Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)(=O)C>[OH:12][C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@H:2]([CH3:3])[CH:1]=[O:4]
Reactant: CCC=O
Reactant: O=Cc1ccccc1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](C=O)[C@H](O)c1ccccc1
Reaction time: 16 h
Yield: 81 %

Procedure:
A solution of freshly distilled propionaldehyde (72 μL, 1.0 mmol) in 500 μL dimethylformamide pre-cooled to 4° C. was added slowly over the course of 16 h to a stirring suspension of benzaldehyde (1.02 mL, 10 mmol), L-proline (11.5 mg, 0.10 mmol) and 4.5 mL dimethylformamide at 4° C. After 16 hours, the resulting solution was diluted with ethyl acetate and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions of dichloromethane. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated. Flash chromatography (4:1 hexanes:ethyl acetate) afforded the title compound as a clear, colorless oil in 81% yield (132 mg, 0.81 mmol), 99% ee and 3:1 anti:syn. Analytical data for this compound are identical in every respect to that previously reported (Mahrwald, supra) with the exception of optical rotation which has not been reported. [α]D=+9.1 (c=1.0, CHCl3). The product ratios were determined by HPLC analysis of the corresponding alcohol (obtained by NaBH4 reduction) using a Chiracel AD and AD guard column (1.0% isopropanol/hexanes, 1 mL/min); (2S, 3S) anti isomer tr=147.5 min, (2R, 3R) anti isomer tr=161.1 min, (2R, 3S) and (2S, 3R) syn isomers tr=173.0, 200.0 min.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[O-:12][CH2:13][CH3:14].[Na+].C(O)C>CN(C)C=O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([O:12][CH2:13][CH3:14])[N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOc1nc(Cl)ccc1C(N)=O
Temperature: 15 °C
Reaction time: 0.67 h
Yield: 95 %

Procedure:
Refer to synthesis of D46 for preparation of 2,6-dichloro-nicotinamide (1). Freshly prepared sodium ethoxide solution in ethanol (12.1 mL of 2.17 M, 26.2 mmol) was slowly added over 10 min to a solution of 1 (5.01 g, 26.2 mmol) in dimethylformamide (30 mL) at 15° C. [Note: a water bath was used to maintain reaction temperature around 14-16° C.; sodium ethoxide was prepared from reaction of Na solid (1.50 g, 65.2 mmol) with anhydrous EtOH (30.0 mL)]. Upon completion of sodium ethoxide addition, the reaction was stirred for 40 min at 14-16° C. [Note: An aliquout (0.3 mL) of reaction was concentrated. A 1H NMR of aliquout recorded in d6-DMSO showed ˜98% conversion to desired 2]. The reaction was poured into water (500 mL) and extracted with EtOAc (3×400 mL). All organics were combined, dried over Na2SO4, filtered and concentrated to give the title compound as a light gray solid (5.20 g, 95% purity as established by 1H NMR). The title compound was carried forward without further purification. 1H NMR 400 MHz (d6-DMSO) δ 8.16 (d, J=8.2 Hz, 1H), 7.76 (br s, 1H), 7.57 (br s, 1H), 7.17 (d, J=7.8 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1)=O)([CH3:4])[CH3:3].[CH:21]([Mg]Br)=[CH2:22]>O1CCCC1>[C:2]([S:5][NH:7][C@@H:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1)[CH:21]=[CH2:22])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(OCC(F)(F)F)cn1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=C[C@@H](NSC(C)(C)C)c1ccc(OCC(F)(F)F)cn1
Temperature: -78 °C
Yield: 73.5 %

