Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.Br.Br.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1>CN(C)C=O>[OH:28][C:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:36]2)=[CH:33][CH:34]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccc(O)cc2)CC1
Temperature: 20 °C
Reaction time: 6 h
Yield: 19.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (70.3 g), triethylamine (105 cc) and 1(4-hydroxyphenyl)piperazine dihydrobromide (85.2 g) in dimethylformamide (2100 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring.is continued for 6 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane and then a mixture of dichloromethane and ethyl acetate (50-50 vol) as eluant, and recrystallization from boiling acetonitrile (1150 cc), 2-{3-[4-(4-hydroxyphenyl)-1- piperazinyl]propyl}naptho[1,8-cd]isothiazole 1,1-dioxide (20.5 g) is obtained, m.p. 185° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[CH2:8]([N:10]([CH2:18][CH3:19])[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH3:9].C(=O)([O-])O.[Na+]>ClCCl>[CH2:5]([O:4][C:2]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([N:10]([CH2:18][CH3:19])[CH2:8][CH3:9])=[CH:16][CH:15]=1)=[O:3])[CH3:6]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(N(CC)CC)cc1
Reaction time: 96 h
Yield: 72.4 %

Procedure:
Ethyl chloroformate 5.0 mL, 52 mmol) was added to a stirred mixture of N,N-diethyl-p-phenylenediamine hydrochloride (10 g, 50 mmol) and sodium hydrogen carbonate (23.0 g) in dichloromethane (120 mL) at room temperature under nitrogen. After four days at room temperature, the precipitate which had formed was removed by filtration through a pad of celite. The solid residue was washed with dichloromethane and the combined dichloromethane extracts were concentrated to produce a black oil, which was redissolved in dichloromethane (110 mL) and stirred with silica (100 cc) for 30 minutes. The silica was then removed by filtration through celite. The residue was washed with additional dichloromethane (3×30 mL) and the combined dichloromethane extracts were concentrated to give N-ethoxycarbonyl-4-diethylaminoaniline (8.55 g, 73% yield) as a pale gray solid which melted at 31°-33° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[P:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[I-].[Na+].S(=O)(O)[O-:44].[Na+]>C1(C)C=CC=CC=1>[C:29]1([P:28]([CH2:14][C:13]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[N:11][C:12]=2[CH:16]([CH3:18])[CH3:17])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:44])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: O=S([O-])O
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CP(=O)(c1ccccc1)c1ccccc1
Temperature: 108 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
512 mg (1.45 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 8 ml of toluene and admixed with 96 mg (2.20 mmol) of sodium hydride (55 percent dispersion in mineral oil). After 1 h, 333.5 mg (1.44 mmol) of chlorodiphenylphosphine in 2.5 ml of toluene was added at room temperature with vigorous stirring over a period of 5 min. The mixture was admixed with 28.7 mg (0.19 mmol) of sodium iodide and heated at 108° C. for 22 h. After 6 h, a further 28.7 mg (0.19 mmol) of sodium iodide were added. After cooling to room temperature, the mixture was admixed with 30 ml of 38 to 40percent strength sodium bisulfite solution and extracted with 50 ml of ethyl acetate. The organic phase was separated off and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic phases were subsequently concentrated under reduced pressure. This gave 740 mg of crude product which was purified by silica gel chromatography (mobile phase:ethyl acetate), and 212.7 mg (27.3 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:5]2[C:6]([C:16]([O:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.C(OCC)(=O)C.Cl>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:5]=3[C:6]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(OC(C)C)cc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(OC(C)C)cc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Methyl 6-amino-2-(4-fluorophenyl)-5-isopropoxybenzofuran-3-carboxylate (0.6 g, 1.75 mmol) was dissolved in dichloromethane. Pyridine (0.71 mL, 8.74 mmol) and methanesulfonyl chloride (0.27 mL, 3.5 mmol) were added and the resulting yellow orange solution was stirred at room temperature 15 hours. The solvent was removed in vacuo leaving an oily residue. The oil was redissolved in 100 mL ethyl acetate and 25 mL 10% aqueous HCl. The layers were separated and the organic layer was washed with 10% aqueous sodium bicarbonate and 10% aqueous sodium chloride, dried over anhydrous sodium sulfate(s), filtered and the solvent was removed in vacuo leaving an off-white solid, 0.65 g, 88%.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15](=O)[NH:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=O)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4].C([O-])(=O)C.[NH4+:32]>>[CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]3[NH:32][C:18]([C:20]4[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=4)=[CH:17][N:16]=3)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4]
Reactant: [NH4+]
Reactant: COC(=O)N1CC(=O)N2C(CCC2C(=O)NCC(=O)c2ccc(Br)cc2)C1
Agent: CC(=O)[O-]
Product: COC(=O)N1CC(=O)N2C(CCC2c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Temperature: 130 °C
Yield: 60 %

