Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[N:3]=1.[N:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:11]=[N-:12].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][N:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:12]=[N:11]1)[CH3:18]
Reactant: C#Cc1cccc(Br)n1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)Cn1cc(-c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Bromo-6-ethynylpyridine (Example 465, Step 1) (350 mg, 1.92 mmol) and ethyl azidoacetate (1.08 ml, 1.92 mmol) were combined in t-BuOH (4.0 mL) and water (2.0 mL). CuSO4.5H2O (24 mg, 0.096 mmol) in water (1.0 mL) was added, followed by sodium ascorbate (76 mg, 0.39 mmol) in water (1.0 mL). The reaction was stirred at room temperature for 5 h, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to a yellow residue that was purified by flash chromatography (0-30% EtOAc/hexanes) to afford the title compound as a colorless solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH3:13].[Al]>C(Cl)(Cl)Cl>[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:21]([O-:9])=[CH:20][C:19]=2[N:28]=1)[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3cccnc3c2n1Cc1ccccc1
Agent: [Al]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3cccnc3c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroperbenzoic acid (3.7 g, 13.4 mmol) was added in 3 portions to a solution of 2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine (3.9 g, 12.2 mmol) in chloroform (100 mL) in a flask covered with aluminum foil. The reaction mixture was stirred at ambient temperature overnight; and then it was washed twice with dilute aqueous sodium bicarbonate and once with brine. The chloroform layer was divided into two portions. One portion was used in the example below. The second portion was concentrated under vacuum. The residue was recrystallized from isopropyl alcohol to provide 2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine-5-oxide as a solid, m.p. 187.5-189° C. Analysis: Calculated for C19H18N4O2+¼ H2O: %C, 67.52; %H, 5.49; %N, 16.58; Found: %C, 67.56; %H, 5.36; %N, 16.77.
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[N:4]=1)#[N:2].[OH-:45].[Na+].OO.Cl>CS(C)=O.C(O)C>[CH3:32][O:31][C:9]1[C:8]2[C:3]([C:1]([NH2:2])=[O:45])=[N:4][C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH3:38])=[O:35])=[CH:6][C:7]=2[N:11]([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C#N)c12
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C(N)=O)c12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
(R)-1-(4-cyano-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (70 mg, 0.121 mmol, synthesized from Intermediate 42B following Scheme 3-Step 2/Method A) was taken up in DMSO (605 μl) and Ethanol (605 μl). NaOH (1.8 ml, 1.815 mmol) was added followed by dropwise addition of hydrogen peroxide (180 μl, 2.056 mmol). The reaction was heated to 60° C. and was allowed to stir for 30 minutes. Room temperature was attained and 1N HCl was added and the products were extracted into EtOAc (3×). The organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give (R)-3-methoxy-6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carboxamide. The products were carried forward without purification. MS: [M+H]+ m/z 597.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)([C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[OH:21])[CH:18]=3)[N:13]3[N:36]=[N:37][N:38]=[C:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1.C(Cl)Cl>CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)([C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[OH:21])[CH:18]=3)[N:13]3[N:36]=[N:37][N:38]=[C:12]3[NH:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(O)(c2ccc3c(c2)C(c2cccc(Cl)c2)Nc2nnnn2-3)c2cncn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
NaBH4 (0.003 mol) was added portionwise at room temperature to a mixture of intermediate 16 (0.003 mol) in methanol (15 ml). The mixture was stirred at room temperature for 2 hours and poured out into ice water. DCM was added. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1.3 g, 86%) was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding 1 g (67%) of 5-(3-chlorophenyl)-4,5-dihydro-α-(4-methoxyphenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol (intermediate 17), mp. 220° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Cl.[NH2:17][NH:18][C:19]([NH2:21])=[O:20].C([O-])(=O)C.[Na+]>C(O)C.O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[N:17][NH:18][C:19]([NH2:21])=[O:20])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: NNC(N)=O
Reactant: O=Cc1ccc(Oc2ccncc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)NN=Cc1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a solution of 4-(4-pyridinoxy)benzaldehyde (570 mg, 2.86 mmol) in ethanol (10 mL) was added a solution of semicarbazide hydrochloride (350 mg, 3.03 mmol) and sodium acetate (235 mg, 2.86 mmol) in water (5 mL). The mixture was stirred at room temperature for 30 min., diluted with ethyl acetate (75 mL), washed with 2N NaOH, water and brine, dried over Na2SO4, concentrated in vacuo to yield the title compound as a white solid (720 mg, 2.77 mmol, 97%), mp: 212-213° C. 1H NMR (DMSO-d6): δ 10.29 (s, 1H), 8.49 (d, J=4.9, 2H), 7.87 (s, 1H), 7.84 (d, J=8.5, 2H), 7.19 (d, J=8.5, 2H), 6.96 (d, J=4.9, 2H), 6.53 (s, 2H).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([O:10]C)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:13][S:14][CH2:15][CH2:16][C:17](=[O:43])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH:28]([O:36][C:37](=[O:42])[CH2:38][C:39](=[O:41])[CH3:40])[O:29][C:30](=[O:35])[NH:31][CH2:32][CH2:33][CH3:34])[CH:20]=1>CCOCC>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[C:39]([CH2:38][C:37]([O:36][CH:28]([O:29][C:30](=[O:35])[NH:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26][O:25][C:21]1[CH:20]=[C:19]([NH:18][C:17]([CH2:16][CH2:15][S+:14]([CH3:1])[CH3:13])=[O:43])[CH:24]=[CH:23][CH:22]=1)=[O:42])(=[O:41])[CH3:40]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CCCNC(=O)OC(CCOc1cccc(NC(=O)CCSC)c1)OC(=O)CC(C)=O
Solvent: CCOCC
Product: CCCNC(=O)OC(CCOc1cccc(NC(=O)CC[S+](C)C)c1)OC(=O)CC(C)=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.2 %

