Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[N:3]=[N:2]1.C[O-].[Na+].[O-]S(C(F)(F)F)(=O)=O.F[N+:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:2]1[N:3]=[C:4]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[CH:5]=[N:1]1
Reactant: F[n+]1ccccc1
Reactant: N#Cc1cccc(-c2c[nH]nn2)c1
Agent: C[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: N#Cc1cccc(-c2cnn(-c3ccccn3)n2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-(1H-1,2,3-Triazol-4-yl)benzonitrile (1.82 g, 10.69 mmol) was suspended in anhydrous MeOH (25 mL) under argon at ambient temperature. To this was added NaOMe (21.4 mL of 0.5 M solution in MeOH, 10.69 mmol), and the resulting reaction mixture was cooled to −78° C. A solution of N-fluoropyridinium triflate (2.95 g, 8.91 mmol) in anhydrous MeOH (5 mL) was then added dropwise via syringe. The reaction mixture was stirred at −78° C. for 30 min, then warmed to ambient temperature and stirred for an additional 18 h. The reaction mixture was partitioned between EtOAc (300 mL) and 1N aqueous NaOH (100 mL). The EtOAc layer was washed with additional 1N aqueous NaOH (6×50 mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude material was then chromatographed on silica gel eluting with hexanes:EtOAc (2:1) to afford EXAMPLE 5 3-(2-pyridin-2-yl-2H-1,2,3-triazol-4-yl)benzonitrile as a tan solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7]C=O)[CH:4]=[C:3]1[C:10]([Cl:12])=[O:11].C(N(C(C)C)CC)(C)C.[NH2:22][CH2:23][CH2:24][C:25]#[N:26].Cl>O1CCCC1.CO>[ClH:12].[CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[C:3]1[C:10]([NH:26][CH2:25][CH2:24][C:23]#[N:22])=[O:11]
Reactant: N#CCCN
Reactant: Cn1cc(NC=O)cc1C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(N)cc1C(=O)NCCC#N
Reaction time: 1 h

Procedure:
To 1-methyl-4-formylamino-2-pyrrolecarbonyl chloride (II) (16.0 mmol) dissolved in 80 mL of tetrahydrofuran are added diisopropylethylamine (18 mmol) and 3-aminopropionitrile (18 mmol) with continuous stirring for 1 hour. The reaction mixture is evaporated under vacuum and the resulting crude product is washed with water several times and dried to yield crude 3-(1-methyl-4-formylamino-2-carboxamido)propionitrile. This is N-deformylated by treatment with 30 mL of a solution of hydrogen chloride in methanol for 1 hour, the methanol is evaporated and the resulting crude product is crystallized from isopropanol/ethyl acetate to furnish 3-(1-methyl-4-amino-2-pyrrolecarboxamido)propionitrile hydrochloride, whose analytical data are in agreement with the above mentioned literature. This compound is acylated with 1-methyl-4-formylamino-2-pyrrolecarbonyl chloride (II) as above and subjected to the Pinner reaction to yield the hydrochloride of 3-(1-methyl-4-(1-methyl-4-aminopyrrole-2-aminocarbonyl)pyrrole-2-carboxamido)propionamidine (Ib, n=0)) from which Distamycin is obtained as described in Example 4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:18][C@H:19]([C:21]([OH:23])=O)[CH3:20])[CH2:7][S:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[C:24]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)([CH3:27])([CH3:26])[CH3:25].CCOC(OC(OCC)=O)=O>C(N(CC)CC)C>[C:24]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:21](=[O:23])[C@H:19]([CH3:20])[NH:18][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][S:8][CH2:9][CH2:10][S:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CCOC(=O)[C@H](CSCCSc1ccccc1)N[C@@H](C)C(=O)O
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CSCCSc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
Using 3 g of s-isomer of N-[(R)-l-ethoxycarbonyl-2-(2-phenylthioethylthio)ethyl]-alanine prepare in Reference Example 46, 1.58 of (S)-proline t-butyl ester, 1.67 g of DEPC and 1.3 ml of triethylamine and following the general procedure of Example 7, the β-isomer of the title compound was prepared as a colorless oil. Yield 3.41 g.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-:35].[Na+]>CC(C)=O>[CH:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:19]([N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13][N:14]4[C:5]([C:3]([OH:35])=[O:4])=[CH:6][CH:7]=[C:8]4[CH2:9]3)=[O:32])=[CH:25][CH:24]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: [OH-]
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2