Procedure:
A mixture of 6-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (110 mg, 0.25 mmol), ammonium acetate (193 mg, 2.5 mmol) and xylenes (8 mL) was heated to 130° C. After 1 hour the mixture was cooled and the xylenes were removed under reduced pressure. Dichloromethane was added to the resulting residue and the mixture was filtered. The solvent was removed under reduced pressure from the filtrate and the resulting residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 6-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (65 mg, 0.15 mmol, 60%). C18H19BrN4O3 calculated 418.1 observed [M+1]+419.1; rt=1.50 min.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:17][C:18]([NH2:20])=[S:19]>>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:17]=1
Reactant: CCCCON=C(C(=O)CBr)C(=O)OCC
Reactant: NC(N)=S
Product: CCCCON=C(C(=O)OCC)c1csc(N)n1
Yield: 40.5 %

Procedure:
93 g (0.32 mole) of ethyl 4-bromo-2-n-butoxyimino-acetoacetate and 24 g (0.32 mole) of thiourea undergo a condensation reaction analogously to Example 4, stage 3, to give 35.2 g of ethyl 2-(2-aminothiazol-4-yl)-2-n-butoxyimino-acetate of melting point 129.5°-131°.
Reaction SMILES: CCN(C(C)C)C(C)C.Br[C:11]1[C:16]([NH2:17])=[CH:15][N:14]=[CH:13][N:12]=1.[SH:18][CH2:19][CH2:20][CH2:21][OH:22].O>O1CCOCC1>[NH2:17][C:16]1[C:11]([S:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:12][CH:13]=[N:14][CH:15]=1
Reactant: Nc1cncnc1Br
Reactant: OCCCS
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Nc1cncnc1SCCCO
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
DIEA (1.11 g, 8.61 mmol) was added to a solution of 4-bromopyrimidin-5-amine (A) (1.0 g, 5.74 mmol) and 3-mercaptopropan-1-ol (35B1) (0.53 g, 5.74 mmol) in dioxane (5 mL). The reaction mixture was heated to 50° C. under nitrogen and stirred for 30 min. The LC/MS spectrum showed that the reaction had completed. Water (50 mL) was added and a solid precipitated. The off white solid product (35C1) (913 mg, 4.93 mmol) was obtained after filtration and air drying at 25° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH:13]1(CN)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:21]([N:23](CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:13]1([N:23]([CH3:21])[C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCN(CC)CC
Reactant: NCC1CCCCC1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C(=O)c1ccccc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
A solution of 2-nitrobenzoyl chloride (1.0 g, 5.4 mmol) in dichloromethane (1 ml) was added dropwise to a stirred solution of cyclohexylmethylamine (0.068 g, 6 mmol), triethylamine (1.12 ml, 8 mmol) and a catalytic amount of 4-dimethylaminopyridine in dichloromethane (4 ml) at 0° C. After 1 h at 0° C., the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with dichloromethane and washed with hydrochloric acid 1N (10 ml), sodium hydroxide 2N (10 ml) and brine (10 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure to yield N-cyclohexyl-N-methyl-2-nitrobenzamide (1.05 g, 74%) that was used in the next step without further purification.
Reaction SMILES: [OH-].[K+].Cl.[CH:4]1([CH2:7][NH2:8])[CH2:6][CH2:5]1.[CH2:9]([S:11][C:12]1[C:17]2[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)=[N:19][CH2:20][C:21]3[N:22]([C:23]([CH2:26]Cl)=[N:24][N:25]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:10]>O1CCCC1>[CH2:9]([S:11][C:12]1[C:17]2[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)=[N:19][CH2:20][C:21]3[N:22]([C:23]([CH2:26][NH:8][CH2:7][CH:4]4[CH2:6][CH2:5]4)=[N:24][N:25]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:10]
Reactant: CCSc1cccc2c1C(c1cccc(Cl)c1)=NCc1nnc(CCl)n1-2
Reactant: NCC1CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCSc1cccc2c1C(c1cccc(Cl)c1)=NCc1nnc(CNCC3CC3)n1-2

