Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1.[H-].[Na+].Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:12]
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(c2cccc(Br)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.8 %

Procedure:
A solution of (3-bromo-phenyl)-acetic acid methyl ester (0.6 g, 2.62 mmol) in dry N,N′-dimethylformamide is added to a stirred suspension of sodium hydride (60% in mineral oil, 0.26 g, 6.55 mmol) in dry N,N′-dimethylformamide at 0° C. and stirring is continued for 20 minutes. A solution of bis(2-bromoethyl)ether (0.39 mL, 3.14 mmol) in N,N-dimethylformamide is added drop-wise and the reaction mixture is stirred overnight, while warming to room temperature. The reaction is quenched with water, extracted twice with ethyl acetate, the combined extracts is washed with brine and water, dried over sodium sulfate, filtered and concentrated in vacuo to afford 4-(3-bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (610 mg) used in the next step without further purification. LCMS: RT=2.81 minutes; MS: 299, 301 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][O:26]COC)=[CH:21][CH:20]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CO>O>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOCc1ccc(Cn2nc(C(C)(C)C)cc2COc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(COc2ccccc2)n(Cc2ccc(CO)cc2)n1
Yield: 91.5 %

Procedure:
A mixture of 3-tert-butyl-1-{4-[(methoxymethoxy)methyl]benzyl)-5-(phenoxymethyl)-1H-pyrazole (1.66 g, 4.21 mmol), concentrated hydrochloric acid (0.2 mL) and methanol (20 mL) was refluxed overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (1.35 g, yield 91%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4](Cl)=[O:5].[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([Cl:28])=[CH:25][C:26]=2[CH3:27])[NH2:23])=[C:13]([CH2:31][CH2:32][CH3:33])[C:12]=1[OH:34])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:7])[C:4]([NH:23][C:22]1[C:24]([Cl:28])=[CH:25][C:26]([CH3:27])=[C:20]([O:19][CH2:18][CH2:17][CH2:16][O:15][C:14]2[CH:29]=[CH:30][C:11]([C:8](=[O:10])[CH3:9])=[C:12]([OH:34])[C:13]=2[CH2:31][CH2:32][CH3:33])[CH:21]=1)=[O:5]
Reactant: CCCc1c(OCCCOc2cc(N)c(Cl)cc2C)ccc(C(C)=O)c1O
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OCCCOc2cc(NC(=O)C(=O)OC)c(Cl)cc2C)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In the course of approximately 5 minutes a solution of 1.9 ml (21 mmol) of chloro-oxalic acid methyl ester in 8 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 7.0 g (17.8 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-methyl-6-chloroaniline and 22.2 g (21.4 mmol) of triethylamine in 100 ml of methylene chloride. The reaction mixture is stirred for a further 90 minutes at room temperature, poured onto ice-water and the organic phase is separated off. The methylene chloride phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure. Crystallisation of the residue from methylene chloride/ether yields N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-methyl-6-chlorophenyl}-oxamic acid methyl ester having a melting point of 101°-102°.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([NH:13][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]3[CH:10]=[CH:11][S:12][C:6]=23)[CH2:15][CH2:16]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](O)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexanol (0.21 g, 0.72 mmol) (Example 3, Step 1) and N,N-diisopropylethylamine (0.25 mL, 1.4 mmol) in methylene chloride (2 mL) was added methanesulfonyl chloride (0.083 mL, 1.1 mmol). The reaction was stirred at room temperature for 2 h. After dilution with sat. aq. NaHCO3 solution, the resulting mixture was extracted with dichloromethane. The organic layers were concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (0.24 g, 90%). LCMS calculated for C14H18N3O5S2 (M+H)+: m/z=372.1. Found: 372.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:19][C:20]([C:22]2[CH:27]=[C:26]([O:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:25]=[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:23]=2)=[O:21])[CH2:14]CC(O)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:41]([O:43]C(N1CCN(C(=O)[C@@H](NC(C2C=C(OC3CCCC3)N=C(C3C=CC=CC=3)N=2)=O)CCCC(O)=O)CC1)=O)C>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:40])[C@@H:13]([NH:19][C:20]([C:22]2[CH:27]=[C:26]([O:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:25]=[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:23]=2)=[O:21])[CH2:14][CH2:41][OH:43])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCCC(=O)O)NC(=O)c2cc(OC3CCCC3)nc(-c3ccccc3)n2)CC1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3CCCC3)nc(-c3ccccc3)n2)CC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCO)NC(=O)c2cc(OC3CCCC3)nc(-c3ccccc3)n2)CC1

