Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21]>CS(C)=O.C1COCC1>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[C:12]([CH3:4])[C:11]=1[N+:20]([O-:22])=[O:21]
Reactant: COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)c(C)c1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 5 h

Procedure:
1-methoxy-3-methyl-2-nitro-4-(trifluoromethyl)benzene was prepared by a procedure similar to that described in “Synthesis of 3,6-Disubstituted 2-Nitrotoluenes by Methylation of Aromatic Nitro Compounds with Dimethylsulfonium Methylide”, Kitano, Masafumi, Ohashi Naohito, Synthetic Communications, 30(23), 4247-4254, 2000. To a suspension of NaH (60% by wt. in mineral oil, 362 mg, 9.04 mmol) and trimethylsulfonium iodide (1.84 g, 9.04 mmol) in DMSO (17 ml) and THF (6.7 ml) was added 4-methoxy-3-nitrobenzotrifluoride (1.00 g, 4.52 mmol) as a solution in DMSO (2.7 ml). The reaction mixture was allowed to stir at 10-20° C. for 5 hrs. The reaction mixture was quenched by addition to ice water. The aqueous layer was separated and extracted with toluene 7 times. The combined organic extracts were washed with brine, dried over MgSO4, and filtered. The solvent was removed by distillation at reduced pressure. The residue was purified by automated silica gel chromatography (100% hexanes to 98:2 hexanes:ethylacetate) to provide 1-methoxy-3-methyl-2-nitro-4-(trifluoromethyl)benzene.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])=[CH:4][CH:3]=1.[CH:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:12][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: N[C@@H]1C[C@H]1c1ccc(I)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CN[C@@H]2C[C@H]2c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of trans-2-(4-iodophenyl)cyclopropanamine (1.0 g, 3.86 mmol) in methanol (15 mL) were added tert-butyl 4-formylpiperidine-1-carboxylate (0.741 g, 3.47 mmol), acetic acid (0.066 mL, 1.158 mmol), and the mixture was stirred at rt for 1 h. Sodium cyanoborohydride (0.364 g, 5.79 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was concentrated and the residue was treated with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 730 mg of product as pale yellow oil. MS: (M+H)+=457.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.99-1.18 (m, 3H), 1.45-1.51 (m, 9H), 1.69-1.81 (m, 3H), 1.87-1.94 (m, 1H), 2.29-2.37 (m, 1H), 2.62-2.90 (m, 3H), 4.00-4.20 (m, 2H), 6.86-6.88 (m, 2H), 7.57-7.59 (m, 2H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[C:15]=2[O:14]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4C)c3O2)cc1
Agent: [Na+]
Product: Cc1ccccc1-c1cccc2c1OC(CN=[N+]=[N-])C2

Procedure:
Treatment of (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (7.79 g, 19.74 mmol) with sodium azide (5.13 g, 78.99 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.5 g, 10 wt. %) generally according to the procedure described for Example 1 provided 3.63 g (67%) of (±)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >200° C.; Anal. calcd. for C16H17NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 69.83; H, 6.64; N, 5.
Reaction SMILES: [CH3:1]C1(C)CCCC(C)C1=O.[CH3:11][C:12]1([CH3:21])[CH:17]([CH3:18])[CH2:16][CH2:15][CH:14](C)[CH:13]1[OH:20]>>[CH3:1][C:17]1([CH3:18])[CH2:16][CH2:15][CH2:14][C:13](=[O:20])[C:12]1([CH3:11])[CH3:21]
Reactant: CC1CCC(C)C(C)(C)C1O
Reactant: CC1CCCC(C)(C)C1=O
Product: CC1(C)CCCC(=O)C1(C)C

Procedure:
If the procedure of Example 8 is followed but instead of 28 g of 2,2,6-trimethyl-cyclohexanone 31 g of 2,2,3,6-tetramethyl-cyclohexanol are employed, fractional distillation gives 9.6 g of unconverted tetramethyl-cyclohexanone and 21 g (corresponding to 73% of theory, based on ketone converted) of 2,2,3,6-tetramethyl-1-(but-1'-yn-3'-en-1'-yl)-cyclohexanol of boiling point 66°-67° C/0.2 mm Hg and refractive index nD25 = 1.5018. Fragrance note: faintly floral, coniferous, fruity.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[O:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]=1[CH:11]=[O:12].C(O)=O>O>[O:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([CH:11]=[O:12])=[C:6]1[CH:2]=[O:1]
Reactant: O=Cc1c(C2OCCO2)oc2ccccc12
Solvent: O=CO
Solvent: O
Product: O=Cc1oc2ccccc2c1C=O
Reaction time: 2 h
Yield: 92 %

