Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:35][CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[Cl:31])=[O:29]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: NCc1ccccc1Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2Cl)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-chlorobenzylamine
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([Cl:12])=[CH:4][C:3]=1[F:13].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:12][C:5]1[C:6]2[O:7][CH2:8][CH2:9][O:10][C:11]=2[C:2]([N:1]=[C:15]=[O:16])=[C:3]([F:13])[CH:4]=1
Reactant: Nc1c(F)cc(Cl)c2c1OCCO2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1c(F)cc(Cl)c2c1OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.25 g (0.011 mole) of 5-amino-8-chloro-6-fluoro-1,4-benzodioxane in 50 mL of toluene was added slowly 0.67 mL (1.09 g, 0.0055 mole) of trichloromethyl chloroformate. This mixture was stirred at ambient temperature for one hour and then was heated at reflux for approximately 16 hours. At the conclusion of this period the solvent was evaporated from the reaction mixture under reduced pressure, leaving 8-chloro-6-fluoro-1,4-benzodioxan-5-yl isocyanate as a residue which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][O:28][CH2:29][CH2:30][CH2:31][NH:32]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[NH:12][C:11]([CH2:52][C:53]([N:55]2[CH2:60][CH2:59][N:58]([CH:61]3[CH2:67][CH:66]4[N:68]([CH3:69])[CH:63]([CH2:64][CH2:65]4)[CH2:62]3)[CH2:57][CH2:56]2)=[O:54])=[C:10]1[C:70]([O:72][CH3:73])=[O:71].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO.O>[NH2:32][CH2:31][CH2:30][CH2:29][O:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][C:13]1[NH:12][C:11]([CH2:52][C:53]([N:55]2[CH2:60][CH2:59][N:58]([CH:61]3[CH2:62][CH:63]4[N:68]([CH3:69])[CH:66]([CH2:65][CH2:64]4)[CH2:67]3)[CH2:57][CH2:56]2)=[O:54])=[C:10]([C:70]([O:72][CH3:73])=[O:71])[CH:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1=C(CCc2ccccc2COCCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(CC(=O)N2CCN(C3CC4CCC(C3)N4C)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(CCc2ccccc2COCCCN)NC(CC(=O)N2CCN(C3CC4CCC(C3)N4C)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl

Procedure:
A mixture of dimethyl 4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-[2-(2-{[3-(tritylamino)propoxy]methyl}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate (355 mg/0.346 mmol) and p-toluenesulfonic acid monohydrate (246 mg/1.29 mmol) in methanol (9.4 ml) and water (3.5 ml) was stirred at reflux temperature for 4 hours. After cooling, the mixture was poured into saturated NaHCO3 aqueous solution. The whole was extracted with dichloromethane (100 ml×2). The combined organic layer was washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (NH2 gel/200-350 mesh/dichloromethane:methanol=100:1-1100:2-100:5) to afford a yellow amorphous (190 mg/70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Cl[C:12]1[CH:13]=[C:14]([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH3:24])[N:15]=[N:16][CH:17]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[C:20]3[CH3:24])[N:15]=[N:16][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: OB(O)c1cccc(Cl)c1
Product: Cc1nccn1Cc1cc(-c2cccc(Cl)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=285.2 (M+H+), was prepared from 3-chlorophenylboronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: N(OCCCC)=O.[Br:8][C:9]1[N:10]([CH3:29])[N:11]=[C:12]2[C:17](=[O:18])[NH:16][C:15]([C:19]3[C:20]([O:26][CH2:27][CH3:28])=[N:21][CH:22]=[C:23](N)[CH:24]=3)=[N:14][C:13]=12.[I:30]CI>>[Br:8][C:9]1[N:10]([CH3:29])[N:11]=[C:12]2[C:17](=[O:18])[NH:16][C:15]([C:19]3[C:20]([O:26][CH2:27][CH3:28])=[N:21][CH:22]=[C:23]([I:30])[CH:24]=3)=[N:14][C:13]=12
Reactant: ICI
Reactant: CCOc1ncc(N)cc1-c1nc2c(Br)n(C)nc2c(=O)[nH]1
Agent: CCCCON=O
Product: CCOc1ncc(I)cc1-c1nc2c(Br)n(C)nc2c(=O)[nH]1
Temperature: 45 °C
Yield: 23 %

Procedure:
Butyl nitrite (282 mg, 2.74 mmol) was added dropwise to a stirred suspension of the title compound of Example 54 (200 mg, 0.55 mmol) in diiodomethane (2 mL) at room temperature. After 1 h the reaction was warmed for 2 h at 40-50° C. The mixture was cooled and purified directly by flash column chromatography (gradient elution from dichloromethane to 98% dichloromethane/5% methanol) to give the product as a brown solid (60 mg, 23%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)=[O:5]
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1c(C(=O)c2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 189.9 %

