Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:16]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]([OH:19])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[N:34]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:16]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][C:39]([OH:41])([CH3:40])[CH3:42])[N:34]=2)=[O:19])[CH:5]=[CH:6][C:7]=1[S:8]([CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)(=[O:9])=[O:10]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(S(=O)(=O)C2CCCC2)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(=O)(=O)C3CCCC3)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (R)-2-(3-chloro-4-cyclopentanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (0.15 mmol) is dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution is added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 1.2 equiv.) and it is then allowed to warm to 25° C. and stirred 1 h at 25° C. After this time, the reaction is concentrated in vacuo to ⅓ of the original volume. In a separate flask, a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 1.5 equiv.), 2,6-lutidine (2.0 equiv.) and methylene chloride (5 mL) is cooled to 0° C. in an ice bath. To this solution is added the solution of the prepared acid chloride, diluted with another portion of methylene chloride (2 mL) dropwise. After the addition is complete the reaction is then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction mixture is diluted with methylene chloride (10 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (silica gel column) will afford (R)-2-(3-chloro-4-cyclopentanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]=[O:10].[BH4-].[Na+].CCOC(C)=O.CCCCCC>C1COCC1.CO>[F:18][C:17]([F:19])([F:20])[C:14]1[CH:13]=[CH:12][C:11]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][OH:10])=[CH:2][CH:3]=2)=[CH:16][CH:15]=1
Reactant: O=CCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 107.2 %

Procedure:
To a 0° C. solution of (3-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-acetaldehyde (372 mg, 1.31 mmol) in THF/MeOH (10/3 mL) is added portion-wise sodium borohydride (100 mg, 2.62 mmol) and warmed to room temperature. After 1 h TLC (30% EtOAc/hexane) indicates complete consumption of starting material. The reaction mixture is concentrated and the residue is partitioned between EtOAc (100 mL) and 0.2N HCl (20 mL). The aqueous layer is extracted with a second portion of EtOAc (50 mL). The combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound (374 mg, quant.). 1NMR (400 MHz, CDCl3) δ ppm: 7.68 (s, 4H), 7.56 (d, 2H, J=7.9 Hz), 7.35 (d, 2H, J=7.9 Hz), 3.92 (t, 2H, J=6.4 Hz), 2.94 (t, 2H, J=6.6 Hz).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[N:24]([CH3:30])[C:25](=[N:28][CH3:29])[S:26][CH:27]=1>C(#N)C>[CH3:30][N:24]1[C:23]([CH2:22][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:27][S:26]/[C:25]/1=[N:28]\[CH3:29]
Reactant: CN=c1scc(CCl)n1C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C/N=c1\scc(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C
Yield: 98.1 %

Procedure:
tert-Butyl piperazine-1-carboxylate (2.5 g) was dissolved in acetonitrile (50 mL). Potassium carbonate (3.7 g) and N-(4-chloromethyl-3-methyl-1,3-thiazol-2(3H) -ylidene)-N-methylamine hydrochloride (3.2 g) were added thereto, and the mixture was mixed under reflux for 4 hours. The solvent was distilled off, and to the residue was added an aqueous potassium bicarbonate solution. The mixture was then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a basic silica gel column to give the title compound (4.3 g) as a brown oily matter.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)[NH2:12])=[CH:2]1.Br[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>C(O)CCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:12][C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)=[CH:2]1
Reactant: Brc1ncccn1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Solvent: CCCCO
Product: c1ccc(-c2c[nH]c([C@@H](Cc3c[nH]c4ccccc34)Nc3ncccn3)n2)cc1
Temperature: 80 °C
Yield: 20 %