Procedure:
In the manner given in Example 3, a solution of potassium hydroxide and (cyclopropylmethyl)amine hydrochloride is treated with a solution of 7-(ethylthio)-1-(chloromethyl)-6-(m-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran to give 7-(ethylthio)-1-[[(cyclopropylmethyl)amino]methyl]-6-(m-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1](I)[CH3:2].[C:4]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[CH:5].[N-:24]=[N+:25]=[N-:26].[Na+].O>C(OCC)(=O)C.N.[Cu]I>[CH2:1]([N:24]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[N:26]=[N:25]1)[CH3:2]
Reactant: C#Cc1cccc(CCOCCC(=O)OC(C)(C)C)c1
Reactant: CCI
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)nn1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Ethyl iodide (0.216 mL) was added in one portion to a mixture of tert-butyl 3-(3-ethynylphenethoxy)propanoate [Example 4, Step ii)] (564 mg), sodium azide (160 mg) tert-butanol (0.25 mL), water (1 mL) and copper (I) iodide (39 mg) and sealed into a microwave tube. The reaction was heated to 70° C., over a period of 6 h in a microwave reactor. The reaction mixture was diluted with ethyl acetate and 35% ammonia was added. The mixture was stirred for 30 min and separated. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20-100% ethyl acetate in isohexane, then elution gradient 0-10% methanol in ethyl acetate to afford the subtitled compound (396 mg) 1H NMR (300 MHz, CDCl3) δ 7.79 (s, 1H), 7.70 (s, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 4.47 (q, J=7.3 Hz, 2H), 3.73-3.66 (m, 4H), 2.92 (t, J=7.2 Hz, 2H), 2.49 (t, J=6.5 Hz, 2H), 1.61 (t, J=7.3 Hz, 3H), 1.43 (s, 9H).
Reaction SMILES: Cl.[C:2](=[NH:10])(OCC)[CH2:3][CH2:4][CH2:5][CH3:6].[NH2:11]/[C:12](/[C:17]#[N:18])=[C:13](\N)/[C:14]#[N:15]>N1C=CC=CC=1>[CH2:3]([C:2]1[NH:10][C:13]([C:14]#[N:15])=[C:12]([C:17]#[N:18])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(=N)OCC
Reactant: N#C/C(N)=C(/N)C#N
Agent: Cl
Solvent: c1ccncc1
Product: CCCCc1nc(C#N)c(C#N)[nH]1

Procedure:
Ethyl pentanimidate hydrochloride (42.66 g, 257.8 mmol, 1 eq), diaminomaleonitrile (27.90 g, 258.1 mmol, 1 eq) and pyridine (400 mL) were mixed and refluxed for 48 hours under N2. The solvent was removed by rotary evaporation.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=O.C[O-].[Na+].Br[CH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CN(C=O)C.C(O)C>[CH3:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][C:15]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])=[CH:4][C:3]=2[CH:6]=1
Reactant: Cc1ccc(O)c(C=O)c1
Reactant: N#Cc1ccccc1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 68.9 %

