Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.O.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>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(Br)n1
Reactant: OB(O)c1ccc(O)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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2ccc(O)cc2)n1
Temperature: 100 °C
Yield: 45.6 %

Procedure:
A mixture of methyl 6-bromo-2-pyridinecarboxylate (1.35 g, 6.22 mmol, 1 eq), (4-hydroxyphenyl)boronic acid (0.945 g, 6.85 mmol, 1.1 eq), Pd(PPh3)4 (0.718 g, 0.06 mmoles, 0.01 eq) and K2CO3 (1.7 g, 12.4 mmoles, 2 eq) in dioxane (15 mL) and water (8 mL) was heated at 100° C. for 2 h. Then AcOEt was added and the organic phase was washed with water, dried over Na2SO4, filtered and evaporated to dryness. The crude compound was purified on flash chromatography on 50 g silica gel cartridge using a gradient of cyclohexane/ethyl acetate 10/0 to 7/3 as an eluent. Solvents were removed under reduced pressure to give the title compound as a yellow solid (650 mg, 46%). 1H-NMR (CDCl3, 400 MHz): δ 4.03 (3H, s), 5.28 (1H, s), 6.90-7.03 (2H, m), 7.80-7.98 (2H, m), 8.0-8.06 (3H, m). MS: (ES/+) m/z: 230 (M+H)+. C13H11NO3 requires 229.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[H-].[Na+].Cl>C(O)CCCC>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([O:17][CH2:16][CH2:14][CH2:13][CH2:12][CH3:11])[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCO
Product: CCCCCOc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
To a solution of l±)-cis-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.544 g, 2 mmol) in 1-pentanol (10 mL) at 110° C. was added NaH (60% oil dispersion, 0.160g, 4 mmol). The mixture was stirred at 110° C. for 15 minutes, then cooled to room temperature. 1 N HCl was added to adjust the pH to 7.0, and the solvent was removed by evaporation. The residual oil was chromatographed on silica gel. Title compound was eluted with 7% methanol-chloroform; white powder after crystallization from acetonitrile-methanol (0.481g, 76%); mp=139-141° C.;
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:11]N1C(=O)C2=CC=CC=C2C1=O.C1(OC)C=CC=CC=1.O=O.C12(O)CC3CC(CC(C3)C1)C2>C(O)(=O)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Agent: OC12CC3CC(CC(C3)C1)C2
Solvent: COc1ccccc1
Solvent: CC(=O)O
Product: O=C1C2CC3CC(C2)CC1C3
Temperature: 85 °C
Reaction time: 3 h
Yield: 11.3 %

Procedure:
A mixture of 27 g (200 mmol) of adamantane, 3.25 g (20 mmol) of N-hydroxyphthalimide, 0.183 g (0.1 mmol) of V2O5, 240 mL of anisol and 60 mL of acetic acid was stirred for 3 hours at 85° C. and 1 atm (0.101 MPa) in an atmosphere of oxygen. After completion of reaction, the reaction mixture was analyzed by gas chromatography and high performance liquid chromatography, and, as a result, the conversion of adamantane was 13.0%, adamantanol and adamantanone were formed in yield 11.3% (selectivity 86.9%) and yield 0.9% (selectivity 6.9%), respectively. Moreover, in the reaction mixture, 2.12 g of N-hydroxyphthalimide used as a catalyst, 0.68 g of phthalimide, and 0.18 g of phthalic anhydride were contained. The reaction mixture was condensed, 400 mL of hexane was added thereto, and the mixture was stirred for 2 hours at 50° C. After cooling, an insoluble material was filtrated to recover the catalyst and the decomposed product thereof in the form of solid. The filtrate did not contain the catalyst and the decomposed product thereof.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[C:17]=2[CH3:24])=[C:11]([CH3:25])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:23][CH2:22][C:18]1[C:17]([CH3:24])=[C:16]([C:12]2[C:11]([CH3:25])=[CH:10][C:9]([OH:8])=[CH:14][C:13]=2[CH3:15])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1-c1cccc(CO)c1C
Agent: [Pd]
Solvent: CO
Product: Cc1cc(O)cc(C)c1-c1cccc(CO)c1C
Reaction time: 12 h
Yield: 92.7 %