Procedure:
A 5.5 g quantity of methyl p-toluenesulfonate was added to 4.54 g of 2-{3-(2-acetylacetyloxy-3-propylcarbamoyloxypropoxy)phenylcarbamoyl}ethyl methyl sulfide. The mixture was stirred at room temperature for 24 hours. Ether was added to the reaction mixture. The insoluble solid was filtered off, and was recrystallized from acetonitrile-ether, giving 6.10 g of 2-{3-(2-acetylacetyloxy-3-propylcarbamoyloxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium p-toluenesulfonate in 95.2% yield, M.P. 74° to 76° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]=[C:19]=S.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:31][NH2:32]>C1COCC1.O.C(O)(=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[NH:18][C:19]1[C:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]=2[NH:32][N:31]=1
Reactant: O=C1CCc2sccc21
Reactant: NN
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(Nc2n[nH]c3c2Cc2sccc2-3)c(Cl)c1
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 2,4-Dichloro-1-isothiocyanato-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (2,4-Dichloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine as brown solid in 33% yield.
Reaction SMILES: [CH:1]1([C@H:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[O:5][CH2:6][C@H:7]([OH:24])[CH2:8][NH:9][C:10]([CH3:23])([CH3:22])[CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH:40]=[CH:39]1>C(Cl)(Cl)Cl>[CH:1]1([C@H:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[O:5][CH2:6][C@H:7]([O:24][C:38](=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42])[CH2:8][NH:9][C:10]([CH3:23])([CH3:22])[CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:2][CH2:3]1
Reactant: O=C1C=CC(=O)O1
Reactant: Cc1ccccc1[C@H](OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)C1CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccccc1[C@H](OC[C@@H](CNC(C)(C)Cc1ccc2ccccc2c1)OC(=O)/C=C\C(=O)O)C1CC1
Reaction time: 4 h
Yield: 90.7 %

