5-(1-(aminomethyl)cyclopropyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (7 g, 99%), which was used directly in the next step. ESI-MS (EI+, m/z): 370.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(F)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 4-fluorobenzene-sulfonyl chloride (256 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12m as a solid (300 mg, 88.4%). HPLC: 86.16% (Rt=7.72 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]2[C:15]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:16][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:18][CH:19]=2)[CH:5]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[O:8][CH3:9].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[C:40]3[C:44](=[CH:45][CH:46]=2)[C:43](=[O:47])[CH2:42][CH2:41]3)O1>>[C:10]([C:6]1[C:7]([O:8][CH3:9])=[C:2]([C:38]2[CH:39]=[C:40]3[C:44](=[CH:45][CH:46]=2)[C:43](=[O:47])[CH2:42][CH2:41]3)[CH:3]=[C:4]([C:14]2[C:15]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[N:16][C:17]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[N:18][CH:19]=2)[CH:5]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: COc1c(Br)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Product: COc1c(-c2ccc3c(c2)CCC3=O)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C

Procedure:
A solution of Example 2 Part A (0.150 g, 0.32 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (0.092 g, 0.36 mmol) were reacted in the same manner as Example 50 Part A using 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex as catalyst at 100° C. for 1.5 hours in the microwave and for 4 hours at 100° C. in an oil bath to give crude product which was purified by silica gel flash chromatography eluting with ethyl acetate/hexane (0% to 15%) to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[F:17][C:18]1[N:23]=[C:22]2[C:24]([CH3:28])=[CH:25][N:26]([NH2:27])[C:21]2=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:17][C:18]1[N:23]=[C:22]2[C:24]([CH3:28])=[CH:25][N:26]([NH:27][C:14]([C:10]3[C:11]([CH3:13])=[N:12][C:7]([C:2]4[N:1]=[CH:6][CH:5]=[CH:4][N:3]=4)=[N:8][CH:9]=3)=[O:16])[C:21]2=[CH:20][CH:19]=1
Reactant: Cc1nc(-c2ncccn2)ncc1C(=O)O
Reactant: Cc1cn(N)c2ccc(F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ncccn2)ncc1C(=O)Nn1cc(C)c2nc(F)ccc21
Yield: 24.4 %

Procedure:
A solution of 2-pyrimidin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (1.41 mmol), 5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.41 mmol), DIPEA (158 mg, 4.22 mmol) and HATU (1.69 mmol) in anhydrous DMF (8 mL) is stirred at 90° C. for 16 hours. DMF is evaporated off in vacuo. The residue is dissolved in EtOAc (40 mL), washed with water (3×10 mL) and brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 1-20% MeOH in DCM to afford 4-methyl-[2,2′]bipyrimidinyl-5-carboxylic acid (5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (125 mg) as a solid. MS: 364 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.31 (s, 3H), 2.87 (s, 3H), 6.87 (d, H), 7.50 (s, H), 7.66 (t, H), 7.96 (t, H), 9.04 (d, 2H), 9.27 (s, H).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:22]([CH2:24][NH2:25])[OH:23].O>N1C=CC=CC=1>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:23][CH2:22][CH2:24][NH2:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: NCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.5 %

Procedure:
Triphenylchloromethane (1.00 g, 3.58 mmol) (Wako Pure Chemical Industries, Ltd.) and ethanolamine hydrochloride (1.00 g, 10.3 mmol) (Wako Pure Chemical Industries, Ltd.) were dissolved in pyridine (4 mL), and the solution was stirred at room temperature for 3 days. Water (200 mL) was poured into the reaction solution, and the precipitates were suction-filtered. The solid matters were suspended in diethyl ether, and 3 (N) hydrochloric acid (Wako Pure Chemical Industries, Ltd.) was added thereto, followed by stirring at room temperature for 15 minutes. The insoluble matters were suction-filtered. The insoluble matters were dissolved in a mixed solution of ethyl acetate (Wako Pure Chemical Industries, Ltd.) and a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.), and the mixture was shaken, followed by the separation of the organic layer. The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and then suction-filtered and concentrated under reduced pressure, to thereby obtain the title compound (0.31 g, 28% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]1[C:22]([F:23])=[C:21](F)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>CC(N(C)C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:21]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([F:14])[C:22]=2[F:23])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(F)c(F)c1F
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c(F)c2F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of N-Boc-piperazine (0.65 g) in DMA (20 mL) was slowly added a solution of 2,3,4-trifluorobenzonitrile (0.49 g) in DMA (10 mL). The reaction mixture was stirred for 2 hours at 80° C. After such time the solvent was removed in vacuo and purified by column chromatography (SiO2) to yield the title compound as white solid (0.76 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:30])[N:25]([CH2:27][CH2:28][OH:29])[CH3:26])([CH3:22])([CH3:21])[CH3:20].[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[C:19]([O:23][C:24](=[O:30])[N:25]([CH2:27][CH2:28][O:29][CH2:10][CH2:9][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:26])([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(CCOCCN(Cc1ccccc1)Cc1ccccc1)C(=O)OC(C)(C)C
Yield: 32.6 %

