Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C.ON1C2N=CC=CC=2N=N1>[CH3:13][N:14]([O:15][CH3:16])[C:7]([C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=1)=[O:9]
Reactant: CNOC
Reactant: COc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N(C)OC)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
A mixture of 6-methoxynicotinic acid (0.784 g) in DMF (10 ml) was stirred with N,O-dimethylhydroxylamine hydrochloride (0.5 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.16 g) and 1-hydroxy-7-azabenzotriazole (50 mg). Triethylamine (1.67 ml) was added and the reaction mixture was stirred at room temperature for 18 h. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated using a hydrophobic filter tube and the solvent was evaporated to give the title compound as a colourless oil (0.86 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][NH:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:28]=[CH:27]2.[Cl-].[Na+]>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:13][CH2:14][CH3:15])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:36])=[O:35])[CH:28]=[CH:27]2
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: CCOC(=O)CNCC(OCC)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(CC(OCC)OCC)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
The compound obtained in Step 1 (504 mg) was suspended in methylene chloride (20 ml) and to the suspension were added triethylamine (336 ml) and then 6-chloronaphthalene-2-sulfonyl chloride (600 mg) under cooling with ice. After stirring the mixture overnight at room temperature, saturated sodium chloride solution was added and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and thereafter the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=20:1–4:1) to obtain the title compound (750 mg).
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][C:11]([CH3:28])([CH3:27])[CH2:12][C:13]1[N:17]([CH2:18][CH2:19][O:20][CH3:21])[N:16]=[C:15]([C:22]([O:24]CC)=[O:23])[CH:14]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O>[C:3]([O:7][C:8]([NH:10][C:11]([CH3:28])([CH3:27])[CH2:12][C:13]1[N:17]([CH2:18][CH2:19][O:20][CH3:21])[N:16]=[C:15]([C:22]([OH:24])=[O:23])[CH:14]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1cc(CC(C)(C)NC(=O)OC(C)(C)C)n(CCOC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCn1nc(C(=O)O)cc1CC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 37.6 %

Procedure:
Lithium hydroxide (17.1 g, 407 mmol) was added to a solution of ethyl 5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylate (37.6 g, 102 mmol) in methanol (141 mL) and water (47 mL). The reaction mixture was stirred for 2 days and then most of the methanol was removed under reduced pressure. The aqueous residue was cooled in an ice bath and then combined with 1 N hydrochloric acid (350 mL) and tert-butyl methyl ether. The layers were separated. The volume of the organic layer was reduced under vacuum and then diluted with hexanes. A precipitate was isolated by filtration, washed with water, and suction dried to provide 13.09 g of 5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylic acid as a white solid. The aqueous layer was extracted with chloroform while maintaining the pH of the aqueous layer at pH 4-5 by the addition of 1 N hydrochloric acid. The chloroform extracts were combined, dried over sodium sulfate and magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in tert-butyl methyl ether, diluted with hexanes, and then concentrated under reduced pressure. A white solid was isolated by filtration, washed with hexanes, and suction dried to provide an additional 21.8 g of product.
Reaction SMILES: O[CH:2]([C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])[CH2:3][N+:4]([O-:6])=[O:5]>C(Cl)Cl.C(OC(=O)C)(=O)C.CN(C)C1C=CN=CC=1>[N+:4]([CH:3]=[CH:2][C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])([O-:6])=[O:5]
Reactant: COC(=O)c1cc(C(=O)OC)cc(C(O)C[N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(C=C[N+](=O)[O-])cc(C(=O)OC)c1
Temperature: 22 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2.29 g (8.09 mmol) of dimethyl 5-(1-hydroxy-2-nitroethyl)isophthalate in 50 mL of DCM and 10 mL of acetic anhydride at 22° C. was added 100 mg of 4-dimethylaminopyridine. The solution was stirred at 22° C. for 1.5 h, evaporated and then coevaporated with xylenes (the material darkened slightly). The residue was partitioned between 100 mL of DCM and 50 mL of 1 N HCl. The organic layer was washed with water (50 mL), satd NaHCO3, dried (Na2SO4) and evaporated. The resulting residue was purified by flash chromatography on silica gel eluting with DCM to give dimethyl 5-(2-nitrovinyl)isophthalate as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 72.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.27 g, 0.438 mmol) prepared in Example 48a, triethylsilane (0.168 mL, 1.05 mmol), trifluoroacetic acid (3.4 mL) and dichloromethane (3.4 mL), to yield the title compound (0.148 g, 72%) as a colorless solid.
