Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[O:14][C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2].[N+:18]([O-])([OH:20])=[O:19]>C(OC(=O)C)(=O)C>[C:1]([NH:4][C:5]1[C:13]([N+:18]([O-:20])=[O:19])=[C:12]2[C:8](=[CH:7][C:6]=1[O:14][C:15](=[O:17])[CH3:16])[CH2:9][CH2:10][CH2:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cc1OC(C)=O)CCC2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(OC(C)=O)cc2c(c1[N+](=O)[O-])CCC2

Procedure:
Acetylation of 6-amino-5-indanol with acetic anhydride in ethyl acetate/pyridine gives 6-acetamido-5-acetoxyindan (m.p. 157°-158° C.), reaction of which with nitric acid in acetic anhydride gives 5-acetamido-6-acetoxy-4-nitroindan (m.p. 168°-170° C.). Acid saponification of this compound with hydrochloric acid gives 6-amino-7-nitro-5-indanol (m.p. 196°-198° C.), which is then reacted with 3-chloro-1,2-epoxypropane in dilute aqueous sodium hydroxide solution to give 5-amino-6-(2,3-epoxypropoxy)-4-nitroindan in the form of a dark oil, reaction of which with tert.-butylamine gives 5-amino-6-(2-hydroxy-3-tert.-butylaminopropoxy)-4-nitroindan in the form of an amorphous hydrochloride. Hydrogenation thereof in ethanolic solution in the presence of platinum dioxide gives 4,5-diamino-6-(2-hydroxy-3-tert.-butylaminopropoxy)-indan in the form of an amorphous trihydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=3)[N:21]=2)[CH2:11]1>>[CH3:9][C@@H:10]1[N:15]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:27])([F:26])[F:28])=[N:23][N:24]=3)[N:21]=2)[CH2:11]1
Reactant: C[C@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)CCN1
Reactant: O=Cc1cccnc1
Product: C[C@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)CCN1Cc1cccnc1
Yield: 62 %

Procedure:
A mixture of pyridine-3-carboxaldehyde and 6-[(3S)-3-methylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 6-[(3S)-3-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 62% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH2:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(N(CC)CC)C.C(=O)=O.CC(C)=O.[O:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=O)=[O:33]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][S:32]([C:35]([F:38])([F:37])[F:36])(=[O:33])=[O:31])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2n1C
Reaction time: 0.5 h

Procedure:
The N-Methyl-5-aminoindole2-carboxylic acid ethyl ester (2.4 g, 11 mmol) was added with 100 ml of CH2Cl2 and triethyl amine (2.3 ml, 16.5 mmol). The reaction mixture was brought to −78 degree (dry ice-acetone) under N2. After (CF3SO2)2O (2.0 ml, 12 mmol) was added into it slowly via a syringe, the reaction mixture was stirred at −78 degree for 30 min and slowly brought to room temperature. The reaction was treated with 300 ml of CH2Cl2 and washed with Sat. Na2SO4 (100 ml×3), H2O (100 ml×50, and brine. TLC (20% EA/Hexane) showed two components, the desired product with smaller Rf (0.4) value and the corresponding 5-(N, N-ditrifluoromethanesulfonyl)aminoindole (Rf 0.6). After the solvent was evaporated, the residue was purified either via recrystalization with CH2Cl2/Hexane or Flash Column (20% EA/Hexane). The purified product (1-Methyl-5-trifluoromethansulfonylamino-1H-indole-2-carboxylic acid ethyl ester) was obtained as a light orange solid (1.6 g). 1H-NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H, SNH-5), 7.64 (d, J=8.6 Hz, 1H, H-7), 7.60 (d, J=2.2 Hz, 1H, H-4), 7.31 (s, 1H, H-3), 7.23 (dd, J=2.2, 8.6 Hz, 1H, H-6), 4.33 (q, J=7 Hz, 2H, CH2CH3), 4.02 (s, 3H, NCH3), 1.33 (t, 3H, CH2CH3), MS m/z 349 [M−H].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[NH2:33][C:34]([CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1)=[S:35]>CN(C)C(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:35][C:34]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)=[N:33][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([O:19][CH2:20][CH:21]=[CH2:22])=[O:23])[C:12]=2[F:24])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Product: C=CCOC(=O)Nc1cccc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)sc2-c2ccnc(Cl)n2)c1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-carbamate (1.43 g, 4.09 mmol) in N,N-dimethylacetamide (DMA) (15 mL) was added NBS (0.728 g, 4.09 mmol), and the reaction mixture was stirred for 1 h. 1,1-Dimethylethyl 4-(aminocarbonothioyl)-1-piperidinecarboxylate (0.999 g, 4.09 mmol) was added and the reaction mixture was heated to 80° C. for 25 min. The mixture was cooled, quenched with water (30 mL) and extract with EtOAc (3×). The extract was dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (hexane/EtOAc, 0 to 100%) to give 1.34 g of the title compound. MS (ESI): 574.2 [M+1]+.
Reaction SMILES: [O:1]=[C:2]([CH:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])=[CH:10][CH:9]=1)[CH3:7])[C:3](N)=[O:4].[OH-:24].[Na+]>>[O:1]=[C:2]([CH:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:24])=[O:4]
Reactant: [OH-]
Reactant: CC(C(=O)C(N)=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Agent: [Na+]
Product: CC(C(=O)C(=O)O)c1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
A mixture of 2-oxo-3-[4-(1-oxo-2-isoindolinyl)phenyl] butanamide (0.30 g) and 10% aqueous sodium hydroxide solution (10 ml) is refluxed for 1 hour. After cooling the reaction mixture is washed with chloroform. The aqueous layer is acidified with diluted hydrochloric acid. The acidified layer is extracted with chloroform and the chloroform layer is washed with water, dried (Na2SO4) and evaporated. The residue is recrystallized from ethyl acetate to give colorless scales (0.23 g, 76%).
Reaction SMILES: C([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([CH2:8][C:9](=[O:32])[C:10]3[C@H:11]4[C@:23]([CH3:31])([CH2:24][CH2:25][C:26]=32)[C@@H:14]([C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]4)[CH2:6]1)(=O)C.Cl.O>C(O)C.[OH-].[Na+]>[O:32]=[C:9]1[CH2:8][C@@H:7]2[C@:27]([CH3:30])([CH2:28][CH2:29][C@H:5]([OH:4])[CH2:6]2)[C:26]2[CH2:25][CH2:24][C@@:23]3([CH3:31])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]1=2
Reactant: CC(=O)O[C@H]1CC[C@]2(C)C3=C(C(=O)C[C@H]2C1)[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@@H]1CC3=O
Temperature: 25 °C
Yield: 43.8 %