Procedure:
To a mixture of 2-methyl-N-{(1E)-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylidene}propane-2-sulfinamide (10.0 g, 32.4 mmol) and tetrahydrofuran (150 ml) at −78° C. was added dropwise 1.0M vinylmagnesium bromide in tetrahydrofuran (58.4 ml, 58.4 mmol), maintaining temperature during addition below −70° C. Reaction was stirred at −78° C. for an hour. To complete reaction, an additional amount of 1.0M vinylmagnesium bromide (19.4 ml, 19.4 mmol) was required. The reaction was then quenched by pouring mixture into a cold solution of saturated NH4Cl (800 ml) and ethyl acetate (600 ml) with vigorous stirring at 0° C. Layers were separated and organic extracts were combined, dried over Na2SO4, filtered and concentrated in vacuum. The resulting brown oil was purified by flash chromatography (Si2O, 25-100% ethyl acetate in hexanes, gradient) to give 2-{(1R)-1-[(tert-butylthio)amino]prop-2-enyl}-5-(2,2,2-trifluoroethoxy)pyridine as a white solid (8.10 g, 73.5%). 1H NMR (400 MHz, CDCl3) 8.30 (d, J=2.8 Hz, 1H), 7.28 (m, 2H), 5.92-5.83 (m, 1H), 5.34 (dd, J=16 Hz and 33 Hz, 2H), 5.01 (m, 1H), 4.99 (bs, 1H), 4.39 (q, J=8.0 Hz, 2H), 1.28 (s, 9H); MS (Electrospray): m/z 337.1 (+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:24]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.[F:41][C:42]([F:57])([S:53](F)(=[O:55])=[O:54])[C:43]([F:52])([F:51])[C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46]>CN(C)C=O>[F:57][C:42]([F:41])([S:53]([O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:9]3[CH:8]=[C:7]([N:24]4[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]4=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=3[O:11][CH3:12])[CH:14]=2)[CH:19]=1)(=[O:55])=[O:54])[C:43]([F:51])([F:52])[C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46]
Reactant: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reaction time: 0.33 h

Procedure:
A 250-L, 3-neck round-bottom flask equipped with an overhead stirrer was charged with 10 g of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (98 wt %, 23.5 mmol, 1.0 equiv) and 6.5 g of milled potassium carbonate (325 mesh, 47.1 mmol, 2.0 equiv). Acetonitrile (MeCN, 60 mL, 6 volumes with respect to naphthol) and dimethylformamide (dimethylformide, 40 mL, 4 volumes with respect to naphthol) was charged to the reactor and the slurry was stirred. Perfluorobutanesulfonyl fluoride (96 wt %, 8.3 g, 26 mmol, 1.1 equiv) was charged to the well-stirred mixture over 60 minutes by syringe pump. A trace (<0.1 area %) of starting material was detected by HPLC analysis of an aliquot at 20 minutes reaction time. The acetonitrile/dimethylformamide solution was filtered over a coarse fritted funnel to separate the inorganic solids, and the flask and filter was rinsed with 15 mL of 3:2 (v/v) acetonitrile/dimethylformamide. The total mass of solvents employed was approximately 92 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:21](O)=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:25]([O:27][C:28](=[O:35])[C@@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH2:30])[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[CH2:25]([O:27][C:28](=[O:35])[C@@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH:30][C:21](=[O:22])[C@@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH3:26]
Reactant: CCOC(=O)[C@H](N)CCSC
Reactant: Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H](CCSC)NC(=O)[C@@H](Cc1cn(C)c2ccccc12)NC(=O)OC(C)(C)C
Yield: 101.2 %

Procedure:
To a suspension of N-tert-butoxycarbonyl-1-methyl-D-tryptophan (1.60 g) and hydrochloric acid salt of D-methionine ethyl ester (1.06 g) in dry methylene chloride (30 ml) which was cooled on an ice bath and stirred was added a solution of triethylamine (0.50 g) in dry methylene chloride (10 ml). The mixture was stirred for 30 minutes, and to the mixture was added a solution of N,N'-dicyclohexylcarbodiimide (1.04 g) in dry methylene chloride (10 ml). The resulting mixture was stirred overnight. After removal of the solvent, crude residue was taken up with a mixture of ethyl acetate and water, filtered, and organic layer was washed with 10% hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulfate, and evaporated to give crystalline N-tert-butoxycarbonyl-1-methyl-D-tryptophyl-D-methionine ethyl ester (2.43 g).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[S:15][CH:16]=[CH:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C1COCC1.C(=O)(OC(C)(C)C)[O:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[S:15][CH:16]=[CH:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:5]([NH:8][C:27](=[O:26])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:6][CH:7]=1
Reactant: Cc1ccsc1-c1nnc(-c2nc(Br)cnc2N)o1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccsc1-c1nnc(-c2nc(Br)cnc2NC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.1 %

