Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Li+].BrC(Br)C.Cl[Si](C)(C)C.[C:12]([N:19]1[CH2:22][CH:21](I)[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH2:24]([C:26]1[CH:42]=[CH:41][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35](I)=[CH:34][C:33]=2[O:39][CH3:40])=[CH:28][CH:27]=1)[CH3:25].[NH4+].[Cl-]>O1CCCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Zn]>[CH2:24]([C:26]1[CH:42]=[CH:41][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([CH:21]3[CH2:22][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:20]3)=[CH:34][C:33]=2[O:39][CH3:40])=[CH:28][CH:27]=1)[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: CCc1ccc(COc2ccc(I)cc2OC)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(Br)Br
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CCc1ccc(COc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2OC)cc1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
To a suspension of zinc (20.7 g) and lithium chloride (10 g) in THF (120 mL) were added dibromoethane (2 mL) and chlorotrimethylsilane (3 mL) at 70° C. under argon atmosphere. The mixture was stirred at 70° C. for 10 min. A solution of 1-Boc-3-iodoazetidine (67 g) in THF (120 mL) was added dropwise to the mixture at RT. The reaction mixture was stirred for 1 hr. To the mixture were added a solution of 1-(4-ethylbenzyloxy)-4-iodo-2-methoxybenzene (58.1 g) prepared in (1) in THF (120 mL) and bis(triphenylphosphine)palladium (II) dichloride (0.49 g). The reaction mixture was stirred at RT for 3 hr. Saturated aqueous NH4Cl was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=4/1) to give the title compound (32.4 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:6]=2[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][S:45]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:47])=[O:46].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:10][C:9]([C:11]([N:51]3[CH2:52][CH2:53][N:48]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:49][CH2:50]3)=[O:13])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCN(C(=O)c2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1

Procedure:
A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid (1.0 eq), HATU (1.5 eq), hydrochloride salt of 1-methanesulfonylpiperazine (1.5 eq), diisopropylethylamine (3.0 eq) in DMF was stirred for 30 minutes. The solid that precipitated out from the reaction was filtered to give 2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl(4-methylsulfonylpiperazin-1-yl)methanone. MS (Q1) 430 (M)+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:34])[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)Cl>>[N:11]1([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:34])[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)[C@H]2CC[C@H](Cn3c(=O)[nH]c4ccccc4c3=O)CC2)CC1
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2c(=O)n1C[C@H]1CC[C@H](C(=O)N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[trans-4-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)cyclohexanecarbonyl]-piperazine-1-carboxylic acid tert-butyl ester (1.16 g, 2.5 mmol) in DCM (10 mL) H2SO4 (0.26 mL, 5 mmol) was added and the reaction was stirred at room temperature for 18 hours. The reaction mixture was washed with 10 mL of 0.4 M solution Na2CO3 and the organic phase was collected and concentrated under reduced pressure. 0.57 g of the titled compound were obtained (yield 63%).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CNC1C=CC=CC=1>[C:2]1([C:1]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccnc1NC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CNc1ccccc1
Product: c1ccc(-c2cc3cccnc3[nH]2)cc1
Yield: 58 %

Procedure:
2-phenyl-7-azaindole was prepared in two steps. First, 2-amino-3-picoline was reacted with benzoyl chloride in chloroform in the presence of pyridine to produce 2-benzamido-3-picoline in 33% yield. Second, pyrolysis of 2-benzamido-3-picoline in N-methylaniline in the presence of NaH at 280° C. was performed to produce 2-phenyl-7-azaindole (FIG. 18) in 58% yield. This compound was characterized by NMR spectroscopy.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]4=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]4[CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>C1COCC1.[Pt](=O)=O>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]3[C:19]4=[N:20][S:21](=[O:24])(=[O:25])[CH2:22][CH2:23][N:18]4[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.3 %

