Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[NH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1.C(N(CC)CC)C.Cl[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1>O>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)=[N:23][CH:24]=1)([O-:30])=[O:29]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 150 ml of a tetrahydrofuran suspension containing 10 g of trans-4-aminocyclohexanol was added 15 ml of triethylamine, 50 ml of a tetrahydrofuran solution containing 2-chloro-5-nitropyridine was further added thereto under ice-cooling, and then, the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: ethyl acetate-hexane (2:1)) to obtain 8.52 g of trans-4-(5-nitro-2-pyridylamino)cyclohexanol. (2) To 10 ml of a dichloromethane solution containing 1.0 g of the compound obtained in the above (1) was added 1.8 ml of triethylamine, 0.65 ml of methanesulfonyl chloride was further added thereto under ice-cooling, and the mixture was stirred for 1 hour. An aqueous saturated sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and then, the solvent was removed under reduced pressure. 1.37 g of sodium azide was added to a solution of the residue dissolved in 10 ml of dimethylformamide and the mixture was stirred at 50° C. for 3 days. After cooling, an aqueous saturated sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, and then, the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: ethyl acetate-hexane (1:5)) to obtain 758 mg of cis-4-azide-N-(5-nitro-2-pyridyl)cyclohexylamine. (3) A solution comprising 10 ml of tetrahydrofuran-1 ml of water, containing 640 mg of the compound obtained in the above (2) and 704 mg of triphenylphosphine was stirred at room temperature for 2 days. The reaction mixture was concentrated, and the residue was purified by silica gel flash column chromatography (solvent: ethyl acetatemethanol (10:1)) to obtain 531 mg of N-(5-nitro-2-pyridyl)-cis-1,4-cyclohexanediamine (the compound of Reference Example 4 in Table 5).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:10])[CH2:7][C:8]#[N:9].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]=1[OH:20])[CH:15]=O>>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:10])[C:7]([C:8]#[N:9])=[CH:15][C:14]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]([OH:20])=[C:12]([OH:11])[CH:13]=1
Reactant: N#CCC(=O)NCCCO
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: N#CC(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(=O)NCCCO
Yield: 52 %

Procedure:
The procedure described in Example 99 was repeated using N-(3-hydroxypropyl)cyanoacetamide and 3,4-dihydroxy-5-nitro-benzaldehyde. Yield 52%, m.p. 223°-228° C.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[S:15][CH:16]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.CC1C=CC(S(O[CH:31]([CH2:35][CH3:36])[CH2:32][O:33][CH3:34])(=O)=O)=CC=1>O.C(#N)C>[CH3:34][O:33][CH2:32][C@@H:31]([N:11]1[C:7]2[CH:6]=[CH:5][NH:4][C:3](=[O:2])[C:8]=2[C:9]([C:12]2[CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[S:15][CH:16]=2)=[N:10]1)[CH2:35][CH3:36]
Reactant: CCC(COC)OS(=O)(=O)c1ccc(C)cc1
Reactant: COc1nccc2[nH]nc(-c3csc(C(N)=O)c3)c12
Solvent: CC#N
Solvent: O
Product: CC[C@@H](COC)n1nc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21

Procedure:
The racemic form of the title compound was obtained using 4-(4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide obtained in Step A of Example 148 and 1-methoxybutan-2-yl 4-methylbenzenesulfonate, in the same manner as in Step B of Example 148 and Step C of Example 148. The obtained racemic form was resolved by HPLC (column: L-column2 ODS (trade name) 20 mmID×150 mmL, 5 μm, manufactured by Daicel Chemical Industries, mobile phase: water/acetonitrile (containing 10 mM ammonium carbonate)) to give the title compound having a shorter retention time.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)ccc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(OC)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a6) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[OH:9][CH2:10]C1C(O)=C(CO)C=C(C)C=1.O.O.C(O)(=O)C(O)=O.CCOCCOC(C)=O.C=O>O>[C:1]1([CH:10]=[O:9])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[OH:7]
Reactant: Cc1cc(CO)c(O)c(CO)c1
Reactant: Cc1cccc(O)c1
Agent: C=O
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CCOCCOC(C)=O
Product: Cc1cccc(O)c1C=O
Temperature: 70 °C

