Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C:4]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7](=[O:15])(=[O:14])[N:6]([CH2:16][CH2:17][CH2:18][Cl:19])[CH2:5]2)[O:3]C1.Cl>CO>[Cl:19][CH2:18][CH2:17][CH2:16][N:6]1[CH2:5][C:4](=[O:3])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7]1(=[O:15])=[O:14]
Reactant: O=S1(=O)c2ccccc2C2(CN1CCCCl)OCCO2
Agent: Cl
Solvent: CO
Product: O=C1CN(CCCCl)S(=O)(=O)c2ccccc21
Yield: 97.5 %

Procedure:
A mixture of 2-(3-chloropropyl)-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide ethylene ketal (5.0 g, 15.7 mmol.), 3N aqueous hydrochloric acid (30 mL) and methanol (30 mL) was heated under refluxing for 20 min. Methanol was distilled off under reduced pressure. To the residue was added water (30 mL), and the mixture was extracted with ethyl ether. The ethyl ether portion was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off, to give the desired compound (4.19 g, 100%) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH2:15][CH2:14][N:13]([C:16]([O:18]C(C)(C)C)=O)[CH2:12][CH2:11][C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1.[CH2:23]([CH2:26][O:27][CH3:28])OC.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.CCCCCC>[C:16]([N:13]1[CH2:14][CH2:15][C:4]2[C:3]3[C:2]([C:23]4[CH:11]=[CH:5][CH:4]=[CH:15][C:26]=4[O:27][CH3:28])=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:11][CH2:12]1)(=[O:18])[C:2]1[CH:3]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cccc(Br)c3c2CC1
Reactant: COCCOC
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: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccccc1-c1cccc2[nH]c3c(c12)CCN(C(=O)c1ccccc1)CC3
Temperature: 25 °C

Procedure:
tert-Butyl 10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (4.40 g, 11.9 mmol), Pd(PPh3)4 (1.40 g, 1.21 mmol), and dimethoxyethane (60 mL) were stirred at room temperature for 15 minutes then treated with 2-methoxyboronic acid (2.18 g, 14.3 mmol) and a 2 M solution of Na2CO3 (36 mL). The reaction was heated to reflux for 17.0 hours then cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×) and the organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown foam which was passed through a column of silica gel with 40% ethyl acetate/hexane to give 3.87 g (82%) of a white solid as the title compound: mp 218.9-221.6° C. 1H NMR (400 MHz, DMSO-d6) δ 10.95-10.85 (m, 1H), 7.43-7.38 (m, 4H), 7.27-7.23 (m, 2H), 7.17-6.97 (m, 4H), 6.67-6.61 (m, 1H), 3.82 (m, 1H), 3.66-3.53 (m, 5H), 3.27 (m, 1H), 3.09-3.06 (m, 1H), 2.85 (m, 1H), 2.39-2.32 (m, 1H), 2.17-2.13 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 170.1, 169.8, 156.8, 156.7, 137.1, 135.7, 134.8, 134.6, 130.8, 130.5, 130.4, 130.2, 130.0, 128.9, 128.5, 128.3, 128.2, 126.1, 126.0, 120.5, 119.9, 119.8, 119.7, 111.2, 110.5, 110.2, 109.7, 109.5, 54.9, 54.7, 49.6, 48.3, 46.1, 44.2, 29.4, 27.5, 25.7, 24.6; IR (diffuse reflectance) 3202, 3181 (b), 1602 (s), 1500, 1489, 1466, 1434, 1299, 1266, 1249, 1241, 786, 759 (s), 748, 707 cm−1; HRMS (FAB) calcd for C26H24N2O2+H1 397.1916, found 397.1910. Anal. Calcd for C26H14N2O2: C, 78.76; H, 6.10; N, 7.07. Found: C, 78.40; H, 6.22; N, 6.97.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N+:8]([O-:10])[CH3:9])[CH:5]=[N:4][CH:3]=[N:2]1.[C:21]1(/[CH:27]=[CH:28]/[CH:29]=[CH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C.CCCCC>C1(C)C=CC=CC=1>[CH3:9][N:8]1[C:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)([CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH2:30][CH:29](/[CH:28]=[CH:27]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:10]1
Reactant: C=C/C=C/c1ccccc1
Reactant: C[N+]([O-])=C(Cn1cncn1)c1ccc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: CN1OC(/C=C/c2ccccc2)CC1(Cn1cncn1)c1ccc2ccccc2c1

