Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].S(=O)(=O)([OH:16])N.[O-]Cl=O.[Na+]>CC#N.O>[CH3:13][O:12][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([I:1])[C:9]=1[O:10][CH3:11])[C:5]([OH:16])=[O:6]
Reactant: COc1cc(C=O)cc(I)c1OC
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)O)cc(I)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a stirred solution of 3-iodo-4,5-dimethoxybenzaldehyde (25.0 g, 85.6 mmol) in CH3CN (800 mL) at room temperature, was added a solution of sulfamic acid (10.65 g, 109 mmol) in H2O (135 mL). To this was added, dropwise, a solution of NaClO2 (12.65 g, 112 mmol) in H2O (135 mL) over 20 min period. After stirring for a further 30 min at room temperature, the solvent was removed in vacuo. The reaction was diluted with 1.0 M aqueous HCl (700 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (600 mL), dried over Na2SO4 and concentrated in vacuo to give 3,4-dimethoxy-5-iodobenzoic acid (26 g). The product was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3O[CH:8]3[C:7]=2[CH:15]=1)#[N:2].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]([O:27][CH3:28])=[O:26])=[CH:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([O:27][CH3:28])=[O:26])=[CH:17]3)[C:7]=2[CH:15]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c2ccccc12
Temperature: 90 °C
Yield: 48.4 %

Procedure:
To the solution of 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-benzopyran (1.15 g, 5.71 mmol) (prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem., 1986, 29, 2194), and indole-3-carboxylic acid, methyl ester (1.0 g, 5.71 mmol) in dimethylformamide (5.0 mL) under argon was added finely ground potassium carbonate (1.93 g, 14.0 mmol). The reaction mixture was heated at 90° C. for 4 hours and cooled to ambient temperature. It was diluted with ethyl acetate and filtered. The filtrate was washed with water, 10% citric acid, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to yield a colorless foam. It was purified by flash chromatography (5% ethyl acetate in hexanes) to give 1-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-1H-indole-3-carboxylic acid, methyl ester (990 mg), m.p. 177°-180° C. (ether-hexanes): 1H NMR (DMSO-d6) δ 8.3 (s, 1 H), 8.21 (d, J=6.4 Hz, 1 H), 7.80 (dd, J=8.8 and 2.4 Hz, 1 H), 7.35 (m, 3 H), 7.18 (d, 8.2 Hz, 1 H), 6.90 (d, J=1.7 Hz, 1 H), 6.42 (s, 1 H), 3.93 (s, 3 H), 1.68 (s, 6 H); 13C NMR (DMSO-d6) 164.5, 156 9, 136.9, 135.5, 135.2, 130.9, 128.7, 126.7, 126.3, 123.8, 122.7, 121.4, 119.8, 118.8, 118.4, 111.6, 108.4, 103.7, 79.3, 51.3, 27.9 ppm; IR (KBr) 2224, 1705, 1207 cm-1.
Reaction SMILES: [OH:1][C@H:2]1[C:11](=[O:12])[C:10]2[CH:9]=[CH:8][N:7]3[CH:13]=[C:14]([CH3:16])[N:15]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:39](Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>ClCCl>[CH3:16][C:14]1[N:15]=[C:6]2[C:5]3[NH:4][C@H:3]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C@@H:2]([O:1][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:11](=[O:12])[C:10]=3[CH:9]=[CH:8][N:7]2[CH:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)C3=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](OC(=O)C(C)(C)C)C3=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a of 0° C. cooled solution of 10.5 g (35.8 mmol) (8R,9R)-8-hydroxy-2-methyl-9-phenyl-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridin-7-one in dichloromethane (110 ml) is added 5.70 ml (41.2 mmol) triethylamine, 0.22 g (1.80 mmol) dimethylaminopyridine and 5.10 ml (41.2 mmol) pivaloyl chloride dissolved in dichloromethane (10 ml). The reaction is stirred for 2 h at 0° C. and warmed up to 25° C. and stirred for further 24 h. Afterwards 5.70 ml (41.2 mmol) triethylamine, 0.22 g (1.80 mmol) dimethylaminopyridine and 5.10 ml (41.2 mmol) pivaloyl chloride are added to this mixture and it is stirred for 18 h at 25° C. Subsequently the reaction is quenching by adding of water (100 ml). The organic layer is separated, washed with ammonia solution, washed with water two times, dried over sodium sulphate and evaporated in vacuo. The crude product is crystallised from 2-propanol to provide 12.1 g (32.06 mmol/90%) of the title compound as a colourless solid with a melting point of 145–147° C. (2-propanol).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[C:47]1([N:53]=[C:54]=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C>ClC(Cl)C>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:54]([NH:53][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:55])=[O:43]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C=Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2ccccc2)s1
Reaction time: 4 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (5.0 g) was dissolved in dichloroethane (80 ml). Phenyl isocyanate (0.807 ml) and triethylamine (2.8 ml) were added at room temperature, and the mixture was stirred for 4 hours. Then, the reaction mixture was washed with water and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 2.1 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-N'-phenylurea.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].[CH2:15](I)[C:16]([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[CH3:15][C:16]([CH3:19])([CH3:18])[CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CC(C)(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Cn1cc(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
1H-Indole-3-carboxylic acid (208 mg) was dissolved in N,N-dimethylformamide (10 ml), then sodium hydride (154 mg) was added thereto, and the mixture was stirred for 10 minutes at room temperature. Neopentyl iodide (0.25 ml) was added to the reaction solution and stirred for 15 hours at 80° C. Water was added to the reaction mixture which was then washed with ethyl acetate. The aqueous phase was adjusted to pH 6 by 1 N hydrochloric acid, extracted with ethylacetate, and the extract was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; n-hexane:ethyl acetate 4:1) to give the title compound (264 mg, Y.:89%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1.[Br:14]N1C(=O)CCC1=O>ClCCl.N(C(C)(CC(C)(OC)C)C#N)=NC(C)(CC(OC)(C)C)C#N>[Br:14][CH2:1][C:2]1[O:6][C:5]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2cccc([N+](=O)[O-])c2o1
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2cc(CBr)oc12
Yield: 85.8 %