Procedure:
(1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethanamine (2 g; 0.0066 mol; prepared according to experimental conditions analogous to the preceding examples and using the appropriate starting compounds and reaction products) was diluted in 10 ml n-butanol. 2-bromopyrimidine (1 g; 0.0066 mol) and then diisoethylamine (1.15 ml; 0.0066 mol) were added dropwise. The mixture was then heated to around 80° C. for about 16 hours. The n-butanol was evaporated and the residue taken up in water and ethyl acetate. The organic phase was washed with water and then with a saturated solution of sodium chloride before being dried over magnesium sulfate and concentrated using a rotative evaporator. After purification over a silica column (eluent: ethyl acetate-heptane/7-3, followed by CH2Cl2-MeOH-NH4OH/95-4.5-0.5 and ethyl acetate). A white powder was obtained (yield of 20%). Free base. Melting point: 138-140° C. MH+=381.2.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([S:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[N:24]=[C:17]4[C:16]=3[CH:31]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:33].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([S:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[N:24]=[C:17]4[C:16]=3[CH:31]=2)(=[O:33])=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)N1CCC(S(=O)c2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)N1CCC(S(=O)(=O)c2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To an ice-cooled solution of 9-(1-isopropylpiperidine-4-sulfinyl)-2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 198 (50 mg, 0.1145 mmol) in DCM (10 mL) was added TFA (44 μL, 0.573 mmol) followed by a slow addition of a solution of m-CPBA (30 mg, 0.172 mmol) in DCM (1 mL). The resulting mixture was stirred for 2 h at RT. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 5-35% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. Further purification by column chromatography (Si-PCC, gradient 2-8% 2M NH3/MeOH in DCM) afforded 200 as a white solid (39 mg, 75%). LCMS: RT 2.05 min [M+H]+ 453.1. 1H NMR (DMSO, 400 MHz): δ 8.95 (1H, d, J=2.41 Hz), 8.53 (1H, ddd, J=4.81, 1.80, 0.93 Hz), 8.00-7.95 (2H, m), 7.84 (1H, td, J=7.69, 1.84 Hz), 7.69 (1H, dd, J=8.62, 2.43 Hz), 7.30-7.22 (2H, m), 4.65-4.54 (4H, m), 3.23-3.13 (1H, m), 2.82 (2H, bd, J=11.14 Hz), 2.68-2.59 (1H, m), 2.08 (2H, bt, J=11.51 Hz), 1.87 (2H, bd, J=12.10 Hz), 1.51-1.40 (2H, m), 0.89 (6H, d, J=6.55 Hz)
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH:9]([CH3:10])[N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6][N:5]([C:18](=[O:31])[C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)[CH2:4]1>C(OCC)(=O)C>[ClH:1].[CH3:10][CH:9]1[CH:3]([CH3:2])[CH2:4][N:5]([C:18](=[O:31])[C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)[CH2:6][CH2:7][NH:8]1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCN(C(=O)OC(C)(C)C)C(C)C(C)C2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCNC(C)C(C)C2)c1
Reaction time: 0.67 h

Procedure:
Hydrogen chloride gas was bubbled through a 0° C. solution of the compound 1-6 (385 mg, 0.93 mmol) in ethyl acetate (5 mL) for 1 minute. The reaction was sealed and stirred for 40 minutes. Concentration in vacuo gave the titled compound as a white solid. Data for 1-7: LC/MS: m/z (M+Na)=314.2 found; 314.4 calculated.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][C:5]=1[O:30]C)([CH3:3])[CH3:2].B(Br)(Br)Br.O>ClCCl>[OH:30][C:5]1[CH:6]=[C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)[CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)c(O)c1)CO2
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To a solution of N-(3-(4-isopropyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (500 mg, 1.18 mmol) obtained in Example 185 in dichloromethane (5 mL) was added dropwise at −70° C. under an argon atmosphere boron tribromide (1.0 M, dichloromethane solution, 2.36 mL, 2.36 mmol) and the resulting mixture was gradually warmed to room temperature. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 465 mg (yield: 96%) of the title compound. Melting point: 220-221° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C@@H:7]([C:19](=O)[NH2:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH:7]([C:19]#[N:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[CH3:2]
Reactant: CCOC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(N)=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)CCC(C#N)NC(=O)OCc1ccccc1

Procedure:
To a stirred suspension of Cbz-isoglutamine ethyl ester (15.42 g, 50 mmol) and pyridine (8.48 mL, 105 mmol) in 360 mL of anhydrous THF at 0° C. was added dropwise a solution of trifluoroacetic anhydride (7.77 mL, 55 mmol) in 40 mL of THF, at such a rate to maintain a temperature of 0°-5° C. for 1-2 hours or until reaction was complete as evidenced by TLC (5% H2O/94% CH3CN/1% HOAc; Cu(OAc)2 stain.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: COC(=O)c1ccc2occ(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1coc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 60 h
Yield: 95.9 %

