Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][C:14]([CH3:16])=[CH2:15])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].O1CCCC1>[C].[Pd].CO>[OH:12][C:11]1[CH:2]=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: C=C(C)Cc1cc(C(=O)OC)cc(Br)c1O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)c(CC(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
Methyl 3-bromo-4-hydroxy-5-(2-methylprop-2-en-1-yl)benzoate (5.0 g, 24.2 mmol) and 10% palladium-carbon (50% water-containing product, 1.5 g) were added to a mixed solvent of tetrahydrofuran (70 mL) and methanol (70 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hr. The catalyst was filtered off, and the filtrate was concentrated to give the title compound (4.8 g, yield 95%) as colorless needle crystals.
Reaction SMILES: [C:1]1(=O)N(CCCCNC2CC3C(=CC=CC=3OC)OC2)C(=O)C2=CC=C[CH:27]=[C:2]12.[CH3:29][O:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH:34]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]1[C:51](=[O:52])[CH2:50][C:49]([CH3:54])([CH3:53])[CH2:48][C:47]1=[O:55])[CH2:35][O:36]2>>[CH3:29][O:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH:34]([N:41]([CH2:1][CH2:2][CH3:27])[CH2:42][CH2:43][CH2:44][CH2:45][N:46]1[C:47](=[O:55])[CH2:48][C:49]([CH3:53])([CH3:54])[CH2:50][C:51]1=[O:52])[CH2:35][O:36]2
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)CC(C)(C)CC1=O)CO2
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Product: CCCN(CCCCN1C(=O)CC(C)(C)CC1=O)C1COc2cccc(OC)c2C1
Yield: 77 %

Procedure:
Using the procedure described in Example 2, but replacing the compound of Example 1 by the compound of Example 16, the expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:34](Cl)(=[O:45])[O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:16][C:34](=[O:45])[O:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
(S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (0.15 g, 0.38 mmol) was dissolved in dichloromethane (5 mL) at room temperature. Solid powdered K2CO3 (0.52 g, 3.8 mmol) was added followed by 4-nitrophenyl carbonochloridate (0.11 g, 0.56 mmol). The resulting slurry was stirred at room temperature for 14 h, diluted with DCM (ca. 50 mL) and washed with sat. NaHCO3 (ca. 4×20 mL). The organic portion was dried over anhydrous Na2SO4, decanted and concentrated yielding (S)-4-nitrophenyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylcarbamate as a pale brown oil, (0.20 g, crude quantitative yield). LCMS: 2.26 min [M+1] 560.2 (2 min gradient, MeOH/H2O 0.1% TFA)
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]2[CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:46])[CH2:24][C:25]([C:28]3[C:33](=[O:34])[C:32]([CH3:35])=[C:31]([CH2:36][CH2:37][C:38]([O:40]CC=C)=[O:39])[C:30](=[O:44])[C:29]=3[CH3:45])([CH3:27])[CH3:26])=[O:15])[S:8][CH2:9][CH:4]2[NH:3]1.N1CCOCC1>C1COCC1.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>[O:1]=[C:2]1[NH:6][CH:5]2[CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:46])[CH2:24][C:25]([C:28]3[C:33](=[O:34])[C:32]([CH3:35])=[C:31]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:30](=[O:44])[C:29]=3[CH3:45])([CH3:27])[CH3:26])=[O:15])[S:8][CH2:9][CH:4]2[NH:3]1
Reactant: C=CCOC(=O)CCC1=C(C)C(=O)C(C(C)(C)CC(=O)OCCCCCNC(=O)CCCCC2SCC3NC(=O)NC32)=C(C)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1=C(CCC(=O)O)C(=O)C(C)=C(C(C)(C)CC(=O)OCCCCCNC(=O)CCCCC2SCC3NC(=O)NC32)C1=O
Yield: 36.5 %

