Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[C:13]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C:21]1([C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]1)[CH2:20][CH2:19]2)(O)=[O:14].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[O:31]=[C:27]1[NH:26][C:21]2([CH2:20][CH2:19][C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:13]([NH:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[C:7]5[C:12]=4[N:11]=[CH:10][CH:9]=[CH:8]5)=[O:14])[CH:17]=3)[CH2:22]2)[C:29](=[O:30])[NH:28]1
Reactant: NCc1cccc2cccnc12
Reactant: O=C1NC(=O)C2(CCc3cc(C(=O)O)ccc3C2)N1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C1NC(=O)C2(CCc3cc(C(=O)NCc4cccc5cccnc45)ccc3C2)N1

Procedure:
A mixture of 8-(aminomethyl)quinoline (14 mg, 0.088 mmol), (±)-6′-carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione (described in Intermediate 1) (15 mg, 0.058 mmol), EDC (22 mg, 0.115 mmol), and HOBT (13 mg, 0.088 mmol) was stirred in DMF (0.8 mL) at ambient temperature for 18 h. The crude mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a tan solid. MS: m/z=401 (M+1). HRMS: m/z=401.1584; calculated m/z=401.1608 for C23H21N4O3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:20]([O:22][CH3:23])=[O:21])[C:7]([NH:9][CH:10]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11]([OH:13])=O)=[O:8].C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:37]([NH:40][CH2:41][CH2:42][CH3:43])[CH2:38][CH3:39]>ClCCl>[CH2:37]([N:40]([CH2:41][CH2:42][CH3:43])[C:11](=[O:13])[CH:10]([NH:9][C:7](=[O:8])[C:6](=[C:2]1[S:1][CH:5]=[CH:4][S:3]1)[C:20]([O:22][CH3:23])=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:38][CH3:39]
Reactant: COC(=O)CCC(NC(=O)C(C(=O)OC)=C1SC=CS1)C(=O)O
Reactant: CCCNCCC
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)C(CCC(=O)OC)NC(=O)C(C(=O)OC)=C1SC=CS1
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
2-((2-(1,3-Dithiol-2-ylidene)-3-methoxy-3-oxopropanoyl)amino)-5-methoxy-5-oxopentanoic acid (4) (239 g) was dissolved in dichloromethane (1.5 l), followed by the addition of 70.7 g of triethylamine. To the resulting solution, 71.8 g of ethyl chlorocarbonate were added dropwise at 5-10° C. under stirring over 30 minutes. Subsequent to further stirring at 15-20° C. for 3 hours, di-n-propylamine (70.7 g) was added dropwise at 5-10° C., followed by stirring at room temperature for 12 hours. The solvent was removed under reduced pressure, and ethyl acetate (2 l) was then added to the residue. The resulting precipitate was filtered off. After the ethyl acetate layer was washed with 0.5 N hydrochloric acid and then with water, the solvent was removed under reduced pressure. Diethyl ether (800 ml) was added to the residue and the resulting precipitate was collected by filtration, whereby methyl 5-(dipropylamino)-4-((2-(1,3-dithiol-2-ylidene)-3-methoxy-3-oxopropanoyl)amino)-5-oxopentanoate (5) (113 g, yield: 57%) was obtained as pale yellow crystals.
Reaction SMILES: C[O:2][CH:3](OC)[C:4](=O)[CH3:5].[CH2:9]([C:16]1[C:17]([NH2:28])=[N:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C:16]1[NH:21][C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][N:18]2[C:3](=[O:2])[C:4]([CH3:5])=[N:28][C:17]=12)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(OC)C(C)=O
Reactant: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Product: Cc1nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn-2c1=O

