Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[C:10]([C:12]1[C:13]([S:23](Cl)(=[O:25])=[O:24])=[N:14][N:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17][C:16]=12)#[N:11]>N1C=CC=CC=1.CC(O)C>[C:10]([C:12]1[C:13]([S:23]([NH:4][C:3]2[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:9])(=[O:24])=[O:25])=[N:14][N:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17][C:16]=12)#[N:11]
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)c(C#N)c2n1
Reactant: Nc1c(Cl)cccc1Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)c(C#N)c2n1
Temperature: 70 °C
Reaction time: 24 h
Yield: 55.4 %

Procedure:
A solution of 0.67 g (4.1 mmole) of 2,6-dichloroaniline was stirred at room temperature as a solution of 1.1 g (4.1 mmole) of 3-cyano-5,7-dimethylpyrazolo-[1,5-a]pyrimidine-2-sulfonyl chloride in 3 ml pyridine was added. The mixture was heated at 70° C. for 15 hours, then at 130° C. for 24 hours, and cooled to room temperature. The mixture was diluted with 2-propanol and stirred at room temperature for 1 hour. The tan solid was collected by filtration, washed well with 2-propanol and dried to give 0.9 g tan powder. This was completely dissolved in 2N NaOH and extracted with CH2Cl2. The aqueous layer was separated and acidified with glacial HOAc, which gave a precipitate. This was collected by filtration, washed well with water and dried to give 0.2 g (12.3-percent) of the product as an off-white solid, m.p. 280°-285° C. (decomposition and degassing). 1H NMR (DMSO-d-6): 11.1 (br., 1H, NH), 7.5-7.4 (m, 3H, benzene), 7.5 (s, 1H, pyrazolopyrimidinyl H-6), 2.67 (s, 3H, CH3), 2.63 (s, 3H, CH3). 13C NMR (DMSO-d-6): 165, 156, 150, 148, 136, 130, 129, 114, 111, 80, 24, 16. IR (KBr): 3220, 2240, 1620, 1540, 1440, 1355, 1170 cm-1.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[CH:8]=2)[N:3]=1.C(O)C.[Cl:28]([OH:32])(=[O:31])(=[O:30])=[O:29]>>[Cl:28]([O-:32])(=[O:31])(=[O:30])=[O:29].[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH+:3]=[C:2]([CH3:1])[C:10]2([CH3:12])[CH3:11]
Reactant: CC1=Nc2ccc(CN3C(=O)c4ccccc4C3=O)cc2C1(C)C
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Product: CC1=[NH+]c2ccc(CN3C(=O)c4ccccc4C3=O)cc2C1(C)C
Product: [O-][Cl+3]([O-])([O-])[O-]
Temperature: -10 °C

