Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([P:8]([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])(=[O:16])[O:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]=[CH2:15])([F:7])[C:3]([F:6])([F:5])[F:4].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:7][C:2]([P:8]([C:17]([F:22])([F:23])[C:18]([F:21])([F:20])[F:19])(=[O:9])[O-:16])([F:1])[C:3]([F:6])([F:5])[F:4].[CH2:13]([O:12][CH2:11][CH2:10][N+:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH2:15]
Reactant: c1ccncc1
Reactant: C=CCOCCOP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Product: C=CCOCC[n+]1ccccc1
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(Allyloxy)ethyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)O—CH2CH2OCH2CH═CH2, (2.407 g; 6.2 mmol) is slowly added dropwise to dry and cooled (0° C.) pyridine (0.502 g; 6.3 mmol) in a 25 ml glass flask. An orange, more highly viscous solution forms spontaneously, which is stirred at 0° C. for 1 h, warmed and stirred at room temperature for 2 h. The readily volatile constituents are removed in vacuo (10−3 mbar) at room temperature. N-[2-(Allyloxy)ethyl]pyridinium bis(pentafluoroethyl)phosphinate, [CH2═CHCH2OCH2CH2Py][(C2F5)2P(O)O], is isolated (2.829 g; 6.1 mmol) as highly viscous, intensely red-brown liquid in quantitative yield and a purity of 89%.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[C:10]2[C@H:17]1[O:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][CH2:25][NH:26][CH3:27])[CH2:18]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[CH:37]=O.CC=C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[CH2:37][N:26]([CH3:27])[CH2:25][CH2:24][CH2:23][N:19]1[CH2:18][C@@H:17]([C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([O:6][CH3:5])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)[O:21][C:20]1=[O:22]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CNCCCN1C[C@@H](c2ccnc3ccc(OC)cc23)OC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2nccc([C@@H]3CN(CCCN(C)Cc4cc5ccccc5[nH]4)C(=O)O3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.5 %

Procedure:
Acetic acid (30 ul, 0.475 mmol) was added to a solution of (R)-5-(6-methoxy-quinolin-4-yl)-3-(3-methylamino-propyl)-oxazolidin-2-one (150 mg, 0.475 mmol) and 1H-indole-2-carbaldehyde [19005-93-7] (72 mg, 0.475 mmol) in methylene chloride stabilized over amylene (4.5 ml) and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (230 mg, 1.01 mmol) was then added and stirring was maintained for 48 hours at room temperature. Then water (5 ml) was added, the organic phase was decanted, washed with water dried over magnesium sulfate and concentrated. The residue was chromatographed on silicagel eluting with methylene chloride-methanol (9-1) to give a first crop of pure (R)-3-{3-[(1H-indol-2-ylmethyl)-methyl-amino]-propyl}-5-(6-methoxy-quinolin-4-yl)-oxazolidin-2-one (18 mg) and a less pure fraction of 90 mg (estimated yield >50%).
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH2:17]([C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][CH:23]2O)[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:23]2[C:24]3[C:20](=[C:19]([CH2:17][CH3:18])[CH:27]=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: CCc1cccc2c1CCC2O
Reactant: CCO[C@@H](CC(=O)OC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCO[C@@H](CC(=O)OC)c1ccc(OC2CCc3c(CC)cccc32)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Methyl (3S)-3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.446 mmol) produced in Example 41 (41C) and 4-ethylindan-1-ol (109 mg, 0.669 mmol) synthesized in (44B) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:17][C:18]1C=[CH:20][C:21](S(O)(=O)=O)=[CH:22][CH:23]=1.C1N=C[N:30]([C:33](N2C=NC=C2)=[O:34])C=1.N1CCCCCC1>C1COCC1.O>[CH2:10]([O:9][C:7](=[O:8])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH:1][C:33]([N:30]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:18][CH2:17]1)=[O:34])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C1CCCNCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
TEA (0.73 ml) was added dropwise to a suspension of Leu-OBzl.TsOH (1.97 g) and CDI (0.85 g) in THF (10 ml) at 0°~5° C. over a period of 5 min and the mixture was stirred at the same temperature for 1 h. Perhydroazepine (0.67 ml) was added and the reaction mixture was stirred at room temperature for 14 h, and poured into water (100 ml). The resulting precipitate was collected by filtration to afford the product (1.75 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27](Cl)=[O:28]>>[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:28]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1cc2ccccc2s1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cc5ccccc5s4)nc23)CC1
Yield: 45.5 %

