Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:36]([O:38]C)=[O:37])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:12]=[C:11]([O:24][C@@H:25]([CH3:35])[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:10]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:36]([OH:38])=[O:37])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:12]=[C:11]([O:24][C@@H:25]([CH3:35])[CH2:26][O:27][Si:28]([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:30])[CH3:29])[CH:10]=1
Reactant: COC(=O)c1cnc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)Nc3ccn(C)n3)c2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ncc(C(=O)O)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of methyl 5-chloro-6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylate (1.2 g, 2.09 mmol) in THF (50 mL) was added a solution of lithium hydroxide monohydrate (0.219 g, 5.22 mmol) in water (30 mL). The mixture was allowed to stir under RT overnight. The THF was removed in vacuo and the resulting solution was partitioned between water (50 mL) and ethyl acetate (75 mL), and the ethyl acetate layer separated, washed with brine and dried (MgSO4). The aqueous layer was then adjusted to pH 7 by addition of 1N hydrochloric acid (5.2 mL) and partitioned between ethyl acetate (75 mL). The ethyl acetate layer was separated, washed with brine and dried (MgSO4). The ethyl acetate layers were combined and evaporated to give the required product (1.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2)CC1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and aniline (2.23 g) was treated in the same manner as described in Preparation Example 37 to give white needles of the title compound.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[ClH:10].O.[CH3:12]O>C1COCC1>[ClH:10].[NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([O:7][CH3:12])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCNCC1
Reactant: CO
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CCNCC1
Reaction time: 2.5 h

