Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC(F)=CC=3)C=2)=[O:7])=[C:4]([CH3:28])[N:3]=1.C[C@H]1CNC[C@@H](C)N1>>[CH3:28][C:4]1[N:3]=[CH:2][CH:27]=[CH:26][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1
Agent: C[C@@H]1CNC[C@H](C)N1
Product: Cc1ncccc1C(N)=O

Procedure:
6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)-2-methylnicotinamide (0.15 mmol) was used in general procedure 3 with cis-2,6-dimethylpiperazine (0.77 mmol). The product was purified by RP-HPLC to give N-(4-fluorobenzamido)phenyl))-6-(3S-,5R)-3-5-dimethylpiperazine-1-yl)-2-methylnicotinamide. MS (Q1) 496.0 (M)+
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.O.O.[Sn](Cl)Cl>CN(C)C=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
0.999 g (4.5 mmol) of 1-methyl-4-(4-nitrophenyl)piperazine, 10.15 g (45 mmol) of tin(II)chloride dihydrate and 20 ml of dimethylformamide were mixed and stirred overnight at 80° C. Most of dimethylformamide was evaporated under vacuum. The remaining slurry was poured into ice water, neutralized with a sodium bicarbonate (sat.) solution, and filtered. The filtrate was extracted several times with ethylacetate and chloroform to provide 0.636 g (74%) of 4-(4-methylpiperazin-1-yl)aniline.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30](O)=[O:31])[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.O.[CH:53]([C:56]1[CH:62]=[CH:61][CH:60]=[CH:59][C:57]=1[NH2:58])([CH3:55])[CH3:54].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(Cl)Cl>[CH:53]([C:56]1[CH:62]=[CH:61][CH:60]=[CH:59][C:57]=1[NH:58][C:30](=[O:31])[CH2:29][CH2:28][O:27][C:17]1[C:16]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=2)(=[O:12])=[O:13])[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:18]=1)([CH3:55])[CH3:54]
Reactant: CC(C)c1ccccc1N
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)Nc1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
3-[6-(4-t-Butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid (80 mg) was dissolved in dimethylformamide-methylene chloride (1:1, 6 ml). N-Hydroxybenzotriazole·H2O (42.2 mg), 2-isopropylaniline (133.2 mg), and 1-(3-dimethylaminopropyl) -3-ethylcarbodiimide-HCl (32.6 mg) were added to the mixture. The reaction mixture was stirred overnight at room temperature. After the solvent was evaporated, ethyl acetate was added. The organic layer was successively washed with sat. aq. NaHCO3, 0.5N-HCl, and brine, was dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1), to thereby obtain 97.2 mg (yield: 100%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[Cl:18])[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccccc3Cl)c(=O)n12
Temperature: 105 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.12 g, 0.38 mmol) and (2-chlorophenyl)boronic acid (0.072 g, 0.46 mmol) in 1,4-dioxane (3 mL) was added a 1N solution of sodium carbonate in water (0.57 mL, 0.57 mmol) and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.014 g, 0.019 mmol). The mixture was stirred at 105° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated, and purified on silica gel (0-30% ethyl acetate/hexanes) to give the desired product (0.062 g). LCMS calculated for C15H13ClN5OS (M+H)+: m/z=346.1. Found: 346.0.
Reaction SMILES: [C:1]([N:4]1[CH:8](O)[CH2:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:3])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([N:4]1[CH2:8][CH2:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)C(c2ccccc2)CC(O)N1C(C)=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)C(c2ccccc2)CCN1C(C)=O
Reaction time: 0.75 h
Yield: 100 %