Procedure:
The compounds of Examples 12 and 13 were prepared using a method analogous to that of Example 11, starting from 4-{(S)-4-carboxy-2-[(6-cyclopentyloxy-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester and 4-{(S)-5-carboxy-2-[(6-cyclopentyloxy-2-phenyl-pyrimidine-4-carbonyl)-amino]-pentanoyl}-piperazine-1-carboxylic acid ethyl ester respectively.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](C3OC(C)(C)C(C)(C)O3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:32]([NH:34][C:35]([C:37]2[N:38]=[C:39](Cl)[O:40][CH:41]=2)=[O:36])[CH3:33])[CH:23]=[C:24]([F:31])[C:25]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:20]1[CH:21]=[C:22]([CH:32]([NH:34][C:35]([C:37]2[N:38]=[C:39]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:9]=3)[O:40][CH:41]=2)=[O:36])[CH3:33])[CH:23]=[C:24]([F:31])[C:25]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC1(C)OC(c2cccc(C3CC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cccc(C3CC3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 33.3 %

Procedure:
2-(3-Cyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3]dioxolane (63 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (20 mg, 33%) after purification by flash chromatography on silica gel (% EtOAc in hexane=25%˜100%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH3:18])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CC(C)(C)CN
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CC(C)(C)CNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), 2,2-dimethylpropan-1-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 331 (M+, 1), 274 (74), 203 (20), 141 (32), 100 (bp), 72 (74).
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:23](OCC)(=[O:27])[C:24]([O-])=[O:25].CC(C)([O-])C.[K+].Cl>C1COCC1>[F:22][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:24](=[O:25])[C:23]([OH:27])=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:10]2(=[O:12])=[O:11])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(=O)[O-]
Reactant: O=S(=O)(Cc1ccccc1)NCc1ccc(OC(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1C(O)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 90.8 %

Procedure:
N-[4-(Difluoromethoxy)benzyl]-1-phenylmethanesulfonamide (0.6 g, 1.83 mmol) and ethyl oxalate (0.32 g, 2.20 mmol) were mixed in THF (4 mL, dry). Under an atmosphere of nitrogen, potassium tert-butoxide (0.27 g, 2.38 mmol) was added and the reaction mixture was heated in a microwave reactor at 150° C. for 10 mins and then at 150° C. for 5 mins. The mixture was then cooled in an ice-bath and HCl (10%, 1 mL) was added, pH˜1. The mixture was evaporated to remove THF and the residue was extracted with DCM (20 mL). The extract was dried (MgSO4) and evaporated to give the crude product (0.634 g). It was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:11]=[CH:12]\[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O>C(O)(=O)C.ClCCl.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6](/[CH:11]=[CH:12]\[C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: COc1cc(/C=C\c2ccc(C)c([N+](=O)[O-])c2)cc(OC)c1OC
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(/C=C\c2ccc(C)c(N)c2)cc(OC)c1OC
Reaction time: 1 h
Yield: 49.1 %

