Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:30])([F:31])[F:29])[C:9]=4[CH:17]=3)=[CH:19][CH:20]=2)=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=570.90 (M+H+); retention time=0.98 minutes.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=2)=[CH:10][CH:9]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][C@H:38]3[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]3)=[CH:32][CH:31]=2)[C:25]([C:45]#[N:46])=[C:24](SC2C=CC=CC=2)[N:23]=1.O>COCCOC>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][C@H:38]3[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]3)=[CH:34][CH:35]=2)[C:25]([C:45]#[N:46])=[C:24]([O:20][CH2:19][C:17]2[N:18]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=3)[O:15][CH:16]=2)[N:23]=1
Reactant: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(Sc4ccccc4)c3C#N)cc2)O1
Reactant: OCc1coc(-c2ccc(Cl)cc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(OCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cc2)O1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
122 mg (1.09 mmol) of potassium tert-butoxide are suspended in 2 ml of dry 1,2-dimethoxyethane. 229 mg (1.09 mmol) of the compound from Example 100A and 100 mg (0.22 mmol) of the compound from Example 98A are then added successively. The reaction mixture is stirred at 60° C. for 2 h and, after cooling, at RT for a further 10 h. 5 ml of water are then added to the mixture. The precipitate formed is filtered off with suction and washed once with about 2 ml of cold water. This is followed by purification by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:32])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:43][CH2:44][CH2:45][NH2:46])[CH:36]=[CH:35][N:34]=1>O1CCCC1>[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:43][CH2:44][CH2:45][NH:46][C:11](=[O:32])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:36]=[CH:35][N:34]=1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Reactant: NCCCc1cccc2ccncc12
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCc2cccc3ccncc23)c2ccc(OC)cc2)cc1
Yield: 68.4 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-methoxyphenyl) -2,4-pentadienoic acid 4-nitrophenyl ester (0.24 g) and 8-isoquinolinepropanamine (0.103 g) in tetrahydrofuran (5 mL) was stirred for 17 hours at room temperature and was worked up in the usual manner. The crude amide was purified by HPLC (ethyl acetate) and then was crystallized from ethyl acetatehexane to afford 0.181 g of (E)-N-[3-(8-isoquinolinyl) propyl]-5,5-bis(4-methoxyphenyl)-2,4-pentadienamide, mp 115°-118° C.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(=O)(SC)OCCO[C:25](=O)[C:26]1C=CC=C[CH:27]=1>>[C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[C:2]1[CH:4]=[CH:27][CH:26]=[CH:25][CH:3]=1
Reactant: CSC(=O)OCCOC(=O)c1ccccc1
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Product: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)c1ccccc1

Procedure:
Following the procedures for synthesizing [(1-isobutanoyloxyethoxy)carbonyloxy]succinimide (17) and replacing compound (2) with compound (215) affords [(1-benzoyloxyethoxy)carbonyloxy]succinimide (216).
Reaction SMILES: [C:1]1(S(C2C=CC3C4CCN(CCO)CC=4OC=3C=2)(=O)=O)C=CC=C[CH:2]=1.[C:26]1([CH2:32][S:33]([O:36][C:37]2[CH:38]=[CH:39][C:40]3[O:49][CH:44]4[CH2:45][NH:46][CH2:47][CH2:48][C:43]4([CH3:50])[C:41]=3[CH:42]=2)(=[O:35])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.BrCC>>[C:26]1([CH2:32][S:33]([O:36][C:37]2[CH:38]=[CH:39][C:40]3[O:49][CH:44]4[CH2:45][N:46]([CH2:1][CH3:2])[CH2:47][CH2:48][C:43]4([CH3:50])[C:41]=3[CH:42]=2)(=[O:35])=[O:34])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c3c(oc2c1)CN(CCO)CC3
Reactant: CC12CCNCC1Oc1ccc(OS(=O)(=O)Cc3ccccc3)cc12
Solvent: CCBr
Product: CCN1CCC2(C)c3cc(OS(=O)(=O)Cc4ccccc4)ccc3OC2C1