Procedure:
To a solution of diethyl 1-acetyl-5-hydroxy-3-phenylpyrrolidine-2,2-dicarboxylate (116.0 g, 331 mmol) and triethylsilane (80 ml, 497 mmol) in dichloromethane (675 ml) was added trifluoroacetic acid (254 ml, 3.32 mol) dropwise with stirring over 45 min. The reaction was allowed to stir for 2.5 h at rt and was then concentrated and redissolved in EtOAc. The organics were washed with sat'd sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo to yield diethyl 1-acetyl-3-phenylpyrrolidine-2,2-dicarboxylate as an oil (100%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:24])[CH:16]=1.[C:25](=O)([O:28]C)[O:26]C>C1COCC1>[C:25]([CH2:24][C:17]1[CH:16]=[C:15]([O:14][CH3:13])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])([OH:28])=[O:26]
Reactant: COC(=O)OC
Reactant: COc1ccc(C(=O)O)c(C)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(CC(=O)O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
A solution of diisopropylamine (3.43 ml, 24.07 mmol) in THF (3 mL) was cooled to −78° C. and n-butyllithium (9.63 ml, 24.07 mmol) was added dropwise and allowed the solution to warm to 0° C. for 5 min and then re-cooled to −78° C. 4-methoxy-2-methylbenzoic acid (1 g, 6.02 mmol) and dimethyl carbonate (1.013 ml, 12.04 mmol) in THF (3 mL) was added dropwise. After the addition is complete, the reaction is allowed to slowly warm to RT and stir for 4 h. The reaction was quenched with 10 mL of H2O and allowed to stir for 16 h. The layers were separated, washed the organics with H2O (2×), combined all the aqueous extractions and adjusted the pH to 2-3 with 6N HCl while in an ice bath. The resulting in a white precipitate was filtered and dried under vacuum to afford the title compound (1.09 g, 86%) as a white solid. LCMS (ES+) m/z 211.05 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([C:2]2[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)c1ccnc(I)c1
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CN(C)c1ccnc(-c2ccccc2)c1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
A mixture of 2-iodo-4-dimethylaminopyridine (3.3 g, 13.3 mmol), phenylboronic acid (2.5 g, 20 mmol) and K2CO3 (8.3 g, 60 mmol) in toluene (60 ml) and water (10 ml) were degased with nitrogen for 15 minutes. Pd(PPh3)4 (800 mg, 0.66 mmol) was added and the resulting mixture was heated to 90° C. for 48 hours under nitrogen. After being cooled to room temperature, the aqueous phase was separated and extracted with EtOAc (3×100 ml). The combined organic fractions were washed with brine, dried over MgSO4, filtered and evaporated to afford a brown oil. The following oil was dissolved in Et2O and extracted with 10% HCl solution (3×50 ml). The combined aqueous fractions were washed with Et2O (2×100 ml) and neutralized with concentrated NaOH solution. The resulting mixture was extracted with EtOAc (4×100 ml), the combined organic fractions were washed with brine (50 ml), dried over MgSO4, filtered and evaporated to dryness. The obtained residue was then purified by column chromatography (SiO2, CH2Cl2/MeOH, 97/3) to afford 1.2 g (46%) of the titled compound as a colorless oil, which solidify upon standing.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]4[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:3][CH2:2]1.Cl[Si](C)(C)C>CO>[NH:20]1[CH2:19][CH:18]([CH2:17][S:14]([C:12]2[CH:11]=[CH:10][C:9]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:6]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:7][C:8]=3[CH:13]=2)(=[O:16])=[O:15])[CH2:21]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CN(C(=O)OC(C)(C)C)C3)ccc2n1CC1CC1
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CNC3)ccc2n1CC1CC1
Yield: 107.9 %

Procedure:
To a solution of tert-butyl 3-((1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)methyl)azetidine-1-carboxylate (STEP E, 1.48 g, 3.11 mmol) in methanol (10 mL) was added chlorotrimethylsilane (1.35 g, 12.4 mmol). The resulting mixture was refluxed for 1 h. The reaction mixture was concentrated to give the title compound (1.26 g) as an amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(C1C=CC(C2C=CC(OCCCCCCCCCC)=CC=2)=CC=1)#N>CC(=O)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCCCCCCCCCBr
Agent: CCCCCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1

Procedure:
Quantities: 4-bromo-4′-hydroxybiphenyl (67) (20.00 g, 0.08 mol), 1-bromodecane (22.12 g, 0.10 mol), anhydrous potassium carbonate (57.10 g, 0.413 mol), potassium iodide (trace), butanone (500 ml). The experimental procedure was as described for the preparation of compound 57. The cooled mixture of product and inorganic salts was filtered off and washed carefully with dilute hydrochloric acid to remove the potassium carbonate. The white product was then washed with water until acid-free and heated under reflux with a minimum volume of ethanol to remove traces of 1-bromodecane. The product was filtered off, washed with cold ethanol and dried in vacuo to yield colourless crystals.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]1=[O:27].[OH-].[Na+]>>[CH2:20]([N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])[C:12]1=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CCCCCCCn1c(=O)n(Cc2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1c(=O)n(Cc2ccccc2)c2ccccc21

