Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.CC(OC(C)=O)=O.[N+:25]([O-])([OH:27])=[O:26].C(O)(=O)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:25]([O-:27])=[O:26])=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(c1)C1CCCCC1CC2=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1[N+](=O)[O-])C1CCCCC1CC2=O
Reaction time: 3 h
Yield: 34 %

Procedure:
Combine 6-methoxy-2,3,4,4a,10,10a-hexahydro-1H-phenanthren-9-one (0.936 g, 4.06 mmol), Ac2O (5.0 mL), and a solution of 90% HNO3/acetic acid (0.8 mL), and stir under Nitrogen atmosphere at 0° C. After 3 hours, add ethyl acetate. Wash the ethyl acetate with sodium bicarbonate solution and then brine, dry over sodium sulfate, and concentrate in vacuum. Flash chromatograph using dichloromethane (isocratic) to yield the titled compound (0.378 g, 34%) as a solid. TLC Rf=0.25 in dichlormethane. 1H NMR (CDCl3): 8.22 (d, 1H, J=8.8 Hz), 7.04 (d, 1H, J=8.8 Hz), 3.99 (s, 3H), 2.96 (m, 2H), 2.49 (m, 2H), 1.63 (m, 8H).
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11]([Mg]Cl)[C:12]([CH3:15])([CH3:14])[CH3:13]>C1COCC1.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: BrC1=Cc2ccccc2C1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)CC1=Cc2ccccc2C1
Reaction time: 8 h

Procedure:
To a mixture of 2-bromoindene (7.5 g, 39 mmol) and 2.5 g of NiCl2(PPh3)2 in 150 mL of THF was added over 1 hour 50 mL of neopentyl magnesium chloride (1.0 M in THF; 50 mmol). The mixture was stirred overnight and then quenched by adding 150 mL of 1.0 M aqueous hydrochloric acid. The product was isolated and purified (hexanes/silica) as for 2-benzyl-indene. Yield: 4.75 g, 66 percent
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[C:5]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH2:14])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]>O.Cl.Cl.Cl[Pt](Cl)(Cl)Cl.CCCCCCC>[C:5]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][CH2:14][Si:2]([Cl:4])([Cl:3])[Cl:1])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: Cl[Pt](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: CCCCCCC
Product: CC(=O)Oc1ccc(CC[Si](Cl)(Cl)Cl)cc1

Procedure:
Trichlorosilane (56.9 grams, 0.42 mole), 4-acetoxystyrene (64.6 grams, 0.40 mole), and 200 ml heptane were placed in a round bottom flask equipped with a water condenser and nitrogen inlet. Hydrogen hexachloroplatinate(IV) hydrate (20 mg) was added to this solution and heated to reflux for 18 hours. Afterwards, the solution was filtered hot through a frit funnel. The solvent and the unreacted reagents were distilled off at atmospheric pressure and the residue was purified by distillation under reduced pressure. 4-acetoxyphenylethyl trichlorosilane (91.2 grams) was collected between 105-125° C. at 1 mm Hg pressure as a waxy solid.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:9][C:10]#N)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:16].S(=O)(=O)(O)[OH:18]>>[CH:1]1([CH2:7][CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:9][C:10]([OH:18])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCC(CC#N)CC1CCCCC1
Reactant: O
Reactant: O=S(=O)(O)O
Product: CCCCC(CC(=O)O)CC1CCCCC1

