Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:23])[CH:5]=2)[CH2:3][CH2:2]1.COCCOC.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH:42]=[CH:41][CH:40]=[N:39]2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>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(OCC)(=O)C.O>[N:38]1([C:35]2[CH:36]=[CH:37][C:32]([CH2:31][C:13]3[C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:5][C:6]([OH:23])=[C:7]([CH:12]=3)[C:8]([O:10][CH3:11])=[O:9])=[CH:33][CH:34]=2)[CH:42]=[CH:41][CH:40]=[N:39]1
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C2CC2)cc1O
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: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C2CC2)cc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of methyl 4-cyclopropyl-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.36 g) in a mixed solvent of DME (5.70 mL)-water (1.90 mL) were added 1-(4-(bromomethyl)phenyl)-1H-pyrazole (0.27 g), tetrakis(triphenylphosphine)palladium(0) (0.07 g) and sodium carbonate (0.24 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, water and ethyl acetate were added thereto, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.26 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.C(OCC)(=O)C.O1CCCC1.C(N(CC)CC)C>CO.[C].[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1cc(-c2ccc(F)cc2)cnc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
2-Amino-5-(4-fluorophenyl)-3-nitropyridine (200 mg, 0.86 mmol) was suspended in a mixture of methanol (5 mL), ethyl acetate (5 mL), tetrahydrofuran (5 mL) and triethylamine (2 mL). After addition of 10% palladium carbon (100 mg), the mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (C-300, chloroform:methanol=50:1) to give the title compound (76 mg, 44%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([OH:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].[CH2:22](I)[CH3:23].CCCCCC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][C:11]([O:19][CH2:22][CH3:23])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C1(O)CCN(c2ncc(Br)cn2)CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)C1(OCC)CCN(c2ncc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.4 %

Procedure:
To an ice-cold solution of ethyl 1-(5-bromopyrimidin-2-yl)-4-hydroxypiperidine-4-carboxylate (0.50 g, 1.51 mmol) in DMF (5 mL) was added NaH (0.066 g, 1.67 mmol, 60% dispersion in mineral oil) portion wiseand the mixture stirred at 0° C. for 10 minutes followed by drop wise addition of ethyl iodide (0.58 mL, 7.57 mmol). The reaction was stirred at 0° C. for 2 h. After completion of reaction (by TLC), the reaction was quenched with saturated NH4Cl solution (100 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with water and brine and dried over Na2SO4. The crude residue was purified over 100-200 M silica-gel using 10% EtOAc:hexane to obtain the desired product as a yellow liquid (0.24 g, 44% yield). 1H NMR (DMSO-d6): δ 8.27 (s, 2H), 4.31 (m, 2H), 4.22 (q, J=6.40 Hz, 2H), 3.44 (m, 4H), 1.96 (m, 4H), and 1.28 (m, 6H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1[O:13][C:14](=[O:16])[CH3:15])(=[O:3])[CH3:2].[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]=[CH:26][C:25](=[O:32])[C:24]=2[C:23]2([S:36][CH2:35][CH2:34][S:33]2)[CH2:22]1)(=[O:19])[CH3:18]>C1(C)C(C)=CC=CC=1>[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]3[CH:26]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:8]4[C:7]([CH:6]3[O:13][C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:25](=[O:32])[C:24]=2[C:23]2([S:36][CH2:35][CH2:34][S:33]2)[CH2:22]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC1(C(C)=O)CC2=C(C(=O)C=CC2=O)C2(C1)SCCS2
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)OC1c2ccccc2C(OC(C)=O)C2C(=O)C3=C(CC(OC(C)=O)(C(C)=O)CC34SCCS4)C(=O)C12
Yield: 78.8 %

Procedure:
A solution of 220 mg (1.0 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 234 mg (0.66 mmol) of rac-3'-acetoxy-3'-acetyl-1',2',3',4',5',8'-hexahydro-5',8'-dioxospiro[1,3-dithiolane-2,1'-naphthalene] [prepared as described in Example 5(A)] in 15 ml of dry xylene was stirred and heated under reflux under an atmosphere of nitrogen for 30 minutes. The pale orange solution was evaporated and the resulting yellow oil was triturated with 15 ml of diethyl ether to yield 298 mg (79%) of rac-3',6',11'-triacetoxy-3'-acetyl-1',2',3',4',5',5a',6',11',11a',12'-decahydro-5',12'-dioxospiro[1,3-dithiolane-2,1'-naphthacene] in the form of a pale yellow solid of melting point 135°-145° C.