Procedure:
65 mg of (Z)-1-(3-nitro-4-methylphenyl)-2-(3,4,5-trimethoxyphenyl) ethene were dissolved in 4 ml of acetic acid and 4 ml of dichloromethane, and 300 mg of zinc were added thereto and stirred for one hour. The reaction liquid was filtered, concentrated and purified by silica gel column chromatography (dichloromethane:hexane=2.1 by volume) to obtain 29 mg of the intended compound. The yield was 46.5%.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:17](=[O:19])[NH:16][C:15]=2[CH:20]=1.[H-].[Na+].[C:23]([O:26][CH2:27][CH2:28]Br)(=[O:25])[CH3:24].Cl>CN(C)C=O.O>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:17](=[O:19])[N:16]([CH2:28][CH2:27][O:26][C:23](=[O:25])[CH3:24])[C:15]=2[CH:20]=1
Reactant: CC(=O)OCCBr
Reactant: Cc1c(-c2ccc3sc(=O)[nH]c3c2)nc2ccccn12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCn1c(=O)sc2ccc(-c3nc4ccccn4c3C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
A mixture of 5-(3-methylimidazo[1,2-a]pyridin-2-yl)-2-benzothiazolinone (2.8 g) and sodium hydride (50% suspension in oil, 0.96 g) in dry dimethylformamide (30 ml) was stirred at ambient temperature for 30 minutes. To the resultant mixture was added 2-bromoethyl acetate (3.34 g) at ambient temperature and stirred for 5 hours under the same condition. The reaction mixture was poured into water and adjusted to pH 7.0 with 10% hydrochloric acid. The neutrallized solution was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel eluting with a mixture of ethyl acetate and diisopropyl ether (8:2). The fractions containing the desired compound was combined and evaporated in vacuo. The crystalline residue was recrystallized from ethyl acetate to afford 5-(3-methylimidazo[1,2-a]pyridin-2-yl)-3-(2-acetoxyethyl)-2-benzothiazolinone (1.3 g). mp. 113°-115° C.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][NH2:7])=[CH2:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:18][C:19]1[C:24]2[N:25]=[CH:26][S:27][C:23]=2[CH:22]=[C:21]([C:28](OC)=[O:29])[C:20]=1[NH:32][C:33]1[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=1[F:40]>C1COCC1>[F:18][C:19]1[C:24]2[N:25]=[CH:26][S:27][C:23]=2[CH:22]=[C:21]([C:28]([NH:7][O:6][CH2:5][CH2:4][O:3][CH:1]=[CH2:2])=[O:29])[C:20]=1[NH:32][C:33]1[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=1[F:40]
Reactant: COC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of O-(2-(vinyloxy)ethyl)hydroxyl-amine (172 mg, 1.62 mmol) in THF (6 mL) was added LiHMDS (2.5 mL, 1 M in THF, 2.5 mmol) at −78° C. After stirring at this temperature for 10 min, a solution of methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate (360 mg, 0.81 mmol) in THF was syringed dropwisely. Then the mixture was allowed to warm to ambient temperature, quenched with saturated NH4Cl (aq., 20 mL) and extracted with ethyl acetate (15 mL×3). The combined organic extract was washed with water (10 mL×3) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. After purification by flash chromatography (petroleum ether/ethyl acetate, 10:1, v/v), the desired product was obtained (410 mg, 98% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.85 (s, 1H), 8.98 (s, 1H), 8.04 (s, 1H), 7.89 (s, 1H), 7.55 (d, J=10.8 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 6.53 (dd, J=13.9, 6.6 Hz, 1H), 6.42 (d, J=6.0 Hz, 1H), 4.21 (d, J=14.5 Hz, 1H), 4.01 (m, 3H), 3.83 (m, 2H).
Reaction SMILES: [C:1]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH:4]([CH2:5][CH3:6])[CH2:3][CH:2]=[CH:1][C:7]#[N:8])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccccc1
Reactant: N#CC1=CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(CC=CC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cyclohexenecarbonitrile (9 mL, 80.6 mmol) and benzene (75 mL) was treated portionwise with AlCl3 (13 g, 97 mmol) then stirred at room temperature for 2 hours. The mixture was poured onto ice and extracted with ethyl acetate. The extract was washed sequentially with water and brine, dried (MgSO4), and concentrated. The residue was distilled at 125° C. (0.6 mm Hg) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:11].Br[C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>C(O)(C)C.CN1CCOCC1.[Cu].[Cu]I>[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:13]3[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=[O:16])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:5]1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: Cn1ncc2c(N)cccc21
Agent: [Cu]
Agent: [Cu]I
Solvent: CN1CCOCC1
Solvent: CC(C)O
Product: Cn1ncc2c(Nc3c(C(=O)O)cccc3[N+](=O)[O-])cccc21
Yield: 5 %

