Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:35]([C:37]1[CH:38]=[CH:39][C:40]([CH2:43][CH2:44]O)=[N:41][CH:42]=1)[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[N:32]=[CH:31][C:30]([O:33][CH2:44][CH2:43][C:40]3[CH:39]=[CH:38][C:37]([CH2:35][CH3:36])=[CH:42][N:41]=3)=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ncc(O)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCc1ccc(CCO)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(C)n(-c2ncc(OCCc3ccc(CC)cn3)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
4′-{[4-butyl-1-(5-hydroxypyrimidin-2-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (50 mg, 0.111 mmol), 2-(5-ethylpyridin-2-yl)ethanol (16.8 mg, 0.111 mmol) and triphenylphosphine (44 mg, 0.167 mmol) were dried for 3 hrs in vacuo, purged with argon, added tetrahydrofuran (1 mL) and diethyl azodicarboxylic acid (2.2 mol/L toluene solution, 76 μL, 0.167 mmol), and stirred at room temperature for 2 hrs. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (hexane/ethyl acetate) to obtain 4′-{[4-butyl-1-{5-[2-(5-ethylpyridin-2-yl)ethoxy]pyrimidin-2-yl}-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl]biphenyl-2-carbonitrile (49 mg, 76%).
Reaction SMILES: [F:1][C:2]([F:15])([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH:3]([F:5])[F:4].[C-:16]#[N:17].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:2]([F:15])([F:1])[CH:3]([F:4])[F:5])[CH:8]=1)[C:16]#[N:17]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC(O)c1cccc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (222 mg, 1.0 mmol) in ethyl acetate (5 mL) was added a solution of KCN (195 mg, 3.0 mmol) and NaHSO3 (312 mg, 3.0 mmol) dissolved in H2O (10 mL). The reaction was stirred at rt for 8 h. Another portion of KCN (195 mg, 3.0 mmol) and NaHSO3 (312 mg, 3.0 mmol) dissolved in H2O (10 mL) was added. It was left stirring overnight before it was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried and concentrated to give 130A as an oil. It was used for next step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 5.57 (s, 1H) 5.78-6.04 (m, 1H) 7.28 (d, J=6.15 Hz, 1H) 7.39 (s, 1H) 7.43-7.52 (m, 2H). 19F NMR (376 MHz, CDCl3) δ ppm −136.72, −88.04.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][N:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[C:30]1(=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:30]1([NH:26][CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:20][C:19]2[CH:28]=[CH:29][C:16]([CH2:15][N:7]([CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)[CH2:8][C:9]3[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=3)=[CH:17][CH:18]=2)[CH3:27])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C1CCCCC1
Reactant: CN(CCCCN)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCCCNC1CCCCC1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
The compound (110.0 mg) obtained in Example 103-7 was dissolved in anhydrous methanol (4.4 ml). Then, the solution was added with cyclohexanone (0.058 ml) and sodium cyanoborohydride (52.8 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 16.5 hours. After the reaction, the solvent was distilled off. Subsequently, the residue was added with a 1 mol/l sodium hydroxide aqueous solution (3.0 ml), followed by extraction with chloroform. The extract was dried with magnesium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (96.7 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:4](=[O:8])[O:5][CH2:6]Cl)[CH3:2].[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O-:36])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16].[Na+]>>[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O:36][CH2:6][O:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[O:8])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CCN(CCC(C)C)C(=O)OCCl
Agent: [Na+]
Product: CCN(CCC(C)C)C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 47.4 %

Procedure:
In the same manner as in step b) in Example 125, 213 mg of the title compound was prepared from 202 mg of chloromethyl N-ethyl-N-isoamylcarbamate and 328 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[O:21][CH:22](C)[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:33]O>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1([CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH2:27]1
Reactant: COC(=O)c1ccc(C=Cc2ccc(OC)c(OC(C)CCCc3ccccc3)c2)cc1
Reactant: CO
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCc2ccc(OC)c(OCCCCC3(C)C=CC=CC3)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (1.18 g, 2.74 mmol, 1.0 eq) methyl 4-[2-[4-methoxy-3-(1-methyl-4-phenylbutoxy)phenyl]ethenyl]benzoate and 0.600 g of 10% Pd/C in 30 ml methanol and 30 ml tetrahydrofuran was placed on a Parr hydrogenation apparatus and shaken under 20 psi H2 at room temperature for 1.5 hours. The reaction mixture was filtered through celite, concentrated in vacuo, and flash chromatographed on a silica gel column eluting with 20% ether-hexane to afford 1.00 g, 84%, of a clear oil. Elemental Analysis Calc'd for C28H32O4 : Calc'd: C, 77.75; H, 7.46. Found: C, 77.55; H, 7.55.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6](O)[C:7]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=3[S:10][C:8]=2[N:9]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:6]1[C:7]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=3[S:10][C:8]=2[N:9]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=1
Reactant: COCc1nc(O)c2c3c(sc2n1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COCc1nc(Cl)c2c3c(sc2n1)CCCC3
Temperature: 92.5 °C