Procedure:
Isonipecotic acid (40 g, 310 mmol) was suspended, with stirring, in 250 mL of dry methanol and treated with HCl gas (lecture bottle) until solution was obtained. The solution was then cooled in an ice bath and treatment with HCl gas continued for an additional 20 min. After 2.5 h, the reacion mixture was stripped of solvent using a water aspirator (30° C.) and the resulting heavy, white cake suspended in 150 mL dry THF and filtered. The filter cake was washed with two portions of 50 mL THF, followed by washing with 3×50 ml Et2O, dried briefly in air (suction). The pale-yellow filtrate was discarded. Drying the slightly off-white solid was completed over-night in a desiccator (CaSO4) under high vacuum. The title compound (43.25 g) was obtaind analytically pure. Anal. (C7H14ClNO2) calcd: C, 46.80; H, 7.86; N, 7.80; Cl, 19.73. found C, 46.66; H, 7.78; N, 19.82. TLC Rf=0.63 (silica gel, 3:1 ethanol/conc. aq. ammonium hydroxide).
Reaction SMILES: ClCCl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:15][C@@H:16]([C@@H:23]1[C@@:27]2([CH3:43])[CH2:28][CH2:29][C@@H:30]3[C@@:35]4([CH3:41])[CH2:36][CH2:37][C@H:38]([OH:40])[CH2:39][C:34]54[O:42][CH:33]5[CH2:32][C@H:31]3[C@@H:26]2[CH2:25][CH2:24]1)[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]>CCOCC>[OH:42][CH:33]1[C:34]2[C@:35]([CH3:41])([CH2:36][CH2:37][C:38](=[O:40])[CH:39]=2)[C@@H:30]2[C@H:31]([C@H:26]3[C@:27]([CH3:43])([CH2:28][CH2:29]2)[C@@H:23]([C@H:16]([CH3:15])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:24][CH2:25]3)[CH2:32]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC(O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
Dichloromethane (50 ml) was added to pyridinium chlorochromate (2.78 g, 12.9 mmol) and molecular shieves (3 A) (4.37 g) and the mixture was stirred under a nitrogen atmosphere at room temperature for 15 minutes. To the resulting mixture was added a dichloromethane solution (30 ml) of 5,6-epoxycholesterol (α:β=5:1) (3.323 g, 8.6 mmol) prepared by the method of Fieser and Fieser (L. F. Fieser and H. Fieser, Reagents for Organic Synthesis, Vol. 1: 136, 1967) and the mixture was stirred for 3 hours. Ether (300 ml) was added to the reaction solution and the resulting solution was filtered through silica gel-magnesium sulfate. The organic layer was washed twice with 50 ml of a saturated saline solution and dried. The solvents were distilled off and the residue was purified by column chromatography. 6-Hydroxy-4-cholesten-3-one (α:β=5:1) was obtained as a colorless crystal from the hexane-ethyl acetate (5:1) eluate (yield: 51.7%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]=[C:7]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].Cl[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:39][CH3:40])=[C:29]([S:31]([NH:34][CH2:35][C:36]([NH2:38])=[O:37])(=[O:33])=[O:32])[CH:30]=1.[Li+].[Br-].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]=[C:7]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:39][CH3:40])=[C:29]([S:31]([NH:34][CH2:35][C:36]([NH2:38])=[O:37])(=[O:33])=[O:32])[CH:30]=3)[CH2:18][CH2:17]2)[O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCOCc1nc(C2CCNCC2)oc1-c1ccccc1
Reactant: COc1ccc(CCCl)cc1S(=O)(=O)NCC(N)=O
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOCc1nc(C2CCN(CCc3ccc(OC)c(S(=O)(=O)NCC(N)=O)c3)CC2)oc1-c1ccccc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
4-(4-ethoxymethyl-5-phenyl-oxazol-2-yl)-piperidine (450 mg, 1.4 mmol), prepared as in Intermediate 4, and 2-[5-(2-chloro-ethyl)-2-methoxy-benzenesulfonylamino]-acetamide (644 mg), prepared as in Intermediate 6, LiBr (182 mg), and diisopropyl ethylamine (0.73 mL) in dioxane (15 mL) is stirred at 100° C. for 18 h. The solvent is evaporated and the residue purified by chromatography on silica using 3% MeOH:CHCl3 as eluent to afford the product as a white foam.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]([CH2:14][CH2:15]O)[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:5]([N:12]([CH2:14][CH2:15][Cl:3])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CN(CCCl)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (2 ml) was added dropwise to a stirred, ice cooled solution of 2-[N-benzyl-N-methylamino]ethanol (4 g) obtained in preparation 8, in dry benzene (10 ml). The resulting mixture was stirred at 0° C. for 2 h and then diluted with ethyl acetate (40 ml), washed with saturated aqueous sodium bicarbonate solution (2×25 ml), water (50 ml), brine (50 ml) and dried. The ethyl acetate layer was evaporated and the residue was chromatographed on silica gel with 20% ethyl acetate in petroleum ether as eluent to give 2.6 g of the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>O>[CH3:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=1[C:36]1[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cccc(C)c1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(C)c1-c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of methyl 2-trifluoromethanesulfonyloxy-3-methylbenzoate (900 g, in toluene), potassium carbonate (629.6 g), tetrahydrofuran (2700 mL) and deionized water (5400 mL) under nitrogen is added tetrakis (triphenylphosphine)palladium (0) (104.6 g). To this is added the above solution of p-trifluoromethylphenylboronic acid and the mixture is heated at reflux for 2 days. The reaction mixture is filtered and evaporated to dryness. The residue is partitioned between water and ethyl acetate. The ethyl acetate layer is separated and evaporated to dryness. The residue is taken up in heptane-ethyl acetate (9:1), the mixture is filtered and the filtrate is evaporated to dryness to give methyl 6-methyl-4′-trifluoromethylbiphenyl-2-carboxylate as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:22]3[NH:26][N:25]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cn1)c1ncccc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: c1ccc(COc2ccc(-c3n[nH]c4cccnc34)nc2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of [5-(benzyloxy)pyridin-2-yl] (3-fluoropyridin-2-yl)methanone (2.85 g) and hydrazine monohydrate (1.348 mL) in EtOH (10 mL) was stirred at 50° C. overnight. After cooling, insoluble material was filtrated and washed with EtOH. The filtrate was evaporated, treated with water and extracted with AcOEt. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (0.232 g).
Reaction SMILES: O[CH:2]([CH3:10])[CH2:3][NH:4][C:5]([CH3:9])([CH3:8])[CH2:6]O.[NH3:11]>O>[CH3:9][C:5]1([CH3:8])[CH2:6][NH:11][CH:2]([CH3:10])[CH2:3][NH:4]1
Reactant: CC(O)CNC(C)(C)CO
Reactant: N
Solvent: O
Product: CC1CNC(C)(C)CN1
Yield: 48 %

Procedure:
In this example, a sample of 2,2,5-trimethylpiperazine was prepared by substantially following the procedure set forth in Example II. However, in this example, 120 g of crude N-(2'-hydroxypropyl)-2-amino-2-methyl-1-propanol, 90 g of water, 60 g of a Ni-Cu-Cr catalyst, and 102 g of ammonia were charged. GLC analysis showed that a 48% yield of 2,2,5-trimethylpiperazine was obtained with 55% dialkanolamine conversion.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17](O)[CH3:18]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:16])[CH2:11][CH2:12][C:13]([O:15][CH2:17][CH3:18])=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(CCC(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: CCO
Product: CCOC(=O)CCC(C)c1ccc([N+](=O)[O-])cc1
Yield: 97 %

