Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[C:12]([NH:14][C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH3:16])=[O:13])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C(O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([NH:14][C:12](=[O:13])[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:36])=[O:2])=[CH:9][CH:8]=2)[C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:26][CH:25]=2)[CH3:16])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(CN(C(=O)N[C@@H](C)c2ccc(Cl)cc2)c2ccc(C3CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](NC(=O)N(Cc1ccc(C(=O)O)cc1)c1ccc(C2CCCCC2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-[3-[1(S)-(4-Chlorophenyl)ethyl]1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid methyl ester (35.0 g, 69.3 mmol) was dissolved in ethanol (400 ml). 4 N aqueous sodium hydroxide (100 ml) was added and the clear solution was stirred at room temperature for 3 hours. The solution was neutralised with 4 N hydrochloric acid (100 ml), and placed upon an ice bath to initiate crystallization. The crystals were collected, washed extensively with water, and dried in vacuo over night. Yield: 34.25 g (100%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18](OC)[O:19]C)=[C:14]([F:23])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.ClCCl>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[C:14]([F:23])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: COC(OC)c1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(C=O)c(F)c2)C(=O)O1

Procedure:
BAL resin immobilized 5-(S)-acetamidomethyl-3-[4′-dimethoxymethyl-3′-fluorophenyl]-oxazolidine-2-one (0.100 g, 0.029 mmol) was suspended in 60% trifluoroacetic acid in dichloromethane (2 ml) for 2 h at room temperature. The mixture was filtered, and supernatant was evaporated under vacuum to give the crude product. The crude product was purified by preparative HPLC to afford the desired product as an oil. Yield 4.9 mg, (60%). Rt 3.0 min. MS (m/z): 281.1 [M+H]+. 1H NMR.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]=1.[CH:28]1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[S:33][C:32]=2[C:31]([C:41]2[CH:42]=[CH:43][C:44]3[NH:45][C:46]4[C:51]([C:52]=3[CH:53]=2)=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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].CCCCCC.C1(C)C=CC=CC=1>[CH:28]1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[S:33][C:32]=2[C:31]([C:41]2[CH:42]=[CH:43][C:44]3[N:45]([C:6]4[CH:7]=[CH:2][CH:3]=[C:4]([C:8]5[C:21]6[C:16]([C:15]([C:22]7[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=7)=[C:14]7[C:9]=5[CH:10]=[CH:11][CH:12]=[CH:13]7)=[CH:17][CH:18]=[CH:19][CH:20]=6)[CH:5]=4)[C:46]4[C:51]([C:52]=3[CH:53]=2)=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:30][CH:29]=1
Reactant: Brc1cccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)c1
Reactant: c1ccc2c(c1)[nH]c1ccc(-c3cccc4c3sc3ccccc34)cc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: c1ccc(-c2c3ccccc3c(-c3cccc(-n4c5ccccc5c5cc(-c6cccc7c6sc6ccccc67)ccc54)c3)c3ccccc23)cc1
Yield: 73.8 %

Procedure:
In a 50-mL three-neck flask were put 1.2 g (3.0 mmol) of 9-(3-bromophenyl)-10-phenylanthracene, 1.1 g (3.0 mmol) of 3-(dibenzothiophen-4-yl)-9H-carbazole, and 0.87 g (9.1 mmol) of sodium tert-butoxide. After the air in the flask was replaced with nitrogen, to this mixture were added 20 mL of toluene and 0.2 mL of tri(tert-butyl)phosphine (a 10 wt % hexane solution). This mixture was degassed by being stirred while the pressure was reduced. After the degassing, 87 mg (0.15 mmol) of bis(dibenzylideneacetone)palladium(0) was added to this mixture. This mixture was stirred at 110° C. for 5 hours under a nitrogen stream. After the stirring, the obtained mixture was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). The filtrate was concentrated to give a yellow solid. The obtained solid was recrystallized from toluene. The obtained crystal was purified by high performance liquid column chromatography (abbreviation: HPLC) (chloroform as the developing solvent). The obtained fraction was concentrated to give 1.5 g of a pale yellow solid in 72% yield. The synthesis scheme of Step 2 is illustrated in (b-11).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(O)(=O)C.[C:23]([O:26][C@H:27]1[C@H:40]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:39]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[O:38][C@@H:29]([O:30][Si](C(C)(C)C)(C)C)[C@@H:28]1[N:54]=[N+:55]=[N-:56])(=[O:25])[CH3:24].[Cl:57][C:58]([Cl:62])([Cl:61])[C:59]#[N:60].C1CCN2C(=NCCC2)CC1>C1COCC1>[Cl:57][C:58]([Cl:62])([Cl:61])[C:59](=[NH:60])[O:30][C@H:29]1[O:38][C@H:39]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:40]([O:41][Si:42]([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:44])[CH3:43])[C@H:27]([O:26][C:23](=[O:25])[CH3:24])[C@H:28]1[N:54]=[N+:55]=[N-:56]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: N#CC(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
TBAF (1.0 M in THF, 1.4 mL) and glacial acetic acid (80 μL, 5.9 mmol) were added dropwise to a solution of tert-butyldimethylsilyl 3,6-di-O-acetyl-2-azido-4-O-tert-butyldimethylsilyl-2-deoxy-β-D-glucopyranoside (590 mg, 1.14 mmol) in THF (12 mL) under nitrogen at 0° C. The reaction mixture was warmed to room temperature, stirred for 1.5 h and quenched with saturated NaHCO3 solution. After extraction with CH2Cl2 (3×), the combined organic phases were dried over MgSO4, filtered and the solvents were removed in vacuo. The crude material was dried by coevaporation with anhydrous toluene and vacuum for 1 h and dissolved in CH2Cl2 (25 mL). Trichloroacetonitrile (1.3 mL, 12.50 mmol) and freshly activated 4 Å powdered molecular sieves (300 mg) were added and the mixture was stirred for 30 minutes at room temperature. After cooling to 0° C., DBU (30 μl, 0.2 mmol) was added and the temperature was allowed to rise to room temperature. After 1 h, the mixture was filtered through Celite and the solvents were removed in vacuo. Flash chromatography on silica gel (Hexanes:EtOAc 85:15) afforded 13α (437 mg, 0.80 mmol, 70%) and 13β (94 mg, 0.17 mmol, 15%). 13α: 1H-NMR (500 MHz, CDCl3) δ 8.81 (s, 1H, NH), 6.44 (d, J=3.6 Hz, 1H, H-1), 5.43 (dd, J=8.8, 10.4 Hz, 1H, H-3), 4.41 (dd, J=1.9, 12.0 Hz, 1H, H-6a), 4.12-3.99 (m, 2H, H-6b, H-5), 3.87 (t, J=9.1 Hz, 1H, H-4), 3.58 (dd, J=3.6, 10.7 Hz, 1H, H-2), 2.17 (s, 3H, OCH3), 2.01 (s, 3H, OCH3), 0.86 (s, 9H, C(CH3)3), 0.08 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3); 13C-NMR (125 MHz, CDCl3) δ 170.5, 169.7, 160.8, 94.7, 72.77, 69.1, 62.5, 61.5, 25.9, 21.6, 21.0, 18.2, −3.8, −4.6. 13β: 1H-NMR (500 MHz, CDCl3) δ 8.81 (s, 1H, NH), 5.73 (d, J=8.2 Hz, 1H, H-1), 5.03 (dd, J=8.8 Hz, J=9.8 Hz, 1H, H-3), 4.40 (dd, J=2.1 Hz, J=11.9 Hz, 1H, H-6a), 4.13 (dd, J=4.2 Hz, J=11.9 Hz, 1H, H-6b), 3.87 (t, J=9.5 Hz, 1H, H-4), 3.58 (m, 2H, H-2, H-5), 2.17 (s, 3H, OCH3), 2.08 (s, 3H, OCH3),0.84 (s, 9H, C(CH3)3), 0.05 (s, 3H, SiCH3), 0.04 (s, 3H, SiCH3); 13C-NMR (125 MHz, CDCl3) δ 170.7, 169.9, 160.8, 96.6, 75.3, 68.8, 64.1, 62.4, 25.9, 25.8, 25.8, 21.5, 21.1, 18.1, −3.9, −4.8.
