Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[C:4]([NH:6][C:7](=[NH:20])[CH2:8][O:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1)=[O:5].CC([O-])(C)C.[K+]>>[Cl:25][C:22]1[CH:23]=[N:24][C:2]2[N:20]=[C:7]([CH2:8][O:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=3)[NH:6][C:4](=[O:5])[C:3]=2[CH:21]=1
Reactant: N=C(COCCc1ccc(F)c(Cl)c1)NC(=O)c1cc(Cl)cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=c1[nH]c(COCCc2ccc(F)c(Cl)c2)nc2ncc(Cl)cc12

Procedure:
In analogy to the procedure described in example 78.4, 2,5-dichloro-N-{2-[2-(3-chloro-4-fluoro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide was treated with KOtBu to obtain 6-chloro-2-[2-(3-chloro-4-fluoro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one as orange crystals. MS: m/e=368.0 [M+H+].
Reaction SMILES: C(OC([NH:8][N:9]=[CH:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C:20](=[O:31])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:9](=[CH:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C:20](=[O:31])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])[NH2:8]
Reactant: CC(C)(C)OC(=O)NN=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: NN=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 1 h

Procedure:
To a solution of 3-(2-tertiary butoxycarbonylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (247 mg) in methylene chloride (1 ml) are added anisole (0.6 ml) and trifluoroacetic acid (0.6 ml), and the mixture is kept at room temperature for 1 hour. After removing trifluoroacetic acid and methylene chloride, the reaction mixture is diluted with ether. The separated cyrstals are collected by filtration and dried to give 3-hydrazonomethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid in nearly quantitative yield. m.p. 164°-169° C (decomposition). IR: νmaxNujol 3260, 1787, 1657, 1542cm-1. UV: λmaxCH3OH 230.5nm(ε=12900); 304nm(ε=6900); 402nm(ε=12400). NMR: δd 6-DMSO (60MHz) 3.79s2H, 3,84d(12Hz)2H, 5.20d(5Hz)1H, 5.84dd(8;5Hz)1H, 6.8-7.5m3H, 7.55s+7.78s1H, 9.12d(8Hz)1H. [α]D23.5 +66.2°(c=0.5022, DMSO).
Reaction SMILES: [CH3:1][CH:2]([CH3:45])[C@@H:3]([NH:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([CH2:28][O:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:26]=3)[N:21](COCC[Si](C)(C)C)[CH:20]=2)[CH:18]=1)[C:4]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].[F-].[Cs+]>CS(C)=O>[CH3:1][CH:2]([CH3:45])[C@@H:3]([NH:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([CH2:28][O:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:26]=3)[NH:21][CH:20]=2)[CH:18]=1)[C:4]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5]
Reactant: CC(C)[C@@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(COCCN4CCCC4)cc23)c1)C(=O)NCC(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)[C@@H](Nc1cncc(-c2c[nH]c3ncc(COCCN4CCCC4)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 140 °C
Yield: 6.8 %

