Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[N:11]=[CH:10][C:9]([CH:12](OS(C)(=O)=O)[CH3:13])=[C:8]([I:19])[CH:7]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN(C=O)C.C(Cl)(Cl)Cl>[N:1]([CH:12]([C:9]1[C:8]([I:19])=[CH:7][C:6]([F:5])=[N:11][CH:10]=1)[CH3:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)c1cnc(F)cc1I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 42 h
Yield: 75.3 %

Procedure:
Add sodium azide (0.45 g, 7 mmol) and tetra-N-butylammonium bromide (0.12 g, 0.4 mmol) to a solution of methanesulfonic acid 1-(6-fluoro-4-iodo-pyridin-3-yl)-ethyl ester (1.2 g, 3.5 mmol) in DMF (20 mL) at 0° C. Stir the mixture at RT for 42 h. Dilute the reaction mixture with chloroform. Wash the organic phase with water and saturated aqueous sodium chloride. Dry the organic phase over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (20% ethyl acetate in hexane) to afford the title compound as a white solid (0.77 g, 76%). 1H NMR (400 MHz-CDCl3) δ 1.56 (d, J=6.8 Hz, 1H), 4.90 (m, 1H), 7.45 (d, J=3.2 Hz, 1H), 8.17 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:14])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:14][C:5]1[N:4]=[N:3][C:2]([N:24]2[CH2:25][CH2:26][N:21]([C:16]3[N:15]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:22][CH2:23]2)=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1
Reactant: Cc1cc(-c2ccccc2)c(Cl)nn1
Reactant: c1cnc(N2CCNCC2)nc1
Product: Cc1cc(-c2ccccc2)c(N2CCN(c3ncccn3)CC2)nn1
Reaction time: 168 h
Yield: 40 %

Procedure:
A synthetic reaction scheme for the preparation of6-methyl-4-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine (MW01-7-057) is depicted in FIG. 26, and synthesis was carried out as described herein. A mixture of 3-chloro-6-methyl-4-phenylpyridazine (100 mg, 0.5 mmol), 1-(2-pyrimidyl)piperazine (400 mg, 2.0 mmol) in 3 ml of 1-BuOH was heated with stirring at 130 C for 7 days. The solvent was removed by evaporation in vacuo, the residue was treated with water to give a suspension. The solid was then filtered off, washed with water, then 1:3, Ethyl Acetate: Petroleum ether, dried over filter funnel in vacuo to give, light yellow solid (68 mg, 0.20 mmol, yield 41.7%). Purity>95%; ESI-MS: m/z 333.1 (M+H+). 1H NMR (CDCl3): d 8.310 (d, J=5.0, 2H), 7.678 (d, J=7.5, 2H), 7.476 (m, 3H), 7.119 (s, H), 6.509 (t, J=4.5, 1H), 3.785 (t, J=4.5, J=5.0, 4H), 3.277 J=4.5, J=5.0, 4H), 2.669 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH:4]=[N:3][N:2]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>CN(C=O)C>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([NH:14][NH:15][C:16]([NH2:18])=[S:17])=[O:13])[C:5]=2[CH:4]=[N:3][N:2]=1
Reactant: O=C(O)c1cccc2cnncc12
Reactant: NNC(N)=S
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)c1cccc2cnncc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a 100 mL round bottom flask was added phthalazine-5-carboxylic acid (0.50 g, 2.9 mmol) 1,1′-carbonyldiimidazole (0.93 g, 5.7 mmol) and DMF (2.2 mL). The mixture was stirred at 70° C. for 1 hour and treated with thiosemicarbazide (0.81 g, 8.9 mmol). The resulting mixture was stirred at 70° C. for 30 minutes. The mixture was concentrated under vacuum to remove almost all of the DMF. The remaining residue was treated with 2 N HCl with stirring until the solution reached pH 4. Upon standing, a yellow solid formed. The precipitate was recovered by filtration, washing with water and air dried to provide 1-(phthalazine-5-carbonyl)thiosemicarbazide (0.45 g, 63%).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:8]=[C:7]2[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1.[O-]CC.[Na+].[CH:50]([C:52]1[N:53]([CH3:57])[CH:54]=[CH:55][N:56]=1)=O.O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9](/[CH:16]=[CH:50]/[C:52]1[N:53]([CH3:57])[CH:54]=[CH:55][N:56]=1)[N:8]=[C:7]2[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1
Reactant: COc1ccc(-c2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: Cn1ccnc1C=O
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc(/C=C/c3nccn3C)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
[6,7-Dimethoxy-4-(3,4-dimethoxyphenyl)quinazolin-2- yl]methyltriphenylphosphonium chloride (9.1 g) was added at room temperature to a solution of sodium ethoxide in ethanol (prepared from Na (0.394 g) and ethanol (100 ml)). Then a solution of 2-formyl-l-methylimidazole (1.7 g) in ethanol (10 ml) was added dropwise. The mixture was stirred at room temperature for 3 hours, poured into water and extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4), and the solvent was distilled off. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform/methanol (20:1, v/v), (E)-6,7-dimethoxy-4-(3,4-dimethoxy- phenyl)-2-[2-(1-methylimidazol-2-yl)vinyl]quinazoline (5.1 g, 82%) was obtained and recrystallized from ethanol/chloroform.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3Br)[CH2:5][C:4]=2[N:3]=1.NC1N=[C:30]([CH3:32])[C:29]2[C:28](=O)[CH2:27][CH:26](C3C=CC=CC=3C3C=CC=CC=3)[CH2:25][C:24]=2[N:23]=1>>[NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:24]=3[NH:23][CH:32]=[CH:30]4)[CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1Br)C2
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1ccccc1)C2
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1cccc3cc[nH]c13)C2

