Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[O:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:21][CH:20]=4)=[N:16][N:15]=3)[C:11]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:10][CH:9]=2)=[CH:4][CH2:3]1.CCN(CC)CC.[C:50](Cl)(=[O:53])[CH2:51][CH3:52]>C(Cl)Cl>[C:39]([O:38][C:36]([NH:35][C:11]1[C:12]([C:14]2[O:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:23][CH:24]=3)=[N:16][N:15]=2)=[N:13][C:8]([C:5]2[CH2:6][CH2:7][CH:2]([NH:1][C:50](=[O:53])[CH2:51][CH3:52])[CH2:3][CH:4]=2)=[CH:9][N:10]=1)=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCC(=O)Cl
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(N)CC4)cnc3NC(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC1CC=C(c2cnc(NC(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)o3)n2)CC1
Yield: 110.5 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[6-(4-aminocyclohexen-1-yl)-3-(tert-butoxycarbonylamino)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (20 mg, 0.03 mmol) in anhydrous DCM (200 μL) was added Et3N (5 mg, 7 μL, 0.05 mmol) and the reaction mixture was cooled in an ice water bath. A solution of propanoyl chloride (3.843 mg, 3.625 μL, 0.04154 mmol) in DCM (0.1 mL) was added dropwise to the above reaction mixture. The reaction mixture was diluted with DCM and washed once with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using 10% MeOH in EtOAc to yield tert-butyl N-[[4-[5-[3-(tert-butoxycarbonylamino)-6-[4-(propanoylamino)cyclohexen-1-yl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (21 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Cl:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:13](=[O:14])[CH2:12][CH2:11][Cl:10])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: O=C(CCCl)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,4-Dichloroaniline (25.5 grams), β-chloropropionyl chloride (20 grams) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is washed with dilute aqueous sodium bicarbonate, with dilute hydrochloric acid and with water. The washed mixture is then dried over anhydrous magnesium sulfate, filtered and stripped of benzene under reduced pressure to yield the desired product N-(3,4-dichlorophenyl)-β-chloropropionamide as the residue.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>N1C=CC=CC=1>[C:23]([O:20][CH2:19][N:15]1[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]2[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:4](=[O:22])[CH2:5]2)[CH2:17][C:16]1=[O:18])(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCN1C(=O)CN(CCN2CC(=O)N(COC(=O)C(C)(C)C)C(=O)C2)CC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
To a mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (0.94 g, 3.0 m mol) and pyridine (25 ml), pivaloyl chloride (0.78 g, 6.5 m mol) dissolved in pyridine (5 ml) was added gradually at 0° C., and then the mixture was stirred for 18 hours at room temperature. The solvent was removed from the reaction mixture under reduced pressure, and the residue was extracted with ethyl acetate (200 ml). The extract solution was washed with a saturated sodium bicarbonate aqueous solution and successively with water and was dried over magnesium sulfate. The residue obtained by removing the solvent from the extract under reduced pressure was purified by silica gel column chromatography (ethyl acetate, Rf value=0.8) to give the titled compound (0.75 g; yield 52%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)=[CH:27][CH:26]=3)[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)=[CH:29][CH:30]=3)[CH:16]=2)=[CH:13][CH:14]=1
Reactant: Nc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2-c1ccc(OCCn2ccnc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(O)cc1)cn2-c1ccc(OCCn2ccnc2)cc1

Procedure:
0.5 g of 5-(4-benzyloxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine is hydrogenated for 22 h in a hydrogen atmosphere at normal pressure and about 50° C. in 15 ml of THF in the presence of 0.1 g of 5% palladium/carbon. After filtration through Celite and crystallization by addition of ether, 5-(4-hydroxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 210°-212° C. is obtained.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([NH:18][CH3:19])=[O:17])=[N:14][CH:15]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([NH:18][CH3:19])=[O:17])=[N:14][CH:15]=1
Reactant: CNC(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(C4=NC[C@H](C)O4)[nH]3)c2)cn1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(-c3ccc(C4=NC[C@H](C)O4)[nH]3)c2)cn1
Reaction time: 1 h
Yield: 68.9 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-N-methylpyridine-2-carboxamide (176 mg, 0.38 mmol) synthesized in Example (123b) was dissolved in methylene chloride (5 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 0.50 mL, 0.50 mmol) was added at −78° C. Subsequently, the temperature was brought back to room temperature, followed by stirring for 1 hour. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with methylene chloride. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (118 mg, yield 69%) as a white solid.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:13][N:14]([CH:16]=[O:17])C>N1C=CC=CC=1>[CH3:13][NH:14][C:16]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:17]
Reactant: CN(C)C=O
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Solvent: c1ccncc1
Product: CNC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 60 °C
Yield: 85 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3-adamantanediol and one drop of pyridine were dissolved in 10 ml of DMF. To the mixture, 10 mmole of methylisocyanato was added dropwise with stirring. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3-adamantanediol was 99% and 1-(N-methylcarbamoyloxy)-3-adamantanol (yield 85%) was formed.