Procedure:
In a microwave vial containing (R)-3-methyl-2-(5-(5-((2-(pyrrolidin-1-yl)ethoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-N-(2,2,2-trifluoroethyl)butanamide 9-1a (60.7 mg, 0.094 mmol), added DMSO (1 ml, 0.094M) followed by Cesium Fluoride (284 mg, 1.871 mmol). The reaction mixture was heated at 140° C. for one hour on an oil bath open to air. LC/MS indicated conversion to product, the reaction mixture was filtered through a fine filter funnel and purified on the Gilson HPLC instrument using acetonitrile: water with 0.1% TFA buffer system using 10-60% gradient to give the title compound 9-1 (3.32 mg, 5.61%). LRMS (ESI) m/z 519.3 [(M+H)+; calcd for C26H33F3N6O2: 519.3]
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH:27]3[CH2:29][CH2:28]3)([CH3:26])[CH3:25])[NH:10][CH:9]2[C:30](O)=[O:31])[CH:5]=[CH:6][CH:7]=1.CC1(C)[O:39][C@@H:38]([CH2:40][CH2:41][NH2:42])[CH2:37][O:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:39][C@H:38]([CH2:37][OH:36])[CH2:40][CH2:41][NH:42][C:30]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:33])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH:27]2[CH2:28][CH2:29]2)([CH3:25])[CH3:26])[NH:10]1)=[O:31]
Reactant: CC(C)(CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1CC1
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1CC1
Yield: 68.5 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid prepared in Example 99c (0.41 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.43 mL, 2.5 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.33 g, 70%).
Reaction SMILES: C(O)(=O)C.C([O:7][C:8](=[O:39])[CH:9]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[NH:38])[NH2:37])=[CH:32][CH:31]=1)[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[C:12]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[C:11]=1[F:28])C.[Li+].[OH-].C(O)(=O)C>C1COCC1>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([NH:29][CH:9]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[C:12]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:11]=2[F:28])[C:8]([OH:39])=[O:7])=[CH:31][CH:32]=1)(=[NH:37])[NH2:38]
Reactant: CCOC(=O)C(Nc1ccc(C(=N)N)cc1)c1cc(OCC)cc(OCC2CCN(C)CC2)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOc1cc(OCC2CCN(C)CC2)c(F)c(C(Nc2ccc(C(=N)N)cc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
A solution of 340 mg (RS)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-acetic acid ethyl ester acetate in 5 ml THF was treated with 2.8 ml 1N LiOH and stirred at room temperature for 2 hours. The reaction mixture was neutralized with acetic acid and evaporated in vacuo. The residue was stirred in 1.5 ml of water. Suction filtration and drying gave 173 mg (RS)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-acetic acid. Mp.: 232° C. Light brown solid. MS: 459 ([M+H]+).
Reaction SMILES: CO.[CH3:3][C:4]1[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[C:11]([CH3:18])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[OH-].[Li+]>O1CCCC1>[CH3:9][O:8][C:6]([C:5]1[C:4]([CH3:3])=[CH:13][C:12]([C:14]([OH:16])=[O:15])=[C:11]([CH3:18])[CH:10]=1)=[O:7]
Reactant: COC(=O)c1cc(C)c(C(=O)OC)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(C(=O)O)cc1C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
Methanol (20 ml) was added to a solution of dimethyl 2,5-dimethylterephthalate (3.95 g, 17.8 mmol) in tetrahydrofuran (40 ml) and the resulting mixture was cooled on a water bath. A 2N-aqueous lithium hydroxide solution (9.8 ml, 19.6 mmol) was slowly added thereto and stirred for 3 hours. The solvent was distilled off under reduced pressure and the residue was adjusted to pH 1 to 2 with a 1N-hydrochloric acid and extracted with ethyl acetate (×3). The extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel chromatography (eluent: chloroform/methanol=30/1) to obtain 4-(methoxycarbonyl)-2,5-dimethylbenzoic acid (2.77 g, 75%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[C:3]=1[F:11].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:10][C:4]1[C:3]([F:11])=[C:2]([C:22]2[N:18]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[N:19]=[CH:20][CH:21]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)c(F)c1Cl
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1c(F)cc(-c2ccnn2C2CCCCO2)c(F)c1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
4-Bromo-2-chloro-3,6-difluoroaniline (12.37 mmol, 3 g) and 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (12.37 mmol, 3.44 g) were dissolved in DME. Bis(triphenylphosphine)palladium(II) chloride (0.619 mmol, 0.434 g) and sodium carbonate, 2 M solution (12.37 mmol, 1.311 g) were added. The reaction mixture was refluxed at 80° C. for 4 h and the stirring was continued at 50° C. overnight. The solvent was evaporated and the residue was extracted three times with EtOAc. The combined organics were washed with water and brine. The organics were dried, filtered and evaporated. The crude product was purified by flash chromatography. 1.935 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 1.49-1.79 (m, 2H), 1.80-1.88 (m, 1H), 1.93-2.19 (m, 2H), 2.33-2.47 (m, 1H), 3.47-3.77 (m, 1H), 3.96-4.07 (m, 1H), 5.09-5.43 (m, 1H), 6.30-6.39 (m, 1H), 7.04-7.13 (m, 1H), 7.50-7.63 (m, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([CH3:20])[C:12]([CH3:19])=[CH:13][C:14]=2[CH3:18])[O:9]1.Br[CH2:25][C:26]([O:28][CH2:29]C)=[O:27].[OH-].[Na+].Cl>C1COCC1.O.CO>[CH3:7][C:8]1([CH2:21][CH2:22][O:23][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([CH3:20])[C:12]([CH3:19])=[CH:13][C:14]=2[CH3:18])[O:9]1
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CCO)CC2
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COCCC1(C)CCc2c(C)cc(C)c(C)c2O1
Temperature: 52.5 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium tert-butoxide (1.92 g) in THF (10 ml) was added dropwise to a solution of 2-(2,5,7,8-tetramethylchroman-2-yl)ethanol (4.00 g) and ethyl bromoacetate (2.00 ml) in THF (20 ml) at 0-10° C. and the mixture was stirred for 30 minutes under same condition. After addition of ethyl bromoacetate (1.90 ml), a solution of potassium tert-butoxide (1.92 g) in THF (10 ml) was added dropwise and the mixture was stirred at 0-10° C. for 30 minutes. This procedure was repeated 3 times. A solution of NaOH (5.0 g) in water (10 ml) was added and heated at 50-55° C. for 5 hours. The mixture was adjusted to pH 3 with 6N hydrochloric acid (6N HCl) and extracted with AcOEt. The organic phase was dried over MgSO4 and concentrated under reduced pressure to give a syrup. A mixture of the syrup and a cation-exchange resin, Amberlyst® 15 (1 g) in MeOH (100 ml) was heated under reflux for 30 hours. After removal of catalyst, the solution was concentrated under reduced pressure to give a syrup. The syrup was purified by chromatography over silica gel (AcOEt-hexane 5:95) to give methyl [2-(2,5,7,8-tetramethylchroman-2-yl)ethoxy]acetate as an oil (3.37 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([OH:17])=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10]([CH:13]=1)[CH:11]=[O:12])[CH2:2][CH2:3][CH3:4].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC.C1(C)C=CC=CC=1>[CH2:18]([O:17][C:7]1[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: CCCCOc1cc(C=O)c([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCCOc1cc(C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
One heats for 2 hours under reflux and stirring a mixture of 5-butoxy 4-hydroxy 2-nitro benzaldehyde (31 g, 0.13 mole) of benzyl chloride (20.2 g, 0.18 mole) and of potassium carbonate (22.11 g, 0.16 mole), in 80 ml of dimethylformamide. One pours the reacting mixture in 200 ml ice cold water and filters the precipitate. One obtains after recrystallization in a mixture of hexane-toluene the 4-benzyloxy 5-butoxy 2-nitro benzaldehyde (30.2 g, yield 71%, yellow powder) fusion=94° C.
Reaction SMILES: [NH2:1][C:2](=[O:38])[C@@H:3]([NH:8][C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])C.N1CCC[C@H]1C(N)=O>>[C:2]([C@@H:3]1[CH2:4][CH2:5][CH2:7][N:8]1[C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:38])[NH2:1]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C)C(N)=O
Agent: NC(=O)[C@@H]1CCCN1
Product: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)N2CCC[C@H]2C(N)=O)C(C)(C)C)C1

