Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9](/[CH:11]=[CH:12]/[C:13]3[N:18]=[C:17]([NH2:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[NH:8][C:5]2=[N:6][CH:7]=1.C(O)(=O)C>CO.O=[Pt]=O>[NH2:19][C:17]1[CH:16]=[C:15]([CH3:20])[CH:14]=[C:13]([CH2:12][CH2:11][C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]3[N:10]=2)[N:18]=1
Reactant: Cc1cc(N)nc(/C=C/c2nc3cc(Br)cnc3[nH]2)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(N)nc(CCc2nc3cc(Br)cnc3[nH]2)c1
Reaction time: 65 h
Yield: 73.7 %

Procedure:
930 mg of 6-[(E)-2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-vinyl]-4-methyl-pyridin-2-ylamine (compound A11) are suspended in 300 ml of methanol. Subsequently, 805 μl acetic acid and 96 mg of Adam's catalyst [platin(IV) oxide] are added. The suspension is vigorously stirred for 65 h. Thereafter, the solution is passed through kieselguhr, which is rinsed with methanol. The filtrate is evaporated to dryness and the remaining residue (1.20 g) purified by chromatography on silica gel (eluent: dichloromethane/methanol=20:1) to afford 690 mg of the title compound as colorless powder after lyophilization from 15.0 ml dioxane and 3.0 ml water. M.p. 216° C. ESI-MS: 332.1/334.2 (MH+, 97%/100%). TLC: Rf=0.35 (dichloromethane/methanol 10:1).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]([F:13])([F:12])/[C:7](=[N:10]/[OH:11])/[S:8][CH3:9]>>[F:5][C:6]([F:13])([F:12])/[C:7](=[N:10]/[O:11][C:3](=[O:4])[NH:2][CH3:1])/[S:8][CH3:9]
Reactant: CS/C(=N\O)C(F)(F)F
Reactant: CN=C=O
Product: CNC(=O)O/N=C(\SC)C(F)(F)F
Yield: 95.6 %

Procedure:
A mixture of 17.12 g (0.3 mol) of methyl isocyanate and 47.74 g (0.3 mol) of S-methyl (Z)-2,2,2-trifluoro-N-(hydroxy)thioacetimidate was sealed in a glass tube and heated at 100° in a steam bath for 17 hours. The contents of the tube were distilled at reduced pressure to give 62.02 g (96%) of S-methyl (Z)-2,2,2-trifluoro-N-(methylcarbamoyloxy)thioacetimidate as a colorless, viscous liquid: bp 96° (0.6 mm); nD25 1.4638; ir (neat) 5.73μ (C=O); 19F NMR (CFCl3) δ-64.6 ppm (q, J=1.2 Hz); 1H NMR (CFCl3) δ2.63 ppm (q, J=1.2 Hz, 3H), 2.88 ppm (d, J=4.5 Hz, 3H) and 6.47 ppm (NH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][C:15]3=[O:23])[CH:11]=[C:10]([C:24](O)=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[N:29]=[CH:30][C:31]([CH2:34][NH2:35])=[N:32][CH:33]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:27][C:28]1[N:29]=[CH:30][C:31]([CH2:34][NH:35][C:24]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH:13]=[C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][C:15]3=[O:23])[CH:11]=2)=[O:25])=[N:32][CH:33]=1
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3C(=O)Cc4ccccc43)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc(N3C(=O)Cc4ccccc43)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
The 4′-methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid from step 3 was added to DMF (3 mL), together with C-(5-methyl-pyrazin-2-yl)-methylamine (0.1 mL), HOAt (15 mg, catalytic amount), NMM (0.4 mL) and EDCI (200 mg). The reaction mixture was stirred overnight at room temperature, then partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (7% MeOH in dichloromethane) to give 20 mg (5% overall) of 4′-methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide, MS (M+H)=449.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.[CH3:18][N:19]=[C:20]=[S:21]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:20]([NH:19][CH3:18])=[S:21])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CN=C=S
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: ClCCl
Product: CNC(=S)NC1c2cc3nonc3cc2OC(C)(C)C1O
Temperature: 25 °C
Yield: 46.5 %

Procedure:
To a mixture of 200 mg (0.850 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole and 20 ml of dichloromethane were added 68 mg (0.935 m mol) of methylisothiocyanate with stirring at the room temperature, followed by stirring for 23 hours. The precipitated crystals were separated by filter to obtain 122 mg of the intended compound as colorless crystals. (yield: 47%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([NH:8][OH:9])=[O:7].N1C=CC=CC=1.[CH2:21]([C:23]([CH2:30][CH3:31])([C:27](Cl)=[O:28])[C:24](Cl)=[O:25])[CH3:22]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([N:8]1[C:24](=[O:25])[C:23]([CH2:30][CH3:31])([CH2:21][CH3:22])[C:27](=[O:28])[O:9]1)=[O:7]
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)NO)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1(CC)C(=O)ON(C(=O)c2ccc(OC)c(OC)c2)C1=O
Yield: 73.4 %