Procedure:
A solution of the product of step (a) (130 g) in dry DMF (400 ml) was added dropwise to a solution of sodium methoxide (56.2 g) in ethanol (400 ml) mechanically stirred under nitrogen. After a further 20 mins, a solution of 2-(bromomethyl)benzonitrile (182.2 g) in dry DMF (400 ml) was added dropwise. The mixture was then heated to 75° C. for 30 min. The solution was allowed to cool for 1 h. A slurry of sodium methoxide (56.2 g) in dry DMF (100 ml) was added and the mixture heated at reflux for 1.5 h. The mixture was concentrated in vacuo and then poured into iced water. The solid was collected, and then triturated with methanol to give the title compound (Intermediate 2) as a beige solid (149.4 g).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH:15]2[C:17]([OH:19])=O)=[O:13])=[CH:7][CH:6]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:35][CH:36]([CH3:43])[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH:15]2[C:17]([NH:35][CH:36]([CH3:43])[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:19])=[O:13])=[CH:9][CH:10]=1
Reactant: NN=Cc1ccc(NC(=O)C2CC2C(=O)O)cc1
Reactant: CCOC(=O)CC(C)N
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)NC(=O)C1CC1C(=O)Nc1ccc(C=NN)cc1
Reaction time: 8 h

Procedure:
To 1.0 g (0.0035 mol) 2-[[[4-(aminoiminomethyl)phenyl]amino]carbonyl]cyclopropyl-carboxylic acid hydrochloride in 100 mL dry DMF was added 0.36 g (0.39 mL, 0.0035 mol) N-methyl-morpholine and 0.48 g (0.46 mL, 0.0035 mol) isobutylchloroformate. The reaction was allowed to proceed for ten minutes at room temperature then 0.515 g (0.576 mL, 0.0035 mol) ethyl 3-aminobutyrate was added. The reaction was allowed to proceed overnight. The volatiles were removed under vacuum at 55° C. until a viscous oil remained. The residue was dissolved in water (60 mL) and purified by preparative RPHPLC. Two diastereomers were obtained and separated by HPLC. The faster eluting diastereoisomer, isomer 1, was collected and lyophilized to 0.9 g of a white solid: 1H NMR (300 MHz) d6 -DMSO δ 1.17 (m, 8H), 2.07 (m, 1H), 2.38 (m, 1H), 4.04 (m, 3H), 7.77 (s, 4H), 8.28 (d, J=7.9), 8.80 (bs, 2H), 9.16 (bs, 2H), 10.78 (s, 1H); MS (FAB) 361.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:26]=[C:25]3[C:21]([C:22]([C:27]4[NH:28][C:29]5[CH2:34][CH2:33][NH:32][CH2:31][C:30]=5[N:35]=4)=[N:23][NH:24]3)=[CH:20][CH:19]=2)[C:15]([CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:14][C:13]=1[OH:41]>>[CH2:27]([NH:28][CH2:29][CH3:30])[CH3:22].[F:11][C:12]1[C:13]([OH:41])=[CH:14][C:15]([CH2:36][C:37]([F:38])([F:39])[F:40])=[C:16]([C:18]2[CH:26]=[C:25]3[C:21]([C:22]([C:27]4[NH:28][C:29]5[CH2:34][CH2:33][N:32]([C:6]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=6)=[O:8])[CH2:31][C:30]=5[N:35]=4)=[N:23][NH:24]3)=[CH:20][CH:19]=2)[CH:17]=1
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Reactant: O=C(O)c1ccc(F)cc1
Product: CCNCC
Product: O=C(c1ccc(F)cc1)N1CCc2[nH]c(-c3n[nH]c4cc(-c5cc(F)c(O)cc5CC(F)(F)F)ccc34)nc2C1
Yield: 63.3 %