Procedure:
The title compound was prepared from 2-amino-7-(2-bromo-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/i stage 2/3), following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 5/a stage 1) using 7-boronic acid-1H-indole instead of phenyl-boronic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28](O)=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH3:32][N:33]1[CH2:38]CO[CH2:35][CH2:34]1.C[N:40]1C(=O)CCC1>>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28]([NH:40][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCOCC1
Reactant: CN1CCCC1=O
Reactant: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Product: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reaction time: 2 h
Yield: 60.2 %

Procedure:
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (73.3 mg, 0.23 mmol) was added to a stirred solution of 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (85 mg, 0.19 mmol), 4-methylmorpholine (0.052 mL, 0.48 mmol) and N1,N1-dimethylethane-1,2-m diamine (0.025 mL, 0.23 mmol) dissolved in NMP (1.2 mL) at room temperature. The resulting solution was stirred for 2 hrs. The reaction mixture was purified by preparative HPLC using a Waters SunFire reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated, triturated with diethyl ether and dried to afford 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (59.2 mg, 60.2%) as a white solid. Mass Spectrum: M+H+ 517. NMR Spectrum: (DMSOd6) 1.57 (d, 3H), 2.15 (s, 6H), 2.37 (t, 2H), 3.26-3.34 (m partially hidden by H2O, 2H), 3.50-3.62 (m, 4H), 3.70-3.79 (m, 4H), 5.03-5.12 (m, 1H), 5.61 (s, 1H), 6.34 (dd, 1H), 6.49 (d, 1H), 6.64 (ddd, 1H), 6.82 (d, 1H), 8.10 (d, 1H), 8.32 (d, 1H), 8.61 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH2:3][C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]=2[CH2:11][CH:12]=1.[Cl:13]N1C(=O)CCC1=O.C1C=CN=CC=1.[FH:27].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1([F:27])[CH:12]([Cl:13])[CH2:11][C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=2[CH2:3]1)=[O:7]
Reactant: O=C1OC(=O)C2=C1CC=C(Cl)C2
Reactant: O=C1CCC(=O)N1Cl
Reactant: F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1OC(=O)C2=C1CC(Cl)C(F)(Cl)C2
Reaction time: 2 h

