Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)([OH:12])[CH2:8][CH2:7]1)=O)C.[H-].[Na+].[CH3:26]I.O>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2([O:12][CH3:26])[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]2)=[CH:14][C:15]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CI
Reactant: CCOC(=O)N1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
4-[4-Chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid ethyl ester (2.0 g) was dissolved in dimethylformamide and the mixture was cooled to 0° C. Sodium hydride (250 mg) was added thereto, and the mixture was stirred for 30 min. Then, methyl iodide (0.4 ml) was added, and the mixture was further stirred for 30 min and warmed to room temperature. Water was added thereto, and the mixture was extracted three times with methylene chloride. The organic layer dried over magnesium sulfate and the solvent was evaporated under reduced pressure. Ethanol (20 ml) and a 6N aqueous sodium hydroxide solution (15 ml) were added to the obtained residue, and the mixture was heated under reflux for hr. The reaction mixture was allowed to cool to room temperature, neutralized with 12N aqueous hydrochloric acid, and extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-methoxypiperidine (1.56 g, yield 93%).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[NH2:26][CH2:27][CH2:28][OH:29]>>[OH:29][CH2:28][CH2:27][NH:26][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Reactant: NCCO
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NCCO)nn1
Yield: 23 %

Procedure:
As described for example 69, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (100 mg, 0.29 mmol) was converted, using 2-aminoethanol instead of isopropylamine, to the title compound (24 mg, 23%) which was obtained as a light yellow solid. MS: m/e=356.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])[CH2:11][C:10]2=[O:17])=[CH:4][CH:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:18]([NH:25][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])[CH2:11][C:10]2=[O:17])=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CCCC1CC(=O)N(Cc2ccc(Cl)nc2)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCCC1CC(=O)N(Cc2ccc(NCc3ccccc3)nc2)C1
Yield: 10.9 %

Procedure:
To a solution of 1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one 228 (100 mg, 0.396 mmol, 1 eq), benzylamine (65 μl, 0.61 mmol, 1.6 eq) and potassium carbonate (274 mg, 1.98 mmol, 5 eq) is added a stirred solution of Pd2(dba)3 (Tris(dibenzylideneacetone)dipalladium(0), 18 mg, 0.02 mol, 0.05 eq) and BINAP (13 mg, 0.02 mol, 0.05 eq) in 2 ml of 1,4-dioxane. The mixture is heated at reflux for 36 h, filtered and concentrated. The crude product is dissolved in water and extracted three times with CH2Cl2. The organic phase is dried over MgSO4, filtered and evaporated to dryness. The crude is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 97/3/0.3 (v/v/v)) to afford 14 mg of 1-{[6-(benzylamino)pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one 229.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3](O)=[O:4].C1C=CC2N(O)N=[N:19][C:17]=2C=1.C(Cl)CCl.C(N(CC)CC)C.CN>ClCCl>[CH3:1][C:2]([CH3:12])([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([NH:19][CH3:17])=[O:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(Cc1cccs1)C(=O)O
Agent: CN
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)C(C)(C)Cc1cccs1
Reaction time: 0.33 h

Procedure:
A solution of 2,2-dimethyl-3-thiophen-2-yl-propionic acid (315 mg, 1.589 mmol) in 10 ml of dichloromethane was treated successively with HOBt (257 mg, 1.9 mmol), EDC (364 mg, 1.9 mmol) and triethylamine (0.223 ml, 1.6 mmol). The mixture was stirred for 20 minutes, then methylamine (0.621 ml, 8 mmol) was added and stirring was continued for 18 hours. The solvent was then evaporated and the crude was redissolved in ether, washed with 2N-HCl, saturated sodium bicarbonate and brine. Drying over sodium sulfate and evaporation gave a yellow-brown oil which was used without further purification. Yield: 244 mg (78%).
Reaction SMILES: N#N.CC([O-])(C)C.[K+].[CH2:9]([OH:12])[CH2:10][OH:11].Cl[C:14]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]=[O:29])=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2>O>[OH:11][CH2:10][CH2:9][O:12][C:14]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]=[O:29])=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: N#N
Agent: [K+]
Solvent: O
Product: O=Cc1c2ccccc2c(OCCO)c2ccccc12
Reaction time: 0.5 h