Reaction SMILES: [CH:1]1([C:7]2([CH2:22][OH:23])[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(C)C)(C)C.CN(C1C=CC=CN=1)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH:1]1([C:7]2([CH2:22][O:23][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(CO)(C1CCCCC1)C2
Agent: CN(C)c1ccccn1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(COS(C)(=O)=O)(C1CCCCC1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 3-cyclohexyl-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (3-3) (0.870 g, 2.69 mmol) in methylene chloride was added diisopropylamine (0.562 mL, 3.23 mmol), dimethylaminopyridine (32.5 mg, 0.269 mmol), and methanesulfonyl chloride (0.229 mL, 2.97 mmol). The mixture was stirred at room temperature for four hours and diluted with methylene chloride, washed with water, a saturated aqueous solution of NaHCO3, and 1 N HCl aqueous solution, dried over anhydrous MgSO4, filtered, and concentrated to give (3-4) as a colorless oil.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:36])[N:29]([CH2:33][CH2:34][OH:35])[CH:30]([CH3:32])[CH3:31])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:36])[N:29]([CH2:33][CH2:34][OH:35])[CH:30]([CH3:31])[CH3:32])[N:27]=2)[CH2:20]1
Reactant: CC(C)N(CCO)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)N(CCO)C(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 98.1 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[N-(2-hydroxyethyl)-N-isopropyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (2.49 g, 4.75 mmol) (obtained as described in Reference Example 59(1)) in anhydrous tetrahydrofuran (100 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (5.70 ml, 5.70 mmol) in an ice bath. The mixture was stirred in the ice bath for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 3-hydroxy-1-{4-[N-(2-hydroxyethyl)-N-isopropyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (1.33 g, yield 98%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][NH2:16].[BH4-].[Na+].O>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:15][NH:16][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CN
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: O
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
3.8 mL (13 mmol) of titanium isopropoxide and 2 g (10 mmol) of 1-tert-butoxycarbonyl-piperidin-4-one are added to 3.7 mL (30 mmol) of a 33% solution of methylamine in ethanol. The solution is stirred for 5 hours at room temperature then 378 mg (10 mmol) of sodium borohydride is added. Stirring is continued for a further 2 hours then 2 mL of water is added. The reaction mixture is filtered then the solvents are evaporated to give 1.18 g (55%) of 4-methylamino-1-tert-butoxycarbonyl-piperidine in the form of an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)#[N:21]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: N#Cc1ccc(C(=O)NCCCCn2cnc3c(N)nc4ccccc4c32)cc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 4-cyanobenzoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-cyanobenzamide as a white powder, m.p. 222.8-225.3° C. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (t, J=5.7 Hz, 1H), 8.22 (s, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.93 (s, 4H), 7.61 (dd, J=8.4, 1.2 Hz, 1H), 7.43 (dt, J=7.6, 1.5 Hz, 1H), 7.21 (dt, J=7.6, 1.2 Hz, 1H), 6.61 (s, 2H), 4.64 (t, J=7.2 Hz, 2H), 3.33 (m, 2H), 1.96 (quintet, J=7.2 Hz, 2H), 1.58 (quintet, J=7.2 Hz, 2H); IR (KBr) 3441, 3337, 3136, 2945, 2228, 1641, 1545, 1531, 1481, 1396, 1309, 1257, 857, 755 cm−1; MS (EI) m/e 384.1699 (384.1699 calcd for C22H20N6O).
