Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)CC)C.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:26]1[C:34]2[C:29](=[C:30]([CH2:35][C:36](O)=[O:37])[CH:31]=[CH:32][CH:33]=2)[CH:28]=[N:27]1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:36](=[O:37])[CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[C:34]3[C:29]=2[CH:28]=[N:27][N:26]3[CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2]
Reactant: O=C(O)Cc1cccc2c1cnn2C1CCCCO1
Reactant: CCOC(=O)c1sc(N)nc1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1sc(NC(=O)Cc2cccc3c2cnn3C2CCCCO2)nc1C
Temperature: 60 °C
Yield: 73.2 %

Procedure:
A solution of 2-Amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.74 g, 9.343 mmol) and triethylamine (5.2 mL, 37.31 mol) in anhydrous THF (40 mL) was heated to 60° C. and [1-(Tetrahydro-pyran-2-yl)-1H-indazol-4-yl]acetic acid (1.85 g, 7.107 mmol) in anhydrous THF (20 mL) was added followed by the addition of 1-propanephosphonic acid cyclic anhydride, 50 wt. % solution in ethyl acetate (5.2 mL, 8.735 mmol) over 1 min. The reaction mixture was heated at 60° C. for 40 min, cooled, diluted with water (150 mL) and extracted with ethyl acetate (3×150 mL). The organic layers were combined, washed with 1/1 aqueous 2N HCl/brine (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (33% EtOAc in hexanes) to give 4-Methyl-2-{2-[1-(tetrahydro-pyran-2-yl)-1H-indazol-4-yl]-acetylamino}-thiazole-5-carboxylic acid ethyl ester (2.23 g, 73%) as a yellow foam. MS m/e 429.5 (M+H+).
Reaction SMILES: Cl[C:2]1([Cl:11])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]1[Cl:10].P(OCC)(OCC)O[CH2:14][CH3:15].P(Cl)(=O)([O-])OCC>>[Cl:10][C:3]1[C:2]([Cl:11])([CH2:14][CH3:15])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]=1[Cl:9]
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Reactant: CCOP(OCC)OCC
Agent: CCOP(=O)([O-])Cl
Product: CCC1(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl
Temperature: 0 °C
Yield: 93.4 %

Procedure:
A solution of 272.8 g. (1.0 mole) of hexachlorocyclopentadiene in 300 ml. of petroleum ether (pentane range) was charged to a 2 liter 3 neck flask equipped with stirrer, thermometer, dropping funnel and an exit line protected with a drying tube. The flask was immersed in ice-water and triethyl phosphite (182.8 g., 1.1 mole) was added slowly from the dropping funnel at such a rate that the temperature of the reaction mixture did not exceed +15°C. After the addition was completed (which required 5 hours) the clear, brown solution was, after the stripping of the solvent, fractionated in vacuum through a 20 inch column, filled with glass helices. A lower boiling fraction, 161 g., b.p. 39°C. at 0.4 mm., nD25 1.4253 consisted of pure ethyl phosphorochloridate, Cl(EtO)2PO, which, accordingly, was obtained in 93.4% yield. Then the temperature rose fast in the column and a pale yellow oil distilled over sharply at 50°C. and 0.18 mm. Infrared and elemental analyses indicated that the yellow oil, nD25 1.5394, is pure 1,2,3,4,5-pentachloro-5-ethylcyclopentadiene.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>O1CCCC1>[C:16]([Si:13]([CH3:15])([CH3:14])[N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([I:1])=[CH:3]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Ic1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)n1cc(I)c2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.1 %

