Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.[I:12](O)(=O)=O>C(O)(=O)C.O.ClCCl.S(=O)(=O)(O)O>[CH:7]([C:1]1[CH:6]=[CH:5][C:4]([I:12])=[CH:3][CH:2]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1ccccc1
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1ccc(I)cc1
Temperature: 85 °C
Yield: 94 %

Procedure:
(C9H11I), FW=246.09 g/mol. Cumene (45.0 g, 377 mmol), iodine (38.25 g, 151 mmol) and iodic acid (15.38 g, 87.4 mmol) were dissolved in a solution of acetic acid (188 mL), water (30 mL), dichloromethane (19 mL), and sulfuric acid (7.5 mL). The solution was heated to 85° C. for three hours. Once the reaction was complete, the reaction was worked up with water and dichloromethane. The dichloromethane was washed with sodium hydrosulfite, dried over magnesium sulfate and concentrated, yielding a red liquid in 94% yield. Rf 0.63 (hexanes) 1H NMR (300 MHz, CDCl3, ppm) d 7.58 (d, 2H, J=8.3 Hz), 6.96 (s, 2H, J=8.3 Hz), 2.83 (septet, 1H, J=6.9 Hz), 1.20 (d, 6H, J=6.9 Hz); 13C NMR (75.5 MHz, CDCl3, ppm) d 148.2, 137.2, 128.5, 90.7, 33.6, 23.8; LR MS (EI) m/z 246.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[CH3:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23]Br)=[CH:18][CH:17]=1.Cl>CO>[CH2:10]([O:9][C:1]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][CH3:13])=[CH:17][CH:18]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COCc1ccc(CCBr)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCOC(=O)C(CCc1ccc(COC)cc1)C(=O)OCC

Procedure:
Diethyl malonate (0.32 g) is added to a solution of 0.05 g sodium in 10 mL of methanol. The 1-(methoxymethyl)-4-(2-bromoethyl)benzene (13) (0.5 g) is then added and allowed to react for 8 h. The solution is neutralized with methanolic HCl and is extracted with ether. The ether extract is dried over Na2SO4, and evaporated to yield 1-[3,3-di(ethoxycarbonyl)propyl]-4-methoxymethylbenzene (14). The methyl group is removed by treatment with aqueous HBr in acetic acid, followed by neutralization with aqueous NaOH and extraction with ether. The ether extract is dried over Na2SO4, and evaporated to yield 1-[3,3-di(ethoxycarbonyl)propyl]-4-hydroxymethylbenzene (4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[F:9][C:10]([F:18])([F:17])[C:11]([F:16])([F:15])C([O-])=O.[Na+].C1(C)C(C)=CC=CC=1.CN1CCCC1=O>[Cu]I.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([F:16])([F:15])[C:10]([F:18])([F:17])[F:9])=[CH:4][N:3]=1
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: Clc1ccc(I)cn1
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1C
Solvent: O
Product: FC(F)(F)C(F)(F)c1ccc(Cl)nc1
Temperature: 160 °C

Procedure:
A mixture of 2-chloro-5-iodopyridine (20.0 g), sodium pentafluoropropionate (77.8 g), copper (I) iodide (31.8 g), xylene (84 ml) and N-methylpyrrolidone (84 ml) was heated to 160° C., and stirred while heating under reflux 6 hours. The reaction mixture was cooled to room temperature, and water was poured thereto. Then, the mixture was extracted with methyl-tert-butyl ether. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 2-chloro-5-pentafluoroethyl pyridine.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]([NH2:11])=[O:10].CCN(CC)CC.[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(Cl)Cl.[OH-].[Na+]>[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:6]2[CH2:7][C@@H:2]3[CH2:8][C@H:5]2[CH2:4][N:3]3[C:9]([NH2:11])=[O:10])=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(Oc2nc3ccccc3s2)cc1
Reactant: NC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.1 %

