Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])[CH:3]=1.Cl[CH2:17][C:18](=O)[CH3:19].C([O-])(O)=O.[Na+]>C(O)C>[CH3:19][C:18]1[N:8]=[C:5]2[C:4]([CH:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[CH:3][C:2]([CH3:1])=[N:7][N:6]2[CH:17]=1
Reactant: CCCC(CCC)c1cc(C)nnc1N
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCC(CCC)c1cc(C)nn2cc(C)nc12
Temperature: 75 °C
Yield: 70.6 %

Procedure:
A 250 mL round bottom flask is charged with 6-methyl-4-(1-propyl-butyl)-pyridazin-3-ylamine (0.611 g, 0.00295 moles, 1 equiv), ethanol 2B (30 mL), and chloroacetone (0.382 g, 0.328 ml, 0.00412 moles, 1.4 equiv). The reaction mixture is heated at 75° C. overnight and then cooled to room temp. NaHCO3 (0.371 g, 0.00442 moles, 1.5 equiv) is slowly added to the reaction mixture that is then heated to 100° C. overnight. The reaction mixture is cooled and the solvent is evaporated. Dichloromethane is added and the reaction mixture is passed through filter paper. The solvent is evaporated to obtain a brown oil which is purified via silica gel chromatography. The material is eluted with a hexanes and ethyl acetate gradient to obtain 0.511 g of the final products. Two peaks are identified in the lc/ms. The mixture is used “as is” in the next reaction. MS (APCI): 246 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[O:3]1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:25]([O:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:3]1)(=[O:27])[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(O)O2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1CCC(COS(=O)(=O)c2ccc(C)cc2)O1
Reaction time: 1 h

Procedure:
To a stirring solution of (±)2-hydroxy-5-(p-toluenesulfonyloxymethyl)-tetrahydrofuran (example 58) (4.20 g, 15.44 mmol), pyridine (2.75 mL, 33.97 mmol) and DMAP (catalytic) in methylene chloride (100 mL) at rt was added acetic anhydride (2.91 mL, 30.88 mmol). After stirring the solution for 1 h, it was washed with water (50 mL), 1N HCl (50 mL), saturated NaHCO3 (50 mL), dried (MgSO4) and concentrated to give the title compound as a 1:1 mixture of cis and trans isomers (4.85 g, 100%).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[N:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-]>CN(C=O)C.Cl.O>[F:33][C:30]([F:31])([F:32])[C:27]1[N:26]=[CH:25][C:24]([NH:23][C:20]2[N:19]=[CH:18][C:17]([C:14]3[CH:13]=[CH:12][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:34])=[O:2])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)=[CH:22][N:21]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CC1CCC(c2ccc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Temperature: 50 °C

Procedure:
To a glass vial add 6-trifluoromethyl-pyridin-3-ylamine (35 mg, 0.217 mmol), {4-[4-(2-chloro-pyrimidin-5-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (50 mg, 0.145 mmol), Pd(OAc)2(5 mg, 5% mol), X-Phos (7 mg, 10% mol), and Cs2CO3 (118 mg, 0.363 mmol). Flush with N2. Add tBuOH (0.25 mL), toluene (0.75 mL), and seal the tube. The reaction mixture is heated to 150° C. for 30 min by microwave irradiation. The reaction is diluted with EtOAc and filtered. The filtrate is concentrated and chromatographed on silica gel (25-50% EtOAc/Hexanes) to afford (4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester as 90% pure. (4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester (45 mg, 0.096 mmol) is taken up in DMF (1.5 mL) and 4 M LiOH (0.5 mL) and stirred at room temperature for 16 h. The reaction is heated to 50° C. for 12 h and then heated to 70° C. for 8 h. The reaction is diluted with 1 N HCl (2 mL) and H2O (2 mL). The precipitate is collected by filtration and purified by HPLC (Xterra C8 30×100 mm, 22-50% ACN/H2O+ 5 mM NH4OH) to afford (4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.18 (m, 2 H) 1.43-1.56 (m, J=12.95, 12.66, 12.66, 3.16 Hz, 2H) 1.68-1.87 (m, 6 H) 2.08 (d, J=6.57 Hz, 2 H) 7.35 (d, J=8.34 Hz, 2 H) 7.65 (d, J=8.34 Hz, 2 H) 7.85 (d, J=8.59 Hz, 1 H) 8.55 (dd, J=8.59, 2.02 Hz, 1 H) 8.91 (s, 2 H) 9.06 (d, J=2.27 Hz, 1 H) 10.42 (s, 1 H); (M+H)+ 457.0.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]=2[N:7]=[CH:6]1)[CH3:2].Cl[CH2:19][CH2:20][CH2:21][CH2:22][P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26]>>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][P:23](=[O:27])([O:28][CH2:29][CH3:30])[O:24][CH2:25][CH3:26])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]=2[N:7]=[CH:6]1)[CH3:2]
Reactant: CCOCn1cnc2c1c(=O)[nH]c(=O)n2CC
Reactant: CCOP(=O)(CCCCCl)OCC
Product: CCOCn1cnc2c1c(=O)n(CCCCP(=O)(OCC)OCC)c(=O)n2CC