Procedure:
2,2,2-Trichloro-1-[(10-cyclohexylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]bernzodiazepin-3-yl]-ethanone of Example 7 (5.83 g) was added to a mixture of acetone (100 mL) and 2.5 N sodium hydroxide (8.5 mL). The reaction mixture was refluxed for one hour and then evaporated to dryness. Water was added to the residue and the solution was extracted with dichloromethane. The aqueous layer was acidified with glacial acetic acid and evaporated to dryness. The residual oil crystallized to provide the title compound as a light tan solid (3.03 g), m.p. 193–194° C.
Reaction SMILES: N[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:15])[CH:3]=1.[BrH:16].N([O-])=O.[Na+].S(=O)(=O)(O)O>>[Br:16][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:15])[CH:3]=1
Reactant: Br
Reactant: COC(=O)C(C)c1cc(F)c(N)cc1F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)C(C)c1cc(F)c(Br)cc1F
Temperature: 2.5 °C
Yield: 77.6 %

Procedure:
To a solution of compound (29a) (3.0 g, 13.9 mmol) in 40% hydrobromic acid (8.0 mL, 54.4 mmol), an aqueous solution (17 mL) of sodium nitrite (1.1 g, 15.7 mmol) was added dropwise under stirring at 0 to 5° C. The solution was allowed to reach room temperature. To the solution, CuBr (1.1 g, 11.2 mmol) and 96% sulfuric acid (0.1 mL) were added, and the mixture was refluxed under stirring for 1 hour. After cooling and subsequent extraction with ethyl acetate, the obtained residue was dissolved in methanol (50 mL). To the obtained mixture, a catalytic amount of concentrated hydrochloric acid (0.1 mL) was added and refluxed for 3 hours. After cooling, the solvent was distilled off and the obtained product was treated with ether (50 mL). The organic layer was dried (over sodium sulfate) and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution to give 3.01 g (73%) of compound (30a) as pale yellow liquid matter.
Reaction SMILES: FC1C=C(C[C@H](N[C:25](=[O:40])[CH2:26][N:27]2[C:35]3[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=3[C:29]([C:36]([F:39])([F:38])[F:37])=[N:28]2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH2:64])[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1.FC(F)(F)C1C2CCCCC=2N(CC(O)=O)N=1>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH:64][C:25](=[O:40])[CH2:26][N:27]2[C:35]3[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=3[C:29]([C:36]([F:38])([F:37])[F:39])=[N:28]2)[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1
Reactant: NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1
Reactant: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Agent: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 33G and 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid. 1H NMR (400 MHz, DMSO) δ 9.07 (d, J=8.1 Hz, 1H), 8.51 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 6.98 (t, J=9.6 Hz, 1H), 6.87 (d, J=7.6 Hz, 2H), 5.41-5.30 (m, 1H), 4.80-4.64 (m, 2H), 3.35 (s, 2H), 3.25-3.12 (m, 1H), 3.07 (dd, J=13.4, 6.8 Hz, 1H), 2.33 (s, 1H), 2.23 (s, 1H), 1.63 (s, 4H). MS (m/z) 565.1 [M+H]+.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([OH:49])=[C:44]([CH2:50][CH3:51])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:52]=[CH:53][CH:54]=[CH:55][C:6]=2[NH:5]1.Cl>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([OH:49])=[C:44]([CH2:50][CH3:51])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:52]=[CH:53][CH:54]=[CH:55][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(CC)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.7 mg (0.15 mmol) LiOH in 3 mL water was added to a solution of 73 mg (0.1 0 mmol) (R)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-1-(3-ethyl-4-hydroxy-5-methyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 11.2) in 5 mL THF and the reaction mixture was stirred for 2 h at RT. The THF was eliminated i.vac., 1 M HCl was added until an acidic reaction was obtained and the mixture was evaporated down again i.vac. The residue was taken up in DMF and purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: C(O[NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[SH:13])(C)(C)C.[CH:14](O)=O>>[S:13]1[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N:6]=[CH:14]1
Reactant: CC(C)(C)ONc1cnccc1S
Reactant: O=CO
Product: c1cc2scnc2cn1