Procedure:
0.50 g of 3β-acetoxy-7-oxo-5α-cholest-8-ene (Fieser, L F J Am Chem Soc (1953) 4395) was refluxed in a mixture of 30 ml of ethanol and 20 ml of 1 M aqueous sodium hydroxide for 1 hour. After cooling to room temperature, 23 ml of 1M hydrochloric acid and 100 ml of water were added. After cooling on an ice bath, the precipitate was filtered off, washed with water and dried to give 0.435 g of the crude compound which was purified by chromatography on silica gel (methylene chloride/methanol, 40:1 (w/w)) and crystallized from methanol/water to give 0.198 g of the title compound. Melting point: 115-117° C. The 1H-NMR spectrum (CDCl3,d) showed characteristic signals at: 0.59 (s,3H); 1.18 (s,3H); 3.64 (m,1H). The 13C-NMR spectrum (CDCl3, 100.6 MHz) showed characteristic signals at: 69.5; 132.8; 164.8; 198.6.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:7]([C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6]1)=[O:4].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27].NC(N)=O>O1CCOCC1>[CH3:1][O:2][C:3]([N:5]1[CH2:9][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:7]([C:15](=[O:22])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:25][N:26]([CH3:28])[CH3:27])[CH2:6]1)=[O:4]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)C1=C(N2CCCC2)CN(C(=O)OC)C1
Agent: NC(N)=O
Solvent: C1COCCO1
Product: CCOC(=O)C(=CN(C)C)C(=O)C1=C(N2CCCC2)CN(C(=O)OC)C1