Procedure:
A stirring suspension of 2-Methoxymethyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol (2.0 g, 0.008 mol) in POCl3 (20 ml) was heated to 90-95° C. for 4 h and progress was monitored by TLC. After completion of reaction, excess of POCl3 was distilled off to get oily mass which was poured onto ice-water solution (200 ml) and basified with saturated solution of NaHCO3 to pH ˜8. The aqueous phase was extracted well with ethyl acetate (2×250 ml). Combined organic layers were washed with brine solution (100 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to get brown colored crude compound 4-Chloro-2-methoxymethyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine which was forwarded as such for the next step reaction. Yield: (2 g, 93%); 1H NMR (400 MHz, CDCl3) δ ppm=4.60 (s, 2H), 3.37 (s, 3H), 3.00-2.99 (m, 2H), 2.88 (m, 2H), 1.85-1.83 (m, 4H); LCMS: [M+H]=269.1.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.[NH2:21][C:22]1[N:27]=[C:26](Cl)[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[N:23]=[C:24]([CH3:31])[C:25]([C:29]#[N:30])=[C:26]([NH:20][C@H:18]([C:8]2[N:7]=[C:6]3[CH:5]=[CH:4][N:3]([CH3:2])[C:11]3=[CH:10][C:9]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:19])[N:27]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccccn2)c1C#N
Temperature: 120 °C
Yield: 29 %

Procedure:
(S)-1-(1-Methyl-6-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (151 mg, 0.522 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (80 mg, 0.475 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.248 mL, 1.42 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 20-35% ACN in water. The fractions containing the desired compound were combined and concentrated in vacuo. The residue was taken up in DMF and further purified by preparative HPLC (acid mode) eluting with 1-25% ACN in water. The fractions containing the desired compound were combined, neutralized with NaHCO3, and extracted with EtOAc (200 mL). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to give the title compound (53 mg, 29%). 1H NMR (500 MHz, CD3OD) δ ppm 1.34-1.41 (m, 3 H), 2.31 (d, J=1.46 Hz, 3 H), 3.88 (d, J=1.46 Hz, 3H), 5.68-5.79 (m, 1 H), 6.67 (d, J=2.44 Hz, 1 H), 7.47 (dd, J=7.32, 4.88 Hz, 1 H), 7.58-7.61 (m, 1 H), 7.67 (d, J=7.81 Hz, 1 H), 7.86 (s, 1 H), 7.99 (t, J=7.81 Hz, 1 H), 8.68-8.73 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H20N8, 385; found 385.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:3]=1.[CH3:16][C:17]1([CH3:24])[O:21][CH:20]([CH2:22][OH:23])[CH2:19][O:18]1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH3:16][C:17]1([CH3:24])[O:21][CH:20]([CH2:22][O:23][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)[N:3]=2)[CH2:19][O:18]1
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1ccc(CSc2nsc(Cl)n2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CSc2nsc(OCC3COC(C)(C)O3)n2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
To 2 g of N,N-dimethylformamide, 0.257 g of 5-chloro-3-(4-methylbenzyl)thio-1,2,4-thiadiazole and 0.145 g of 2,2-dimethyl-1,3-dioxolane-4-methanol were dissolved, and added 48 mg of sodium hydride (60% in oil) at about 0° C., followed by stirring at about 0° C. for 30 minutes and at room temperature for 4 hours. Then, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with tert-butylmethylether. The organic layer was concentrated, and the residue obtaind was subjected to silica gel column chromatography to obtain 0.27 g of 5-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy-3-(4-methylbenzyl)thio-1,2,4-thiadiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:20]12[C:27]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:26]3[C:25](=[O:32])[O:24][C:22](=[O:23])[C:21]1=[CH:33][CH:34]=[CH:35][CH:36]=2.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:22]([C:21]1[CH:33]=[CH:34][CH:35]=[CH:36][C:20]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([NH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:32])([OH:24])=[O:23]
Reactant: O=c1oc(=O)c2ccccc2c2ccccc12
Reactant: Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (252 mg), diphenic anhydride (224 mg), triethylamine (202 mg) and catalytic amount of 4-dimethylaminopyridine in dichloromethane (15 ml) was stirred for 8 hours at ambient temperature. The mixture was evaporated in vacuo and diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate aqueous solution, brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and triturated from ethyl acetate to give 1-{4-[2-(2-carboxyphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (400 mg).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:25]=C)(=[O:5])[CH2:2][CH2:3][CH3:4].[O:27]=[O+][O-]>CO.ClCCl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:25]=[O:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1cccc2c(Nc3ccc(O)cc3C)c(C(=O)CCC)cnc12
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: CCCC(=O)c1cnc2c(C=O)cccc2c1Nc1ccc(O)cc1C
Temperature: 25 °C
Yield: 42 %