Procedure:
Synthesized using method B with 1,1-dimethoxypropan-2-one and 3-benzyl-5-phenylpyrazin-2-amine as starting materials. Exact mass calculated for C20H18N30+ m/z+316.14, found m/z+316.
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]([NH:19][CH3:20])=[O:18])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:20][NH:19][C:17]([C:9]1[NH:10][C:11]2[C:16]([C:8]=1[CH:6]=[CH2:1])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:18]
Reactant: [Li]CCCC
Reactant: CNC(=O)c1[nH]c2ccccc2c1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1c(C(=O)NC)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5M in hexanes) (48.6 mL, 121.7 mmol) was added dropwise to an ice-cooled solution of methyl triphenylphosphoniumbromide (43.5 g, 121.7 mmol) in THF (500 mL). The mixture was stirred at 0° C. for 1 h then at rt for 2 h. 3-Formyl-N-methyl-1H-indole-2-carboxamide (1.96 g, 9.7 mmol) in THF (100 mL) was added and the mixture stirred at rt for 2 h. The solvent was evaporated and the residue dissolved in ethyl acetate and washed twice with water. The organic phase was dried over magnesium bromide and evaporated in vacuo. The crude mixture was chromatographed over silica gel eluting with 40% ethyl acetate in hexanes to afford the title compound (730 mg (38%). 1H NMR (300 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.04 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.33 (d, J=18 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.09 (t, J=7.2 Hz, 1H), 5.77 (d, J=18.4 Hz, 1H), 5.27 (d, J=11.6 Hz, 1H), 2.81 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:17][C:18]([NH:20][C:21]1[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([OH:30])=[CH:23][C:22]=1[CH:31]([CH3:33])[CH3:32])=[O:19]>C(#N)C.O>[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:17][C:18]([NH:20][C:21]2[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([OH:30])=[CH:23][C:22]=2[CH:31]([CH3:33])[CH3:32])=[O:19])[CH2:12][CH2:11]1
Reactant: OCCN1CCNCC1
Reactant: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
Potassium carbonate (1.52 g, 11 mmol) was added to a solution of 1-(2-hydroxyethyl)piperazine (1.43 g, 11 mmol) and 2-bromo-N-(2,6-diisopropyl-4-hydroxyphenyl)acetamide in acetonitrile (50 ml) and the mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively and dried oven anhydrous sodium sulfate and the solvent was evaporated therefrom. The crude crystals were recrystallized from acetone-hexane to provide 2.5 g (yield 69%) of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-(2,6-diisopropyl-4-hydroxyphenyl)acetamide as colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][O:9][CH2:8][C:7]2=C.C[OH:14].C(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][O:9][CH2:8][C:7]2=[O:14]
Reactant: CO
Reactant: C=C1COCc2c(F)cccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1COCc2c(F)cccc21
Temperature: -78 °C

Procedure:
8-Fluoro-4-methylene-3,4-dihydro-1H-isochromene (400 mg) was dissolved in a solution of 1:1 MeOH/DCM (50 mL) and 1 mL of pyridine added. The mixture was chilled to −78° C. and ozone was bubbled through the mixture for 40 min. The reaction monitored by TLC. The mixture was purged with nitrogen at −78° C. for 10 min and then treated with PPh3. After concentration, the resulting residue was purified by preparative TLC to offer 300 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1ccc(OC)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccc(OC)cc1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(4-methoxyphenyl)acetate hydrochloride (prepared by the Bucherer Modification of the Strecker procedure as described in J. P. Greenstein et al., “The Chemistry of Amino Acids”, Vol. 1, p. 698, Wiley, New York (1961)), the title compound was prepared as a solid (mp=170-174° C.). The reaction was monitored by tlc (Rf=0.1 in 98:2 CHCl3/MeOH) and the product was purified by silica gel chromatography using 98:2 CHCS3/MeOH as the eluent.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][NH:6][CH3:7].C1(=O)CCCC1.[C-]#N.[K+].CN(C)[C:19]1([C:24]#[N:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>O>[CH3:7][N:6]([CH2:5][CH2:4][O:3][CH3:2])[C:19]1([C:24]#[N:25])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CNCCOC
Reactant: CN(C)C1(C#N)CCCC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O=C1CCCC1
Solvent: O
Product: COCCN(C)C1(C#N)CCCC1
Yield: 82 %