Procedure:
A solution of 4-nitroindazole (prepared according to the literature procedures Davies, R. R. J.C.S., 1955, 2412-2423; Porter, H. D. Org. Synth. Collect. Vol I, 20, 73-74.) (2.01 g, 12.3 mmol) was added slowly to a cold (ice/water), stirred suspension of NaH (440 mg, 18.4 mmol) in DMF (20 mL) under N2. The mixture was stirred for 30 min, and a solution of MeI (1.91 g, 13.5 mmol) in DMF (10 mL) was then added. Workup gave 1-methyl-4-nitroindazole (1.79 g, 82%); mp (EtOAc/petroleum ether) 138-139° C. Hydrogenation of this (6.70 g, 37.9 mmol) in absolute EtOH (300 mL) in the presence of Pd/C (1.00 g) gave 4-amino-1-methylindazole (4.23 g, 76%). A mixture of 4-amino-1-methylindazole (4.10 g, 27.9 mmol) and 2-bromo-3-nitrobenzoic acid (6.86 g, 27.9 mmol) were then reacted in a mixture of isopropanol/N-methylmorpholine in the presence of copper powder and CuI as above, giving 2-[(1-methyl-1H-indazol-4-yl)amino]-3-nitrobenzoic acid (439 mg, 5 %); mp (EtOAc/n-hexane) 257-260° C.; Reductive cyclisation of 2-[(1-methyl-1H-indazol-4-yl)amino]-3-nitrobenzoic acid with NaBH4 in 2 M NaOH as above gave 3-methyl-3H-pyrazolo[4,3-a]phenazine-10-carboxylic acid as a dark yellow solid (54%); mp (acetone) 320-323° C. [(CD3)2SO] δ 4.28 (s, 3 H, NCH3), 8.07 (t, J=7.9 Hz, 1 H, H-8), 8.10 (d, J=9.6 Hz 1H, H-4 or H-5), 8.39 (d, J=9.6 Hz 1H, H-4 or H-5), 8.52-8.60 (m, 2H, H-7 and H-9), 8.76 (s, 1 H, H-2), 14.90 (br s, 1 H, COOH).
Reaction SMILES: Cl.C([O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:18]([C:19](=[O:35])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)=[C:17]([C:36]3[CH:41]=[CH:40][C:39]([O:42]C(=O)C4C=CC=CC=4)=[CH:38][CH:37]=3)[S:16][C:15]=2[CH:51]=1)(=O)C1C=CC=CC=1.C(O)C.CS(O)(=O)=O>O>[OH:10][C:11]1[CH:12]=[CH:13][C:14]2[C:18]([C:19](=[O:35])[C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:24][CH:25]=3)=[C:17]([C:36]3[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=3)[S:16][C:15]=2[CH:51]=1
Reactant: O=C(Oc1ccc(-c2sc3cc(OC(=O)c4ccccc4)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1)c1ccccc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 20 °C
Reaction time: 72 h

Procedure:
The crude product of Example 2 above, 6-benzoyloxy-2-(4-benzoyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, hydrochloride, was combined with 400 ml. of ethanol, 400 ml. of water and 55 ml. of methanesulfonic acid. The mixture was stirred on the steam bath for 72 hours, and was then evaporated down to an oil which was diluted to about 6 liters with water. The aqueous solution was washed twice with 1 liter portions of diethyl ether, and was then thoroughly degassed under vacuum, cooled to about 20° C., and made basic with aqueous ammonia to pH 8.4. The product which precipitated was collected by filtration and vacuum dried, and was then recrystallized from about 80 ml. of acetone. The product was vacuum dried at 40° C. to obtain 18.1 g. of crystals which was found by nmr, mass spectrum, infrared and ultraviolet analysis to be substantially identical to the product of Example 3.
Reaction SMILES: [F:1][C:2]([CH:5]([C:9]([F:11])=[O:10])[C:6]([F:8])=[O:7])([F:4])[F:3].C(N(CC)CC)C.Cl[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>CCOCC>[CH3:23][C:22]([CH3:24])=[CH:21][CH2:20][C:5]([C:2]([F:4])([F:3])[F:1])([C:6]([F:8])=[O:7])[C:9]([F:11])=[O:10]
Reactant: CC(C)=CCCl
Reactant: O=C(F)C(C(=O)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)=CCC(C(=O)F)(C(=O)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 16 %