Procedure:
The title substance was prepared from 0.01 5 mol of 7-ethoxymethyl-3-ethylxanthine and 0.017 mol of diethyl 4-chlorobutanephosphonate analogously to 53.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH:31]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:32][NH:33]C(OC(C)(C)C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[NH2:33][CH2:32][CH:31]([NH:30][C:26]1[N:25]=[C:24]([C:21]2[N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)[C:16]3=[N:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCC(Nc1cccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: NCC(Nc1cccc(-c2cnc3c(NC4CCC(N)CC4)nccn23)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (4-{3-[6-(2-tert-butoxycarbonylamino-1-phenyl-ethylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (0.38 g, crude) in ethanol (4 mL) was added concentrated HCl (8 mL). The reaction mixture was stirred at room temperature for 15 hour and then concentrated under reduced pressure. The residue was purified by prep-HPLC to give N-{3-[6-(2-amino-1-phenyl-ethylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 47 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1)[NH2:29]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:29]=[C:28]([C:30]4[CH:35]=[N:34][CH:33]=[CH:32][N:31]=4)[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NC(=NO)c1cnccn1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cnccn4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxypyrazine-2-carboximidamide were reacted according to the General Method 1. Yield: 45 mg (50% of theory)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:15])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1)=O.CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:15])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2c(Cl)ccnc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1ccc2c(Cl)ccnc2c1
Temperature: -45 °C

Procedure:
7-Methyloxycarbonyl-4-chloroquinoline (2.1 g, 9.5 mmol) is dissolved in anhydrous THF (25 mL) and anhydrous ether (200 mL). The solution is cooled in a dry ice/acetone bath and treated 1M lithium aluminum hydride in THF (11.0 mL, 11 mmol). The solution is warmed (approximately −45° C.) for 20 minutes and quenched with ethyl acetate. The solution is diluted with ether (100 mL) and treated with water (36 mL), 15% NaOH (36 mL) and water (36 mL) in succession. The mixture is filtered and evaporated to yield the title compound as a residue (2.0 g, 9.7 mmol) which is dried under vacuum and used without further purification. MS m/z: M+=193; 1H NMR (CDCl3, 300 MHz) δ8.65 (d, 1H), 8.15 (d, 1H), 8.0 (d, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 4.8 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])CCC.CCCCCC.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>O1CCCC1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([CH3:9])=[CH:5][C:6]=2[Cl:8])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
A stirred, -60° C. solution of 3,5-dichlorotoluene (805 mg, 5.00 mmol) in tetrahydrofuran (5 mL) under nitrogen atmosphere was treated dropwise over 10 minutes with a 1.6M solution of n-butyllithium in hexane (3.3 mL, 5.25 mmol). After addition was complete residual n-butyllithium in the addition funnel was rinsed into the reaction mixture with tetrahydrofuran (1 mL). The reaction mixture was stirred 30 minutes at -55° and then a solution of p-chlorobenzoylchloride (875 mg, 5.00 mmol) in tetrahydrofuran (1.0 mL) was added dropwise over 15 minutes. The mixture was kept at -55° to -30° C. for 2 hours, stirred 2 hours at ambient temperature, and quenched by addition of saturated aqueous ammonium chloride (1.1 mL). After stirring 15 minutes, sodium sulfate (1.1 g) was added, and the mixture was stirred an additional 15 minutes. The solution was decanted, the solids were washed with diethyl ether, and the combined solution and wash were evaporated under reduced pressure. The residue was recrystallized from ethanol (15 mL) to provide 0.78 g (52%) 4-(4-chlorobenzoyl)-3,5-dichlorotoluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[C:7]([CH:9]=1)[NH2:8].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[C:7]([NH:8][S:30]([C:22]2[O:21][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:23]=2)(=[O:31])=[O:32])[CH:9]=1
Reactant: COc1ccc(SCc2cccc([N+](=O)[O-])c2)c(N)c1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: COc1ccc(SCc2cccc([N+](=O)[O-])c2)c(NS(=O)(=O)c2cc3ccccc3o2)c1
Yield: 55.6 %

Procedure:
Following General Procedure B, the title compound (406 mg, 56%) was prepared from 5-methoxy-2-((3-nitrobenzyl)thio)aniline (450 mg, 1.552 mmol) and benzofuran-2-sulfonyl chloride (335 mg, 1.552 mmol) in pyridine (5 ml).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].CCOCC.S(=O)(=O)(O)O.[CH2:18](O)[CH2:19][CH2:20]C>>[C:1]([O:6][CH2:7][CH2:18][CH2:19][CH3:20])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: CCCCO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: C=C(C)C(=O)OCCCC
Reaction time: 6 h
Yield: 91.2 %