Procedure:
A mixture of 110 g of 4-(4-nitrophenyl)valeric acid, 600 ml of absolute ethanol and 10 ml of concentrated sulfuric was heated under reflux overnight. The ethanol was evaporated in vacuo and the residue was partitioned between ether and water. The ether extract was washed with 5% of sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered and evaporated to give 119 g (97%) of product, bp 127°-128° (1.5 mm).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:42]([C:44]1[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=1)=[O:43].C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:42]([C:44]2[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=2)=[O:43])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 100 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.038 mL of triethylamine in 3 mL of THF was added 46.9 mg of methyl 4-(chlorocarbonyl)benzoate, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 56.0 mg of methyl 4-{[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}benzoate as a colorless foamy substance. FAB+: 607
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][C@@H:23]1OS(=O)(=O)[N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH2:24]1.Cl>CN1C(=O)CCC1>[C:34]([O:33][C:31]([NH:26][CH2:25][CH2:24][C@H:23]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:22])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n([C@H](C)CCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.4 %

Procedure:
A stirred suspension of 60% NaH (840 mg, 21 mmol) in NMP (40 mL) is cooled in an ice bath, and a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 5.8 g, 22 mmol) in NMP (20 mL) is added. The mixture is stirred for 20 min, then a solution of tert-butyl (6S)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (5.0 g, 20 mmol) in NMP (20 mL) is added. The reaction mixture is stirred for 30 min at 0° C. and is warmed to room temperature and stirred for 48 h. The reaction is poured into ice water and the resultant solid is isolated by filtration. The filtrate is acidified to pH 3 with 1N aqueous HCl and extracted with EtOAc. The combined extracts are washed with water 4 times, then brine, dried (Na2SO4) and concentrated to afford the title compound (6.0 g, crude) as an oil which was used in the next step without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:8]=[C:7]2I)([O-:3])=[O:2]>CN(C=O)C.[Cu]I.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>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([S:13]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:12][CH:11]=3)[C:7]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[N:9]([S:13]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)(=[O:15])=[O:14])[CH:8]=3)=[CH:8]2)(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc([N+](=O)[O-])ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ccc([N+](=O)[O-])cc34)c3ccccc32)cc1
Reaction time: 5 h
Yield: 100.4 %

Procedure:
A solution of 222 (0.331 g, 0.748 mmol), crude 206 (0.42 g, 0.748 mmol), catalytic amount of CuI and tetrakis(triphenylphosphine)palladium in DMF (10 mL) was degassed with argon for 10 min (Scheme 16). The mixture was brought to 50° C. and stirred for 5 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (20% ethyl acetate/hexane V:V) to yield 223 (0.22 g, 50%). 1H NMR (CDCl3): 2.36 (s, 3H), 2.38 (s, 3H), 7.26-7.33 (m, 5H), 7.43 (t, 1H. J=7.8), 7.56 (d, 1H, J=7.8), 7.80 (s, 1H), 7.84-7.87 (m, 4H), 7.92 (s, 1H), 8.11 (d, 1H, J=8.4), 8.17 (d, 1H, J=9.1), 8.28 (d, 1 H, J=9.0), 8.48 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1.CN(C=O)C.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O>[CH2:10]([O:9][C:7]([C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:26])([F:27])[F:28])=[O:8])[CH3:11]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CCC(=O)N1Cc1ccccc1C(F)(F)F
Temperature: 80 °C
Yield: 14.7 %

Procedure:
To the solution of (R)-ethyl 5-oxo-pyrrolidine-2-carboxylate (D-pyroglutamic acid ethyl ester; 99% pure; 1403 mg, 8.84 mmol) in 20 ml of DMF 1-(bromomethyl)-2-(trifluoromethyl)benzene (96% pure; 2200 mg, 8.84 mmol), K2CO3 (3660 mg, 26.5 mmol) and a small amount of each KI and 18-crown-6 were added, and the mixture was heated at 80° C. for 6 h. Subsequently the mixture was poured into water and extracted three times with MTBE. The organic layer was washed with brine, dried over MgSO4 and the solvent removed under reduced pressure. Chromatography on silica gel using dichloromethane and dichloromethane/MeOH (99:1) resulted in (R)-5-oxo-1-(2-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid ethyl ester (410 mg, ESI-MS [M+H]+=316.1; yield: 12%), which was hydrolyzed to the corresponding carboxylate by stiffing overnight at room temperature in a solution of 15 ml ethanol and 1.56 mL 2N NaOH (aq). Evaporation of the solvent, followed by addition of water to the residue, extraction with ethyl acetate, subsequent acidification of the aqueous layer to pH 3 using concentrated HCl, extraction with dichloromethane, drying of the combined organic layers with MgSO4 and removal of the solvent under reduced pressure led to the desired product as a white foam.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:7]2>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)[C@@H:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)=C2c1ccc(OCCN2CCCC2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Yield: 93.4 %