Procedure:
To a suspension of NaH (60%, 418 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.659 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-amine (690 mg) in THF (dry) (40 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with IPE/EtOAc, dried in vacuo to give 9-{4-[4-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (579.1 mg) as a slightly yellow solid. Platinum(IV) oxide (30 mg) was added to a solution of 9-{4-[4-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (505 mg) in THF (dry) (15 mL) and NeOH (15 mL) and the mixture was stirred at room temperature under hydrogen for 6 hr. Platinum(IV) oxide (30 mg), NeOH (15 mL) and THF (dry) (15 mL) were added and the mixture was stirred at 50° C. under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (297.2 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[C:12](=[O:13])[O:11][N:10]=[C:9]2[C:14]2[C:18]([NH:19][CH2:20][CH2:21][O:22]C)=[N:17][O:16][N:15]=2)[O:5][CH:6]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[C:12](=[O:13])[O:11][N:10]=[C:9]2[C:14]2[C:18]([NH:19][CH2:20][CH2:21][OH:22])=[N:17][O:16][N:15]=2)[O:5][CH:6]=1
Reactant: COCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=c1onc(-c2nonc2NCCO)n1Cc1cc(Br)co1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 98.5 %

Procedure:
In a round bottom flask under nitrogen atmosphere, 4-[(4-bromo-2-furyl)methyl]-3-{4-[(2-methoxyethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-one (8.2 g, 21 mmol) was stirred in dichloromethane (68 mL). The temperature was brought to −78° C. and a solution of 1.0 M boron tribromide in dichloromethane (43 mL, 43 mmol) was added dropwise over 45 minutes. The reaction stirred at −78° C. for 45 minutes and continued to stir at 0° C. for an additional 30 minutes. While remaining at 0° C., a saturated solution of sodium bicarbonate in water (120 mL) was added dropwise over 25 minutes. After warming to room temperature, the organic layer was collected and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to give the desired product (7.7 g, 97%) along with a small amount of 3-{4-[(2-bromoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[(4-bromo-2-furyl)methyl]-1,2,4-oxadiazol-5(4H)-one. LCMS calculated for C11H11BrN5O5 (M+H)+: m/z=371.7, 374.0. 1H NMR (400 MHz, DMSO-d6): δ 7.89 (s, 1 H), 6.68 (s, 1 H), 6.31 (t, J=5.8 Hz, 1 H), 5.08 (s, 2 H), 4.85 (br s, 1 H), 3.56 (m, 2 H), 3.30 (q, J=5.6 Hz, 2 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](O)=[O:16])=[CH:10][CH:9]=2)[C:6](=[O:18])[CH:5]=[CH:4][C:3]=1[C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27].CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[CH3:48][C:49]([C:52]([O:54][CH:55]1[CH2:59][CH2:58][CH2:57][CH2:56]1)=[O:53])([CH3:51])[NH2:50]>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:50][C:49]([CH3:48])([C:52]([O:54][CH:55]3[CH2:56][CH2:57][CH2:58][CH2:59]3)=[O:53])[CH3:51])=[O:16])=[CH:10][CH:9]=2)[C:6](=[O:18])[CH:5]=[CH:4][C:3]=1[C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27]
Reactant: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1ccc(CC(=O)O)cc1
Reactant: CC(C)(N)C(=O)OC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(NC(=O)Cc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of {4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]phenyl}acetic acid (Intermediate 5) (0.1 g, 0.26 mmol) in DCM/DMF (1:1, 6 ml) were added EDCI (0.055 g, 0.29 mmol), DMAP (0.003 g, 0.03 mmol) and triethylamine (40 μl, 0.29 mmol) followed by the addition of cyclopentyl 2-methylalaninate hydrochloride (Intermediate 7) (0.059 g, 0.29 mmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc (20 ml), washed with water (2×20 ml), brine (20 ml) then dried (MgSO4), filtered and concentrated under reduced pressure to leave a yellow oil. Purification by column chromatography (100% EtOAc) afforded the title compound as a pale yellow solid (68 mg, 48%)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)=[CH:6][N+:7]=1[O-:8].[O:21]1CCOCC1>Br.CC(O)=O>[NH2:1][C:2]1[C:3]([C:19]([NH2:20])=[O:21])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[N:10]=2)=[CH:6][N+:7]=1[O-:8]
Reactant: C1COCCO1
Reactant: CC(C)n1nc(-c2c[n+]([O-])c(N)c(C#N)n2)ccc1=O
Agent: Br
Solvent: CC(=O)O
Product: CC(C)n1nc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Temperature: 22.5 °C
Reaction time: 4 h