Procedure:
A phenolic resin rich in alternating phenolic copolymer block segments was formed by first reacting a mixture of 519.0 g of 99 percent pure m-cresol, 538.2 g 97 percent pure 2,6-bis(hydroxymethyl)-p-cresol and 20 g oxalic acid dihydrate in a solvent mixture of 40 ml deionized water and 200 ml ethyl cellosolve acetate. The reaction mixture was heated to about 70° C. to initiate the reaction forming the alternating copolymer. At 102° C., 32.6 g of 36.9 percent formaldehyde was added in 8 minutes to the reaction mixture to form substantially m-cresol-formaldehyde block segments and to chemically bond these segments to the previously formed alternating copolymer. After heating the mixture at reflux for three hours, the amount of heat was increased to remove the water and solvent by distillation. Partial vacuum was applied at about 220° C. and gradually increased to 4 mm Hg to remove the unreacted monomers. Maximum mixture temperature during vacuum stripping was about 226° C. The copolymer was poured from the reaction kettle and allowed to cool. About 840 g of a block copolymer resin having a number average molecular weight, Mn, of 1241 Daltons and a Tg of 112° C. were obtained.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[C:18]([F:23])[CH:17]=1)(=[O:15])=[O:14])[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)(C)(C)C.C([Li])CCC.[C:30]1([C:36]2[N:43]=[CH:42][CH:41]=[CH:40][C:37]=2[CH:38]=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>O1CCCC1.O.C(OCC)(=O)C>[F:23][C:18]1[CH:17]=[C:16]([S:13]([NH:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)(=[O:14])=[O:15])[CH:21]=[CH:20][C:19]=1[CH:38]([OH:39])[C:37]1[C:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N(c1nccs1)S(=O)(=O)c1ccc(F)c(F)c1
Reactant: O=Cc1cccnc1-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccs1)c1ccc(C(O)c2cccnc2-c2ccccc2)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
100 mg (0.26 mmol) of tert-butyl((3,4-difluorophenyl)sulfonyl)(thiazol-2-yl)carbamate was dissolved in 5 mL of tetrahydrofuran under nitrogen gas, and cooled to −78° C. After adding 0.25 mL (0.39 mmol) of n-butyllithium (1.6 M in tetrahydrofuran) slowly, the mixture was stirred for 30 minutes as maintaining −78° C. 24.3 mg (0.13 mmol) of 2-phenylnicotinaldehyde was dissolved in 0.5 mL of tetrahydrofuran, and added to the above reacting solution. As warming from −78° C. to room temperature, the reacting solution was stirred for 24 hours. Ethyl acetate and water/1 N-hydrochloride were added to the reacting solution, and it was stirred. After separating layers, the organic layer only was collected and concentrated under reduced pressure. The obtained residue was separated by column chromatography (developing solvent, hexane:ethyl acetate=1:1) to obtain 9 mg (7.6% yield) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[CH:4]=1.[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][CH2:25][NH:26][CH3:27].C([O-])(O)=O.[Na+]>CS(C)=O>[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[CH:4]=1
Reactant: ClCc1ccnc(Nc2ncc(-c3ccccc3)s2)c1
Reactant: CNCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCCN(C)Cc1ccnc(Nc2ncc(-c3ccccc3)s2)c1
Temperature: 25 °C