Procedure:
3-(Cyclohexylmethyl)heptanenitrile (1.43 g) in 10 ml of 50% aqueous sulfuric acid was heated under reflux overnight. The cooled mixture was then poured into water (100 ml) and extracted twice with ether. The ethereal extracts were washed with water, dried (MgSO4) and evaporated to give 3-(cyclohexylmethyl)heptanoic acid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:20]([F:21])=[C:19]([F:22])[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:23])[C:8]=1[F:24].[Cl:25]/[CH:26]=[CH:27]\[CH2:28]I.[Cl-].[NH4+]>O1CCCC1>[Cl:25][CH:26]=[CH:27][CH2:28][C:7]1[C:20]([F:21])=[C:19]([F:22])[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:23])[C:8]=1[F:24]
Reactant: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1Br
Reactant: Cl/C=C\CI
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1CC=CCl
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (2.5 M in hexane, 3 cm3) was added portionwise to a solution of 2-[4-bromo-2,3,5,6-tetrafluorobenzyloxy]-tetrahydropyran (1.7 g) in dry tetrahydrofuran (10 cm3) under an atmosphere of dry nitrogen, whilst the reaction temperature was maintained at -70° C. After 30 minutes, copper (I) bromide - dimethyl sulphide complex (1.54 g) was added in one portion and the reaction temperature allowed to warm to 0° C., for a period of 15 minutes. After cooling to -70° C., a solution of Z-1-chloro-3-iodoprop-1-ene (2.03 g) in dry tetrahydrofuran (3 cm3) was added portionwise, and the reaction mixture stirred for a further hour at -70° C. After warming to the ambient temperature, (ca. 25° C.), aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. After drying, the solvent was evaporated under reduced pressure to give an orange oil. The residue was then subjected to medium pressure column chromatography on a silica gel column using a Gilson apparatus, eluting with petroleum ether (boiling range 40°-60° C.) containing diethyl ether (5% by volume) to give 2-[4-(3-chloroprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyloxy]-tetrahydropyran, as a mixture consisting predominantly of the Z isomer.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]=2[CH:31]=1.C(O)(=O)C.C[N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH:42]=O.C([BH3-])#N.[Na+]>CO>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]=2[CH:31]=1)[CH2:42][C:38]1[NH:37][CH:41]=[CH:40][N:39]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCc1nc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2n1CCC
Temperature: 0 °C
Reaction time: 48 h

Procedure:
The compound (64.0 mg) obtained in Example 126-1 was dissolved in methanol (1.3 ml) and added with acetic acid (0.065 ml) and 1-methyl-2-imidazole carboxaldehyde (16.6 mg), followed by cooling to 0° C. Then, the solution was added with sodium cyanoborohydride (14.2 mg) and stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. After washing with a 1 mol/l sodium hydroxide aqueous solution, the solution was subjected to extraction with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (30.0 mg) of the subject compound as a white solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[ClH:1].[NH:37]([C:38]([NH:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 16 h

Procedure:
A solution of 80 mg (0.21 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 4 ml of THF is mixed with 59.6 μl (0.43 mmol) of triethylamine and 50.9 mg (0.43 mmol) of phenyl isocyanate. After 16 h at room temperature, the reaction mixture is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 35 mg (35.8% of theory) of the title compound are obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[C:42](=[O:45])([O-])[O-].[K+].[K+].O>C(COC)OC>[OH:45][C:42]1[C:14]([CH3:13])=[CH:15][C:7]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])=[CH:8][C:12]=1[CH3:11]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc(C)c1O
Yield: 102.4 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in dimethoxyethane (9.6 mL), and the solution was treated with 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (42.0 mg, 0.168 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (5.5 mg, 0.0067 mmol), potassium carbonate (58.0 mg, 0.421 mmol) and water (0.030 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-(4-hydroxy-3,5-dimethylphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (39.1 mg, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Clc1cccc2c1CCN2
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4c(Cl)cccc43)c2cc1OC
Yield: 92 %

Procedure:
Utilizing a procedure analogous to that described in Example 2, this product was prepared in 92% yield from 4-chloro-indoline (2 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 172°-179° C. (dec); LC-MS: 342 (MH+); anal. RP18-HPLC RT: 4.60 min.).
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5]>CO>[P:4]([O:9][CH3:10])([O:6][CH2:7][CH3:8])([O:3][CH2:2][CH3:1])=[O:5].[CH:12]1[C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=[C:10]([OH:9])[CH:11]=1
Reactant: CCOP(=O)(OCC)Oc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: CCOP(=O)(OC)OCC
Product: O=[N+]([O-])c1ccc(O)cc1

Procedure:
Paraoxon, when placed in an appropriately buffered methanol solution containing La3+ions held in a sspH region between 7 and 11, underwent rapid methanolysis at ambient temperature to produce diethyl methyl phosphate and p-nitrophenol. A detailed reaction scheme is given in Scheme 1.
Reaction SMILES: [C:1]1([CH2:17][OH:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[Br:19][CH2:20][C:21](Br)=[O:22]>CN(C=O)C.ClCCl>[Br:19][CH2:20][C:21]([O:18][CH2:17][C:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1)=[O:22]
Reactant: OCc1ccc2ccc3cccc4ccc1c2c34
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CBr)OCc1ccc2ccc3cccc4ccc1c2c34
Temperature: 23 °C
Reaction time: 17 h
Yield: 100.6 %