Procedure:
2-Methyl-3-nitrobenzoyl chloride (9.98 grams; 0.05 mole) was dissolved in 35 mls. of dry benzene and the solution was added to a slurry of aluminum chloride (13.3 grams; 0.10 mole) in 40 mls. of dry benzene over a period of 10 minutes. The resulting reaction mixture was stirred at room temperature for 26 1/2 hours, then heated at reflux for 2 hours and cooled to room temperature. The cooled reaction mixture was poured into 200 mls. of dilute hydrochloric acid, stirred for about 15 minutes and allowed to settle. The organic phase was separated and the aqueous phase was back extracted with 200 mls. of benzene. The benzene layer was separated and combined with the organic phase and the combined solution was washed successively with water, a dilute aqueous solution of sodium carbonate, and water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and distilled to obtain 2-methyl-3-nitrobenzophenone (11.45 grams; 95% yield; b.p. 183° C at 2 mm; m.p. 42° C after recrystallization from petroleum ether).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][C:9]2[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=2)[N:11]=1.Cl.Cl.[NH2:21][CH:22]1[CH2:29][CH:28]2[N:30]([CH3:31])[CH:24]([CH2:25][CH2:26][CH2:27]2)[CH2:23]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:31][N:30]1[CH:24]2[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH:22]([NH:21][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[Br:1])=[N:11][C:10]=13)=[O:18])[CH2:23]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3sccc3Br)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4sccc4Br)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
A mixture of 2-(3-bromothiophen-2-yl)benzoxazole-4-carboxylic acid (188 mg, 0.58 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (159 mg, 0.70 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (222 mg, 1.16 mmol) and 1-hydroxybenzotriazole (157 mg, 1.16 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.40 mL, 2.9 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (30 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×30 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and recrystallized from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3-bromothiophen-2-yl)benzoxazole-4-carboxamide (199 mg, 75%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.11 (d, J=6.5 Hz, 1H), 8.22 (dd, J=7.5, 1.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.58 (d, J=5.5 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.24 (d, J=5.5 Hz, 1H), 4.68-4.59 (m, 1H), 3.22-3.13 (m, 2H), 2.70-2.55 (m, 5H), 2.13-1.98 (m, 3H), 1.63-1.49 (m, 3H), 1.26-1.12 (m, 2H); MS (ESI+) m/z 460 (M+H); HPLC>99% (AUC), tR=13.09 min.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:23]1([C:29]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:30][C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:46]1([CH3:52])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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:23]1([C:29]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:30][C:31]2[CH:36]=[C:35]([C:2]3[C:3]4[C:8]([C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:48]6[CH:49]=[CH:50][CH:51]=[C:46]([CH:52]=[C:2]([C:3]7[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=7)[C:15]7[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=7)[CH:47]=6)=[CH:18][CH:17]=5)=[C:10]5[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]5)=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccccc1
Reactant: OB(O)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Reactant: Brc1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
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: ClCCl
Product: C(=C(c1ccccc1)c1ccccc1)c1cccc(-c2ccc(-c3c4ccccc4c(-c4cccc(C=C(c5ccccc5)c5ccccc5)c4)c4ccccc34)cc2)c1

Procedure:
Under an atmosphere of argon, 9-bromo-10-(4-bromophenyl)-anthracene (3.0 g, 7.3 mmole), 4-(2,2-diphenylvinyl)phenylboronic acid (6.6 g, 22 mmole, 3 eq) and tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.29 mmole, 2% Pd) were suspended into toluene (60 ml). To the obtained suspension, a 2 M aqueous solution of sodium carbonate (7.0 g, 66 mmole, 3 eq/35 ml) was added and the resultant mixture was heated under refluxing for 10 hours. The reaction mixture was filtered and washed with toluene, water and methanol and a gray solid (1.4 g, the first crop, 25%) was obtained. From the filtrate, the organic layer was separated, washed with a saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent was removed by distillation and a deep brown oil was obtained. When the obtained oil was dissolved in dichloromethane, crystals were formed soon. The formed crystals were separated by filtration and washed with a mixed solvent composed of hexane and dichloromethane and a white solid (3.3 g, the second crop, 59%) was obtained. The obtained crude crystals (3.5 g) were suspended in boiling toluene (40 ml), cooled while being left standing, filtered and washed with toluene and a light yellow solid (2.4 g) was obtained.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[C:50]([F:56])[C:49]=3[F:57])[CH:41]=2)([O:38][CH3:39])[O:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[CH2:15]([O:14][C@H:13]1[C@H:12]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[C:50]([F:56])[C:49]=3[F:57])[CH:41]=2)([O:38][CH3:39])[O:9][C@@H:8]1[CH2:7][OH:6])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.4 %