Procedure:
The product is produced as described in example 22 from 4.3 g. of 8-(3-benzyl-2-oxo-benzimidazolin-1-yl)-caprylic acid methyl ester and 0.5 g. of sodium hydroxide.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:14]=2)[C:9]1=[O:22])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:14]=2)[C:9]1=[O:22]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(OS(C)(=O)=O)cc2C1=O
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)Oc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 0.92 h
Yield: 85 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 55 minutes while stirring through a solution, cooled to -70°, of 11.3 g of (RS)-2-(2-buten-1-yl)-6-mesyloxy-1-indanone in 300 ml of anhydrous dichloromethane and 60 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4.51 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 250 ml of dichoromethane and, after the addition of 25 ml of water and 25 ml of trifluoroacetic acid, stirred at room temperature for 4 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 9.38 g (85%) of (RS)-2-(2-oxoethyl)-6-mesyloxy-1-indanone were obtained as a light brown solid with m.p. 85°-87°.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C1([OH:20])C=CC=CC=1>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:20])=[CH:3][CH:4]=2)[CH:9]=1
Reactant: Oc1ccccc1
Reactant: Nc1ccc(-c2cccnc2)cc1
Product: Oc1ccc(-c2cccnc2)cc1

Procedure:
Using the procedure described above, 3-(4'-aminophenyl)pyridine (10.0 g, 0.059 mol) is converted to the phenol. A total of 7.66 g of product is obtained, after chromatography, which is then recrystallized from acetone-hexane to give 6.52 g (65% of theory) of off-white crystals which have as melting point of 202°-203° C.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]([F:28])([F:27])[C:11]([N:13]([CH2:20][P:21]([O:25]Cl)([O:23]Cl)=[O:22])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12]>CCOCC>[F:9][C:10]([F:28])([F:27])[C:11]([N:13]([CH2:20][P:21]([O:25][NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O:23][NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)CN(CP(=O)(ONNc1ccccc1)ONNc1ccccc1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.9 %

Procedure:
To a solution of phenylhydrazine (4.5 g, 0.0423 mole) in 40 ml. of ether was added dropwise with good stirring ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (3.3 g, 0.01 mole) dissolved in ether. The reaction was stirred at room temperature for two hours, then filtered and the filtrate concentrated in vacuo to give a gum-solid. This was triturated with petroleum ether, then ether. The ether insoluble solid was washed with water to give ethyl N-trifluoroacetyl-N-(bis(phenylhydrazino)phosphonomethyl)glycinate (0.6 g), m.p. 113°-116° C. (glass), 143°-145° C. with decomposition.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O>CN(C=O)C>[F:33][C:32]([F:35])([F:34])[CH2:31][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2
Reactant: CC(C)(C)OC(=O)N1CCc2c(O)cccc2C1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2OCC(F)(F)F)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a resealable tube was added tert-butyl 5-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (200 mg, 0.802 mmol) and cesium carbonate (601 mg, 1.845 mmol) in DMF (2 mL) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (1005 mg, 4.33 mmol). The reaction mixture stirred at 70° C. overnight. The crude material was purified by reverse-phase preparative HPLC using 0.1% TFA in CH3CN/H2O, gradient 55% to 95% over 10 min to provide tert-butyl 5-(2,2,2-trifluoroethoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (120 mg) as colorless oil.
Reaction SMILES: C([O:4][CH2:5][CH:6]1[CH2:13][N:12]2[C:8](=[N:9][C:10]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:11]=32)[N:7]1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[N:7]1[C:8]2=[N:9][C:10]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:11]=3[N:12]2[CH2:13][CH:6]1[CH2:5][OH:4]
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(COC(C)=O)N3c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(CC)c1cccc2nc3n(c12)CC(CO)N3c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of [1-(2,4-dichlorophenyl)-5-(diethylamino)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-2-yl]methyl acetate (30.5 mg, 0.0682 mmol) in methanol (0.7 mL) was added potassium carbonate (9.4 mg, 0.0682 mmol) at room temperature. After 1 hr, the mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (24.1 mg, 0.0593 mmol, 87%). Analytically pure material was obtained by recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:19]2[CH:20]=[CH:21][C:22]([C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][C:5]3[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=3)=[CH:23][C:18]=2[F:17])=[CH:34][N:35]=1
Reactant: N#Cc1cc(Oc2ccccc2Br)ccn1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: N#Cc1cc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)ccn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)picolinonitrile and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H14FN5O, 383.12; m/z found, 384.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.50 (d, J=5.7, 1H), 8.40 (d, J=1.3, 2H), 7.61 (dd, J=7.9, 2.0, 2H), 7.53 (dd, J=11.1, 5.0, 2H), 7.48-7.42 (m, 1H), 7.36 (dd, J=12.1, 1.5, 1H), 7.31 (dd, J=11.5, 5.0, 2H), 7.11 (dd, J=5.7, 2.5, 1H), 6.86 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:31])[CH:18]([N:21]4[C:25]([CH3:26])=[CH:24][C:23]([C:27](O)([CH3:29])[CH3:28])=[N:22]4)[CH2:19][CH3:20])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:31])[CH:18]([N:21]4[C:25]([CH3:26])=[CH:24][C:23]([C:27]([CH3:29])=[CH2:28])=[N:22]4)[CH2:19][CH3:20])[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)n1nc(C(C)(C)O)cc1C
Agent: Cl
Product: C=C(C)c1cc(C)n(C(CC)C(=O)N2CCCc3c2cnn3-c2ccc(F)cc2)n1