Procedure:
5-bromo-3-[5-(3-methyl-2-thienyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-amine (11.49 g, 33.98 mmol) and DMAP (415.1 mg, 3.398 mmol) were suspended in DCM (172.4 mL) and THF (172.4 mL) and cooled in an icebath. tert-butoxycarbonyl tert-butyl carbonate (22.24 g, 101.9 mmol) was added portionwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was filtered through plug of silica gel and concentrated in vacuo. The residue was dissolved in ethylacetate, washed with aq NaHCO3 (×1), brine (×1), dried over MgSO4 and passed through short silica gel column. The mixture was concentrated in vacuo to low bulk, diluted with petrol and stirred at 50° C. for 5 min. The mixture was filtered to give tert-butyl (5-bromo-3-(5-(3-methylthiophen-2-yl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)carbamate as a colourless solid (16.4 g, 89%). H NMR (400.0 MHz, DMSO-d6) δ 1.4 (9H, s), 2.7 (3H, s), 7.0 (1H, d), 7.5 (1H, d), 8.7 (1H, s); LC/MS m/z 440.1 [M−100+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30].[Cl:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(C(C)C)C(C)C)C>C(O)C>[ClH:31].[ClH:30].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([CH2:32][CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCCC1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(CCN1CCCC1)CC2
Temperature: 60 °C

Procedure:
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (180 mg, 0.46 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (95 mg, 0.56 mmol), (i-Pr)2EtN (0.25 mL, 1.4 mmol) were combined in ethanol (2 mL) and heated at 60° C. for 2 h. Purification by preparative HPLC and conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound as a white solid: mp 285-289° C.; 1H NMR (300 MHz, D2O) δ 7.50 (d, J=8.3 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.42-7.31 (m, 6H), 6.96 (dd, J=8.3, 1.6 Hz, 1H), 6.27 (dd, J=7.7, 2.6 Hz, 1H), 6.10 (d, J=2.6 Hz, 1H), 5.90 (s, 2H), 4.59 (br s, 2H), 3.81-3.59 (m, 8H), 3.55 (s, 3H), 3.20 (t, J=5.7 Hz, 2H), 3.18-3.05 (br m, 2H), 2.15-1.90 (m, 4H); ESI MS m/z 483 [M+H]+; HPLC (Method B) 98.8% (AUC), tR=11.3 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[S:14](Cl)(=[O:16])=[O:15])[CH2:6]1)=[O:4].[Br:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][C@H:30]([CH3:32])[NH:29][C@H:28]([CH3:33])[CH2:27]2)[CH:22]=[CH:23][C:24]=1[Cl:25].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Br:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:27][C@@H:28]([CH3:33])[N:29]([S:14]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:12]=3[CH2:13][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]4)(=[O:16])=[O:15])[C@@H:30]([CH3:32])[CH2:31]2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: C[C@@H]1CN(c2ccc(Cl)c(Br)c2)C[C@H](C)N1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C1Cc2cccc(S(=O)(=O)N3[C@H](C)CN(c4ccc(Cl)c(Br)c4)C[C@@H]3C)c2C1
Temperature: 55 °C

