Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH:36]([CH3:38])[CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH:36]([CH3:38])[CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)Oc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)Oc1ccc2c(c1CN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-isopropoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0740 g, 0.143 mmol) in methylene chloride (2 mL) was added with trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was added with water (6 mL) and saturated aqueous sodium hydrogencarbonate (6 mL), and thereby made basic, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was subjected to suction filtration, and the resulting solid was washed with water to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-isopropoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0301 g, 50%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].[C:12]([NH:15][CH:16]([C:18](O)=[O:19])[CH3:17])(=[O:14])[CH3:13].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[C:12]([NH:15][C@H:16]([C:18]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11])=[O:19])[CH3:17])(=[O:14])[CH3:13]
Reactant: COc1ccc(N)c(O)c1
Reactant: CC(=O)NC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)[C@H](C)NC(C)=O)c(O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.8 %

Procedure:
To a solution of 2-amino-5-methoxyphenol hydrochloride (5.24 g, 29.8 mmol), N-acetyl-D,L-alanine (3.91 g, 29.8 mmol) and 1-hydroxybenzotriazole (4.03 g, 29.8 mmol) in DMF (5 mL) were added triethylamine (4.15 mL, 29.8 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.72 g, 29.8 mmol), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 1N hydrochloric acid, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate to methanol:ethyl acetate=1:4), and triturated with ethyl acetate to give the title compound (740 mg, yield 9.8%).
Reaction SMILES: IC.[C:3]([O:7][C:8]([N:10]1[CH2:17][C:16]2[O:15][C:14]([C:18]([OH:20])=[O:19])=[N:13][C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:21][O:19][C:18]([C:14]1[O:15][C:16]2[CH2:17][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][C:12]=2[N:13]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1Cc2nc(C(=O)O)oc2C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1nc2c(o1)CN(C(=O)OC(C)(C)C)C2
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 52.6 %

Procedure:
Iodomethane (0.098 mL, 1.58 mmol) was added to a stirred solution of 4,6-dihydro-pyrrolo[3,4-d]oxazole-2,5-dicarboxylic acid 5-tert-butyl ester (0.10 g, 0.39 mmol) and K2CO3 (0.10 g, 0.78 mmol) in DMF (2 mL). The mixture was stirred at 100° C. for 5 minutes under microwave irradiation, diluted with H2O and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 4,6-dihydro-5H-pyrrolo[3,4-d]oxazole-2,5-dicarboxylic acid 5-(1,1-dimethylethyl) 2-methyl ester (0.055 g, 96% yield) as a pale yellow solid that was used in the next step without further purification. C12H16N2O5 LCMS: Rt 2.31, m/z 269 [M+H]+ (using method, LC-MS Method 4).
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[N:21]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][N:32](C(OCC5C=CC=CC=5)=O)[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[C:19]([C:45](=[O:47])[NH2:46])=[CH:18][CH:17]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CCO.[Pd]>[C:1]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]([C:45]([NH2:46])=[O:47])=[C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]4)=[CH:27][CH:28]=3)[N:21]=2)[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)nc1Nc1ccc(N2CCNCC2)cc1
Yield: 98.5 %

