Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[S:10][N:9]=[C:8]([CH3:11])[CH:7]=1>O1CCCC1>[CH3:11][C:8]1[CH:7]=[C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[S:10][N:9]=1
Reactant: CN=C=O
Reactant: Cc1cc(N)sn1
Solvent: C1CCOC1
Product: CNC(=O)Nc1cc(C)ns1
Yield: 54.5 %

Procedure:
Methylisocyanate (1.96 milliliters, 0.04 mole) was added dropwise to a thirty (30) milliliter solution of the distilled tetrahydrofuran containing the above mentioned 5-amino-3-methylisothiazole (5.0 grams, 0.04 mole), and then the resulting yellow solution was refluxed for 3 hours, during which time a white precipitate formed. The solution was cooled and filtered, giving 3.73 grams of N-(3-methyl-5-isothiazolyl)-N'-methylurea, also referred to as 3-methyl-5-N-methylureiodisothiazole.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1.C(N(C(C)C)CC)(C)C>>[C:1]([NH:5][C:11]1[CH:10]=[C:9]([Cl:14])[N:8]=[C:7]([Cl:6])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1cc(Cl)nc(Cl)n1
Reaction time: 72 h

Procedure:
Tert-butylamine (II, 6.23 ml) is slowly added to 2,4,6-trichloropyrimidine (I, 10.0 g) at -20° (temp. rose to -14°). Diisopropylethylamine (9.50 ml) is added and the mixture is stirred at 20°-25° for 72 hours. Basic workup (ethyl acetate, 1N potassium bicarbonate, magnesium sulfate) and purification by flash chromatography eluting with hexane/ethyl acetate (9/1), pooling and concentrating the desired fractions gives the title compound, mp 192°-193°; NMR (CDCl3) 6.29, 1.44δ.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].[Br:11]Br>ClCCl>[Br:11][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:10]=1
Reactant: CC(C)c1ccccc1N
Reactant: BrBr
Solvent: ClCCl
Product: CC(C)c1cc(Br)ccc1N
Yield: 135.3 %

Procedure:
To a cooled solution of 2-iso-propyl aniline (714 mg, 5.28 mmol) in dichloromethane (20 mL) at −50° C. in a dry ice/acetone bath was added a solution of bromine (269 μl, 5.28 mmol) in dichloromethane (5 mL) over 20 min. After completion of the addition, the reaction mixture was stirred for an additional hour. Purification by column chromatography (silica gel, hexane/ethyl acetate) gave 4-bromo-2-iso-propyl-phenylamine as a brown oil (1.53 g, 57%); 1H NMR (300 MHz, DMSO-d6): δ 7.01 (m, 2H), 6.55 (d, 1H, J=13 Hz), 5.05 (bs, 2H), 2.92 (m, 1H), 1.11 (d, 6H, J=7 Hz); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=Hexane/ethyl acetate [10:1]; Rf=0.11
Reaction SMILES: [CH2:1]([CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[NH:6][CH2:5]1)[CH2:2][CH3:3].[Br:14][CH2:15][CH2:16][CH2:17]Br>>[CH2:1]([CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]([CH2:17][CH2:16][CH2:15][Br:14])[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CNc2ccccc2O1
Reactant: BrCCCBr
Product: CCCC1CN(CCCBr)c2ccccc2O1
Yield: 33 %