Procedure:
(2R)-1-[(1R)-(Cyclopropyl)-(2-methylphenyl)methoxy]-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propan-2-ol (1.25g) was dissolved in chloroform (10 ml) and, under ice-cooling, pyridine (0.485 ml) and maleic anhydride (294 mg) were added and the mixture was stirred for 4 hr. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the obtained residue. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (1.40 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]([N:11]2[C:15]3=[CH:16][S:17][CH:18]=[C:14]3[N:13]=[C:12]2[S:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=2)=[O:10])=[CH:5][CH:4]=1.[OH:30]P([O-])(O)=O.[K+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[C:15]3=[CH:16][S:17][CH:18]=[C:14]3[N:13]=[C:12]2[S:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=2)=[O:30])=[O:10])=[CH:28][CH:29]=1
Reactant: COc1ccc(COC(=O)n2c(SCc3ccc(C)cn3)nc3cscc32)cc1
Reactant: O=P([O-])(O)O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(COC(=O)n2c(S(=O)Cc3ccc(C)cn3)nc3cscc32)cc1
Temperature: 25 °C

Procedure:
850 mg (2 mmol) of the title compound from Example 21 were dissolved in 50 ml of CH2Cl2, and 50 ml of aqueous Na2HPO4 /KH2PO4 buffer solution (pH 7.5; 7.4 ml of KH2PO4 solution (45.35 g/l)+42.5 ml of Na2HPO4 solution (59.5 g/l) were added. While stirring vigorously at room temperature, 500 mg (2.5 mmol) of m-chloroperbenzoic acid dissolved in CH2Cl2 were added dropwise. The organic phase was dried over MgSO4 and concentrated, and the residue was chromatographed on silica gel using ethyl acetate. The title compound crystallized from isopropanol. Melting point 119°-120° C.
Reaction SMILES: C(O)C.[CH2:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.O.O.[CH2:15]([N:17]([CH2:21][CH3:22])[C:18](=[S:20])[S-:19])[CH3:16].[Na+]>O>[CH2:15]([N:17]([CH2:21][CH3:22])[C:18](=[S:19])[S:20][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:16]
Reactant: ClCc1ccccc1
Reactant: CCN(CC)C(=S)[S-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=S)SCc1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 93 %

Procedure:
More specifically, 10 ml of ethanol solution containing benzyl chloride (4.8 g, 38 mmol, Mw. 126.58) was added dropwise into 50 ml of ethanol solution containing sodium N,N-diethyldithiocarbamate trihydrate (10.3 g, 46 mmol, Mw. 225.31) in nitrogen atmosphere at 0° C. After agitating the reaction solution for 23 hours at room temperature, 150 ml of water was added and extracted by diethylether (200 ml×3 times). The organic layer was washed with water (100 ml×3 times) and was dried by sodium sulfate. Solvent was distilled away under reduced pressure using an evaporator so as to obtain benzyl N,N-diethyldithiocarbamate (colorless liquid). Yield point was 17.6 g (yield: 93%), 1H-NMR: δ7.407 ppm to 7.271 ppm (m, 5H, Ar—H), δ4.540 ppm (s, 2H, Ar—CH2S), δ4.082 ppm to 4.012 ppm (q, 2H, —N—CH2—), δ3.763 ppm to 3.692 ppm (q, 2H, —N—CH2—), δ1.311 to 1.252 ppm (m, 6H, —CH2—CH3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@@H:9]([C@H:10]([C:12](=C(C)C)[OH:13])[OH:11])[O:8][C:6](=[O:7])[C:5]=1[OH:17])[CH3:2]>O.C(O)C>[CH2:1]([O:3][C:4]1[C@@H:9]([C@H:10]([CH2:12][OH:13])[OH:11])[O:8][C:6](=[O:7])[C:5]=1[OH:17])[CH3:2]
Reactant: CCOC1=C(O)C(=O)O[C@@H]1[C@@H](O)C(O)=C(C)C
Solvent: O
Solvent: CCO
Product: CCOC1=C(O)C(=O)O[C@@H]1[C@@H](O)CO
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
12.4 g of the 3-O-ethyl-isopropylidene ascorbic acid prepared in Example 1 was dissolved in the mixed solvent of distilled water (10 ml)/ethanol (90 ml) together with 1.1 g of Nafion H, followed by stirring at 60° C. for 2 hours. Nafion H was eliminated by filtering and the mixture was concentrated into crude crystalline 3-ethyl-ascorbic acid. The crude crystalline 3-ethyl-ascorbic acid was re-crystallized in ethylacetate/ethanol (8:2) to give 7.6 g of white crystalline 3-O-ethyl-ascorbic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11](Cl)(=[O:13])=[O:12])[C:4]=2[O:3]1.[OH-].[NH4+:17]>O1CCCC1>[CH3:1][C:2]1([CH3:15])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:17])(=[O:13])=[O:12])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(S(=O)(=O)Cl)c2O1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Cc2cccc(S(N)(=O)=O)c2O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 26 g of 2,3-dihydro-2,2-dimethyl-7-benzofuransulfonyl chloride prepared in Example 1, in 130 ml of tetrahydrofuran, was cooled in an ice-water bath while about 30 ml of concentrated aqueous ammonium hydroxide was added portionwise at 10° to 30° C. The resulting suspension was stirred at room temperature for 3 hours, then the solvent was evaporated under reduced pressure. The residue was stirred in 150 ml of water for 0.5 hour, then filtered. The crude, wet solid was dissolved in chloroform and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give a dry solid. The solid was washed once with about 100 ml of hot toluene to give 20 g of 2,3-dihydro-2,2-dimethyl-7-benzofuransulfonamide, m.p. 163°-165° C.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][S:35]([NH:38][CH2:39][CH2:40][NH2:41])(=[O:37])=[O:36].Cl>O>[ClH:1].[ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH2:32][NH:41][CH2:40][CH2:39][NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)NCCN
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Agent: Cl
Solvent: O
Product: CS(=O)(=O)NCCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Yield: 156 %