Procedure:
4-Chlorosulfonyl-indan-2(R,S)-carboxylic acid methyl ester (225 mg, 0.82 mmol) was added to a mixture of 1-(3-bromo-4-chlorophenyl)-cis-3,5-dimethylpiperazine (569 mg, 1.87 mmol), potassium carbonate (500 mg, 3.6 mmol), and acetonitrile (8 mL) at rt under nitrogen, and the reaction was heated at 55° C. for 3 h. After allowing the reaction to cool to rt, it was poured into water (40 mL) and extracted with dichloromethane (40 mL×2). The combined organic extracts were dried, filtered, concentrated, and purified by silica gel chromatography (9:1→3:1; hexanes:ethyl acetate) to give methyl 4-(4-(3-bromo-4-chlorophenyl)-cis-2,6-dimethylpiperazin-1-ylsulfonyl)-2,3-dihydro-1H-indene-2(R,S)-carboxylate: MS (ESI): 541.2 (M+H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH3:3].[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>CN(C)C=O>[N:16]([C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1)=[C:17]=[S:18]
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 101.3 %

Procedure:
A solution of 4-[4-(1-methylethyl)-1-piperazinyl]benzenamine (1.6 g,˜6.8 mmol) (from Step B above) in N,N-dimethylformamide (25 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyldiimidazole (1.4 g, 7.7 mmol) (Aldrich) in N,N-dimethylformamide (30 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, then the cooling bath was removed and the solution was stirred for 1 h. Ice-water was added and the mixture was extracted with ether. The ether layer was dried (MgSO4), filtered, and evaporated to give 1-(4-isothiocyanatophenyl)-4-(1-methylethyl)piperazine (1.8 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[CH:22]1([C:25]2[S:26][CH:27]=[C:28]([CH2:30][NH2:31])[N:29]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[S:26][CH:27]=[C:28]([CH2:30][NH:31][C:14]([C:12]3[CH:11]=[CH:10][C:9]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:13]=3)=[O:16])[N:29]=2)[CH2:24][CH2:23]1
Reactant: NCc1csc(C2CC2)n1
Reactant: O=C(O)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Product: O=C(NCc1csc(C2CC2)n1)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 41 using 6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (example AW) and 2-cyclopropyl-4-thiazolemethanamine (CAN. 1083299-53-9) as starting materials, LC-MS (UV peak area/ESI) 95.5%, 440.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]([CH2:31][CH:32]2[CH2:34][CH2:33]2)[C:5]=1[OH:35])=[O:3].[C:36](OCC)(=O)C.CCCCCC>>[NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]([CH2:31][CH:32]2[CH2:33][CH2:34]2)[C:5]=1[O:35][CH3:36])=[O:3]
Reactant: CCOC(C)=O
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CC2CC2)cccc1OCC(=O)OCC
Solvent: CCCCCC
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)cccc1OCC(=O)OCC

Procedure:
The compound of Example 70 is exposed to the conditions described in Example 25. Chromatography of the crude product on silica gel using ethyl acetate/hexane, (3:7) as eluant affords the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:35])[C:11](C(O)=O)=[CH:12][N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C([N:45](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][NH:16][C:15]([C:14]1[N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH:12]=[C:11]([NH2:45])[C:10](=[O:35])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: CCN(CC)CC
Reactant: COC(Cn1cc(C(=O)O)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(Cn1cc(N)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1 g) obtained in Example 161, Step 4 in tetrahydrofuran (15 ml)-toluene (15 ml) were added triethylamine (0.61 ml) and diphenylphosphoryl azide (0.47 ml) and the mixture was stirred at room temperature for 30 min. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran (8 ml). Triethylamine (0.61 ml) and diphenylphosphoryl azide (0.47 ml) were added again and 2 hr later, and 3 hr later, triethylamine (1.22 ml, 0.61 ml) and diphenylphosphoryl azide (0.94 ml, 0.47 ml) were respectively added, and stirring was continued. After confirmation of disappearance of the starting material, 9-fluorenylmethanol (7.7 g) and toluene (10 ml) were added, and the mixture was stirred under reflux with heating. After 20 min, triethylamine (2.5 ml) was added, and stirring was continued with heating for 1.5 hr. The mixture was concentrated, water was added to the residue and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layer was washed with brine, dried and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1-chloroform:methanol=15:1) to give 5-amino-3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (886 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].ClCCCC(C1C=CC=CC=1)=O.Cl.[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37][CH:36]=2)=[O:34])[CH2:29][CH2:28]1.Cl.N1CCC(C(C2C=CC3C(=CC=CC=3)C=2)=O)CC1>>[ClH:1].[C:35]1([C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:2][CH2:3][CH2:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)=[O:6])[CH2:28][CH2:29]2)=[O:34])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: O=C(c1cccc2ccccc12)C1CCNCC1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: Cl
Agent: O=C(CCCCl)c1ccccc1
Agent: O=C(c1ccc2ccccc2c1)C1CCNCC1
Product: O=C(CCCN1CCC(C(=O)c2cccc3ccccc23)CC1)c1ccc(F)cc1