Procedure:
A mixture consisting of 1.97 g (0.0100 mol) of 3,4-dimethoxybenzohydroxamic acid, mp 170°-173° C. (dec.) (lit, mp 167°-168° C., F. Aljundi, E. Hannig, and K. Bohm, Pharmazie, 28, 362 (1973)), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round bottom flask. The mixture was cooled in an ice bath, and 1.977 g (0.0100 mol) of diethylmalonyl chloride was added dropwise over a 15 minute period with stirring. The reaction mixture was stirred for 1 hour at room temperature after which time all the hydroxamic acid has dissolved. The solution was extracted three times with 50 ml portions of water, four times with 50 ml portions of 5% hydrochloric acid, and two times with 50 ml portions of 5% sodium carbonate. The methylene chloride was dried (MgSO4) and evaporated to dryness under reduced pressure to give 2.36 g (73.5%) of crude 2-(3,4-dimethoxybenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a solid residue. Recrystallization of the solid from absolute ethanol gave pure 2-(3,4-dimethoxybenzoyl)-4,4-diethylisoxazolidine-3,5-dione as a white solid: mp 108°-109° C.; IR (Nujol) 1805 (s, C=O), 1752 (s, C=O), 1693 cm-1 (s, C=O); 1H NMR (400 MHz, CDCl3) δ7.40-7.54 (m, 2H), 6.94-6.96 (d, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 1.97 (q, 4H), 1.02 (t, 6H); High resolution MS, calc'd for: C16H19NO6 : 321.1212. Found: 321.1208. Anal. Calc'd for: C16H19NO6 : C, 59.80; H, 5.96; N, 4.36. Found: C, 60.04; H, 6.05; N, 4.44.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH2:34][O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:31]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH2:34][O:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:31]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[N:30][C:25]=3[CH:26]=[N+:27]([O-:9])[C:28]=2[CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Reaction time: 2.5 h
Yield: 96.5 %

Procedure:
mCPBA (77% pure, 0.36 g, 1.6 mmol) was added to a solution of tert-butyl {4-[7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-2-yl]butyl}carbamate (0.89 g, 1.6 mmol) in dichloromethane (50 mL), and the reaction was stirred for 2.5 hours under a nitrogen atmosphere. Additional mCPBA (150 mg) was added, and the reaction was stirred over two nights. The solution was washed with water, saturated aqueous sodium bicarbonate, water, and brine, dried over sodium sulfate, and concentrated under reduced pressure to provide 0.90 g of tert-butyl {4-[7-benzyloxy-5-oxido-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-2-yl]butyl}carbamate as a tan foam.
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])[NH:9][CH:8]=[CH:7][C:6]2=[S:15].Br[C:17]1[S:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[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[S:15][C:17]1[S:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(Br)s1
Reactant: COc1cc2[nH]ccc(=S)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2nccc(Sc3ccc([N+](=O)[O-])s3)c2cc1OC
Yield: 55.4 %

Procedure:
6,7-Dimethoxy-1H-quinolin-4-thione (2.21 g, 10.0 mmol), 2-bromo-5-nitrothiophene (2.29 g, 11.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were stirred in dimethylformamide (30 ml) at room temperature for 1 hour. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with 1N aqueous sodium hydroxide, water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:hexane=3:1), and the fraction containing the target substance was concentrated to obtain the title compound (1.93 g, 5.54 mmol, 55%) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([O:18]C)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH3:20])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([OH:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH3:20])=[CH:6][CH:7]=1
Reactant: COc1cccc2c1cc(C)n2Cc1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1ccc(F)cc1
Yield: 84.2 %