Procedure:
In formic acid (60 ml) was dissolved 3-(tert-butoxyamino)-4-mercaptopyridine (9.20 g), followed by heating under reflux for 4 hours. After the reaction mixture was concentrated under reduced pressure and a 5N aqueous solution (100 ml) of potassium hydroxide was added to the residue, the resulting mixture was extracted with ether. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. Diethyl ether was added to the residue and the solid so precipitated was collected by filtration, whereby the title compound was obtained as a colorless solid (3.97 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][NH:31][C:30](=[O:34])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][N:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=2)[C:30](=[O:34])[CH:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1cc(OCc2ccccc2)ccn1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
1-Bromomethyl-4-trifluoromethoxybenzene (3.32 g, 13.04 mmol) and potassium carbonate (3.51 g, 25.46 mmol) were added to a mixture of 4-benzyloxy-1H-pyridin-2-one (2.5 g, 12.42 mmol) in acetonitrile (10 ml). The reaction mixture was heated at reflux temperature for 24 hours. After cooling to room temperature, it was filtered through diatomaceous earth, the solid residues were washed with methanol and the combined organic extracts were evaporated in vacuo. The crude residue thus obtained was precipitated with DIPE to yield intermediate D14 (4.5 g, 96%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:12][C@H:13]1[CH2:17][N:16](C(OC(C)(C)C)=O)[C@H:15]([C:25]([O:27][CH3:28])=[O:26])[CH2:14]1.[ClH:29]>O1CCOCC1>[ClH:29].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:12][C@H:13]1[CH2:17][NH:16][C@H:15]([C:25]([O:27][CH3:28])=[O:26])[CH2:14]1
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2ncnc3ccc(Br)cc23)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@@H](Oc2ncnc3ccc(Br)cc23)CN1

Procedure:
To a solution of 1-tert-butyl 2-methyl (2S,4R)-4-[(6-bromoquinazolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate (3.46 g, 6.65 mmol) in dioxane (80 mL) at 0° C. was introduced anhydrous HCl (g) over 30 min. The reaction was complete by HPLC/MS. The reaction mixture was concentrated and the resulting solids were azeotroped with diethyl ether (50 mL) to give the title compound (3.0 g). LRMS (M+H)+=352.2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH2:60])[NH:56][C:55]=2[CH:54]=[CH:53][C:52]=1[O:61][CH3:62])=[O:50]>CN(C=O)C.[Cl-].[Na+].O>[CH3:47][O:48][C:49]([C:51]1[C:59]2[NH:58][C:57]([NH:60][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:56][C:55]=2[CH:54]=[CH:53][C:52]=1[O:61][CH3:62])=[O:50]
Reactant: COC(=O)c1c(OC)ccc2[nH]c(N)nc12
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(OC)ccc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Yield: 28.3 %