Procedure:
When in the procedure of Example 19, 4-chloro-1-(4-fluorophenyl)-1-butanone is substituted for 4-chloro-1-phenyl-1-butanone and 1-naphthyl 4-piperidyl ketone hydrochloride is substituted for 2-naphthyl 4-piperidyl ketone hydrochloride, 4-[4-(1-naphthoyl)-1-piperidyl]-1-(4-fluorophenyl)-1-butanone hydrochloride is produced. M.P. 239°-41°.
Reaction SMILES: [O:1]=[C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.O=[C:24]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CO.ClCCl>[F:13][C:12]([F:14])([F:15])[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([NH:4][CH2:3][C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH:28]2[CH2:24][CH2:25][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:27]2)[CH2:19]1)=[O:1])=[O:16]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3)C2)C1
Reaction time: 16 h
Yield: 109.9 %

Procedure:
To a solution of N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide (500 mg, 1.59 mmol; prepared according to WO2004/050024A2) in methanol (5 mL) at room temperature was added benzyl 3-oxopyrrolidine-1-carboxylate (434 mg, 1.98 mmol) followed by sodium triacetoxyborohydride (470 mg, 2.22 mmol); the reaction mixture was stirred for 16 hours. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford, as a mixture of diastereomers, benzyl (3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidine-1′-carboxylate (906 mg, 88%) as a white solid. 1H-NMR (CDCl3) δ: 1.30-1.44 (m, 2H), 1.50-1.68 (m, 2H), 1.80-2.00 (m, 2H), 2.10-3.29 (m, 1H), 2.30-2.43 (m, 1H), 2.55-23.05 (m, 3H), 3.15-3.28 (m, 1H), 3.58-4.20 (m, 3H), 4.30-4.50 (m, 1H), 5.09 (s, 2H), 6.70-6.87 (m, 1H), 7.20-7.50 (m, 6H), 7.52 (t, J=8.7 Hz, 1H), 7.72 (d, J=7.2 Hz, 1H), 7.99 (d, J=7.2 Hz, 1H), 8.09 (s, 1H). MS m/z: 519 (M+1)
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3].Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3]
Reactant: NC(=O)Nc1cc(-c2cccc(O)c2)sc1C(N)=O
Reactant: CN(C)CCCl
Product: CN(C)CCOc1cccc(-c2cc(NC(N)=O)c(C(N)=O)s2)c1

Procedure:
Prepared by the method of Example 9(b) using the product of Example 6 and N-(2-chloroethyl)dimethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:6]([O:8]CC)=[O:7].OS(O)(=O)=O.CC(O)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(OCCS(C)(=O)=O)c(OC)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)ccc1OCCS(C)(=O)=O
Temperature: 90 °C

Procedure:
Ethyl 3-methoxy-4-(2-(methylsulfonyl)ethoxy)benzoate (30 mg, 0.099 mmol) was taken up in water (1.2 mL), H2SO4 (200 μL, 3.8 mmol), and AcOH (1300 μL, 23 mmol). The mixture was heated at 90° C. for 6 h before it was cooled to ambient temperature and was concentrated under vacuum. The residue was purified by column chromatography (1-40% MeOH/DCM) to give 3-methoxy-4-(2-(methylsulfonyl)ethoxy)benzoic acid. ESI-MS m/z talc. 274.1, found 275.1 (M+1)+; Retention time: 0.69 minutes (3 min run).