Procedure:
In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.200 g, 0.436 mmol) was reacted with 2-(methanesulphonamido)ethylamine (0.350 g, 2.53 mmol). On completion of the reaction the mixture was acidified with dilute HCl and diluted with water, but no solid was formed. The mixture was concentrated in vacuo, and the residue was washed with acetone, 2N HCl and acetone again, and dried at 60° C. in vacuo to give the title compound as a yellow solid (0.210 g, 0.340 mmol, 78%); δH [2H6]DMSO 12.01 (1H, s), 9.82 (1H, br s), 9.77 (1H, s), 8.88 (1H, s), 8.40 (1H, d), 8.02 (1H, d), 7.76 (2H, d), 7.31-7.53 (6H, m), 7.14 (2H, d), 6.84 (1H, d), 5.18 (2H, s), 4.40 (2H, s), 3.34-3.48 (2H, m), 3.08-3.18 (2H, m), 2.96 (3H, s); m/z (M+1+) 544.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH3:21][NH2:22]>>[CH3:21][NH:22][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]3[O:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: CN
Product: CNc1cccc2nc(NCc3ccc(C)o3)ccc12

Procedure:
The title compound, MS: m/e=268.4 (M+H+), was prepared in accordance with the general method of example 3 from 5-bromo-2-chloroquinoline, 5-methyl-2-furanmethanamine and methylamine (solution in ethanol).
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C(OC([N:15]1[C@@H:19]([C@@H:20]([OH:22])[CH3:21])[CH2:18][CH2:17][C@H:16]1[C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)=O)(C)(C)C>C(OCC)(=O)C>[Cl:1][C:26]1[CH:27]=[CH:28][C:23]([C@H:16]2[NH:15][C@@H:19]([C@@H:20]([OH:22])[CH3:21])[CH2:18][CH2:17]2)=[CH:24][CH:25]=1
Reactant: Cl
Reactant: C[C@H](O)[C@H]1CC[C@@H](c2ccc(F)cc2)N1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@H]1CC[C@@H](c2ccc(Cl)cc2)N1
Reaction time: 3 h