Procedure:
(4′-(Benzyloxy)-2,2′,6′-trimethylbiphenyl-3-yl)methanol 12c (190 mg, 0.57 mmol) was dissolved in 5 mL of methanol, followed by addition of Pd/C (20 mg, 10%) under hydrogen atomosphere. The reaction solution was stirred for 12 hours. The resulting solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 3′-(hydroxymethyl)-2,2′,6-trimethylbiphenyl-4-ol 12d (128 mg) as a yellow solid, which was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[I:10]I.[OH-].[Na+]>O>[OH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[I:10]
Reactant: N#Cc1cnccc1O
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cncc(I)c1O
Temperature: 85 °C
Yield: 61.3 %

Procedure:
A mixture of 4-hydroxynicotinonitrile (45.7 g, 381 mmol), iodine (96.6 g, 381 mmol) and NaOH (19.8 g, 825 mmol) in water (600 mL) was heated at 85° C. overnight, cooled to r.t. and diluted with water. The precipitate was collected by filtration and washed with water to give 57.5 g (61%) of 4-hydroxy-5-iodonicotinonitrile as a tan solid. Mp>245° C.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].Cl[C:6]1[N:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][C@@H:18]3[CH2:20][C@H:15]2[CH2:16][N:17]3[C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH3:32])=[C:25]([CH3:33])[C:24]=2[CH3:34])[CH3:22])=[O:13])=[CH:8][CH:7]=1>C1COCC1.CN1CCCC1=O.[Cl-].[Na+].O>[CH2:1]([C:6]1[N:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][C@@H:18]3[CH2:20][C@H:15]2[CH2:16][N:17]3[C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH3:32])=[C:25]([CH3:33])[C:24]=2[CH3:34])[CH3:22])=[O:13])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CC[Mg+]
Reactant: CCCOc1ccc([C@H](C)N2C[C@@H]3C[C@H]2CN3C(=O)c2ccc(Cl)nc2)c(C)c1C
Agent: [Br-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCOc1ccc([C@H](C)N2C[C@@H]3C[C@H]2CN3C(=O)c2ccc(CC)nc2)c(C)c1C
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Fe(acac)3 (5 mg) followed by EtMgBr (0.73 mL, 1N in THF) is added to a solution of the amide obtained in Example 4 (129 mg) in 3 mL of THF and 0.3 mL of N-methylpyrrolidinone at room temperature under N2. The dark purple reaction mixture is stirred at room temperature for 50 min and then diluted with brine and extracted 3 times with EtOAc (10 mL). The combined extracts are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by preparative thin layer chromatography, developing 2 times with 25-1 CHCl3-MeOH (25-1) to afford the desired product. LC/MS: 422 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](Cl)(=[O:12])=[O:11])(=[O:4])=[O:3].[NH3:14]>C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH2:14])(=[O:12])=[O:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1sccc1S(=O)(=O)Cl
Reactant: N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1sccc1S(N)(=O)=O

Procedure:
To 10 g of (XXVIII) in 200 ml of ethyl acetate was added 5 ml of liquid ammonia with stirring at 0°. The mixture was allowed to attain room temperature, evaporated and the solid product was washed with ice-water. A dried sample of (XXV) had m.p. 242°-244°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:16]=[CH:15][C:14]3[N:13]4[CH2:17][CH2:18][NH:19][C:20](=[O:21])[C:12]4=[CH:11][C:10]=3[CH:9]=2)[CH2:3][CH2:2]1.[CH:22]1([CH:25]=O)[CH2:24][CH2:23]1.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH:22]1([CH2:25][N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8]3[CH:16]=[CH:15][C:14]4[N:13]5[CH2:17][CH2:18][NH:19][C:20](=[O:21])[C:12]5=[CH:11][C:10]=4[CH:9]=3)[CH2:5][CH2:6]2)[CH2:24][CH2:23]1
Reactant: O=C1NCCn2c1cc1cc(OC3CCNCC3)ccc12
Reactant: O=CC1CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C1NCCn2c1cc1cc(OC3CCN(CC4CC4)CC3)ccc12
Temperature: 55 °C
Reaction time: 18 h
Yield: 0 %