Procedure:
[2-(2-Dibenzylamino-ethoxy)-ethyl]-methyl-carbamic acid tert-butyl ester (200 mg) was prepared by following General Procedure S starting from dibenzyl-(2-chloro-ethyl)-amine (400 mg), (2-hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester (525 mg), 50% (w/w) KOH solution (1.8 mL) and tetrabutylammonium bromide (57.7 mg) in dioxane (1.8 mL).
Reaction SMILES: [OH:1][CH:2]([C:19]1[O:20][C:21]([C:24]2[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=2)=[CH:22][N:23]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:12]([CH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][C:2]([C:19]2[O:20][C:21]([C:24]3[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=3)=[CH:22][N:23]=2)=[O:1])=[CH:10][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(-c2cnc(C(O)CCc3ccc(COc4ccccc4)cc3)o2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.6 %

Procedure:
Methyl 6-(2-(1-hydroxy-3-(4-(phenoxymethyl)phenyl)propyl)oxazol-5-yl)pyridine-2-carboxylate (121 mg, 0.272 mmol) was dissolved in anhydrous CH2Cl2 (3 mL) and Dess-Martin periodinane (173 mg, 0.408 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 2.5 h. The addition of saturated aqueous NaHCO3 quenched the reaction and the organic layer was washed with saturated aqueous Na2S2O3 then saturated aqueous NaCl. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, 0-1% MeOH/CH2Cl2) to provide methyl 6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate as a yellow oil (109 mg, 91%): 1H NMR (CDCl3, 600 MHz) δ 8.10 (d, 1H, J=7.8 Hz), 8.00 (d, 2H, J=6.6 Hz), 7.95 (t, 1H, J=7.8 Hz), 7.36 (d, 2H, J=7.9 Hz), 7.29-7.27 (m, 4H), 6.97-6.93 (m, 3H), 5.02 (s, 2H), 4.02 (s, 3H), 3.47 (t, 2H, J=7.6 Hz), 3.11 (t, 2H, J=7.6 Hz); 13C NMR (CDCl3, 150 MHz) δ 187.2, 165.0, 158.7, 157.3, 152.3, 148.4, 146.4, 140.0, 138.2, 135.0, 129.4, 128.6, 127.9, 127.7, 125.1, 123.2, 120.8, 114.7, 69.6, 53.0, 40.5, 29.3; HR ESI-TOF m/z 443.1606 (M+H+, C26H22N2O3, requires 443.1601).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[C:7][C:8]1[C:9]([NH:24]C(=O)C(F)(F)F)=[C:10]([CH:21]=[CH:22][CH:23]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[C@@H]1(N)CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.[Cu](I)I>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:24][C:9]2[C:8]([CH:7]=1)=[CH:23][CH:22]=[CH:21][C:10]=2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(OCc1ccccc1)c1cccc(C#Cc2nccs2)c1NC(=O)C(F)(F)F
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)c1cccc2cc(-c3nccs3)[nH]c12
Yield: 69.9 %

Procedure:
A solution (50 mL) of benzyl 3-(1,3-thiazol-2-ylethynyl)-2-[(trifluoroacetyl)amino]benzoate (2.21 g), copper iodide (0.146 mg), trans-cyclohexane-1,2-diamine (0.177 g) and tripotassium phosphate (3.27 g) in anhydrous 1,4-dioxane was stirred with heating under reflux for 2 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50) to give the title compound (1.20 g, yield 70%) as a pale-yellow oil.
Reaction SMILES: CC([N:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]3[N:18]=[N:19][N:20]=[C:9]3[C:8]=2[N:7]=[CH:6]1)(C)C.Cl.[OH-].[Na+]>O>[N:18]1[N:10]2[C:11]3[C:16]([C:17]4[NH:5][CH:6]=[N:7][C:8]=4[C:9]2=[N:20][N:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CC(C)(C)n1cnc2c1c1ccccc1n1nnnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)c1[nH]cnc1c1nnnn21
Temperature: 25 °C
Yield: 81.4 %

Procedure:
6-(1,1-Dimethylethyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline (1 g, 3.8 mmole, Example 20) was added to hydrochloric acid (5 mL of 6N); water (20 mL) was added and the mixture was heated on a steam bath for 1 hour. The reaction mixture was allowed to cool to ambient temperature then made basic (pH 11) by the addition of sodium hydroxide solution. The resulting precipitate was isolated by filtration, dried then recrystallized from N,N-dimethylformamide to provide 0.65 g of the desired product as a solid. A sample of this material was refluxed in a large amount of dichloromethane/methanol, isolated by filtration, then dried to provide 6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a solid, m.p. >300° C. Analysis: Calculated for C10H6N6 : % C, 57.14; % H, 2.88; % N, 39.98; Found: % C, 56.89; % H, 3.10; % N 39.34. The structure was confirmed by both mass spectroscopy and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][C:8](=[O:14])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:5]=32)[N:3]1[CH2:15][C:16]([O:18][CH3:19])=[O:17].[C:20](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:20][N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:4]3[N:3]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2](=[O:1])[N:6]([C:5]=23)[CH2:7][C:8]1=[O:14]
Reactant: COC(=O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cn1c(=O)n2c3c(cccc31)N(C)C(=O)C2
Reaction time: 16 h

