Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)c1ccccc1
Reaction time: 18 h
Yield: 32.7 %

Procedure:
A solution of the compound of Example 69, 1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.98 g, 2.98 mmol) in 20 mL CH2Cl2 was treated with triethylamine (1.04, 7.45 mmol) and chilled in an ice water bath. With vigorous stirring, the solution was treated dropwise with benzoyl chloride (0.363 mL, 3.13 mmol). After 18 h, the reaction was treated with 25 mL water and 25 mL CH2Cl2 and the layers were separated. The organic portion was washed with 1% Na2CO3 solution, water, brine, dried over Na2SO4, filtered and concentrated to yield a yellow foam. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) followed by recrystallization from CH2Cl2/hexanes gave 422 mg of N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)benzamide as a light yellow powder. mp=154-156° C.; 1H NMR (300 MHz, DMSO-d6) δ8.36 (t, J=5.3 Hz, 1 H), 8.08 (d, J=8.0 Hz, 1 H), 7.82-7.73 (m, 2 H), 7.62 (d, J=8.3 Hz, 1 H), 7.55-7.40 (m, 4 H), 7.20 (t, J=8.2 Hz, 1 H), 6.58 (s, 2 H), 4.82 (t, J=5.3 Hz, 2 H), 4.75 (s, 2 H), 3.91 (t, J=5.2 Hz, 2 H), 3.54-3.45 (m, 4 H), 3.38 (q, J=5.2 Hz, 2 H), 1.13 (t, J=7.0 Hz, 3 H); 13C NMR (75 MHz, DMSO-d6) δ166.7, 152.3, 149.9, 145.6, 134.8, 133.5, 131.4, 128.6, 127.5, 127.1, 126.7, 121.4, 120.8, 115.1, 69.5, 69.2, 65.7, 64.7, 45.7, 15.3; MS m/z 434 (M+H)+; Anal. Calcd for C24H27N5O3: C, 66.50; H, 6.28; N, 16.15. Found: C, 66.24; H, 6.31; N, 15.96.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]2[C@H:16]([OH:17])[C@@H:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=3)[CH2:14][S:13](=[O:31])(=[O:30])[CH2:12]2)[CH:7]=[CH:6][C:5]=1[N+:32]([O-:34])=[O:33].BrCC1C=CC([N+]([O-])=O)=C(C=1)C(OC)=O.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][NH:18][C@H:15]1[CH2:14][S:13](=[O:31])(=[O:30])[CH2:12][C@@H:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]([N+:32]([O-:34])=[O:33])=[C:4]([CH:9]=2)[C:3]([OH:35])=[O:2])[C@@H:16]1[OH:17])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1cc(C[C@@H]2CS(=O)(=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)ccc1[N+](=O)[O-]
Agent: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3ccc([N+](=O)[O-])c(C(=O)O)c3)[C@@H]2O)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 5-[(3S*,4S*,5R*)-5-(3-tert-butyl-benzylamino)-4-hydroxy-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-3-ylmethyl]-2-nitro-benzoic acid methyl ester (434 mg, 0.86 mmol; prepared from methyl 5-(bromomethyl)-2-nitrobenzoate using a procedure analogous to that used in example 1) and NaOH (30% in H2O, 1 mL, 7.4 mmol) in anhydrous THF (5 mL) was stirred at 80° C. for 1 h. The reaction mixture was diluted with EtOAc and quenched with 2N aq. HCl to pH 2. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated to yield the product as a yellow gum: ESIMS [M+H]+=491, LCMS RtI=0.97 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=[O:13])[C:10]=1[Cl:11])[N:7](C(OC(C)(C)C)=O)[CH:6]=[CH:5]2.O.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=[O:13])[C:10]=1[Cl:11])[NH:7][CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)c(Cl)c(C(=O)O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(Cl)c(Br)cc2cc[nH]c12
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 100.1 %

Procedure:
To a mixture of 5-bromo-1-(tert-butoxycarbonyl)-6-chloro-1H-indole-7-carboxylic acid (0.3 g), water (2.0 mL), and methanol (6.0 mL) was added potassium carbonate (0.6 g) at room temperature. The reaction mixture was stirred at 70° C. for 5.5 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added thereto, followed by acidification with 1 M hydrochloric acid. Then, a liquid-separation operation was carried out, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to obtain 5-bromo-6-chloro-1H-indole-7-carboxylic acid (0.22 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.C(=O)(O)[O-].[K+].NC1C=CC=CN=1>>[N+:11]([C:5]1[CH:4]=[N:3][CH:2]=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Agent: Nc1ccccn1
Agent: O=C([O-])O
Agent: [K+]
Product: O=[N+]([O-])c1cncc([N+](=O)[O-])c1
Yield: 81 %