Reaction SMILES: [CH:1]([C:4]([OH:10])([CH:7]([CH3:9])[CH3:8])[C:5]#[CH:6])([CH3:3])[CH3:2].Br[C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:16][CH:17]=1>>[F:24][C:23]([F:25])([F:26])[C:22]([NH:21][CH2:20][CH2:19][CH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:6]#[C:5][C:4]([OH:10])([CH:7]([CH3:9])[CH3:8])[CH:1]([CH3:3])[CH3:2])[CH:13]=1)=[O:27]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(O)(C(C)C)C(C)C
Product: CC(C)C(O)(C#Cc1cccc(CCCNC(=O)C(F)(F)F)c1)C(C)C

Procedure:
Coupling of 3-isopropyl-4-methylpent-1-yn-3-ol with bromide 10 following the method used in Example 13 gave 2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-isopropyl-4-methylpent-1-ynyl)phenyl)propyl)acetamide as a pale yellow oil. Yield (1.375 g, 66%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (br s, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.17-7.22 (m, 3H), 4.81 (s, 1H), 3.17 (q, J=6.8 Hz, 2H), 2.56 (t, J=8.0 Hz, 2H), 1.86 (quint, J=6.8 Hz, 2H), 1.76 (quint, J=7.6 Hz, 2H), 0.99 (d, J=6.8 Hz, 6H), 0.94 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:22]=[C:23](OS(C(F)(F)F)(=O)=O)[C:24]4[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:25]=4[N:26]=3)=[CH:16][CH:15]=2)=[CH:12][N:11]=[CH:10]1>O1CCOCC1>[CH2:1]([NH:8][C:23]1[C:24]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:25]=2[N:26]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]3[O:9][CH:10]=[N:11][CH:12]=3)=[CH:19][CH:18]=2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NCc3ccccc3)c2C1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Benzylamine (0.061 mL, 0.55 mmol) was added to tert-butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.3 g, 0.55 mmol, Example 3c) in dioxane (4 mL) and the reaction mixture was stirred over night at 25° C. The solvent was removed under reduced pressure and the reaction mixture was redissolved in DCM and washed with water. The organic layer was dried (MgSO4), filtered and concentrated to give tert-butyl 4-(benzylamino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.238 g, 86%). MS (ESI+)/(ESI−) m/z 499/497
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]2[CH3:24])[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC1CCCCN1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(N2CCCCC2C)ncn1
Temperature: 120 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 99 mg of 2-methylpiperidine was added therein, and the mixture was stirred for 4 hours at 80° C. and 3 hours at 120° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 66 mg of 4-(2-butynyloxy)-6-(2-methylpiperidino)pyrimidine (hereinafter, referred to as Compound (20)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[NH2:20][OH:21].Cl.C([O-])(=O)C.[Na+]>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N:20][OH:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-benzyloxybenzaldehyde (4.24 g, 20 mmol) was dissolved with stirring in a mixed solution of ethanol and water (3:1, 100 ml) at 0.2 M. To this added were NH2OH.HCl (2.78 g, 40 mmol) and sodium acetate (2.46 g, 30 mmol,) and the mixture was stirred at room temperature for about 30 minutes. The completion of the reaction was confirmed by liquid chromatography, and then water and ethanol were distilled under reduced pressure to obtain a pale yellow solid compound. The solid compound was extracted three times with water and ethyl acetate, the organic solvent layer was distilled off under reduced pressure, and then a crude compound was recrystallized from ethyl acetate/hexane (1:10) to obtain a white solid compound. The following reaction was performed on the thus-obtained solid without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([OH:23])[CH:9]=[C:10]([C:12]2[NH:13][C:14]([C:17]3[O:18][C@@H:19]([CH3:22])[CH2:20][N:21]=3)=[CH:15][CH:16]=2)[CH:11]=1.F[C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([C:12]2[NH:13][C:14]([C:17]3[O:18][C@@H:19]([CH3:22])[CH2:20][N:21]=3)=[CH:15][CH:16]=2)[CH:11]=1)[O:23][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)(=[O:33])=[O:34])=[CH:28][CH:27]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (40 mg, 0.12 mmol) synthesized in Example (116d) and 1-[(4-fluorophenyl)sulfonyl]-4-methylpiperazine (25 mg, 0.15 mmol) synthesized in Example (116a) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (51 mg, 0.37 mmol) was added, followed by stirring at 100° C. for 1 hour under nitrogen atmosphere. 1-[(4-Fluorophenyl)sulfonyl]-4-methylpiperazine (30 mg) was added again, and the mixture was stirred at 90° C. overnight. The reaction solution was cooled to room temperature, water (10 mL) was added, and extraction was carried out twice with ethyl acetate (10 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (25 mg, yield 35%) as a white solid.