Procedure:
Pyrenemethanol (Pyr-OH) (109.6 mg, 0.47 mmol) in 1.0 mL DMF (anh) was treated with 180 μL TEA (anh, 1.29 mmol) and 2-bromoacetyl bromide (132.2 μL, 1.50 mmol) in 1 mL dichloromethane. The mixture was stirred at RT (˜23° C.) for 17 hours. After the solvent was evaporated, the crude product was purified by silica gel column (Hex/EtOAc=2/1) to give 167 mg final product as a yellow solid (yield 90%). 1H NMR (CDCl3, 500 MHz): δ 8.28-8.03 (m, 9H, ArH), 5.94 (s, 2H, ArCH2), 3.90 (s, 2H, CH2Br). ESI: 375, [M+Na]+.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([NH2:11])[CH2:10][CH2:9]1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:16](Cl)=[O:17].O>O1CCCC1>[CH:8]1([NH:11][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:13]([CH3:12])[CH:14]=2)[CH2:10][CH2:9]1
Reactant: NC1CC1
Reactant: Cc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC2CC2)ccc1[N+](=O)[O-]
Reaction time: 12 h
Yield: 76.2 %

Procedure:
3.35 g (33 mmol) of triethylamine was added to a solution containing 1.65 g (29 mmol) of cyclopropylamine in 50 ml of tetrahydrofuran, then 5.0 g (28 mmol) of 3-methyl-4-nitrobenzoyl chloride was added dropwise while cooled with iced water. The reaction mixture was allowed to room temperature and after stirred for 12 hours, poured into iced water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 4.7 g of the desired compound. This was used in the next reaction without being purified.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11]C)[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Br.O>C(O)(=O)C>[CH3:1][C:2]1([CH3:19])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[OH:11])[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cccc2c1CC(C)(C)C2N1CCCCC1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)Cc2c(O)cccc2C1N1CCCCC1

Procedure:
A mixture of the 4-methoxy compound from Step 3. above (5 g) and 48% aq. HBr (50 ml) in glacial acetic acid (50 ml) is refluxed for three hours. The mixture is poured into H2O, the pH adjusted to 8-10 and extracted with methylene chloride. The organic extract is washed with sat'd NaCl, dried, filtered, evaporated and the residue chromatographed (silica gel, hexane/ether) affording the desired product as a green solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(Oc2ccc(CC(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Yield: 43 %

Procedure:
A solution of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.200 g, 0.79 mmol), methyl 2-(4-hydroxyphenyl)acetate (0.131 g, 0.79 mmol) and potassium carbonate (0.546 g, 3.95 mmol) in acetonitrile (5 mL) was heated to 85° C. for 7 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/dichloromethane) to afford the title compound (0.130 g, 65%). MW=382.84. 1H NMR (CD3OD, 500 MHz) δ 8.21 (t, J=1.8 Hz, 1H), 8.16-8.12 (m, 1H), 7.46-7.35 (m, 4H), 7.21-7.17 (m, 2H), 6.77 (s, 1H), 3.73 (s, 2H), 3.72 (s, 3H), 2.83 (q, J=7.6 Hz, 2H), 1.35 (t, J=6.4 Hz, 3H); APCI MS m/z 383 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]([CH2:21]OS(C3C=CC=CC=3)(=O)=O)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:32]>CC(C)=O>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]([CH2:21][I:32])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(OCC1CN(S(=O)(=O)c2ccccc2)CC1c1ccccc1)c1ccccc1
Reactant: [I-]
Solvent: CC(C)=O
Product: O=S(=O)(c1ccccc1)N1CC(CI)C(c2ccccc2)C1
Yield: 96.8 %