Procedure:
The title compound (3.39 g; 82%) was prepared from N-(2-methoxyethyl)methylamine hydrochloride (2.84 g; 22.6 mmol), cyclopentanone (1.90 g, 22.6 mmol) and potassium cyanide (1.47 g; 22.6 mmol) in water (15 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 1.83 (6H, m). 2.20 (2H, m), 2.48 (3H, s), 2.68 (2H, t), 3.46 (3H, s), 3.5 (2H, t).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH2:14][C:15](=[O:20])[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:21])[CH3:2].CO.Cl.C(=O)(O)[O-].[Na+]>O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(=O)CC4
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 2 h

Procedure:
Add 13β-ethyl-gon-5(10)-en-3,17 -dione (1 g.) with stirring under nitrogen to methanol (25 cc.) containing 11N hydrochloric acid (1.75 cc.) and water (1.1 cc.). Stir for 2 hours, add sodium bicarbonate (1.75 g.) and filter the mixture. Evaporate the filtrate to dryness and recrystallize the residue from ethyl acetate to obtain the title compound; ultraviolet absorption peak at 240 mμ (ε 17,800); infrared absorption peaks at 5.78, 6.00, 6.17 μ.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[O:24])[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]1)=[N:9]2)=[O:4].Br[CH2:32][C:33]1[CH:37]=[C:36]([C:38]2[S:39][C:40]([Cl:43])=[CH:41][CH:42]=2)[O:35][N:34]=1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:25][CH2:26][C:27]([F:28])([F:29])[F:30])=[C:8]2[C:12]=1[N:11]([CH2:32][C:33]1[CH:37]=[C:36]([C:38]3[S:39][C:40]([Cl:43])=[CH:41][CH:42]=3)[O:35][N:34]=1)[C:10]([C:13](=[O:24])[NH:14][CH:15]1[CH2:16][CH2:17][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:20]1)=[N:9]2)=[O:4]
Reactant: COC(=O)c1sc(OCC(F)(F)F)c2nc(C(=O)NC3CCN(C(C)C)CC3)[nH]c12
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Product: COC(=O)c1sc(OCC(F)(F)F)c2nc(C(=O)NC3CCN(C(C)C)CC3)n(Cc3cc(-c4ccc(Cl)s4)on3)c12

Procedure:
3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-6-(2,2,2-trifluoro-ethoxy)-3H-thieno[3,4-d]imidazole-4-carboxylic acid methyl ester was prepared by a procedure according to example 81 starting from 68.0 mg (0.15 mmol) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-6-(2,2,2-trifluoro-ethoxy)-3H-thieno[3,4-d]imidazole-4-carboxylic acid methyl ester and 42.2 mg (0.15 mmol) 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole. Purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compound as its formiate in form of a white amorphous solid. Structural assignment was achieved by NOE-spectroscopy.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[N+](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][O:4][CH:2]([CH3:3])[CH3:1])[CH3:12]
Reactant: CC(C)O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To a solution of 2-propanol (0.776 mL, 10.0 mmol) in dichloromethane (33 mL) is added rhodium (II) acetate dimer (22 mg) followed by ethyl diazoacetate (1.05 mL, 10.0 mmol). The reaction mixture is stirred at RT for 30 min. The reaction mixture is filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 750 mg of the product 405. 1H NMR (CDCl3) δ 4.21 (q, 2 H), 4.06 (s, 2 H), 3.73 (m, 1 H), 1.29 (t, 3 H), 1.22 (s, 3 H), 1.19 (s, 3 H); MS: m/z 147 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@@H:4]([N:8]=[C:9]=[O:10])[CH:5]([CH3:7])[CH3:6].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH2:22][NH2:23].CCN(CC)CC>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH2:22][NH:23][C:9](=[O:10])[NH:8][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:3]([O:2][CH3:1])=[O:11]
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](NC(=O)NCc1ccc(OC)cc1OC)C(C)C
Temperature: 25 °C

