Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][CH2:27][C@H:28]([N:30]([CH3:34])[C:31](=[O:33])[CH3:32])[CH3:29])[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[CH3:35]>>[CH3:34][N:30]([C@H:28]([CH3:29])[CH2:27][O:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:2][C:3]3[N:4]=[CH:5][S:6][CH:7]=3)=[C:10]([CH3:35])[CH:11]=1)=[N:17][CH:18]=[N:19]2)[C:31](=[O:33])[CH3:32]
Reactant: ClCc1cscn1
Reactant: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Product: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(C)c3)c12
Yield: 13 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and N-[(1R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide (obtained as described in Example 93, preparation of starting materials) to give the title compound as a white solid in 13% yield; NMR spectrum (DMSO-d6 373K) 1.22 (d, 3H), 1.86 (s, 3H), 2.24 (s, 3H), 2.85 (s, 3H), 4.33 (m, 1H), 4.42 (t, 1H), 5.09 (m, 1H), 5.25 (s, 2H), 7.09 (d, 1H), 7.18 (d, 1H), 7.34 (d, 1H), 7.39 (s, 1H), 7.50 (d, 1H), 7.70 (m, 2H), 8.41 (s, 1H), 9.08 (s, 1H), 9.51 (s, 1H); Mass spectrum MH+ 478.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:4]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:5]=1[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.CC[N:45]([CH:49](C)C)C(C)C.C(Cl)(Cl)=[O:53].C1(C)C=CC=CC=1.N>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=1)[CH2:14][N:7]([CH2:6][C:5]1[CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:4]=1[CH:3]([O:2][CH3:1])[CH:37]1[CH2:38][CH2:39][N:40]([C:49]([NH2:45])=[O:53])[CH2:41][CH2:42]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: O=C(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCNCC1
Agent: N
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCN(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of N-(2-(methoxy(piperidin-4-yl)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (19.5 mg, 0.030 mmol) in methylene chloride (0.2 mL) at room temperature was added Hunig's base (7 mg, 10 μL, 0.06 mmol) followed by phosgene in toluene (20%, 25 μL, 0.048 mmol). The mixture was stirred at room temperature for 1 hour. Aqueous ammonia (0.2 mL) was added. The mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 1-7% methanol in methylene chloride) to afford the title compound (13 mg, 62%). 1H NMR (400 MHz, CDCl3) δ ppm 1.15-1.21 (m, 1H) 1.23-1.37(m, 2H) 1.61-1.76(m, 3H) 1.88(d, J=12.45 Hz, 1H) 2.57-2.73 (m, 2H) 3.04 (s, 3H) 3.86-3.97 (m, 2H) 4.18 (d, J=7.05 Hz, 1H) 4.21 (s, 3H) 4.66-4.73 (m, 3H) 4.87 (d, J=16.18 Hz, 1H) 7.36 (s, 1H) 7.50 (d, J=7.88 Hz, 1H) 7.58 (d, J=8.30 Hz, 1H) 7.64 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 653.2, Found: 654.6 (M+1)
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH2:9]=[O:10].C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.O>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([O:10][CH2:9][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOP([O-])OCC
Reactant: C=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(COS(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 87 °C
Reaction time: 5.25 h
Yield: 60 %

Procedure:
In a reactor containing an inert atmosphere, e.g., nitrogen, a mixture of diethyl phosphite (0.80 kg), paraformaldehyde (0.22 kg), and triethylamine (0.06 kg) in toluene (0.11 kg) is heated at 87° C. for about 2 hours, then refluxed for about 1 hour, until the reaction is complete as monitored by TLC showing a trace or no detectable diethyl phosphite. During the reaction, the inert atmosphere is maintained. Toluene is necessary to moderate the reaction, which may otherwise explode. Reaction completion is optionally confirmed by 1H NMR (diethyl phosphite peak at δ 8.4-8.6 ppm no longer detected). The solution is cooled to about 1° C. (typically about -2 to 4° C.) and p-toluenesulfonyl chloride (1.0 kg) is added and then triethylamine (0.82 kg) at about 5° C. is slowly added (exothermic addition) while maintaining the temperature at no more than about 10° C. (typically 0 to 10° C.). The resulting mixture is warmed to 22° C. and stirred for at least about 5 hours (typically about 4.5 to 6.0 hours), until the reaction is complete as shown by TLC (trace or no p-toluenesulfonyl chloride detectable) and optionally confirmed by 1H NMR (p-toluenesulfonyl chloride doublet at δ 7.9 ppm no longer detected). The solids are removed by filtration and washed with toluene (0.34 kg). The combined washings and filtrate are washed either twice with water (1.15 kg per wash), or optionally with a sequence of water (1.15 kg), 5% aqueous sodium carbonate (3.38 kg), and then twice with water (1.15 kg). After each wash, the reactor contents are briefly agitated, allowed to settle and the lower aqueous layer is then discarded. If the reaction results in an emulsion, brine (0.23 kg of water containing 0.08 kg NaCl) may be added to the first organic/water mixture, followed by agitating the reactor contents, allowing the solids to settle, discarding the lower aqueous layer, adding 1.15 kg water, agitating, allowing solids to settle and again discarding the lower aqueous layer. The organic phase is distilled in vacuo at no more than 50° C. (to LOD at 110° C. of no more than 10% and water content, by KF titration, no more than 0.3%), affording a yield of about 60-70% of the title compound as an oil of about 85-95% purity, exclusive of toluene.