Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:23]2[CH:22]=[C:21]3[NH:24][C:25]([NH:27][C:28]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[O:29])=[N:26][C:20]3=[CH:19][C:18]=2[C:17]([CH3:37])([CH3:36])[C:16]1=[O:38])(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:23]2[CH:22]=[C:21]3[NH:24][C:25]([NH:27][C:28](=[O:29])[C:30]4[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=4)=[N:26][C:20]3=[CH:19][C:18]=2[C:17]([CH3:37])([CH3:36])[C:16]1=[O:38]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4cccnc4)[nH]c3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)N(Cc2ccccc2N)c2cc3[nH]c(NC(=O)c4cccnc4)nc3cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
(2-{7,7-Dimethyl-6-oxo-2-[(pyridine-3-carbonyl)-amino]-6,7-dihydro-3H-imidazo[4,5-f]indol-5-ylmethyl}-phenyl)-carbamic acid tert-butyl ester (33.2 mg) is dissolved in CH2Cl2 (4 ml) and TFA (1.5 ml). The mixture is stirred at RT for 0.5 h. Saturated K2CO3 solution is added and the aqueous layer is extracted with CH2Cl2. The organic layer is dried over MgSO4, evaporated to dryness and the residue is purified by RP-HPLC, eluted with MeCN/water to give the desired product (4,5 mg).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][NH:8]1)=[O:6])[CH3:3].[CH2:13](Br)[C:14]#[CH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1[CH2:15][C:14]#[CH:13])=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@@H]1COCCN1
Reactant: C#CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCN1CCOC[C@H]1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (3S)-3-ethoxycarbonylmorpholine hydrochloride (0.3 g), propargyl bromide (0.34 ml) and potassium carbonate (0.91 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 1 hour and then the solvent was removed under reduced pressure. Ethyl acetate and sodium hydrogen carbonate solution were added to the residue and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (3:7) as an eluent to give (3S)-3-ethoxycarbonyl-4-(2-propynyl)morpholine (0.22 g) as an oil.
Reaction SMILES: C(OC([N:8]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:9]1[C:14]([Cl:15])=[C:13]([CH2:16][CH3:17])[N:12]=[CH:11][N:10]=1)=O)(C)(C)C.C(=O)=O.FC(F)(F)C(O)=O>ClC(Cl)C>[Cl:15][C:14]1[C:9]([NH:8][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:10][CH:11]=[N:12][C:13]=1[CH2:16][CH3:17]
Reactant: CCc1ncnc(N(C(=O)OC(C)(C)C)C2CCNCC2)c1Cl
Agent: O=C=O
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ncnc(NC2CCNCC2)c1Cl

Procedure:
20.7 g (0.61 mmol) of 4-(tert-butoxycarbonylpiperidin-4-ylamino)-5-chloro-6-ethylpyrimidine (Example A) were dissolved in 100 ml of dichloroethane and 148.0 g of trifluorocetic acid were added slowly. After the evolution of CO2 had ceased, stirring was continued for 2 more hours. After the solvent and the trifluoroacetic acid had been stripped off, the mixture was concentrated and the residue was taken up in dichloromethane/water. After the mixture had been rendered weakly alkaline by addition of dilute sodium hydroxide solution, the organic phase was separated off, dried and concentrated. This gave 12.3 g (83.9% of theory) of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:15])[C:4]([C:12]([OH:14])=O)=[CH:5][N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:47]([N:49]=[S:50]([C:53]1[CH:58]=[CH:57][C:56]([CH2:59][NH2:60])=[CH:55][CH:54]=1)([CH3:52])=[O:51])#[N:48]>CN(C=O)C>[C:47]([N:49]=[S:50]([C:53]1[CH:58]=[CH:57][C:56]([CH2:59][NH:60][C:12]([C:4]2[C:3](=[O:15])[C:2]([Br:1])=[C:7]([CH3:8])[N:6]([CH:9]([CH3:10])[CH3:11])[CH:5]=2)=[O:14])=[CH:55][CH:54]=1)([CH3:52])=[O:51])#[N:48]
Reactant: CS(=O)(=NC#N)c1ccc(CN)cc1
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=NC#N)cc2)cn1C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1c, 270 mg, 0.99 mmol), TBTU (316 mg, 0.99 mmol) and DIPEA (513 μL, 2.97 mmol) in DMF (3.00 mL) is stirred for 10 min at room temperature. Then, a solution of (4-(N-cyano-S-methylsulfonimidoyl)phenyl)methanamine (preparation 6, 247 mg, 1.18 mmol) in DMF (1.00 mL) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is purified by preparative reversed phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% TFA, 60° C.). Yield: 70 mg (15% of theory); ESI mass spectrum: [M+H]+=465 (bromine isotope pattern); r.t. HPLC: 0.86 min (Z017_S04).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][C:14]=2[Cl:16])[N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[C:8]=1[CH3:28]>C1COCC1.CO>[Cl:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[N:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:8]([CH3:28])=[C:7]([CH2:6][C:5]([OH:29])=[O:4])[C:15]=12
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2)c2nccc(Cl)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2c(Cl)ccnc2n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1M Aqueous NaOH (0.5 ml) is added to a stirring solution of [4-chloro-1-(4-methanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (38 mg, 0.093 mmol) in 1:1 THF/MeOH (1 ml). After stirring at room temperature for 4 hours, the reaction mixture is filtered to remove any undissolved material and is evaporated to dryness. The resulting oil is dissolved in water (1 ml) and acidified to pH 2. The resulting precipitate collected by filtration and dried in vacuo to afford [4-chloro-1-(4-methanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid. (MH+ 393)
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14](O)=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1.[NH4+:24].[OH-]>>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([NH2:24])=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(N)=O
Yield: 96 %