Reaction SMILES: C(=[C:4]([OH:22])[C@H:5]1[O:9][C@@H:8]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[C@H:7]([OH:20])[C@@H:6]1[OH:21])(C)C.[OH-:23].[K+].[Mn]([O-])(=O)(=O)=O.[K+]>O>[C@@H:8]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:5]([CH:4]([C:5]([O:9][CH2:8][CH3:7])=[O:23])[OH:22])[C@@H:6]([OH:21])[C@H:7]1[OH:20]
Reactant: [OH-]
Reactant: CC(C)=C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
11.7 g. of Isopropylidene adenosine were dissolved in 3.5 liters of water and the pH was adjusted to 12.2 by the addition of 5.85 g. of potassium hydroxide. 23.7 g. of potassium permanganate in 825 ml. of water were added dropwise with stirring over a period of 33/4 hours. The solution was then allowed to sit at room temperature overnight. The excess permanganate was destroyed by the dropwise addition of 30% hydrogen peroxide and the reaction mixture was filtered through a layer of NH3 -washed celite. The yellow filtrate was concentrated in vacuo at 35°-45° to 600 ml. and the acid precipitated in an ice bath by adjusting the pH to 4.5 by the dropwise addition of 1:3 HCl. The white precipitate was washed with dilute (1:1000) acetic acid and dried at 135°C. to yield 7.93 g. of the crude isopropylidene product, m.p. 265-8°. The material was taken up in 100 ml. of dilute NH3, and recrystallized by adjusting the pH to 4.5 by the addition of 1:3 acetic acid to yield 7.7 g. of 2',3'-isopropylidene adenosine-5'-carboxylic acid, m.p. 272-3°.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([S:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:25]=3)[NH:20][N:19]=2)(=[O:17])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.O>CN(C=O)C>[N:1]([CH2:29][CH2:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[S:15]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)(=[O:16])=[O:17])=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
Sodium azide (0.79 g, 12 mmol) was added to a solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (2.06 g, 3.94 mmol) in DMF (20 mL). The reaction mixture was stirred at 80° C. for 12 hours in a sealed tube. After cooling to ambient temperature, it was poured into excess water and extracted with ethyl acetate. The organic phase was washed with 10% ammonium chloride/water solution, water and brine. It was dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 72° C. in vacuo for 40 minutes to yield 5-(2-azido-ethoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as a amber gum/foam (1.34 g, 86.5%). Mass spectrum (−EI, [M−H]−) m/z 392. 1HNMR (400 MHz, DMSO-d6): δ8.78 (d, 1H, J=8.70 Hz), 8.56 (dd, 1H, J=7.43 Hz and 1.16 Hz), 8.29 (d, 1H, J=8.35 Hz), 8.06 (d, 1H, J=7.66 Hz), 7.72-7.76 (m, 1H), 7.57-7.67 (m, 3H), 7.31 (d, 1H, J=2.32 Hz), 7.12 (dd, 1H, J=9.16 Hz and 2.32 Hz), 4.22-4.24 (m, 2H), 3.67-3.69 ppm (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=[O:4].FC(F)(F)C([O-])=O.