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]1=O)=[O:4].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19]([NH2:21])=[NH:20]>C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([C:19]2[N:20]=[C:3]([OH:4])[C:5]3[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=3[N:21]=2)[CH:22]=1
Reactant: N=C(N)c1cc(Cl)ccc1F
Reactant: COC(=O)C1CC(C)(C)CC1=O
Solvent: CCO
Product: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(O)c2C1
Yield: 58.8 %

Procedure:
A solution of 4,4-Dimethyl-2-oxo-cyclopentanecarboxylic acid methyl ester (2.08 g, 12.21 mmol) and 5-Chloro-2-fluoro-benzamidine (2.32 g, 13.44 mmol) in 100% ethanol (40 mL) was heated to reflux overnight, then cooled and evaporated. The residue was dissolved in 1N (aq.) NaOH (50 mL) and washed with methylene chloride (2×50 mL). The aqueous layer was then acidified with glacial acetic acid to pH 4 and extracted with methylene chloride (2×100 mL). The organic extracts were dried (brine and MgSO4) and evaporated to give crude product, which was purified by chromatography (CH2Cl2, 0-10% MeOH) to give the desired product as a cream solid (2.10 g, 59% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 105.9 %

Procedure:
Methanesulfonyl chloride (186.3 mg, 125.9 μL, 1.626 mmol) was added dropwise to a stirred solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (350 mg, 1.626 mmol) and DIPEA (222.8 mg, 300.3 μL, 1.724 mmol) in DCM (5 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature over 16 hours then treated with water. The phases were separated and the aqueous phase extracted with DCM (×3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the sub-title compound as a white solid (505 mg, >100% Yield) that was used directly assuming 100% yield and purity. MS (ES+-t-Bu) 238.0.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH3:18])[C:13]([C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[CH:12][CH:11]=1.CI.[C:30](=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:9][C:10]1[N:15]=[C:14]2[C:13]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[C:4]([CH2:3][CH2:2][C:1]([O:7][CH3:30])=[O:8])[C:5](=[O:6])[N:16]2[CH2:17][CH3:18])=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCNc1nc(Cl)ccc1C(=O)c1cccc(Cl)c1
Reactant: O=C1CCCC(=O)O1
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CCn1c(=O)c(CCC(=O)OC)c(-c2cccc(Cl)c2)c2ccc(Cl)nc21
Temperature: 150 °C

Procedure:
Glutaric anhydride and 6-chloro-3-(3-chlorobenzoyl)-2-ethylaminopyridine were reacted under heating at 150° C. and then worked up in a usual manner. The resulting compound was reacted with methyl iodide in 2-butanone in the presence of potassium carbonate at 60° C. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain methyl 3-[7-chloro-4-(3-chlorophenyl)-1-ethyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoate as a colorless solid. MS: 405.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:41]([CH2:45][CH:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)[C:42]([OH:44])=O)[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([CH3:40])=[N:38][N:37]=[N:36]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:42](=[O:44])[CH:41]([C:31]2[CH:32]=[CH:33][C:34]([N:35]3[C:39]([CH3:40])=[N:38][N:37]=[N:36]3)=[C:29]([Cl:28])[CH:30]=2)[CH2:45][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50]2)=[N:53][CH:54]=1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A solution of triphenylphosphine (236 mg, 0.9 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (160 mg, 0.9 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with the 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionic acid (prepared in Example 3, 151 mg, 0.45 mmol). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-amino−5-bromopyridine (234 mg, 1.35 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (30 mL) and water (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionamide (90 mg, 42%) as an amorphous white solid: EI-HRMS m/e calcd for C21H22BrClN6O (M+) 489.0727, found 489.0727.