Procedure:
To a solution of the compound L (34 mg, 53 μmol) in 4 mL of THF was added tetrakis(triphenylphosphine)palladium(0) (6 mg, 5.3 μmol) followed by morpholine (46 μL, 0.53 mmol). After evaporation of the solvent, the residue was purified by flash chromatography using a gradient solvent system 10% MeOH/CH2Cl2 to 100% MeOH to give 12 mg (40%) of the compound M as a yellow solid. 1H NMR 400 MHz (CDCl3) δ7.05 (s, 1H), 6.10 (s, 1H), 5.16 (s, 1H), 4.51 (dd, J=8 Hz, 4.5 Hz, 1H), 4.35 (dd, J=8 Hz, 4.5 Hz, 1H), 3.93 (t, J=7 Hz, 2H), 3.72 (t, J=5.4 Hz, 1H), 3.17 (m, 2H), 2.93 (s, 2H), 2.90 (m, 1H), 2.72 (m, 2H), 2.40 (t, J=8 Hz, 2H), 2.19 (t, J=7.5 Hz, 2H), 2.12 (s, 3H), 1.98 (s, 3H), 1.78-1.52 (br, 6H), 1.52-1.38 (br, 4H), 1.42 (s, 6H), 1.30 (m, 2H).
Reaction SMILES: [CH:1]([N:4]([CH:6]([CH3:8])[CH3:7])O)([CH3:3])[CH3:2].[H-].[Na+].[N+:11]([C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[C:24]([CH2:27]Cl)=[N:25][N:26]=[C:22]3[CH2:21][N:20]=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:18]=2[CH:36]=1)([O-:13])=[O:12]>CN(C)C=O>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[C:24]([CH2:27][N:4]([CH:6]([CH3:8])[CH3:7])[CH:1]([CH3:3])[CH3:2])=[N:25][N:26]=[C:22]3[CH2:21][N:20]=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:18]=2[CH:36]=1)([O-:13])=[O:12]
Reactant: CC(C)N(O)C(C)C
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2)C(C)C

Procedure:
In the manner given in Example 16, a solution of N,N-diisopropylhydroxylamine in dimethylformamide is treated with sodium hydride suspended in mineral oil, and the mixture is treated with 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine to give 8-nitro-1-[(diisopropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:21])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:8][CH2:7]1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[O:32][CH3:33]>>[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][CH2:2][CH2:3][CH:4]([OH:21])[CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:10][CH2:11]2)=[O:28])=[CH:25][C:24]=1[O:32][CH3:33]
Reactant: NCCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: COc1cc(C(=O)O)ccc1N
Product: COc1cc(C(=O)NCCC(O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)ccc1N

Procedure:
Prepared as described in Example 1 from 4-amino-1-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol (0.26 g) and 4-amino-3-methoxybenzoic acid (0.130 g). Title compound obtained as white solid (0.080 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([Cl:16])[N:7]=1)C.[NH3:18].CO>>[Cl:16][C:8]1[N:7]=[C:6]([CH2:5][C:4]([NH2:18])=[O:3])[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: CCOC(=O)Cc1nc(Cl)cc2ccccc12
Reactant: N
Solvent: CO
Product: NC(=O)Cc1nc(Cl)cc2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(3-chloro-isoquinolin-1-yl)-acetic Acid Ethyl Ester (2.5 g, 10 mmol) is dissolved in 4N NH3/MeOH (50 ml). The solution is transferred into an autoclave and kept at 120° C. for 48 hours. After cooling to RT the solvent is removed and the resulting crude product is purified on silica gel using methylene chloride (100%)→ methylene chloride/methanol (95/5) as eluent, affording 2-(3-chloro-isoquinolin-1-yl)-acetamide as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[N:22]#[C:23][NH2:24].[F:25][C:26]([F:32])([F:31])[S:27]([OH:30])(=[O:29])=[O:28]>C1COCC1>[OH:30][S:27]([C:26]([F:32])([F:31])[F:25])(=[O:29])=[O:28].[C:23](=[NH:22])([O:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:18]([F:19])([F:20])[F:21])[CH:4]=2)=[CH:14][CH:13]=1)[NH2:24]
Reactant: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: N#CN
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 55 °C
Yield: 62.7 %