Procedure:
A mixture of 2-(1H-1,2,4-triazol-1-yl)-N-methyl-1-(2-naphthalenyl)ethanimine N-oxide (15.0 g, 0.056 mol) and trans-1-phenyl-1,3-butadiene (11.0 g, 0.084 mol) in 500 ml toluene is heated to 95°-105° C. for 48 hours, then cooled and evaporated to dryness. The resulting oil is decolorized with carbon and purified by flash chromatography on silica gel (eluent comprised of 90% ethyl acetate and 10% hexane by volume) giving two diastereomers. Isomer A (5.66 g) has a melting point of 80°-84° C. (ethyl acetate-pentane). Isomer B (1.64 g) has a melting point 157°-160° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.Cl.[N:36]12[CH2:43][CH2:42][CH:39]([CH2:40][CH2:41]1)[CH:38]([NH2:44])[CH2:37]2.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][NH:44][CH:38]5[CH:39]6[CH2:42][CH2:43][N:36]([CH2:41][CH2:40]6)[CH2:37]5)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: NC1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CNC4CN5CCC4CC5)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (100 mg) in 1,2-dichloroethane (5 mL) were added 1-azabicyclo[2.2.2]octan-3-amine dihydrochloride (100 mg) and triethylamine (150 μL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (65.0 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (30.0 mg, yield 24%) as a colorless amorphous solid. MS: 575 (MH+).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[N:6]([CH3:26])[C:7]([C:16]2[S:17][C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH2:25])[C:23]=3[N:24]=2)=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1>CO>[CH3:1][O:2][C:5]1[N:6]([CH3:26])[C:7]([C:16]2[S:17][C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH2:25])[C:23]=3[N:24]=2)=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1
Reactant: C[O-]
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Yield: 78 %

Procedure:
Sodium methoxide (31 mg) was added to a solution of 2-(2-bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (22 mg) in MeOH (1 mL). The reaction was stirred and refluxed for 4 days with further sodium methoxide (31 mg) added each day. The solvent was evaporated in vacuo and water (5 mL) added. Extracted with DCM (2×5 mL) and the combined organics were dried over MgSO4, filtered and the solvent evaporated in vacuo to give a white solid (15 mg, 78%);
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][N:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][CH2:30][C:29]3([CH3:37])[CH3:36])[CH:12]=2)=[CH:7][CH:6]=1.[C:38]([N:45]([CH2:47][CH:48]=O)[CH3:46])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C.O>[C:41]([O:40][C:38](=[O:39])[N:45]([CH2:47][CH2:48][N:31]1[CH2:30][C:29]([CH3:37])([CH3:36])[N:28]([CH2:27][C:13]2[CH:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=3)[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]=23)[CH2:33][C:32]1([CH3:35])[CH3:34])[CH3:46])([CH3:44])([CH3:43])[CH3:42]
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)NCC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(-c2cc(CN3CC(C)(C)N(CCN(C)C(=O)OC(C)(C)C)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Yield: 404.2 %

Procedure:
To a solution of 290 mg of 6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine and 1040 mg N-Boc-(methylamino)acetaldehyde in 5 ml dichloromethane was added 250 mg of sodium triacetoxyborohydride. After 1 h at rt the reaction was diluted with ethyl acetate and water. The phases were separated. The aqueous phase was extracted with ethyl acetate twice. The combined organic phases were dried over sodium sulphate, filtrated and concentrated in vacuo. 1535 mg of a crude product of the title compound were obtained, which was used without purification in the next step.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>C(Cl)Cl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:35]([N:37]([CH3:38])[CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCN(C(=O)N(C)C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(C(=O)N(C)C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(dimethylaminocarbonyl)-n-pentylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=O)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH3:23].O>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:12])=[CH:7][CH:6]=2)(=[O:10])=[O:11])[C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH3:23]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(C)cc1OC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)c2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, a mixture of 500 g of polyphosphoric acid and 47.6 g (250 mmol) of p-toluenesulphonic acid monohydrate is heated to 100° and then added to 41.9 g (275 mmol) of 1,2-dimethoxy-4-methylbenzene (4-methylveratrole). The reddish suspension is stirred at 105° for 30 minutes, cooled to 80°, 1500 ml of water are added and the whole is cooled to room temperature. The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water, dried, treated with activated carbon and concentrated by evaporation. The resulting solid substance is recrystallised from toluene, but can also be further reacted directly. The 1,2-dimethoxy-4-methyl-5-(4-methylphenylsulphonyl)benzene is obtained from toluene in the form of white crystals having a melting point of 133°-134.5°.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]I)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]C(C)(C)C.[CH3:24][O:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30](=[O:43])[C:31]([CH3:42])([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[CH2:32][O:33]2)=[CH:28][CH:27]=1.[NH4+].[Cl-]>CCCCC.C(OCC)C.C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:30]1([OH:43])[C:29]2[C:34](=[CH:35][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[O:33][CH2:32][C:31]1([CH3:42])[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCCI
Reactant: COc1ccc2c(c1)OCC(C)(c1cccnc1)C2=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)OCC(C)(c1cccnc1)C2(O)CCCCCCCCCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
To a solution of 9-(t-butyldimethylsilyloxy)nonyl iodide (1.05 g, 2.7 mmol) in pentane (10 ml) and diethylether (7 ml) was added at −78° C. t-BuLi (1.64M in pentane, 3.62 ml, 5.94 mmol), which was stirred for 10 minutes and then stirred for 1 h at room temperature. The mixture was cooled to −78° C. again, and a solution of 7-methoxy-3-methyl-3-(3-pyridyl)chroman-4-one (436 mg, 1.62 mmol) dissolved in THF (5 ml) was added thereto. The resulting solution was stirred at −78° C. for 30 minutes, and then stirred for 1 h at room temperature. The reaction solution was neutralized under ice-cooling using saturated aqueous NH4Cl solution, extracted with AcOEt, and washed with brine. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The recidue was purified by chromatography on silica-gel with 70% AcOEt/hexane to give 642 mg (75%) of 4-[9-(t-butyldimethylsilyloxy)nonyl]-4-hydroxy-7-methoxy-3-methyl-3-(3-pyridyl)chroman.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH2:35]Br)[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].C(OCC(C[C:70]#[N:71])COCCCCCCCCCCCCCCCC)(=O)C1C=CC=CC=1>CS(C)=O>[C:1]([O:9][CH2:10][CH:11]([CH2:35][C:70]#[N:71])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCOCC(CC#N)COC(=O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CBr)COC(=O)c1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CC#N)COC(=O)c1ccccc1
Yield: 95.5 %