Procedure:
Beginning with 0.41 gm (1.8 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.46 gm (2.33 mMol) 2-benzothiophenecarbonyl chloride, 0.32 gm (46%) of the title compound were prepared essentially by the procedure described in Example 4.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]2[CH2:13][NH:14][C:15](=[O:16])[CH:10]2[CH2:9]1)C1C=CC=CC=1>C(O)C.C(#N)C.[Pd]>[C:15]1(=[O:16])[CH:10]2[CH2:9][NH:8][CH2:12][CH:11]2[CH2:13][NH:14]1
Reactant: O=C1NCC2CN(Cc3ccccc3)CC12
Agent: [Pd]
Solvent: CC#N
Solvent: CCO
Product: O=C1NCC2CNCC12
Reaction time: 16 h

Procedure:
A solution of 5-benzylhexahydropyrrolo[3,4-c]pyrrole-1-one, (7.2 g; 33 mmol) in absolute ethanol (100 ml) is placed in a 250 ml autoclave and palladium-on-charcoal at 5% (1.5 g) is then added. After having purged with nitrogen, the autoclave is placed under 5-6 bar of hydrogen at 70° C. for 16 hours. After returning to 20° C., the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The compound obtained is taken up in acetonitrile (15 ml) at reflux, filtered, under hot conditions, through paper and then crystallized. After crystallization, the solid obtained is filtered off, washed with acetonitrile (3 ml) and then with diethyl ether (20 ml) and, finally, dried under reduced pressure at constant weight. Hexahydropyrrolo[3,4-c]pyrrole-1-one, (1.3 g; 31%) is isolated, the characteristics of which are as follows:
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][C:15]2[CH:16]=[N:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=3)=[N:19][CH:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:25][CH:26]=3)=[N:19][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCCCCCOc1ccc(-c2ncc(C=CCCCCCCCC3CCCC3)cn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCCCOc1ccc(-c2ncc(CCCCCCCCCC3CCCC3)cn2)cc1

Procedure:
A solution of 1.86 g of 5-(9-cyclopentyl-non-1-enyl)-2-(4-heptyloxy-phenyl)-pyrimidine in 35 ml of toluene is hydrogenated with 0.24 g of 5% palladium/charcoal at room temperature and normal pressure until the hydrogen uptake comes to a standstill. Recrystallization from ethanol of the crude product obtained after filtration and concentration of the filtrate yields pure 5-(9-cyclopentyl-nonyl)-2-(4-heptyloxy-phenyl)-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C@H:49]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:48][C@H:49]([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[C:50]2[CH:51]=[CH:52][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:54][CH:55]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Reactant: CCOP(C)(=O)c1ccc([C@H](N)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (2.5 g, 12.11 mmol) and Et3N (4.3 mg, 43 mmol) in MeCN (50 ml) was added HATU (4.83 mg, 12.72 mmol). The mixture was stirred for 5 min at room temperature and then ethyl 4-((R)-amino(phenyl)methyl)phenyl(methyl)phosphinate hydrochloride, 23-c, (3.5 g, 12.1 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (petroleum ether:ethyl acetate=2/1) to provide the product, 23-d, (4 g, 69%).
Reaction SMILES: [CH:1]([N:4]([C:6]#[N:7])[NH2:5])([CH3:3])[CH3:2].[OH-].[Na+].[CH2:10]([SH:12])[CH3:11].[CH2:13]([O:15]C(Cl)=O)C>O>[CH:1]([N:4]1[C:6]([S:12][CH2:10][CH3:11])=[N:7][C:13]([OH:15])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCS
Reactant: CC(C)N(N)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCSc1nc(O)nn1C(C)C
Temperature: 25 °C