Procedure:
From 2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.65 g, 1 eq, 9.3 mmol) obtained in step (iii) above, and 1,3-dibromo propane (9.4 ml, 10 eq, 93 mmol) and following the procedure of step (iv), preparation 17 title compound (915 mg, yield 33%) was obtained as viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH2:25][CH2:24][CH:23]([NH:26]C(=O)C)[CH2:22][CH2:21]1.[OH-].[Na+].[ClH:32]>>[ClH:32].[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH2:21][CH2:22][CH:23]([NH2:26])[CH2:24][CH2:25]1
Reactant: CC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCC4C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1CCc2c(N3CCC(N)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
A mixture of 2 g of 9-fluoro-8-(4-acetylamino-1-piperidyl)-5-methyl-6,7dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 50 ml of a 10% aqueous sodium hydroxide solution was heated for 10 hours. After completion of reaction, the reaction mixture was cooled and adjusted to pH 4 with dilute hydrochloric acid (10%) to form precipitations, which then were recrystallized from ethanol-water to give 0.7 g of 9-fluoro-8-(4-amino-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride. m.p. not lower than 300° C., white rhombic crystals.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20](O)=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:38])=O>C(Cl)Cl>[F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([Cl:38])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(/N=c1\[nH]c2ccc(CN3CCOCC3)cc2n1[C@H]1CC[C@@H](C(=O)O)CC1)c1ccc(F)cc1
Solvent: ClCCl
Product: O=C(/N=c1\[nH]c2ccc(CN3CCOCC3)cc2n1[C@H]1CC[C@@H](C(=O)Cl)CC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. suspension of cis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (0.5 g, 1.041 mmol) in DCM (10.41 mL) was added thionyl chloride (0.380 mL, 5.20 mmol). The suspension was stirred for 30 minutes at 0° C. The reaction was concentrated, resuspended in ACN (5 mL), and reconcentrated to generate cis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonyl chloride (0.50 g, 96% yield) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23][C:24]3[CH:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32](OC(F)(F)F)[CH:31]=4)[CH:27]=[CH:26][N:25]=3)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:41][C:42]([F:54])([F:53])[O:43]C1C=CC(B(O)O)=CC=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23][C:24]3[CH:29]=[C:28]([C:30]4[CH:31]=[CH:32][C:33]([O:43][C:42]([F:54])([F:53])[F:41])=[CH:34][CH:35]=4)[CH:27]=[CH:26][N:25]=3)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(-c4cccc(OC(F)(F)F)c4)ccn3)C2)cc1
Product: O=[N+]([O-])c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(-c4ccc(OC(F)(F)F)cc4)ccn3)C2)cc1

Procedure:
(1R,2R)—N1-((S)-1-(4-Nitrophenyl)piperidin-3-yl)-N2-(4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)cyclohexane-1,2-diamine (1.4 mg, 0.003 mmol, 6.0% yield) was synthesized as described in General Procedure I using Intermediate A from Example 23 (20 mg, 0.04 mmol) and 4-(trifluoromethoxy)phenylboronic acid (12.2 mg, 0.04 mmol). The desired fraction from RP prep-HPLC method D was concentrated to give the title compound as a pale yellow solid. Anal. Calcd. for C29H32F3N5O3 m/z 555.2, found: 556.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (d, J=5.6 Hz, 1H), 8.01 (d, J=9.2 Hz, 2H), 7.57 (d, J=4.4 Hz, 2H), 7.30 (d, J=8 Hz, 2H), 6.78 (d, J=5.6 Hz, 1H), 6.66 (d, J=9.3 Hz, 2H), 6.51 (s, 1H), 4.7 (bs, 1H), 3.72 (m, 1H), 3.62 (m, 2H), 3.54 (m, 1H), 3.05 (m, 1H), 2.9 (m, 2H), 2.53 (m, 1H), 2.14 (m, 3H), 1.96 (m, 1H), 1.78 (m, 4H), 1.27 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:18])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH2:22][CH3:23]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][CH2:22][CH3:23])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Nc1ncnc2ccc(-c3cccc(F)c3)nc12
Agent: [H-]
Agent: [Na+]
Product: CCNc1ncnc2ccc(-c3cccc(F)c3)nc12

Procedure:
Following the same reaction and purification procedure, the amine 1 (150 mg, 0.62 mmol) was treated with sodium hydride 60% dispersion in mineral oil (37 mg, 0.94 mmol) and iodoethane (0.05 mL, 0.62 mmol) to provide 6-(3-fluorophenyl)-N-ethylpyrido[3,2-d]pyrimidin-4-amine 29.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC([O-])(C)C.[Na+]>O1CCOCC1>[C:2]1([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: NCCCCNc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(NCCCCNc2ccccc2)cc1
Temperature: 80 °C
Yield: 89.9 %

Procedure:
Following general procedure F, a mixture of chlorobenzene (51 μL, 0.5 mmol), N1-phenylbutane-1,4-diamine (98 mg, 0.6 mmol), NaOt-Bu (97 mg, 1.0 mmol), 10 (4 mg, 1 mol %), 1 (2.5 mg, 1 mol %), and dioxane (0.5 mL) was heated to 80° C. for 2 h. The crude product was purified via the Biotage SP4 (silica-packed 50 g snap; 0-75% EtOAc/hexanes) to provide the title compound as a clear oil (108 mg, 91%). 1H NMR (300 MHz, CDCl3) δ: 7.28 (t, J=7.0 Hz, 4H), 6.80 (t, J=7.0 Hz, 2H), 6.68 (d, J=7.0 Hz, 4H), 3.68 (s, 2H), 3.22 (m, 4H), 1.78 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3) δ: 148.6, 129.6, 117.6, 113.1, 44.0, 27.4 ppm. IR (neat, cm−1): 3407, 3050, 2934, 2861, 1603, 1507, 1477, 1321, 1257, 1179, 749, 693. Anal. Calcd. for C16H20N2: C, 79.96; H, 8.39. Found: C, 80.20; H, 8.48.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[Cl:14][C:8]([C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]1)=[O:10]
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1(C(=O)Cl)CC1