Procedure:
3-Butyryl-4-(4-hydroxy-2-methylphenylamino)-8-vinylquinoline (5.0 g, 14.4 mmol) was stirred at -60° C. in a mixture of methanol (100 ml) and dichloromethane (200 ml) and ozone bubbled through for 15 minutes. The ozone mixture was flushed out of the reaction with nitrogen. Dimethylsulphide (2.5 ml) was added and the mixture allowed to warm to room temperature. The solvent was evaporated and the residue was chromatographed (silica gel, methanol 1% in dichloromethane) to afford 3-butyryl-4-(4-hydroxy-2-methylphenylamino)quinoline-8-carbaldehyde (2.1 g, 42%) as an oil.
Reaction SMILES: [C:1]([CH:3]([Na])[C:4](=[O:6])[CH3:5])#[N:2].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17]>CN(C=O)C.[Cl-].[NH4+]>[Cl:17][C:11]1[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH:3]([C:4](=[O:6])[CH3:5])[C:1]#[N:2]
Reactant: CC(=O)C([Na])C#N
Reactant: Clc1cccc(CBr)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
To a solution of (1-cyano-2-oxopropyl)sodium (1.28 g, 12.16 mmol) in DMF (80 mL) was added 1-(bromomethyl)-2,3-dichlorobenzene (2.043 g, 8.51 mmol) dropwise over a period of 30 min at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. Then this solution was diluted with saturated aq. ammonium chloride solution. The resulting solution was extracted with ethyl acetate (80 mL×3). The combined organic layers were washed with water and brine, dried over sodium sulphate, concentrated under reduced pressure to give the crude product (2.19 g, 100%), which was used for the next step without further purification. LC/MS: MS (ES+) m/e 242 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].I[CH3:21].[H-].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:21])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(4-fluoro-3-nitro-phenyl)-benzamide (1.60 g, 6.15 mmol) in anhydrous DMF was added iodomethane (3.49 g, 24.60 mmol, 1.53 ml) under argon. 60% Sodium hydride (0.37 g, 9.23 mmol) was then added portionwise to the cooled solution (0° C.) and the reaction mixture was then stirred at room temperature for 24 h. The solution was poured slowly into water and the aqueous layer was extracted 3× with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate (4:1) to give N-(4-fluoro-3-nitro-phenyl)-N-methyl-benzamide. (1.47 g, 87%)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[N:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[NH2:26]>C(O)CCC>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([NH:14][CH:15]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)[N:3]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(N)cc1Cl
Reactant: OC1CCC(Nc2nc(Cl)cc(-c3ccccc3)n2)CC1
Solvent: CCCCO
Product: COc1ccc(Nc2cc(-c3ccccc3)nc(NC3CCC(O)CC3)n2)cc1Cl
Yield: 53 %

Procedure:
4-[4-(3-Chloro-4-methoxy-phenylamino)-6-phenyl-pyrimidin-2-ylamino]-cyclohexanol was prepared by reacting compound 4-(4-chloro-6-phenyl-pyrimidin-2-ylamino)-cyclohexanol (0.15 g, 0.49 mmol) with 3-chloro-4-methoxyaniline (85 mg, 0.54 mmol) in 1-butanol according to the procedure described above. Yield: 53%.
Reaction SMILES: C([O:8][C:9](=[O:38])[CH:10]([O:35][CH2:36][CH3:37])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](=[O:33])[CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[C:14]([CH3:34])[CH:13]=1)C1C=CC=CC=1.CO>CCOC(C)=O>[CH2:36]([O:35][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](=[O:33])[CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[C:14]([CH3:34])[CH:13]=1)[C:9]([OH:38])=[O:8])[CH3:37]
Reactant: CCOC(Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)c(C)c1)C(=O)OCc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)c(C)c1)C(=O)O

