Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[NH:17][C:18]([C:23]4[CH:28]=[C:27]([N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:26]=[CH:25][N:24]=4)=[CH:19][C:20](=[O:22])[CH:21]=3)[CH:11]=2)[CH2:6][CH2:5]1>C(#N)C>[CH2:35]([N:32]1[CH2:31][CH2:30][N:29]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([C:18]3[NH:17][C:16]([C:12]4[CH:11]=[C:10]([N:7]5[CH2:6][CH2:5][N:4]([CH2:3][CH2:12][CH2:16][CH3:21])[CH2:9][CH2:8]5)[CH:15]=[CH:14][N:13]=4)=[CH:21][C:20](=[O:22])[CH:19]=3)[CH:28]=2)[CH2:34][CH2:33]1)[CH2:11][CH2:10][CH3:15]
Reactant: CN1CCN(c2ccnc(-c3cc(=O)cc(-c4cc(N5CCN(C)CC5)ccn4)[nH]3)c2)CC1
Solvent: CC#N
Solvent: CI
Product: CCCCN1CCN(c2ccnc(-c3cc(=O)cc(-c4cc(N5CCN(CCCC)CC5)ccn4)[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.124 ml (1.99 mmol) of methyliodide are added dropwise to a suspension of 568 mg (0.994 mmol) 4,4″-bis-(4-methy-piperazin-1-yl)-1′H-[2,2′;6′,2″]terpyridin-4′-on in 18 ml acetonitril. The solution is stirred for 16 h at room temperature. The obtained whitish product (C33H49I2N7O) is filtered off and washed (with acetonitrile).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[C:10](=[O:33])[N:11]2[CH2:16][C:17]1[C:18]2[CH:26]=[C:25]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[S:24][C:19]=2[N:20]=[C:21]([CH3:23])[N:22]=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[CH:27]1([C:25]2[S:24][C:19]3[N:20]=[C:21]([CH3:23])[N:22]=[C:17]([CH2:16][N:11]4[C:10](=[O:33])[CH:9]5[CH2:15][CH2:14][CH:12]4[CH2:13][NH:8]5)[C:18]=3[CH:26]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1nc(CN2C(=O)C3CCC2CN3Cc2ccccc2)c2cc(C3CCCCC3)sc2n1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cc1nc(CN2C(=O)C3CCC2CN3)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a mixture of 5-benzyl-2-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]-2,5-diazabicyclo[2.2.2]octan-3-one (140 mg) and DCE (5 mL) was added 1-chloroethyl chloroformate (50 μL), followed by stirring at room temperature overnight. The reaction solution was purified by silica gel column (chloroform/MeOH/saturated aqueous NH3) without concentration. The residue was dissolved in MeOH, and heated to reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column (chloroform/MeOH/saturated aqueous NH3) to obtain 2-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]-2,5-diazabicyclo[2.2.2]octan-3-one (87 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:31]#[C:32][CH2:33][OH:34])[CH:14]=2)[N:9]=1>CO.[Pd]>[OH:34][CH2:33][C:32]#[C:31][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[N:17]=[C:16]2[NH:18][C@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Agent: [Pd]
Solvent: CO
Product: OCC#Cc1ccc2nc(-c3ccccc3O)nc(N[C@H]3CCNC3)c2c1
Reaction time: 12 h
Yield: 25.6 %