[C:15]([C:18]1[CH:19]=[C:20]([CH:45]=[CH:46][CH:47]=1)[CH2:21][N:22]1[C:30]2[C:25](=[C:26]([O:31][CH3:32])[CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:33]([NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][N+:41](C)=[CH:40][CH:39]=1)=[O:34])(=[NH:17])[NH2:16].Cl.NO.C(N(CC)CC)C>C(O)C>[N:41]1[CH:42]=[CH:43][C:38]([CH2:37][CH2:36][NH:35][C:33]([C:23]2[N:22]([CH2:21][C:20]3[CH:45]=[CH:46][CH:47]=[C:18]([C:15](=[NH:17])[NH:16][OH:4])[CH:19]=3)[C:30]3[C:25]([CH:24]=2)=[C:26]([O:31][CH3:32])[CH:27]=[CH:28][CH:29]=3)=[O:34])=[CH:39][CH:40]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc2c1cc(C(=O)NCCc1cc[n+](C)cc1)n2Cc1cccc(C(=N)N)c1
Agent: Cl
Agent: NO
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cccc2c1cc(C(=O)NCCc1ccncc1)n2Cc1cccc(C(=N)NO)c1
Yield: 54 %

Procedure:
The starting material 1-(3-cyano-benzyl)-4-methoxy-1H-indole-2-carboxylic acid 2-(4-pyridyl)-ethyl amide (example 41) was dissolved in ethanol, 2.4 equivalents of hydroxylamine hydrochloride and 2.4 equivalents of triethylamine were added and the mixture was refluxed for 6.5 h. The precipitate was filtered off to give 54% of the desired product. M.p. 220-222° C. MS: 444.3 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C[Si](C)(C)N[Si](C)(C)C>>[CH2:7]([C:8]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: C1CNCCN1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: O=C(Cc1ccccc1)N1CCNCC1
Yield: 82.2 %

Procedure:
The procedures of Example 1 were followed except that phenyl acetic acid (3.4 grams, 25 mmole), piperazine (4.3 grams, 50 mmole) and 1,1,1,3,3,3-hexamethyldisilazane (4.0 grams, 25 mmole) were reacted for 5 hours under 110° C. After extraction purification, 4.2 grams of Compound 10 was obtained. Yield: 82%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]3[CH:14]=[CH:13][N:12](COCC[Si](C)(C)C)[C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:2]1.[CH2:23]([S:25]([N:28]1[CH2:31][C:30](=[CH:32][C:33]#[N:34])[CH2:29]1)(=[O:27])=[O:26])[CH3:24].N12CCCN=C1CCCCC2>C(#N)C>[CH2:23]([S:25]([N:28]1[CH2:29][C:30]([CH2:32][C:33]#[N:34])([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[C:7]4[CH:14]=[CH:13][NH:12][C:8]=4[N:9]=[CH:10][N:11]=3)=[CH:2]2)[CH2:31]1)(=[O:26])=[O:27])[CH3:24]
Reactant: CCS(=O)(=O)N1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cc[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCS(=O)(=O)N1CC(CC#N)(n2ccc(-c3ncnc4[nH]ccc34)c2)C1
Reaction time: 4 h

Procedure:
A solution of 4-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.100 g, 0.318 mmol) and [1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile (0.118 g, 0.636 mmol, prepared as in Example 68) in acetonitrile (1 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (24 μL, 0.16 mmol). The mixture was stirred for 4 hours. The solvent was evaporated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution, then extracted with two further portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted and concentrated. The crude product was stirred with 25% TFA/DCM (8 mL) overnight. The solvents were evaporated. The product was then stirred with ethylenediamine (0.3 mL) in methanol (5 mL). Preparative HPLC-MS (eluting with a gradient of methanol and water containing 0.15% NH4OH) was used to purify the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[CH:11]=[N:10]1.[C:16]([Cu])#[N:17]>CN1C(=O)CCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[C:3]([N:9]2[C:13](=[O:14])[N:12]([CH3:15])[CH:11]=[N:10]2)[CH:4]=1