Procedure:
To a suspension of (R)-benzyl 4-(4-(6-(3-benzamidopiperidin-1-yl)-3-carbamoylpyridin-2-ylamino)phenyl)piperazine-1-carboxylate (1.12 g, 1.767 mmol) in EtOAc (10 mL) and EtOH (10.00 mL) was added Pd/C (0.188 g, 0.177 mmol) under nitrogen. The resulting mixture was hydrogenated at 50 psi in a parr shaker overnight. The reaction mixture was filtered and the filtrate was concentrated to give 870 mg of (R)-6-(3-benzamidopiperidin-1-yl)-2-(4-(piperazin-1-yl)phenylamino)nicotinamide. LCMS: (M+H)+=500.14. 1H NMR (400 MHz, CDCl3-MIX) δ ppm 10.64 (1H, s), 7.51-7.59 (3H, m), 7.35-7.44 (3H, m), 7.28-7.34 (2H, m), 6.96 (1H, d, J=7.03 Hz), 6.75 (2H, d, J=9.23 Hz), 6.01 (1H, d, J=8.79 Hz), 4.10 (1H, br. s.), 3.75-3.83 (1H, m), 3.66-3.73 (1H, m), 3.58-3.66 (1H, m), 3.47-3.57 (1H, m), 3.15-3.20 (4H, m), 2.88-2.95 (4H, m), 1.82-1.96 (2H, m), 1.65-1.76 (1H, m), 1.54-1.65 (1H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[CH2:20]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][CH2:7][C:6]2[CH:9]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])[CH2:15][CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(O)cc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
5-Hydroxy-2-nitro-benzaldehyde (5 g, 29.9 mmol) and 4-amino-1-benzylpiperidine (5.6 mL, 29.9 mmol) were combined in ethanol (30 mL). The resulting suspension was stirred at room temperature for 20 min before a solution of sodium borohydride (1.13 g, 29.9 mmol) in ethanol (10 mL) was added dropwise over 10 min. After the addition was complete, the reaction was stirred at room temperature for 1 h, cooled to 0° C. and concentrated ammonium chloride added to the reaction mixture until no bubbling was observed. The solvents were evaporated in vacuo and the resultant crude mixture was dissolved in water (30 mL) and methylene chloride (40 mL). The layers were separated and the organic layer washed with water (2×), brine (2×), dried over sodium sulfate, filtered, and concentrated to afford 5.8 g (57%) of the desired product. LC/MS: tR=0.95 min, 342.27 (MH)+.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[CH2:7][N:8]([CH2:17][CH:18]1[CH:23]2[CH:19]1[CH2:20][N:21]([CH2:24][C:25]([O:27]CC1C=CC=CC=1)=[O:26])[CH2:22]2)[C:9]([C:11]1[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=1)=[O:10]>CO.[OH-].[OH-].[Pd+2]>[F:39][C:2]([F:1])([F:38])[O:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[CH2:7][N:8]([CH2:17][CH:18]1[CH:19]2[CH:23]1[CH2:22][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20]2)[C:9]([C:11]1[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=1)=[O:10]
Reactant: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)CC2C3CN(CC(=O)OCc4ccccc4)CC32)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)CC2C3CN(CC(=O)O)CC32)c1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a par bottle charged with benzyl 2-(6-((N-(3-(trifluoromethoxy)benzyl)-1-methyl-1H-imidazole-4-carboxamido)methyl)-3-aza-bicyclo[3.1.0]hexan-3-yl)acetate (2.7 gm, 5.07 mmol) in 80 mL CH3OH, was added 300 mg palladium hydroxide on carbon (20%). The mixture was hydrogenated under 40 psi H2 at room temperature for 1 hour. The mixture was filtered over a celite, the celite pad was washed with CH3OH and the resulting solution was concentrated to yield 2.3 gm of 2-(6-((N-(3-(trifluoromethoxy)benzyl)-1-methyl-1H-imidazole-4-carboxamido)methyl)-3-aza-bicyclo[3.1.0]hexan-3-yl)acetic acid as a yellow solid; 400 MHz 1H NMR (CDCl3) δ 7.54 (s, 1H), 7.23-7.33 (m, 3H), 7.15 (s, 1H), 7.05 (d, J=7.9 Hz, 1H), 5.4 (brs, 2H), 4.81 (brs, 1H), 3.96 (brs, 1H), 3.68 (s, 3H), 3.49 (s, 2H), 3.28 (brs, 1H), 3.12 (brs, 2H), 1.76 (brs, 1H), 1.66 (brs, 2H); MS (M+1) 452.1.
Reaction SMILES: Br[C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([Cl:10])[C:4]=2[CH:3]=1.[O:12]1C[CH2:15][CH2:14][CH2:13]1.C(O)C#C.C(N(CC)C(C)C)(C)C>[Cu]I.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.O>[Cl:10][C:9]1[C:4]2[CH:3]=[C:2]([C:15]#[C:14][CH2:13][OH:12])[NH:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C1CCOC1
Reactant: Clc1ncnc2[nH]c(Br)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#CCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: OCC#Cc1cc2c(Cl)ncnc2[nH]1
Yield: 31 %