Procedure:
2-(1,3-Dioxolan-2-yl)-1-benzofuran-3-carbaldehyde (3.63 g, 16.6 mmol) is dissolved in formic acid (16.3 ml, 433 mmol) with water (4.1 ml). After 2 hours, additional formic acid (10 ml) and water (2.5 ml) are added to alleviate the slurry. The reaction stirred 12 h and is diluted with water (30 ml). The resulting slurry is filtered, dried in an air stream, affording 2.66 g (92%) of 1-benzofuran-2,3-dicarbaldehyde as an orange solid. MS (EI) m/z: 174 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].IC.N#N>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(-c2nn[nH]n2)cc1
Agent: N#N
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1nnc(-c2ccc(F)cc2)n1
Temperature: 82 °C
Yield: 70.9 %

Procedure:
A mixture of 5-(4-fluorophenyl)-2H-tetrazole (6.61 g, 40.3 mmol), K2CO3 (6.68 g, 48.3 mmol), and iodomethane (3.02 mL, 48.3 mmol) in acetonitrile (115 mL) was heated to reflux (ca. 82° C.) for one hour. After cooling, the mixture was concentrated to dryness and the residue was partitioned between water (75 mL) and EtOAc (100 mL). The layers were separated, the aqueous layer was back-extracted with EtOAc (50 mL) and the combined organic layers were washed with water (50 mL) and brine (50 mL). The organic layer was dried over anh. MgSO4, filtered and concentrated to give 9.5 g as a colorless oil that solidified upon standing. The residue was purified by flash chromatography to give 2 main products: Intermediate 35B as the N2 isomer: 5-(4-fluorophenyl)-2-methyl-2H-tetrazole (5.09 g, 70.9% yield) as a white solid: No NOE observed between the methyl group at 4.42 ppm and the aromatic protons; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.42 (s, 3H) 7.33-7.45 (m, 2H) 8.03-8.14 (m, 2H); MS m/z 179.2 (M+H)+; HPLC >99.5%, RT=1.75 minutes.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[OH:8][NH:9][CH2:10][CH2:11][CH2:12][P:13](=[O:16])([OH:15])[OH:14]>C(O)=O>[CH:5]([N:9]([CH2:10][CH2:11][CH2:12][P:13](=[O:14])([OH:16])[OH:15])[OH:8])=[O:7]
Reactant: O=P(O)(O)CCCNO
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN(O)CCCP(=O)(O)O
Reaction time: 0.17 h

Procedure:
Formic acid (20 ml.) was added dropwise to acetic anhydride (40 ml.) at 0°-5° C. in the course of 15 minutes with stirring. After stirring was continued at the same temperature for 10 minutes and then at 45°-50° C. for 15 minutes, the mixture was cooled down to 0°-5° C. To this cooled mixture was added dropwise a solution of 3-(N-hydroxyamino)propylphosphonic acid (32.8 g.) in formic acid (60 ml.) at the same temperature in the course of 20 minutes, stirred for additional 45 minutes at ambient temperature, and then the resultant mixture was concentrated under reduced pressure. The residue was dissolved in ethanol (300 ml.), treated with activated charcoal (6 g.) and then filtered. The filtrate was diluted with ethanol (200 ml.) and treated with 28% aqueous ammonia (28 ml.) with stirring under ice-cooling to give an oily precipitate. The precipitate was separated by decantation and dissolved in water (120 ml.). The aqueous solution was treated with activated charcoal (4 g.), and filtered. To the aqueous filtrate was added ethanol (800 ml.) at 80° C. and allowed to stand overnight at ambient temperature to give crystalline monoammonium salt of 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (30.55 g.), mp 158°-160.5° C. (dec.) The same monoammonium salt (4.35 g.) was recovered additionally from the mother liquor, by concentrating it to about 100 ml under reduced pressure mixing with ethanol (300 ml.) and allowing to stand at ambient temperature for 2 hours.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[C:35]([NH2:38])[CH:36]=[CH:37][C:30]=2[CH2:29][CH2:28]1>>[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:28][CH2:29][C:30]2[CH:37]=[CH:36][C:35]([NH:38][C:2]3[N:7]=[C:6]([NH:8][C@@H:9]4[C@@H:14]5[CH2:15][C@@H:11]([CH:12]=[CH:13]5)[C@@H:10]4[C:16]([NH2:18])=[O:17])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=3)=[CH:34][C:31]=2[CH2:32][CH2:33]1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2C(F)(F)F)[C@H]2C=C[C@@H]1C2
Product: COCCN1CCc2ccc(Nc3ncc(C(F)(F)F)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)cc2CC1