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].C[SH-][C:15]([SH-]C)=[N:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.O>CN(C=O)C>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[NH:16][C:15]1[NH:9][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[N:10]=1
Reactant: C[SH-]C(=Nc1nc2ccccc2s1)[SH-]C
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2[nH]c(Nc3nc4ccccc4s3)nc2c1
Temperature: 153 °C
Yield: 60.1 %

Procedure:
O-phenylenediamine (21.6 g (0.2 mol)) was dissolved in 944 g of DMF, and thereto was added dropwise a solution obtained by dissolving 50.9 g (0.20 mol) of S,S′-dimethyl-N-(2-benzothiazolyl)-carbonimidodithioate in 1258 g of DMF. The resulting mixture was then heated to 153° C., refluxed under a nitrogen atmosphere for 13 hours, and then cooled to 0° C. Thereto was added dropwise 2000 g of water, and a precipitate was filtered off, washed with water, and dried to obtain 32.0 g of 2-(2-benzothiazolylamino)benzoimidazole (L8: see Table 1 below). The yield was 60.1% based on o-phenylenediamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]1)=[O:19])[C@H:9]([CH:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[F:36][C:37]([F:50])([F:49])[O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>ClCCl.C(OCC)(=O)C>[F:25][C@H:22]1[CH2:23][CH2:24][N:20]([C:18]([C@@H:8]([NH:7][C:6](=[O:26])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C@H:9]([CH:11]2[CH2:16][CH2:15][CH:14]([NH:17][S:45]([C:42]3[CH:41]=[CH:40][C:39]([O:38][C:37]([F:36])([F:49])[F:50])=[CH:44][CH:43]=3)(=[O:47])=[O:46])[CH2:13][CH2:12]2)[CH3:10])=[O:19])[CH2:21]1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H](C1CCC(N)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](C1CCC(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1

Procedure:
To a solution of the material from Step B of Example 24 (32 mg, 0.085 mmol) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (0.022 mL, 0.13 mmol), and 4-(trifluoromethoxy)-benzenesulfonyl chloride (0.034 mL, 0.094 mmol). After 2 h at ambient temperature the reaction was diluted with 100 mL of ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, dried (magnesium sulfate) and concentrated in vacuo. Purification by preparative thin layer chromatography (65% ethyl acetate in hexanes) afforded the title compound as a white solid. LC/MS 496.1 (M+1-Boc).
Reaction SMILES: [C:1]1([CH2:9]Br)[C:2](CBr)=[CH:3][CH:4]=[CH:5][CH:6]=1.CNN.C[N:15]1C=C2[C:17](C=CC=C2)=[CH:16]1>O=O>[CH3:17][C:16]1[NH:15][C:2]2[C:1]([CH:9]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2
Reactant: BrCc1ccccc1CBr
Reactant: Cn1cc2ccccc2c1
Agent: CNN
Agent: O=O
Product: Cc1cc2ccccc2[nH]1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A 2-liter 4-neck flask equipped with a dropping funnel, a stirrer, a thermometer, and a nitrogen-introducing inlet was charged with 15.0 g (0.057 mole) of o-xylylene dibromide, and this o-xylylene dibromide was dissolved in 150 ml of oxygen-removed anhydrous diethyl ether. Then, 10.5 g (0.23 mole) of methylhydrazine was dropped into the solution with stirring at 20° C. over a period of 30 minutes, and the mixture was stirred at room temperature for 12 hours. The formed white precipitate was recovered by filtration and a 20% aqueous solution of caustic soda, which had been subjected to the oxygen-removing treatment, was added to the recovered solid. The mixture was then stirred for 3 hours in a nitrogen atmosphere. Then, the formed suspension was extracted with 150 ml of chloroform and the chloroform solution was washed twice with 100 ml of water, and the chloroform solution was dried with potassium carbonate and concentrated under a reduced pressure. The formed yellow solid was placed in a sublimation device and heated on an oil bath under a reduced pressure, and 2.6 g (0.020 mole) of 2-methylisoindole in the form of a white needle crystal was obtained at 85° C./10 mmHg in the bottom of a cooling zone of the sublimation device. When the nuclear magnetic resonance spectrum (1H-NMR) of the obtained product was determined in deuterated chloroform by using TMS as the internal standard, the following results were obtained:
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>CC#N>[NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)[CH2:3]1
Reactant: NC1CCCCNC1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CC#N
Product: NC1CCCCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Yield: 92.3 %

Procedure:
A solution of 3-aminohomopiperidine (1.71 g, 15 mmol) in CH3CN (45 mL) was treated with p-chlorobenzyl chloride (463 mg, 2.9 mmol) and K2CO (828 g, 6 mmol) and heated to 70° C. for 9 h. The reaction mixture was cooled to 25° C. and concentrated to afford a yellow solid. The residue was partitioned between H2O (5 mL) and EtOAc (50 mL), and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4) and concentrated. The resulting yellow oil was purified by chromatography (SiO2, 5-20% CH3OH—CH2Cl2 gradient elution) to afford the desired product as a yellow oil (639 mg, 93%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([Sn](CCCC)(CCCC)CCCC)=[CH:3][CH:2]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.Br/[C:37](/[C:45]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:53][CH2:52]2)=[C:47]([O:54][CH3:55])[N:46]=1)=[CH:38]\[C@@H:39]1[NH:43][C:42](=[O:44])[CH2:41][CH2:40]1.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:51]1([C:48]2[CH:49]=[CH:50][C:45](/[C:37](/[C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:38]/[C@@H:39]3[NH:43][C:42](=[O:44])[CH2:41][CH2:40]3)=[N:46][C:47]=2[O:54][CH3:55])[CH2:52][CH2:53]1
Reactant: COc1nc(/C(Br)=C/[C@H]2CCC(=O)N2)ccc1C1CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccncc2)ccc1C1CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
4-Pyridyltributyltin (218 mg), tris(dibenzylideneacetone)dipalladium (27 mg) and tri(2-furyl)phosphine (42 mg) were added to a solution of (5R)-5-[(Z)-2-bromo-2-(5-cyclopropyl-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one obtained in Reference Example 4-24 (100 mg) in 1,4-dioxane (2 mL), and the mixture was stirred at 90° C. for four hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give (5R)-5-[(E)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(pyridin-4-yl)ethenyl]pyrrolidin-2-one as a colorless amorphous (42 mg).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][N:5]=[C:4]([S:13]([CH3:16])(=[O:15])=[O:14])[N:3]=1.[CH3:17][N:18]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:37].[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.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].CC(=O)OCC>[CH:10]1([CH2:9][O:8][C:7]2[C:2]([C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:37])[N:18]([CH3:17])[CH:27]=3)=[N:3][C:4]([S:13]([CH3:16])(=[O:15])=[O:14])=[N:5][CH:6]=2)[CH2:12][CH2:11]1
Reactant: CS(=O)(=O)c1ncc(OCC2CC2)c(Cl)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O
Temperature: 80 °C
Yield: 68.1 %

Procedure:
The title compound of step 4 (5.00 g, 19.08 mmol), the title compound of Example 89, step 1 (5.98 g, 20.99 mmol), K3PO4 (12.13 g, 57.24 mmol), and Pd(dppf)Cl2 (1.40 g, 1.91 mmol) in dioxane/H2O (50 mL/5 mL) were N2 purged and heated at 80° C. for 8 h. Silica gel chromatography (PE: EA=10/1-1/1) to gave the title compound (5.01 g, yield: 68%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ8.53 (s, 2H), 7.67-7.63 (m, 2H), 7.57-7.52 (m, 2H), 4.06 (d, J=6.8 Hz, 2H), 3.71 (s, 3H), 3.37 (s, 3H), 1.17 (m, 1H), 0.61 (m, 2H), 0.30 (m, 2H). LCMS: 386.1 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[O:25][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccccc1C(=O)Cl
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccccc1C(=O)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (200 mg, 0.76 mmol) was dissolved in dichloromethane (5 mL) at -78° C. and treated with 4-methylmorpholine (0.17 mL, 1.55 mmol, 2 eq.) and 2-methoxy-benzoyl chloride (0.11 mL, 0.74 mmol). The solution was allowed to warm to 0° C. and stir for 1 hour. The solution was washed with 1N HCl and 5% sodium bicarbonate and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with a gradient of 50% ethyl acetate in hexane to 3% methanol in dichloromethane to give 268 mg (90%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([CH:24]1[O:26][CH2:25]1)Br>CC(CC)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][O:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5]