Procedure:
To solution of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (144 mg, 1 mmol) was added 2M oxalyl dichloride (1.0 mL, 2.0 mmol) in DCM followed by a few drops of DMF. The reaction mixture was stirred until gas evolution ceased (˜1 h). Excess oxalyl chloride and DCM were evaporated to afford methyl 1-(chlorocarbonyl)cyclopropanecarboxylate. To a solution of methyl 1-(chlorocarbonyl)cyclopropanecarboxylate in DCM (2 mL) was added 4,4-difluoropiperidine/HCl (173 mg) and DIPEA (0.384 mL) at 0° C., and then the reaction mixture was allowed to warm to rt. The reaction mixture was purified by silica gel FCC to yield Cap P-20. 1H NMR (500 MHz, CDCl3) δ ppm 3.77-3.82 (2H, m), 3.75 (3H, s), 3.64 (2H, t, J=5.42 Hz), 1.96-2.09 (4H, m), 1.51-1.57 (2H, m), 1.33-1.39 (2H, m). Hydrolysis of methyl 1-(4,4-difluoropiperidine-1-carbonyl)cyclopropanecarboxylate (by 2 mL of 1N NaOH, 1 mL of THF and 1 mL of MeOH) to afford Cap P-20 as a white solid (194 mg). 1H NMR (500 MHz, CDCl3) δ ppm 3.78-3.73 (4H, m), 1.97-2.10 (4H, m), 1.59-1.65 (2H, m), 1.42-1.48 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[CH2:20][CH2:19][C:5]2[N:6]([CH2:14][CH2:15][C:16](O)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.FC(F)(F)C([O-])=O>ClCCl>[CH3:1][N:2]1[CH2:20][CH2:19][C:5]2[N:6]([CH2:14][CH2:15][C:16]([N:21]3[CH2:22][CH2:23][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:25][CH2:26]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CCC(=O)O)CCN(C)C1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)CCN(C)C1
Yield: 6.1 %

Procedure:
The title compound, tert-butyl 1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate, was obtained as follows. 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoic acid (500 mg, 1.8 mmol) (See Example 54B) was stirred with tert-butyl piperidin-4-ylcarbamate (0.366 ml, 1.8 mmol), EDCI-HCl (0.35 g, 1.8 mmol) and triethyl amine (0.253 ml, 1.8 mmol) in dichloromethane (20 ml) to obtain 50 mg of tert-butyl 1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate as a trifluoroacetate salt after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient followed by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[C:19]([C:32](O)=[O:33])=[CH:18]2>>[OH:12][CH2:11][C:9]1[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=[C:2]([NH:1][C:32]([C:19]3[N:20]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:21]4[C:17]([CH:18]=3)=[CH:16][C:15]([F:14])=[CH:23][CH:22]=4)=[O:33])[CH:3]=[C:4]2[N:10]=1
Reactant: Cn1c(CO)nc2cc(N)cnc21
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Product: Cn1c(CO)nc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc21

Procedure:
Compound 6 is synthesized according to a process similar to that described in Example 1.2, starting with 6-amino-2-hydroxymethyl-3-methyl-3H-imidazo[4,5-b]-pyridine described in the preceding step and 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid described in step 1.1.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([CH2:13]I)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[S:20][C:19]([Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[N:18][CH:17]=1>>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:16]1[S:20][C:19]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:22]([CH3:23])[CH3:24])=[N:18][CH:17]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](c1ncc(Br)s1)(C(C)C)C(C)C
Reactant: COC(=O)[C@@H](CI)C(=O)OC(C)(C)C
Product: COC(=O)[C@H](Cc1cnc([Si](C(C)C)(C(C)C)C(C)C)s1)C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in a manner analogous to that described Example 408, using (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 5-bromo-2-(triisopropylsilyl)thiazole (prepared according to Stangeland, Eric L.; Sammakia, Tarek, Use of Thiazoles in the Halogen Dance Reaction: Application to the Total Synthesis of WS75624 B, Journal of Organic Chemistry (2004), 69(7), 2381-2385). MS m/z: 443.3 (100%, M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:14][C:15](=[O:17])[CH3:16])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:27]=[C:26]([Cl:28])[C:25]([O:29][CH3:30])=[CH:24][C:22]=1[NH2:23].Cl.N1C=CC=CC=1>C(OCCO)C>[C:18]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:23][C:22]1[CH:24]=[C:25]([O:29][CH3:30])[C:26]([Cl:28])=[CH:27][C:21]=1[Cl:20])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH:14][C:15](=[O:17])[CH3:16])[CH:7]=2)#[N:19]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1NC(C)=O
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc(Nc2c(C#N)cnc3cc(NC(C)=O)c(OC)cc23)c(Cl)cc1Cl
Temperature: 135 °C
Yield: 70.9 %