Procedure:
19.8 g (0.2 mole) of 1-isopropyl-1-cyanohydrazine is added dropwise to a solution of 8.0 g (0.2 mole) of sodium hydroxide and 12.4 g (0.2 mole) of ethyl mercaptan in 150 ml of water, whereby a slightly exothermic reaction occurs. An addition is then made dropwise, at 20° to 25° C, of 21.7 g (0.2 mole) of chloroformic acid ethyl ester, and the reaction mixture is subsequently refluxed for 11/2 hours. On cooling of the reaction mixture to room temperature, there is precipitated an oil. The reaction mixture is extracted twice with 150 ml of chloroform each time; the extract is dried over sodium sulphate and the solvent is evaporated off in vacuo. The white crystalline residue is dissolved in 75 ml of methanol, the solution is treated with animal charcoal and crystallisation is effected at -70° C. There is obtained in this manner 1-isopropyl-3-hydroxy-5-ethylthio-1,2,4-triazole, m.p. 109°-113° C.
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].CCOCC>CO.O>[Br:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)CC)c(OCCOC)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)c1ccc(C(=O)O)c(Br)c1OCCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To 7.26 g (0.02 mole) of the ethyl 2-bromo-3-(2-methoxyethoxy)-4-ethylsulfonylbenzoate in 50 ml of 80% methanol/water was added 1.2 g (0.03 mole) of sodium hydroxide. After stirring at room temperature overnight, 100 ml of ether was added and the organic phase was extracted three times with 50 ml of 1N NaOH. The combined base extracts were acidified and extracted three times with methylene chloride. The methylene chloride was dried and concentrated to yield 6.6 grams of 2-bromo-3-(2-methoxy-ethoxy)-4-ethylsulfonylbenzoic acid as a viscous oil.
Reaction SMILES: [CH2:1]([N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=[C:24]([S:27](C)=O)SC)[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(Cl)Cl.[OH2:34].[CH3:35][O:36][CH2:37][CH2:38][O:39]C>>[CH2:1]([N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:37][C:38]([OH:39])=[O:34])[C:9]1[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:36][CH3:35])=[S:27])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: COCCOC
Reactant: CSC(=Cc1ccccc1N(Cc1ccccc1)c1c(Cl)cccc1Cl)S(C)=O
Agent: Cl
Solvent: ClCCl
Product: COC(=S)Cc1ccccc1N(Cc1ccccc1)c1c(Cl)cccc1Cl
Product: O=C(O)Cc1ccccc1N(Cc1ccccc1)c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 14 %
Yield: 81 %

Procedure:
In 26 ml of 1,2-dimethoxyethane, 1.2 g (0.0026 mole) of 1-[N-benzyl-o-(2,6-dichloroanilino)phenyl]-2-methylsulfinyl-2-methylthioethylene was dissolved and then, 13 ml of conc. HCl was added and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was cooled and 80 ml of methylene chloride and 10 ml of water were added to extract the reaction product and the separated water phase was further mixed with 70 ml of methylene chloride to extract the reaction product. Both of methylene chloride phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was separated by a column chromatography (silica gel: Wako gel Q-23 manufactured by Wako Junyaku and developing solvent:n-hexane:acetone=2:1) to obtain 0.14 g (yield: 14%) of N-benzyl-o-(2,6-dichloroanilino)phenyl acetic acid and 0.88 g (yield: 81%) of methyl N-benzyl-o-(2,6-dichloroanilino)phenylthioacetate.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15](=O)[CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CCO>[C:17]1([S:23][C:15]2([S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:10]=3)[C:9]3[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=3[CH2:12][CH2:13][CH2:14]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Sc1ccccc1
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)CCC2
Agent: Cl
Solvent: CCO
Product: CCNC(=O)Nc1nc2c(s1)C(Sc1ccccc1)(Sc1ccccc1)CCC2
Temperature: 20 °C
Reaction time: 2 h
Yield: 200.4 %