Procedure:
To the solution of 0.27 g (0.95 mmol) 8-(piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one in 6 mL tetrahydrofuran, 20 μL water, 11 μL (99 μg, 1.42 mmol) cyclopropanecarboxaldehyde, 0.16 mL (0.17 g, 2.8 mmol) acetic acid and 1.42 mL (1.42 mmol, 1M solution in tetrahydrofuran) sodium cyanoborohydride were added and the reaction mixture was stirred for 18 hours at 55° C. The mixture was poured on 10% aqueous sodium bicarbonate and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel with dichloromethane: methanol:ammonia (9:1:0.1 v/v) as eluant to give 96 μg (30%) of the desired compound as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2].[C:24]([N:27]=[C:28]=[S:29])(=[O:26])[CH3:25]>CC(C)=O>[C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH:22][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[S:29])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Reactant: CC(=O)N=C=S
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1NC(=S)NC(C)=O
Reaction time: 18 h
Yield: 54 %

Procedure:
To a suspension of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (1.2 g.; 0.0036 mole) in acetone (15 ml.) is added acetyl isothiocyanate (0.37 g.; 0.0036 mole). The reaction mixture is heated to reflux and then allowed to stand at room temperature for 18 hours. The product is collected by filtration, washed successively to afford 0.85 g. (54% yield) of 3-(3-carbomethoxythioureido)-4-(3-acetylthioureido)benzophenone, m.p. 210° C., dec.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH:12]([CH3:14])[CH3:13].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:16])=[CH:6][C:5]=1[O:11][CH:12]([CH3:13])[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1OC(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC(C)C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
A mixture of 2-isopropoxy-4-methyl-benzoic acid methyl ester (1.00 g, 4.8 mmol), N-bromosuccinimide (0.940 g, 5.28 mmol), 2,2′-azo-bis-isobutyronitrile (50 mg, 0.30 mmol) and carbon tetrachloride (20 mL) is stirred under a bright lamp for 3 h. The mixture is concentrated and the residue is purified via flash chromatography (0 to 50% EtOAc-heptane) to provide the title compound (0.85 g, 62%) as an orange oil. ES/MS m/e 288.7 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([O:16]C)[CH:11]=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[CH:11]=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1cnn(-c2cc(Cl)cc(Cl)c2)c(=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1cc(O)cnn1-c1cc(Cl)cc(Cl)c1

Procedure:
2-(3,5-Dichlorophenyl)-5-methoxypyridazin-3-one (0.25 g, 0.92 mmoles) was suspended in ethanol (40 ml) and potassium hydroxide (0.12 g, 1.8 mmoles) was added in water (5 ml). Refluxed overnight with stirring to give a yellow solution. Evaporated to dryness and added 2M hydrochloric acid. Extracted with ethyl acetate (×2) and washed with water and dried over anhydrous magnesium sulphate. Filtered and evaporated to give a yellow solid. Triturated with dichloromethane to give a pale yellow solid. (0.1 g, 42%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:30].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[Br:30])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)NN=C2COc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 4-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (Example #71, Step B, 0.50 g, 1.249 mmol) in DCM (5 mL) and MeOH (5 mL) was added tetrabutylammonium tribromide (0.662 g, 1.373 mmol) in portions and the mixture was stirred for 30 min at ambient temperature. The reaction was quenched by addition of saturated aqueous Na2S2O3 solution (5 mL) and the pH was adjusted to 7 with saturated aqueous NaHCO3 solution. The mixture was extracted with DCM (3×20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.34 g, 57%). LC/MS (Table 1, Method 2) Rt=1.289 min.; MS m/z: 479/481 [M+H]+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:2][C:3]1[CH:4]=[C:5]([N:10]2[C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[NH:11]2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(NN)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1