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].Br[C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([N:16]2[CH:26]=[C:19]3[CH:20]=[N+:21]([O-:25])[CH:22]=[C:23]([F:24])[C:18]3=[N:17]2)=[C:11]([Cl:27])[CH:10]=1.C(Cl)(Cl)Cl>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:13]1[CH:14]=[C:9]([CH:1]=[CH2:2])[CH:10]=[C:11]([Cl:27])[C:12]=1[N:16]1[CH:26]=[C:19]2[CH:20]=[N+:21]([O-:25])[CH:22]=[C:23]([F:24])[C:18]2=[N:17]1
Reactant: [O-][n+]1cc(F)c2nn(-c3c(Cl)cc(Br)cc3Cl)cc2c1
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCCO
Product: C=Cc1cc(Cl)c(-n2cc3c[n+]([O-])cc(F)c3n2)c(Cl)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
Triethylamine (3.5 mL, 25 mmol) was added to a mixture of 2-(4-bromo-2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine 5 oxide (1.88 g, 5.0 mmol), potassium vinyl trifluoroborate (1.0 g, 7.5 mmol) and Pd(dppf)Cl2.CHCl3 (408 mg, 0.5 mmol) in propan-1-ol (50 mL) and the reaction mixture was heated at 100° C. for 1.5 hours. The resultant mixture was allowed to cool to room temperature before being partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (4-5% methanol in DCM) to afford the title compound as a beige solid (1.0 g, 62% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.00 (d, J=2.6 Hz, 1H), 8.89 (d, J=1.4 Hz, 1H), 8.35 (dd, J=6.3, 1.5 Hz, 1H), 7.97 (s, 2H), 6.85 (dd, J=17.6, 11.0 Hz, 1H), 6.24 (d, J=17.6 Hz, 1H), 5.60 (d, J=11.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:31]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Product: CC(C)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3,4-difluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 35 mg, 42%). mp 169-171° C. 1H NMR (300 MHz, DMSO-d6) δ 0.78 (d, 6H), 1.84, (m, 1H), 4.2 (d, 2H), 7.54 (m, 3H), 7.6 (m, 1H), 7.82 (m, 3H), 7.91 (d, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 436 (M+H)+, 453 (M+NH4)+. Anal. calc. for C20H19F2N3O4S.0.25H2O: C, 55.17; H, 4.40; N, 9.65. Found: C, 54.19; H, 4.25; N, 9.35
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[Br:9][C:10]1[N:14]2[N:15]=[C:16](F)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1>>[Br:9][C:10]1[N:14]2[N:15]=[C:16]([NH:1][CH2:2][C@H:3]3[NH:7][C:6](=[O:8])[CH2:5][CH2:4]3)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: NC[C@@H]1CCC(=O)N1
Product: O=C1CC[C@@H](CNc2ccc3ncc(Br)n3n2)N1
Yield: 62 %

Procedure:
The (S)-5-(aminomethyl)pyrrolidin-2-one was reacted with 3-bromo-6-fluoroimidazo[1,2-b]pyridazine under the amine displacement conditions described in example 5.6.42, Part A, to obtain the titled in 62% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.90-2.04 (m, 1H) 2.24-2.50 (m, 3H) 3.46-3.56 (m, 2H) 4.09 (quin, J=5.84 Hz, 1H) 6.74 (d, J=9.70 Hz, 1H) 7.43 (s, 1H) 7.60 (d, J=9.70 Hz, 1H); LRMS (ESI) m/310.0 doublet [(M+H)+, calcd for C11H12BrN5O 309.0].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][C@@H:10]([CH3:14])[C@H:9]2[CH3:15])[N:5]=[C:4]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:26][CH:25]([F:27])[C:17]1[N:16]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][C@@H:10]([CH3:14])[C@H:9]3[CH3:15])[CH:7]=[C:2]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:3]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1
Reactant: C1COCCN1
Reactant: C[C@@H]1OCCN(c2cc(Cl)nc(-n3c(C(F)F)nc4ccccc43)n2)[C@@H]1C
Product: C[C@@H]1OCCN(c2cc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)[C@@H]1C
Temperature: 70 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
0.84 g (5 mmol) of 2-difluoromethylbenzimidazole dissolved in DMF (25 ml) was added and reacted with 60% sodium hydride (0.24 g, 6 mmol) at room temperature for 30 minutes. This suspension was added to a solution of 2,4,6-trichloropyrimidine (0.92 g, 5 mmol) dissolved in DMF (25 ml) and stirred at room temperature for 1.5 hours. The reaction solution was poured into water and the resulting precipitates were recrystallized from methanol to obtain 0.98 g (yield: 62%) of 4,6-dichloro-2-(2-difluoromethylbenzimidazol-1-yl)pyrimidine. (2) 0.32 g (1.0 mmol) of 4,6-dichloro-2-(2-difluoro-methylbenzimidazol-1-yl)pyrimidine, 0.16 g (1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g (2.2 mmol) of anhydrous