Procedure:
A solution of (S)-methyl-2-isocyanato-3-methylbutanoate (4.46 mL, 29.9 mmol) in CHCl3 (50 mL) was added drop-wise to a solution of (2,4-dimethoxyphenyl)-methanamine (5.00 g, 29.9 mmol) and NEt3 (8.34 mL, 59.8 mmol) in CHCl3 (100 mL) at ambient temperature. The resultant mixture was heated at 60° C. for 12 hours, then cooled to ambient temperature. The cooled reaction mixture was concentrated to provide (S)-methyl 2-(3-(2,4-dimethoxybenzyl)ureido)-3-methylbutanoate as a white solid, 1.25 g (13%). LCMS (APCI+) m/z 325 [M+H]+.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])([O-])=O>[Fe].C(O)(=O)C>[NH2:3][C:6]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2ccccc2)cc1N
Temperature: 25 °C

Procedure:
3.1 g of iron powder was added to a mixed solution of 24 mL of methanol and 24 mL of acetic acid containing 4.8 g of methyl 2-nitro-4-phenylbenzoate, and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate added to the filtrate. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure, Hexane was added to the obtained residue and a solid substance was separated by filtration to obtain 1.8 g of methyl 2-amino-4-phenylbenzoate as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19].Cl>ClCCl>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18](=[O:20])[CH3:19])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(NC(C)=O)cc1
Reaction time: 1 h

Procedure:
4-Ethoxyaniline (40 g, 0.29 mol) and triethylamine (61 mL, 0.44 mol) were dissolved in dichloromethane (200 mL). Acetic anhydride (30 mL, 0.32 mol) was added in drops thereto, and the mixture was stirred for 1 h at 0° C. to room temperature. 1N hydrochloric acid solution was added, and the reaction mixture was extracted with ethyl acetate, washed with sodium chloride solution, and dried over anhydrous magnesium sulfate to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[S:22]([NH:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1cc(N)c2ncccc2c1
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)c2ncccc2c1
Yield: 52.2 %

Procedure:
In a similar fashion using route 14 general procedure 26, 6-methoxyquinolin-8-amine (Intermediate 23) (60 mg, 0.35 mmol), 2,4-dichlorobenzenesulfonyl chloride (110 mg, 0.45 mmol) gave the title compound (70 mg, 53%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [OH-].[K+].C([CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:9](=[O:11])[CH3:10])(OCC)=O.S(=O)(=O)(O)O.O>CO>[CH:19]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:8][C:9](=[O:11])[CH3:10])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(CCCCCCOC(C)C)C(C)=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)CCCCCCCOC(C)C
Temperature: 25 °C

Procedure:
1.4 g (0.025 mol) of solid potassium hydroxide are dissolved in 30 cc of 50% aqueous methanol. 4.1 g (0.015 mol) of 3-carbethoxy-9-isopropoxy-2-nonanone are added to this solution and the mixture is heated to boiling temperature. After 1 hour at reflux the reaction mixture is cooled to 50°, neutralized with 50% sulphuric acid, cooled to room temperature after 10 minutes, and 50 cc of water added. The product is extracted from the heterogeneous mixture with ether, the ether extract is washed with saturated salt solution, dried with sodium sulphate and evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate 9:1. Pure 9-isopropoxy-2-nonanone is obtained as a colourless oil.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]3[C:13]=2[C:14](=[O:26])[N:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=2)[N:16]=3)[CH2:3][CH2:2]1.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH2:32]>O1CCCC1>[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH:32][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([N:15]2[C:14](=[O:26])[C:13]3=[C:4]([CH:1]4[CH2:3][CH2:2]4)[NH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:12]3=[N:16]2)=[CH:25][CH:24]=1
Reactant: CN(C)CCCN
Reactant: O=C(Cl)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
To a partial solution of 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoyl chloride (0.1 g, 0.28 mmol) in tetrahydrofurane (6 ml) under nitrogen was added a solution of 3-dimethylamino-propyl amine (0.03 g, 0.3 mmol) in tetrahydrofurane (3 ml). The mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure and the yellow solid was washed with a little saturated sodium bicarbonate, water and dried under vacuo to yield N-(3-Dimethylamino propyl)-4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]-quinolin-2-yl]-benzamide (57 mg, 47%) as a yellow solid. LCMS m/z 430.11 [M+H]+ @ RT 0.99 min: 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:16]([O:18]C)=O)[C:8]([C:12]([O:14]C)=O)=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[C:7]3[C:16]([OH:18])=[N:31][N:30]([C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[C:12](=[O:14])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Yield: 112 %