Procedure:
By the method used in Example 1, Part D, 1.1 g (4.1 mmol) of 1-[(4-fluorophenyl)methyl]-4-methoxy-2-methyl-1H-indole was O-demethylated by treating it with 16.4 mL of 1M BBr3 /CH2Cl2 to give 881 mg (84% yield) of crude 1-[(4-fluorophenyl)methyl]-4-hydroxy-2-methyl-1H-indole.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:27])([F:26])[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][C:18]([C:21](OCC)=[O:22])=[N:17]2)=[CH:12][CH:11]=1>CCOCC>[F:27][C:8]([F:7])([F:26])[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[N:17]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(OC(F)(F)F)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1ccn(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
LiAlH4 (0.137 g, 3.61 mmol) was added to a solution of ester 66 (1.081 g, 3.60 mmol) in Et2O (20 mL) at 0° C. and the stirred mixture was warmed to room temperature for 1 h, then cooled to 0° C. and quenched with ice. The mixture was diluted with Et2O (100 mL) and saturated aqueous sodium potassium tartrate (100 mL) and then filtered through Celite. The organic layer was dried and chromatographed on silica gel, eluting with CH2Cl2:EtOAc (95:5), to give {1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-3-yl}methanol (67) (0.888 g, 96%) as a white solid: mp 53-54° C.; 1H NMR [(CD3)2SO] δ 8.44 (d, J=2.5 Hz, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.5 Hz, 2H), 6.50 (d, J=2.5 Hz, 1H), 5.15 (t, J=5.8 Hz, 1H), 4.51 (d, J=5.8 Hz, 2H). APCI MS m/z 259 [M+H]+.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Rh]>[CH:2]1([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: c1ccc(C2CCCNC2)cc1
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: C1CCC(C2CCCNC2)CC1
Reaction time: 96 h

Procedure:
Combine 3-phenyl-piperidine hydrochloride (0.206 g, 1.04 mmol) and 5% rhodium on alumina (0.112 g, 0.0544 mmol) in methanol (50 mL) and stir at 50° C. at a 12 pressure of 60 psi. After 4 d, purify the reaction mixture by ion exchange chromatography (SCX resin, methanol→2 M ammonia/methanol) to provide 0.164 g (3:1 mixture of product:starting material) which was used in the next step without further-purification: mass spectrum (electrospray): m/z=168.1 (M+1-product), 162.1 (M+1-starting material).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:29][O:28][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[N:13]=[CH:12][CH:11]=[C:10]2[O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=1[C:25](=[O:27])[CH3:26]
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
1-{2-[7-(3-Chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone (compound 318) (77 mg), morpholine (49 mg), and potassium carbonate (131 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (60 mg, 68%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1[Cl:18])=S.N1C=CN=C1.Cl>C1(C)C=CC=CC=1>[Cl:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:7]=[C:5]1[NH:4][CH2:3][CH2:2][NH:1]1
Reactant: NCCNC(=S)Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)c(N=C2NCCN2)c(Cl)c1
Temperature: 25 °C

Procedure:
The thiourea (7) (0.50 g, 1.6 mmole) was suspended in 10 mL of toluene and imidazole (0.16 g, 1.6 mmole) was then added. The yellow mixture was heated at reflux for approximately 24 hours, then cooled to ambient temperature and treated with 1M HCl. The aqueous phase was separated, the toluene phase was extracted with 1M HCl, and the combined aqueous phases were brought to pH 8-9 with 1N NaOH. The resulting yellow solid was collected by filtration, washed successively with water and hexane, and then air dried to provide 0.30 g (68%) of nitroclonidine contaminated by a trace of a higher Rf impurity by TLC.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[C:10]([F:13])([F:12])[F:11].Cl[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:18].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:17]([C:16]1[O:1][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:18]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: O=C(c1ccc(O)cc1O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1Cl)c1oc2cc(O)ccc2c1C(F)(F)F
Temperature: 90 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
To a solution of 1-(2,4-dihydroxy-phenyl)-2,2,2-trifluoro-ethanone (1.00 g, 4.85 mmol) and 2-chloro-1-(2,4-dichlorophenyl)ethanone (1.08 g, 4.85 mmol, 1.0 eq) in anhydrous N,N-dimethylformamide (10 mL) was added potassium carbonate (1.01 g, 7.28 mmol, 1.5 eq). The reaction mixture was stirred at 90° C. for 16 h. The mixture was cooled to room temperature and then poured into ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2×100 mL), dried over Na2SO4, filtrated, and evaporated in vacuo. The residue was purified by column chromatography eluted with 5% EtOAc/hexane then 30% EtOAc/hexane solution to afford a yellow solid (610 mg, 33.5%) as product. 1H-NMR (CDCl3): δ 7.76 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.50 (d, J=1.7 Hz, 1H), 7.41 (dd, J=8.1, 1.9 Hz, 1H), 7.01 to 6.95 (m, 2H), 5.49 (s, 1H); LC-MS (MH+=375/377).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]Cl.CN(C)C=O>C(OCC)(=O)C>[CH2:32]1[C:27]2[C:26](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:1]1[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Reactant: ClCc1ccccc1CCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cn2cc(Oc3cccc(N4Cc5ccccc5C4)c3)ccc2n1)C1CC1
Temperature: 50 °C
Reaction time: 14 h
Yield: 34 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (19.4 mg, 0.063 mmol), 1,2-bis(chloromethyl)benzene (13.5 mg, 0.077 mmol) and N,N-dimethylformamide (2.0 mL) was stirred at 50° C. for 14 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated, and the residue was purified by preparative HPLC to give the title compound (8.8 mg, 34%).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.IC.[C:13](=O)(O)[O-].[Na+]>CN(C)C=O.O>[C:1]1([CH3:10])[C:2]([C:7]([O:9][CH3:13])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccccc1C
Reaction time: 3.5 h
Yield: 90.8 %