Procedure:
A solution of 12.41 g of N-methoxycarbonyl-3-carboethoxyacetyl-4-pyrrolidino-2,5-dihydropyrrole, 9.64 ml of N,N-dimethylformamide dimethylacetal and 10 mg of urea in 50 ml of dioxane is stirred under nitrogen for 16 hours. Evaporation of the solvent yields N-methoxycarbonyl-3-(2-ethoxycarbonyl-3-dimethylaminoacryloyl)-4-pyrrolidino-2,5-dihydropyrrole as an oil.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][S:9]([CH2:11][C:12]([OH:14])=[O:13])=[O:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:15][C@H:16]1[C@:33]([OH:38])([C:34]([CH2:36]O)=[O:35])[C@:32]2([CH3:39])[C@H:18]([C@H:19]3[C@:29]([F:41])([C@@H:30]([OH:40])[CH2:31]2)[C@:28]2([CH3:42])[C:22](=[CH:23][C:24]([CH:26]=[CH:27]2)=[O:25])[CH2:21][CH2:20]3)[CH2:17]1.C1CCC(N=C=NC2CCCCC2)CC1.CCOC(C)=O>C1COCC1.CN(C1C=CN=CC=1)C>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:1]([O:6][CH2:7][CH2:8][S:9]([CH2:11][C:12]([O:14][CH2:36][C:34]([C@:33]1([OH:38])[C:32]2([CH3:39])[CH:18]([C@H:19]3[C@:29]([F:41])([C@@H:30]([OH:40])[CH2:31]2)[C@:28]2([CH3:42])[C:22](=[CH:23][C:24](=[O:25])[CH:26]=[CH:27]2)[CH2:21][CH2:20]3)[CH2:17][C@H:16]1[CH3:15])=[O:35])=[O:13])=[O:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCS(=O)CC(=O)O
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)C(=O)O
Product: C=C(C)C(=O)OCCS(=O)CC(=O)OCC(=O)[C@@]1(O)[C@H](C)CC2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)CC21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
5 (0.54 g, 2.4 mmol, 1.05 eqv.) was dissolved in dry THF (5 mL) and DMAP (0.14 g, 1.2 mmol, 0.5 eqv.) was added to the solution under nitrogen. After cooling on ice, a dexamethasone solution (0.91 g, 2.3 mmol, 1 eqv.) in dry THF (25 mL) and DCC (0.525 g, 2.5 mmol, 1.1 eqv.) were added to the mixture. The reaction mixture was slowly warmed to room temperature and stirred overnight at RT. The completion of the reaction was confirmed by TLC (EtOAc/Hex, 20:1 (v/v), Rf: 0.24). Most of the solvent was evaporated and the remaining solution was purified on a 20 cm silica gel column (EtOAc/Hex, 20:1 (v/v)). 1 g (73% yield) DMSL2 was obtained as a yellow fluffy solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([P:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+]([O-])(O)=[O:14]>>[N+:1]([C:4]1[CH:5]=[C:6]([P:10]([OH:14])(=[O:12])[OH:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1cccc(P(O)O)c1
Product: O=[N+]([O-])c1cccc(P(=O)(O)O)c1

Procedure:
According to my invention phenylphosphorus dichloride is converted to benzenephosphonous acid (B), which is nitrated (I) with nitric acid at a temperature around 0° C. to form m-nitrobenzenephosphonous acid (E) which, to my knowledge, is a compound not previously described in the literature. Compound E is conveniently oxidized by heating (II) the reaction mixture in the presence of additional nitric acid to form m-nitrobenzenephosphonic acid (C), and then compound (D) by subsequent reduction. My contribution, then, includes the nitration of benzenephosphonous acid (B), which is considerably less costly than benzenephosphonic acid (A), to form the novel compound m-nitrobenzenephosphonous acid (E), followed by oxidation to form m-nitrobenzene phosphonic acid (C) which is converted by conventional reduction to form the desired m-aminobenzenephosphonic acid (D).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2Br)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1OCc1ccccc1
Reactant: CCOC(=O)c1cccc(-c2ccccc2Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(-c2ccccc2-c2ccccc2OCc2ccccc2)c1
Temperature: 90 °C
Yield: 41 %

Procedure:
2′-Bromobiphenyl-3-carboxylic acid ethyl ester (153 mg, 0.5 mmol) and 2-benzyloxyphenylboronic acid (125 mg (0.55 mmol) were dissolved in 1:1 toluene:ethanol (5 ml) under nitrogen. Potassium carbonate (552 mg, 4 mmol) and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) were added and the mixture heated at 90° C. for 3 h. After cooling, the solvent was evaporated. The residue was partitioned between diethyl ether and water and the organic phase washed with water, dried (MgSO4) and the solvent removed in vacuo. The residue was flash chromatographed (silica gel, 2-10% EtOAc-isohexane) to give the title compound as a clear oil (84 mg, 41%). LC/MS Rt=4.09 [(M−OEt)H+]=363.1.
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:18]([C:15]1[N:14]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:8])[C:17]=2[N:16]=1)[CH3:19]
Reactant: CCc1nc2c(OCc3ccccc3)cccc2n1Cc1ccccn1
Agent: [Pd]
Solvent: CCO
Product: CCc1nc2c(O)cccc2n1Cc1ccccn1
Reaction time: 8 h