Procedure:
To a solution of tert-butyl-dimethyl-[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]silane 21j (72.7 g, 86 mmol) in tetrahydrofuran (300 mL) was added tetrabutylammonium fluoride (172 mL, 172 mmol, 1 M in tetrahydrofuran) at room temperature. The mixture was stirred at room temperature for 12 hours, and then ethyl acetate was added (300 mL). The resulting mixture was washed with water (400 mL×4), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 21k as yellow oil (21.0 g, 33.4%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.42-7.29 (m, 13H), 7.27-7.17 (m, 3H), 7.01 (m, 2H), 6.74-6.66 (m, 1H), 6.63-6.53 (m, 1H), 4.99-4.88 (m, 3H), 4.72 (m, 1H), 4.54 (d, 1H), 4.15-4.09 (m, 2H), 3.99-3.89 (m, 3H), 3.87 (s, 3H), 3.83 (d, 1H), 3.78-3.66 (m, 2H), 3.34 (d, 1H), 3.10 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.COC[C:25]1[C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][O:38][CH3:39])[CH:32]=2)=[CH:29][CH:28]=[C:27]([C:40]([OH:42])=O)[CH:26]=1.[C:43](N1C=CN=C1)(N1C=CN=C1)=[O:44]>>[CH2:18]([CH:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][C:40]([C:27]2[CH:26]=[CH:25][C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([O:38][CH3:39])[O:44][CH3:43])[CH:32]=3)=[CH:29][CH:28]=2)=[O:42])=[CH:6][CH:7]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][CH3:21]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCC(Cc1ccc(OCCN)cc1)C(=O)OCC
Reactant: COCc1cccc(-c2ccc(C(=O)O)cc2COC)c1
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(C(OC)OC)c3)cc2)cc1)C(=O)OCC
Yield: 98.7 %

Procedure:
In a similar manner to that described in Example 5, a reaction was carried out using ethyl 3-[4-(2-aminoethoxy)phenyl]-2-butylpropionate (1.55 g), which is the product of Reference example 6, 3′-dimethoxymethylbiphenyl-4-carboxylic acid (1.44 g), which is the product of reference example 14(c), and carbonyldiimidazole (1.03 g) and the reaction mixture was treated to afford the desired compound (2.72 g) as a syrup.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[C:18]([NH:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:15])=[CH:11][C:10]=1[C:18]([NH:20][C:21]1[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(=O)N2CCCCC2)ccc1OCc1ccccc1
Yield: 56.4 %

Procedure:
Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid (compound of Example 84(2)) and piperidine as the raw materials, the same operation as the Example 84(3) gave the title compound.
Reaction SMILES: [CH3:1]C1C(C)=C(N)C=CC=1OC.CC1C=C(N)C=C(C)C=1OC.[NH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([O:34][CH3:35])=[CH:26][CH:25]=1>CS(C)=O>[NH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([O:34][CH3:35])=[CH:26][C:25]=1[CH3:1]
Reactant: COc1ccc(N)c(C)c1C
Reactant: COc1ccc(N)c2ccccc12
Agent: COc1c(C)cc(N)cc1C
Solvent: CS(C)=O
Product: COc1cc(C)c(N)c2ccccc12
Yield: 67.4 %

Procedure:
In recent years, attempts were made to produce 4-alkoxyanilines in one step from the nitrobenzenes of the above general formula (I) in the presence of noble catalysts in a substantially anhydrous mixed solvent composed of an alcohol and sulfuric acid. For example, Journal of the Chemical Society of Japan [1979 (11), page 1532] reported that 2,4-dimethoxyaniline was obtained in a maximum yield of 27.8% from o-nitroanisole as a material by adding dimethyl sulfoxide (DMSO for short) as a catalyst poison to the reaction system. Journal of the Chemical Society of Japan [1980 (2), page 245] states that 2.2% of p-anisidine was obtained from nitrobenzene, and particularly, when o-methylnitrobenzene was used as a starting material, 2-methyl-4-methoxyaniline was obtained in a maximum yield of 70.2% by adding DMSO (in the absence of DMSO, the yield was 48.3%). Journal of the Chemical Society of Japan [1982 (7), page 1237], subsequently published, reported that 2,3-dimethyl-p-anisidine, 2,6-dimethyl-p-anisidine, 1 -amino-4-methoxy-naphthalene, and 1-amino-2-methyl-4-methoxy-naphthalene were obtained from the corresponding nitro compounds in the presence of DMSO in a maximum yield of 67.4% (63.7% in the absence of DMSO), 72.1% (45.2% in the absence of DMSO), 68%, and 55%, respectively. Furthermore, it was reported long ago that p-anisidine was obtained in a yield of about 40% from phenylhydroxylamine in a mixed solvent of methanol and sulfuric acid [Ber., 31, 1500 (1898)].
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[NH3:10]>>[NH2:10][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8]
Reactant: N
Reactant: Cc1noc(C)c1CCl
Product: Cc1noc(C)c1CN