Procedure:
2-(2,3,3-Trimethyl-3H-indol-5-ylmethyl)-isoindole-1,3-dione (126 g, 0.396 mol; Sigma-Aldrich) was placed in 1 L one-necked flask equipped with magnetic stir bar and a reflux condenser. 500 mL Ethanol (500 mL, 8 mol; Pharmco) were added to the flask followed by addition of perchloric acid (35 mL, 0.40 mol; Aldrich). The reaction mixture was stirred with heating under reflux until all solids dissolved. The solution was then cooled at −10° C. for 3 hours and the separated crystals were filtered, washed with cold ethanol (100 mL), diethyl ether (2*100 mL) and dried. The yield was 166 g (100% of theoretical).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)C(C)C)(C)C.CC(C)([O-])C.[K+]>ClCCl.O1CCCC1>[NH3:4].[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][N:24]4[CH2:26][CH2:27][CH2:28][S:29]4(=[O:31])=[O:30])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)N1CCC(Oc2ccc(C3(CN)CCOCC3)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc(C3(CN4CCCS4(=O)=O)CCOCC3)cc2)CC1
Product: N
Temperature: 40 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
A solution of (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine (100 mg, 0.30 mmol), 3-chloropropanesulphonyl chloride (51 μl, 0.40 mmol) and N,N-diisopropylethylamine (521 μl, 0.30 mmol) in dichloromethane (2 ml) was stirred at room temperature for 18 hrs. The reaction mixture was concentrated in vacuo and then partitioned between dichloromethane (10 ml) and sodium bicarbonate solution (10 ml). The aqueous layer was extracted with a further 10 ml dichloromethane and the combined organics dried over sodium sulphate and concentrated in vacuo to give an oil. This was dissolved in tetrahydrofuran (2 ml). Potassium tert-butoxide (65 mg, 0.60 mmol) was added to the solution and the reaction mixture stirred at 40° C. for 18 hrs. This was then concentrated in vacuo and partitioned between diethyl ether (10 ml) and water (10 ml). The aqueous layer was extracted with a further 10 ml diethyl ether and the combined organics dried over sodium sulphate and concentrated in vacuo to give a pale yellow oil. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 96:4:0.4 to give the title compound as a pale yellow oil (19 mg, 15%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 6.90 (d, 2H), 4.26 (m, 2H), 3.80 (m, 2H), 3.58 (m, 2H), 3.15 (s, 2H), 2.99 (t, 2H), 2.80 (m, 2H), 2.75 (m, 2H), 2.40 (t, 2H), 2.38 (m, 2H), 2.16 (m, 2H), 2.02 (m, 4H), 1.90 (m, 2H) 1.81 (m, 2H), 1.03 (d, 6H); HRMS (ESI+) 437.2457 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH2:5]([NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH3:12])[CH3:6]>O>[CH2:5]([N:7]1[CH2:8][CH2:9][N:10]([CH2:11][CH3:12])[CH2:3][C:1]1=[O:2])[CH3:6]
Reactant: O=CC=O
Reactant: CCNCCNCC
Solvent: O
Product: CCN1CCN(CC)C(=O)C1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
To 10.0 g (69.0 mmoles) of 40 percent glyoxal and 200 ml of distilled water is rapidly added 8.0 g (69.0 mmoles) of N,N'-diethylethylenediamine. The solution is heated rapidly to reflux and heating maintained for 5 minutes. The dark brown solution is allowed to cool to room temperature and is then evaporated at 60° C. under water pump vacuum to a viscous brown oil. The oil is distilled in a short path distillation apparatus to yield 10 g (93 percent yield) of 1,4-diethylpiperazin-2-one in the form of a yellow oil. Purity is greater than 99 percent by capillary gas chromatograph.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:28]1[N:29]=[C:25]([NH:24][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:22])[S:26][CH:27]=1)[CH3:35]
Reactant: O=C(O)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CCO2
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCO3)n1

Procedure:
The title compound, MS (ISP)=492.0 (M−H)−, was produced as described in example 1, steps 1-6. Step 3 was performed using 3-chlorobenzenesulfonyl chloride, furnishing 4-(3-chlorobenzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 4, leading to 4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 2-amino-4-thiazoleacetate in step 5 and yielded (2-{[4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)acetic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1.C([O-])([O-])=O.[K+].[K+].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CC#N>[N:23]1([CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[CH:7]=[CH:6]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc2ccn(CCCCl)c2c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2ccn(CCCN3CCOCC3)c2c1
Yield: 100.1 %

Procedure:
A solution of compound 148 (2.35 g, 9.845 mmol) in dry CH3CN (40 mL) was treated with K2CO3 (13.6 g, 98.458 mmol), KI (16.3 g, 98.458 mmol) and morpholine (8.58 mL, 98.458 mmol) at room temperature. The resulting mixture was refluxed for overnight (15 h). The reaction was brought to room temperature and the solvent was evaporated. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate layer was washed with water (25 mL), brine (20 mL) and dried (Na2SO4). The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (EtOAC: 2M NH3 in methanol/CH2Cl2, 1:1) to obtain compound 149 (2.85 g, quantitative) as a syrup. 1H-NMR (CDCl3) δ 1.97-2.06 (m, 2H), 2.23 (t, 2H, J=6.3 Hz), 2.38 (brs, 4H), 3.75 (t, 4H, J=4.5 Hz), 4.33 (t, 2H, J=6.6 Hz), 6.59 (d, 1H, J=3.0 Hz), 7.39 (d, 1H, J=3.0 Hz), 7.64 (d, 1H, J=8.7 Hz), 8.00 (dd, 1H, J=1.8, 8.7 Hz), 8.42 (brs, 1H).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2=O)=O.[CH3:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)=O.[OH-:38].[K+]>C(O)C.O>[F:37][C:36]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:28]1[CH:29]=[CH:30][C:25]([C:23]2[C:22]([CH3:21])=[C:11]([C:12]([OH:17])=[O:38])[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][CH2:6][NH2:5])[CH:9]=3)[N:13]=2)=[CH:26][CH:27]=1
Reactant: CCC(=O)c1ccc(-c2ccccc2F)cc1
Reactant: O=C1Nc2ccc(CCNC(=O)C(F)(F)F)cc2C1=O
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ccc(-c3ccccc3F)cc2)nc2ccc(CCN)cc2c1C(=O)O
Yield: 62.4 %