Procedure:
Methyl 3-methyl-1-benzofuran-5-carboxylate (365 mg, 1.9 mmol) is dissolved in MeOH (7 mL), diluted with H2O (3.5 mL) and treated with 3N NaOH (1.41 mL, 4.2 mmol). The mixture is diluted with MeOH (3.5 mL) to homogeneity, stirred at RT for 2.5 days then concentrated to dryness. The residue is dissolved in H2O (5 mL) and acidified to pH 2 with concentrated HCl. The resulting solid is filtered and dried in a vacuum oven at 40° C. for 18 h to afford 321 mg (95%) of 3-methyl-1-benzofuran-5-carboxylic acid as a white solid. HRMS (FAB) calcd for C10H8O3+H: 177.0552, found: 177.0553 (M+H)+.
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-:3])=[O:2].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccn2)c1
Yield: 50.5 %

Procedure:
5-Nitroindazole (10.0 g, 61.3 mmol) was dissolved in THF (100 mL), and 2-(chloromethyl)pyridine hydrochloride (8.60 g, 52.4 mmol) and potassium carbonate (24.4 g, 184 mmol) were added. The mixture was heated for 4 h to 75° C. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (eluent: gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate) to yield 6.73 g (43%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)=[O:28]>O1CCCC1>[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:15][CH2:14]2)=[O:35])=[CH:32][CH:31]=1)=[O:28]
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
2.34 g of 1-[2-(4-chlorophenyl)ethyl]piperazine and 1.57 g of Hunig base (=N-ethyldiisopropylamine) are introduced into 40 ml of tetrahydrofuran. 2.36 g of 4-chloroacetylaminobenzoic acid chloride [see J. Med. Chem. 28 (1985) 910] are added thereto in small portions. After 30 minutes at 40°, the solution is concentrated by evaporation. The residue is chromatographed over silica gel, and recrystallisation is carried out from acetone, yielding 1-(4-chloroacetylaminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 146°-147°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1>O1CCCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCSCC2)nc1
Temperature: 25 °C

Procedure:
To a solution of 20 g (126 mmol) of 2-chloro-5-nitropyridine in 200 ml tetrahydrofuran were added dropwise 32.5 ml (315 mmol) thiomorpholine within 10 min. The reaction mixture was refluxed for additional 2 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was re-dissolved in 200 ml ethyl acetate. The organic phase was washed with 200 ml 1 N sodium bicarbonate solution, dried (magnesium sulfate) and evaporated to give 29.3 g (quantitative) of the title compound as a yellow solid.
Reaction SMILES: C([O:3][P:4]([C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:6]CC)=[O:5])C.C[Si](Br)(C)C>>[P:4]([C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:6])([OH:5])=[O:3]
Reactant: CCOP(=O)(C#Cc1ccccc1)OCC
Agent: C[Si](C)(C)Br
Product: O=P(O)(O)C#Cc1ccccc1