Procedure:
A mixture of 1.76 g (3.10 mM) of 2-bromomethyl-3-n-octadecylcarbamoyloxypropyl benzoate, 185 mg (3.26 mM) of 95% sodium cyanide in 30 ml of dimethylsulfoxide is allowed to react by the same procedure as described in the (136) and 1.49 g (95.5% yield) of the titled compound n5' is obtained.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1cccc(-c2nc(N)nnc2Br)c1
Product: COc1cccc(-c2nc(N)nnc2-c2cccc(Cl)c2)c1
Yield: 9.6 %

Procedure:
6-(3-Chlorophenyl)-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine (18 mg 9%) was prepared from 6-bromo-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine (0.18 g, 0.60 mmol) and 3-chlorophenylboronic acid (0.10 g, 0.60 mmol) according to the general procedure of Example 1.
Reaction SMILES: C([O:3][C:4](=[O:32])[C@@H:5]([O:30][CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>>[CH3:31][O:30][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[C:4]([OH:32])=[O:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(N3CCNCC3)cc2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(N3CCNCC3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-2-methoxy-3-{4-[3-(4-piperazin-1-yl-phenoxy)-propoxy]-phenyl}-propionic acid ethyl ester (Step A) by standard hydrolysis procedure C (NaOH). 1H-NMR (MeOD 300.15 MHz): δ 7.18 (d, 2H, J=8.5), 6.89–6.83 (m, 4H), 6.72 (d, 2H, J=9.1), 4.30 (t, 2H, J=6.3), 4.07 (t, 2H, J=6.1), 3.86–3.82 (m, 1H), 3.62–3.59 (m, 4H), 3.36 (s, 3H), 3.07–2.83 (m, 6H), 2.12 (qn, 2H, J=6.3).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14](Cl)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C[Si]([C:26]#[C:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)(C)C.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[O:15]=[C:14]([C:13]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)[CH:12]=1)[C:26]#[C:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C#CC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3 g (10 mmol) of 3-(1-adamantyl)-4-methoxybenzoyl chloride, 2.3 g (10 mmol) of the above compound (a) and 100 ml of dichloromethane were introduced into a round-bottomed flask. 4.7 g (35 mmol) of AlCl3 were added portionwise, at 0° C., and the mixture was stirred at room temperature for 8 hours. The reaction medium was poured into ice and extracted with dichloromethane. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and hexane (80/20). 970 mg (23%) of the expected compound, having a melting point of 156°-8° C., were recovered.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:12]1[CH:25]=[CH:24][C:23]2[O:22][C:21]3[C:16](=[CH:17][C:18]([C:26](OCC)([O:31]CC)[CH2:27][CH2:28][CH2:29]Cl)=[CH:19][CH:20]=3)[CH2:15][C:14]=2[CH:13]=1)(OCC)[O:6]CC.[I-].[K+].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>O1CCCC1>[O:42]1[CH2:43][CH2:44][N:39]([CH2:2][CH2:3][CH2:4][C:5]([C:12]2[CH:25]=[CH:24][C:23]3[O:22][C:21]4[C:16](=[CH:17][C:18]([C:26](=[O:31])[CH2:27][CH2:28][CH2:29][N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)=[O:6])[CH2:40][CH2:41]1
Reactant: CCOC(CCCCl)(OCC)c1ccc2c(c1)Cc1cc(C(CCCCl)(OCC)OCC)ccc1O2
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCN1CCOCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCOCC3)ccc1O2
Temperature: 110 °C

