Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:13]Br>C(O)(=O)C.CO.S([O-])([O-])(=O)=S.[Na+].[Na+]>[NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([C:9]([Br:13])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1C
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1c(Br)ccc(N)c1C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
To a mixed solution of methyl 3-amino-2-methylbenzoate (5.00 mL, 34.7 mmol) in acetic acid (100 mL) and methanol (200 mL) was added bromine (5.55 g, 34.7 mmol) under ice-cooling and the mixture was stirred for 5 min. The reaction solution was diluted with saturated aqueous sodium thiosulfate solution, and the organic solvent was evaporated under reduced pressure. The residual aqueous solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→20/80) to give the title compound (4.66 g, yield 55%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[C:7]1([C:13](=O)[CH2:14][CH2:15][CH2:16]Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(C)C>[CH3:1][N:2]1[C:3](=[S:6])[NH:4][N:5]2[CH2:16][CH2:15][CH2:14][C:13]12[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNC(=S)NN
Reactant: O=C(CCCCl)c1ccccc1
Solvent: CC(C)O
Product: CN1C(=S)NN2CCCC21c1ccccc1

Procedure:
4.2 g of 4-methyl-thiosemicarbazide and 8.0 g of 1-phenyl-4-chlorobutan-1-one in 200 ml of isopropanol is refluxed for 48 hours. The solvent is then evaporated and the residue is dissolved in methylene chloride. The resulting solution is washed with saturated aqueous sodium bicarbonate and with saturated aqueous sodium chloride and then dried over sodium sulfate. Evaporation of the solvent leaves a brownish oil which crystallizes partially. This is treated with ether to give a light yellow powder which is purified by flash chromatography, using 10% ethyl acetate/methylene chloride as the eluent to give 5,6,7,7a-tetrahydro-1-methyl-7a-phenyl-1H-pyrrolo[1,2-b][1,2,4]triazole-2(3H)-thione as colorless crystals melting at about 148°-151° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:30](=[O:31])[CH2:29][C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: O=C(O)Cc1ccncc1
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)Cc3ccncc3)c21
Yield: 27 %

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-(pyridin-4-yl)acetic acid in 27% yield. 1H NMR (DMSO-d6, 400 MHz, 80° C.): 1.21-1.37 (m, 1H), 1.48-1.70 (m, 4H), 1.71-1.82 (m, 1H), 3.01 (m, 1H), 3.78 (br s, 3H), 4.22 (br s, 1H), 4.43 (t, J=8 Hz, 1H), 5.05 (br s, 1H), 6.64 (d, J=8 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 7.21 (d, J=8 Hz, 2H), 7.42 (t, J=8 Hz, 1H), 7.82 (br s, 2H), 8.43 (d, J=8 Hz, 2H), 10.67 (s, 1H). M+H=430.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Na+].[Na+].Cl.CN1C(C)=C(CN2CCN(C3C(C4C=CC(C(OC)C)=CC=4)=NC=CN=3)CC2)C=N1>[Pd](Cl)Cl.C1(P(CNCP(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.C(O)C>[CH3:20][N:18]1[CH:19]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:29]4[CH:30]=[CH:31][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][CH:28]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[C:16]([CH3:21])=[N:17]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1nn(C)cc1CN1CCN(c2nccnc2Cl)CC1
Agent: Cl[Pd]Cl
Agent: COC(C)c1ccc(-c2nccnc2N2CCN(Cc3cnn(C)c3C)CC2)cc1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COC(=O)c1ccc(-c2nccnc2N2CCN(Cc3cn(C)nc3C)CC2)cc1
Temperature: 140 °C
Reaction time: 0.13 h
Yield: 26 %