Procedure:
Prepared as described for 2-[7-(phenylsulfonyl)-3,4-dihydro[1]benzofuro[2,3-c]pyridin-2(1H)-yl]ethanol (Example 592) starting from 4a-methyl-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridin-6-yl phenylmethanesulfonate (Example 757) and bromoethane. MS m/z 388 [M+H]+
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1[C:30]2[C:25](=[CH:26]C=C[CH:29]=2)[CH:24]=[CH:23][C:22]=1[S:31]([CH:34]1[S:38][C:37](=[O:39])[NH:36][C:35]1=[O:40])(=[O:33])=[O:32].C(N(CC)CC)C.ClCCl>O>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:36]2[C:35](=[O:40])[CH:34]([S:31]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:30][CH:29]=3)(=[O:32])=[O:33])[S:38][C:37]2=[O:39])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1NC(=O)C(S(=O)(=O)c2ccc3ccccc3n2)S1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)C2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Triphenylmethyl chloride (2.67 g, 9.58 mmol) was added to a stirred, room temperature solution of 5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione [(V), from Example 12, 1.30 g, 4.79 mmol], triethylamine (0.67 mL, 4.79 mmol) and dichloromethane (6.5 mL). After 1 h, water (300 mL) was added and the organic material was extracted with ethyl acetate (2×200 mL). The combined extracts were dried (brine, MgSO4), concentrated and purified by flash chromatography (4:1 petroleum ether:ethyl acetate) to provide the title compound as a white solid (1.1 g, 45%): mp 105°-110° C.; NMR (CDCl3): δ7.85 (d, J=8.3 Hz, 2H, ArH), 7.48 (d, J=8.1 Hz, 6H, CPh3H), 7.38 (d, J=8.3 Hz, 2H, ArH),7.23 (m, 9H, CPh3H), 5.13 (s, 1H, CH), 2.46 (s, 3H, CH3).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C:11]2[C:15]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[N:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[N:18][C:10]=2[CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O.O1CCOCC1>[CH2:22]([N:19]([CH2:20][CH3:21])[C:17]1[N:16]=[C:15]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][C:10]=2[N:18]=1)[CH3:23]
Reactant: CCN(CC)c1nc2c(c(-c3ccc(F)cc3)n1)CCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCN(CC)c1nc2c(c(-c3ccc(F)cc3)n1)CCCNC2
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 2-diethylamino-4-(4-fluoro-phenyl)-5,6,7,9-tetrahydro-pyrimido[4,5-c]azepine-8-carboxylic acid tert-butyl ester (0.058 g, 0.14 mmol) in EtOAc (1 mL) was added 4 M HCl in dioxane (2 mL). After 16 h, the mixture was concentrated, diluted with saturated (satd.) aqueous (aq.) NaHCO3, and extracted with CH2Cl2. The combined organic layers were dried and concentrated. Purification by FCC (2 M NH3 in MeOH/CH2Cl2) provided the title compound (>90%). HPLC: Rt=9.7 min. MS (ESI): mass calcd. for C18H23FN4, 314.4; m/z found, 315.4 [M+H]+. 1H NMR (CDCl3): 7.47 (dd, J=8.7, 5.5, 2H), 7.11 (t, J=8.7, 2H), 3.96 (5, 2H), 3.64 (q, J=7.0, 4H), 3.21-3.18 (m, 1H), 2.80-2.76 (m, 2H), 1.93-1.86 (m, 2H), 1.71-1.67 (m, 1H), 1.17 (t, J=7.0, 6H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:37]([C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1)([O-:39])=[O:38].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.O>[N:1]([CH2:4][C@@H:5]1[C@@H:9]([O:10][C:44]([C:43]2[CH:42]=[CH:41][C:40]([N+:37]([O-:39])=[O:38])=[CH:48][CH:47]=2)=[O:45])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CN=[N+]=[N-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a solution of the compound 3 (1.30 g) in tetrahydrofuran (25 mL), triphenylphosphine (3.10 g), 4-nitrobenzoic acid (2.24 g) and 2.2 mol/L of a solution (5.4 mL) of diethyl azodicarboxylate in toluene were added at 0° C. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was added water and extracted with ethyl acetate. The extract was washed with aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→4:1) to obtain the title compound (1.22 g) having the following physical properties.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([S:15](Cl)(=[O:17])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:8]([S:15]([NH:19][C:20]1[CH:32]=[C:31]([CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=[CH:29][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:17])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NS(=O)(=O)Cc1ccccc1
Reaction time: 2 h