Procedure:
5-(2-trifluoroacetylaminoethyl)-isatin (572 mg, 2.0 mmol) and 4-(2-fluorophenyl)propiophenone (457 mg, 2.0 mmol) were suspended in ethanol (6 ml) and treated with a solution of KOH (1.01 g, 18.0 mmol) in water (3 ml). The mixture was heated at reflux for 48 hours. The mixture was then cooled, diluted with additional water, concentrated in vacuo to remove the ethanol, and filtered. The solid was washed with water, and the combined aqueous filtrate was adjusted to pH 8 with dilute aqueous HCl. The resulting solid was collected by filtration, rinsed thoroughly with water and dried to provide the title hapten as a cream-colored solid (500 mg, 62%): mp >250° C.; NMR (CF3COOD) δ 8.61 (d, 1H), 8.44 (s, 1H), 8.33 (d, 1H), 8.12 (d, 2H), 7.95 (d, 2H), 7.69 (t, 1H), 7.57 (m, 1H), 7.43 (t, 1H), 7.35 (m, 1H), 3.92 (bs, 2H), 3.71 (bt, 2H), 2.95 (s, 3H); mass spec (NH3 -CI) m/z 401 (100%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11](F)[CH:10]=1.C(N(CC)CC)C>CS(C)=O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[S:3][C:15]=2[CH:16]=1
Reactant: CCOC(=O)CS
Reactant: O=Cc1ccc(Br)cc1F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2ccc(Br)cc2s1
Yield: 91.8 %

Procedure:
A solution of ethyl thioglycolate (0.65 g, 5.42 mmol), 4-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) and triethylamine (1.25 mL, 12.3 mmol) in DMSO (5 mL) was heated at 75° C. for 2 h. The mixture was partitioned between H2O (50 mL) and CH2Cl2 (2×50 mL), and the combined organic layers were dried over Na2SO4. The drying agent was filtered off, and the solvent was removed in vacuo to give the title compound as an oil (1.29 g, 92%).
Reaction SMILES: [CH3:1][C:2]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C(O)=O.C([N:20](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[Cl:42]C(Cl)(Cl)CO>C1COCC1.[Zn].C(O)(=O)C.O>[ClH:42].[CH3:1][C:2]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)([NH2:20])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(Cc1ccccc1)(C(=O)O)c1cccs1
Reactant: OCC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(N)(Cc1ccccc1)c1cccs1
Product: Cl
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The acid from step (a) (25 g, 0.102 mol) was dissolved in THF(390 mL) and triethylamine (14.1 mL) was added. Diphenylphosphoryl azide (23.4 mL) was added and the mixture was heated at 65° C. for 5 hours. The reaction was cooled to room temperature and 2,2,2-trichloroethanol (46.1 mL) was added portionwise and then the reaction was heated to reflux for 40 hours. The reaction was cooled to 0° C. and water (40 mL), glacial acetic acid (360 mL) and zinc dust (132 g) were added. The ice bath was removed and the reaction was stirred overnight. After filtration of the reaction mixture through a bed of celite the filtrate was concentrated and the residue was dissolved in ethyl acetate (800 mL). The ethyl acetate was washed with 1N.NaOH (800 mL) and water (800 ml). The ethyl acetate layer was separated, dried (MgSO4) and concentrated to dryness. The residual oil was converted to the hydrochloride salt with ethanolic hydrogen chloride and precipitated by the addition of diethyl ether. A 1 g portion of the hydrochloride was recrystallized from ethyl acetate(20 mL)/MeOH(5 mL)/hexanes(15 mL) to give the title compound (0.8 g), mp 205°-206° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[CH:34]1([O:39][C:40](=[O:54])[C@@H:41]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42][CH2:43][CH2:44]O)[CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)Cl>[CH:34]1([O:39][C:40](=[O:54])[C@@H:41]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42][CH2:43][CH2:44][Br:1])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO)C(=O)OC1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](CCCBr)C(=O)OC1CCCC1
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a slurry of N-bromo succinimide (3.54 g, 19.9 mmol, 3 eq) in DCM (30 ml) was added a solution of triphenyl phosphine (4.87 g, 18.8 mmol, 2.8 eq) in DCM (15 ml). The solution was stirred for a further 5 minutes before addition of pyridine (644 μl, 7.96 mmol, 1.2 eq) and a solution of (S)-2-tert-butoxycarbonylamino-5-hydroxy-pentanoic-acid cyclopentyl ester (2.0 g, 6.64 mmol) in DCM (20 ml). The solution was stirred for 18 hours, concentrated in vacuo and the residual solvent azeotroped with toluene (3×30 ml). The residue was triturated with diethyl ether (30 ml) and ethyl acetate:heptane (1:9, 2×30 ml). The combined ether and ethyl acetate/heptane solutions was concentrated onto silica and purified by column chromatography using ethyl acetate/heptane (1:9 to 2:8) to provide the title compound as a clear oil (1.34 g, 55% yield).
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1)#[N:2].[CH2:15]([Mg]Br)[CH3:16].[BH4-].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:2][CH:1]([C:3]1([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1)[CH2:15][CH3:16]
Reactant: N#CC1(c2ccc(F)cc2)CC=CC1
Reactant: CC[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC(N)C1(c2ccc(F)cc2)CC=CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.2 %