Procedure:
3-Iodo-1H-pyrrolo[2,3-b]pyridine 634 (1.11 g, 4.6 mmol) was dissolved in tetrahydrofuran (120 mL). Sodium hydride (60% dispersion in mineral oil, 0.13 g, 5.5 mmol) was added, followed by tert-butyldimethylsilyl chloride (0.85 g, 5.5 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the compound as a white solid (636, 100 mg, 15%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[CH2:13][NH:12]1)[CH2:8]2.C(N(C(C)C)CC)(C)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.O>ClCCl>[CH3:35][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:12]2[CH2:13][C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CNN1C1C2CC3CC(C2)CC1C3
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC(=O)N2C2C3CC4CC(C3)CC2C4)cc1
Reaction time: 12 h
Yield: 85.5 %

Procedure:
A solution of 2-(adamantan-2-yl)-1,2-diazetidin-3-one (5.00 mg, 0.0240 mmol)prepared in Process 5 of Example 1 in dichloromethane (1 mL) was added with diisopropylethylamine (9.30 mg, 0.0720 mmol) and p-toluenesulfonyl chloride (6.80 mg, 0.0360 mmol) at room temperature, and the resultant was stirred at the same temperature for 12 hours. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (7.40 mg, 83.3%) was obtained as a white crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]2(C(F)(F)F)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].ClC1C(OCC2CCCCC2)=C[C:28](F)=[C:29]([CH:33]=1)[C:30](O)=O>>[Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][C:29]([CH3:33])([CH3:30])[CH3:28])=[O:8]
Reactant: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Reactant: O=C(O)c1cc(Cl)c(OCC2CCCCC2)cc1F
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 2 and making variations as required to replace 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)benzoic acid with 5-chloro-4-(cyclohexylmethoxy)-2-fluorobenzoic acid, the title compound was obtained as a colorless oil (15.37 g, 43%): MS (ES+) m/z 381.2 (M+39).
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([CH2:14][CH:15]=[CH2:16])=[C:12]([O:17][CH3:18])[C:11]([CH3:19])=[C:10]2[C:6]=1[C:7](=[O:20])[O:8][CH2:9]2)(=[O:3])[CH3:2].Br[C:22]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(=O)([O-])[O-].[Ag+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:1]([O:4][C:5]1[C:13]([CH2:14]/[CH:15]=[CH:16]/[C:22]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[C:12]([O:17][CH3:18])[C:11]([CH3:19])=[C:10]2[C:6]=1[C:7](=[O:20])[O:8][CH2:9]2)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(C)c1Br
Reactant: C=CCc1c(OC)c(C)c2c(c1OC(C)=O)C(=O)OC2
Agent: [Ag+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1/C=C/Cc1c(OC)c(C)c2c(c1OC(C)=O)C(=O)OC2
Temperature: 100 °C
Reaction time: 6 h

Procedure:
4-Acetoxy-5-allyl-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran (0.6 g), methyl 2-bromo-3-methylbenzoate (0.92 g), silver carbonate (1.3 g), palladium acetate (0.1 g), triphenylphosphine (0.14 g) and dimethylformamide (70 ml) were heated with stirring at 100° C. for 6 hours, then stirred at ambient temperature for 18 hours. The mixture was poured into ice water and the pH adjusted to 3 by addition of 2N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was dried and evaporated. The residue was chromatographed on silica gel, eluting with 7:3 hexane:ethyl acetate, to give methyl (E) 2-[3-(4-acetoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-prop-1-en-1-yl]-3-methylbenzoate, mp 104°-111° C. (ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2](=[N:41][OH:42])[C:3]1[CH:4]=[CH:5][C:6]([CH3:40])=[C:7]([N:9]([CH2:26][C:27]([N:29]([N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32]2)[CH3:30])=[O:28])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH3:18])=[O:12])[CH:8]=1.[F:43][CH:44]([F:48])[C:45](O)=O.CCN=C=NCCCN(C)C>O1CCOCC1.C(OCC)(=O)C.CCCCCC>[F:43][CH:44]([F:48])[C:45]1[O:42][N:41]=[C:2]([C:3]2[CH:4]=[CH:5][C:6]([CH3:40])=[C:7]([N:9]([CH2:26][C:27]([N:29]([N:31]3[CH2:32][C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:39]3)[CH3:30])=[O:28])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:17][CH3:18])=[O:12])[CH:8]=2)[N:1]=1
Reactant: O=C(O)C(F)F
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc(C(N)=NO)ccc1C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc(-c2noc(C(F)F)n2)ccc1C)C(=O)OC(C)(C)C
Yield: 21.7 %