Procedure:
To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (0.500 g, 1.69 mM) in ethanol (17 mL) was added 4-methoxyphenyl hydrazine hydrochloride (2.07 g, 11.83 mM). Triethylamine (1.88 mL, 13.52 mM) was added, and the mixture was heated to reflux for 40 hours. The resulting suspension was filtered hot, and the collected solids were washed with ethanol to give the 4-methoxyphenyl hydrazine salt of the title compound (0.700 g) as a light tan solid. This material was heated to reflux in glacial acetic acid (20 mL) for 2 hours to give a brown suspension. The suspension was cooled to room temperature. The solids were collected and washed with glacial acetic acid, methanol and ether to give the title compound (0.331 g, 53%) as a tan powder, mp 365° C. (decomp.); MS(CI): 370 (M+H).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[CH:5]([C:7]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH:8]=1)=[O:6].[Cl-].[NH4+].C(O)(=O)C>O1CCCC1>[OH:6][CH:5]([C:7]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH:8]=1)[CH:1]=[CH2:2]
Reactant: C=C[Mg]Cl
Reactant: O=Cc1coc(Cc2ccc(F)cc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CC(O)c1coc(Cc2ccc(F)cc2)c1
Reaction time: 15 h

Procedure:
46.5 ml of a 1.5M solution of vinylmagnesium chloride in tetrahydrofuran are initially taken in 60 ml of absolute tetrahydrofuran at 0° C. 11.9 g of 3-formyl-5-(p-fluorobenzyl)-furan in 60 ml of absolute tetrahydrofuran are added dropwise at 0°-10° C. to the stirred mixture in the absence of moisture, and stirring is continued for 15 hours at room temperature. 100 ml of a saturated ammonium chloride solution and 20 ml of glacial acetic acid are added carefully to the reaction mixture, the precipitate dissolving. The mixture is extracted three times by shaking with ether, after which the combined ether extracts are washed with water, dried over sodium sulfate and evaporated down under reduced pressure. The oil obtained (14 g) is purified by column chromatography over silica gel using toluene/acetone (9/1) as the eluent. 7.1 g of 3-(1-hydroxy-2-propenyl)-5-(p-fluorobenzyl)-furan are obtained as an oil (nD22 : 1.5370). ##STR15##
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:10]=13)[CH2:2]2.Cl[C:28](Cl)([O:30][C:31](=O)[O:32]C(Cl)(Cl)Cl)Cl.CO>ClCCl>[CH3:28][O:30][C:31](=[O:32])[NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:13]2[N:12]=[C:11]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Solvent: CO
Solvent: ClCCl
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)OC)cc3)nc21

Procedure:
A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (150 mg, 0.43 mmol) in dichloromethane (5 mL) was treated with triphosgene (64 mg, 0.21 mmol). After the passage of 5 minutes, an excess of methanol was added to the mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide methyl{4-[1-ethyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}carbamate. MS (ES+): 409.0 (M+H)+