Procedure:
1-cyano-1-(4-fluorophenyl)cyclopent-3-ene (117, 1.4 g, 7.48 mmol) was dissolved in toluene (3.5 mL) and ethyl magnesium bromide (5 mL, 15 mmol, 3M in ether) added. After stirring for 2.5 hours, the reaction mixture was added dropwise to ice cold methanol (50 mL), followed by sodium borohydride (560 mg, 15 mmol). The mixture was warmed to room temperature and stirred overnight. The white suspension was treated with sodium hydroxide solution (aq, 1M, 125 mL) and then extracted with dichloromethane/isopropanol (3/1). The organic phase was washed with brine, dried over sodium sulphate and evaporated to give 1.2 g of a yellow oil. This was taken up in dichloromethane and extracted twice with dilute hydrochloric acid (2M). The combined aqueous layers were made basic with aqueous sodium hydroxide solution (5M) and re-extracted with dichloromethane/isopropanol (3/1). Drying over sodium sulphate and evaporation gave 348 mg of the desired product Rt=2.37 min (Method 2). Detected mass: 220.1 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:29])[CH2:16][N:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[CH:10][C:9]=2[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)C.O1CCCC1.C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[CH2:22]([N:17]([CH2:16][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:8]2[C:13]=1[CH:14]=[C:6]([CH2:4][OH:3])[NH:7]2)[OH:29])[C:18]([CH3:20])([CH3:19])[CH3:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)(C)C)ccc(OCc3ccccc3)c2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccc(OCc2ccccc2)c2[nH]c(CO)cc12
Yield: 92.4 %

Procedure:
4 g of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)-2-indolecarboxylic acid ethyl ester is combined with 75 ml of absolute tetrahydrofuran and 150 ml of diethyl ether and stirred under ice cooling for 9 hours with 1.2 g of lithium aluminum hydride. Then a small amount of water is added to the reaction mixture, the precipitate is vacuum-filtered, washed with ethyl acetate/diethyl ether, the combined filtrates are concentrated, and the residue is recrystallized from diisopropyl ether, thus obtaining 3.4 g of 2-(N-benzyl-N-tert-butylamino) -1-(7-benzyloxy-2-hydroxymethylindol-4-yl)ethanol, mp 135.5°-136.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=12)=[O:5])[CH3:2].[CH3:20]I>CN(C=O)C.[Ag]=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:20])[C:11](=[O:19])[C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1c(=O)[nH]c1ccccc12
Reactant: CI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2c1c(=O)n(C)c1ccccc12
Yield: 62.7 %