Procedure:
400 mg (2.0 mmol) of isoquinoline-3-carboxylic acid and 800 mg (2.1 mmol) of HBTU were dissolved in 2.0 mL of DMF and 1.3 mL of DIEA and treated with 300 mg (1.5 mmol) of 2-amino-5-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester as described in general procedure A. Upon completion, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc, and dried under vacuum to produce 160 mg (28%) of 2-[(isoquinoline-3-carbonyl)-amino]-5-methoxy-3H-benzoimidazole-4-carboxylic acid methyl ester. LCMS: 377 (M+1)+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Li]CCCC.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([F:24])=[CH:19][N:18]=1>C1COCC1.[Br-].[Zn+2].[Br-].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>[Cl:16][C:17]1[N:22]=[C:21]([C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[C:20]([F:24])=[CH:19][N:18]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Brc1cnc2ccccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1cnc(Cl)nc1-c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-imidazo[1,2-a]pyridine (1 g, 5.1 mmol) in dry THF (25 mL) under N2 at −78° C. was added n-BuLi (1.6 M in hexanes, 3.8 mL, 6.12 mmol) and the reaction mixture was stirred at that temperature for 1 hour. Then freshly dried zinc bromide (1.7 g, 7.65 mmol) in dry THF (15 mL) was added slowly and the reaction mixture was slowly warmed up to room temperature and 2,4-dichloro-5-fluoro-pyrimidine (848 mg, 5.1 mmol) and Pd(PPh3)4 (294 mg, 0.26 mmol) was added. After 16 hours at 75° C., the reaction mixture was then concentrated and directly purified by purified by flash chromatography (SiO2, 95:5:0.5/EtOAc:MeOH:TEA) to give 3-(2-chloro-5-fluoro-pyrimidin-4-yl)-imidazo[1,2-a]pyridine (Int-1) MS found for C11H16ClN4F as (M+H)+ 249.51. 1H NMR (400 MHz, CDCl3): δ 10.00 (d, J=6.8 Hz, 1H); 8.62 (s, 1H); 8.48 (d, J=3.2 Hz, 1H); 7.93 (d, J=9.2 Hz, 1H); 7.60 (t, J=7.2 Hz, 1H); 7.21 (t, J=7.2 Hz, 1H) To a solution of Int-1 (71 mg, 0.286 mmol), 4-amino-benzoic acid (47 mg, 0.344 mmol) in dioxane (3 mL), p-TSA (54 mg, 0.286 mmol) was added and heated in pressure vessel at 130° C. for 12 hours. Additional 4-amino-benzoic acid (23 mg, 0.172 mmol) and p-TSA (27 mg, 0.143 mmol) was added and heated at 130° C. After 12 hours, the reaction mixture was cooled to room temperature and diluted with dioxane gave 4-(5-Fluoro-4-imidazo[1,2-a]pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid (Int-2) as a tan solid which was filtered and dried. MS found for C18H12FN5O2 as (M+H)+ 350.30. To Int-2 (100 mg, 0.29 mmol) in DMF (8 mL), was added HATU (163 mg, 0.43 mmol), O-(tert-butyldimethylsilyl)hydroxylamine (84 mg, 0.57 mmol) and DIPEA (0.15 mL, 0.86 mmol) and stirred at room temperature. After 16 hours, the reaction mixture was diluted with and 1N HCl (3 mL and stirred at room temperature for 12 hours. The reaction mixture was then directly purified by preparative HPLC affording the title compound as tan solid, after lyophilization. MS found for C18H13FN6O2 as (M+H)+ 365.09. 1H NMR (400 MHz, dmso-d6): δ 11.03 (brs, 1H); 10.16 (d, J=7.2 Hz, 1H); 10.05 (s, 1H); 8.64 (d, J=3.6 Hz, 1H); 8.46 (d, J=4.0 Hz, 1H); 7.87-7.74 (m, 5H); 7.62 (t, J=7.6 Hz, 1H); 7.24 (t, J=6.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([OH:34])([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:31]2([CH3:32])[C@H:16]([C@H:17]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C:20]([CH2:21][C@H:22]([CH2:24][C@@H:25]2[OH:33])[OH:23])=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)[CH3:12])[C:4]([F:7])([F:6])[F:5].[C:37]([O:40]C(=O)C)(=[O:39])[CH3:38]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:37]([OH:40])(=[O:39])[CH3:38].[C:37]([OH:40])(=[O:39])[CH3:38].[C:37]([OH:40])(=[O:39])[CH3:38].[F:1][C:2]([F:35])([F:36])[C:3]([OH:34])([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:31]2([CH3:32])[C@H:16]([C@H:17]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C:20]([CH2:21][C@H:22]([CH2:24][C@@H:25]2[OH:33])[OH:23])=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)[CH3:12])[C:4]([F:5])([F:7])[F:6]
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: C[C@H](CCCC(O)(C(F)(F)F)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: CC(=O)O