Reactant: N#C[Cu]
Reactant: Cn1cnn(-c2cc(F)ccc2Br)c1=O
Solvent: CN1CCCC1=O
Product: Cn1cnn(-c2cc(F)ccc2C#N)c1=O
Yield: 78.5 %

Procedure:
A mixture of 1-(2-bromo-5-fluorophenyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (0.484 g, 1.78 mmol), CuCN (0.319 g, 3.56 mmol), and 8 mL of NMP was subjected to microwave irradiation at 120° C. for 3 h. The brown mixture was filtered over Celite® and washed with DMF. This solution was treated with 10% aqueous NH4OH (28-30% solution) and extracted with EtOAc. The combined organic fractions were successively washed with 10% aqueous NH4OH (28-30% solution), saturated aqueous NH4Cl, water, brine and dried over Na2SO4. The resulting mixture was concentrated in vacuo and the residue was purified with a Biotage column chromatography system on silica gel with hexanes:ethyl acetate (3:7 to 2:8) gradient as the eluent to afford the title compound as a pink solid (0.305 g, 79% yield): 1H NMR (400 MHz, CDCl3) δ 7.76 (1H, dd, J=8.8, 5.8 Hz), 7.72 (1H, dd, J=9.6, 2.5 Hz), 7.64 (1H, s), 7.10 (1H, ddd, J=8.7, 7.4, 2.7 Hz), 3.40 (3H, s); LCMS (+ESI, M+H+) m/z 219.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[N:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]2)=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(N)cn2)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Yield: 38.8 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1.0 mmol) was reacted with tert-butyl 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate (419 mg, 1.5 mmol) to afford the desired product (215 mg, 39%) as a yellow solid. ESI MS m/z 553 [C26H29BrN6O3+H]+
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([O:13]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:3][CH2:2]1.[NH:23]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:24]1.O>ClCCl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:26][CH2:27][N:23]([C:11]([N:4]3[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[O:1][CH2:2][CH2:3]3)=[O:13])[CH2:24]2)[CH:29]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCOc2ccccc21
Reactant: c1cncc(C2CCNC2)c1
Solvent: ClCCl
Solvent: O
Product: O=C(N1CCC(c2cccnc2)C1)N1CCOc2ccccc21
Temperature: 100 °C
Yield: 92.2 %

Procedure:
0.2 g of 4-nitrophenyl 2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate, 0.1 g of 3-(pyrrolidin-3-yl)pyridine and 1.5 ml of water are introduced into a 10 ml glass tube. The tube is sealed and then heated at 100° C. under microwave irradiation for 35 minutes. Dichloromethane is added. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane/methanol gradient from 1/0 to 95/5. 0.19 g of 4-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazine is obtained.