Procedure:
Charge a microwave tube with 3′-chloro-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.150 g, 0.490 mmoles), bis[(diphenylphosphanyl)methyl]-amine palladium (II) dichloride polymer bound (0.061 g, 0.049 mmoles, 0.1 eq), 4-(methoxycarbonyl)phenylboronic acid (0.176 g, 0.98 mmoles, 2 eq), sodium carbonate (0.192 g, 1.8 mmoles, 3.7 eq) and 3 ml of ethanol. Seal the reaction and heat under microwave conditions at 140° C. for 30 min. Cool down reaction and apply crude material to an SCX column prewashed with 10 ml methanol. Wash material with 10 ml of methanol, and release the product with 20 ml of a 2 N-ammonia/methanol solution. Purify the crude brown oil by reverse phase chromatography (28% isocratic acetonitrile/0.01 M ammonium bicarbonate in water, 80 ml/min., for 8 min., on a 30×75 mm, C18 Xterra column) to provide methyl 4-(3-(4-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)pyrazin-2-yl)benzoate as a white solid (0.051 g, 26% yield, ES+(m/z) 407 [M+H]). Convert the purified material to the hydrochloride salt by stirring a solution of the free base (0.045 g, 0.294 mmoles) in acetonitrile (5 ml) at room temperature and add 1 N HCl in water (0.294 ml, 0.294 mmoles) to give a yellow solution. After 5 min., freeze the solution and lyophilize to give the title compound as a white solid (0.056 g, 100% yield, ES+(m/z) 407 [M+H]).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C)C=O>[CH3:7][O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[C:17]([O:18][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: COC(=O)CCc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ncccc1OCCCC/C=C/c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.8 %

Procedure:
1.02 g of cesium carbonate is added to a solution of 300 mg of 3-(3-hydroxy-2-pyridyl)-propionic acid methyl ester and 450 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene in 6 ml of dimethylformamide, and the suspension is stirred under argon atmosphere for 20 hours at room temperature. The reaction mixture is filtered, the filter residue is washed with dichloromethane and the filtrate is concentrated by evaporation. The residue is added to water, shaken out with ethyl acetate, the organic phase is washed with saturated common salt solution, dried with sodium sulfate and concentrated by evaporation. The crude product is purified by high-pressure liquid chromatography on reversed-phase silica gel (Nova-Pak HR C18) with methanol/water=8/2. 280 mg of 3-{3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1C
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
To a solution of the product of Example 308B (940 mg, 2.33 mmol) in ethyl acetate (50 mL) was added SnCl2.2H2O (1.85 g, 8.18 mmol) and the reaction was heated at reflux for 1 hour. The reaction mixture was cooled and basified to pH8 gradually with solid NaHCO3, stirred overnight, and extracted with ethyl acetate. The ethyl acetate extract was concentrated and the residue was purified by chromatography on silica gel (5% methanol-ethyl acetate) to give the aniline (450 mg, 52%) as an oil.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH3:34])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH3:34])=[CH:30][CH:31]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC[C@H](NC(=O)OC(C)(C)C)c1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 69.7 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (640 mg, 2.1 mmol) was reacted with (S)-tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (1.13 g, 3.12 mmol) to afford the desired product (680 mg, 71%) as a light brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[CH:21]=1.O.O.O.[O-]C1C=CC=CC=1.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[O:13])=[CH:3][C:2]=1[NH:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[CH:21]=1)#[N:9]
Reactant: CC(C)C[C@@H](Nc1ccc(C#N)c(Br)c1)C(N)=O
Reactant: Cc1cc(N)on1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)ccc2C#N)on1
Yield: 15.8 %

Procedure:
A mixture of (R)-2-(3-bromo-4-cyanophenylamino)-4-methylpentanamide (120 mg, 0.387 mmol), 5-amino-3-methylisoxazole (60 mg, 0.612 mmol), sodium phenoxide trihydrate (100 mg, 0.588 mmol), xantphos (25 mg, 0.043 mmol) and Pd2(dba)3 (20 mg, 0.021 mmol) in dioxane (3 mL) was degassed with Ar, then was heated at 170 C for 15 min by microwave. It was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(4-cyano-3-(3-methylisoxazol-5-ylamino)phenylamino)-4-methylpentanamide (20 mg).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@H:4]1[NH:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:18]([N:6]1[CH2:7][CH2:8][C@@H:3]([O:2][CH3:1])[C@H:4]([NH:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH2:5]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(N[C@@H]1CNCC[C@H]1OC)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOP(=O)(N[C@@H]1CN(Cc2ccccc2)CC[C@H]1OC)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
A mixture of diethyl trans-4-methoxypiperidin-3-ylphosphoramidate (1.30 g, 4.88 mmol), benzaldehyde (0.74 mL, 7.32 mmol) and acetic acid (0.56 mL, 9.76 mmol) in methanol (20 mL) was stirred at 0° C. for 30 minutes. NaCNBH3 (0.46 g, 7.32 mmol) was added at 0° C. The resulting solution was warmed to room temperature and stirred at room temperature for 1 hour. The solvent was removed in vacuo and saturated sodium bicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo to give diethyl trans-1-benzyl-4-methoxypiperidin-3-ylphosphoramidate (1.70 g, 98%), which was used directly in the next step without purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:3]=1[CH3:21].[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[NH:25][CH2:24]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[N:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=3)[C:3]=2[CH3:21])[CH2:24]1
Reactant: Cc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1cncc(-c2nc3cc(F)cc(F)c3c(N3CC(C)(C)c4ncc(N5CCOCC5)cc43)c2C)c1