Procedure:
To a solution of methyl (2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetate (300 mg, 1.15 mmol, described in Intermediate 9) in DMF (5 mL) were added cesium carbonate (748 mg, 2.3 mmol) and iodomethane (326 mg, 2.3 mmol). After 16 h, the reaction mixture was quenched with brine (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=276 (M+1).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:17]([C@@H:24]1[CH2:29][C@@H:28]([N:30]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][CH:39]=2)[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH2:27][CH2:26][NH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(Cl)Cl>[CH2:17]([C@@H:24]1[CH2:29][C@@H:28]([N:30]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][CH:39]=2)[C:31](=[O:36])[C:32]([F:34])([F:35])[F:33])[CH2:27][CH2:26][N:25]1[C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reaction time: 3 h

Procedure:
72 μl (0.515 mmol) of triethylamine and 54 μl (0.468 mmol) of benzoyl chloride are added to a solution of 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine in 4 ml of methylene chloride. The reaction mixture is stirred at 0° for 3 hours, water is added, extraction with methylene chloride is carried out. The organic phases are dried over magnesium sulfate and evaporated to dryness. The yellow oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (1000:50:1). The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.72, FD-MS: M+ =531.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:38]=[CH:37][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30]C(C)(C)C)=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1.Cl>O1CCOCC1>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:35][CH:36]=3)[N:12]=2)=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(OCCBr)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Nc2nc(NCc3ccc(OCCBr)cc3)nc(OCC(F)(F)F)n2)cc1

Procedure:
Tert-butyl 4-((4-((4-(2-bromoethoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (2.91 g, 4.85 mmol) and 4 N HCl in Dioxane (20 mL) were stirred for 16 hs then concentrated under vacuum to give 4-((4-((4-(2-bromoethoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid which was carried to the next step without purification.
Reaction SMILES: Br[C:2]1[C:3]([OH:18])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.[N:19]1[NH:20][N:21]=[CH:22][CH:23]=1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I.C(OCC)(=O)C>[CH:14]1([C:12]([N:8]2[C:9]3[C:4](=[C:3]([OH:18])[C:2]([N:20]4[N:21]=[CH:22][CH:23]=[N:19]4)=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:17])=[O:13])[CH2:16][CH2:15]1
Reactant: C[C@H]1CCc2c(ccc(Br)c2O)N1C(=O)C1CC1
Reactant: c1cn[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1CCc2c(ccc(-n3nccn3)c2O)N1C(=O)C1CC1
Temperature: 120 °C
Reaction time: 24 h
Yield: 13.4 %

Procedure:
A mixture of (S)-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (1.20 g, 3.87 mmol), 2H-1,2,3-triazole (0.258 g, 3.74 mmol), copper (I) iodide (0.030 g, 0.16 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.044 g, 0.31 mmol), and potassium carbonate (1.60 g, 11.61 mmol) in N,N-dimethylformamide (20 mL) stirred for 24 h at 120° C. The reaction mixture was cooled to room temperature and poured into ethyl acetate (100 mL). The mixture was washed with water (3×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 1:3, ethyl acetate/petroleum ether) to afford (S)-cyclopropyl(5-hydroxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.150 g, 13%) as light yellow oil. MS (ESI, pos. ion) m/z 299 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[C:10]=1[Cl:11])[C:5](Cl)=[O:6].[N+:16](=[CH2:18])=[N-:17]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH:18]=[N+:16]=[N-:17])[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[C:10]=1[Cl:11]
Reactant: C=[N+]=[N-]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)cc(Br)c1Cl
Product: [N-]=[N+]=CC(=O)c1cc(Br)c(Cl)c(S(N)(=O)=O)c1

Procedure:
33 g of 3-bromo-4-chloro-5-sulfamoyl-benzoyl chloride were reacted in a manner analogous to the method described in Example 1 b) with diazomethane to yield the 3'-bromo-4'-chloro-5'-sulfamoyl-diazoacetophenone and worked up. M.p. 193° C (decomposition).
Reaction SMILES: [CH2:1]([C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28]C(C)(C)C)=[O:27])=[CH:16][CH:15]=2)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>>[CH2:1]([C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([OH:28])=[O:27])=[CH:16][CH:15]=2)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc2cccnc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc2cccnc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
To neat 2-propyl-1-[(2'-(t-butoxycarbonyl)-[1,1']-biphenyl-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine is added trifluoroacetic acid (1 mL/10 mg of starting material) at room temperature. After 8 h the product is isolated by first concentration at room temperature then partitioning between EtOAc and 5% aqueous NaHCO3 then concentration of the organic layer and ultimately purified by flash chromatography (80:20:1 CH2Cl2 -MeOH--NH4OH).