Procedure:
To 17.6 g (0.10 mol) of trifluoromethylmalonyl fluoride and 50 ml of ether stirred at -80°C was added dropwise a solution of 9.2 g (0.09 mol) of triethylamine in 25 ml of ether. Then 12.5 g (0.12 mol) of 1-chloro-3-methyl-2-butene was added, and the mixture was stirred at 25°C until homogeneous. After standing at 25°C for 3 days, the mixture was distilled to give 3.9 g (16%) of (3-methyl-2-butenyl)-trifluoromethylmalonyl fluoride, bp 43°-45°C (20 mm); ir (CCl4): 3.31, 3.37 and 3.42 (CH), 5.36 (C=O) and 7.5-8.5 μ (CF).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39](Cl)=[O:40])=[CH:34][CH:33]=1>C1COCC1>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([NH:1][C:2]2[CH:10]=[C:9]3[C:5](=[CH:4][CH:3]=2)[CH2:6][O:7][C:8]3=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[O:40])=[CH:34][CH:33]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(=O)Nc2ccc3c(c2)C(=C2C(=O)Nc4ccccc42)OC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added 4-methoxyphenylacetyl chloride (28.9 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was warmed briefly, stirred 10 min at room temperature, filtered and rinsed with MeOH and EtOAc/hexanes (1:1) to afford the title compound (48.3 mg, 62%) as a yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([S:23](Cl)(=[O:25])=[O:24])[CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([S:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)(=[O:25])=[O:24])[CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CCN(CC1CCN(S(=O)(=O)Cl)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC1CCN(S(=O)(=O)N2CCOCC2)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-chlorosulfonylpiperidin-4-ylmethyl)amine (0.18 grams, 0.45 mmole), morpholine (0.04 grams, 0.45 mmol) and diisopropylethylamine (0.12 grams, 0.93 mmole) in tetrahydrofuran (10 ml) was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was dried over potassium carbonate and evaporated to give a residue, which was purified by flash chromatography on silica gel using 40% ethyl acetate in hexane. Appropriate fractions were combined and evaporated to give (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-[1-(morpholine-4-sulfonyl)-piperidin-4-ylmethyl]amine as an oil, (0.17 g, 85%), M+H 452. Analysis % of the hydrochloride salt: Found: C, 54.06; H, 7.62; N, 8.24. Requires: C, 54.01; H, 8.00; N, 8.22.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2(O)[C:14]3[O:13][N:12]=[C:11]([CH3:15])[C:10]=3[CH2:9][CH2:8][CH2:7]2)=[CH:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[O:13][N:12]=[C:11]([CH3:15])[C:10]=3[CH2:9][CH2:8][CH:7]=2)=[CH:2]1
Reactant: Cc1noc2c1CCCC2(O)c1ccoc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1noc2c1CCC=C2c1ccoc1
Yield: 49.1 %

Procedure:
To a mixture of 7.6 g (0.034 mol) of 7-(3-furyl)-3-methyl-4,5,6,7-tetrahydro-benzisoxazol-7-ol in 300 ml of toluene was added 100 mg of p-toluenesulfonic acid and the mixture was placed on a Rotovap, and the solvent was distilled in vacuo (80° C.) until an oil residue was obtained. Toluene (200 ml) was added to the above residue, the mixture was placed on Rotovap, and the solvent was distilled in vacuo to complete the reaction. The oil was chromatographed (silica, 1:1 hexane/methylene chloride) to afford 3.36 g (95%) of 7-(3-furyl)-3-methyl-4,5-dihydrobenzisoxazole, (Formula III: R2 =H; ##STR8## R4 =3-furanyl) as a clear oil.