Procedure:
To a solution of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethanol (2.63 g, 8.30 mmol) and cyanamide (0.419 g, 9.97 mmol) in dry THF (25 mL) under argon was added trifluoromethanesulfonic acid (0.885 mL, 9.97 mmol). The mixture was heated to 55° C. for 3 hrs. Purification via a reverse phase biotage with TFA then afforded the title compound (2.65 g, 62.8% yield). LCMS: rt=2.906 min, [M+H+]=359
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[CH3:24][NH2:25]>CCO>[CH3:24][NH:25][C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1
Reactant: CN
Solvent: CCO
Product: CNc1cc(C)nc2c(S(=O)(=O)c3ccc(C)cc3)c(SC)nn12

Procedure:
In an analogous manner to that described in Example 3, from 7-chloro-5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl) -pyrazolo[1,5-a]pyrimidine and methylamine in EtOH there was obtained methyl-[5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine as colorless crystals, m.p. >230°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:32])=[C:14]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28]CC)=[O:27])=[CH:21][C:20]=3[CH3:31])=[O:17])[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:32])=[C:14]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][C:20]=3[CH3:31])=[O:17])[CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cc(OCc3cccc(Cl)c3)ccc2C)c(C)c1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(CC(=O)O)ccc1NC(=O)c1cc(OCc2cccc(Cl)c2)ccc1C
Reaction time: 8 h

Procedure:
Ethyl (4-{[(5-{[(3-chlorophenyl)methyl]oxy}-2-methylphenyl)carbonyl]amino}-3-methylphenyl)acetate (174 mg, 0.39 mmol) was taken up in acetic acid (10 ml) and 2M HCl (10 ml) and heated at 90° C. for 2 hours. The reaction mixture was allowed to cool and stirring continued at room temperature overnight. The reaction mixture was extracted with ethyl acetate (50 mls), dried using a hydrophobic frit and then evaporated to dryness to give a yellow solid/gum, 155 mg. This was purified by MDAP to give the title compound as a white solid, 39 mg. MS (ES+) m/z 424 [M+H]+ (C24H2235ClNO4). 1H-NMR (400 MHz, d6-DMSO) δ 2.24 (3H, s), 2.34 (3H, s), 3.52 (2H, s), 5.17 (2H, s), 7.02-7.15 (4H, m), 7.22 (1H, d, J 8.4), 7.31 (1H, d, J 8.0), 7.39-7.44 (3H, m), 7.53 (1H, s), 9.71 (1H, s), 12.33 (1H, bs).
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]([CH2:7][CH2:8][OH:9])[CH2:5][OH:6].Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.O>CN(C=O)C>[CH3:3][C@@H:4]([CH2:7][CH2:8][O:9][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:5][O:6][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: C[C@H](CO)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](CCOc1ccc(C#N)cc1)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Sodium hydride (2.88 g, 120 mmol) was dispersed in 50 ml DMF and then added with (S)-2-methyl-1,4-butanediol (5.21 g, 50.0 mmol) while being iced with ice. The reaction mixture after being cooled with ice for another one hour was stirred at room temperature for 2 hours and then added with 4-chlorobenzonitrile (15.3 g, 120 mmol), followed by reaction for 20 hours. After completion of the reaction, the reaction mixture was added carefully with 5 ml water to inactivate excess sodium hydride, followed by vacuum-distillation of DMF. After addition of 200 ml water, a precipitate thus obtained was filtrated and recrystallized from 100 ml ethanol thereby providing the intended product (12.5 g, 40.8 mmol, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].Cl[C:24]1C=CC(B(O)O)=C(F)[C:25]=1[O:34]C>C(C(C)=O)C(C)C>[C:25]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22])(=[O:34])[CH3:24]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1Cl