Procedure:
A mixture of 2-methyl-7-nitrobenzo[b]furan (2.66 g), N-bromosuccinimide (3.21 g) and 2,2'-azobis-(2,4-dimethyl-4-methoxyvaleronitrile) (270 mg) in dichloromethane (30 ml) was refluxed for 1 hour. The reaction mixture was washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from diethyl ether to give 2-bromomethyl-7-nitrobenzo[b]furan (3.3 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[C:4](=O)[CH2:3]1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.C([BH3-])#N.[Na+]>CO.O>[CH3:1][C:2]1([CH3:12])[O:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[CH:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:3]1
Reactant: C1CCNC1
Reactant: CC1(C)CC(=O)c2sccc2O1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CC(N2CCCC2)c2sccc2O1
Reaction time: 24 h
Yield: 53.6 %

Procedure:
A solution of 5,6-dihydro-5,5-dimethylthieno[3,2-b]pyran-7-one (1.0 g, 5,5 mmol), pyrrolidine (2.3 ml, 27.4 mmol) sodium cyanoborohydride (0.345 g, 5,5 mmol) and 1N aqueous hydrochloric acid (5,5 ml, 5,5 mmol) in methanol (15 ml)-was stirred at rt for 1 day. Additional sodium cyanoborohydride (0.345 g, 5,5 mmol) was added and the solution was stirred an additional 1 day; additional sodium cyanoborohydride (1.0 g, 15.9 mmol) was added again and the mixture stirred 5 additional days. The mixture was poured into water (100 ml) and extracted with dichloromethane. The dichloromethane solution was washed with water and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by medium pressure chromatography using 2% methanol in dichloromethane as the eluant to give the product 0.70 g (54%) as a yellow solid; mp 49°-50° C.; IR(KBr): 2971, 1560 and 1394 cm-1 ; MS:m/z 238 (MH+); H NMR-(CDCl3): δ 1.27(s,3H), 1.45(s3H), 1.80(m,4H), 1.91(m,2H), 2.76(m,4H), 4.09(m,1H), 6.57(d,J=5.4 Hz,1H), and 7.04(d,J=5.4 Hz,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[Cl:20])[C:6]([CH3:12])=[N:7]2.[Br:21]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:21][CH2:12][C:6]1[C:5]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[N:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3nc2CBr)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
5-chloro-3-(2-chloro-5-fluorophenyl)-2-methylquinoxaline (0.3013 g, 0.981 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (0.280 g, 0.981 mmol) were suspended in carbon tetrachloride (9.81 mL, 0.981 mmol). To the mixture was added benzoyl peroxide (0.0317 g, 0.0981 mmol) and the mixture was heated at reflux. After 22 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 5% gradient of EtOAc in hexane over 10 min, then 5% isocratic of EtOAc for 25 min, then 5 to 20% gradient of EtOAc in hexane over 20 min, then 20% isocratic of EtOAc for 4 min as eluent to give 2-(bromomethyl)-5-chloro-3-(2-chloro-5-fluorophenyl)-quinoxaline as a light yellow syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.12-8.21 (2 H, m), 7.92-8.00 (1 H, m), 7.76 (1 H, dd, J=9.0, 5.1 Hz), 7.71 (1 H, dd, J=8.6, 3.1 Hz), 7.49-7.58 (1 H, m), 4.74 (2 H, br. s.); LC-MS (ESI) m/z 387.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7](=[CH:23][N:24]([CH3:26])[CH3:25])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCN=C(c2ccccc2Cl)c2cc(Cl)ccc21
Product: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O