Reaction SMILES: [C@H:1]12[N:8]([C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.Cl[C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:31][C:26]1[CH:27]=[C:28]([CH3:30])[N:29]=[C:24]([N:3]2[CH2:4][CH2:5][C@H:6]3[C@H:1]([N:8]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[O:21][N:20]=[C:19]([CH3:22])[N:18]=4)=[O:10])[CH2:7]3)[CH2:2]2)[N:25]=1
Reactant: Cc1noc(-c2ccccc2C(=O)N2C[C@H]3CCNC[C@H]32)n1
Reactant: Cc1cc(C)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(C)nc(N2CC[C@@H]3CN(C(=O)c4ccccc4-c4nc(C)no4)[C@@H]3C2)n1
Temperature: 200 °C
Yield: 59.6 %

Procedure:
A mixture of Intermediate 12 (50 mg, 0.17 mmol), 2-chloro-4,6-dimethylpyrimidine (24 mg, 0.17 mmol) and DIPEA (0.87 mL, 0.5 mmol) in ACN (1 mL) was heated in the microwave at 200° C. for 90 min. The mixture was concentrated in vacuo and was purified on a Prep Agilent system with a XBridge C18 OBD 50×100 mm column eluting with 5 to 99% 0.05% NH4OH in H2O/ACN over 17 min to afford the desired product as a colorless foam (41 mg, 60%). MS (ESI) mass calculated for C22H24N6O2, 404.20; m/z found, 405.2. 1H NMR (500 MHz, CDCl3): 8.12-8.03 (m, 1H), 7.59-7.49 (m, 2H), 7.41-7.36 (m, 1H), 6.31-6.26 (m, 1H), 4.41-4.23 (m, 3H), 4.11-4.05 (m, 1H), 4.05-3.78 (m, 2H), 3.68-3.64 (m, 0H), 3.05-2.83 (m, 2H), 2.46-2.40 (m, 3H), 2.34-2.24 (m, 6H), 2.15-2.04 (m, 1H), 2.00-1.86 (m, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:35])[C@H:5]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:6][C:7](=[O:26])[C@H:8]([CH2:24][OH:25])[NH:9][C:10](=[O:23])[C@H:11]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[NH2:12].[CH2:36]([O:43][C:44]([NH:46][C@H:47]([C:53](O)=[O:54])[CH2:48][CH2:49][C:50](=[O:52])[NH2:51])=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH3:2][O:3][C:4](=[O:35])[C@H:5]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)[NH:6][C:7](=[O:26])[C@H:8]([CH2:24][OH:25])[NH:9][C:10](=[O:23])[C@H:11]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[NH:12][C:53](=[O:54])[C@H:47]([CH2:48][CH2:49][C:50](=[O:52])[NH2:51])[NH:46][C:44]([O:43][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:45]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A mixture of the product from (c) above, 1.4 g. of Nα -benzyloxycarbonyl-L-glutamine, 670 mg. of 1-hydroxybenztriazole and 50 ml. of dimethylformamide is stirred and cooled to -10° C., and 0.7 ml. of triethylamine is added. After 15 minutes, it is treated with 1.2 g. of dicyclohexylcarbodiimide and stirred a few hours at -10° C., then at room temperature for two days and finally let stand an additional three days. The solution is filtered and the filtrate evaporated at 50° C. under reduced pressure. The residue is precipitated from methanol with water and then crystallized from methanol three times; m.p. 245°-248° C.; [α]D25 -4.4° (c 1, DMF); ultraviolet in methanol, λmax 290 E11 75.7; λmax 280 E11 100.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:7][N:6]1[C:2]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:25])=[CH:3][N:4]=[CH:5]1
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cn1cncc1Br
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-1-methyl-1H-imidazole (3.22 g, 19.982 mmol) in DCM (15 mL) was added ethyl magnesium bromide (6.66 mL, 19.982 mmol; 3.0 M in diethyl ether) dropwise over a 10 minute period. The resulting orange-red solution was stirred at room temperature for 15 minutes, cooled in an ice bath to 0° C. and N-methoxy-N-methyl-4-nitrobenzamide (3.5 g, 16.652 mmol, Intermediate 15: step a) dissolved in DCM (10 mL) was added dropwise. The cold bath was removed and the solid suspension stirred at room temperature for 48 hours. Water was added followed by 6 M aqueous HCl to a neutral pH (pH=6-7). The aqueous mixture was extracted with DCM, dried over Na2SO4, filtered and concentrated. Et2O was added and the mixture sonicated. The precipitate was collected by filtration and dried to provide the title compound as a tan solid.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:12][CH:13]([F:16])[CH2:14][OH:15]>>[F:12][CH:13]([F:16])[CH2:14][O:15][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OCC(F)F
Reactant: Cc1cc(F)ncc1C(=O)O
Product: Cc1cc(OCC(F)F)ncc1C(=O)O
Yield: 87 %

Procedure:
The title compound is prepared in 87% yield (849 mg, a pale yellow solid) from 6-fluoro-4-methylnicotinic acid (700 mg, 4.51 mmol) and 2,2-difluoroethanol (555 mg, 6.77 mmol) instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.