Reactant: BrCC1CO1
Reactant: COC(=O)CCC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CCC(=O)c1ccccc1OCC1CO1
Yield: 104.7 %

Procedure:
A well stirred mixture of methyl 3-(2-hydroxybenzoyl)propionate (63.3 g, 0.3 mole), potassium carbonate (48.4 g, 0.35 mole), epibromohydrin (117 ml, 1.4 mole), and dry ethyl methyl ketone (2000 ml) was heated under reflux for 28 hours. Evaporation of the filtered solution under reduced pressure gave methyl 3-[2-(2,3-epoxypropoxy)benzoyl]-propionate (83 g, 100%). (Found: M+, 264; C14H16O5 requires M, 264).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[O:18])=[CH:15][C:14]=2[O:29][CH3:30])[N:3]=1.[C:31]1([OH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CO>[CH3:30][O:29][C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([O:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[C:17]([NH:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:18]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Oc2ccccc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (50 mg) and phenol (21.3 mg) are dissolved in dioxane (0.3 mL). Pyridine (36.4 μL) and Cs2CO3 (235 mg) are added and the suspension is stirred overnight at 80° C. Then the reaction mixture is diluted with methanol (5 mL) and mixed with isolute. The solvent is eliminated in vacuo and then the mixture is purified by preparative HPLC. (PTK2 IC50=35 nmol)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[CH:34]2.[OH-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[CH:34]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Oc1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4ncccc4c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 54.5 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67 mmol), potassium carbonate (106 mg, 0.77 mmol) and 6-hydroxyquinoline (112 mg, 0.77 mmol) in DMF (7.5 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The reaction mixture was treated with 1M aqueous sodium hydroxide solution (40 ml) and stirred at ambient temperature for a few minutes. The crude solid was collected by filtration and washed with water. The resultant solid was dissolved in dichloromethane (2 ml) and filtered through phase separating paper. The filtrate was evaporated under vacuum and the residue was triturated with ether, collected by filtration and dried to give 6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-6-yloxy)quinazoline (163 mg, 55%).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[C:18]([C:31]([F:34])([F:33])[F:32])[CH:17]=2)[C:6]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][O:14][CH3:15])[C:7]=2[N:8]=1.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:36].[Na+].C(=O)C.C([O-])(O)=O.[Na+]>ClC(Cl)C.C(Cl)(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[Cl:2][C:3]1[N:4]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([CH2:35][CH3:36])[CH2:27][CH2:26]3)=[C:18]([C:31]([F:32])([F:33])[F:34])[CH:17]=2)[C:6]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][O:14][CH3:15])[C:7]=2[N:8]=1
Reactant: COCCn1ccc2c(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)nc(Cl)nc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCN1CCC(CCOc2ccc(-c3nc(Cl)nc4c3ccn4CCOC)cc2C(F)(F)F)CC1
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
Triethylamine (0.35 mL) was added to a suspension of 2-chloro-7-(2-methoxyethyl)-4-{4-[2-(piperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-7H-pyrrolo[2,3-d]pyrimidine monohydrochloride (440 mg) in dichloroethane (8 mL) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. After the reaction mixture was ice-cooled, acetic acid (0.24 mL), sodium triacetoxyborohydride (359 mg), and acetaldehyde (0.14 mL) were added thereto, and the mixture was stirred for 1 hour under ice-cooling. After a saturated aqueous NaHCO3 solution was added to the reaction mixture, extraction thereof was performed using CHCl3, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (CHCl3), whereby 2-chloro-4-{4-[2-(1-ethylpiperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidine (431 mg) was obtained as a colorless oil.