Procedure:
An embodiment of the present disclosure includes a method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate. The method comprises adding methyl isobutyl ketone to an aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenylboronic acid to form an organic phase comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid and an aqueous phase. The organic phase and the aqueous phase are separated. The 4-chloro-2-fluoro-3-methoxyphenylboronic acid is reacted with methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate in methyl isobutyl ketone to produce methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, which is deacetylated to produce methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.CN([CH2:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:16][C:17]1[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2
Reactant: CN(C)Cc1c[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCN(Cc1c[nH]c3ncccc13)C2
Yield: 32 %

Procedure:
A mixture of 6-methoxy-1,2,3,4-tetrahydroisoquinoline (prepared by the method of Helfer, Helv. Chim. Acta, 1924, 7, 945) (0.55 g, 3.36 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.59 g, 3.36 mmol) in toluene (3 ml) was heated at reflux under nitrogen for 18 h. The mixture was allowed to cool and the crystallised product collected. Recrystallisation from toluene afforded the title compound (0.31 g, 32%), m.p. 144°-146° C.; (Found: C, 73.04; H, 6.43; N, 14.10. C18H19N3O.0.1H2O requires C, 73.24; H, 6.55; N, 14.23%); δH (DMSO-d6) 2.67 (2H, br s, CH2), 2.76 (2H, t, J 5.4 Hz, CH2), 3.49 (2H, s, CH2), 3.69 (3H, s, OCH3), 3.78 (2H, s, CH2), 6.65 (2H, m, ArH), 6.89 (1H, d, 9 Hz, ArH), 7.01 (1H, dd, J 7.9, 4.7 Hz, 5-H), 7.40 (1H, d, J 2.2 Hz, ArH), 8.03 (1H, dd, J 7.7, 1.3 Hz, 4-H), 8.19 (1H, dd, J 4.6, 1.4 Hz, 6-H), and 11.47 (1H, br s, NH); m/z (CI+, NH3) 294 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4([C:31]#[N:32])[CH2:30][CH2:29]4)[CH:23]=3)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[N:5]=2.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:6]3[N:5]=[C:4]4[S:3][C:2]([NH:1][C:37]([CH:34]5[CH2:36][CH2:35]5)=[O:38])=[N:10][C:9]4=[CH:8][CH:7]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2n1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.3 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (528.0 mg, 1.15 mmol) in pyridine (10 mL) were added N,N-dimethylpyridine-4-amine (52.1 mg, 426 μmol) and cyclopropanecarbonyl chloride (1 mL, 11.0 mmol), and the mixture was stirred at room temperature for 6 hr. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), washed with water (50 mL), 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate/hexane=5/95→80/20) and recrystallized from acetone to give the title compound (280 mg, 46%) as colorless crystals.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[C:7]([O:23]C)[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].B(Br)(Br)Br>>[C:27]1([CH:26]=[CH:25][C:5]2[CH:4]=[C:3]([OH:2])[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:7]([OH:23])[CH:6]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCCCCCCCCCCCCCc1c(OC)cc(C=Cc2ccccc2)cc1OC
Agent: BrB(Br)Br
Product: CCCCCCCCCCCCCCc1c(O)cc(C=Cc2ccccc2)cc1O

Procedure:
This material was synthesized from 1-(3,5-dimethoxy-4-n-tetradecanylphenyl)-2-phenylethene and BBr3 by the same method as described in example 6. 1HNMR (CDCl3, ppm): δ 0.95 (m, 6H), 1.30 (m, 22H), 2.65 (m, 2H), 4.80 (s, 2H), 6.60 (s, 2H), 7.00 (s, 2H), 7.26 (m, 1H), 7.36 (m, 2H), 7.52 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[CH:10]=[O:11])[C:5]#[N:6].P([O-])(O)(O)=[O:14].[K+].Cl([O-])=O.[Na+]>CS(C)=O.O>[C:5]([C:4]1[CH:3]=[C:2]([F:1])[C:9]([C:10]([OH:14])=[O:11])=[C:8]([F:12])[CH:7]=1)#[N:6]
Reactant: N#Cc1cc(F)c(C=O)c(F)c1
Reactant: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(F)c(C(=O)O)c(F)c1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 3,5-difluoro-4-formylbenzonitrile (0.2 g, 1.1 mmol) in dimethylsulfoxide (10 mL), were added a aqueous solution of potassium dihydrogen phosphate (0.41 g, 2.9 mmol in 0.4 mL of water), sodium chlorite (0.216 g, 2.3 mmol in 4 mL of water) in one lot at an ambient temperature. The resulting reaction mixture was stirred for about 1 hour. The reaction mass was diluted with water (100 mL). The aquoeus phase was extracted with ethyl acetate (3×100 mL). The combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated to afford 4-cyano-2,6-difluorobenzoic acid (200 mg, 91.32%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH3:9])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: Clc1ccc(CCCBr)cc1Cl
Reactant: CCc1ccncc1C
Product: Cc1cnccc1C(C)CCCc1ccc(Cl)c(Cl)c1
Yield: 37.2 %