Procedure:
To a solution cold solution (ice bath) of 7-benzyloxy-2-ethyl-1H-benzimidazole prepared above (0.8 g, 3.17 mmol) in DMF (10 mL) was added sodium hydride (0.41 g, 10.47 mmol), followed by 2-(bromomethyl)pyridine hydrobromide (0.88 g, 3.49 mmol). After addition of the bromide the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate. Ethyl acetate layer was separated, dried (MgSO4), and concentrated to give 4-benzyloxy-2-ethyl-1-pyridin2-ylmethyl-1H-benzoimidazole as a solid which was crystallized in ethyl acetate to give 4-benzyloxy-2-ethyl-1-pyridin2-ylmethyl-1H-benzoimidazole, 0.35 g. LCMS 344 (M+1). 1HNMR (400 MHz, CDCl3) δ 1.38 (t, 3H), 2.90 (q, 2H), 5.40-5.42 (m, 4H), 6.65-8.60 (12H, Ar) 4-benzyloxy-2-ethyl-1-pyridin2-ylmethyl-1H-benzoimidazole (0.35 g, 1.2 mmol) was dissolved in ethanol and in presence of Pd/C, 10% and stirred under a hydrogen balloon overnight. The solution was filtered through celite and concentrated to give 2-ethyl-1-pyridin-2-ylmethyl-1H-benzoimidazole-4-ol. 1HNMR (400 MHz, CDCl3) δ 1.28 (t, 3H), 2.87 (q, 2H), 5.40 (s, 2H), 6.49 (d, 1Har), 6.51 (m, 2H, Ar), 6.92 (m. 1H Ar), 7.09 (m, 1H, Ar), 7.73 (m, 1H, Ar), 8.49 (m, 1H, Ar), 9.57 (1H, OH).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1)[CH3:14].CI.Cl>O1CCCC1>[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:1])[C:23]#[N:24])=[CH:18][CH:17]=1)[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCOc1ccc(CC#N)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOc1ccc(C(C)C#N)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of 8.8 g of diisopropylamine in 150 ml of dry tetrahydrofuran were added 50 ml (1.5 mmole/ml) of n-butyl lithium at -50° C. After stirring at -20° C. for 30 minutes, 10.0 g of 4-ethoxyphenylacetonitrile was added thereto at -50° C. After stirring at the same temperature for 1 hour, 10.1 g of methyl iodide was added dropwise at -50° C. After stirring at the same temperature for 3 hours and then at 20° C. for 10 hours, the reaction solution was poured into 10% aqueous hydrochloric acid and extracted with ethyl acetate. After concentrating the ethyl acetate layer, the residual oil was column-chromatographed on silica gel (developing solvent, n-hexane: ethyl acetate=20:1) to obtain 9.50 g of the desired 2-(4-ethoxyphenyl) propionitrile [corresponding to the compound represented by the foregoing formula (II) wherein R1 is an ethoxy group, R2 is a hydrogen atom and R4 is a methyl group] as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(OC(N1CCC(C(=O)NC2CCCCC2)CC1)=O)(C)(C)C>>[CH:18]1([NH:24][C:14]([C:11]2([CH3:17])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: NC1CCCCC1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)NC2CCCCC2)CC1
Product: CC1(C(=O)NC2CCCCC2)CCNCC1

Procedure:
The title compound is prepared according to the reaction sequence 3.01a-2.01b described above using 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid instead of 1-(tert-butoxycarbonyl)-piperidine-4-carboxylic acid and cyclohexylamine instead of cyclohexylamine as in 3.01a: LC-MS A: tR=0.50 min; [M+H]+=225.17.
Reaction SMILES: C[N:2](C)[NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])=[O:5].Cl[C:16]([Cl:26])(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH2:27](Cl)Cl>>[Cl:26][C:16]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[C:4](=[O:5])[N:3]([CH3:27])[N:2]=1
Reactant: Cc1ccccc1NC(=O)NN(C)C
Reactant: ClCCl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: Cc1ccccc1-n1c(Cl)nn(C)c1=O
Yield: 64 %

Procedure:
To a solution of 11.1 g 2,2-dimethyl-N-(2-methylphenyl) hydrazine carboxamide dissolved in 600 mL methylene chloride under N2 was added 17.1 g triphosgene. The solution was heated at refulx overnight, cooled, then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with water, then saturated aqueous NaCl. The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (30 -50% ethyl acetate/hexanes as eluent) to afford 8.25 g (64%) of the title compound of Step B. 1H NMR (CDCl3) δ7.42 -7.30 (m,3H), 7.17 (d,1H), 3.54 (s,3H), 2.22 (s,3H).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].CCN(CC)CC.[P:33]([O-:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([O:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:2]([P:33]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])=[O:40])=[C:3]([CH:14]=1)[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(Cc1cc(NC(=O)OC(C)(C)C)ccc1Br)C(=O)OC(C)(C)C
Reactant: CCOP([O-])OCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccc(NC(=O)OC(C)(C)C)cc1CN(C)C(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 48 h
Yield: 53.3 %