Procedure:
A solution of 1-{2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine hydrochloride (nafoxidene hydrochloride) (1.0 g, 2.16 mmol) in 20 mL of absolute ethanol containing 1.0 g of palladium hydroxide on carbon was hydrogenated at 50 psi at 20° C. for 19 hours. Filtration and evaporation provided 863 mg (93%) of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine: 1H-NMR (CDCl3): d 3.50-3.80 (m, 3H), 3.85 (s, 3H), 4.20-4.40 (m, 3H), 6.80-7.00 (m, 3H); MS 428 (P+ +1).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([CH2:11][C:12](OC)=O)=[CH:4][NH:3]1.[C-]#[N:17].[Na+].CS(C)=O>C(OCC)(=O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([CH2:11][C:12]#[N:17])=[CH:4][NH:3]1
Reactant: COC(=O)Cc1c[nH]c(=O)c2ccoc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1c[nH]c(=O)c2ccoc12
Temperature: 25 °C
Yield: 97.9 %

Procedure:
Combine methyl (4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)acetate (4.42 g, 21.3 mmol), sodium cyanide (5.22 g, 106 mmol), and dimethylsulfoxide (44 mL) and heat at 80° C. for 1 hour. Cool to room temperature, pour into ethyl acetate, wash sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dry over magnesium sulfate, filter, and concentrate under reduced pressure to provide the desired compound (3.63 g, 63%).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[I:13])[NH:4][C:3]1=O.[N+:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C-:16]>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[I:13])[N:4]2[CH:16]=[N:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:3]12
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Cn1c(=O)[nH]c2cccc(I)c2c1=O
Product: CCOC(=O)c1ncn2c3cccc(I)c3c(=O)n(C)c12

Procedure:
M.p. 266°-267° C. by reaction between 3-methyl-5-iodo-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and ethyl isocyanoacetate.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]([C:10]3[N:11]=[N:12][N:13]([C:15]4[CH:16]=[C:17]([CH:39]=[CH:40][C:41]=4[CH3:42])[C:18]([NH:20][C:21]4[CH:26]=[C:25]([C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])[CH:24]=[C:23]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]=4[O:37][CH3:38])=[O:19])[CH:14]=3)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[C:43](C1N(C)C(C2(C)CC2)=NC=1)#C>>[OH:29][CH2:28][C:27]([C:25]1[CH:24]=[C:23]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([O:37][CH3:38])=[C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:39]=[CH:40][C:41]([CH3:42])=[C:15]([N:13]3[CH:14]=[C:10]([C:7]4[N:8]([CH3:9])[C:4]([C:1]5([CH3:43])[CH2:3][CH2:2]5)=[N:5][CH:6]=4)[N:11]=[N:12]3)[CH:16]=2)[CH:26]=1)([CH3:31])[CH3:30]
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C5CC5)n4C)nn3)c2)cc(C(C)(C)CO)cc1NS(C)(=O)=O
Reactant: C#Cc1cnc(C2(C)CC2)n1C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C5(C)CC5)n4C)nn3)c2)cc(C(C)(C)CO)cc1NS(C)(=O)=O

Procedure:
Example 134 was prepared in the same manner as 3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[5-(2-hydroxy-1,1-dimethyl-ethyl)-3-methane-sulfonylamino-2-methoxy-phenyl]-4-methyl-benzamide (Example 133) with 1.5 equivalents of 5-ethynyl-1-methyl-2-(1-methyl-cyclopropyl)-1H-imidazole. ESI MS m/z 608 [C30H37N7O5S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=1.C1C(=O)N([Cl:41])C(=O)C1>>[Cl:41][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)cc1
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)cc1
Yield: 56.5 %

Procedure:
Following General Procedure H, tert-butyl 2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (180 mg, 0.39 mmol) was reacted with NCS (57 mg, 0.42 mmol) to afford the desired product (110 mg, 56%) as a yellowish solid. ESI MS m/z 499 [C26H27ClN2O4S+H]+.