Procedure:
(S)-tert-Butyl 3-(2-(2-hydroxyphenyl)-6-(3-hydroxyprop-1-ynyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (prepared as shown in Synthesis 59-A, 0.030 g, 0.065 mmol) in methanol (3 mL) was hydrogenated at atmospheric pressure in the presence of 10% Pd on carbon (0.003 g) for 16 hours. The mixture was filtered through a pad of kieselguhr and concentrated. The crude alcohol was dissolved in methanol (1 mL) and 4 M HCl in dioxane (2 mL) added. After stirring for 12 hours, the solution was concentrated and purified by ion exchange chromatography on SCX-2 (solute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by preparative thin layer chromatography, eluting with 20% methanol in dichloromethane, gave the title compound as a yellow solid (0.006 g, 25%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][N:10]1[C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]([CH3:18])=[N:11]1>N1C=CC=CC=1.ClCCCl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([C:14]2[N:10]([CH3:9])[N:11]=[C:12]([CH3:18])[CH:13]=2)=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc(I)c1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1cc(C(=O)Nc2cccc(I)c2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-iodoaniline (131 mg, 0.60 mmol) in 1.5 ml pyridine at room temperature was added over 2 minutes a solution of 1,3-dimethylpyrazole-5-carbonyl chloride (79 mg, 0.50 mmol) in 0.3 ml 1,2-dichloroethane. The reaction was stirred at room temperature for 30 minutes, quenched into a NaHCO3 solution, and extracted into EtOAc. The EtOAc solution was washed with NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resultant gummy solid was recrystallized from hexane/EtOAc to give the title compound as solid white needles (135 mg, 80%).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[N:3]([CH3:13])[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Cn1c(Cl)c(C=O)c2ccccc21
Reactant: C1CNCCN1
Product: Cn1c(N2CCNCC2)c(C=O)c2ccccc21
Yield: 24 %

Procedure:
2-Chloro-1-methyl-1H-indole-3-carboxaldehyde (1.0 g, 5.5 mmol) is reacted with piperazine as described in Example 2 to yield the title compound (24%) as an orange-brown solid. MS 244 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([C:31]1[O:32][CH:33]=[CH:34][C:35]=1[CH3:36])=[O:30])#[CH:21]>>[CH3:36][C:35]1[CH:34]=[CH:33][O:32][C:31]=1[C:29]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]#[C:21][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:30]
Reactant: C#Cc1ccccc1NC(=O)c1occc1C
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: Cc1ccoc1C(=O)Nc1ccccc1C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Yield: 43.3 %

Procedure:
In a manner similar to that described for Example 460 (step 2), (S)-5-bromo-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide (0.050 g, 0.148 mmol) and 3-methyl-furan-2-carboxylic acid (2-ethynyl-phenyl)-amide (0.050 g, 0.222 mmol) were reacted to give the title compound (0.031 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=1
Reactant: CO
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(Cl)cc1

Procedure:
A suspension of 300 g of 4-chlorocinnamic acid (J. Am. Chem. Soc., 89:3803, 1967) and 25 ml of concentrated sulfuric acid in 1.7 liters of methanol is heated to reflux for 24 hours. The solution is concentrated, and filtered to give as a white solid, p-chlorocinnamic acid methyl ester, mp 74°-5° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:20]=[CH:19][C:9]2[O:10][C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].C(=O)([O-])[O-:22].[Cs+].[Cs+]>O.C(#N)C>[CH:7]1[C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[O:10][C:9]=2[CH:19]=[CH:20][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][OH:22]
Reactant: O=C([O-])[O-]
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCCC3
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=C(CO)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 7.2 %

Procedure:
A mixture of 2-chloro-N-6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-ylacetamide (0.115 g, 0.51 mmol) and cesium carbonate (0.34 g) in water (2 mL) and acetonitrile (4 mL) was heated in the microwave for 15 min. The reaction mixture was concentrated and the crude material was purified by HPLC to provide N-6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl-2-hydroxyacetamide (0.010 g). MS (ESI) m/z 274 ([M+H]+);MS (ESI) m/z 272 ([M−H]−).
Reaction SMILES: C[Si](OP(=O)=O)(C)C.[NH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[OH:16].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:22](O)=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:22]2[O:16][C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=2)[CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: Nc1cnccc1O
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Agent: C[Si](C)(C)OP(=O)=O
Product: COc1cc(-c2nc3cnccc3o2)ccc1-c1ccccn1
Temperature: 200 °C