Procedure:
A 3-L 2-neck flask fitted with thermometer, condenser, stirring bar, N2 line and bubbler was charged with KOtBu (MCB Manufacturing Chemists, Inc., 2909 Highland Ave., Cincinnati, OH, 45212, 25 g, 0.22 mol), ethyleneglycol (1500 mL) and 10-chloro-9-anthraldehyde (Aldrich, 50 g, 0.207 mol). The mixture was stirred at 100° for 1.5 h. An additional 5 g (45 mmol) of KOtBu was added and the stirring continued for an additional 0.5 h. The reaction mixture was cooled and poured into 1500 mL of cold H2O, stirred for 10 minutes before the precipitate was collected by filtration. The yellow solid was dissolved in 1 L of CH2Cl2 and passed through a 100 g plug of SiO2 using CH2Cl2 (9 L). The CH2Cl2 contained impurities only and was discarded. The desired material was then eluted with EtOAc (12 L). The appropriate fractions were combined and the solvent removed to give after drying at 50° 10-(2-hydroxyethyloxy)-9-anthracenecarbaldehyde 28.82 g (53%), mp 142°-144°, (CH2Cl2 /hexane), (C,H).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]=1[CH3:26])#[N:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH2:37](Br)[CH:38]=[CH2:39].[Cl-].[NH4+]>O1CCCC1>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([CH:15]([CH2:39][CH:38]=[CH2:37])[C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:4]=1[CH3:26])#[N:2]
Reactant: COC(=O)Cc1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)OC)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.1 %

Procedure:
Methyl (4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)acetate (I-295) (2.215 g, 6.40 mmol) was dissolved in tetrahydrofuran (45 ml), and under nitrogen atmosphere at −78° C., potassium hexamethyldisilazide (0.5 M toluene solution) (19.2 ml, 9.59 mmol) was dropwise added, taking 10 minutes. After stirring at the same temperature for 1 hour, allyl bromide (847 μl, 9.59 mmol) was gradually added. The solution was gradually warmed up to 0° C., taking 1.5 hours, followed by stirring at the same temperature for 2 hours. At 0° C., aqueous saturated ammonium chloride solution was added to the solution, followed by stirring for 15 minutes. Under reduced pressure, THF was evaporated away, and the residue was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=4:1, v/v) to obtain the entitled compound (1.709 g, 69%) as a colorless gel. 410 mg (18.5%) of unreacted methyl (4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)acetate was recovered.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:15]2[O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:14]=2[CH:13]=[CH:12][CH:11]=1)([O-])=O.P(OCC)(OCC)OCC>ClC1C=CC=CC=1Cl>[CH:22]1[C:17]2[O:16][C:15]3[C:10]4[C:5]5[C:4]([NH:1][C:11]=4[CH:12]=[CH:13][C:14]=3[C:18]=2[CH:19]=[CH:20][CH:21]=1)=[CH:9][CH:8]=[CH:7][CH:6]=5
Reactant: O=[N+]([O-])c1ccccc1-c1cccc2c1oc1ccccc12
Agent: CCOP(OCC)OCC
Solvent: Clc1ccccc1Cl
Product: c1ccc2c(c1)[nH]c1ccc3c4ccccc4oc3c12

Procedure:
20 g of 4-(2-nitrophenyl)dibenzofuran (69 mmol) and 48 ml of triethyl phosphite (276 mmol) are heated at the boil in 800 ml of 1,2-dichlorobenzene under a protective-gas atmosphere for 48 h. After this time, the remaining triethyl phosphite and the 1,2-dichlorobenzene are removed by distillation. The residue which remains is recrystallised from heptane/ethyl acetate. The yield is 13 g (45 mmol, 65%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[C:5]([F:18])[C:3]=1[NH2:4].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[N:30]=[C:31]=[O:32]>C1COCC1>[F:18][C:5]1[CH:6]=[C:7]([B:9]2[O:13][C:12]([CH3:14])([CH3:15])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:8]=[C:2]([F:1])[C:3]=1[NH:4][C:31]([NH:30][C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=[CH:25][C:20]=1[F:19])=[O:32]
Reactant: CC1(C)OB(c2cc(F)c(N)c(F)c2)OC1(C)C
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc(F)c(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)OC1(C)C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.300 g, 1.18 mmol) in THF (2 mL) was added 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (0.314 g, 1.53 mmol). The reaction was stirred at 45 C overnight. Solid product was present in the reaction vessel. Product was further precipitated by the addition of 1:3 ether/hexanes. The solids were collected by filtration, dried under hi vacuum and found to be clean title compound in 71% yield. 1H-NMR (DMSO-d6) δ 7.03 (dd, J=6.6, 1.8 Hz, 2H), 5.76 (s, 2H), 1.26 (s, 12H); MS [M+H]+=461.2, LCMS RT=4.11 min
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.C(O)(=[O:16])C>C(OC(=O)C)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[C:3]2[C:4](=[O:13])[O:12][C:5](=[O:16])[NH:6][C:7]=2[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: CC(=O)O
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C1=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2c(=O)o1
Yield: 72 %