Procedure:
The title compound was prepared from 2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-acetoxy]-phenyl}-propionic acid benzyl ester (0.63 g, 1.22 mmol) in the same manner as described for example 1 with the difference that MeOH was used as the solvent instead of EtOAc. The crude product was purified by column chromatography using DCM/iPrOH (95:5) as the eluent and the title compound was obtained as a solid (0.303 g, 58.3%). 1H NMR (500 MHz, CDCl3): δ 7.99-8.02 (m, 2H), 7.43-7.46 (m, 3H), 7.08-7.11 (m, 2H), 6.96-6.97 (d, 1H), 4.01-4.03 (m, 1H), 3.85 (s, 2H), 3.61 (m, 1H), 3.37 (m, 1H), 3.04-3.07 (dd, 1H), 2.95-2.97 (dd, 1H), 2.43 (s, 3H), 2.13 (s, 3H), 1.12-1.14 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]=[CH:5][N:6]([CH3:24])[C:7]=2[N:8]2[N:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=[C:9]2[N:10]=1.[NH2:25][CH2:26][CH2:27][OH:28]>>[CH3:24][N:6]1[CH:5]=[N:4][C:3]2[C:2]([NH:25][CH2:26][CH2:27][OH:28])=[N:10][C:9]3=[CH:11][C:12]([O:14][CH2:15][CH2:16][O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:13][N:8]3[C:7]1=2
Reactant: NCCO
Reactant: Cn1cnc2c(Cl)nc3cc(OCCOc4ccccc4)nn3c21
Product: Cn1cnc2c(NCCO)nc3cc(OCCOc4ccccc4)nn3c21
Yield: 62 %

Procedure:
A solution of Example 84 Part D (22.6 mg, 0.066 mmol) in 2-aminoethanol (5 mL) was heated at 100° C. for 24 h. 2-aminoethanol was then removed under vacuum, and the residue was purified by prep-HPLC, furnishing the title compound (15 mg, 62% yield). ESI m/z=369.24 [(M+H)+; calcd for C18H20N6O3+H: 369.17].
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[CH2:13]([N:20]=[N+:21]=[N-:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[ClH:1].[CH2:13]([N:20]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]2[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=2)[N:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCCc2cn(Cc3ccccc3)nn2)c[nH]1
Yield: 52.4 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.081 g, 0.437 mmol) was reacted with benzyl azide (0.071 g, 0.533 mmol) following the general procedure for click reactions outlined above to produce 4-[3-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-propyl]-1H-imidazol-2-ylamine hydrochloride (0.073 g, 53%) as a pale yellow solid. 111 NMR (300 MHz, DMSO) δ 7.93 (s, 1H), δ 7.37-7.27 (m, 5H), δ 6.63 (s, 2H), δ 6.44 (s, 1H), δ 2.61 (t, 2H), δ 2.40 (t, 2H), δ 1.82 (m, 2H) ppm; 13C NMR (75 MHz, DMSO) δ 163.5, 148.1, 147.4, 135.9, 129.4, 128.7, 128.5, 128.4, 122.8, 122.8, 115.9, 109.9, 53.3, 28.5, 25.0; HRMS (ESI) calcd for C15H18N6 (M+) 282.1665, found 282.1674.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)Cl>[C:20]([N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8]1)(=[O:22])[CH3:21]
Reactant: COc1cccc2c1CCNC2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1CCN(C(C)=O)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To a solution of the product of step (b) (6.26 g, 31.4 mmol) and triethylamine (9.6 ml, 69.0 mmol) in CH2Cl2 (150 ml) was added acetyl chloride (2.7 ml, 37.7 mmol) at 0° C. over a period of 15 min. The reaction mixture was stirred at room temperature for 18 h after which time the solution was washed sequentially with H2O and saturated aqueous sodium bicarbonate solution, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified on silica gel eluting with EtOAc to afford the subtitle compound as an orange oil (6.07 g, 94%). Rf 0.65 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/s 206 (MH+).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)=[O:13])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>C(O)CCC>[CH:19]1([NH:24][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12]([C:14]4[O:15][CH:16]=[CH:17][CH:18]=4)=[O:13])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCC1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C(Nc1nc2cccc(NC3CCCC3)n2n1)c1ccco1
Reaction time: 0.33 h
Yield: 45.6 %

Procedure:
A sealed vessel containing furan-2-carboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (61 mg, 0.20 mmol, 1 mol eq.), cyclopentylamine (26 mg, 0.30 mmol, 1.5 mol eq.), di-iso-propylethylamine (60 pt, 0.32 mmol, 1.6 mol eq.) and n-butanol (0.75 ml) was irradiated at 220° C., with stirring, for 20 minutes. The solvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (28.4 mg, 46%). HPLC, Rt: 2.32 min (purity: 97%). LC/MS M+(ESI): 312.3.