Procedure:
4-chloro-3,6-dihydrophthalic anhydride (0.63 g) and N-chlorosuccinimide (0.47 g) in methylene chloride (6.2 ml) was added to pyridinium poly(hydrogen fluoride) at room temperature. The reaction mixture was stirred for 2 hours and then carefully poured into a two phase system containing solid sodium carbonate and methylene chloride. The suspension was filtered, the methylene chloride layer was dried over magnesium sulfate and the solvent removed under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])[CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>ClCCl>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CC(=O)OC(C)(C)C)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(CC(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 1,1-dimethylethyl (6-methyl-2-pyridinyl)acetate (711 mg, 3.43 mmol), triethylsilane (1.370 mL, 8.58 mmol) in Dichloromethane (DCM) (10 mL) was added TFA (3.44 mL, 44.6 mmol) dropwise via syringe. The reaction was stirred for overnight at room temperature. LCMS indicated good conversion, so the reaction was concentrated to a colourless oil, and diethyl ether (6 mL) was added. A white precipitate formed which was collected by filtration, dried at the pump for 10 mins, then under high-vacuum to afford (6-methyl-2-pyridinyl)acetic acid TFA salt (771 mg) as a white solid. LC-MS (ES) m/z=152 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.62 (s, 3H), 3.95 (s, 2H), 7.54 (d, J=7.33 Hz, 2H), 8.11 (br. s., 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[F:5][C:6]([F:17])([F:16])[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[OH-:18].[Na+]>CO>[F:5][C:6]([F:16])([F:17])[O:3][C:2]1[CH:4]=[CH:12][C:11]([CH:10]=[CH:9][C:8](=[O:18])[CH:15]=[CH:12][C:11]2[CH:14]=[CH:15][C:8]([O:7][C:6]([F:17])([F:16])[F:5])=[CH:9][CH:10]=2)=[CH:14][CH:1]=1
Reactant: [OH-]
Reactant: CC(C)=O
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Solvent: CO
Product: O=C(C=Cc1ccc(OC(F)(F)F)cc1)C=Cc1ccc(OC(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 1.75 h
Yield: 41 %

Procedure:
Acetone (8.7 g; 0.15 mole) is added to a solution of p-trifluoromethoxybenzaldehyde (57.0 g; 0.30 mole) in methanol (200 ml). The solution is cooled to 20° C. and 10% aqueous sodium hydroxide (8 ml) is added dropwise in about 5 minutes. The reaction mixture is then stirred at room temperature for 1.5 to 2 hours. During this period a yellow solid precipitates from the solution. The mixture is chilled overnight, filtered and the isolated yellow solid dried to afford 24.8 g (41%) of title product, m.p. 121°-123° C. NMR (acetone-d6) [δ=7.0-8.0 (M, 12H, aromatics and vinyl)]; IR 1590-1650 cm-1 (several bands).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:34][C:35]1[CH:36]=[C:37]([C:43]2[C:44](C)=[C:45](OS(C)(=O)=O)[C:46](=[O:53])[N:47]([CH2:49][CH:50]([CH3:52])[CH3:51])[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42].CN1CCNCC1>>[Cl:34][C:35]1[CH:36]=[C:37]([C:43]2[CH:44]=[C:45]([CH2:6][N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[C:46](=[O:53])[N:47]([CH2:49][CH:50]([CH3:51])[CH3:52])[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2nn(CC(C)C)c(=O)c(OS(C)(=O)=O)c2C)cc1Cl
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC(C)C)n2)cc1Cl
Yield: 76.1 %

Procedure:
Following the procedure of Example 1 (10), 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 76.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[N:30]1([CH2:36][CH2:37][NH2:38])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:30]1([CH2:36][CH2:37][NH:38][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]2)=[O:29])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: NCCN1CCNCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCCN2CCNCC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 42.3 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (82.2 mg, 0.20 mmol) prepared in Example 1d was reacted with 2-piperazin-1-yl-ethylamine (38.7 mg, 0.30 mmol), HATU (76.0 mg, 0.20 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-piperazin-1-yl-ethyl)-amide (45.9 mg, 58.0%). HRMS (ES+) m/z Calcd for C29H37Cl2N5O+H [(M+H)+]: 542.2448. found: 542.2445.
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:57][O:58][C:59](=[O:66])[C:60]([CH3:65])([CH3:64])[CH2:61][O:62][CH3:63]>O.C(OCC)(=O)C>[NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[N:15]=[C:14]([O:16][CH2:57][O:58][C:59](=[O:66])[C:60]([CH3:65])([CH3:64])[CH2:61][O:62][CH3:63])[N:13]([C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:22]=3)[N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: COCC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 35.8 %