Procedure:
A mixture of 2-chloro-3,5-dinitropyridine (20.4 g, 0.10 mole) 15 ml absolute ethanol, potassium bicarbonate (11.0 g, 0.11 mole), and 2-aminopyridine (28.2 g, 0.30 mole) was refluxed for 24 hours. The mixture was concentrated to one-half of its volume and diluted with several volumes of water to precipitate solid. After further washing and drying 2-α-pyridylamino)-3,5-dinitropyridine (81% yield) was obtained as a golden, yellow solid. Anal. Calcd. for C10H7N5O4 : C, 46.0; H, 2.7; N, 26.8 Found: C, 46.1; H, 2.9; N, 27.0.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[C:16]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: OCc1ccncc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)OCc1ccncc1
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of 4-hydroxymethylpyridine (10.02 g) and triethylamine (9.27 g) in tetrahydrofuran (100 ml) was dropped a solution of hexadecanoyl chloride (25.2 g) in tetrahydrofuran (80 ml) under cooling in an ice bath and stirring, which was continued for one hour at the same temperature. A resulting precipitate was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in diether ether, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (250 g) using methylene chloride-ethyl acetate as an eluent to give 4-hexadecanoyloxymethylpyridine (14.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(Cl)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-chloro-2-fluoro-nitrobenzene (500 mg), phenol (270 mg), and potassium carbonate (400 mg) were dissolved in dimethyl sulfoxide (10 ml), and stirred at room temperature for 2 hours. The mixture was added with water and ethyl ether to extract an organic layer. The resulting organic layer was washed with saturated brine, and water was removed with sodium sulfate, and the solvent was removed by distillation under reduced pressure. The yellow target compound obtained by removing the solvent was used in the subsequent reaction without further purification (500 mg).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:26]=[C:25]([CH3:27])[C:20]([O:21][CH2:22][CH2:23][OH:24])=[C:19]([CH2:28][CH3:29])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:30][CH3:31])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C1COCC1.CC(=O)OCC>[CH3:41][S:42]([O:24][CH2:23][CH2:22][O:21][C:20]1[C:25]([CH3:27])=[CH:26][C:17]([C:14]2[N:13]=[C:12]([C:10]3[CH:9]=[C:8]([O:30][CH3:31])[N:7]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:11]=3)[O:16][N:15]=2)=[CH:18][C:19]=1[CH2:28][CH3:29])(=[O:44])=[O:43]
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
To a solution of 2-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)ethanol (638 mg, 1.51 mmol) in THF, DIPEA (389 mg, 3.01 mmol) is added. The mixture is cooled to 0° C. before methanesulfonyl chloride (207 mg, 1.81 mmol) is added. The mixture is stirred at rt for 30 min before it is diluted with EA (100 mL) and washed with sat. aq. NaHCO3 solution (50 mL) and brine (50 mL). The org. extract is dried over MgSO4, filtered and concentrated to give 2-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)ethyl methanesulfonate (733 mg) as a yellow oil; LC-MS: tR=1.19 min, [M+H]+=502.05.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.[NH2:12][C:13]1[N:18]=[N:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[F:36][C:33]([F:34])([F:35])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]([N:22]1[CH2:21][CH2:20][N:19]([C:16]2[N:17]=[N:18][C:13]([NH:12][C:7](=[O:9])[CH2:6][O:5][CH2:4][CH2:3][C:2]([F:1])([F:11])[F:10])=[CH:14][CH:15]=2)[CH2:24][CH2:23]1)=[O:26]
Reactant: O=C(O)COCCC(F)(F)F
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(COCCC(F)(F)F)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use (3,3,3-trifluoropropoxy)acetic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (50% yield). 1H NMR (300 MHz, CDCl3) δ 9.03, 8.32, 7.75, 7.63, 7.56, 7.37, 7.03, 4.13, 4.03-3.98, 3.94-3.89, 3.84, 3.71-3.63, 3.60-3.58, 3.35-3.32, 2.56-2.48. MS (ES+) m/z 506.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4](O)[NH:5][C:6]2=[O:11].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11]
Reactant: O=C1NC(O)c2c(F)cccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2c(F)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.05 g (about 24.2 mmol) of 4-fluoro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one were initially charged in 10 ml of dichloromethane, 22.4 ml (290.8 mmol) of trifluoroacetic acid and 7.7 ml (48.5 mmol) of triethylsilane were added and the mixture was stirred at RT overnight. The reaction mixture was then concentrated and the residue was dissolved in dichloromethane and washed with sodium bicarbonate solution. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 3:1 to 1:1). This gave 890 mg (24.2% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C@:10]3([C@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](O)=[O:26])[C@@H:11]3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:38].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([F:38])=[O:26])[CH:11]3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: Cc1ccccc1[C@H]1N(CC(=O)O)C(=O)C[C@@H](c2cccc(Cl)c2)[C@]12C(=O)Nc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(hydroxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.24 mmol) prepared in example 31 in dichloromethane (40 mL) at 0° C. was added cyanuric fluoride (48 mg, 0.35 mmol) (Alfa) and pyridine (37 mg, 0.48 mmol). After the mixture was stirred at 0° C. for 2 h, the mixture was partitioned between H2O and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO4, concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow gum and used for the next step without further purification (Yield: 0.12 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)[C:10]([F:13])([F:12])[F:11].Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+]>>[CH3:32][O:31][C:29](=[O:30])[C:28]1[CH:33]=[CH:34][CH:35]=[C:26]([CH2:25][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)[CH:27]=1
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cccc(COc2ccc(C(C)C(O)(c3cnc(C)cn3)C(F)(F)F)c(Cl)c2)c1