Procedure:
The title compound was prepared from (1S,2S,3R,4R)-3-(2-Chloro-5-trifluoromethylpyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 933 to afford a yellow solid (41 mg, 70%). Mp: 125-7° C. LCMS (m/e) 517 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.13 (s, 1H), 7.48 (d, J=8 Hz, 1H), 7.37-7.17 (m, 3H), 7.05 (d, J=8 Hz, 1H), 6.32 (m, 2H), 6.85 (br s, 1H), 6.63 (br s, 1H), 4.40 (m, 1H), 3.59 (m, 2H), 3.38 (s, 3H), 3.09 (s, 1H), 2.84 (m, 5H), 3.76 (m, 6H), 2.45 (d, J=8 Hz, 1H), 2.20 (d, J=8 Hz, 1H), 1.62 (d, J=8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12>ClCCl.FC(F)(F)C(O)=O>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[N:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCCNC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 104.2 %

Procedure:
A mixture of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (700 mg, 1.44 mmol, 1.00 equiv) in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to yield 580 mg of crude 3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].O([C:17]1[C:18]2[C:23]([N:24]=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)C1C=CC=CC=1.CCOCC>C1(O)C=CC=CC=1>[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:17]1[C:18]2[C:23]([N:24]=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:9])=[O:8]
Reactant: c1ccc(Oc2c3ccccc3nc3ccccc23)cc1
Reactant: NCCCCCC(=O)O
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: O=C(O)CCCCCNc1c2ccccc2nc2ccccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
6-Aminohexanoic acid (1.47 g, 11.2 mmol) was added to a solution of 9-phenoxyacridine (2.7 g, 10 mmol) in phenol (15 g). The suspension was stirred at 120° C. for 2 h. The solution was cooled to room temperature and poured into ether whereby the product precipitated as a yellow-green solid. It was triturated with hot ethanol, filtered then washed with ethanol, giving crude 9-(5-carboxypentyl) aminoacridine.Yield 2.4 g (78%).
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:19](=[O:29])[NH:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)C1C=CC=CC=1>CCO.C1(C)C=CC=CC=1.[Pd]>[C:25]([O:24][C:22]([CH2:21][NH:20][C:19]([C@H:12]([NH2:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:29])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)CNC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CNC(=O)[C@H](N)c1ccccc1
Reaction time: 5.5 h
Yield: 98.7 %

Procedure:
(R)-N-Benzyloxycarbonyl-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 1; 12.8 g, 32.2 mmol) was dissolved in EtOH (99%, 200 ml) and toluene (50 ml). Pd/C (10%, 0.65 g) was added and hydrogenation was performed at atmospheric pressure for 5.5 hours at room temperature. The reaction mixture was filtered through diatomaceous earth and the solvents were evaporated to give the title compound (8.4 g, 99%). NMR (600 MHz, CDCl3): 1.45 (s, 9H), 3.93 (m, 2H), 4.54 (s, 1H), 7.31–7.42 (m, 5H), 7.51 (brs, 1H).
Reaction SMILES: [C:1](=[NH:25])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][CH:19]=2)=[C:8]([F:24])[CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:33]([CH:35]([CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[N:45][CH:46]=1)[C:36](OC)=O)=[O:34].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:12][C:10]1[CH:11]=[C:6]([CH:7]=[C:8]([F:24])[C:9]=1[O:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:21])([F:22])[F:23])=[N:16][CH:15]=1)[CH2:5][CH2:4][O:3][C:1]1[NH:2][CH:36]=[C:35]([CH2:40][C:41]2[CH:46]=[N:45][CH:44]=[N:43][CH:42]=2)[C:33](=[O:34])[N:25]=1
Reactant: N=C(N)OCCc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Reactant: COC(=O)C(C=O)Cc1cncnc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1nc(OCCc2cc(F)c(Oc3cnc(C(F)(F)F)nc3)c(F)c2)[nH]cc1Cc1cncnc1
Temperature: 80 °C
Yield: 33.8 %