Procedure:
To 7 mL trimethylsilyl polyphosphate was added 3-aminopyridin-4-ol (330 mg, 3.00 mmol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (460 mg, 2.00 mmol). The mixture was heated at 200° C. for 2 h, quenched over ice, and made basic (pH 14) with 1N NaOH. The aqueous phase was extracted with MTBE (3×200 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (50–100% EtOAc/hexanes followed by 10% MeOH/CHCl3) to give 2-(3-Methoxy-4-pyridin-2-ylphenyl)[1,3]oxazolo[4,5-c]pyridine as a yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 9.16 (s, 1H), 8.71 (d, 1H), 8.62 (d, 1H), 8.03–7.84 (m, 6H), 7.39 (t, 1H), 4.00 (s, 3H); MS (ESI) 304 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[CH:38]([Mg]Br)=[CH2:39].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]([OH:9])[CH:38]=[CH2:39]
Reactant: C=C[Mg]Br
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(C=O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 6-(N-(3-chloro-4-formylphenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1.17 g, 2.16 mmol) in THF (20 mL) was cooled to 0° and treated with vinylmagnesium bromide (1 M in THF, 4.76 mL). The reaction mixture was allowed to warm to rt as the bath melted. An additional portion of vinylmagnesium bromide (0.43 mL,) was added after a few h. Stirring was continued and the reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc (2×). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography (silica gel, gradient of 0 to 60% EtOAc in hexanes) afforded the title compound (0.87 g, 71%) as a white foam. Enantiomers were separated by supercritical fluid chromatography (Chiral Tech ADH, 30% methanol, 140 bar, 40° C., 90 mL/min). Both enantiomers were white foams. The earlier eluting enantiomer 1 weighed 380 mg and the later eluting enantiomer 2 weighed 370 mg. Enantiomer #1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (q, 1H), 8.11 (s, 1H), 7.93-8.01 (m, 2H), 7.35-7.55 (m, 5H), 7.18 (s, 1H), 5.90 (ddd, 1H), 5.70 (d, 1H), 5.35 (t, 1H), 5.22 (dt, 1H), 5.08 (dt, 1H), 3.40 (s, 3H), 2.83 (d, 3H), 2.10-2.20 (m, 1H), 0.77-1.06 (m, 3H), 0.40-0.53 (m, 1H). LCMS (m/z, ES+)=569 (M+H+). Enantiomer #2 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (q, 1H), 8.11 (s, 1H), 7.93-8.01 (m, 2H), 7.36-7.56 (m, 5H), 7.18 (s, 1H), 5.90 (ddd, 1H), 5.70 (d, 1H), 5.35 (t, 1H), 5.22 (dt, 1H), 5.08 (dt, 1H), 3.40 (s, 3H), 2.83 (d, 3H), 2.09-2.20 (m, 1H), 0.76-1.06 (m, 3H), 0.40-0.54 (m, 1H). LCMS (m/z, ES+)=569 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.Br[C:27]1[S:28][CH:29]=[CH:30][N:31]=1>CC(O)C>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCNc2nccs2)c2cccc(Cl)c2)C1
Reaction time: 96 h
Yield: 49.2 %