Procedure:
A portion of 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[3-(1-hydroxy-1-methyl-ethyl)-5-methyl-pyrazol-1-yl]butan-1-one was treated with 6 M HCl until complete. The reaction slurry was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide 12 mg of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.44 (m, 2H), 7.14 (t, J=8.6 Hz, 2H), 6.14 (s, 1H), 5.42 (br s, 1H), 5.22 (dd, J=7.1, 8.2 Hz, 1H), 5.02 (br s, 1H), 3.80 (ddd, J=3.1, 7.8, 10.1 Hz, 1H), 3.47 (ddd, J=2.8, 9.0, 12.1 Hz, 1H), 2.74 (m, 2H), 2.33 (m, 1H), 2.23 (s, 3H), 2.15 (m, 1H), 2.10 (s, 3H) 1.87 (m, 1H), 1.78 (m, 1H), 0.98 (t, J=7.4 Hz, 3H); MS: (ES) m/z calculated for C23H27FN5O [M+H]+ 408.2, found 408.2.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:25][C:26]1[CH:34]=[C:33]([C:35]([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=2)=[O:36])[CH:32]=[C:31]([CH3:46])[C:27]=1[C:28]([OH:30])=O.[CH3:47][O:48][C:49](=[O:58])[CH:50]([P:52]([O:56][CH3:57])([O:54][CH3:55])=[O:53])[NH2:51].COC(=O)C(P(OC)(OC)=O)NC(OCC1C=CC=CC=1)=O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CO.C(OCC)(=O)C>[CH3:47][O:48][C:49](=[O:58])[CH:50]([P:52]([O:54][CH3:55])([O:56][CH3:57])=[O:53])[NH:51][C:28](=[O:30])[C:27]1[C:31]([CH3:46])=[CH:32][C:33]([C:35]([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=2)=[O:36])=[CH:34][C:26]=1[Cl:25]
Reactant: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)O
Reactant: COC(=O)C(N)P(=O)(OC)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 65 h
Yield: 15 %

Procedure:
O-(Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (645 mg, 1.7 mmol) was added to a solution of 2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoic acid (Example 112; 520 mg, 1.6 mmol) and rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (370 mg, 1.9 mmol). 1-hydroxybenzotriazole (255 mg, 1.9 mmol) was then added, followed by diisopropylethylamine (1.25 mL, 7.2 mmol). The solution was stirred at room temperature for 65 h and then it was evaporated to dryness under high vacuum to remove N,N-dimethylformamide. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (25 mL). The ethyl acetate layer was washed with brine, 0.5N hydrochloric acid solution and brine. Each of the aqueous layers was extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered, evaporated and the residue was chromatographed over silica gel (50-100% ethyl acetate/hexanes, then 5-25% methanol/ethyl acetate) to give rac.-N-[2-chloro4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (120 mg, 15% yield).