Procedure:
1.83 g (15.1 mmol) of 3-methyl-4-ethylpyridine and 4.05 g (15.1 mmol) of 1-bromo-3-(3,4-dichlorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 1.73 g of the desired compound (yield:37.3%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])=O.[NH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[NH2:21]>CN(C)C=O>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([N:20]2[CH2:2][CH2:3][C:4]([C:6]3[CH:15]=[CH:14][C:13]4[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:18])([CH3:19])[C:8]=4[CH:7]=3)=[N:21]2)=[CH:30][CH:29]=1)([OH:28])=[O:27]
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCCl)ccc21
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(C3=NN(c4ccc(C(=O)O)cc4)CC3)ccc21

Procedure:
2.8 g (10 millimoles) of 6-3-chloropropionyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (for preparation see Example 9) and 1.5 g (10 millimoles) of 4-hydrazinobenzoic acid in 40 ml of dimethylformamide was stirred until the reaction was complete (check by thin-layer chromatography). The mixture was poured onto water and the resulting crystals were filtered off under suction and washed with water and ethanol. Drying gave 2.2 g of the title compound of melting point 276°-278° C.
Reaction SMILES: [Si]([O:8][C:9]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[C:12]([C:23]([F:26])([F:25])[F:24])[N:11]([CH:27]([CH2:30][F:31])[CH2:28][F:29])[N:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[CH2:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:13]2[C:9](=[O:8])[NH:10][N:11]([CH:27]([CH2:30][F:31])[CH2:28][F:29])[C:12]=2[C:23]([F:24])([F:25])[F:26])=[CH:20][CH:19]=1)[CH3:22]
Reactant: CCc1ccc(Cc2c(O[Si](C)(C)C(C)(C)C)nn(C(CF)CF)c2C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2c(C(F)(F)F)n(C(CF)CF)[nH]c2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
3-t-Butyldimethylsilyloxy-4-((4-ethylphenyl)methyl)-1-(1,3-difluoro-2-propyl)-5-(trifluoromethyl)pyrazole (1.95 g; 4.22 mmol) was dissolved in tetrahydrofuran (30 ml) and cooled to 0° C. A 1 M tetrabutylammonium fluoride-tetrahydrofuran solution (6.33 ml; 6.33 mmol) was gradually added, then the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was purified on a silica gel column chromatography (ethyl acetate-hexane=1:4) to give the desired compound (684 mg; 1.96 mmol). (46%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:34]([N:13]([C:12]1[C:3]([O:2][CH3:1])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=2)[CH2:18][CH2:17]1)=[O:15])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4ccccc4nc3OC)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)N(Cc3ccccc3)c3cc4ccccc4nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
1-[(2-Methoxyquinolin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(114 mg, 0.27 mmol) was dissolved in dimethylformamide(15 ml) and sodium hydride(6.6 mg, 0.27 mmol) was added and the solution was stirred at room temperature for 15 min. Benzylbromide(46 mg, 0.27 mmol) was added to the above solution. The mixture was stirred at room temperature for 16 hours and concentrated under the reduced pressure to remove dimethylformamide. The concentrate was purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.