Procedure:
A mixture of 18.6 g (61 mmole) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one and 149 ml of dimethylformamide dimethyl acetal was gently heated (ca 50° C.) for 12 hr. The mixture was concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of ether and methylene chloride to give a yellow solid, mp 170°-171° C. Recrystallization from ether gave yellow prisms, mp 170°-171° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]=[C:27]=[S:28].C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[CH3:18])=[S:28])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(Cl)ccc1N=C=S
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)ccc1NC(=S)Nc1ncccc1OCc1c(F)cccc1Cl

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (2 g, 0.008 mol), (2-methyl-4-chlorophenyl isothiocyanate (1.76 g, 0.0096 mol) and toluene (10 ml) was heated under reflux for 5 hours, then cooled and diluted with ether to induce crystallisation of the product. Yield 2.72g (77%), m.p. 176°-177 ° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:19](=[O:20])[N:18]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[C:13]([CH3:14])[C:8]=2[CH:7]=1)=[O:5])[CH3:2].CN.C[CH2:29][N:30](CC)CC.CN(C=O)C>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:19](=[O:20])[N:18]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]2[N:10]=[C:11]([NH:30][CH3:29])[N:12]=[C:13]([CH3:14])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cc2c(C)nc(S(C)=O)nc2n(C2CCCC2)c1=O
Agent: CN
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)nc(NC)nc2n(C2CCCC2)c1=O
Yield: 72.2 %

Procedure:
A solution of example 87 (16.0 g, 0.044 mol), methylamine (10.15 g, 0.088 mol, 27% in EtOH), Et3N (8.9 g, 0.088 mol) and a catalytic amount of DMF in acetonitrile (60 mL) was refluxed for 48 hours under a N2 balloon. TLC (petroleum ether/EtOAc 1:2) indicated the starting material was consumed completely. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc from 15:1 to 4:1) to yield the crude product. Re-crystallization from CH2Cl2/petroleum ether (10 mL/150 mL) afforded pure title compound (10.5 g, 72.2%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14][CH3:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14]([CH3:15])=[O:31])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CSc1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reaction time: 2 h
Yield: 101.7 %

Procedure:
A mixture of 281 (1.1 g, 3.2 mmol) and m-CPBA (77%, 890 mg, 12.8 mmol) in DCM at 0° C. was stirred for 2 hours, diluted with DCM, washed with ice water, NaHCO3 solution and water again; dried and concentrated to give the title compound 284 (1.15 g, quantitative) as a yellowish solid. MS (m/z): 354.0 (M+H) (found).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[H-].[Na+].Br[CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:16])[F:17])[C:11]([CH3:18])=[N:10]2)=[CH:6][C:7]=1[O:8][CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25]
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: COC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
To a stirred mixture of 1.5 g (0.0051 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one and 0.12 g (0.0051 mole) of sodium hydride in 50 mL of N,N-dimethylformamide was added 0.85 g (0.0051 mole) of methyl 2-bromopropionate. After complete addition the reaction mixture was heated at reflux for two hours, then cooled to room temperature and stirred for approximately 18 hours. The solvent was removed by evaporation under reduced pressure leaving a residue. This residue was partitioned between diethyl ether and water. The organic phase was washed with an aqueous 10% sodium hydroxide solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.5 g of methyl 2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate as an oil, Compound 3.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(B(O)O)=CC=1.BrC1C=CC(C#[N:38])=CC=1>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:38])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: N#Cc1ccc(Br)cc1
Agent: OB(O)c1ccc(C(F)(F)F)cc1
Product: N#Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
Prepared by the method of intermediate D2 using 4-trifluoromethylbenzeneboronic acid and 4-bromobenzonitrile. 1H-NMR (DMSO) δ 7.99-7.94 (6H, m) 7.86 (2H, d); MS(APCI+) found (M+1)=248, C14H8NF3requires 247.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]4)[CH2:13]3)=[CH:7][N:8]=2)[N:3]=1.[NH2:25][C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:29]=2[N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH:22]([N:19]1[CH2:20][CH2:21][N:16]([CH:14]2[CH2:15][N:12]([C:6]3[CH:5]=[C:4]4[C:9]([CH:10]=[CH:11][C:2]([C:32]5[CH:33]=[CH:34][C:28]6[O:27][C:26]([NH2:25])=[N:30][C:29]=6[CH:31]=5)=[N:3]4)=[N:8][CH:7]=3)[CH2:13]2)[CH2:17][CH2:18]1)([CH3:24])[CH3:23]
Reactant: CC(C)N1CCN(C2CN(c3cnc4ccc(Cl)nc4c3)C2)CC1
Reactant: Nc1nc2cc(B(O)O)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N1CCN(C2CN(c3cnc4ccc(-c5ccc6oc(N)nc6c5)nc4c3)C2)CC1
Yield: 42.5 %