Procedure:
To a solution of (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid amide hydrochloride (35.6 g, 200 mmol) in THF (250 mL) was added Et3N (62 mL, 440 mmol), and the resulting suspension was stirred at rt for 5 min. A solution of 4-(benzothiazol-2-yloxy)-benzaldehyde (38 g, 149 mmol) in THF (320 mL) was added. The reaction mixture was allowed to stir at rt for 2 h. Sodium triacetoxyborohydride (37.9 g, 180 mmol) was added in 3 equal portions over 10 min at 0° C. The mixture was then stirred at rt overnight. The reaction was diluted with CH2Cl2 (500 mL) and 1 N NaOH (300 mL). The layers were allowed to separate and the aqueous layer was further extracted with CH2Cl2 (300 mL). The combined organic layers were washed with satd. aq. NaCl (200 mL), dried (MgSO4) and concentrated. The crude material was dissolved in refluxing EtOAc (400 mL) for 5 h. Upon cooling the solution to rt, the product precipitated as a white solid. This solid was purified by silica gel flash chromatography (4:1 CH2Cl2/CH3OH) to afford the desired product (25 g, 44%) as a white powdery solid. The EtOAc solution recovered after filtration of the white solid was concentrated and purified by silica gel flash chromatography (4:1 CH2Cl2/CH3OH) followed by recrystallization to provide additional desired product as a white solid (8 g, 14%). MS (ESI): mass calcd. for C20H20N4O2S, 380.47; m/z found, 381.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.75 (d, J=8.1 Hz, 1H), 7.69 (dd, J=8.0, 0.7 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.42-7.39 (m, 1H), 7.35-7.26 (m, 3H), 4.49-4.32 (m, 3H), 3.79 (s, 2H), 3.62-3.53 (m, 2H), 3.25 (dd, J=8.8, 2.2 Hz, 1H), 2.93 (d, J=9.7 Hz, 1H), 2.77 (d, J=9.7 Hz, 1H), 1.95 (d, J=9.7 Hz, 1H), 1.77 (d, J=9.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12]O)=[CH:9][CH2:8][CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[C:6]1=[O:27].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:9][CH2:8][CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[C:6]1=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CN1CC(CO)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN1CC(CS(C)(=O)=O)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of {6-hydroxymethyl-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 19, (1.35 g, 3.52 mmol) in 10 mL CH2Cl2is treated with triethyl amine (1.3 mL, 8.81 mmol) and methanesulfonyl chloride (0.61 mL, 7.93 mmol) at −78° C. After stirring at −78° C. for 2 hours, the reaction mixture is poured into a CH2Cl2/saturated NaCl solution. The organic layer is collected and washed with saturated NaHCO3, saturated NaCl, dried (Na2SO4) and concentrated in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.CCOC(C)=O.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]>[OH:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OB(O)c1cccc(O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N#Cc1ccc2c(c1)c(-c1cccc(O)c1)nn2C1CCCCO1
Yield: 69.9 %

Procedure:
3-Bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (7.9 g, 24.2 mmol), 3-hydroxyphenylboronic acid (5 g, 36.3 mmol), Pd(dppf)Cl2 (1.97 g, 2.42 mmol) and K3PO4 (25.62 g, 120.8 mmol) were refluxed in 90 mL DME for 24 h. The reaction was cooled and diluted with EtOAc. The reaction mixture was filtered through a celite pad and the filtrate was washed with water, brine, dried (Na2SO4) and filtered. The filtrate was concentrated and the residue purified by column chromatography using 20–75% EtOAc in hexanes to provide 5.4 g (74% yield) of the title compound. 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.6 (s, 1H), 7.9 (dd, 2H), 7.4 (m, 3H), 6.8 (dd, 1H), 6.0 (m, 1H), 3.95–3.7 (m, 2H), 2.45 (m, 2H), 2.05 (m, 2H), 1.6 (m, 2H); ES-MS (m/z) 320 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[C:11]=[O:12].[N-]=C=O>C1C=CC=CC=1>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]([NH:10][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)=[O:12])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1I
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: [N-]=C=O
Solvent: c1ccccc1
Product: Cc1cc(NC(=O)Nc2cccc(C(F)(F)F)c2)ccc1I
Temperature: 90 °C

Procedure:
To a solution of 4-iodo-3-methylaniline (200 mg, 0.86 mmol) in benzene (5 mL) in a sealable tube was added 1-isocyanato-3-(trifluoromethyl)benzene (0.133 mL, 0.94 mL; “E” is an electrophilic group disussed in scheme 3, and here is an isocyanate). The tube was sealed and heated at 90° C. for 4 h. The mixture was allowed to cool to room temperature before filtering. The off white solid was washed with additional benzene (10 mL) and used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:9]=23)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[I:36]I>O1CCCC1.O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C:15]([I:36])=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: COc1ccc(F)cc1-c1ccnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 87A (4.24 g, 11.09 mmol) in tetrahydrofuran at −78° C. was added dropwise 2M lithium diisopropylamide (8.32 mL, 16.63 mmol) in tetrahydrofuran/heptane/ethylbenzene. After 30 minutes, iodine (5.63 g, 22.18 mmol) in tetrahydrofuran (50 mL) was cannulated into the mixture. The mixture was stirred at −78° C. for 3 hours, quenched with aqueous sodium thiosulfate and extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated until a precipitate formed. The solids were filtered, washed with ethyl acetate and dried under vacuum to afford the title compound. MS (ESI+) m/z 508.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[Cs+].[Cs+]>O.[Cu]I.O1CCOCC1>[F:1][C:2]1[C:3]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: c1cn[nH]c1
Reactant: O=C(O)c1cccc(F)c1I
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(F)c1-n1cccn1
Temperature: 100 °C
Yield: 72.8 %