Reaction SMILES: C(O[C@H:5]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:7]3[C@:8]4([O:27][C:6]1=3)[O:26][C@H:9]4[C@@H:10]1[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[CH2:15][CH3:16])(=O)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C[C:46](C)=[O:47]>>[O:27]1[C:6]2=[C:7]3[C@:21]([CH3:24])([CH2:22][CH2:23][CH2:5]2)[C@@H:20]2[C@H:10]([C@H:11]4[C@:17]([CH3:25])([CH2:18][CH2:19]2)[C@@H:14]([CH:15]([CH:46]=[O:47])[CH3:16])[CH2:13][CH2:12]4)[C@@H:9]2[O:26][C@:8]123
Reactant: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4OC(C)=O)[C@H]3CC[C@]12C
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 48 %

Procedure:
In 5 ml of acetone was dissolved 24.3 mg (0.05 mmole ) of 20-(5,5-dimethyl-1,3 -dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3β-yl acetate, followed by addition of 2.5 mg (0.01 mmole) of pyridinium p-toluenesulfonate. The mixture was refluxed for 2 hours. The reaction mixture thus obtained was cooled to room temperature and the solvent was distilled off under reduced pressure. To the residue was added methylene chloride and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:ethyl acetate-hexane=1:5, v/v) to recover 9.6 mg of 3β-acetoxy-1α,2α;6α,7α-diepoxypregn-4-ene-20-carbaldehyde (yield: 48%).
Reaction SMILES: C([O:4][CH:5]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][CH2:19]2)=[CH:15][CH:14]=1)[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=O)C.C[O-].[Na+].CO.[ClH:27].C(O)C>CO.C(O)C>[ClH:27].[CH2:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([CH:5]([OH:4])[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:11])[CH3:12])[CH:21]=2)[CH:17]=[CH:18]1
Reactant: CC(=O)OC(COCCN(C)C)c1ccc2c(c1)CC=C2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CN(C)CCOCC(O)c1ccc2c(c1)CC=C2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In 0.5 ml of methanol was dissolved 80 mg of 1-acetoxy-1-(1H-inden-6-yl)-2-[2-(N,N-dimethylamino)ethoxy]ethane. To the solution was added 80 mg of a 28% sodium methoxide-methanol solution with ice cooling. The resulting mixture was stirred at room temperature for 20 minutes. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant:chloroform/methanol=20/1) to obtain a yellow oily product. The oily product was dissolved in 0.1 ml of ethanol. To the solution was added 0.1 ml of a 5.9N dry hydrogen chloride-ethanol solution at room temperature. The resulting crystals were collected by filtration to obtain 20 mg of 1-(1H-inden-6-yl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol hydrochloride (compound No. 298).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10]([CH3:12])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:9][C:10]1([CH3:12])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: CC(C)=O
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)Oc2ccccc2O1
Reaction time: 24 h

Procedure:
A mixture of catechol (55 g, 0.5 moles), acetone (150 ml), benzene (150 ml) and p-toluenesulfonic acid (15 mg) was refluxed in a Soxlet extractor containing 140 g of baked 4Å molecular sieves for 24 hours, as described in E. R. Cole, et al., Aust. J. Chem. 33, 675 (1980). The sieves were replaced with fresh sieves and refluxing continued for another 24 hours. The solvents were removed in vacuo and the residue was triturated with 1 liter of hexane. The light yellow solution was decanted and washed with 10% NAOH until the washes were colorless. The organic layer was dried (Na2SO4) and evaporated to 32.4 g (43%) of title compound as an oil which was used without further purification. 1H-NMR(CDCl3): δ=1.73 (s,6H); 6.78 (s,4H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1([C:21]2[N:25]=[C:24](S(C3C=CC(C)=CC=3)(=O)=O)[S:23][N:22]=2)[CH2:20][CH2:19]1>C(#N)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:24]2[S:23][N:22]=[C:21]([C:18]3([Cl:17])[CH2:20][CH2:19]3)[N:25]=2)[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4]
Reactant: Cc1cc(N)c(Cl)cc1O
Reactant: Cc1ccc(S(=O)(=O)c2nc(C3(Cl)CC3)ns2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(N)c(Cl)cc1Oc1nc(C2(Cl)CC2)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