Procedure:
To a stirred solution of 4,6-dichloro-1H-indole-2,3-dione (5.00 g, 23.2 mM) in acetic acid (21 mL) and acetic anhydride (21 mL) at 80° C. was added in small portions chromium trioxide (4.12 g, 41.3 mM). The temperature of the reaction mixture was maintained between 80°-90° C. during the addition of the chromium trioxide. After the addition was complete, the reaction mixture was diluted with water (100 mL) and then filtered to separate the precipitated solids. The solids were washed thoroughly with water and then dried to obtain the title compound as a yellow solid (4.13 g, 72%); MS(CI): 232 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:32]=[N:33][N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:35]=2)[CH:19]=[CH:18]3)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].Cl.[OH-].[Na+].O>CO>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][N:34]=[N:33][N:32]=2)[CH:19]=[CH:18]3)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3-c3nnn[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
852 mg (1.21 mmol) of 2-ethyl-5,7-dimethyl-3-{[2-[2-(2-(triphenylmethyl)-2H-tetrazol-5-yl)phenyl]quinolin-6-yl]methyl}-3H-imidazo[4.5-b]pyridine obtained in Example 14 were suspended in 12 ml of methanol and 12 ml of concentrated hydrochloric acid were added thereto over an iced water bath. After stirring at room temperature for 24 hours, the reaction mixture was cooled with ice and acidified with a 10 N sodium hydroxide solution. 10 ml of water was added thereto followed by filtration and the filter cake were washed with 10 ml of a 1N sodium hydroxide solution. The filtrate was acidified by adding concentrated hydrochloric acid dropwise thereto with stirring and then extracted with 100 ml of ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain 518 mg of 2-ethyl-5,7-dimethyl-3-{[2-[2-(1H-tetrazol-5-yl)phenyl]quinolin-6-yl]methyl}-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1.[CH3:29]OS(OC)(=O)=O.C(=O)(O)[O-].[Na+]>CC(C)=O.CCOCC>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:29])[C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(OCc2ccccc2)c(Cl)cc1F
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCc3ccccc3)c(Cl)cc2F)c1=O
Yield: 62.2 %

Procedure:
A mixture of 1.85 g (4.46 mmol) of 3-[4-chloro-2-fluoro-5-(phenylmethoxy)phenyl]-6-(trifluoromethyl)-2,4(1H, 3H)-pyrimidinedione, 492 μL (5.20 mmol) of dimethylsulfate, and 749 mg (8.92 mmol) of sodium bicarbonate in 20 mL of acetone was warmed under reflux for 3 h. Evaporation removed the solvent to give a viscous residue. It was dissolved in 50 mL of ether and washed twice with 30 mL of water, dried (MgSO4) and concentrated in vacuo to give white solid which was flash chromatographed over silica gel, eluting with a 1:4 v:v mixture of ethyl acetate and hexane to give 1.19 g of the title compound as a white solid, m.p.: 145°-147° C.; 1H-NMR (CDCl3, 200 MHz) ppm 7.4 (m, 6H), 6.85 (d, 1H), 6.4 (s, 1H), 5.1 (s, 2H), 3.55 (s, 3H).
Reaction SMILES: C([O:8][C:9](=[O:45])[CH2:10][C@@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42](=[O:44])[NH2:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])C1C=CC=CC=1.C([C@H](NC(=O)[C@H](N1C=CC(C2C=CC(C3C=CC(C(=O)N)=CC=3)=CC=2)=C1)CC(O)=O)CO)C1C=CC=CC=1.[K+].[Br-]>>[CH2:18]([CH:15]([NH:14][C:12](=[O:13])[C@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42](=[O:44])[NH2:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[CH2:10][C:9]([OH:45])=[O:8])[CH2:16][OH:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1ccc(-c2ccc(-c3ccn([C@H](CC(=O)OCc4ccccc4)C(=O)N[C@H](CO)Cc4ccccc4)c3)cc2)cc1
Agent: NC(=O)c1ccc(-c2ccc(-c3ccn([C@H](CC(=O)O)C(=O)N[C@H](CO)Cc4ccccc4)c3)cc2)cc1
Agent: [Br-]
Agent: [K+]
Product: NC(=O)c1ccc(-c2ccc(-c3ccn([C@H](CC(=O)O)C(=O)NC(CO)Cc4ccccc4)c3)cc2)cc1
Yield: 95 %