Procedure:
A mixture of o-toluic acid (15 g, 0.11 mole), iodomethane (51 g, 0.36 mole) and anhydrous sodium bicarbonate (25.2 g, 0.3 mole) in dry dimethylformamide (60 ml) was stirred at 70° (oil bath temperature) under an atmosphere of nitrogen for 3.5 hours. The resulting mixture was diluted with water (200 ml) and extracted with ethyl ether (3×100 ml). The combined extracts were washed several times with water, dried over anhydrous MgSO4 and evaporated in vacuo to give the title ester compound (15 g, 90.6%) as an oil with a consistent H1 -NMR spectrum.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[C:3]=1[I:11].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[I:11][C:3]1[C:4]2[S:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[O:1][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc2ncsc2c1I
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc4ncsc4c3I)c2cc1OC
Temperature: 140 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
6-Hydroxy-7-iodo-benzothiazole (210 mg), 4-chloro-6,7-dimethoxyquinoline (567 mg), and 4-dimethylaminopyridine (390 mg) were suspended in o-dichlorobenzene (15 ml), and the suspension was stirred at 140° C. for 3 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (151 mg, yield 43%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[Br:21][C:22]1[CH:23]=[CH:24][C:25](I)=[C:26]([CH:29]=1)[C:27]#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([NH:1][C:2]2[N:11]=[CH:10][C:9]3[CH2:8][CH2:7][C:6]4[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=4[C:4]=3[N:3]=2)=[C:26]([C:27]#[N:28])[CH:29]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Reactant: N#Cc1cc(Br)ccc1I
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(Br)cc3C#N)nc1-2
Temperature: 80 °C
Yield: 24.6 %

Procedure:
To a solution of ethyl 8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (207 mg, 0.753 mmol) in dioxane (6 mL), 5-bromo-2-iodobenzonitrile (260 mg, 0.627 mmol) and cesium carbonate (290 mg, 0.753 mmol) were added and the flask was evacuated and backfilled with argon. [Pd2(dba)3] (13 mg, 0.014 mmol) and X-phos (19 mg, 0.033 mmol) were then charged and the mixture was heated at 80° C. under argon for 8 hours. After cooling to room temperature, the reaction mixture was concentrated, suspended in water (10 mL) and extracted with ethyl acetate. The organic phase was anidrified on Na2SO4, filtered and evaporated to dryness, the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 98/2) to afford 70 mg (20% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.Cl.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:30][C:31]1([F:35])[CH2:34][N:33]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]4[N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:21]=[CH:20][CH:19]=4)=[N:10]3)[CH:4]=2)[CH2:32]1
Reactant: FC1(F)CNC1
Reactant: COc1cn(-c2cc(I)ccc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cn(-c2cc(N3CC(F)(F)C3)ccc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 40.6 %

Procedure:
A mixture of 1-(2-fluoro-5-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), 3,3-difluoroazetidine hydrochloride (77.7 mg, 0.6 mmol), NaOtBu (125 mg, 1.3 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd2(dba)3 (18.3 mg, 0.02 mmol) in 1,4-dioxane (2.5 mL) was heated to 90° C. for 13 h under Ar. The mixture was diluted with saturated NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with EtOH/hexane to yield the title compound (92 mg, 41% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): 8 ppm 3.77 (3H, s), 4.25 (4H, t, J=12.2 Hz), 6.48 (1H, dd, J=6.4, 3.0 Hz), 6.63-6.72 (1H, m), 6.90 (1H, d, J=1.5 Hz), 7.25-7.48 (6H, m), 7.79 (1H, d, J=1.9 Hz), 8.45 (1H, d, J=1.9 Hz). Anal. Calcd for C23H18F3N5O2: C, 60.93; H, 4.00; N, 15.45. Found: C, 60.97; H, 3.94; N, 15.47.