Procedure:
The product was prepared in 96% yield by reaction of the mixed anhydride from BOC-β-Nal-OH (682 mg, 2.17 mmol) with conc. NH4OH according to the procedure of Rzeszotarska, B., Makowski, M., and Kubica, Z. Org. Prep. Proc. Int.1984, 16:136-139. 1H-NMR (CDCl3): δ1.40 (s, 9H), 3.24 (m, 2H), 4.47 (m, 1H), 5.10 (br s, 1H), 5.37 (br s, 1H), 5.75 (br s, 1H), 7.49 (dd, J=2 Hz and 9 Hz, 1H), 7.47 (m, 2H), 7.69 (s, 1H), 7.80 (m, 3H). MS (DCl): m/e 315 (M+H)+, 259, 215.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:20])[CH:14]=[C:15]([NH2:19])[O:16][CH2:17][CH3:18])[CH3:11]>>[CH2:10]([O:12][C:13]([C:14]1[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:15]([O:16][CH2:17][CH3:18])=[N:19][C:15]=1[NH2:19])=[O:20])[CH3:11]
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)C=C(N)OCC
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1ccc(C)cc1
Yield: 47 %

Procedure:
Upon heating a solution of 6 g of 4-methylbenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 6 hours, 2-amino-4-(4-methylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 119° C (ethyl acetate/petroleum ether) is obtained. Yield: 47% of theory.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15](Cl)[CH:14]=3)=[N:10][C:9]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:18]=3[C:19]([F:21])([F:22])[F:20])=[N:10][C:9]=2[CH:24]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2oc(-c3cc(Cl)ncc3C(F)(F)F)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2oc(-c3ccncc3C(F)(F)F)nc2c1
Yield: 52.6 %

Procedure:
A mixture of 0.40 g of 5-tert-butyl-2-(2-chloro-5-trifluoromethylpyridin-4-yl)benzoxazole, 0.59 g of 5% palladium on carbon and 25 ml of acetic acid was stirred under about one atmosphere of hydrogen at room temperature for 15 hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.19 g of 5-tert-butyl-2-(3-trifluoromethylpyridin-4-yl)benzoxazole (hereinafter, referred to as “active compound 107”).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([OH:18])=O.[CH3:19][CH:20]([CH3:40])[CH2:21][NH:22][C@@H:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][C@H:25]([C:36]([O:38][CH3:39])=[O:37])[CH2:24]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:22]([CH2:21][CH:20]([CH3:40])[CH3:19])[C@@H:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][C@H:25]([C:36]([O:38][CH3:39])=[O:37])[CH2:24]1)=[O:18]
Reactant: COC(=O)[C@@H]1C[C@H](NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCn1c(C(=O)O)cc2ccccc21
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)cc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 7.4 %