Procedure:
A solution of 12B (25 mg, 0.060 mmol), bis(tri-t-butylphosphine)palladium (0) (3.08 mg, 6.02 μmol), Et3N (0.042 mL, 0.301 mmol) and diethyl phosphite (0.039 mL, 0.301 mmol) in toluene (0.6 mL) was degassed with Ar by evacuating and filling (4×). The sealed vessel was stirred for 2 days at 105° C. The reaction mixture was concentrated and purified by column chromatography (0 to 30% EtOAc in hexanes) to yield 12C (15 mg, 0.032 mmol, 52.7% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=3[CH:30]=2)[C@@H:11]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][O:38][CH2:39][C@H:40]([O:42][CH2:43][CH3:44])[CH3:41])=[CH:33][CH:32]=2)[C@H:10]([CH:45]=O)[CH2:9]1)=O)(C)(C)C.[Cl-].[O:48]=[C:49]([N:70]1[CH2:74][CH2:73][CH2:72][CH2:71]1)[CH2:50][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O(C)[Na]>CO>[CH2:43]([O:42][C@H:40]([CH3:41])[CH2:39][O:38][CH2:37][C:34]1[CH:33]=[CH:32][C:31]([C@@H:11]2[C@@H:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=4[CH:30]=3)[CH2:13][NH:8][CH2:9][C@H:10]2[CH2:45][CH2:50][C:49]([N:70]2[CH2:74][CH2:73][CH2:72][CH2:71]2)=[O:48])=[CH:36][CH:35]=1)[CH3:44]
Reactant: O=C(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)N1CCCC1
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](C=O)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Agent: CO[Na]
Agent: [Cl-]
Solvent: CO
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CCC(=O)N3CCCC3)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 mmol of (3S,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-formyl-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (example 12b) and 1.1 mmol of (2-oxo-2-pyrrolidin-1-yl-ethyl)-triphenyl-phosphonium chloride in 5 ml MeOH is added 1.05 mmol of NaOCH3 The reaction mixture is stirred at RT overnight. The reaction mixture is quenched by addition of 0.1 N HCl and H2O. The phases are separated and the organic phase is washed with saturated aqueous NaHCO3 solution and brine. The combined aqueous phases are extracted with TBME. The combined organic layers are dried over Na2SO4 and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and is identified based on the Rf value.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[Cl:5][C:6]([Cl:12])([Cl:11])[CH2:7][CH:8]1[O:10][CH2:9]1.C1OC1C>C(O)(C)C.C(O)C>[CH2:1]([NH2:4])[CH2:2][NH2:3].[Cl:5][C:6]([Cl:12])([Cl:11])[CH2:7][CH:8]([OH:10])[CH3:9]
Reactant: ClC(Cl)(Cl)CC1CO1
Agent: CC1CO1
Solvent: CCO
Solvent: CC(C)O
Solvent: NCCN
Product: CC(O)CC(Cl)(Cl)Cl
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a solution of 10.0g (0.17 mole) ethylenediamine in 100 ml isopropanol and 50 ml ethanol heated at 60° C. under nitrogen was added, dropwise, a mixture of 58.5g (0.33 mole) 4,4,4-trichloro-1,2-epoxybutane and 58.5g (1.0 mole) propylene oxide over a period of one hour. The reaction mixture was refluxed at 70° C. for one hour and an additional 17.2g (0.30 mole) of propylene oxide was then added dropwise. Refluxing with agitation was continued for an additional five hours and the mixture allowed to stand overnight. Evaporation of the solvent via vacuum afforded 74g of an addition product between ethylenediamine, 2-hydroxypropane, and 4,4,4-trichloro-2-hydroxybutane; hydroxyl number = 518. Analysis: (Calculated) %Cl, 29.52; %N, 6.47. (Found) %Cl, 29.22; %N, 6.31. On the basis of the analytical data one mole of ethylenediamine reacted with 1.2 moles 4,4,4-trichloro-1,2-epoxybutane and 2.8 moles propylene oxide.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=2)[N:6]=1.[ClH:20]>>[ClH:20].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[N:6]=1
Reactant: CCOC(=O)c1ccc(CCc2csc(N)n2)cc1
Agent: Cl
Product: Nc1nc(CCc2ccc(C(=O)O)cc2)cs1

Procedure:
Ester 21-3 (1.5 g, 5.43 mmol) was treated with 6N HCl for 16 h at RT then 16 h at 50°. Concentration provided 21-4 as an off-white solid.