Procedure:
74.1 g (1.0 mole) of n-butanol, 250.2 g (2.5 moles) of methyl methacrylate, 0.25 g of hydroquinonemonomethyl ether and 2.45 (0.025 mole) of concentrated sulfuric acid were added to a flask to conduct a reaction in the same manner as in Example 1. The reaction was carried out for 6 hours. The reaction results were 96.5% conversion of n-butanol and 91.2% yield of n-butyl methacrylate. However, it was found by gas chromatography that a high boiling point by-product was present and 0.004 mole of methacrylic acid (2660 ppm. based on n-butyl methacrylate) was produced as a by product.
Reaction SMILES: CS(OCCC[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:21][CH3:22])[C:15]=2[O:19][CH3:20])[CH:10]=1)(=O)=O.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:20][O:19][C:15]1[C:14]([O:21][CH3:22])=[C:13]([O:23][CH3:24])[CH:12]=[C:11]2[C:16]=1[CH:17]=[CH:18][C:9]([CH2:10][CH2:9][CH2:18][N:25]1[CH2:30][CH2:29][N:28]([CH2:12][CH2:11][CH2:16][C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:21][CH3:22])[C:15]=4[O:19][CH3:20])[CH:10]=3)[CH2:27][CH2:26]1)=[CH:10]2
Reactant: C1CNCCN1
Reactant: COc1cc2cc(CCCOS(C)(=O)=O)ccc2c(OC)c1OC
Product: COc1cc2cc(CCCN3CCN(CCCc4ccc5c(OC)c(OC)c(OC)cc5c4)CC3)ccc2c(OC)c1OC

Procedure:
2-(3-Methanesulfonyloxypropyl)-5,6,7-trimethoxynaphthalene (213 mg) and piperazine (26 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[O:24][CH3:25].Cl>ClCCCl.CCCCCC>[Cl:23][C:22]1[C:17]([Cl:16])=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][C:21]=1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])=[O:5]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2F)c(Cl)c1Cl
Temperature: 43 °C
Reaction time: 0.5 h

Procedure:
To a solution of 52.23 g of 2,4-difluorobenzoylchloride in 200 ml of 1,2-dichloroethane, 40 g of AlCl3 is added over a 30 minute period. A solution of 48.3 g of 2,3-dichloroanisole in 100 ml 1,2-dichloroethane is added dropwise. There is a slow evolution of gas and the temperature rises to approximately 30° C. The reaction mixture is warmed to 43° C. and the gas continues to evolve for approximately 30 minutes. The mixture is poured over concentrated HCl and ice. The organic layer is separated and the aqueous layer is extracted two times with CHCl3. The combined organic layers are washed with water, dried (Na2SO4) and evaporated to give an oil. Trituration with hexane yields 2,3-dichloro-4-methoxy-2',4'-difluorobenzophenone which is recrystallized from ether, mp 139°-141° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:22][CH2:23][CH2:24][NH2:25])(C)(C)C.Cl>O1CCOCC1>[F:13][C:12]([F:15])([F:14])[C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:22][CH2:23][CH2:24][NH2:25])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: C1COCCO1
Product: NCCNc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 125 °C

Procedure:
A mixture of 120 mg of 4-chloro-7-trifluoromethylquinoline and 250 mg of tert-butyl-N-(2-aminoethyl)carbamate was heated to 125° C. for two h. The mixture was cooled to room temperature and partitioned between 10% IPA/chloroform and saturated sodium bicarbonate. The aqueous layer was back extracted with 10% IPA/chloroform and the organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in EtOAc and washed with water, and the organic layer was dried over sodium sulfate, filtered, and concentrated. The product was dissolved in MeOH (0.5 mL) and stirred with five equiv. of 4.0 M HCl in dioxane for 18 h. The reaction mixture was concentrated and the residue was recrystallized from MeOH to afford the title compound. MS (M+H)+=256.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[NH:4][C:3]=1[C:9]#[N:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:11]([O:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([Br:1])=[CH:7][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1[nH]c(=O)ccc1Br
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: N#Cc1nc(OCc2ccccc2)ccc1Br