Procedure:
To a mixture of 3-fluoro-2-iodobenzoic acid (1.4 g, 5.26 mmol), 1H-pyrazole (0.72 g, 10.5 mmol), trans-N,N′-dimethyl-cyclohexane-1,2-diamine (0.17 mL, 1.05 mmol), CuI (50.1 mg, 0.26 mmol), dioxane (50 mL) and water (0.028 mL) was added Cs2CO3 (3.43 g, 10.5 mmol). The reaction mixture was heated to 100° C. for 1 h. The reaction mixture was cooled to ambient temperature then diluted with water. The aqueous layer was acidified to pH2 and extracted with EtOAc (30 mL) three times. The organic layers were combined, dried over Na2SO4, filtered and concentrated. Purification (FCC), (DCM to 10% MeOH/1% HOAC/DCM) afforded the title compound as a colorless oil (790 mg, 72%). 1H NMR (400 MHz, CDCl3): 7.85-7.73 (m, 1H), 7.54-7.44 (m, 1H), 7.44-7.34 (m, 1H), 6.55 (s, 1H).
Reaction SMILES: CC(=[O:7])C(C)(C)C.[OH-].[Na+].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]([OH:7])=[O:16])=[CH:13][CH:12]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: CC(=O)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=Cc1ccc(Cl)cc1
Agent: [Br-]
Solvent: O
Product: O=C(O)c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
Pinacolone (400.0 g, 94% pure, 3.76 moles), NaOH (40.0 g, 40 wt % in water, 0.40 moles), tetrabutylammonium bromide (6.0 g, 98% pure, 0.018 moles) and water (2.0 g) were charged into a 2 liter oil-jacketed cylindrical reactor fitted with a mechanical stirrer, thermometer, steam-jacketed addition funnel and a reflux condenser. The reactants were heated to 50° C. and then melted p-chlorobenzaldehyde (280.0 g, 98% pure, 1.95 moles) was added to the reaction mixture via the addition funnel uniformly over 30 minutes. After the addition of the aldehyde was complete, the temperature of the reaction mixture was raised to 60° C. and heated at that temperature for 4 hours. Analysis of the reaction mixture by LC (after neglecting the pinacolone and a small amount of p-chlorobenzoic acid formed by air oxidation of the p-chlorobenzaldehyde) indicated that the organic phase contained 96.2% Phenyl aldol and 0.2% unreacted p-chlorobenzaldehyde. The reaction mixture was then neutralized with 50% aqueous sulfuric acid to pH 8.79 and subjected to steam distillation with the oil temperature in the jacket set to 120° C. to recover all the excess pinacolone. The phases were allowed to settle and the lower (aqueous) phase was discarded. The upper (organic) phase was collected as the product Phenyl aldol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[CH:38]=1)[CH3:36])[C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: CC1c2[nH]c3ccc(Cl)cc3c2CCN1C
Reactant: CC(=CBr)c1ccc(F)c(F)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(Cl)ccc31)CCN(C)C2C)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.9 %

Procedure:
6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (84 mg, 0.36 mmol) was dissolved in DMF (6 mL). To this solution was added CuI (8 mg, 0.035 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.862 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.431 mmol). The reaction mixture was heated at 80° C. overnight. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 43 mg of 6-chloro-9-(2-(3,4-difluorophenyl)prop-1-enyl)-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (CD3OD) OXALATE SALT 7.62 (m, 1H), 7.60 (s, 1H), 7.50 (m, 1H), 7.36 (m, 1H), 7.22 (m, 2H), 7.05 (s, 1H), 4.80 (m, 2H), 3.60 (m, 1H), 3.10 (m, 2H), 3.0 (s, 3H), 1.90 (s, 3H), 1.60 (d, 3H).
Reaction SMILES: [Mg].[C:2]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1.O>C(OCC)C.O1CCCC1.C(O)(=O)C>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]3([O:23][CH2:13][CH2:14][O:15]3)[CH2:17][CH2:18]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Mg]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc(C2(O)CCC3(CC2)OCCO3)cc1