Procedure:
An amount of 9.7 g (0.035 mol) of N-(4-chloro-3-cyano-6-methoxy-7-quinolinyl)acetamide was stirred in 97 ml of 2-ethoxyethanol. To this were added 2,4-dichloro-5-methoxyaniline (7.4 g, 0.038 mol), and 4.1 g (0.035 mol) pyridine hydrochloride, and the mixture was heated at 135° C. for 3 hours. The solvent was evaporated and the solid was stirred in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine solution, dried over sodium sulfate and evaporated to dryness to give a brown solid (10.7 g, 71% yield), mp 267-270° C.; 1H NMR (DMSO-d6) δ 9.94 (s, 1H), 9.01 (s, 1H), 8.99 (s, 1H), 8.42 (s, 1H), 7.97 (m, 1H), 7.86 (s, 1H), 7.53 (m, 1H), 4.12 (s, 3H), 3.88 (s, 3H), 2.27 (s, 3H); MS (ES) m/z 431.1 (M+1). Analysis for C20H16Cl2N4O3.7H2O: Found: C, 43.23; H, 3.35; N, 10.24. Calcd: C, 43.06; H, 5.38; N, 10.05.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)[CH:7]=[CH:6]2.C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>O1CCCC1>[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH:13][C@H:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]2)[CH:7]=[CH:6]3)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a cooled (ice bath) and stirred solution of (6-aminomethyl-quinolin-2-yl)-(R)-indan-1-yl-amine (130 mg, 0.45 mmol) and triethyl amine (50 mg, 0.49 mmol) in tetrahydrofurane (2.6 ml) was added 4-fluorobenzoyl chloride (78 mg, 0.49 mmol) and the mixture was allowed to stir at room temperature for 1 h. Evaporation and purification by flash chromatography (ethyl acetate/heptane) on silica gel yielded the title compound as white foam (150 mg, 81%). MS: m/e=412.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[NH:18][C:17]2[C:16](=[O:19])[N:14]([CH3:15])[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:24]([O:26][CH2:27][CH2:28][CH:29]([C:33](O)=[O:34])[C:30](O)=[O:31])[CH3:25]>CN(C)C=O>[CH2:1]([N:8]1[C:9]2=[N:10][C:11]3[N:12]([CH3:21])[C:13](=[O:20])[N:14]([CH3:15])[C:16](=[O:19])[C:17]=3[N:18]2[C:33]([OH:34])=[C:29]([CH2:28][CH2:27][O:26][CH2:24][CH3:25])[C:30]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2[nH]c(NCc3ccccc3)nc2n(C)c1=O
Reactant: CCOCCC(C(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCc1c(O)n2c3c(=O)n(C)c(=O)n(C)c3nc2n(Cc2ccccc2)c1=O
Temperature: 50 °C

Procedure:
To a stirred suspension of 7.43 g of 8-benzylaminotheophylline in 104 ml of dry N,N-dimethyl-formamide add portionwise over 10 minutes 1.19 g of a 60% dispersion of sodium hydride. Heat the mixture to 50° C. under a nitrogen atmosphere for 30 minutes. Add 13.30 g of the diethyl ester of β-ethoxyethylmalonic acid. Heat the mixture to 150° C. under a nitrogen atmosphere for approximately 37 hours. Allow the system to cool to room temperature and remove the solvent in vacuo. Add a mixture of water:chloroform (1:2.5) to the resulting semisolid. Acidify the aqueous portion with 3M HCl. Extract the product from the aqueous portion with chloroform. Wash the chloroform extracts with brine, dry over anhydrous sodium sulfate, filter and remove the solvent in vacuo to give the crude product. Triturate the crude product with ether. Purify the crude product by column chromatography on silica gel and triturate the major fraction with hexane to give the title compound, mp 156.5°-157.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=2)[NH:8][N:7]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)[C:14]=23)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: ClCCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CN1CCNCC1
Product: CN1CCN(CCCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 22 %