Procedure:
(4-Chloromethyl-pyridin-2-yl)-(5-phenyl-thiazol-2-yl)-amine 8-8 (0.050 g, 0.166 mmol) was dissolved in 0.50 mL DMSO. N,N,N′-trimethyl-1,3-propanediamine was added and the reaction was stirred at RT. After 1 h a copious amount precipitate had formed. Saturated NaHCO3 (aq) was added and the resulting precipitate was filtered and washed with water to afford pure compound 8-9. 1H NMR (CDCl3) δ 9.16 (bs, 1H), 8.31 (d, 1H, J=5.1 Hz), 7.63 (s, 1H), 7.59 (d, 2H, J=7.4 Hz), 7.38 (t, 2H, J=7.6 Hz), 7.26 (overlapping with CHCl3), 6.91 (s, 1H), 6.88 (d, 1H, J=5.1 Hz), 3.49 (s, 2H), 2.43 (t, 2H, J=7.4 Hz), 2.30 (t, 2H, J=7.5 Hz), 2.34 (s, 3H), 2.21 (s, 6H), 1.68 (overlapping with water). MS [M+H]+382.3. mp 190-193.
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[Br:31][C:32]1[N:37]=[C:36]([CH:38]=O)[CH:35]=[CH:34][CH:33]=1.[C:40]([BH3-])#[N:41].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:41]([CH2:40][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)[CH2:38][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([Br:31])[N:37]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: O=Cc1cccc(Br)n1
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3cccc(Br)n3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (104.9 mg) obtained in Example 47-3 was dissolved in methanol (3.2 ml) and then added with 6-bromopyridine-2-aldehyde (55.8 mg) and sodium cyanoborohydride (31.4 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (91.9 mg) of the subject compound as a white solid.
Reaction SMILES: C([Li])CCC.O.Cl.[Cl-].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1.[Si:35]([O:42][CH:43]1[CH2:55][CH2:54][C:46]2([CH2:51][CH2:50][CH:49]([CH:52]=O)[CH2:48][CH2:47]2)[CH2:45][CH2:44]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>O1CCCC1>[Si:35]([O:42][CH:43]1[CH2:55][CH2:54][C:46]2([CH2:47][CH2:48][CH:49](/[CH:52]=[CH:15]/[C:11]3[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=3)[CH2:50][CH2:51]2)[CH2:45][CH2:44]1)([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:37])[CH3:36].[Si:35]([O:42][CH:43]1[CH2:55][CH2:54][C:46]2([CH2:47][CH2:48][CH:49](/[CH:52]=[CH:15]\[C:11]3[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=3)[CH2:50][CH2:51]2)[CH2:45][CH2:44]1)([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:37])[CH3:36]
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC2(CCC(C=O)CC2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCC2(CCC(/C=C/c3cccnc3)CC2)CC1
Product: CC(C)(C)[Si](C)(C)OC1CCC2(CCC(/C=C\c3cccnc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (0.92 ml; 1.6M solution in hexane) was added to a suspension of 0.217 g of (3-picolyl)triphenylphosphonium chloride hydrochloride monohydrate (Baker B. R. et al. J. Med. Chem. 1971, 14, 797) in 5 ml of anhydrous tetrahydrofuran, at 0° C. under nitrogen atmosphere. The yellow-orange mixture was stirred at room temperature for 0.5 hrs, then a solution of 0.05 g of 9-tert-butyldimethylsilyloxy-3-formyl-spiro[5.5]undecane (V, Prep. 8) in 1 ml of anhydrous tetrahydrofuran was added and the mixture was stirred at room temperature overnight. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified by flash chromatography (SiO2 ; n-hexane/diethylether 70/30) to give 0.020 g of (E)-9-tert-butyldimethylsilyloxy-3-(2-(3-pyridyl)vinyl)-spiro[5.5]undecane and 0.020 g of (Z)-9-tert-butyldimethylsilyloxy-3-(2 -(3-pyridyl)vinyl)-spiro[5.5]undecane as white amorphous solids.
Reaction SMILES: NC[C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9]C2C=NC=CC=2)=[O:8])=[CH:5][CH:4]=1.ClC1N=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[C:7]([NH2:9])(=[O:8])[C:6]1[CH:16]=[CH:17][CH:3]=[CH:4][CH:5]=1
Reactant: NCc1ccc(C(=O)Nc2cccnc2)cc1
Agent: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: c1ccncc1
Product: NC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (250 mg, 1.1 mmol) and 6-chloro-3-pyridinesulfonyl chloride (233 mg, 1.1 mmol) in dry pyridine (10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated and the residue stirred in ice/water (20 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography, eluting with a gradient (0-30%) of MeOH/EtOAc, to give benzamide I-2 (279 mg, 63%) as a white powder: mp (MeOH/EtOAc) 226-228° C.; 1H NMR δ 10.36 (s, 1 H, NHCO), 8.93 (d, J=2.2Hz, 1 H, H-2′), 8.75 (dd, J=2.6, 0.6Hz, 1 H, H-2″), 8.61 (br s, 1 H, NHSO2), 8.32 (dd, J=4.6, 1.5Hz, 1 H, H-6′), 8.10-8.20 (m, 2 H, H-4′, H-6″), 7.90 (br d, J=8.3Hz, 2 H, H-2, H-6), 7.72 (dd, J=8.4, 0.6Hz, 1 H, H-5″), 7.36-7.42 (m, 3 H, H-3, H-5, H-5′), 4.19 (s, 2 H, CH2N); 13C NMR δ 165.4, 153.6, 147.7, 144.6, 142.0, 141.2, 137.9, 136.6, 135.8, 133.1, 127.8 (2), 127.6 (2), 127.3, 125.0, 123.5, 45.7; MS m/z 404.0 (MH+, 100%), 406.0 (MH+, 60%). Anal. calcd for C18H15ClN4O3S: C, 53.67; H, 3.75; N, 13.91. Found: C, 53.37; H, 3.81; N, 14.03%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][NH:10][CH:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2=CC(c3cccs3)NN2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cc(-c3cccs3)[nH]n2)cc1
Yield: 56.2 %