Procedure:
0.082 mL of triethylamine, 39 mg of benzylsulfonyl chloride and 2.0 mL of methylene chloride were added to 1.0 mL of methylene chloride solution containing 50 mg of tert-butyl 2-amino-4-phenethylbenzoate at room temperature and stirred at the same temperature for 2 hours. 380 mg of aminomethylated polystyrene was added to she reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(benzylsulfonamido)-4-phenethylbenzoate.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.N#N.[C:17]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:22]=[CH:21][C:20]([NH:23][C:24]2[CH:36]=[CH:35][C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]([CH3:38])([CH3:37])[C:26]=3[CH:25]=2)=[CH:19][CH:18]=1.[Br:45][C:46]1[CH:51]=[CH:50][C:49](I)=[CH:48][CH:47]=1>C1(C)C=CC=CC=1.[Cu]Cl.O>[C:17]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:22]=[CH:21][C:20]([N:23]([C:49]2[CH:50]=[CH:51][C:46]([Br:45])=[CH:47][CH:48]=2)[C:24]2[CH:36]=[CH:35][C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]([CH3:38])([CH3:37])[C:26]=3[CH:25]=2)=[CH:19][CH:18]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC1(C)c2ccccc2-c2ccc(Nc3ccc(-c4ccccc4)cc3)cc21
Agent: Cl[Cu]
Agent: N#N
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)c2ccccc2-c2ccc(N(c3ccc(Br)cc3)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 130 °C

Procedure:
A degassed solution of 490 mg (0.16 mmol) of copper(I) chloride and 906 mg (5 mmol) of 1,10-phenanthroline in 100 ml of toluene is saturated with N2 for 1 h and heated to 130° C. 18 g (50 mmol) of N-[1,1-biphenyl]-4-yl-9,9-dimethyl-9H-fluoren-2-amine and 14 g (50 mmol) of 1-bromo-4-iodobenzene are subsequently added to the solution, which is then heated at 180° C. for 2 h. After cooling, 180 ml of water are added to the mixture, the organic phase is separated off, and the solvent is removed in vacuo. The product is recrystallised from n-hexane.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:10][C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]([N+:19]([O-])=O)=[CH:13][CH:12]=2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.C(OCC)(=O)C.O>CO.[Fe]>[NH2:19][C:14]1[C:15]([C:17]#[N:18])=[N:16][C:11]([S:10][C:5]2[CH:4]=[C:3]([Cl:2])[CH:8]=[C:7]([Cl:9])[CH:6]=2)=[CH:12][CH:13]=1
Reactant: N#Cc1nc(Sc2cc(Cl)cc(Cl)c2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1nc(Sc2cc(Cl)cc(Cl)c2)ccc1N

Procedure:
10 ml of concentrated HCl is added to a solution of 6-(3,5-dichlorophenylthio)-3-nitropicolinonitrile (3.4 g, 0.01 mol) in 50 ml of methanol under stirring. The reaction medium is refluxed, added together with 1.68 g (0.03 mol) of iron and stirred for 10 minutes. After returning to room temperature, the reaction mixture is added together with 100 ml of ethyl acetate and 50 ml of water. The pH is adjusted to 10 using 30% soda solution and the organic phase is extracted and then dried on anhydrous sodium sulfate before being concentrated. The residue is purified by silica gel chromatography (ethyl acetate/petroleum ether) to yield, after concentration of the fractions, 2.82 g (91%) of a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:11][N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>C(#N)C>[CH3:31][O:30][C:28](=[O:29])[CH2:27][N:16]1[CH2:17][CH2:18][CH:13]([C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:12][N:11]=2)[CH2:14][CH2:15]1
Reactant: COC(=O)CBr
Reactant: Fc1ccc(-c2nnc(C3CCNCC3)o2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CN1CCC(c2nnc(-c3ccc(F)cc3)o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 2-(4-fluorophenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (160 mg, 0.55 mmol) in acetonitrile (15 mL) was added triethylamine (0.192 mL, 1.4 mmol), then methyl 2-bromoacetate (0.066 mL, 0.715 mmol). The mixture was stirred overnight at room temperature for 8 h. The white precipitate was filtered, washed with acetonitrile, then ether. The mother liquor which contained the desired product was evaporated yielding the title compound as a white solid (100 mg) which was used without further purification. 1H NMR (400 MHz, chloroform-d) δ ppm 8.03 (dd, J=9.09, 5.05 Hz, 2H) 7.19 (t, J=8.59 Hz, 2H) 3.74 (s, 3H) 3.30 (s, 2H) 2.93-3.10 (m, 3H) 2.35-2.54 (m, 2H) 2.12 (dd, 4H). MS (m/z, MH+): 320.5
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[I:18][CH2:19][CH2:20][CH3:21]>CC(=O)C(C)(C)C.CC(C)=O>[I-:18].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][N+:15]([CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Reactant: CCCI
Solvent: CC(=O)C(C)(C)C
Solvent: CC(C)=O
Product: CCC[n+]1ccc(-c2ccc([N+](=O)[O-])c(OC)c2)cc1
Product: [I-]
Temperature: 102 °C
Yield: 65.6 %