Procedure:
Compound 74 was prepared according to the procedure described for the synthesis of compound 72 by replacing leucine amide with (S)-pyrrolidine-2-carboxamide. LCMS (+ESI) m/z=521.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[CH:11][C:12]([NH:21][CH3:22])=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:23]([O:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH2:34][C:35]([CH2:41]Cl)=[CH:36]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([O:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH2:34][C:35]([CH2:41][N:21]([C:12]1[CH:11]=[N:10][C:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=1)[CH3:22])=[CH:36]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCC1=Cc2cccc(OCc3ccccc3)c2CC1
Reactant: CNc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC1=Cc2cccc(OCc3ccccc3)c2CC1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
Under an argon atmospshere, 0.97 g of 60% sodium hydride was suspended in anhydrous N,N-dimethylformamide and 0.97 g of 5,6-diphenyl-2-(methylamino)-pyrazine was added in three portions. After stirring at 80° C. for 30 minutes, the reaction solution was ice-cooled and a solution of 0.97 g of 5-(benzyloxy)-2-(chloromethyl)-3,4-dihydronaphthalene in 5 ml of anhydrous N,N-dimethylformamide was added dropwise. After stirring for 30 minutes, the reaction solution was diluted with ice water and then extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.81 g of the desired compound as a pale yellow amorphous.
Reaction SMILES: [CH3:1][NH:2][NH2:3].Cl[C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH3:14])[N:12]=[CH:13][C:6]=12>C(O)C>[CH3:1][N:2]1[C:5]2=[N:10][CH:9]=[N:8][C:7]([N:11]([CH3:14])[NH2:12])=[C:6]2[CH:13]=[N:3]1
Reactant: CNN
Reactant: Cn1ncc2c(Cl)ncnc21
Solvent: CCO
Product: CN(N)c1ncnc2c1cnn2C