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[Li]CCCC.[PH4+].[C:30]([C:35]1[O:36][C:37]([CH:40]=O)=[CH:38][CH:39]=1)([O:32][CH2:33][CH3:34])=[O:31]>C1COCC1.CCCCCC.[Cl-].[Na+].O.CCOCC>[C:30]([C:35]1[O:36][C:37]([CH:40]=[C:2]([CH3:4])[CH3:3])=[CH:38][CH:39]=1)([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)c1ccc(C=O)o1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(C=C(C)C)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a suspension of 24.2 g (0.056 mol) of isopropyltriphenylphosphonium iodide in 300 mL of THF at -20° C. was added 37.3 mL of a 1.5M solution of n-BuLi (0.056 mol) in hexane over a 20-min period. The dark brown solution was warmed to 0° C. and maintained at this temperature for 30 min, when almost all of the solid phosphonium salt had disappeared. A solution of 9.42 g (0.056 mol) of 2-carbethoxy-5-furaldehyde in 20 mL of THF was added over a period of 10 min. The resulting clear yellow solution was stirred at room temperature for 20 h and at 50°-60° C. for 1 h. The mixture was diluted with 500 mL of brine and 300 mL of Et2O. The organic layer was washed twice with 300 mL of brine, dried (Na2SO4), and evaporated to afford 11.0 g of the crude product, which was purified on 150 g of SiO2 (12.5% Et2O/hexane) to give 9.0 g of the pure product as a very pale yellow oil: IR (film) 2990, 2950, 1720, 1670, 1590, 1510, 1460, 1380, 1350, 1320, 1270, 1230, 1190, 1160, 1140, 1030, 980, 850, 800, 760 cm-1 ; 1H NMR (CDCl3) δ1.25 (t, J=7 Hz, 3, CO2CH2CH3), 6.05 (s, 1, C=CH), 6.17 (d, J=4 Hz, 1, 3'H), 7.07 (d, J=4 Hz, 1, 4'H); MS calcd for C11H14O3 194.0943, found 194.0946.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=12.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.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:60]1([C:63]([NH2:65])=[O:64])[CH2:62][CH2:61]1>C1(C)C=CC=CC=1.O.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]>[CH3:11][C:9]1[NH:8][C:7]2=[C:2]([NH:65][C:63]([CH:60]3[CH2:62][CH2:61]3)=[O:64])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=1
Reactant: NC(=O)C1CC1
Reactant: Cc1cc2ccnc(Cl)c2[nH]1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc2ccnc(NC(=O)C3CC3)c2[nH]1
Temperature: 110 °C
Reaction time: 4 h
Yield: 31.7 %

Procedure:
To a solution of 7-chloro-2-methyl-1H-pyrrolo[2,3-c]pyridine (1.1 g, 06 mmol) in toluene were added tris (dibenzylidene acetone)dipalladium (302 mg, 0.3 mmol), Xantphos (0.286 g, 0.49 mmol), cesium carbonate (4.3 g, 13.2 mmol), and cyclopropanecarboxamide (0.842 g, 9 mmol). The resulting reaction mixture was heated to 110° C. and stirred for about 4 hours. The reaction mixture cooled to room temperature diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography to afford N-(2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (0.45 g, 40% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.Br.[OH-].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(-c3ccc(F)cc3)csc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2c(-c3ccc(F)cc3)csc2c1
Yield: 70.6 %

Procedure:
29.96 g 3-(4-Fluoro-phenyl)-6-methoxy-benzo[b]thiophene in 230 ml acetic acid were treated with 130 ml (62% aq) HBr at 125° C. for 4 h. The solution was added slowly to a cooled solution of 210 g NaOH in 600 ml water, the pH was adjusted to 8-9, and the inorganic phase was extracted with EtOAc. The combined organic phases were washed with brine and dried with Na2SO4. Column chromatography on silica gel with hexane:EtOAc 4.1 yielded 20.0 g (73%) 3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-ol as light brown solid, MS: 244(M).