Procedure:
A mixture of 43.2 g (0.08 mole) 2,7-bis(4-chloro-1,1-diethoxybutyl)xanthene, 2 g. of potassium iodide, 100 ml. of morpholine and 100 ml. tetrahydrofuran was heated for 24 hours with stirring in a Paar bomb at 110°C. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The residue was cooled, dissolved in 300 ml. of 10% HCl and refluxed for 1 hour. The solution was cooled, filtered, the filtrate made alkaline, and extracted with chloroform. The chloroform extract was evaporated to dryness and the residue was recrystallized twice from a 1:4 mixture of benzene in heptane. Upon drying under vacuum, the desired product was obtained. M.P. 110°-111.5°C.
Reaction SMILES: C1(=O)[NH:5]C(=O)C2=CC=CC=C12.Br[CH2:13][CH:14]=[CH:15][C:16]#[C:17][C:18]([CH3:21])([CH3:20])[CH3:19]>CN(C)C=O>[CH3:19][C:18]([CH3:21])([CH3:20])[C:17]#[C:16]/[CH:15]=[CH:14]/[CH2:13][NH2:5]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)C#CC=CCBr
Solvent: CN(C)C=O
Product: CC(C)(C)C#C/C=C/CN

Procedure:
As an alternative method of synthesizing the above compound, phthalimide and 1-bromo-6,6-dimethyl-2-hepten-4-yne (a mixture of E and Z forms in a ratio of about 3:1) are reacted in dimethylformamide. The resulting (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)phthalimide (by recrystallization from hexane, it is separated into an E form and a Z form, m.p. 106°-108° C.) is reacted with hydrazine to produce (E)-6,6-dimethyl-2-hepten-4-ynylamine. This compound is reductively alkylated by using equimolar proportions of 3-benzyloxybenzaldehyde and sodium borohydride in methanol to give the captioned compound.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:30])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=O)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:31])[C:5]([C:32]([OH:34])=[O:33])=[CH:4]1)[CH3:2].Cl.[CH3:36][O:37][NH2:38]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:30])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20](=[N:38][O:37][CH3:36])[C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[CH2:17][CH2:18]3)[CH:11]=2)[C:6](=[O:31])[C:5]([C:32]([OH:34])=[O:33])=[CH:4]1)[CH3:2]
Reactant: CON
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(OC)cc4)CC3)cc21
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=NOC)c4ccc(OC)cc4)CC3)cc21

Procedure:
1-Ethyl-6-fluoro-7-{4-[2-methoxyimino-2-(4-methoxyphenyl)ethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was prepared from 1-ethyl-6-fluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.23 g, 0.5 mmol) and O-methylhydroxylamine hydrochloride (0.08 g, 1 mmol) by a method similar to that described for Example 3 (68% yield). Mp: 165° C. (dec). 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J=7.0), 2.61 and 3.23 (two m, 8H), 3.69 and 3.79 (m, 6H), 3.89 (s, 2H), 4.54 (q, 2H, J=7.0), 6.93 (m, 2H), 7.13 (d, 1H, J=7.2), 7.73 (m, 2H), 7.89 (d, 1H, J=13.2), 8.90 (s, 1,H) 15.35 (br s, 1H). Anal. Calcd. for C26H29FN4O5H2O: C, 60.69; H, 6.07; N, 10.88. Found: C, 60.90; H, 5.77; N, 10.62.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: Fc1ccc(C(OCCN2CCCCC2)c2ccc(F)cc2)cc1
Yield: 26.4 %

Procedure:
1-[Bis(4-fluorophenyl)methoxy]-2-chloroethane (3) (1.03 g, 3.6 mmol) was added to a flask containing acetonitrile (70 ml) and potassium carbonate (1.54 g, 11.1 mmol). This was followed by addition of piperidine (0.69 g, 8.1 mmol). The resulting mixture was heated to reflux for 48 hours under an atmosphere of nitrogen. At the end of this time, the solution was added to ether (75 ml), washed with water (100 ml) followed by brine (100 ml). The solution was then dried over magnesium sulfate, filtered and the solvents were evaporated under reduced pressure. The resulting clear yellow oil was then chromatographed on silica gel and eluted with 3:1 ethyl acetate/methanol to afford the desired product (5) (315 mg, 26.1%) as a clear and colorless oil.