Procedure:
A suspension of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile 4-oxide (500 mg) in 25% hydrogen bromide in AcOH (3 ml) was stirred at 20-25° C. for 4 hours. After addition of dioxane (9 ml), a precipitate was collected by filtration. The precipitate was added in water (3 ml) and adjusted to pH 8 with 1N aq. NaOH solution. The solid was collected by filtration and dried under reduced pressure to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxamide 4-oxide (366 mg).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C@@H:17]([CH2:31][CH3:32])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.O[C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][CH:35]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH:38]([C:37]1[CH:40]=[CH:41][C:34]([O:27][C:26](=[O:28])[C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:16])[CH2:31][CH3:32])=[CH:30][CH:29]=2)=[CH:35][CH:36]=1)=[O:39]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC[C@H](C)CCCOc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)CCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
3.7 g of N,N'-dicyclohexylcarbodiimide were added portionwise at 0° C. while stirring to a solution of 3.4 g of (S)-p-(4-methylhexyloxy)benzoic acid, 1.76 g of p-hydroxybenzaldehyde and 0.15 g of 4-(dimethylamino)-pyridine in 100 ml of dichloromethane. The mixture was stirred at 0° C. for a further 1 hour and at room temperature for 2 hours, then filtered and the filtrate was washed with 2N sodium carbonate solution and then with water, dried over sodium sulphate and concentrated. Chromatography of the residue on 120 g of silica gel with hexane/ethyl acetate (vol. 9:1) gave 4.2 g of pure (S)-p-(4-methylhexyloxy)benzoic acid p-formylphenyl ester.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](Cl)=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].Cl.[CH3:32][O:33][C:34](=[O:38])[CH2:35][NH:36][CH3:37]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([N:36]([CH3:37])[CH2:35][C:34]([O:33][CH3:32])=[O:38])=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: COCc1cc(-c2nc(-c3cccc(C(=O)Cl)c3)no2)ccc1-c1ccccc1C
Reactant: CNCC(=O)OC
Agent: Cl
Product: COCc1cc(-c2nc(-c3cccc(C(=O)N(C)CC(=O)OC)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in example 121 starting from 3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride, prepared as in example 130, and sarcosine methyl ester hydrochloride. The title compound was obtained as a sticky solid. 1H NMR: (DMSO-d6, 300 MHz) δ 8.42 (brs, 1H), 8.28 (m, 2H), 8.17 (m, 1H), 7.61 (m, 2H), 7.34-7.22 (m, 4H), 7.12 (m, 1H), 4.32 (s, 1H), 4.22 (s, 1H), 3.80 (m, 3H), 3.32 (s, 3H), 3.1 (m, 3H). LC/MS (Method B): 486.2 (M+H)+ no (M−H)−. HPLC (Method A) Rt: 5.66 min (purity: 98.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[O:18][C:17]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:32]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[O:18][C:17]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N+:21]([O-:32])[CH:22]=[CH:23][CH:24]=3)=[N:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2nnc(-c3cccnc3C(F)(F)F)o2)cc([N+](=O)[O-])c1OC
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nnc(-c3ccc[n+]([O-])c3C(F)(F)F)o2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-trifluoromethyl-pyridine (0.45 g, 1.13 mmol) in dichloromethane (10 mL)) cooled in an ice-water bath was added urea hydrogen peroxide complex (0.23 g, 2.45 mmol) in one portion followed by trifluoroacetic anhydride (0.47 g, 2.24 mmol) dropwise. The resulting mixture was allowed to stir at room temperature overnight and then the insoluble material was filtered off. The filtrate was washed with water and brine, then dried over anhydrous sodium sulphate, filtered and evaporated to leave an off-white solid. Recrystallisation from ethanol afforded 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-trifluoromethyl-pyridine 1-oxide, 0.39 g (83%).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([O:16][CH3:17])[CH:8]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:18])=[CH:8][C:9]=2[O:16][CH3:17])=[O:13])[CH2:31][CH2:32]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ccc(C)cc2C)CC1
Yield: 81.3 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methoxybenzoic acid (285 mg) described in Preparation Example 19 and 1-(2,4-dimethylphenyl)piperazine (199 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (377 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1.N.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O>[NH2:23][C:16]1/[C:21](=[N:1]/[C:2]2[C:3](=[O:15])[N:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:5]([CH3:8])[C:6]=2[CH3:7])/[CH:20]=[CH:19][C:18](=[NH:22])[CH:17]=1
Reactant: Nc1cccc(N)c1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Agent: N
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: Cc1c(/N=C2\C=CC(=N)C=C2N)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Yield: 29.3 %