Procedure:
To 4-[3-(methyloxy)-4-nitrophenyl]pyridine (5 g, 21.72 mmol) in 50 mL of pinacolone was added, 1-iodopropane (14.77 g, 86.87 mmol). The mixture was heated to 102° C. for 24 h. The mixture was cooled and diluted with acetone. The resulting slurry was filtered and washed with acetone. The product was dried under vacuum to give the title compound of step B (5.7 g, 14.24 mmol, 65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (d, J=6.78 Hz, 2H), 8.64 (d, J=6.78 Hz, 2H), 8.09 (d, J=8.42 Hz, 1H), 7.90 (d, J=1.65 Hz, 1H), 7.75 (dd, J=8.42, 1.65 Hz, 1H), 4.59 (t, J=7.33 Hz, 2H), 4.06 (s, 3H), 1.91-2.01 (m, 2H), 0.90 (t, J=7.33 Hz, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.[CH:20](=O)[CH:21]([CH3:23])[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:1]1([CH:20]([NH:17][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:21]([CH3:23])[CH3:22])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CC(C)C=O
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)C(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21

Procedure:
Benzotriazole, 4-chlorobenzamide, isobutyraldehyde, and p-toluenesulfonic acid were processed as in Example 53A to provide the desired product.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]([OH:22])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClC(Cl)=C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([N:8]1[C:12]([C:13](=[O:22])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CCc1ccccc1)c1cncn1Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)=C(Cl)Cl
Product: O=C(CCc1ccccc1)c1cncn1Cc1ccccc1

Procedure:
1-benzyl-5-(1-hydroxy-3-phenylpropyl)-1H-imidazole is oxidized with manganese dioxide in tetrachloroethylene, as it is described in Example 7 c).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:5]([OH:26])[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:8]([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C1C[O:41][CH2:40]C1.C(OC=O)(=O)C.N>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:29]1[CH:28]=[CH:27][C:4]([CH:5]([OH:26])[CH2:6][N:7]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]([CH3:18])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[CH:3][C:2]=1[NH:1][CH:40]=[O:41])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C1CCOC1
Reactant: COc1ccc(CC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(N)c2)cc1
Agent: CC(=O)OC=O
Agent: N
Solvent: Cc1ccccc1
Product: COc1ccc(CC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(NC=O)c2)cc1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
3-amino-4-benzyloxy-α-[N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)aminomethyl]benzyl alcohol (100 gms, 0.2 M), toluene 0.2 lit and 0.2 lit THF, were charged in a reactor. The reaction mass was cooled to 15° C. and 35 ml of 3:2 formic acid-acetic anhydride was introduced maintaining temperature below 20° C. The reaction mass was further stirred at 20-30° C. for 1 hour and concentrated under reduced pressure. The residue obtained was dissolved in toluene (0.65 lit) and basified with liquor ammonia. The organic layer was separated, washed with water and concentrated under reduced pressure below 35° C. to yield the title compound. (100 gms, 94.66%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([OH:14])[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.Cl.[NH:45]1[CH2:48][CH:47]([N:49]2[CH2:52][CH:51]([NH:53][C:54](=[O:57])[CH:55]=[CH2:56])[CH2:50]2)[CH2:46]1>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:45]2[CH2:46][CH:47]([N:49]3[CH2:52][CH:51]([NH:53][C:54](=[O:57])[CH:55]=[CH2:56])[CH2:50]3)[CH2:48]2)=[O:13])=[C:4]([OH:14])[CH:3]=1
Reactant: O=C(O)CNc1cc(Cl)c(Cl)cc1O
Reactant: C=CC(=O)NC1CN(C2CNC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(=O)NC1CN(C2CN(C(=O)CNc3cc(Cl)c(Cl)cc3O)C2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 2.9 %