Procedure:
A solution of 216 mg of the triol (5) and catalytic amounts (ca 20 mg) of 4-dimethylaminopyridine in acetic anhydride (1.5 ml) and pyridine (3 ml) was stirred for 20 hr at room temperature. After the reaction mixture was concentrated in vacuo, the residue was chromatographed on silica gel (n-hexane-AcOEt, 10:1) to give 263 mg (98%) of the triacetate (6), which was dried at 70° C. (5 mm Hg) for 20 hr. 6: glass; MS m/e 592(M+ -AcOH), 532(M+ -2AcOH), 517, 413, 253; NMR(CDCl3)δ0.66(s, 18-H3, 0.94(d, J=6 Hz, 21-H), 1.10(s, 19-H3)2.03, 2.06 and 2.16(9H, each s, acetyl), 4.98(1H, m, 3-H), 5.06(1H, m, 1-H), 5.53(1H, m, 6-H).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([Cl:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1=O>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([Cl:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(Cl)cc1F
Reactant: NC1CNC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(Cl)cc1F
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3-chloro-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidone, and the mixture was stirred at 90° C. for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 95 mg of the title compound as a colorless powder.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([C:21]2[N:29]=[C:28]([CH3:30])[N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:9]([NH:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[N:10][CH:11]=1.Cl>O1CCCC1>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([NH:12][C:9]2[C:8]([C:21]3[N:29]=[C:28]([CH3:30])[N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][N:25]4[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][N:10]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(Nc2ncc(C3OCCO3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.5 %

Procedure:
5-(1,3-Dioxolan-2-yl)-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (3.042 g, 6.21 mmol) was dissolved in tetrahydrofuran (50 mL) and then 2.0 M hydrochloric acid (15.5 mL, 31.0 mmol) was added via syringe, followed by a THF rinse (1.5 mL). The reaction was stirred at room temperature for 20 minutes, diluted with water (20 mL), and filtered. The solid was washed with water, collected, and dried under high vacuum over the weekend to afford 6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (1.7 g, 61% yield). MS (ESI pos. ion) m/z 446 (M+H)+. 1H NMR (CDCl3, 400 MHz) δ 13.33 (s, 1H), 10.29 (d, J=2.15 Hz, 1H), 10.00 (s, 1H), 8.78 (d, J=1.96 Hz, 1H), 8.48 (d, J=2.74 Hz, 1H), 8.35 (s, 1H), 8.25 (dd, J=8.8 Hz, 2.74 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.89 (dd, J=10.47 Hz, 2.05 Hz, 1H), 4.23 (d, J=11.74 Hz, 1H), 3.98 (s, 3H), 3.88-3.82 (m, 1H), 2.93 (s, 3H), 2.23-2.03 (m, 3H), 1.90-1.65 (m, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20]C)[CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][NH2:7])[CH3:2].CNCC[OH:26]>>[NH2:7][CH2:6][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][N:3]([CH3:20])[CH2:1][CH2:2][OH:26]
Reactant: CNCCO
Reactant: CCN(CC)CC(CN)(c1ccccc1)c1ccccc1
Product: CN(CCO)CC(CN)(c1ccccc1)c1ccccc1

Procedure:
The title material was prepared as described for the synthesis of N1,N1-diethyl-2,2-diphenylpropane-1,3-diamine (Example Q) in using 2-(methylamino)ethanol. LC/MS (M+H)+: 285. HPLC ret. time (Condition B): 1.405 min.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([CH:23]4[CH2:25][CH2:24]4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH2:6]1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([CH:23]4[CH2:25][CH2:24]4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH2:6]1)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCN(S(C)(=O)=O)C2)c2nc(C3CC3)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCCC(NC(=O)c2c[nH]c3ncc(C4CC4)nc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
In a 10 mL round-bottomed flask, 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-piperidin-3-yl)-amide (173 mg, 0.35 mmol) was dissolved in CH2Cl2 (1.4 mL). Trifluoroacetic acid (1.1 mL) was added and the light yellow reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was taken up in toluene (3 mL), concentrated and then dried under high vacuum. The residue was dissolved in CH2Cl2 (1.4 mL) and ethylenediamine (1.4 mL) was added. The reaction mixture was stirred at room temperature for 2 h then H2O and EtOAc were added. The resultant suspension was filtered, rinsing with H2O and EtOAc and dried under high vacuum to afford 103 mg (81%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-piperidin-3-yl)-amide as an off-white solid. MS: (M+H)+=364; mp=284.0-287.0.