Procedure:
A solution of 3,4-dimethylphenylhydrazine hydrochloride (17.7 g; 0.1 mol.), ethyl acetoacetate (13.0 g; 0.1 mol.) and sodium acetate (8.2 g; 0.1 mol.) in glacial acetic acid (250 mL) was stirred and heated under reflux for 24 h.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([Cl:23])=[C:21]([Cl:24])[CH:20]=[CH:19][C:18]=2[N+:25]([O-])=O)[CH:13]([C:28]([OH:30])=O)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]>[Fe]>[C:1]([N:11]1[CH2:16][CH2:15][N:14]2[C:17]3[C:18]([NH:25][C:28](=[O:30])[CH:13]2[CH2:12]1)=[CH:19][CH:20]=[C:21]([Cl:24])[C:22]=3[Cl:23])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [Fe]
Product: O=C1Nc2ccc(Cl)c(Cl)c2N2CCN(C(=O)OCc3ccccc3)CC12
Yield: 50.7 %

Procedure:
By the same procedure described for Example 7 B, from 0.75 g of 4-carbobenzyloxy-1-(5,6-dichloro-2-nitrophenyl)piperazine-2-carboxylic acid and 0.28 g of iron powder, there was obtained 0.34 g (49%) of the desired product as a brown solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([N:20](S(C2C=CC(C(C)(C)C)=CC=2)(=O)=O)[S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[N:10]([CH3:47])[N:9]=1)(=O)C.[OH-].[Na+]>C(O)C>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([S:21]([NH:20][C:11]2[N:10]([CH3:47])[N:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:22])=[O:23])=[CH:29][CH:28]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(=O)OCCOc1nn(C)c(N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 16 h
Yield: 48 %

Procedure:
To 2-{[5-(bis{[4-(tert-butyl)phenyl]sulfonyl}amino)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 4) (80 mg) in ethanol (20 ml) at room temperature was added 2M sodium hydroxide (2 ml) and the mixture was stirred for 16 hrs. The mixture was reduced in volume to 10 ml by rotary evaporation, diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with dichloromethane to yield the title compound as a white solid (25 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11]2.[CH3:20][C:21]1[C:22]([CH:31]2[CH2:33][O:32]2)=[CH:23][C:24]2[CH2:28][O:27][C:26](=[O:29])[C:25]=2[CH:30]=1>CCO>[OH:32][CH:31]([C:22]1[C:21]([CH3:20])=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[CH:23]=1)[CH2:33][N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11]3)[C:2](=[O:1])[CH2:7]1
Reactant: Cc1cc2c(cc1C1CO1)COC2=O
Reactant: N#Cc1ccc2cc(N3CCNCC3=O)ccc2c1
Solvent: CCO
Product: Cc1cc2c(cc1C(O)CN1CCN(c3ccc4cc(C#N)ccc4c3)C(=O)C1)COC2=O
Temperature: 140 °C

Procedure:
A mixture of 6-(2-Oxopiperazin-1-yl)naphthalene-2-carbonitrile [I-5] (40 mg, 0.16 mmol) and 6-methyl-5-(oxiran-2-yl)-2-benzofuran-1(3H)-one [I-16] (30 mg, 0.16 mmol of the fast eluting isomer) in EtOH (1.5 mL) was heated to 140° C. for 1 hour. The reaction mixture was concentrated to dryness, and dissolved in MeOH, filtered and shot into Mass-directed HPLC for purification to give the title product. LC-MS (IE, m/z): 442 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18].S(Cl)(Cl)=O.O1CCOC[CH2:32]1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:32])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)O)cn2c1=O
Reactant: C1COCCO1
Solvent: O=S(Cl)Cl
Product: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)OC)cn2c1=O