Procedure:
In analogy to Example 1, step 7, 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 1, step 6) was reacted with methyl 3-(bromomethyl)benzoate and potassium carbonate to give the title compound as a colorless viscous oil. MS (m/e, ISP neg. ion)=492.6 [M−H−].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@H:18]([CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH2:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a 50 mL round-bottomed flask was added 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (235 mg, 0.85 mmol) [prepared according to the procedure of Example 96], 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (290 mg, 0.82 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (479 mg, 1.02 mmol) in chloroform (8.5 mL). DIEA (742 μL, 4.25 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (174 mg, 0.30 mmol, 36%): LC-MS (ES) m/z=575 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:19].[C:20](=[O:23])([O-])[O-:21].[K+].[K+]>CO.O.C(Cl)Cl>[C:4]([O:21][C:20]([N:8]1[CH2:9][CH2:10][C:4]2[C:3]([OH:19])=[C:2]([Cl:1])[CH:18]=[CH:17][C:5]=2[CH2:6][CH2:7]1)=[O:23])([CH3:10])([CH3:5])[CH3:3]
Reactant: O=C(N1CCc2ccc(Cl)c(O)c2CC1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(O)c2CC1
Yield: 209.4 %

Procedure:
Dissolve 7-chloro-3-(2,2,2-trifluoroacetyl)-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.0 g, 6.80 mmol) in methanol (100 mL). Add potassium carbonate (14.08 g, 102 mmol) in water (50 mL) slowly. Stir the reaction at RT for 2 h, add tert-butoxycarbonyl anhydride (1.59 g, 7.48 mmol) in DCM (70 mL) and stir vigorously for 17 h. Concentrate the organic layer, wash the aqueous layer with DCM (3×50 mL), combine the organic layers, dry (MgSO4) and concentrate to give the title compound (2.12 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[O:14][CH2:13][O:12][C:4]=2[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-])=O.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[C:3]2[O:14][CH2:13][O:12][C:4]=2[CH:5]=[C:6]([CH3:11])[C:7]=1[NH2:8]
Reactant: [H][H]
Reactant: Cc1cc2c(c(C)c1[N+](=O)[O-])OCO2
Agent: [Pd]
Solvent: CCO
Product: Cc1cc2c(c(C)c1N)OCO2
Yield: 66.2 %

Procedure:
3,5-Dimethyl-4-nitro-I,2-(methylenedioxy)benzene (5.0 g) and 10% palladium on charcoal catalyst (1.2 g) in ethanol (250 ml) was shaken in a hydrogen atmosphere (50 p.s.i.) at 40° C. for 4 hours. The mixture was filtered through celite and evaporated to leave 2,6-dimethyl-3,4-(methylenedioxy)aniline (2.8 g, 68%) as a dark oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[C:8]([Cl:20])[CH:7]=2)[CH2:2]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]([C:34](OCC)=[O:35])=[N:31][N:30]=2)=[CH:25][CH:24]=1>>[Cl:20][C:8]1[CH:7]=[C:6]([CH:19]=[CH:18][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)[O:5][CH:3]1[CH2:4][N:1]([C:34]([C:32]2[O:33][C:29]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[N:30][N:31]=2)=[O:35])[CH2:2]1
Reactant: CN1CCN(Cc2ccc(OC3CNC3)cc2Cl)CC1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCN(C)CC5)c(Cl)c4)C3)o2)cc1
Yield: 64 %