Procedure:
A suspension of N-ethyl-N′-(7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)urea (1.0 g, 4.18 mmol) and thiophenol (0.59 mL, 4.74 mmol) in EtOH (20 mL) was saturated with HCl (g) at about 0° C. The reaction mixture was stirred at about 20° C. for about 2 hrs then a second portion of thiophenol (0.59 mL, 4.74 mmol) was added and the reaction mixture stirred for about another 2 hrs. The ethanol was removed in vacuo and H2O was added. The aqueous phase was neutralized by addition of 2M NaOH and the product was extracted into CH2Cl2 (4 times). The combined organic phases were dried over MgSO4. Evaporation of the solvent gave 1.85 g (quantitative yield) pure product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:24][O:15][C:14]([C:11]1([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a stirred 4-(4-chloro-phenyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (852 mg, 2.5 mmol) in methanol (5 ml)-benzene (17.5 ml) was added 15 ml (trimethylsilyl)diazomethane (2.0 M solution in hexanes) at room temperature. The mixture was stirred for 16 hours at room temperature and concentrated in vacuo. The residual yellow oil was purified by silica gel chromatography eluting with hexane-ethyl acetate (9:1) to give the corresponding ester (780 mg, 88%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:20].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>CN(C=O)C>[Br:20][C:15]1[C:14]([O:18][CH3:19])=[C:10]([C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C(=O)O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)O
Reaction time: 18 h

Procedure:
A mixture of Example 151A (730 mg, 2.7 mmol) and tetrabutylammonium tribromide (1.3 g, 2.7 mmol) in DMF (15 mL) was treated dropwise with water (15 mL), stirred for 18 hours, and partitioned between water (250 mL) and ethyl acetate (250 mL). The organic phase was concentrated, diluted with dichloromethane (250 mL), washed with water (7×250 mL) and brine, dried (Na2SO4), filtered, concentrated and purified on silica gel with dichloromethane to provide the desired product. MS (ESI(+)) m/e 363, 365 (M+NH4)+, 368, 370 (M+Na)+; (ESI(−)) m/e 344, 346 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.50 (br s, 1H), 8.92 (s, 1H), 7.65 (d, 1H), 7.36 (d, 1H), 3.79 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[CH2:14]([O:16][C:17](=[O:29])[CH2:18][C@H:19]1[C:27]2[C:22](=[CH:23][C:24](O)=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[C@H:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:29])[CH2:20][CH2:21]3)=[N:7][CH:8]=1)#[N:11]
Reactant: N#Cc1ccc(OCCCO)nc1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C#N)cn3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
To a solution of 6-(3-hydroxypropoxy)nicotinonitrile (Example 257) (0.86 g, 4.83 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.89 g, 4.02 mmol) in THF (20 mL) was added triphenylphosphine (1.49 g, 5.63 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (1.44 g, 5.63 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h and concentrated under reduced pressure. The product (1.22 g, 80%) was isolated after purification by silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 8.47 (dd, 1H), 7.79 (dd, 1H), 7.05 (d, 1H), 6.82 (d, 1H), 6.77 (d, 1H), 6.69 (dd, 1H), 4.56 (t, 2H), 4.16 (q, 2H), 4.11 (t, 2H), 3.51 (qt, 1H), 2.95-2.78 (m, 2H), 2.70 (dd, 1H), 2.44-2.32 (m, 2H), 2.30-2.20 (m, 2H), 1.80-1.70 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10][CH:9]1[C:17]([O-:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH:24][C:17]([CH:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)[O-]
Reactant: Nc1c(F)cccc1F
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a suspension of lithium 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (589 mg, 2.18 mmol, Eq: 1.00) and 2,6-difluoroaniline (480 mg, 0.4 mL, 3.72 mmol, Eq: 1.71) in pyridine (7 mL) (ice-bath) was added dropwise phosphoryl trichloride (660 mg, 0.4 mL, 4.3 mmol, Eq: 1.97). The cooling bath was removed and the resulting yellow/orange suspension was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was treated with water (20 mL). The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were washed with brine (1×5 mL). The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 100% EtOAc in DCM/hexanes (1:1)). After the combined fractions were concentrated, the off-white solid was treated with 5% MeOH/ether (˜10 mL) to give tert-butyl 2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate as a white solid (532 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: Cc1cccc(C)c1N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(C)cccc1C

Procedure:
reacting 2,6-dimethylaniline with acetic anhydride to form N-(2,6-dimethylphenyl) acetamide,