Procedure:
In an atmosphere of nitrogen, 0.23 g of magnesium powder was suspended in 2 ml of anhydrous ethyl ether. While refluxing the suspension, a solution of 2.00 g of 4-tert-butyl-1-bromobenzene in 10 ml anhydrous ethyl ether was dropwise added. After stirring the resulting mixture under reflux for one hour, a solution of 1.17 g of 1,4-cyclohexandione monoethylene ketal in 10 ml anhydrous tetrahydrofuran was dropwise added at 0-5° C., and the temperature was elevated to ambient temperature. After stirring the mixture at the same temperature as above, the reaction mixture was poured into a mixture of water and acetic acid, stirred at ambient temperature for 20 minutes, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=3:1] gave 1.25 of 8-[4-(tert-butyl)phenyl]-1,4-dioxaspiro[4.5]decan-8-ol as a light yellow oily product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.Cl[C:15]([O:17][CH3:18])=[O:16]>CN(C1C=CN=CC=1)C.O1CCCC1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:15](=[O:16])[O:17][CH3:18]
Reactant: Nc1nccs1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Nc1nccs1
Temperature: 25 °C
Yield: 107.6 %

Procedure:
2-Aminothiazole (10.00 g, 99.86 mmole), triethylamine (20.2 g, 200 mmol) and a catalytic amount of 4-(N,N-dimethylamino)pyridine in anhydrous tetrahydrofuran (200 mL) were stirred at 0° C. Methyl chloroformate (18.9 g, 200 mmol) was added slowly to the mixture at 0° C. Then the reaction mixture was stirred at room temperature for several hours. The tetrahydrofuran was evaporated, the residue was dissolved in chloroform, and the resulting solution was washed with water, dried through magnesium sulfate, filtered, and then the solvent was evaporated. The residue was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the sub-title compound as a pale yellow solid (17.0 g), m/z 159 (MH+).
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=4)[N:22]=3)=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([C:23]2[N:22]=[C:21]([C:19]([N:16]3[CH2:15][CH2:14][N:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:12][CH:11]=4)[CH2:18][CH2:17]3)=[O:20])[CH:26]=[CH:25][CH:24]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH3:34]
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(N)cc4)CC3)n2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(NS(C)(=O)=O)cc4)CC3)n2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a THF (2.5 ml) solution of 211 mg of 1-(4-aminophenyl)-4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazine were added 63.5 mg of methanesulfonyl chloride and 76.8 μl of triethylamine, followed by overnight stirring at room temperature. Further, 79 mg of methanesulfonyl chloride and 103 μl of triethylamine were added in twice thereto, and the whole was stirred at room temperature for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) and then crystallization was carried out from ethyl acetate-diisopropyl ether to obtain 175 mg of 4′-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}methanesulfonanilide as pale purple crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C:32]1([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.CCCCCC>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:42]([NH:41][C:39](=[O:40])[CH2:38][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:43])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4F)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (66.2 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.5 ml) at room temperature, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure. The resultant residue was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=97:3) to provide the titled compound (49.5 mg, 55%) as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.COC1C=CC(C[CH2:30][NH2:31])=CC=1.C1CCN2C(=NCCC2)CC1.FC(F)(F)C(O)=O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:31][CH3:30])[CH:12]=3)[CH:7]=1
Reactant: CCn1c(=O)c(-c2cc(N)ccc2C)cc2cnc(Cl)cc21
Reactant: COc1ccc(CCN)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(N)ccc2C)cc2cnc(NC)cc21
Yield: 42.6 %

Procedure:
Using a procedure analogous to Example A26, 3-(5-amino-2-methylphenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (1.9 g, 6.4 mmol), 4-methoxybenzylmethylamine (1.5 g, 9.6 mmol), DBU (1.6 g, 9.6 mmol), and trifluoroacetic acid (10 mL, 134 mmol) were combined to give 3-(5-amino-2-methylphenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.84 g, 43% yield, 2 steps). 1H NMR (300 MHz, DMSO-d6): δ 8.36 (s, 1 H), 7.56 (s, 1 H), 6.91-6.82 (m, 2 H), 6.47-6.39 (m, 2 H), 6.22 (s, 1 H), 4.80 (s, 2 H), 4.13 (q, J=6.9 Hz, 2 H), 2.84 (d, J=4.8 Hz, 3 H), 1.92 (s, 3 H), 1.19 (t, J=6.9 Hz, 3 H); MS (ESI) m/z: 308.9 [M+H]+.