Procedure:
A mixture comprising 3.00 g (12.9 mmol) 6-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS-No: 784150-41-0), 90 mL tetrahydrofuran, 3.0 mL prop-2-yn-1-ol, 246 mg copper(I) iodide, 746 mg tetrakis(triphenylphosphine)palladium(0) and 3.93 mL N,N-diisopropylethylamine was heated at 80° C. for 4 hours. Water was added and the mixture extracted with ethylacetate/methanol (8:2). The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvents the residue was purified by chromatography to give 833 mg (31%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11]CC.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]([CH2:7][CH:8]=[CH:9][CH2:10][CH3:11])[C:19](=[O:20])[CH:18]([Cl:22])[Cl:17]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCCCC=CCNCc1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: CCC=CCN(Cc1cccc(Cl)c1)C(=O)C(Cl)Cl
Temperature: 25 °C

Procedure:
2 g of N-(3-chlorobenzyl)-N-(2-heptenyl)amine was dissolved in 40 ml of toluene, to which 1.7 g of 2,2-dichloroacetyl chloride was dropped under stirring gradually at a room temperature. After stirring for 20 min, deposited insoluble matters were filtered and then 50 ml of toluene was added. The toluene solution was washed with an aqueous saturated solution of sodium hydrogen carbonate and with a saturated solution of sodium chloride respectively each by twice. After dying with anhydrous sodium sulfate, it was concentrated in an evaporated to obtain an aimed oily product quantitatively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:22])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[H-].[Na+].I[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:22])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)([O:15][CH3:26])[C:11]([F:12])([F:13])[F:14]
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccncc1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccncc1)(C(C)c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared from 3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-2-pyridin-4-yl-butan-2-ol (Example 11) by O-methylation: 3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-2-pyridin-4-yl-butan-2-ol (45 mg) was dissolved in dry DMF (4 mL) under argon at room temperature. To the mixture was added sodium hydride (8.4 mg, 50% in mineral oil) and the mixture was allowed to stir for 30 minutes. Iodomethane (22 mg, 0.01 mL) was added and stirring was continued for 1 hour at room temperature. The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (20 g silica gel, gradient of ethyl acetate in heptane (10 to 40%) to give the desired material as light yellow oil (28 mg). MS (m/e)=364.1 [MH+].
Reaction SMILES: [CH:1]1([C:17]([O:19]C)=[O:18])[CH:4]([C:5]([O:7]C)=[O:6])[CH:3]([C:9]([O:11]C)=[O:10])[CH:2]1[C:13]([O:15]C)=[O:14]>Cl>[CH:2]1([C:13]([OH:15])=[O:14])[CH:1]([C:17]([OH:19])=[O:18])[CH:4]([C:5]([OH:7])=[O:6])[CH:3]1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C1C(C(=O)OC)C(C(=O)OC)C1C(=O)OC
Agent: Cl
Product: O=C(O)C1C(C(=O)O)C(C(=O)O)C1C(=O)O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
The resultant tetramethyl cyclobutane-1,2,3,4-tetracarboxylate (1224 g, 4.25 mol) and aqueous hydrochloric acid (3000 ml) were added to a 5-liter flask; reacted at a controlled temperature of 85° C. for 24 hours; cooled to room temperature; concentrated; and dried to obtain cyclobutane-1,2,3,4-tetracarboxylic acid (870 g, 3.75 mol).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>CCCCCC.C(OCC)(=O)C>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[C:3]([CH3:29])=[C:2]([C:35]4[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:19])[CH3:18]
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)cc1
Yield: 40 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (4-methoxyphenyl)boronic acid, the title compound was synthesized in the same manner as in Example 101. Yield: 40%. Melting point: 129-131° C. (hexane-ethyl acetate).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[I:25]CCI.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[I:25][C:10]1[N:5]2[N:4]=[C:3]([S:2][CH3:1])[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: ICCI
Reactant: CSc1nn2ccccc2c1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving tert-butyl N-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (21.6 g) in tetrahydrofuran (1 L), a solution of n-butyllithium in hexane (1.6 M; 130 mL) was added dropwise at −78° C. under a nitrogen stream, and the mixture was stirred for 30 minutes. A solution of 1,2-diiodoethane (24 g) in tetrahydrofuran (50 mL) was added to the reaction mixture, and stirring was continued for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, the temperature was raised to room temperature, extraction was performed with ethyl acetate and the extract was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound was obtained from the n-hexane:ethyl acetate (5:1) fraction as yellow crystals.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]=1[CH3:14])=[O:4].[CH3:15][C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([CH3:22])[NH:17]1>>[CH3:15][C@H:16]1[NH:17][C@@H:18]([CH3:22])[CH2:19][N:20]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]=2[CH3:14])=[O:4])[CH2:21]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: COc1cccc(NC(=O)CCl)c1C
Product: COc1cccc(NC(=O)CN2C[C@@H](C)N[C@@H](C)C2)c1C