Procedure:
According to the procedure described in Example 1(a), N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester was hydrogenolyzed to N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid in 95% yield, mp 218-20° C. 1H NMR (DMSO-d6): ∂ 8.12 (d, 1H, J=8.5 Hz), 7.97 (s, 1H), 7.88 (d, 2H, J=8.5 Hz), 7.72 (d, 2H, J=8.5 Hz), 7.57 (d, 2H, J=8.1 Hz), 7.33 (bs, 1H), 7.24 (s, 1H), 7.22-7.11 (m, 6H), 6.80 (bs, 1H), 6.42 (bs, 1H), 4.98-4.90 (bm, 1H), 4.80-4.72 (m, 1H), 3.82-3.76 (m, 1H), 2.82-2.70 (m, 2H), 2.62-2.50 (m, 1H). IR (KBr): 3402, 2925, 1658, 1601, 1400, 1202, 825, 782, 702, 633 cm−1. HRFABMS: Calculated for C30H29N3O5Cs (M+Cs+): 644.1162. Found: 644.1147. Anal. Calculated for C30H29N3O5.0.3CHCl3: C, 66.49; H, 5.40; N, 7.68. Found: C, 66.30; H, 5.50; N, 7.50.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:11]([P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[CH2:12])=[CH2:10])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O.O.O.O.O.O.O.O.O.[S-2:30].[Na+].[Na+]>C(O)C>[CH2:16]([O:15][P:13]([CH:11]1[CH:9]([P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][S:30][CH2:12]1)([O:18][CH2:19][CH3:20])=[O:14])[CH3:17]
Reactant: C=C(C(=C)P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(OCC)C1CSCC1P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.3 %

Procedure:
In ethanol, 2.02 g (6.19 mmols) of 2,3-bis(diethoxyphosphoryl)-1,3-butadiene was dissolved, to which 1.63 g (6.81 mmols) of commercially available sodium sulfide nonahydrate was added, followed by stirring at room temperature for 3 days. After completion of the reaction, the reaction mixture was dried over anhydrous sodium sulfate for 1 hour. Ethyl acetate was added to and the resulting mixture was charged into a silica gel column to dissolve out the specified substance with ethyl acetate. Thereafter, the solvent was removed, and the resulting crude product was purified with a silica gel column (ethyl acetate:chloroform=1:2) to obtain the specified substance in the form of a yellow oil at a yield of 1.88 g (yield: 84.3%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=2.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].I[CH2:25][CH3:26].C(OCC)(=O)C>CN(C=O)C>[CH2:25]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=2)[CH:10]=[C:2]1[CH3:1])[CH3:26]
Reactant: Cc1cc2ccc([N+](=O)[O-])cc2[nH]1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(C)cc2ccc([N+](=O)[O-])cc21
Reaction time: 2 h
Yield: 100 %

Procedure:
Cool a solution of 2-methyl-6-nitro-1H-indole, 18 (0.31 g, 1.76 mmol) in anhydrous DMF (5 mL) under inert atmosphere at 0° C. Add sodium hexamethyldisilazide (1.0M in THF, 1.9 mL, 1.9 mmol) and stir 5 minutes. Add iodoethane (filtered through basic alumina) (0.43 mL, 5.28 mmol), warm to ambient temperature, and stir 2 hours. Quench the reaction with saturated aqueous sodium bicarbonate, add ethyl acetate, and wash with saturated aqueous sodium bicarbonate followed by saturated aqueous brine. Dry the organic layer over sodium sulfate, filter, and concentrate in vacuo. Chromatograph over silica gel using hexanes/ethyl acetate (9:1) to afford the title compound, (0.36 g, 100%). 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 31), 4.18 (q, J=7.1 Hz, 2), 6.23 (s, 3H), 7.48 (d, J=8.8 Hz, 1H), 7.95 (dd, J=1.9, 8.6 Hz, 1H), 8.23 (d, J=1.9 Hz, 1H).
Reaction SMILES: [CH2:1]([C@@:4]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:20])[NH:5]1)[CH:2]=C.CC([OH:31])(C)C>C1COCC1.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:8][CH2:9][CH2:10][C@@:4]([CH2:1][CH2:2][OH:31])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:5][C:6]2=[O:20])[CH3:12])=[CH:14][CH:15]=1
Reactant: CC(C)(C)O
Reactant: C=CC[C@@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](c1ccc(Br)cc1)N1CCC[C@@](CCO)(c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 1517.5 %