Reaction SMILES: [C:1]1([CH2:13][C:14]#[N:15])[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]3[O:10][CH2:11][CH2:12][C:6]=3[C:5]=12>N.CO.[Co]>[C:1]1([CH2:13][CH2:14][NH2:15])[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]3[O:10][CH2:11][CH2:12][C:6]=3[C:5]=12
Reactant: N#CCc1cnn2ccc3c(c12)CCO3
Agent: [Co]
Agent: N
Solvent: CO
Product: NCCc1cnn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
8,9-Dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-ylacetonitrile (250 mg, 1.25 mmol) and Raney cobalt (2.5 g) were suspended in 2M ammonia/methanol solution (50 mL), and the suspension was stirred at room temperature for 12 hr under a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (238 mg, yield 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2.[Cl:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[Cl:14][CH2:15][C:16]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:13])[NH:11]2)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc2c1NC(=O)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCl)c2c1NC(=O)CC2
Reaction time: 15 h
Yield: 38.7 %

Procedure:
13 g of 8-hydroxy-3,4-dihydrocarbostyril (VII) and 20 g of chloroacetyl chloride were dissolved in 100 ml of nitrobenzene, and 40 g of aluminum chloride was added slowly to the mixture followed by stirring at a temperature of 70° to 75° C for 15 hours. The nitrobenzene was then steam-distilled. After allowing the mixture to cool, the precipitated crystals were filtered, washed with hot water and recrystallized from methanol to give 7.2 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril (IV) as light yellow crystals having a melting point of 189° to 190° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C-:20]#[N:21].[Na+]>CN(C=O)C.C(OCC)C>[OH:19][CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:20]#[N:21]
Reactant: [C-]#N
Reactant: CCCCCC(O)CCCCCCCCCCCBr
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCC(O)CCCCCCCCCCCC#N
Temperature: 90 °C
Yield: 91.8 %

Procedure:
To 17-bromoheptadecan-6-ol (1.0 g, 2.98 mmol) in dry DMF, was added NaCN (175 mg, 3.58 mmol) and the resulting reaction mixture heated at 90° C. for 16 hours. After cooling to room temperature, the mixture was diluted with diethyl ether (100 ml), the organic layer was washed with cold water (3×20 ml), brine solution, dried over MgSO4 and concentrated. The crude product was purified over a silica gel column (10% EtOAc in hexane) to give 13-hydroxyoctadecanenitrile as a colorless liquid (0.77 g, 92%).
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:7]([Cl:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].[CH:21]1(CN2C=CC(O)=CC2=O)CC1.C(N1C=CC(O)=CC1=O)CCC.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1.C1(CBr)CC1>>[Cl:19][C:7]1[C:6](=[O:20])[N:5]([CH2:1][CH2:2][CH:3]([CH3:21])[CH3:4])[CH:10]=[CH:9][C:8]=1[O:11][S:12]([C:15]([F:16])([F:17])[F:18])(=[O:14])=[O:13]
Reactant: CCCCn1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1=O
Reactant: O=c1cc(O)ccn1CC1CC1
Agent: BrCC1CC1
Agent: CCCCn1ccc(O)cc1=O
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Product: CC(C)CCn1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1=O

Procedure:
Intermediate D6 was prepared following the same procedure implemented for the synthesis of D4, using as starting material 1-cyclopropylmethyl-4-hydroxy-1H-pyridin-2-one which was prepared by the same method used for the synthesis of intermediate D2, by reaction of 4-benzyloxy-1H-pyridin-2-one with cyclopropylmethyl-bromide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)=[O:17])[CH:11]=[CH:12][C:13]=1[CH3:14])=[O:6].Cl[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][O:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)=[O:17])[CH:11]=[CH:12][C:13]=1[CH3:14])=[O:6]