Procedure:
A 25 mL flask was charged with (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (100 mg, 0.27 mmol) and 2-bromo-thiazole (22 mg, 0.135 mmol) dissolved in propan-2-ol (5 mL) and stirred for 96 hr under reflux. The solvent and excess reagent was removed in vacuo to afford a residue purified by chromatography to give the pure (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(thiazol-2-ylamino)ethoxy)methyl)piperidine-1-carboxylate (30 mg, 25%)
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]2)=[CH:4][C:3]=1[F:17].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>[Cu]I.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.C1COCC1>[F:17][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH2:6][N:7]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CN(Cc2ccc(C#C[Si](C)(C)C)c(F)c2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate (25.00 g, 82.7 mmol), copper (I) iodide (3.14 g, 16.5 mmol), (trimethylsilyl)acetylene (81.9 mL, 579 mmol), bis(triphenylphosphine)palladium(II) chloride (5.81 g, 8.27 mmol), and Hunig's base (115 mL, 662 mmol) were combined in a sealable tube along with 100 mL THF. The tube was sealed and heated to 80 deg. C. under vigorous stirring for 24 h. The mixture was then cooled to room temperature, filtered, and evaporated. The resulting oil was purified by Biotage (75 L, 0-50% EtOAc/hexanes), affording methyl 1-(3-fluoro-4-(2-(trimethylsilyl)ethynyl)benzyl)azetidine-3-carboxylate as a transparent brown oil. MS (ESI) m/z: Calculated: 319.1; Observed: 320.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([O:12]C(C)C)=[O:11].S(=O)(=O)(O)O>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:9]
Reactant: Oc1ccc(F)cc1F
Reactant: CC(C)O[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)cc(F)c1O
Yield: 83.4 %

Procedure:
To a stirred solution of 2,4-difluorophenol (0.65 g, 5 mmol) in dichloromethane (7 mL) at room temperature was added tetrabutylammoniumhydrogen sulphate (0.085 g, 5 mol %) followed by isopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid (96%, 0.65 mL) was then added dropwise to the mixture causing gentle reflux of the solvent. The reaction mixture was then stirred for fifteen minutes and then poured onto water (50 mL). The phases were separated and the aqueous phase was extracted by dichloromethane (10 mL). The combined organic layers were washed by brine, dried over anhydrous sodium sulphate and filtered through a short pad of silica gel. Evaporation of the solvent (40° C., water aspirator pressure) afforded a yellow solid, identified by NMR as the title compound (0.73 g, 83%). (ortho-selectivity 100%, no nitro-isomers detected).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH2:15][C:16]2([CH2:21][CH2:22][CH3:23])[O:20][CH2:19][CH2:18][O:17]2)[CH:9]=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>CO>[CH3:12][C:11]1[C:6]([CH2:5][OH:4])=[N:7][CH:8]=[CH:9][C:10]=1[O:13][CH2:14][CH2:15][C:16]1([CH2:21][CH2:22][CH3:23])[O:20][CH2:19][CH2:18][O:17]1
Reactant: CCCC1(CCOc2ccnc(COC(C)=O)c2C)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC1(CCOc2ccnc(CO)c2C)OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
The (3-methyl-4-(2-(2-propyl-1,3-dioxolan-2-yl)ethoxy)pyridin-2-yl)methyl acetate (1.19 g, 3.68 mmol) obtained in the step (3d) was mixed with a 1N aqueous sodium hydroxide solution (5 ml) and methanol (10 ml). The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was suspended in tetrahydrofuran and sodium sulfate was added to the suspension, and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in a solution mixture containing heptane and ethyl acetate at a ratio of 2:1 and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=2/1) to obtain the title compound (0.88 g, 85%) as a colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][CH:12]1[C@H:16]([CH2:17][OH:18])[C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14][N:13]1[C@H:26]([CH2:37][CH:38]1[CH2:40][CH2:39]1)[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][CH:12]1[C@H:16]([CH:17]=[O:18])[C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14][N:13]1[C@H:26]([CH2:37][CH:38]1[CH2:40][CH2:39]1)[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]
Reactant: CC1[C@H](CO)[C@@H](c2cccc(F)c2)CN1[C@H](CC1CC1)C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1[C@H](C=O)[C@@H](c2cccc(F)c2)CN1[C@H](CC1CC1)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
Oxalyl chloride (0.022 mL, 0.25 mmol) was added to 5 mL of CH2Cl2 in a dry flask under nitrogen. The solution was cooled to −78° C., DMSO (0.040 mL, 0.57 mmol) was added, and the reaction mixture was stirred for 15 minutes. A solution of 2-(R)-(2-Methyl-3-(R)-hydroxymethyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclopropyl)propionic acid, benzyl ester (88 mg, 0.21 mmol, from Step C) in 0.75 mL of CH2Cl2 was added, and the reaction mixture was stirred at −78° C. for 30 min. Triethylamine (0.153 mL, 1.1 mmol) was added and the reaction mixture was warmed to room temperature, diluted with CH2Cl2 and washed twice with 1N NaOH and brine. The solution was dried over Na2SO4, filtered and concentrated to provide 54 mg (63% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ0.02-0.19 (m, 2H), 0.39-0.55 (m, 2H), 0.78-0.86 (m, 1H), 1.28 (d, 3H), 1.50-1.57 (m, 1H), 1.78-1.85 (m, 1H), 2.60-2.66 (m, 1H), 3.05-3.15 (m, 2H), 3.36-3.47 (m, 2H), 3.69-3.75 (m, 1H), 5.15-5.26 (m, 2H), 6.89-6.96 (m, 1H), 7.00-7.04 (m, 2H), 7.21-7.30 (m, 1H), 7.32-7.43 (m, 5H), 9.57 (d, 1H); ESI-MS (M+H): 410.3; HPLC A: 2.54 min.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[N:6]1[C:15]2[CH:14]=[CH:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1>C(OCC)(=O)C>[NH2:5][CH:13]1[CH2:14][C:15]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12]1
Reactant: C1=Cc2ncccc2CC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: NC1CCc2cccnc2C1