Procedure:
The subtitle compound was prepared from 2-chloro-N-(3-methoxy-2-methylphenyl)acetamide (10.72 g) and cis-2,6-dimethylpiperazine (6.29 g) by the method of Example 58 step (i) as a tan solid. Yield: 13.13 g
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[Cs+].[Cs+].O>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(S([O-])(=O)=O)=CC=2C(C)C)CCCCC1.[Na+].C(#N)C>[C:11]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCC
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CC(C)c1cc(S(=O)(=O)[O-])cc(C(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCCCCCCCC#Cc1ccc(C(=O)O)cc1
Yield: 85.9 %

Procedure:
The general procedure described in Example 27 was used with 4-chlorobenzoic acid (79 mg, 0.50 mmol), 1-decyne (0.136 mL, 0.75 mmol), PdCl2(CH3CN)2 (3.2 mg, 0.0125 mmol, 1.25 mol %), sodium 2′-(dicyclohexyl-phosphanyl)-2,6-diisopropyl-biphenyl-4-sulfonate (20.0 mg, 0.0375 mmol, 3.75 mol %), Cs2CO3 (650 mg, 2.00 mmol), water (1.0 mL), acetonitrile (1.0 mL), 12 h, 100° C. The product was isolated as a white solid (111 mg, 86%). Mp=103° C. 1H NMR (400 MHz, CDCl3) δ: 11.0 (br-s, 1H), 8.04 (d, 2H, J=8.4 Hz), 7.49 (d, 2H, J=8.4 Hz), 2.46 (t, 2H, J=6.8 Hz), 1.64 (p, 2H, J=6.8 Hz), 0.89-1.49 (m, 13H). 13C NMR (125 MHz, CDCl3) δ: 169.3, 132.6, 130.9, 130.8, 130.4, 94.6, 81.2, 33.2, 30.5, 30.4, 30.2, 29.9, 23.9, 20.2, 14.6 IR (neat, cm−1): 3402 (br), 2920, 2849, 2214, 1686, 1607, 1428, 1319, 1283, 1178, 1112, 929, 862, 769. Anal. Calcd for C17H22O2: C, 79.03; H, 8.58. Found: C, 78.84; H, 8.48.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:12](=O)[CH2:13][CH3:14].CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:12][CH2:13][CH3:14]
Reactant: CCC=O
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCNc1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.2 %