Procedure:
Using a similar protocol as described in Example 16 employing 49A (2.7 g, 9.1 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (2.5 g, 10.0 mmol) as starting materials afforded 2.9 g (64%) of 49 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.28 (s, 3H), 2.3-2.7 (m, 8H), 3.56 (s, 2H), 3.88 (s, 3H), 4.32 (dd, 1H), 4.63 (dd, 1H), 4.74 (dd, 1H), 5.05 (m, 1H), 5.11 (m, 1H), 6.67 (dd, 1H), 6.78 (d, 1H), 7.02 (d, 2H), 7.39 (d, 1H), 8.09 (d, 2H), MS (APCI+) m/z 498 [M+H]+, LC purity: 95%.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1)#[N:2].[CH:12]([CH2:14][C:15]([OH:17])=[O:16])=[CH2:13].Cl[O-].[Na+]>O1CCCC1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[CH2:13][CH:12]([CH2:14][C:15]([OH:17])=[O:16])[O:9][N:8]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C=CCC(=O)O
Reactant: N#Cc1ccc(C=NO)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C2=NOC(CC(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a solution of 4-cyanobenzaldoxime (see Ex 2) (312 g, 2.13 mol) in tetrahydrofuran (3 L) at room temperature was added vinylacetic acid (552 g, 6.41 mol). The yellow solution was cooled in an ice bath and sodium hypochlorite solution (5200 mL)was added in a dropwise fashion over 2 h. After stirring overnight at room temperature the reaction was quenched with a 5% citric acid solution and diluted with 200 mL ether. The layers were separated and the aqueous acidified to pH 4 using citric acid. The acid layer was washed twice with 200 mL ether, the ether layers combined and extracted with saturated sodium bicarbonate solution. After acidifying the basic layer with citric acid, the product was extracted into 400 mL ether. The organic phase was washed three times with 150 mL water, once with brine, dried (MgSO4) and concentrated to give 220 g of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid as a white solid. Recrystallization from 25% water/ethanol yielded 165 g of analytically pure material; 1H NMR (300 MHz, CDCl3) δ 7.77-7.76 (d, J=1.8 Hz, 2H), 7.72-7.71 (d, J=1.8 Hz, 2H), 5.22-5.14 (m, 1H), 3.63-3.54 (dd, J=10.6 Hz, 16.8 Hz, 1H), 3.19-3.11 (dd, J=7.3 Hz, 16.8 Hz, 1H), 3.00-2.93 (dd, J=6.2 Hz, 16.5 Hz, 1H), 2.79-2.72 (dd, J=7.3 Hz, 16.5 Hz, 1H); IR (KBr): 3202, 2244, 1736, 1610, 1432, 1416, 1194, 1152, 928, 840, 562 cm-1. Anal. Calcd for C12H10N2O3 : C, 62.61; H, 4.38; N, 12.17. Found: C, 62.37; H, 4.47; N, 11.71.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Si:8]([O:15][CH2:16][CH:17]=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>S([O-])([O-])(=O)=O.[Cu+2].C(Cl)Cl>[Si:8]([O:15][CH2:16]/[CH:17]=[N:7]/[S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/CO[Si](C)(C)C(C)(C)C
Yield: 115.5 %

Procedure:
A three necked round bottom flask fitted with a mechanical stirrer, nitrogen inlet and temperature probe was charged with (S)-(−)-2-Methyl-2-Propanesulfinamide (113 g, 0.929 mol) and DCM (2.0 L) at RT (endotherm to 9° C.). Copper(II) Sulfate (309 g, 1.94 mol) was then added followed by (tert-butyldimethylsilyl-oxy)acetaldehyde (150 g, 0.774 mol). After 36 hours the reaction was filtered through a plug of Celite, plug rinsed with DCM (3×200 mL), and concentrated to provide 248 g of the title compound as a light yellow syrup (87 wt %). 1H NMR (CDCl3) δ 8.08 (1H, s), 4.56 (2H, s), 1.22 (9H, s), 0.95 (9H, s), 0.12 (6H, s).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([O:32][CH2:33][CH3:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[O:16])=[CH:8][CH:7]=1.[Li+].[OH-]>O1CCCC1>[CH2:33]([O:32][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[O:16])=[CH:8][CH:7]=1)[C:3]([OH:35])=[O:2])[CH3:34]
Reactant: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)OC)cc1)C(=O)Nc1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)O)cc1)C(=O)Nc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
A solution of 2-ethoxy-3-{4-[2-(1-heptyl-3-p-tolyl-ureido)-ethyl]-phenyl}-propionic acid methyl ester (40 mg, 0.083 mmol) and 1 M LiOH (0.25 mmol, 0.25 mL) in tetrahydrofuran (2 mL) was allowed to stir at room temperature for 16 hours. The solution was quenched by the addition of 2 N HCl until the solution had a pH<2. After dilution with twice its volume in water, the aqueous layer was extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (2×), dried over anhydrous sodium sulfate, and concentrated to a crude oil. The crude oil was chromatographed on silica gel (2% methanol/methylene chloride gradient to 15% methanol/methylene chloride) to give 2-ethoxy-3-{4-[2-(1-heptyl-3-p-tolyl-ureido)-ethyl]-phenyl}-propionic acid as a white waxy-solid (32 mg, 82%).