Procedure:
To a mixture of N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (Example 1a, 45 mg) and DMF (2 mL), cesium carbonate (29 mg) and 3-methoxy-2,2-dimethylpropionic acid chloromethyl ester (20 mg) were sequentially added, and the resulting mixture was stirred at 60° C. for 4 hours. The resulting mixture was poured into ethyl acetate (30 mL) and water (20 mL). After shaking the mixture, the organic layer was collected. The organic layer was sequentially washed twice with water (30 mL) and with saturated aqueous sodium chloride solution (20 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (20 mg).
Reaction SMILES: C(=O)C(C)C.[NH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]3[CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[CH2:23]3)=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.N1C[CH:35]=[C:34]([C:37]2C=CC(NC(N3CC4C(=CC=CC=4)C3)=O)=CC=2)[CH2:33][CH2:32]1>>[CH3:35][CH:34]([CH3:37])[CH2:33][CH2:32][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]3[CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[CH2:23]3)=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1
Reactant: O=C(Nc1ccc(OC2CCNCC2)cc1)N1Cc2ccncc2C1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Agent: CC(C)C=O
Product: CC(C)CCN1CCC(Oc2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 429, substituting 3-methylbutanal for isobutyraldehyde and N-(4-(piperidin-4-yloxy)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, Pyridine-d5. Temp=90° C.) δ ppm 8.53-8.57 (m, 2H) 8.09 (s, 1H) 7.70-7.78 (m, 2H) 7.10 (d, J=5.19 Hz, 1H) 6.98-7.04 (m, 2H) 4.79-4.89 (m, 4H) 4.26 (d, J=3.66 Hz, 1H) 2.72-2.83 (m, 2H) 2.34-2.41 (m, 2H) 2.21-2.30 (m, 2H) 1.96-2.03 (m, 2H) 1.79-1.91 (m, 2H) 1.54-1.68 (m, 1H) 1.35-1.44 (m, 2H) 0.86-0.90 (m, 6H); MS (APCI(+)) m/e 408 (M+H)+.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]([CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1>CO>[ClH:2].[Cl:2][CH2:3][C:4]1[N:5]([CH2:17][CH2:18][CH2:19][NH2:20])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3cccnc3c21
Agent: Cl
Solvent: CO
Product: NCCCn1c(CCl)nc2cnc3cccnc3c21
Reaction time: 48 h
Yield: 184.5 %