Procedure:
4-Chloromethyl-3,5-dimethylisoxazole (700 mg, 4.8 mmol) is suspended in concentrated aqueous ammonia at 20-25 degrees C., and vigorously stirred overnight. The reaction mixture is extracted with isopropyl alcohol/chloroform (10/90, 2×). The combined organic phases are concentrated under nitrogen flow. The residue is purified by flash chromatography methanol/methylene chloride (5-20%, 1% triethylamine) to give the title compound, MR (CDCl3, 300 MHz) delta3.62, 2.37, 2.29, and 1.44.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[ClH:35].[Cl:36]CC1C=[CH:42][N:41]=[CH:40][CH:39]=1.Cl>>[ClH:36].[ClH:35].[CH2:1]([O:8][C:9]1[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=[C:11]([S:22][CH2:23][C:24]2[CH:25]=[CH:42][N:41]=[CH:40][CH:39]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Reactant: ClCc1ccncc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Cc1csc(Nc2ncc(SCc3ccncc3)cc2OCc2ccccc2)n1
Yield: 57.1 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 4-(chloromethyl)pyridine hydrochloride (27.6 mg, 0.17 mmol) were reacted according to the method of Example 43 to afford 3-(benzyloxy)-N-(4-methylthiazol-2-yl)-5-(pyridin-4-ylmethylthio)pyridin-2-amine dihydrochloride (47.9 mg, 57.6% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 8.72 (m, 2H), 7.77 (d, 1H), 7.71 (m, 2H), 7.58 (m, 3H), 7.45-7.34 (m, 3H), 6.73 (s, 1H), 5.30 (s, 2H), 4.42 (s, 2H), 2.27 (d, 3H); Mass spectrum (apci) m/z=421.0 (100), 330.0 (45), 238.0 (40).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([C:19](=O)[CH3:20])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([CH:19]([NH2:28])[CH3:20])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-1-(3-fluorophenyl)-2-naphthyl]ethanone (58 mg, 0.19 mmol) and ammonium acetate (150 mg, 1.94 mmol) in methanol (1.1 mL) and acetonitrile (1.1 mL) was heated at 65° C., in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (24.4 mg, 0.388 mmol) was added to the resulting mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was used directly in the next step (58 mg, 100%). LCMS calculated for C18H13ClF (M−NH2)+: m/z=283.1; Found: 283.0.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([OH:12])[CH2:11][CH:2]1[CH3:1])=[O:19]
Reactant: COc1cccc(C(=O)O)c1
Reactant: CC1CC(O)c2ccccc2N1
Product: COc1cccc(C(=O)N2c3ccccc3C(O)CC2C)c1
Yield: 26.6 %

Procedure:
Starting with 2-methyl-1,2,3,4-tetrahydro-4-quinolinol (3.00 g, 18.3 mmol) synthesized in the published manner and 3-methoxybenzoic acid (3.34 g, 22.0 mmol), the same procedure as shown in Reference Example 19 was repeated to give the titled compound (1.45 g, yield: 27%) as a white crystal. (cis:trans=1:1)
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1>C(OCC)C.C(O)C>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:22][C:20]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=[C:16]([CH3:15])[CH:21]=1)[CH3:14]
Reactant: Cc1cc(C)c([N+](=O)[O-])cn1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1cc(C)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of potassium ethoxide (0.262 g, 2.96 mmol) in diethyl ether (10 mL) and ethanol (1 mL) was added diethyl oxalate (0.404 mL, 2.96 mmol) in one portion and the resulting solution stirred for 10 min at rt. 2,4-Dimethyl-5-nitropyridine (Preparation 63, 0.400 g, 2.63 mmol) was added as a suspension in diethyl ether (1 mL)/ethanol (1.5 mL) and stirring continued for 16 h at rt. The mixture was filtered, washing with cold diethyl ether. The collected precipitate was dissolved in water and the pH adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration and air dried. The solid was partitioned between ethyl acetate (150 mL) and water (50 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (3×20 mL) and the combined organics washed with brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound as a red solid which required no further purification. δH (CDCl3): 1.40 (3H, t), 4.40 (2H, q), 4.52 (2H, s), 7.11 (1H, s), 9.25 (1H, s).