Procedure:
To the solution of 3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenethyl carbamimidate, trifluoroacetate (100 mg, 0.210 mmol) and methyl 2-formyl-3-(pyrimidin-5-yl)propanoate (60 mg, 0.309 mmol) in 1,4-dioxane (1 mL) was added K2CO3 (116 mg, 0.842 mmol). The mixture was heated with a microwave reactor at 80° C. for 0.5 h. Purification via MDAP then afforded the title compound (36 mg, 0.071 mmol, 33.8% yield). LCMS: rt=2.82 min, [M+H]=507
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[C:10]=1[CH3:18].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[C:10]=1[CH3:18]
Reactant: COC(=O)c1c[nH]c(-c2ccc(F)cc2Cl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)c[nH]c1-c1ccc(F)cc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a solution of methyl 5-(2-chloro-4-fluorophenyl)-4-methyl-1H-pyrrole-3-carboxylate (0.64 g, 2.4 mmol) in methanol (10 ml) was added 5N NaOH (10 ml) and the mixture was stirred at 80° C. for 4.0 h. The reaction mixture was concentrated on a rotary evaporator. To the residue was added water and washed with Et2O. The resulting solution was neutralized with conc HCl and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and concentrated on a rotary evaporator to give the title compound (610 mg, quant) as a brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]([OH:23])=[O:22]>>[N:1]1[CH:6]=[CH:5][C:4]([C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]([OH:23])=[O:22])=[CH:3][CH:2]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(O)c1cccc2c(Br)cccc12
Product: O=C(O)c1cccc2c(-c3ccncc3)cccc12

Procedure:
The title compound was prepared from 4-pyridylboronic acid and 5-bromo-1- naphthoic acid (J. Chem. Soc., 1950, 991) using a similar procedure to Example 4, obtained as a white solid (55%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[N:6][C:7](Cl)=[CH:8][CH:9]=1.[F:11][CH2:12][CH2:13][CH2:14][OH:15]>>[F:11][CH2:12][CH2:13][CH2:14][O:15][C:7]1[N:6]=[N:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCCCF
Agent: [H-]
Agent: [Na+]
Product: FCCCOc1ccc(Cl)nn1
Yield: 87 %

Procedure:
3-(3-Fluoropropoxy)-6-chloropyridazine (108c, 557 mg, 87%) was prepared in the same manner as in Example 26 as a white solid using sodium hydride (NaH 60%, 202 mg, 5.04 mmol), 3,6-dichloropyridazine (107, 500 mg, 3.36 mmol) and 3-fluoro-1-propanol (393 mg, 5.04 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14].N1CCCCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[C:15](/[C:13]#[N:14])\[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CC#N
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)/C(C#N)=C1\C(=O)Nc2ccc(Cl)cc21
Reaction time: 8 h
Yield: 90 %