Procedure:
1-Diethylphosphono-2-phenylacetylene was deesterified with TMSBr as described in Step D, Example 1, to provide the title compound (no. 16.01) as a solid. HPLC Rt=3.75 min; negative ion electrospray MS M−1 found: 181.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:30])[CH2:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:16]([CH:21]=2)[C:17]([O:19]C)=[O:18])=[O:10])=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:2]=[CH:3][C:4]([C:7](=[O:30])[CH2:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)=[C:16]([CH:21]=2)[C:17]([OH:19])=[O:18])=[O:10])=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(NC(=O)CC(=O)c2ccc(-c3ccccc3)cc2)ccc1OCCN1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(CC(=O)c1ccc(-c2ccccc2)cc1)Nc1ccc(OCCN2CCCC2)c(C(=O)O)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
0.25 g (0.51 mmol) of methyl 5-(3-biphenyl-4-yl-3-oxopropionylamino)-2-(2-pyrrolidin-1-ylethoxy)benzoate (compound 1.9) is dissolved in 20 mL of methanol, 2.0 mL of 1N sodium hydroxide solution is added, and the mixture is stirred for 3 hours at 50° C. and 12 hours at ambient temperature. After this time, another 1.0 mL of 1N sodium hydroxide solution is added and the mixture is stirred for another 3 hours at 50° C. After cooling, 3.0 mL of 1N hydrochloric acid is added and the mixture is stirred for 1 hour at ambient temperature. The solvent is evaporated down, and the residue is taken up in a little methanol and the precipitate obtained is suction filtered and dried in vacuo at 80° C. Yield: 240 mg (100% of theory); Rf value: 0.20 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1); m.p. 236° C.-240° C.; C28H28N2O5; EII mass spectrum: m/z=473 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH:11]([OH:15])[C:12]([OH:14])=O.O([Si](C(C)(C)C)(C)C)S(C(F)(F)F)(=O)=O.C(OC(Cl)=O)C(C)C.[F:39][C:40]([F:54])([F:53])[C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:44][NH2:45].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O1CCCC1.C(N(CC)CC)C>[F:39][C:40]([F:53])([F:54])[C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([C:49]([F:52])([F:50])[F:51])[CH:48]=1)[CH2:44][NH:45][C:12](=[O:14])[CH:11]([CH2:10][C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:15]
Reactant: O=C(O)C(O)Cc1cc2ccccc2[nH]1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: CC(C)COC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(O)Cc1cc2ccccc2[nH]1
Reaction time: 2 h

Procedure:
Indolelactic acid (2.0 g) suspended in dichloromethane (25 ml) was treated with triethylamine (2.8 ml) and tertbutyldimethylsilyl triflate (2.3 ml) for 16 hours. Triethylamine (2 ml) was then added followed by iso-butylchloroformate (1.5 ml). After stirring for 30 minutes 3,5-bistrifluoromethylbenzylamine (2.5 g) was added and the reaction stirred a further 2 hours. The mixture was washed with 2N hydrochloric acid, aqueous sodium bicarbonate and water, then dried (Na2SO4) and concentrated. Chromatography on silica gel, eluting with ethyl acetate-petroleum ether (1:3) gave an oil which was treated with tetrabutylammonium fluoride (20 ml of a 1M solution in tetrahydrofuran) for 16 hours. The solution was concentrated, diluted with dichloromethane, washed with water, dried and concentrated. The residue was purified by chromatography (eluting with ethyl acetate-petroleum ether), followed by crystallisation from diethyl ether-petroleum ether to give the title compound as a white crystalline solid, mp 119° C.; found: C, 56.08; H, 3.85; N, 6.43; C20H 16 F6N2O2 requires C, 55.82; H, 3.75; N, 6.51.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A round-bottom flask was charged with 3,4-dinitrophenol (11.04 g, 60 mmol, commercially available from Fluka-Sigma-Aldrich), ethyl bromoacetate (11.02 g, 66 mmol), acetonitrile (120 mL) and cesium carbonate (21.6 g). The mixture was stirred at room temperature overnight. The mixture was filtered, and the recovered solid was washed with ethyl acetate. The filtrate was further diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and combined organic solvent was washed with saturated brine, dried and concentrated under reduced pressure. The residue was triturated with ether to give ethyl 2-(3,4-dinitrophenoxy)acetate (13.0 g, 80% yield). 1H-NMR (400 MHz, MeOH-d4): δ 8.15 (d, 1H), 7.55 (s, 1H), 7.35 (d, 1H), 4.95 (s, 2H), 4.23 (q, 2H), 1.25 (t, 3H). MS (EI): 271 (MH+).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:46]([C:50]1[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=1)[CH:47]([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:33]1[CH2:32][CH2:31][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:55]([C:53]3[N:54]=[C:50]([CH2:46][CH:47]([CH3:49])[CH3:48])[S:51][CH:52]=3)=[O:56])[CH2:29]2)[CH2:35][CH2:34]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1
Reactant: CC(C)Cc1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.34 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenyl)ethanol (example 82, step a) (0.2 g), 2-isobutylthiazole-4-carboxylic acid (0.13 g) and triethylamine (0.38 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.2 g.