Procedure:
The compound (406 mg, 0.698 mmol) of step A, difluoroacetic acid (0.12 ml, 1.90 mmol) and WSC (530 mg, 2.76 mmol) were dissolved in 1,4-dioxane (5 ml) and the mixture was heated under reflux for 5 hr. The reaction mixture was diluted with an ethyl acetate-hexane=1:1 mixed solvent, and the organic layer was washed with water, 10% aqueous citric acid solution, diluted aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane→ethyl acetate-methanol) to give the title compound (97 mg, yield 22%) as a pale-yellow amorphous solid
Reaction SMILES: [CH:1]1([C@H:4]([NH:26][C:27](=[O:38])[O:28][C:29]2C=CC([N+]([O-])=O)=C[CH:30]=2)[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:39][N:40](C)[CH2:41]CO>>[CH:1]1([C@H:4]([NH:26][C:27](=[O:38])[O:28][CH2:29][CH2:30][N:40]([CH3:41])[CH3:39])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)CCO
Product: CN(C)CCOC(=O)N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1

Procedure:
A solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethylcarbamate (31-1, 50 mg, 0.096 mmol) in 2-(dimethylamino)ethanol (1 mL) was heated at 100° C. for 1 hour. The reaction mixture was cooled, then partitioned between ethyl acetate (40 mL) and brine (3×40 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (EtOAc initially, grading to 10% saturated NH3/ethanol in EtOAc) to give 2-(dimethylamino)ethyl(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethylcarbamate (31-2) as a pale yellow solid. 1H NMR (500 MHz, CDCl3) showed a 2:1 mixture of rotamers; major rotamer: δ 7.42-7.24 (m, 5H), 7.11-6.95 (m, 3H), 6.41 (br s, 1H), 5.93 (m, 1H), 5.58 (d, 1H, J=7.6 Hz), 5.04 (br d, 1H, J=13.9 Hz), 4.91 (ddd, 1H, J=14.7, 4.4, 1.7 Hz), 4.30 (t, 1H, J=7.8 Hz), 4.15 (m, 2H), 2.54 (m, 2H), 2.27 (s, 6H), 1.14 (m, 1H), 0.57-0.33 (m, 4H). LRMS nil/z (M+H) 470.5 found, 470.2 required.
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].[F:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35](B(O)O)=[CH:34][C:33]=2[CH:40]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[C@H:1]([NH:5][C:6]1[C:7]([C:35]2[O:36][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:40][C:33]=3[CH:34]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cc2cc(F)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-methyl 3-(sec-butylamino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (400 mg, crude) in dioxane (5 mL) was added 5-fluorobenzofuran-2-ylboronic acid (441 mg, 2.45 mmol), K3PO4 (620 mg, 2.94 mmol), and Pd(PPh3)4 (57 mg, 0.05 mmol). The resulting solution was stirred for 1 h at 90° C. and then quenched by the addition of dichloromethane (200 mL) and washed with water (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford (R)-methyl 3-(sec-butylamino)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylate as a yellow solid (100 mg, 24% 2 steps).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][CH3:11])[CH:5]=[O:6].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[Na+].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>[CH2:10]([C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:14]1[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=1)[CH3:11]
Reactant: OB(O)c1cccnc1
Reactant: CCc1ccc(C=O)cc1Br
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: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1ccc(C=O)cc1-c1cccnc1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
To a mixture of 3-bromo-4-ethylbenzaldehyde (2.45 g, 0.0115 mol), pyridine 3-boronic acid (1.42 g, 0.0115 mol, Matrix Scientific), 2M Na2CO3 (15 mL) in 30 mL of toluene was added 1.33 g of Pd (PPh3)4 (1.15 mmol, Aldrich). The mixture was then heated to 80 C under N2 for 16 hours. The mixture was cooled to RT and was diluted with 100 mL of EtOAc and 40 mL of sat. NaHCO3 aq. solution. The organic phase was washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The crude product was chromatographed (silica gel, 20% EtOAc in hexane) to provide yellow oil (1.2 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[C:26]#[C:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]#[C:26][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:18][CH2:17][C:5]2=3)=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Fc1ccc(C#CBr)cc1
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)c1c(n2C#Cc2ccc(F)cc2)CCN(C)C1
Temperature: 82.5 °C
Reaction time: 0.17 h