Procedure:
Concentrated hydrochloric acid (20 mL) was added to a suspension of tert-butyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propylcarbamate (12.55 g, 33.4 mmol) in methanol (135 mL). The resulting yellow solution was stirred for 48 hours and the liquid was removed via filtration. The resulting solid filter cake was dried overnight in a vacuum, oven at 40° C. to afford 9.62 g of 3-[2-(chloromethyl)-1H-imidazo[4,5-c]-1,5-naphthyridin-1-yl]propylamine hydrochloride as a pale yellow solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:39]=[CH:38][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:37])[C:21]3[S:34][C:33]([CH2:35]Cl)=[CH:32][C:22]=3[N:23]([CH2:25][C:26]([N:28]([O:30][CH3:31])[CH3:29])=[O:27])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[O:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[CH:45]([OH:49])[CH2:46][NH:47][CH3:48].O>CN(C=O)C>[Cl:10][C:11]1[CH:39]=[CH:38][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:37])[C:21]3[S:34][C:33]([CH2:35][N:47]([CH2:46][CH:45]([C:41]4[O:40][CH:44]=[CH:43][CH:42]=4)[OH:49])[CH3:48])=[CH:32][C:22]=3[N:23]([CH2:25][C:26]([N:28]([O:30][CH3:31])[CH3:29])=[O:27])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: CON(C)C(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: CNCC(O)c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CN(C)CC(O)c3ccco3)cc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (34 μL, 0.19 mmol) was added to a mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-{2-[methoxy(methyl)amino]-2-oxoethyl}-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (60 mg, 0.13 mmol) and 1-(2-furyl)-2-(methylamino)ethanol (27 mg, 0.19 mmol) in DMF (2.0 mL). The mixture was shaken at 60° C. for 3 hrs. The reaction was cooled to room temperature before the addition of water (5 mL). The resulting ppt was collected by filtration and washed with water. After drying in vacuo, the title compound was obtained as a pale yellow solid (41 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14]CC3C=CC(OC)=C(OC)C=3)[C:12]3[CH:26]=[CH:27][C:28]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:31])=[CH:29][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[O:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C(Cl)Cl.C(Cl)Cl.C[OH:58]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][CH2:49][CH2:48][C:47]([O:46][CH3:50])=[O:58])[C:12]3[CH:26]=[CH:27][C:28]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:31])=[CH:29][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CO
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C#N)cc1)n2CCc1ccc(OC)c(OC)c1
Reactant: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCn1c(-c2ccc(C#N)cc2)nc2cc(C(=O)NCCC(=O)OC)ccc21

Procedure:
The same procedure is used as in (1) using triethylamine as auxiliary base. A 3:1 mixture of tetrahydrofuran and methylene chloride is used as solvent. Rf value: 0.68 (silica gel; methylene chloride/methanol=37:3)
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)[P:13](N(C)C)N(C)C>C1(C)C=CC=CC=1>[N:1]12[P:13]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9][CH2:10]1)[CH2:3][CH2:2]2
Reactant: C1CNCCNCCNC1
Reactant: CN(C)P(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: C1CN2CCN3CCN(C1)P23
Yield: 88.9 %

Procedure:
A solution of 5.00 g of 1,4,7-triazacyclodecane and 5.70 g of hexamethylphosphorous triamide in 50 ml. of toluene is refluxed for 48 hours. The toluene is removed under reduced pressure, and the residue is distilled through a short-path column, to give 5.31 g (89%) of 1,4,7-triaza-11-phosphatricyclo[5.3.1.04,11 ]undecane as a clear, colorless liquid having a boiling point of 96°-98° C at 0.70 mm. The product solidifies on standing at room temperature.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1.C([N:30](CC)CC)C.ClC(OCC)=O.N>ClCCl>[N:1]1([CH2:6][CH:7]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH2:30])=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(COCC(Cn2ccnc2)OCCCCCC(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Product: COc1ccc(COCC(Cn2ccnc2)OCCCCCC(N)=O)cc1
Temperature: 0 °C

Procedure:
A stirred solution of 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoic acid (Example 1; 10 g, 0.027M) and triethylamine (3.0 g, 0.030 mol) in dry dichloromethane (100 ml) at -50° C. was treated dropwise with ethyl chloroformate (3.2 g, 0.029 mol). The solution was allowed to warm up to 0° C. over 0.5 hours, cooled back to -78° C. and treated with gaseous ammonia. The solution was allowed to warm up to room temperature over 6 hours and washed with an aqueous saturated solution of sodium hydrogen carbonate and dried (Na2CO3). The solvent was evaporated off under reduced pressure to give a residue which was purified by column chromatography (silica gel, ethyl acetate to 10% methanol in ethyl acetate) to give 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]-ethoxy]hexanamide as a pale yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1.[I-].[K+].C[N:18](C)C=O>>[NH2:18][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1
Reactant: O=C1COc2ccc(CCBr)cc2N1
Reactant: CN(C)C=O
Agent: [I-]
Agent: [K+]
Product: NCCc1ccc2c(c1)NC(=O)CO2

Procedure:
In a 250-cm3 ground-necked f1ask, 0.01 mol of 6-(2-bromoethyl)-3-oxo-2,3-dihydro-1,4-benzoxazine and 0.3 g of potassium iodide are dissolved in 30 cm3 of dimethylformamide.