Procedure:
1-(4-Methoxybutyl)-1H-indole-2-carboxylic acid (247 mg), 1-tert-butyl 3-methyl (3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (314 mg) and diisopropylethylamine (862 μl) were dissolved in methylene chloride (5 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (337 mg) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give 1-tert-butyl 3-methyl (3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (40 mg) as an oil. The obtained 1-tert-butyl 3-methyl (3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (40 mg) was dissolved in methanol (2 ml), 4M hydrogen chloride-ethyl acetate (2 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give the object product (13 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N:9]2[N:13]=[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:11]3=[N:10]2)[CH:3]=1.[CH2:19]([O:21][C:22](=[O:35])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33]Br)=[CH:26][CH:25]=1)[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:19]([O:21][C:22](=[O:35])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:9]2[N:13]=[C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:11]3=[N:10]2)=[CH:28][CH:29]=1)[CH3:20]
Reactant: Cc1cccc2nn(-c3cc(Cl)ccc3O)nc12
Reactant: CCOC(=O)Cc1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OCCCOc2ccc(Cl)cc2-n2nc3cccc(C)c3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-2-(4-methyl-benzotriazol-2-yl)-phenol (93 mg, 0.36 mmol), [4-(3-bromo-propoxyl)-phenyl]-acetic acid ethyl ester (130 mg, 1.2 eq.) and Cs2CO3 (140 mg, 1.2 eq.) in CH3CN (10 ml) was heated to reflux for I hr. After cooling to r.t., the solid was filtered off and the filtrate was concentrated in vacuo. The crude product was purified on silica gel to give the desired compound.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:25])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Product: Cc1onc(-c2ccccc2F)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 83 %

Procedure:
As described for example 84f, 6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (180 mg, 83%) which was obtained as a colourless oil. MS: m/e=370.1 [M+H]+.
Reaction SMILES: ClN[NH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8].[C:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(OCC)(=O)C>C(O)C>[CH3:15][O:14][C:13]1[C:4]2[NH:3][C:26]3[CH2:27][CH2:28][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24][C:25]=3[C:5]=2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1ccc(OC)c(NNCl)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC)c2[nH]c3c(c12)CN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of Methyl 3-(2-chlorohydrazino)-4-methoxybenzoate (from step 1) (0.0042 mol) and N-Boc-4-piperidone (0.0063 mol) in ethanol (20 ml) was stirred for 18 h at room temperature. Reaction was concentrated under vacuum and product was isolated with silica gel column chromatography using 20% ethyl acetate in petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:13][C:12]=3[O:24][CH3:25])[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:37]1[O:40][C@H:38]1[CH3:39]>CO>[Cl:1][C:2]1[C:3]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH2:37][C@@H:38]([OH:40])[CH3:39])[CH2:20][CH2:19]4)=[CH:13][C:12]=3[O:24][CH3:25])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CN2CCNCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Reactant: C[C@H]1CO1
Solvent: CO
Product: COc1cc(CN2CCN(C[C@H](C)O)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1

Procedure:
(1S,2S,3R,4R)-3-[6-Chloro-2-(2-methoxy-4-piperazin-1-ylmethyl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Compound XLII above) (45 mg, 0.088 mmol) was reacted with (S)-(−)-propylene oxide (7.7 mg, 0.13 mmol) in methanol (5 mL) at 60° C. in a sealed tube for six hours. The reaction was concentrated to afford the title compound as a rust colored solid (14 mg, 28%). Mp 142-6° C. 1H NMR (d-chloroform): 10.76 (br s, 1H), 8.34 (d, J=9 Hz, 1H), 8.04 (s, 1H), 7.12 (m, 2H), 6.37 (m, 3H), 5.57 (d, J=9 Hz, 1H), 5.19 (m, 2H), 4.08 (s, 3H), 3.84 (m, 1H), 3.58 (s, 2H), 3.49 (m, 1H), 3.18 (s, 1H), 2.92 (s 1H), 2.87 (d, J=9 Hz, 1H), 2.72 (m, 2H), 2.62-2.39 (m, 2H), 2.35 (d, J=0 Hz, 1H), 2.26 (m, 1H), 1.76 (d, J=7 Hz, 1H), 1.31 (m, 1H), 1.15 (d, J=9 Hz, 3H). MS: 566.21 (M+H). HPLC retention time: 1.71 minutes (G Method).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].ClCCl.C(N(CC)CC)C.[CH3:60][S:61](Cl)(=[O:63])=[O:62]>>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:61]([CH3:60])(=[O:63])=[O:62])[CH2:46][CH2:45]3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCNCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: -15 °C
Yield: 94.4 %