potassium carbonate were added to DMF (10 ml) and stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.33 g (yield: 84%) of 4-chloro-2-(2-difluoro-methylbenzimidazol-1-yl)-6-(cis-2,3-dimethylmorpholino)-pyrimidine. (3) 0.33 g (0.8 mmol) of the obtained 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-(cis-2,3-dimethyl-morpholino)pyrimidine dissolved in morpholine (0.70 g, 8.0 mmol) was stirred at 70° C. for 1 hour. The solvent was removed under the reduced pressure from the reaction mixture and the residue was purified by silica gel column chromatography to obtain 0.326 g (yield: 90%) of the titled compound as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[CH2:7]2.[CH3:13][N:14](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[O:12]=[C:6]1[CH2:5][CH2:4][C:3]2[CH:2]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=2[CH2:7]1
Reactant: CN(C)C=O
Reactant: O=C1CCc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)CCC(=O)C2

Procedure:
The 5-bromo-2 tetralone (2.0 g, 8.9 mmol), tetrakis(triphenylphosphine)palladium (0.62 g, 0.53 mmol) and zinc cyanide (0.73 g, 6.2 mmol) were added to 4 ml DMF in a 20 ml microwave tube. The mixture was degassed and microwaved at 80° C. for 30 mins. TLC showed no starting material left and the mixture was diluted with ethyl acetate and washed with ammonium hydroxide (2M, ×4 ml). The organic layer was separated and dried over Na2SO4 then filtered. The solvent was evaporated under reduced pressure. The residue was chromatographed through 40 gm Isco Redi-sep column and eluted with 0-30% ethyl acetate-hexane to yield 6-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:16]=[CH:17][CH2:18][CH2:19][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].C[N+]1([O-])CC[O:25]CC1.S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([NH:4][C:1](=[O:3])[CH3:2])([CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:25])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10]
Reactant: CCCC=CC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(CCCCC=O)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl 2-acetamido-2-pentenylmalonate (4.0 g) was dissolved in 210 ml of acetone and 3.3 g of N-methylmorpholine-N-oxide and 36 ml of a 1% aqueous osmium tetraoxide solution were added thereto. The mixture was stirred at room temperature for 2 hours. A solution of 700 mg of sodium sulfite in 20 ml of water was added thereto and the mixture was stirred for 15 minutes. The reaction mixture was concentrated and subjected to silica gel column chromatography using chloroform/methanol (10:1) as an eluent and a fraction having an Rf value: 0.3 (chloroform:methanol=10:1) was concentrated. The residue was dissolved in 630 ml of 1,4-dioxane and 70 ml of a 0.2 M aqueous meta-sodium periodate solution was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtrated, concentrated, extracted with ethyl acetate and washed with water. The hexane layer was dried and concentrated to give 4.17 g of colorless, oily diethyl-2-acetamido-2-(4-formylbutyl)malonate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[NH:5][CH2:6][CH2:7][C:8](O)=O.S(=O)(=O)(O)[OH:16]>>[CH3:1][C:2]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:4]2[C:3]=1[CH:8]=[CH:7][C:6](=[O:16])[NH:5]2
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(C)cc(NCCC(=O)O)c1
Product: Cc1cc(C)c2ccc(=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
β-(3,5-Dimethylanilino)propionic acid (1.2 g) was added by portions to sulfuric acid (60° C., 12 ml), and the mixture was stirred at the same temperature for 0.5 hr. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/benzene=1/5-1/1) to give 750 mg of 5,7-dimethylquinolone as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(O)C.[CH3:29][C:30]1[CH:31]=[C:32]([C:36]([N:38]=[C:39]=[S:40])=[O:37])[CH:33]=[CH:34][CH:35]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:39]([NH:38][C:36](=[O:37])[C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[CH:31]=2)=[S:40])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: Cc1cccc(C(=O)N=C=S)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then 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 (69 mg, yield 91%).