Procedure:
The procedure described in Example 23 was repeated using 3-(3-chloropropoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-methylpiperazine to give the title compound in 22% yield; NMR Spectrum: 1.95-1.99 (m, 2H), 2.12 (s, 3H), 2.20-2.50 (m, partially hidden by DMSO, 8H), 4.33 (t, 2H), 5.29 (s, 2H), 7.23 (d, 1H), 7.37 (t, 1H), 7.54-7.58 (m, 2H), 7.86-7.89 (m, 2H), 8.27 (s, 1H), 8.44 (br s, 1H), 8.59 (d, 1H); Mass Spectrum: 509 (MH+).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=[CH:14][C:13]([CH3:28])=[CH:12][CH:11]=2.Br[CH2:30][C:31]([O:33]CC)=[O:32]>C1COCC1.O.[OH-].[Na+]>[CH3:7][C:8]1[N:9]([CH2:30][C:31]([OH:33])=[O:32])[C:10]2[C:15]([C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1)=[CH:14][C:13]([CH3:28])=[CH:12][CH:11]=2
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc2[nH]c(C)c(Oc3ccc(S(C)(=O)=O)cc3)c2c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c(Oc1ccc(S(C)(=O)=O)cc1)c(C)n2CC(=O)O
Reaction time: 0.17 h

Procedure:
Sodium t-butoxide (220 mg) was added to a solution of the product from step (iii) (600 mg) in THF (20 ml) and stirred for 10 min. Ethyl bromoacetate (250 μl) was added and the reaction stirred for a further 1 h. The mixture was then diluted with water (10 ml), 1M aqueous sodium hydroxide (5 ml) added and stirred for 3 h. The mixture was extracted with EtOAc, washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified using reverse phase preparative chromatography (eluent MeCN/NH3(aq)) to give the title compound. Yield 450 mg.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH2:28]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:29]1[O:33][CH:32]=[CH:31][CH:30]=1>CS(C)=O.C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15]([N:37]5[CH2:38][CH2:39][N:34]([CH2:28][C:29]6[O:33][CH:32]=[CH:31][CH:30]=6)[CH2:35][CH2:36]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1coc(CN2CCNCC2)c1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(N4CCN(Cc5ccco5)CC4)c(F)cc3cc2c1=O
Yield: 59.4 %

Procedure:
Ethyl 1-cyclopropyl-7,9-difluoro-8-(4-furfurylpiperazin-1-yl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was prepared under the conditions of Example 3, but from 1.8 g of ethyl 1-cyclopropyl-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylate and 4.8 g of 4-furfurylpiperazine hydrochloride in 30 cm3 of dimethyl sulphoxide and 5.2 cm3 of triethylamine. 1.5 g of ethyl 1-cyclopropyl-7,9-difluoro-8-(4-furfurylpiperazin-1-yl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate were obtained in the form of a yellow-brown solid melting at about 125-128° C., which solid was used without additional purification in the subsequent stages.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:25]=[CH:24][C:13]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:23]=3)[C:21]#[N:22])=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>>[OH:31][C:5]1[C:6]([CH2:28][CH2:29][CH3:30])=[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([C:21]4[N:32]=[N:33][NH:34][N:22]=4)[CH:23]=3)=[O:15])=[CH:24][CH:25]=2)[CH:26]=[CH:27][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(=O)c3cncc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2ccc(C(=O)c3cncc(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O
Yield: 68.4 %

Procedure:
The title compound is prepared essentially as described in Example 1 using 5-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoyl]-nicotinonitrile (448 mg, 1.08 mmol), sodium azide (703 mg, 10.8 mmol), and triethylamine hydrochloride (1.49 g, 10.8 mmol) to yield the title product as a white solid (338 mg, 66%): 1H NMR (DMSO-d6) δ 0.90 (t, 3H), 1.53 (sextet, 2H), 2.59 (s, 3H), 2.64 (t, 2H), 5.43 (s, 2H), 6.76 (d, 1H), 7.67 (d, 2H), 7.84 (d, 1H), 7.92 (d, 2H), 8.68 (t, 1H), 9.05 (d, 1H), 9.46 (d, 1H), 12.86 (s, 1H); MS (esi negative) m/z (rel intensity) 456 (100).