Procedure:
A 1 L 3-neck round-bottomed flask equipped with a thermometer was charged with 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(piperazin-1-ylmethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (25.1 g, 37.7 mmol) in dichloromethane (500 mL, 37.7 mmol). The suspension was stirred at −15° C. and treated with dropwise with triethylamine (52.4 mL, 377 mmol). The resulting solution was treated with methanesulfonyl chloride (8.92 mL, 113 mmol) and stirred at 0° C. for 1 h. The resulting mixture was sonicated and the solid was filtered, washed with water and dried in vacuo to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (26.5 g, 35.6 mmol, 94% yield). m/z (ESI, positive ion) m/z 744 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:17](=[O:18])[C:16]2[C:15](=[O:19])[C:14]3[CH:13]=[CH:12][C:11]([Cl:20])=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([OH:21])=[N:5]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.CCOCC>CN(C=O)C>[Cl:20][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:19])[C:16]3[C:17](=[O:18])[N:4]([CH2:3][CH2:2][NH:30][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[N:5]=[C:6]([OH:21])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: COc1ccc(N)cc1
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCBr)c(=O)c12
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(NCCn2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
2-(2-Bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quin-oline-1,10-dione (1.00 g, 2.7 mM, prepared in Example 4a. and p-anisidine(1.33 g, 10.8 mM) were stirred and heated to reflux in DMF (20 mL) for 1.5 hours to give a brown solution. The solution was cooled to room temperature and ether (80 mL) was added to give a dark suspension. The suspension was stirred for two hours and filtered. The collected solids were washed with ether (150 mL) to give the title compound as a tan powder(1.17 g, 60%), mp 239°-241° C.; MS(CI): 413.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.ClCCl.[C:21](Cl)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>N1C=CC=CC=1>[C:21]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([O:23][CH2:24][CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:22]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(=O)OCC3c4ccccc4-c4ccccc43)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Thymidine (10 mmol) was dried by coevaporation with dry pyridine (2×30 ml), re-dissolved in dry pyridine (50 ml) and cooled using an acetone/carbon dioxide bath to a temperature of −20° C. The thymidine solution was magnetically stirred and a dichloromethane solution of FMOC-Cl (12 mmol, 1.2 eq. in 20 ml DCM) was added over a period of 60 minutes. The reaction mixture was warmed to room temperature and stirred for additional 60 minutes. The reaction mixture was partitioned between saturated sodium hydrogen carbonate (250 ml) and dichloromethane (3×100 ml). The organic phase was saved, combined, evaporated and dried by coevaporation with toluene (2×50 ml) forming an oily residue. A pure product was crystallized from the oily residue using dichloromethane (30 ml) and benzene (50 ml) as solvent. Yield 76%—white crystals.
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][CH:35]=1)[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:25])[CH2:20][CH2:19]1)C1C=CC=CC=1.[H][H]>[C].[Pd].CC(O)C>[OH:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][CH:35]=1)[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:25])[CH2:22][CH2:23]1
Reactant: O=C(Oc1cccnc1)N1CCC(Oc2cccc(OCc3ccccc3)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C(Oc1cccnc1)N1CCC(Oc2cccc(O)c2)CC1
Yield: 70.8 %

Procedure:
10% Palladium-carbon (catalytic amount) was added to a THF (75 ml)/2-propanol (75 ml) solution containing 3-pyridyl 4-[3-(benzyloxy)phenoxy]-1-piperidinecarboxylate (4.0 g), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 24 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the resulting solid was washed with EtOAc/hexane, and dried under reduced pressure to obtain 3-pyridyl 4-(3-hydroxyphenoxy)-1-piperidinecarboxylate (2.2 g).
Reaction SMILES: C(N(C(C)C)C(Cl)=O)(C)C.[CH:11]([N:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[CH:11]([N:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:15]([CH3:17])[CH3:16])([CH3:12])[CH3:13].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:39]=[CH:40][C:41]([NH:42][C:21]([NH:20][C:18]([N:14]([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:12])[CH3:13])=[O:19])=[S:22])=[CH:43][CH:44]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CC(C)N(C(=O)Cl)C(C)C
Agent: CC(C)N(C(=O)N=C=S)C(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N(C(C)C)C(C)C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
(Diisopropylamino)methanoyl isothiocyanate was prepared using commercially available N,N-diisopropylcarbamic chloride (80 mg) as a starting compound according to the description of the literature. (Diisopropylamino)methanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (50 mg, yield 62%).