Reactant: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1cccc(O)c1
Reactant: ClCc1ccccn1
Product: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1cccc(OCc2ccccn2)c1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 7, N-[3-(3-hydroxybenzamido)-4-methylphenyl]quinoline-6-carboxamide was reacted with 2-chloromethylpyridine to give the title compound in 58% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 5.26 (s, 2H), 7.23 (m, 2H), 7.33 (t, 1H), 7.43 (t, 1H), 7.57 (t, 1H), 7.61 (m, 4H), 7.82 (m, 1H), 7.85 (d, 1H), 8.12 (d, 1H), 8.25 (d, 1H), 8.51 (d, 1H), 8.58 (d, 1H), 8.61 (s, 1H), 8.99 (d, 1H), 9.9 (s, 1H), 10.48 (s, 1H); Mass Spectrum: M+H+ 489.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:39]1[S:43][C:42]([C:44]#[N:45])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.[Cl-].[Na+].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].C(OCC)(=O)C>[CH3:11][CH:9]1[O:8][C:7]([CH3:13])([CH3:12])[C:6]2[CH:14]=[C:2]([C:39]3[S:43][C:42]([C:44]#[N:45])=[CH:41][CH:40]=3)[CH:3]=[CH:4][C:5]=2[NH:10]1
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Reactant: N#Cc1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1Nc2ccc(-c3ccc(C#N)s3)cc2C(C)(C)O1
Temperature: 85 °C
Yield: 25.1 %

Procedure:
A mixture of 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine (3.6 g, 14 mmol), bis(pinacolato)diboron (5 g, 19.7 mmol), potassium acetate (4 g, 41 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.4 g, 0.5 mmol) in DMF (80 mL) was subject to a positive nitrogen flow to remove oxygen and then heated at 85° C. under a blanket of nitrogen for 18 hours. The mixture was allowed to cool to ambient temperature, treated with 5-bromo-2-thiophenecarbonitrile (4 g, 21 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.4 g, 0.5 mmol), and aqueous sodium carbonate solution (2M, 35 mL, 70 mmol), and then heated at 85° C. under nitrogen for 3 hours. The reaction mixture was allowed to cool to ambient temperature, brine (100 mL) and ethyl acetate (150 mL) were added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by a flash silica gel column chromatography (THF:hexane/1:4) to afford the title compound as an off-white solid (1 g, 25%): mp 172-173° C.; 1H-NMR (DMSO-d6) δ 7.88 (d, 1H, J=4.0 Hz), 7.47 (d, 1H, J=4.0 Hz), 7.43 (d, 1H, J=2.0 Hz), 7.32 (dd, 1H, J=8.36, 2.4 Hz), 6.77 (s, 1H), 6.60 (d, 1H, J=8.4 Hz), 4.83 (m, 1H), 1.51 (s, 3H), 1.48 (s, 3H), 1.28 (d, 3H, J 5.6 Hz); MS (ESI) m/z 283 [M−H]−.
Reaction SMILES: Br[CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1.[Cl:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[Cl:27].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[Cl:27])[O:28][CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(COc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
To a solution of 4-(bromomethyl)-N-[(dimethylamino)sulfonyl]-2,5-difluorobenzamide (Preparation 1, 40 mg, 0.11 mmol) in dimethylsulfoxide (0.5 mL) was added 3,4-dichlorophenol (18 mg, 0.11 mmol) followed by addition of potassium carbonate (31 mg, 0.22 mmol). The reaction was left to stir at room temperature for 18 hours. The reaction mixture was poured into water (50 mL) and acidified with 2M HCl (2 mL), then extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (20 mL), then dried over magnesium sulfate and evaporated in vacuo to give a colourless glass (44 mg). The solid was then triturated with 1:1 ether:heptane (4 mL), sonicated and the supernatant decanted. The resulting solid was dried in vacuo to give an off-white solid as the title compound (47 mg, 98%).