Procedure:
To a stirred solution of (R)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-phenyl-1,3-diazepan-2-one (51 mg, 0.12 mmol) in THF (2 mL) and water (2 mL) were added NaIO4 (132 mg, 0.62 mmol) and 2.5% OSO4 in t-BuOH (0.032 mL, 0.003 mmol). The mixture was stirred at rt for 5 h and concentrated under reduced pressure. The residue was partitioned between EtOAc (90 mL) and brine (20 mL). The organic layer was concentrated and the residue was dissolved in MeOH (20 mL). The solution was cooled in an ice bath and NaBH4 (50 mg) was added. The mixture was stirred overnight and concentrated. The residue was taken up in EtOAc (90 mL), washed with 5% aq HCl (20 mL) and satd aq NaHCO3 (20 mL), and dried over Na2SO4. Removal of the solvent left an oil (43 mg) which was purified by prep HPLC to afford (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-hydroxyethyl)-4-phenyl-1,3-diazepan-2-one (19 mg, 37%) as an oil. LC-MS Method 2 tR=8.7 min, m/z=419, 417; 1H NMR (CDCl3) δ 1.0-1.2 (2H), 1.23 (d, 3H), 1.77 (m, 1H), 2.01 (m, 1H), 2.24 (m, 2H), 2.66 (m, 1H), 2.89 (m, 1H), 3.45 (m, 1H), 3.72 (m, 1H), 4.10 (br s, 1H), 5.50 (q, 1H), 6.79 (s, 1H), 7.24 (3H), 7.37 (2H), 7.43 (4H)
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9](B(O)O)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.O>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>[CH2:9]([C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=Cc1ccc(Br)o1
Reactant: CCCCCCB(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCc1ccc(C=O)o1
Temperature: 120 °C
Yield: 92.9 %

Procedure:
According to the method of Molander, et. al. (J. Org. Chem. 2009, 74, 3636), a suspension of 5-bromo-2-formylfuran (695 mg, 3.97 mmol), hexylboronic acid (775 mg, 5.96 mmol), potassium carbonate (1.65 g, 11.91 mmol), palladium(II) acetate (18 mg, 0.079 mmol) and RuPhos (74 mg, 0.16 mmol) in 9:1 toluene/water (22 mL) in a pressure-relief vial under argon was heated in a 120° C. bath for 18 h. After cooling to room temperature, the tion mixture was diluted with water (25 mL) and organics extracted with ether (3×50 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (10% ethyl acetate in hexanes) to give 5-hexyl-2-formylfuran (665 mg, 93%) as a clear oil. Used without further characterization.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])(=O)=O)=CC=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCOCC>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[CH2:31][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CN1CCNCC1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CN2CCN(C)CC2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a solution of {(2S)-1-[(4-methylphenyl)sulfonyl]pyrrolidin-2-yl}methyl 4-methylbenzenesulfonate (9.427 g, 23.13 mmol) (Tetrahedron, 43(14), 3289, 1987) in toluene (150 mL), was added n-methyl-piperazine (12.8 mL, 115.65 mmol) and DBU (0.352 g, 2.313 mmol) and the solution was stirred at 140° C. overnight. The reaction was then diluted with ether and washed with brine. The organic layer was dried over Na2SO4, filtered, concentrated and purified on Biotage flash 40M cartridge silica gel eluting with CH2Cl2/CH3OH/NH4OH (95.5/3/1.5) to give an off white solid (2.570 g, 55% ). NMR (400 Mz, DMSO-d6): consistent. MS (ES+) m/z 338.1 [M+H]. m.p.: 96.5-97.7° C. Reference: (Tetrahedron, 43(14), 3289, 1987).