Procedure:
4 N hydrochloric acid/ethyl acetate (7.5 mL) was added to an ethyl acetate (7.5 mL) solution of (2S,5R)-2-(4-fluorophenyl)-5-((S)-1-hydroxyethyl)-pyrrolidine-1-carboxylic acid t-butyl ester (850 mg, high polarity compound). Stirring was continued for 3 hours at room temperature. The solvent was removed under a vacuum, and sodium bicarbonate aqueous solution was added, and the resultant was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum, and the title compound (580 mg) was obtained. The physical property values are as follows.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH2:20])=[O:19])=[C:12]2[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].C(OC(=O)C)(=O)C.C(N(CC)CC)C>ClCCl>[C:3]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH2:20])=[O:19])=[C:12]2[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22])(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: NC(=O)c1[nH]c2ccc(N)cc2c1S(=O)(=O)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Reaction time: 48 h

Procedure:
5-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide trifluoroacetate salt (22 mg, 0.050 mmol, 1.0 equiv) was suspended in 3 mL of dichloromethane. Acetic anhydride (10 μL, 0.006 mmol, 1.2 equiv) and triethylamine (0.020 μL, 0.13 mmol, 2.5 equiv) were added and the reaction was stirred for 48 hours. The solvent was removed in vacuo and the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 367.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]([CH2:16][CH2:17][NH:18][C:19](=O)[CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>O.C(O)C>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]3[CH2:16][CH2:17][N:18]=[C:19]([CH3:20])[C:13]3=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cccn2CCNC(C)=O)cc1OC
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: COc1ccc(-c2ccc3n2CCN=C3C)cc1OC
Reaction time: 1 h

Procedure:
N-[2-[2-(3,4-Dimethoxyphenyl)pyrrol-1-yl]-ethyl]-acetamide (2.6 g) was treated with 20 ml of phosphorus oxychloride under argon and boiled for 1 hour while stirring. The reaction mixture was hydrolyzed at 0° C. with 100 ml of 2N sodium hydroxide solution and 100 ml of 28% sodium hydroxide solution, diluted with 1200 ml of water and extracted with methylene chloride (1×200 ml, 2×100 ml). The organic extracts were combined, dried with MgSO4 and freed from solvent. 1.4 g of a total of 2.7 g of crude product were chromatographed on 30 g of silica gel with methylene chloride/methanol (19:1) as the eluent. The product, 0.8 g of brown oil, was dissolved in a 40-fold amount of ethanol, treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol and concentrated to a volume of 10 ml. There was obtained 0.8 g of 6-(3,4-dimethoxyphenyl)-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:1.3); m.pt.: 158°-160° C. (dec.). A sample was recrystallized from a 40-fold amount of ethanol and yielded the (1:1) fumarate which melted at 160°-161° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17]([OH:19])=O)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(N(CC)CC)C.C([Cl:36])(=O)OCC.[CH3:37][NH:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42]>C1COCC1>[ClH:36].[ClH:36].[CH3:42][N:41]([CH3:43])[CH2:40][CH2:39][N:38]([CH3:37])[C:17](=[O:19])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[O:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:13]=1
Reactant: CNCCN(C)C
Reactant: Cc1csc(Nc2cc(Oc3ccccc3C(=O)O)ccn2)n1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2cc(Oc3ccccc3C(=O)N(C)CCN(C)C)ccn2)n1
Product: Cl
Yield: 82.3 %

Procedure:
Using the method of Example 32, 2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid (0.1 g, 0.3055 mmol), triethylamine (0.2129 mL, 1.527 mmol), ethyl carbonochloridate (0.03213 mL, 0.3360 mmol), N,N,N-trimethylethylenediamine (0.1191 mL, 0.9164 mmol) in THF (2 mL) were reacted to provide N-(2-(dimethyl-amino)ethyl)-N-methyl-2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzamide dihydrochloride (0.067 g, 44.82% yield) as off white solid. 1H NMR (CDCl3) δ 8.20 (d, 1H), 7.57 (d, 1H), 7.50 (t, 1H), 7.38 (t, 1H), 7.13 (d, 1H), 6.79 (s, 1H), 6.59 (dd, 1H), 6.40 (d, 1H), 3.97 (m, 2H), 3.17 (m, 2H), 3.03 (s, 3H), 2.87 (s, 6H), 2.41 (s, 3H); Mass spectrum (esi) m/z=412 (100) (M+H).