Procedure:
Active manganese dioxide (4.35 g, 50 mM) was added to a solution of 3-(4-chlorophenyl)-5-(2-thienyl)-pyrazoline (2.62 g, 10 mM) in toluene (100 ml). This mixture was heated under reflux for 3 hours, and then filtered while hot. After the filtrate was allowed to cool, the precipitated crystals were collected by filtration, washed with a small volume of cold toluene, and then air-dried to obtain 1.46 g of the desired 3-(4-chlorophenyl)-5-(2-thienyl)-1H-pyrazole, m.p. 217° C., in a 56% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:35][C:36]1[CH:45]=[CH:44][C:43]([F:46])=[C:42]2[C:37]=1[CH:38]=[C:39](OS(C(F)(F)F)(=O)=O)[N:40]=[CH:41]2.C([O-])([O-])=O.[Cs+].[Cs+]>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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:39]4[N:40]=[CH:41][C:42]5[C:37]([CH:38]=4)=[C:36]([Br:35])[CH:45]=[CH:44][C:43]=5[F:46])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: O=S(=O)(Oc1cc2c(Br)ccc(F)c2cn1)C(F)(F)F
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5c(Br)ccc(F)c5cn4)c3)cn2)CC1
Temperature: 100 °C

Procedure:
To a solution of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (370 mg, 0.67 mmol), trifluoromethanesulfonic acid 5-bromo-8-fluoroisoquinolin-3-yl ester (250 mg, 0.67 mmol), and Pd(PPh3)4 (40 mg, 0.03 mmol) in 1,4-dioxane (8.0 mL) in a sealable microwave tube was added a solution of Cs2CO3 (440 mg, 1.3 mmol) in H2O (2 mL). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 100° C. for 30 minutes. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 5% 7M NH3 in MeOH and DCM. One obtained the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=1.24-1.35 (m, 4H), 1.49 (s, 9H), 1.93-2.06 (m, 2H), 2.19 (d, J=2.3 Hz, 1H), 2.86-2.96 (m, 1H), 6.55 (br. s., 2H), 7.17 (dd, J=9.4, 8.3 Hz, 1H), 7.68 (s, 1H), 7.80 (s, 1H), 7.95 (dd, J=8.3, 4.8 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H), 8.31 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 9.57 (s, 1H). MS (ES+): m/z=566.87/567.69 [MH+]. HPLC: tR=3.08 min (ZQ2, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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:9]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:8])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Clc1ccccc1Br
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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccccc2Cl)cc1

Procedure:
To a solution of 2-bromochlorobenzene (0.24 mL, 2 mmol) and 4-formylbenzeneboronic acid (0.35 g, 2.2 mmol) in toluene (20 mL) were added 2M aq. sodium carbonate (2.6 mL) followed by (Ph3P)4Pd (0.34 g, 0.3 mmol). The resulting reaction mixture was refluxed for 3 h, cooled and diluted ethyl acetate. The organic phase was washed with water, saturated aq. sodium bicarbonate, brine and dried over sodium sulfate. The filtrate was concentrated in vacuo and the residue obtained was purified by chromatography (hexane:ethyl acetate; 4:1) to yield the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([Cl:32])[CH2:30][CH3:31]>CC(=O)CC>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:31][CH2:30][CH2:29][Cl:32])[CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNC(=O)OCc2ccccc2)cc1O
Reactant: CCC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(CNC(=O)OCc2ccccc2)cc1OCCCCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
A mixture comprising 20 g of N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 14.43 g of potassium carbonate, 16.44 g of bromochloropropane and 200 ml of 2-butanone, was refluxed under heating with stirring for 16 hours. The mixture was cooled to room temperature. Then, inorganic substances were filtered off, and the filtrate was distilled under reduced pressure. The obtained residue was extracted with chloroform, and the organic layer was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The obtained residue was crystallized from diethyl ether/n-hexane to obtain 23.19 g of the above-identified compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]#[N:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:25](=[CH:5][C:4]2[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]=2[O:2][CH3:1])[C:26]#[N:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(C(C#N)=Cc2ccc(OC)c(OC)c2OC)cc1OC
Yield: 90 %

Procedure:
Following the Procedure A, the reaction was performed with 1.96 g of 2,3,4-trimethoxybenzaldehyde (10 mmol) and 1.77 g 3,4-dimethoxyphenyl-acetonitrile (10 mmol), affording 2-(3,4-dimethoxy-phenyl)-3-(2,3,4-trimethoxy-phenyl)-acrylonitrile as yellow powder (yield 3.2 g, 90%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C>CCOC(C)=O>[F:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1cccc(F)c1
Agent: C
Solvent: CCOC(C)=O
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(F)c1
Yield: 87.5 %

Procedure:
Prepared from 5.00 g of 4-chloro-6-nitroquinoline-3-carbonitrile and 2.86 g of 3-fluoroaniline in the same manner as Example 377. The crude product was dissolved in a large volume of EtOAc, treated with Darco and filtered through Celite. Solvent removal and drying in vacuo (50° C.) gave 5.77 g of 4-(3-fluorophenylamino)-6-nitroquinoline-3-carbonitrile as a yellow-orange solid: mass spectrum (electrospray, m/e): M+H 309.2.