Procedure:
To a solution of 4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (12.4 g) and methyl iodide (98 g) in DMF (1 liter) was added silver oxide (65 g) with stirring. The reaction mixture was stirred at room temperature for 18 hours. After removal of insoluble material the solution was evaporated under oil pump vacuum to dryness. The residue was extracted with chloroform several times. The combined chloroform extracts were washed with water, dried by magnesium sulfate, then evaporated under water aspirator vacuum to give the product as a white solid (8.2 g, 63% yield). Recrystallized from acetonitrile, m.p. 233°-236° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[C:10]([CH3:12])=[CH:11][C:6]2=[N:5][N:4]=1)[CH3:2].[OH:21]O.[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([C:13]3[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:21])=[CH:15][CH:14]=3)[C:10]([CH3:12])=[CH:11][C:6]2=[N:5][N:4]=1)[CH3:2]
Reactant: CCc1nnc2cc(C)c(-c3ccc(C#N)cc3)nn12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nnc2cc(C)c(-c3ccc(C(N)=O)cc3)nn12
Reaction time: 3 h

Procedure:
A 4.5 g. portion of p-(3-ethyl-7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)benzonitrile (prepared as described in Example 3) is dissolved in 50 ml. of ethyl alcohol with warming, then 50 ml. of 30% hydrogen peroxide is added with swirling and finally 50 ml. of 2N sodium hydroxide is added with swirling. The reaction is allowed to stand at room temperature for 3 hours, then is concentrated almost to dryness using as little heat as possible. The concentrate is diluted with water, filtered and the filter cake is then washed with water and air dried. The product is dissolved in acetone and filtered to remove insolubles then is recrystallized to afford a yellow solid as the product of the example, m.p. 210°-213° C.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])[C:4]=3[CH:3]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(Br)ccc21
Agent: OB(O)c1ccccc1
Product: COc1ccc(-c2ccc3c(c2)C(c2cccc(C#N)c2)=NCC(=O)N3C)cc1
Yield: 47 %

Procedure:
Prepared from 3-(7-bromo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 14 using the same method described for Example 1 and instead of using benzene boronic acid, we used 4-methoxyphenyl boronic acid. The title compound (90 mg) was obtained as a yellow solid, (yield=47%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[Cl:18].[OH-].[K+].O>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:19][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10]
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C)c(Oc2ccc(Cl)c(Cl)c2)c1C=O
Temperature: 150 °C
Yield: 54.8 %

Procedure:
5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (500.0 mg, 0.00315 mol), 3,4-dichlorophenol (565 mg, 0.00344 mol) and potassium hydroxide (265 mg, 0.00472 mol) were stirred in DMF (2.0 mL). Mixture was heated at 150° C. for 20 min using microwave. Water was added and resulting mixture was extracted with ethyl acetate. Organic layer was washed with brine twice, dried over MgSO4 and evaporated. The resulting oil was purified by column chromatography (10% to 20% ethyl acetate/heptane) to give 5-(3,4-dichlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (492 mg, 54.7%) as white solid. Step 2:
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1Br.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[CH3:23][S:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[C:2]([C:28]2[CH:29]=[CH:30][C:25]([S:24][CH3:23])=[CH:26][CH:27]=2)=[C:3]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Fc1c(F)c(F)c(Br)c(Br)c1F
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2c(F)c(F)c(F)c(F)c2-c2ccc(F)cc2)cc1
Yield: 126.1 %

Procedure:
Under nitrogen, 1 g of Pd(PPh3)4 was added to a stirred solution of 4.85 g (15.8 mmol) of 1,2-dibromo-3,4,5,6-tetrafluorobenzene (Aldrich), 2.65 g (18.9 mmol) of 4-fluorophenylboronic acid, and 3.17 g (18.9 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 2) in 80 mL of toluene, 50 mL of ethanol, and 35 mL of 2M Na2CO3. After vigorous stirring at reflux overnight, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, washed water, and dried over Na2SO4. Concentration in vacuo gave 7.3 g of 1,2,3,4-tetrafluoro-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]benzene as a yellow oil which was used without further purification.