Procedure:
1.7 g. of methylhydrazine is dissolved in 30 ml. of ethanol. 3.3 g. of 4-chloro-1-methylpyrazolo[3,4-d]pyrimidine is added portionwise. The mixture is refluxed for 30 minutes and then allowed to stand in the refigerator overnight. The mixture is filtered and the product, 1-methyl-4-(1-methylhydrazino)pyrazolo[3,4-d]pyrimidine, is recrystallized from ethanol-methanol, m.p. 213°-215° (yield 4.2 g.).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:22])=[CH:3]\[C:4]([O:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[CH:12][CH:11]=1)=[O:5].[N+:23]([C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][CH:40]=1)[CH:29]=[C:30]([C:35]([CH3:37])=O)[C:31]([O:33][CH3:34])=[O:32])([O-:25])=[O:24]>C1(C)C=CC=CC=1>[CH3:22][C:2]1[NH:1][C:35]([CH3:37])=[C:30]([C:31]([O:33][CH3:34])=[O:32])[CH:29]([C:28]2[CH:38]=[CH:39][CH:40]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)[C:3]=1[C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)=[O:5]
Reactant: C/C(N)=C/C(=O)OCC=Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
2.97 g (10 mM) of 3-[4-(1-imidazolylmethyl)phenyl]-2-propen-1-yl 3-aminocrotonate and 2.49 g (10 mM) of methyl 2-(3-nitrobenzylidene)acetoacetate were dissolved in 50 ml of toluene and then the solution was refluxed for eight hours. After cooling, the crystals were filtered off and then recrystallized from methanol whereby the captioned compound was obtained. The yield was 4.01 g (76%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]=[O:25])=[CH:18][CH:17]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(CC)=C.[OH:31]P([O-])(O)=O.[Na+].Cl([O-])=O.[Na+]>CC(O)(C)C.C1COCC1>[C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]([OH:31])=[O:25])=[CH:20][CH:21]=4)[CH:13]=[N:12][C:11]=23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=P([O-])(O)O
Reactant: O=CCCc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: C=C(C)CC
Product: O=C(O)CCc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Reaction time: 1 h