Procedure:
Prepared according to procedure Y by stirring 4-chloro-5,7-difluoro-3-methyl-2-(5-methylpyridin-3-yl)quinoline (40 mg, 0.131 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (30.6 mg, 0.131 mmol), Pd2dba3 (12.0 mg, 0.013 mmol), XPhos (12.5 mg, 0.026 mmol), sodium tert-butoxide (38 mg, 0.394 mmol), and toluene (1.3 mL) at 105° C. for 2 h. Purification by reverse-phase HPLC (0-60% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-(5-methyl-3-pyridinyl)quinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 8.65-8.72 (1H, m), 8.58-8.61 (1H, m), 7.81-7.84 (1H, m), 7.67-7.72 (1H, m), 7.54-7.57 (1H, m), 7.01-7.08 (1H, m), 5.79-5.82 (1H, m), 3.85-3.92 (1H, m), 3.69-3.82 (5H, m), 3.01-3.08 (4H, m), 2.48 (3H, s), 2.32-2.38 (3H, m), 1.67 (3H, br. s.), 1.60 (3H, br. s.). Mass Spectrum (ESI) m/e=502.2 (M+1).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)[N:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=[O:38])=CC=1.CO.CC(C)=O>C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=4)[N:16]=3)[NH:11][CH:10]=2)=[O:38])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(-c2cnc3[nH]cc(C#Cc4ccccc4)c3n2)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc(-c2cnc3[nH]cc(C(=O)Cc4ccccc4)c3n2)cc(OC)c1OC
Temperature: 100 °C
Yield: 206.6 %

Procedure:
7-Phenylethynyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (405 mg, 1.05 mmol) and p-toluenesulfonic acid monohydrate (40 mg, 0.21 mmol) were placed in a 20 ml microwave vial with 14 ml of a 2:1 mixture of methanol and acetone. The reaction was heated in a microwave reactor at 100° C. for 1.5 hours. The reaction was diluted with ethyl acetate, washed two times with saturated sodium bicarbonate and water, dried and concentrated. The residue was triturated with ethyl acetate and hexanes, filtered, and dried to yield 175 mg of 2-phenyl-1-[2-(3,4,5-trimethoxy-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl]-ethanone. MS: (M+H)+=404. MP=226.0-227.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:15]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.ClC1C=C2C(C(CC(O)=O)=[C:31]([C:35]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][N:38]=3)=[O:36])N2)=CC=1>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[C:13]([Cl:14])[CH:12]=2)[NH:15][C:31]=1[C:35]([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][N:38]=1)=[O:36]
Reactant: COC(=O)/C=C/c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Product: COC(=O)Cc1c(C(=O)c2cc(C)ccn2)[nH]c2cc(Cl)c(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4,5-dichloro-2-(phenylsulfonylamino)cinnamate (step 3) and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described in step 2 of Example 31).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[CH:9]3[O:11][CH:10]3[C:5]=2[CH:4]=1)#[N:2].Cl.[CH2:17]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[CH3:18].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[C@@H:9]([OH:11])[C@H:10]([N:22]=[CH:21][C:20]([O:19][CH2:17][CH3:18])=[O:23])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C=N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
A mixture of 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran (5.0 g, the preparation of which was described in U.K. patent No. 1,511,187), glycine ethyl ester hydrochloride (2.59 g) and sodium hydroxide (0.75 g) in ethanol (100 mls) was refluxed for 7h. Filtration, evaporation, and chromatography gave the title compound (1.5 g). Recrystaisation of a small portion from ethyl acetate-pentane gave crystals of m.p. 98°-100° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][O:22][C:23]([C@@H:25]1[CH2:29][C@@H:28]([OH:30])[CH2:27][NH:26]1)=[O:24].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[CH3:21][O:22][C:23]([C@@H:25]1[CH2:29][C@@H:28]([OH:30])[CH2:27][N:26]1[C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[O:24]
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCCCCC
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
A solution of 2(S)-tert-butoxycarbonylamino-8-nonenoic acid (purchased from RSP Amino Acids)(3.5 g, 12.9 mmol) in 200 mL of DCM was treated sequentially with 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester hydrochloride (2.15 g, 11.8 mmol), N-methyl morpholine (4.25 mL, 38.6 mmol), and HATU (5.37 g, 14.1 mmol). The reaction mixture was stirred at rt under N2 for 3 days, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 4.7 g (˜100%) of 1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester as a colorless oil: 1H NMR (500 MHz, CD3OD) δ 1.33-1.50 (m, 8H), 1.46 (s, 9H), 1.57 (m, 1H), 1.72 (m, 1H) 2.08 (m, 2 H), 2.28 (m, 1H), 3.72 (s, 3H,) 3.75-3.87 (m, 2H), 4.36 (m, 1H), 4.51 (bs, 1 H), 4.57 (t, J=8.2 Hz, 1H), 4.95 (d, J=10.4 Hz, 1H), 5.01 (m, 1H), 5.83 (m, 1 H); MS m/z 399 (M++1).
Reaction SMILES: [O:1]([C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[N:9]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([NH:27][C:28]2[CH:29]=[C:30]([CH:34]3[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]3)[CH:31]=[CH:32][CH:33]=2)=[O:26])=[O:20])[C:8](=[O:47])[NH:7][C:6]=1[CH3:48])=[O:4])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[O:1]([C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[N:9]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25](=[O:26])[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH:29]=2)=[O:20])[C:8](=[O:47])[NH:7][C:6]=1[CH3:48])=[O:4])[CH3:2]
Reactant: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)Nc2cccc(C3CCN(C(=O)OC(C)(C)C)CC3)c2)C1c1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)Nc2cccc(C3CCNCC3)c2)C1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.4 %