Procedure:
To a solution of 2-methyl-3-nitroaniline (0.5 g, 3.3 mmol) and MeOH (20 mL) was added propionaldehyde (2.3 mL, 33 mmol), AcOH (1.9 mL, 33 mmol), and NaBH3CN (2 g, 33 mmol). Reaction was stirred at rt for 2 hours then quenched with H2O and concentrated in vacuo. Diluted with EtOAc (20 mL) and adjusted to pH=7 with saturated NaHCO3. Washed organic layer with H2O (3×10 mL) and brine (3×10 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (5% EtOAc/hex) to afford 0.7 g of the 2-methyl-3-nitro-N-propylaminobenzene. A solution of the product and EtOAc (25 mL) was hydrogenated over 10% Pd/C (70 mg) at rt and 1 atm. After 15 hours filtered reaction mixture through a pad of Celite and concentrated the filtrate to afford the desired Compound 568 (0.10 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[NH:46][C:47](=[NH:52])[C:48]([CH3:51])([CH3:50])[CH3:49]>CN(C=O)C>[C:48]([C:47]1[N:52]=[C:4]([C:3]2[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=2[Cl:1])[O:6][N:46]=1)([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)C(=N)NO
Reactant: O=C(O)c1cc(I)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1noc(-c2cc(I)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.4 %

Procedure:
To a solution of 2-chloro-5-iodobenzoic acid (1.0 g, 3.54 mmol) in 40 mL DMF was added diisopropylethyl amine (1.23 mL, 7.08 mmol) followed by HATU (2.02 g, 5.31 mmol). After stirring the reaction at room temperature for 10 min, N-hydroxy-2,2-dimethylpropanimidamide (0.82 g, 7.08 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1 h and then at 110° C. for 16 h. After cooling to room temperature the reaction was quenched with water and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography (2-5% EtOAc in hexanes) to yield 660 mg of intermediate US1-2.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C:31](Cl)=[O:32]>>[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C:31]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:32]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: CCOC(=NC(=O)c1ccc2ccccc2c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2-naphthoyl chloride, there is obtained ethyl N-(2-naphthylcarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a foam, mass spectrum m/e: M+ 420 (7), 391 (8), 194 (100), 155 (28), 127 (28);
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][NH:11]3)[CH2:3][CH2:2]1.[F:16][C@@H:17]1[C@@H:21]([CH2:22][OH:23])[O:20][C@@H:19](N2C=CC(=O)NC2=O)[CH2:18]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[F:16][C@@H:17]1[C@@H:21]([CH2:22][OH:23])[O:20][C@@H:19]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][CH:14]=[N:15][C:7]=3[N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:18]1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: c1nc(N2CCOCC2)c2nc[nH]c2n1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(N4CCOCC4)ncnc32)C[C@@H]1F
Temperature: 45 °C
Reaction time: 216 h
Yield: 51 %

Procedure:
6-Morpholino-9H-purine (0.50 g, 2.4 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.67 g, 2.9 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 9 days, 140 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (9:1). Solvent was removed and lyophilization yielded 0.396 g of 9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-morpholino-9H-purine (50%): mp 175°-178° C.; [α]D20 -20.2 (c=0.51, DMF); UV λmax (ε×10-3) at pH 7, 278 (21.4); at pH 13, 278 (21.1); 1H NMR (400 MHz, DMSO-d6) δ8.40 and 8.25 (2s, 2H, H2 and H8) 6.41 (dd, 1H, H1', H=9.3 Hz, J=5.7 Hz), 5.43 (dd, 1H, H3', J=53.6 Hz, J=4.4 Hz), 5.40 (m, 1H, OH5'), 4.10-4.30 (b, 5H, H4' and morpholino group), 3.60 (m, 2H, H5' and H5"), and 2.88-3.04 and 2.59-2.69 (m, 2H, H2' and H2" ; MS (ci) 324 (M+1), 304 (M-F), 206 (MH2 --C5H8FO2).