Procedure:
20 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one and 20 mmol of meta-phenylene diamine was dissolved in 30 g of an ice/water mixture and the pH was adjusted to 10 using 20 ml of 20% aqueous ammonia. While stirring, a solution of 24 mmol of ammonium persulfate in 10 ml of water was added dropwise over 30 minutes. The mixture was stirred at 0° C. for 1 h 30 min and the solid formed was separated by filtration and washed with water and acetone and dried in a desiccator under vacuum for 12 hours, which resulted in 1.8 g of expected product, or a yield of 30%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[N:32]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1.CN(C1C=CC=CN=1)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][N:8]([C:37]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:38])[CH2:7][CH2:6]1)=[O:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Reactant: O=C(Cl)N1CCCC1
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)N3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.6 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (400 mg, 1.03 mmol) in chloroform (10 ml) was added triethylamine (208 mg, 2.06 mmol), pyrrolidinecarbonyl chloride (206 mg, 1.54 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 400 mg (87%) of the product as a solid; MS-ES: m/z 449.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1>O1CCOCC1.CCOCC.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:9][C:4]1[CH:3]=[C:2]([B:20]2[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:25])([CH3:17])[O:19]2)[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: CC1(C)OBOC1(C)C
Reactant: Nc1ccc(Br)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Temperature: 100 °C
Reaction time: 20 h
Yield: 51.3 %

Procedure:
To a solution of 4-bromo-2-chloro-phenylamine (4.2 g, 20 mmol), in dioxane (80 mL) was added triethylamine (10 mL, 72 mmol). The pale yellow solution was sparged with nitrogen. During the nitrogen sparge, 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (8.5 mL, 59 mmol) was added dropwise over 10 minutes. After 20 minutes the nitrogen sparge was discontinued and dichloro[1,1′-bis(diphenylphosphino)ferrocene)palladium (II) dichloromethane adduct (603 mg, 0.74 mmol) was added. The reaction was then heated to 100° C. in a temperature controlled heating mantle. After stirring for 20 hours at 100° C., HPLC analysis of the reaction showed clean conversion to a product. The reaction was allowed to cool to ambient temperature and diluted with Et2O (250 mL) and H2O (100 mL). The resulting brown biphasic suspension was filtered to remove some solids that had formed. The layers were separated, and the aqueous layer was extracted with Et2O (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to afford a brown oil, which partially solidified after standing at ambient temperature. This crude product was purified by silica gel column chromatography eluting with a gradient from 0% to 20% ethyl acetate/hexane on silica. The product peak was collected to afford 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (2.6 g, 50% yield) as an off-white solid. 1H-NMR (400 MHz, CDCl3): δ 7.69 (1H, d, J=1.3 Hz), 7.49 (1H, dd, J=8.1, 1.3 Hz), 6.72 (1H, d, J=8.1 Hz), 4.25 (2H, br s), 1.31 (12H, s).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S([CH2:18][CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])(=O)=O)=CC=1>>[CH3:19][N:20]([CH2:28][C:3]1[CH:2]=[C:1]([CH:6]=[CH:5][CH:4]=1)[O:7][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)CCN2C(=O)c3ccccc3C2=O)cc1
Reactant: Oc1ccccc1
Product: CN(C)Cc1cccc(OCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
The following compounds were similarly prepared from the corresponding phenol (A) and 2-[2-(4-methylbenzenesulphonyl)ethyl]-1H-isoindole-1,3(2H)-dione (C).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:25][C:8]2[C:9]3[CH:10]=[CH:11][C:12]([C:16](=[O:24])[NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:13][C:14]=3[S:15][C:7]=2[C:6]=1[O:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:4].O>C1COCC1>[C:28]([CH2:27][O:26][C:6]1[C:7]2[S:15][C:14]3[CH:13]=[C:12]([C:16](=[O:24])[NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:11]=[CH:10][C:9]=3[C:8]=2[S:25][C:5]=1[C:3]([OH:4])=[O:2])([OH:30])=[O:29]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)NC3CCCCC3)ccc12
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1c(C(=O)O)sc2c1sc1cc(C(=O)NC3CCCCC3)ccc12
Yield: 69.2 %

Procedure:
Following General Procedure A, 6-cyclohexylcarbamoyl-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (9 mg, 0.02 mmol) was stirred in THF (1 ml) and water (1 ml) for 24 hr. Work-up yielded 6 mg (75%) of title compounds as light yellow solids.