Procedure:
A stirred mixture of 5-chloro-1H-indole-2,3-dione, starting material VIII, (90.8 g, 0.5 mol) and methyl cyanoacetate (44.1 ml, 0.5 mol) in methanol (1000 ml) was treated with piperidine (2 ml) and heated under reflux for 5 hours before standing overnight at ambient temperature. The crude (5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-cyanoacetic acid methyl ester was removed by filtration, washed with cold methanol (2×150 ml) and dried in vacuo to give 117.6 g (90%) of a dark purple solid. This was a 6.5:1 mixture of geometric isomers which was sufficiently pure by 1H NMR for subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[CH2:28]1[C:31]2([CH2:36][CH2:35][N:34]([C:37](=[O:39])[CH3:38])[CH2:33][CH2:32]2)[CH2:30][NH:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:29]3[CH2:30][C:31]4([CH2:36][CH2:35][N:34]([C:37](=[O:39])[CH3:38])[CH2:33][CH2:32]4)[CH2:28]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(=O)N1CCC2(CC1)CNC2
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Product: CC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 1-(2,7-diaza-spiro[3.5]non-7-yl)-ethanone in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a colourless solid (47 mg, 61%).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:30]([OH:32])[CH3:31])[CH:27]=[CH:28][CH:29]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([OH:32])[CH3:31])[CH:25]=3)=[O:20])=[CH:21][CH:22]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)c1cccc(N)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: CC(O)c1cccc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)c1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 1-(3-aminophenyl)ethanol (33 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-(1-hydroxyethyl)phenyl)benzamide as a white solid. Yield: 38 mg (36%). 1H-NMR: 10.42 (br s, 1H), 8.06 (d, J=8.5 Hz, 2H), 7.77-7.71 (m, 3H), 7.63 (d, J=8.0 Hz, 2H), 7.28 (t, J=8.0 Hz, 1H), 7.24-7.18 (m, 1H), 7.12-7.06 (m, 2H), 5.19 (d, J=4.0 Hz, 1H), 4.74-4.66 (m, 1H), 3.84-3.80 (m, 2H), 2.46 (t, J=7.5 Hz, 2H), 1.67-1.59 (m, 2H), 1.31 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH:9]([OH:24])[CH2:10][NH:11][CH:12]([CH2:14][CH2:15][N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13])[CH:6]=[CH:5][C:4]=1[OH:25].C(OO)(=[O:28])C.C(Cl)(Cl)Cl.CO.N>CO>[CH3:23][N:16]([CH2:15][CH2:14][CH:12]([NH:11][CH2:10][CH:9]([C:7]1[CH:6]=[CH:5][C:4]([OH:25])=[C:3]([S:2]([CH3:1])=[O:28])[CH:8]=1)[OH:24])[CH3:13])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)OO
Reactant: CSc1cc(C(O)CNC(C)CCN(C)c2ccccc2)ccc1O
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(CCN(C)c1ccccc1)NCC(O)c1ccc(O)c(S(C)=O)c1

Procedure:
To 2-methylthio-4-(2-[4-(methylanilino)-2-butylamino]-1-hydroxyethyl)phenol (1.8 g=5 mmol) in 50 ml methanol add a solution of 40% peracetic acid (5.0 mmol) in 10 ml methanol. Stir one-half hour and concentrate to obtain a gum. Chromatograph on 100 g silica gel using chloroform/methanol/ammonia as eluant and combine appropriate fractions and concentrate to obtain 4-(2-[4-(N-methylanilino)-2-butylamino]-1-hydroxyethyl)-2-methylsulfinylphenol. Dissolve this in ether and treat with ethereal hydrogen chloride to obtain the title product.
Reaction SMILES: Cl.[CH3:2]OC(=O)[C@H](N)CCC.[CH2:11]([C@@H:13]1[CH2:18][NH:17][C@@H:16]([CH3:19])[CH2:15][N:14]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH3:12]>>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:14]2[CH2:15][C@H:16]([CH3:19])[NH:17][CH2:18][C@H:13]2[CH2:11][CH2:12][CH3:2])=[CH:26][CH:25]=1
Reactant: CCC[C@@H](N)C(=O)OC
Reactant: CC[C@@H]1CN[C@@H](C)CN1Cc1ccc(OC)cc1
Agent: Cl
Product: CCC[C@@H]1CN[C@@H](C)CN1Cc1ccc(OC)cc1

Procedure:
(2R,5S)-1-(4-Methoxy-benzyl)-5-methyl-2-propyl-piperazine was prepared from (R)-2-amino-pentanoic acid methyl ester hydrochloride in analogy to the synthesis of (2R,5S)-2-ethyl-1-(4-methoxy-benzyl)-5-methyl-piperazine.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(OCC)(=O)C>[CH:17]1[CH:16]=[CH:15][C:14]([N:7]([C:1]2[CH:2]=[CH:3][C:4]([Br:20])=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 1-L Erlenmeyer flask, 25 g (100 mmol) of triphenylamine, 18 g (100 mmol) of N-bromosuccinimide, and 400 mL of ethyl acetate were put and stirred at room temperature in air for 24 hours. After the reaction, the reaction solution was washed twice with a saturated aqueous solution of sodium carbonate to separate into an aqueous layer and an organic layer. The aqueous layer was extracted twice with ethyl acetate and washed with saturated saline together with the organic layer. After the organic layer was dried with magnesium sulfate, natural filtration and enrichment was performed, and the resulting white solid was recrystallized with ethyl acetate and hexane, whereby 22 g of a white powder solid of 4-bromotriphenylamine was obtained at a yield of 66%.