Procedure:
Into a solution of tert-butyl 4-{3-[(4-{[(5-Methoxylcarbonyl-6-(3,4-difluorophenyl)-4-methyl-2-oxo-3,6-dihydro-1(2H)-pyrimidinyl)carbonyl]amino}butanoyl)amino]phenyl}-1-piperidinecarboxylate (378 mg, 0.579 mmol) in dichloromethane (5.00 mL) at 0° C. was slowly added trifluoroacetic acid (659 mg, 5.79 mmol). The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in iso-PrOH/CHCl3 (1:3, 10 mL) and basified to pH 11 with 10% KOH solution, washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (dichloromethane:methanol 5:1) to afford the desired product (93.8 mg, 29.3%): 1H NMR (400 MHz, CDCl3) δ 7.46-7.43 (m, 3H), 7.35-7.29 (m, 2H), 7.12-7.06 (m, 3H), 6.63-6.60 (m, 1H), 6.56-6.52 (m, 2H), 3.26 (s, 3H), 3.22 (s, 3H), 2.72 (dt, 6H, J=2.3, 12.3 Hz), 2.66 (tt, 2H, J=3.6, 11.9 Hz), 2.55 (tt, 1H, J=3.8, 11.9 Hz), 1.88-1.82 (m, 1H), 1.75-1.63 (m, 6H); ESMS m/e: 554.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:32][C:29]4[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 160 °C
Yield: 29.8 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 4-methoxy-phenol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 24 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.2 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Dichloromethane and water were added, and the dichloromethane layer was washed twice with water. The dichloromethane layer was evaporated, and purified by preparative C18 HPLC, eluting with 25-100% acetonitrile/water to give 4-[4-(4-methoxy-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (19 mg, 28%) as an off-white powder. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.95-2.02 (m, 2H), 2.16-2.30 (m, 2H), 2.90-3.04 (m, 2H), 3.85 (s, 3H), 4.22-4.37 (m, 2H), 4.88-4.99 (m, 1H), 6.98 (d, 1H, J=8.7 Hz), 7.16 (d, 1H, J=8.9 Hz), 7.77 (s, 1H), 8.54 (s, 1H). Mass spectrum MH+=426. HRMS Calcd. For C22H28N5O4 (MH+): 426.2136. Found: 426.2134.