Procedure:
Methyl 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole-8-carboxylate (122 mg, 0.5 mmol) was dissolved in toluene (3 mL) and stirred for 10 min. Potassium carbonate (138 mg, 1.0 mmol), copper sulfate (124 mg, 0.05 mmol) and 1,10-phenanthraline (18 mg, 0.1 mmol) were added. The reaction mixture was stirred for 10 min. A solution of 1-(bromoethynyl)-4-fluorobenzene (110 mg, 0.11 mmol) in toluene (2 mL) was added to the reaction mixture, which was heated to 80-85° C. overnight. TLC monitoring showed 10% conversion of reactant to product. As such, more of 1-(bromoethynyl)-4-fluorobenzene (110 mg, 0.5 mmol) was added and heating was continued for 10-12 h. Toluene was removed under reduced pressure to obtain the product, which was purified by column chromatography using silica (100-200 mesh) and 0-5% DCM:MeOH as eluent. The pure compound was converted to its oxalate salt. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.30 (d, 1H), 8.05 (m, 1H), 7.78 (d, 1H), 7.62 (m, 2H), 7.20 (m, 2H), 3.95 (s, 3H), 3.80 (m, 2H), 3.70 (m, 2H), 3.35 (m, 2H), 3.15 (s, 3H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30].O.[NH2:33][NH2:34]>CN(C=O)C>[CH3:30][O:29][C:22]1[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=1[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1
Reactant: NN
Reactant: COc1ccc(OC)c(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC)c(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Yield: 81.8 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(2,5-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (200 mg, 0.48 mmol, prepared in Synthetic Example 21) in DMF (5 ml) was added hydrazine monohydrate (80%, 100 μl, 2.50 mmol, 5.2 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(2,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (162 mg, 82%).
Reaction SMILES: S.[Na].[CH2:3]([O:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Br:20])=[C:14]([F:19])[CH:15]=2)[N:10]([CH:21]2[CH2:23][CH2:22]2)[C:9]=1[S:24]C)=[O:7])[CH3:4].Cl>C1COCC1.O.CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Br:20])=[C:14]([F:19])[CH:15]=2)[N:10]([CH:21]2[CH2:22][CH2:23]2)[C:9]=1[SH:24])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1c(SC)n(C2CC2)c2cc(Br)c(F)cc2c1=O
Agent: Cl
Agent: S
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(S)n(C2CC2)c2cc(Br)c(F)cc2c1=O
Temperature: 45 °C