Procedure:
2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (1,2 g) was reacted with thionyl chloride (0.6 ml) in dioxane (12) at reflux temperature for 1 hour, then the mixture was evaporated to dryness in vacuo. The residue was reacted with excess methanol at 50° C. for 30 minutes, then the solution was concentrated in vacuo and the residue diluted with ice water. Filtration of the precipitate gave 1.2 g of 2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7 -carboxylic acid, methyl ester, m.p. 190°-193° C.
Reaction SMILES: [C:1]([C:4]([C:19]#[N:20])=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])(=[O:3])[NH2:2].[CH2:21]([NH2:24])[C:22]#[CH:23]>C(#N)C>[C:1]([C:4]([C:19]#[N:20])=[C:5]([NH:24][CH2:21][C:22]#[CH:23])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])(=[O:3])[NH2:2]
Reactant: C#CCN
Reactant: CSC(NCCSCc1[nH]cnc1C)=C(C#N)C(N)=O
Solvent: CC#N
Product: C#CCNC(NCCSCc1[nH]cnc1C)=C(C#N)C(N)=O

Procedure:
A mixture of the product of Step A (4.0 g, 12.8 mmole) and propargylamine (8.0 ml) in acetonitrile (40 ml) was stirred at reflux temperature under a positive pressure of nitrogen for 16 hours. The reaction mixture was cooled and evaporated to dryness under reduced pressure, and the residue was placed on silica gel and chromatographed by gradient elution using methylene chloride-methanol. Recrystallization from acetonitrile gave the title compound; mp 88°-94° (partial melt at 66°-69°).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:5]2=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl.[NH:42]1[CH2:45][CH:44]([OH:46])[CH2:43]1.O.FC(F)(F)C(O)=O>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13]([N:42]4[CH2:45][CH:44]([OH:46])[CH2:43]4)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:5]2=[N:6][CH:7]=1
Reactant: OC1CNC1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc(I)c21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc(N3CC(O)C3)c21
Temperature: 150 °C
Yield: 22.1 %

Procedure:
100 mg (0.18 mmol, approx. 95% purity) of 2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 16A) was dissolved in 1-methyl-2-pyrrolidone (3.1 ml) in a reaction vessel suitable for a microwave, and 0.19 ml (1.07 mmol) of N,N-diisopropyl ethylamine and 97 mg (0.89 mmol) of azetidin-3-ol hydrochloride were added. Then the reaction vessel was sealed with a septum and was heated in the microwave at 150° C. for 3 h. After cooling, water/trifluoroacetic acid was added to the reaction mixture and the resultant solid was filtered off. The filtrate was purified by preparative HPLC (acetonitrile:water (+0.1% trifluoroacetic acid) gradient). 19 mg of the title compound was obtained (21% of theor.; purity 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]([C:34](=[O:43])[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])[C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:21][C:20]=2[C:30]([O:32]C)=[O:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.CO>C1COCC1.CO.O.CC(O)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:21][C:20]=2[C:30]([OH:32])=[O:31])[C:34](=[O:43])[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)c1ccc(Cl)cc1Cl
Agent: [Li]O
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1sc(-c2ccccc2)cc1N(CC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)c1ccc(Cl)cc1Cl
Temperature: 55 °C
Yield: 82.9 %

Procedure:
4-{[(2,4-Dichloro-benzoyl)-(2-methoxycarbonyl-5-phenyl-thiophen-3-yl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester (150 mg, 0.24 mmol) was dissolved in a mixture of THF:MeOH:H2O (3:2:1, 2.4 mL) and treated with LiOH.H2O (29.6 mg, 0.7 mmol). The solution was heated at 55° C. for 2 h. The solvents were removed and the residue was acidified using HCl. The product was extracted with EtOAc and the organic layers were washed with brine and dried. The residue was purified by silica gel column chromatography using EtOAc:MeOH:AcOH as eluent to provide 4-{[(2-Carboxy-5-phenyl-thiophen-3-yl)-(2,4-dichloro-benzoyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester (124 mg, 85% yield).