3.00 g (19.04 mmol) of 2-chloro-4-hydroxy-5-methylaniline are introduced into 50 ml of acetonitrile, treated at ambient temperature with 3.16 g (22.84 mmol) of potassium carbonate and stirred at ambient temperature for 30 min. Subsequently, 6.26 g (19.04 mmol) of 3-(1-chlorocyclopropyl)-5-[(4-methylphenyl]sulphonyl]-1,2,4-thiadiazole are added and the reaction mixture is stirred at 50° C. for 12 h. After cooling, the mixture is concentrated on a rotary evaporator, the residue is taken up in dichloromethane and the solution is extracted twice with water, dried over Na2SO4 and freed from solvent under vacuum. The residue is purified by column chromatography. 3.18 g of product are obtained (93.3% purity, 49.4% yield, log P (pH 2.3)=3.50).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[N:7][C:6]=1Cl)=[O:4].[NH3:14]>C(O)C>[CH3:1][N:2]([CH3:13])[C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[N:7][C:6]=1[NH2:14])=[O:4]
Reactant: CN(C)C(=O)c1cc(Cl)nnc1Cl
Reactant: N
Solvent: CCO
Product: CN(C)C(=O)c1cc(Cl)nnc1N
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To 3,6-dichloro-pyridazine-4-carboxylic acid dimethylamide (100 mg, 0.456 mmol) was added saturated ammonia in absolute ethanol (2 mL) and the mixture irradiated in a microwave reactor to 180° C. for 45 min. 1 mL of saturated ammonia in ethanol was added and irradiation continued for an additional 30 min. The sample was concentrated in vacuo, washed with saturated ammonium chloride (1×) and brine (1×). Saturated sodium bicarbonate was added to the aqueous layer and was extracted with ethyl acetate (3×). The combined organics were dried over sodium sulfate to afford 3-amino-6-chloro-pyridazine-4-carboxylic acid dimethylamide (54.9 mg, 60%). MS: m/z 389 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:25]=1)[NH:22][C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:20]2.C(N(CC)CC)C>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:25]=4)[NH:22][C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:20]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: COC(=O)c1cc(N)cc2cc(C(C)(C)C)[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc2cc(C(C)(C)C)[nH]c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.20 mmol) and methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate (49.3 mg, 0.200 mmol) were dissolved in N,N-dimethylformamide (2 mL) containing a magnetic stir bar and triethylamine (0.084 mL, 0.60 mmol). The resulting solution was allowed to stir for 10 minutes at room temperature. The crude product was then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield methyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indole-7-carboxylate. ESI-MS m/z calc. 434.2, found 435.5. (M+1)+. Retention time of 2.12 minutes.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][NH:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](Cl)=[O:24])[CH3:19]>C(Cl)Cl>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:23](=[O:24])[CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:26])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)N1CCCN1
Reactant: CCOC(=O)CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
To a solution of sodium hydroxide (93.0 mL of 1N solution, 93.0 mmol) is added CH2Cl2 (280 mL) followed by pyrazolidine-1-carboxylic acid benzyl ester (15.0 g, 61.8 mmol) and then ethyl-3-chloro-3-oxopropionate (11.1 mL, 86.5 mmol). After stirring the biphasic mixture vigorously for 3 hours at room temperature, the mixture is quenched by pouring into aqueous saturated NH4Cl. The organic phase is dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (10% EtOAc/hexanes) to afford 15.5 g (78% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.38 (s, 5H), 5.23 (dd, J=11.8, 8.4 Hz, 2H), 4.19-4.07 (m, 4H), 3.65 (d, J=15.9 Hz, 1H), 3.31 (d, J=15.9 Hz, 1H), 3.20-3.15 (m, 2H), 2.20-2.04 (m, 2H), 1.26 (t, J=7.2 Hz, 3H); ESI+ MS: m/z (rel intensity) 321.0 (100, M++H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11]>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(I)cc1
Yield: 79.6 %

Procedure:
This compound was prepared according to the procedure of Example 56. A mixture of 22.0 g (0.1 mole) of 4-iodophenol (Aldrich) and 9.1 ml (14.8 g, 0.105 mole) of chlorosulfonyl isocyanate in 100 ml of toluene gave 23.8 g (80%) of the title compound as a white solid, mp 146°-147° C.