Procedure:
Sodium hydrogen sulfide (5 mg, 0.09 mmole, 1.5 equiv.) is added to a stirred solution of 7-Bromo-1-cyclopropyl-6-fluoro-2-methylsulfanyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (5, 24 mg, 0.06 mmole) in THF (tetrahydrofuran, 2 ml) under argon at room temperature. The reaction is then stirred at 45° C. until TLC indicated completion. The reaction mixture is diluted with water and washed with diethyl ether. The aqueous layer is acidified by 1N HCl to a pH of approximately 2, and extracted with EtOAc. The resulting organics are washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product is purified by PTLC (20% CH3OH in CHCl3) to give 6. Alternatively, sodium hydrogen sulfide (20 mg, 0.36 mmole, 1.5 equiv.) is added to a stirred solution of 5 (crude, 96 mg, 0.24 mmole) in DMF (6 ml) under argon at room temperature. The reaction is then stirred at 40° C. until TLC indicates completion. The reaction mixture is diluted with water, acidified by 1N HCl to a pH of approximately 2, and extracted with EtOAc. The resulting organics are washed with brine, dried over Na2SO4, and concentrated. The crude is purified by PTLC (20% CH3OH in CHCl3) to yield 6. 1H NMR (CDCl3) δ: 8.40 (d, 1H), 8.06 (d, 1H), 4.71 (q, 2H), 3.46 (m, 1H), 1.68 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:16]N1C(=O)CCC1=O.CN(C)C=O>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][C:7]=1[Cl:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(N)c(Cl)c1
Yield: 8.6 %

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.2 g), N-chlorosuccinimide (0.135 g) and dimethylformamide (3 ml) was stirred with ice-cooling for an hour. The reaction mixture was poured into water and extracted with chloroform. The extract was concentrated to dryness under reduced pressure and the residue was crystallized from chloroform to give 6-(4-amino-3-chlorophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.02 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[H][H]>[Pd]>[CH3:1][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:4][CH2:3][OH:2]
Reactant: c1ccc2c(c1)CCOC2
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: Cc1ccccc1CCO
Temperature: 150 °C
Reaction time: 5 h

Procedure:
1250 Grams of isochroman having the structure: ##STR64## 25 grams of 5% palladium-on-carbon and 12.5 grams of citric acid are placed in a 4-liter autoclave. The autoclave is sealed, heated to 150° C. and pressurized with hydrogen at 200 psig. After five hours, 12.5 grams of additional citric acid is added to the autoclave and the autoclave is resealed. The autoclave is then heated at a pressure of 200 psig and 150° C. for an additional three hours. At the end of this additional three hour period, the autoclave is opened, the contents filtered and the filtrate is distilled over 2 grams of calcium carbonate through a 24" Goodloe column yielding the following fractions:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][C:14]=1[C:21]([F:24])([F:23])[F:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][Cl:3])=[CH:15][C:14]=1[C:21]([F:24])([F:23])[F:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)c1cc(CCl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (2.0 mL) was added to solution of (4-benzyloxy-3-trifluoromethyl-phenyl)-methanol (CAB03047, 3.10 g, 11.0 mmol) in dichloromethane (20 mL). The solution was stirred for 1 h at room temperature and concentrated under reduced pressure. Then diethyl ether (100 mL) and water (20 mL) were added. The organic layer was separated, washed with conc. sodium bicarbonate solution (10 mL), dried over sodium sulphate and concentrated under reduced pressure. The resulting oil solidified after a few minutes and was dried under high vacuum. Yield: 3.25 g (98%). 1H-NMR (400 MHz, CDCl3) δ=4.57 (s, 2H, —CH2Cl), 5.22 (s, 2H, —OCH2Ph), 7.02 (d, J =8.5 Hz, 1H), 7.31-7.52 (m, 6H), 7.63 (d, J=2.0 Hz, 1H). LRMS (FAB+): 91.1 (100), 265.2 (8), 300.1 (10, [M]+).
Reaction SMILES: [C:1]1([C:7]([OH:11])([C:9]#[CH:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:11][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:8])[C:9]#[C:10][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC(C)(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(C)(O)c3ccccc3)c21

Procedure:
Using Method C above, 2-phenyl-3-butyn-2-ol (70 mg, 0.48 mmol) (Aldrich) was coupled to (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2) using (Ph3P)2PdCl2 (20 mg) (Aldrich) and CuI (10 mg) (Aldrich) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-phenyl-1-butynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 85 mg, 55%).