Procedure:
A mixture of 2-chloro-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridine (C-10) (220 mg, 0.636 mmol, 1.0 eq), 2-aminobenzo[d]oxazol-5-ylboronic acid (135 mg, 0.763 mmol, 1.2 eq), Pd(PPh3)4 (73 mg, 0.06 mmol, 0.1 eq), and Na2CO3 (202 mg, 1.908 mmol, 3.0 eq) were dissolved in a mixture of 1,4-dioxane (30 mL) and water (9 mL). The resulting mixture was degassed and back-filled with argon three times and heated at reflux under an argon atmosphere for 2 h. The reaction was complete based on TLC analysis. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (1:5 MeOH-DCM) to afford the desired product 5-(7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2-yl)benzo[d]oxazol-2-amine (72) (120 mg, 42.5% yield). 1H NMR (300 MHz, DMSO-d6) δ: 8.35 (s, 1H), 8.20 (d, J=8.7 Hz, 1H), 8.02 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.87 (d, J=6.3 Hz, 1H), 7.48 (s, 2H), 7.42 (d, J=8.1 Hz, 1H), 7.08 (s, 1H), 4.12 (m, 2H), 3.85 (m, 2H), 3.36 (m, 1H), 3.23 (m, 4H), 2.47 (m, 1H), 2.37 (m, 4H), 0.95 (d, J=6.9 Hz, 6H); ESI-MS m/z: 444.21 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([Br:30])C(=O)C1>C(Cl)Cl>[Br:30][C:19]1[S:18][C:17]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:21]([CH3:22])[CH:20]=1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sccc3C)c(C)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 8-(1-Ethyl-propyl)-2,6-dimethyl-3-(3-methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazine (8.83 g, 28.17 mmol) and CH2Cl2 (90 mL) is added NBS (5.26 g, 29.58 mmol). The solution is stirred at ambient temperature for 2 hours. The solution is washed with water (3×75 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (10.5 g, 26.76 mmol, 95%). 1H NMR (CDCl3), δ 0.87 (t, J=7.3 Hz, 6H), 1.73-1.93 (m, 4H), 2.09 (s, 3H), 2.44 (s, 3H), 2.51 (s, 3H), 3.26-3.36 (m, 1H), 6.68 (s, 1H), 6.98 (d, J=4.9 Hz, 1H) ppm. LC/MS (m/z): calcd. for C18H22BrN3S (M+H)+: 392.6; found: 392.1, 394.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([CH3:30])([CH3:29])[C:13]([NH:15][CH:16]1[CH:23]2[CH2:24][C:19]3([C:26](O)=[O:27])[CH2:20][CH:21]([CH2:25][CH:17]1[CH2:18]3)[CH2:22]2)=[O:14])(=[O:10])=[O:9].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:53]([NH:55][CH2:56][CH3:57])[CH3:54]>O.C(Cl)Cl>[CH2:53]([N:55]([CH2:56][CH3:57])[C:26]([C:19]12[CH2:18][CH:17]3[CH2:25][CH:21]([CH2:22][CH:23]([CH:16]3[NH:15][C:13](=[O:14])[C:12]([NH:11][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:9])=[O:10])([CH3:29])[CH3:30])[CH2:24]1)[CH2:20]2)=[O:27])[CH3:54]
Reactant: CC(C)(NS(=O)(=O)c1ccccc1Cl)C(=O)NC1C2CC3CC1CC(C(=O)O)(C3)C2
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)C12CC3CC(C1)C(NC(=O)C(C)(C)NS(=O)(=O)c1ccccc1Cl)C(C3)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
In a 25-mL flask, 4-[2-(2-chloro-benzenesulfonylamino)-2-methyl-propionylamino]-adamantane-1-carboxylic acid (100 mg, 0.22 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (85 mg, 0.44 mmol), 1-hydroxybenzotriazol (60 mg, 0.44 mmol), and methylenechloride (10 mL) were charged, and stirred for 15 minutes at room temperature. Then, diethylamine (48 mg, 0.66 mmol) was added thereto, followed by stirring for 12 hours at room temperature. Purified water (5 mL) was added thereto, followed by stirring for 5 minutes. Then, the organic layer was separated, and added with magnesium sulfate (50 mg) so as to remove remaining moisture. The filtrate was concentrated and obtained as a residue. The mixture was purified with column chromatography (MC/MeOH=20:1) to obtain 4-[2-(2-chloro-benzenesulfonylamino)-2-methyl-propionylamino]-adamantane-1-carboxylic acid diethylamide (46 mg, 41.0%).