Procedure:
This compound was prepared from ammonium acetate (1.54 g, 20 mmol) and 5,6-dihydroquinoline (2.31 g, 10 mmol) using the method described in Example 36 and ethyl acetate instead of ether as the extracting solvent.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]([C:23]([NH2:25])=[O:24])[CH2:17]2>C(Cl)Cl>[C:8]([N:19]1[C:20]2[C:16](=[CH:15][C:14]([O:13][CH3:12])=[CH:22][CH:21]=2)[CH2:17][CH:18]1[C:23]([NH2:25])=[O:24])(=[O:10])[CH3:9]
Reactant: COc1ccc2c(c1)CC(C(N)=O)N2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(C(N)=O)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
Triethylamine (0.0106 mole) then acetyl chloride (0.0106 mole) were added to a solution of intermediate (21) (0.0032 mole) in DCM (40 ml) cooled in an ice bath under argon. The mixture was allowed to slowly warm to room temperature and stir overnight. The mixture was cooled in an ice bath and ice cold water (30 ml) was added. After stirring for 10 minutes, the mixture was filtered, and the solid was allowed to dry overnight. The residue was suspended in 50 ml water. The suspension was allowed to stir for 30 minutes, filtered, and dried overnight, yielding 0.40 g of 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carboxamide (intermediate 22, mp. 196-197° C.).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:47][C:48](=[O:56])[C@H:49]([CH2:51][CH2:52][C:53](=[O:55])[NH2:54])[NH2:50])(C)(C)C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:50][C@H:49]([C:48]([OH:56])=[O:47])[CH2:51][CH2:52][C:53](=[O:55])[NH2:54])=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(N)=O
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N[C@@H](CCC(N)=O)C(=O)O)cc2)cc1

Procedure:
The product from Example 233 and L-glutamine tert-butyl ester hydrochloride were processed as described in Example 251A and 258B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.00-12.89 (br.s, 1 H), 8.94 (s, 1 H), 8.13 (d, 1 H), 7.24 (m, 8 H), 6.98 (m, 7 H), 6.82 (d, 2 H), 6.73 (s, 1 H), 4.16 (m, 1 H), 4.05 (s, 2 H), 4.00 (s, 2 H), 3.95 (m, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.29 (t, 2 H), 2.12 (m, 2 H), 1.94 (m, 3 H), 1.74 (m, 1 H), MS (ESI+) m/z 703 (M+H)+.