Procedure:
A solution of 3-bromo-6-oxo-1,6-dihydropyridine-2-carbonitrile (from Example 15/Step 2) (1.0 eq.), silver carbonate (1.3 eq.), and benzyl bromide (1.2 eq.) in toluene (0.16 M) was stirred in the dark at 50° C. overnight. The solvent was concentrated en vacuo, and the resulting residue was purified by a COMBIFLASH® system (ISCO) using 0-20% ethyl acetate in hexane to give 6-(benzyloxy)-3-bromopicolinonitrile.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:7][C:8]([NH:10][C@H:11]([C@H:19]1[O:23][C:22](=[O:24])[C@H:21]([CH3:25])[CH2:20]1)[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@@H:19]([OH:23])[CH2:20][C@@H:21]([CH3:25])[C:22]([NH:2][CH3:1])=[O:24])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CN
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Solvent: CO
Product: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
Gaseous methylamine was introduced into a solution of 0.2 g (0.615 mole) of (3R, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 2) in 6 ml of methanol for 3 minutes, after which the mixture was allowed to stand for 3 hours. The reaction mixture was then concentrated by distillation under reduced pressure, and the resulting residue was triturated with hexane to afford 0.23 g of the title compound as white crystals, melting at 144°-145° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)(=[O:29])=[O:30])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(OCCN3CCCCC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Yield: 49 %

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.4 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.0 g (77%); off white powder; mp 174° C.; MS: 517.6 (M+H)+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[ClH:13].N([O-])=O.[Na+]>[Cu]Cl.O.C(O)(=O)C>[Cl:13][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: Cl
Reactant: COc1cc(N)ccc1C(C)=O
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Cl)ccc1C(C)=O
Temperature: 60 °C
Yield: 76 %

Procedure:
A stirred and cooled (0° C.) solution of 30 parts of 1-(4-amino-2-methoxyphenyl)ethanone in 360 parts of a concentrated hydrochloric acid solution, 75 parts of water and 30 parts of acetic acid is diazotated with a solution of 17.25 parts of sodium nitrite in 200 parts of water. After stirring for 30 minutes at 0° C., the whole is poured onto a solution of 30 parts of copper (I) chloride in 240 parts of a concentrated hydrochloric acid solution while stirring. The mixture is heated for 1 hour at 60° C. After cooling to room temperature, the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed successively with water, a diluted sodium hydroxide solution and again twice with water, dried, filtered and evaporated, yielding 28 parts (76%) of 1-(4-chloro-2-methoxyphenyl)ethanone; mp. 55° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH:23]1[O:25][CH2:24]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CO>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH:23]([OH:25])[CH2:24][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccccc1
Reaction time: 16 h
Yield: 50.9 %

Procedure:
Phenol (1.50 g) and sodium methoxide (380 mg) were added to (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (1.50 g) as obtained in Example 1-A) in methanol (30 ml ), followed by 16 hour' stirring under reflux. The reaction mixture was concentrated and the residue was dissolved in ether. The solution was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated brine in order, and dried over magnesium sulfate, followed by concentration. The residue was purified by silica gel column chromatography (eluate: hexane-ethyl actate) to give 1.10 g of (2S)-1-(t-butoxycarbonyl)-2-(1-hydroxy-2-phenoxyethyl)-pyrrolidine.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20]C)=[O:18].Cl>O.O1CCOCC1>[CH3:20][O:19][C:17]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:18]
Reactant: NCCCCC(=O)O
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)NCCCCC(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
5-aminopentanoic acid hydrochloride (1 g, 6.5 mmol), and potassium carbonate (6.5 g, 47 mmol) were dissolved in water (15 ml) and dioxane (5 ml) then cooled to 0° C. Ethyl chloroformate (3 ml, 31.5 mmol) was added over 30 seconds, then the mixture was stirred for 4 hours at 0° C. Conc. HCl was added until acidic then the mixture was diluted with water and extracted with ether. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 5-[(methoxycarbonyl)amino]pentanoic acid as a white powder (1.07 g).
Reaction SMILES: C(OC([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16](Br)=[CH:15][S:14][C:11]=32)[CH2:7]1)=O)C.[CH3:18][O-:19].[Na+]>CO.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:18][O:19][C:16]1[C:10]2[CH2:9][CH:8]3[CH:12]([C:11]=2[S:14][CH:15]=1)[CH2:13][NH:6][CH2:7]3
Reactant: CCOC(=O)N1CC2Cc3c(Br)csc3C2C1
Reactant: C[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COc1csc2c1CC1CNCC21

Procedure:
The product of step b) (57.8 mg, 0.183 mmol) in MeOH (51 μl) was treated with CuO (7 mg, 0.09 mmol), a 25% solution of sodium methoxide in MeOH (129 μl) and tetra-butylammonium iodide (TBAI) (10 mg) at 100° C. for 12 hours. The reaction mixture was cooled and purified by preparative LC/MS to give the title compound. 1H NMR (300 MHz, CDCl3, ppm) 2.40-2.60 (m, 1H); 2.82-3.01 (m, 2H); 3.05-3.63 (br m, 4H); 3.77 (s, 3H); 3.81-3.98 (br s, 1H); 6.17 (s, 1H); MS calculated for C10H13NOS+H 196, observed 196.