Procedure:
The title compound was prepared from 4-fluoro-benzoic acid (24 mg, 168 μmol) and 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (Preparation 39, 100 mg, 168 μmol) using the method of Example 8. The crude material was purified by HPLC Method A to afford 33.3 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7]C2C=C([N+]([O-])=O)C=CC=2O[CH2:3]1.N[C:16]1[CH:21]=[C:20]([N+]([O-])=O)[CH:19]=[CH:18][C:17]=1[OH:25].C(=O)(O)[O-].[Na+]>C(C(C)=O)C(C)C>[O:25]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:3][C:2](=[O:1])[NH:7]1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1Cc2ccccc2ON1
Temperature: 5 °C

Procedure:
3-Oxo-6-nitro-3,4-dihydro-2H-1,4-benzoxazine. A solution of 2-amino-4-nitrophenol (8.80 g), in methyl isobutyl ketone (30 mL) was treated with sodium bicarbonate (11.5 g) and distilled water (35 mL). The mixture was cooled to 5° C. under a nitrogen atmosphere, treated dropwise with chloroacetyl chloride (5.0 mL) and then heated to reflux for 18 hours. A brown solid was collected from the cooled mixture by filtration. The solid was dried under vacuum at 50° C. for 24 hours yielding benzoxazinone (10.5 g) as a brown solid; mp 235°-236° C.; MS: m/z=195(M+1); NMR: 4.76 (s,2), 7.14 (d,1), 7.74 (d,1), 7.82 (dd,1), 11.07 (broad s,1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O=[Pt]=O.CCO.CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1cc(Cl)ccc1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Compound 4-3 (2.73 g, 7.76 mmol), EtOH/AcOH (1:1, 60 mL) and PtO2 (0.895 g) were shaken in a Parr apparatus (15 psig of hydrogen) for 10 hrs. The reaction mixture was filtered thru Celite®, washing with ethanol. The solution was concentrated, and the residue was diluted with dichloromethane and washed with saturated NaHCO3. The aqueous layer was again extracted with dichloromethane, and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by flash chromatography (gradient elution with 15-50% ethylacetate (0.1% TEA) in heptane. The desired product Compound 4-4 was isolated as thick colorless oil (2.55 g, 93%). 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J=2.3 Hz, 1H), 7.43 (d of d, J=8.5 and 2.3 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 4.22 (m, 2H), 3.91 (s, 3H), 3.52 (m, 1H), 2.82 (m, 2H), 2.8-1.5 (m, 4H), 1.48 (s, 9H); MS (ES+) m/z 253.8 (M-Boc+1); HRMS (FAB+) Calcd for C18H23ClNO4: 352.1316. Found: 352.1329.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:5])C.C1COCC1.O.O[Li].O>O>[C:4]([C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 50 °C
Yield: 94.8 %

Procedure:
To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9 mmol) in a 3:1 THF/water solution (75 mL) was added a solution LiOH.H2O (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50° C. overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a 1M HCl solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-1-nitrobenzene (4.40 g, 95%). Step 3. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].[NH2:27][NH2:28].C(O)(C(F)(F)F)=O>>[N:27]1[N:28]=[CH:21][N:7]2[CH:6]=[C:5]([CH:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])[CH:4]=[CH:3][C:2]=12
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc(Cl)nc1
Reactant: NN
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2nncn2c1
Temperature: 110 °C
Reaction time: 11 h
Yield: 81 %

Procedure:
A mixture of 3-(6-chloropyridin-3-yl)-2,2-dimethyl-3-phenylpropanoic acid (28 mg, 0.10 mmol), potassium carbonate (8 mg), and hydrazine (0.5 mL) was stirred at 110° C. for 11 hr under argon and then concentrated. The residue was mixed with formic acid (1 mL). The mixture was stirred at 100° C. for 2 hr and 120° C. for 1 hr. Concentration and purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 3-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2-dimethyl-3-phenylpropanoic acid (33 mg, 0.081 mmol, 81% yield) as a TFA salt. MS found: (M+H)+=296.25.