Procedure:
A mixture of 2-(4,5-dichloro-2-hydroxyphenylamino)acetic acid (120 mg, 0.51 mmol), EDCI.HCl (147 mg, 0.77 mmol), HOBt (83 mg, 0.61 mmol), Et3N (154 mg, 1.53 mmol) in DMF (20 mL) was stirred at room temperature for 5 min and then N-(1-(azetidin-3-yl)azetidin-3-yl)acrylamide hydrochloride (150 mg, 0.69 mmol) was added. The resulting mixture was stirred at room temperature for 15 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH/NH3.H2O=100:10:1.5) to afford the desired product (6 mg, 3% yield). 1H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 8.59 (d, J=8.0 Hz, 1H), 6.79 (s, 1H), 6.55 (s, 1H), 6.20 (dd, J=10.0, 16.8 Hz, 1H), 6.09 (dd, J=2.0, 16.8 Hz, 1H), 5.62 (dd, J=2.0, 9.6 Hz, 1H), 5.20 (t, J=4.0 Hz, 1H), 4.40-4.35 (m, 1H), 4.19-4.15 (m, 1H), 3.96-3.88 (m, 2H), 3.73-3.69 (m, 3H), 3.53-3.45 (m, 3H), 3.00-2.96 (m, 2H). ESI-MS m/z: 399.2[M+H]+.
Reaction SMILES: C(O)(=O)C.C([O:9][C:10](=O)[CH2:11][CH2:12][CH:13]([OH:31])[C@@H:14]([N:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:15])(C)(C)C.C([O-])(O)=O.[Na+]>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH2:17]([N:16]([C@H:14]([C@H:13]1[O:31][C:10](=[O:9])[CH2:11][CH2:12]1)[CH3:15])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H](C(O)CCC(=O)OC(C)(C)C)N(Cc1ccccc1)Cc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C[C@@H]([C@@H]1CCC(=O)O1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
Glacial acetic acid (0.4 mL) and one drop of methanesulfonic acid were added to a solution of (5S)-5-(N,N-dibenzylamino)-4-hydroxy-hexanoic acid-tert-butyl ester (0.6 g, 1.57 mmol) in dry toluene (15.0 mL) in a 50 mL round bottom flask fitted with a reflux condenser. The reaction mixture was heated at reflux for 12 hours and then cooled to ambient temperature. The pH of the solution was adjusted to 7 by slow addition of a saturated solution of NaHCO3. The organic layer was separated, and the aqueous layer was extracted with Et2O (10 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvent was removed in vacuo. The residue thus obtained was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to obtain 0.41 g (85% yield) of pure (5S)-5[(1S)-1-(N,N-dibenzylamino)-ethyl]-dihydrofuran-2(3H)-one (5a). White solid, mp. 61-62° C., 1H NMR (300.15) δ 1-11 (d, J=6.6 Hz, 3 H), 1.83-2.15 (m, 2 H), 2.44-2.50 (m, 2 2.86 (pentet, J=6.9 Hz, 1 H), 3.71 (ABq, δA =3.87, δB =3.56, JAB=13.8 Hz, 4 H), 4.49 (pentet, J=7.2 Hz, 1 H), 7.10-7.41 (m, 10 H); 13C NMR (75.8 MHz) 10.9, 25.6, 28.7, 54.3, 55.8, 83.1, 126.8, 128.2, 128.7, 139.9, 177.1; MS (10W res.) 310 (M+1, 20%), 224 (MeCHNBn2, 40%), 91 (NBn2, 100%); HRMS for C20H24NO2 : 310.1807 (calc'd 310.1801); Anal calc'd for C20H23NO2 : C 77.64, H 7.49, N 4.53; Found: 77.54, H 7.55, N 4.49.