Procedure:
A solution of 3-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]propanal (2-5, 278 mg, 0.850 mmol, 1 equiv) in a 4:1 mixture of THF and t-BuOH (20 mL) was treated with 2-methyl butene (5 mL), an aqueous solution of sodium phosphate monobasic (0.14 M, 234 mg, 1.70 mmol, 2 equiv) and sodium chlorite (197 mg, 2.18 mmol, 2.57 equiv). After 1 hour at room temperature, additional solid sodium phosphate monobasic (278 mg, 1.70 mmol, 2 equiv) and sodium chlorite (197 mg, 2.18 mmol, 2.57 equiv) were added. The reaction mixture was stirred for an additional 4 hours, concentrated and the residue dissolved in EtOAc (100 mL) then washed with a 25:1 mixture of aqueous 10% sodium bisulfite solution and 10% potassium hydrogen sulfate solution (2×100 mL). The organic layer was dried over sodium sulfate and concentrated to afford 3-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]propanoic acid (4-1) as a yellow solid. LRMS m/z: Calc'd for C21H18N3O2 (M+H) 344.4, found 344.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: [Pd]
Product: Nc1ccc2[nH]ncc2c1
Yield: 63.6 %

Procedure:
By referring to the Step 6 of Example 1, 5-nitroindazole (5.0 g, 30.7 mmol), Pd/C (1.2 g), were used to obtain a product (2.6 g, 62.6%).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.O>C(Cl)Cl>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:9](=[O:10])[O:11][CH2:12][CH3:13])=[CH:27][CH:26]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(OCc2nc3ccccc3s2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 1.5 h
Yield: 88 %

Procedure:
0.14 ml of triethylamine and 0.08 ml of ethyl chloroformate were added to a solution of 250 mg of 4-(benzothiazol-2-ylmethoxy)aniline [prepared as described in Example 3(b) above] in 5 ml of methylene chloride cooled in an ice-water bath, and the resulting mixture was then stirred for 1.5 hours. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The resulting extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 3:1 by volume mixture of hexane and ethyl acetate to give 284.8 mg (yield 88%) of the title compound as a solid having a melting point of 149°-150° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:33])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29](OC)=[O:30])[CH:25]=[N:26][CH:27]=2)=[CH:4][C:3]=1[Cl:34].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]/[C:46]([OH:48])=[O:47]>C1C=CC=CC=1.CCOCC.CO.O>[C:43]([OH:50])(=[O:49])/[CH:44]=[CH:45]/[C:46]([OH:48])=[O:47].[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:33])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][CH2:29][OH:30])[CH:25]=[N:26][CH:27]=2)=[CH:4][C:3]=1[Cl:34]
Reactant: COC(=O)Cc1cncc(CCCOCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCCc2cncc(CCO)c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 156.1 %

Procedure:
Methyl 5-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl]-3-pyridineacetate (800 mg) in benzene (10 ml) was added dropwise to a stirred suspension of lithium aluminum hydride (95 mg) in ether (10 ml) at 0° C. The mixture was stirred overnight at room temperature under nitrogen, and more lithium aluminum hydride (40 mg) was added. After being stirred for a further 3 h, the mixture was treated with water (1 ml), followed by 2N sodium hydroxide (1 ml) and water (3 ml). The suspension was filtered through hyflo and washed with ethyl acetate (3×50 ml). The combined organic extracts were dried and concentrated to give a yellow oil which was purified by FCC eluting with System A (85:5:1) to give a yellow oil. The oil (450 mg), dissolved in methanol (10 ml), was treated with fumaric acid (52 mg) and concentrated to give an oil which was triturated with ether to give the title compound as a yellow solid (420 mg), m.p. 85°-86° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[Cl:1][C:2]1[N:7]=[C:6](/[C:8](=[CH:20]\[N:21]([CH3:23])[CH3:22])/[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1ccc(F)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C(/C(=O)c1ccc(F)cc1)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound prepared in step 2 (4.7 g, 0.017 mol) in 100 mL of dimethylformamide dimethyl acetal was stirred at room temperature overnight. Excess dimethylformamide dimethyl acetal was removed under vacuum to give 4.5 g of crude product as a thick brown oil, which was used without further purification.