Procedure:
A solution of 234 mg (0.51 mmol) of 1-(benzenesulfonyl)-3-(SR)-benzenesulfonyloxymethyl-4-(SR)-phenylpyrrolidine (from Example 1, Step D) and 1.1 g (7.7 mmol) of sodiuim iodide in 8 mL of acetone was heated at reflux for 20 h. The reaction mixture was partitioned between 50 mL of ether and 30 mL of H2O and the layers were separated. The organic layer was washed with 30 mL of sat'd NaCl and dried over MgSO4. The aqueous layers were combined and extracted with 30 mL of ether. The extract was dried; the organic layers were combined. and concentrated in vacuo. Flash chromatography on 25 g of silica gel using 3:2 v/v hexanes/ether as the eluant afforded 211 mg (96%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ2.43 (t, J=9.8, 1H), 2.64-2.74 (m, 2H), 3.30 (dd, J=2.5, 7.8, 1H), 3.47 (q, J=6.7, 1H), 3.67-3.74 (3H), 7.05-7.95 (1OH). Mass Spectrum (NH3-CI): m/z 428 (M+1).
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[NH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[N:27]=[C:28]=[O:29]>>[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[N:18][C:28]([NH:27][C:21]1[C:20]([CH3:19])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:26])=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N=C1CCCN1Cc1ccccc1
Reactant: Cc1cccc(C)c1N=C=O
Agent: F[B-](F)(F)F
Product: Cc1cccc(C)c1NC(=O)N=C1CCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The fluoroborate salt of 1-benzyl-2-iminopyrrolidine (6.55 g.; 0.025 mole) is converted to free base (4.36 g; 0.025 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 3.68 g. (0.025 mole) of 2,6-dimethylphenylisocyanate is added. The reaction mixture is stirred at room temperature for 1 hour and then evaporated to dryness in vacuo to give an oily residue of 1-(1-benzyl-2-pyrrolidylidene)-3-(2,6-dimethylphenyl)urea which is dissolved in ether and converted to the hydrochloride salt. Recrystallizations from methanol yields the product, 1-(1-benzyl-2pyrrolidylidene)-3-(2,6-dimethylphenyl)urea HCl, m.p. = 185°-195° C. (dec.) EXAMPLE XXXIV
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])=O.[CH:14]([NH2:16])=[S:15].[CH3:17]CO>>[CH3:17][O:10][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([C:3]2[N:16]=[CH:14][S:15][CH:2]=2)[CH:6]=1
Reactant: O=C(O)c1cccc(C(=O)CBr)c1
Reactant: NC=S
Reactant: CCO
Product: COC(=O)c1cccc(-c2cscn2)c1
Reaction time: 18 h

Procedure:
A solution of 3-(2-bromo-acetyl)-benzoic acid (1.22 g) and thioformamide (0.46 g) in EtOH (5 mL) was heated to 80° C. for 1 h. The mixture was partitioned between AcOEt and brine and the organic layer was dried and evaporated. The residual oil was dissolved in a mixture of MeOH (20 mL) and 4NHCl/Et2O (5 mL). After being kept at 20° C. for 18 h, the solution was concentrated in vacuum, diluted with AcOEt, washed with sat. NaHCO3 solution and brine, dried and evaporated. The residue was chromatographed on silica gel using AcOEt/hexane (1:3) as eluent to give 3-thiazol-4-yl-benzoic acid methyl ester (0.98 g) as off-white solid, MS (ISP) 220.2 [(M+H)+].
Reaction SMILES: [CH2:1]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[CH:2]1[O:4][CH2:3]1.[CH3:16][C:17]([NH2:28])([CH3:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[OH:4][CH:2]([CH2:1][O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[CH2:3][NH:28][C:17]([CH3:27])([CH3:16])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: C1C2CC3CC1CC(OCC1CO1)(C2)C3
Product: COc1ccc(CC(C)(C)NCC(O)COC23CC4CC(CC(C4)C2)C3)cc1
Yield: 53.4 %

Procedure:
Using the method of Example 16, supra, 1-adamantyl glycidyl ether (350 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 207 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 338 (M+1, 0.1), 372 (0.3), 266 (65), 163 (1), 135 (100), 121 (16); 1H-NMR (CDCl3) δ 7.02 (2H, d, J=8.3), 6.74 (2H, d, J=8.6), 3.70 (3H, s), 3.64 (1H, m), 3.38 (4H, m), 2.71 (1H, dd, J=11.5 and 4.0), 2.57 (3H, m), 2.06 (3H, broad s), 1.64 (6H, broad s), 1.53 (6H, m), 1.13 (4H, apparent t, J=6.9), 0.98 (3H, s), 0.97 (3H, s); 13C-NMR (CDCl3) δ 157.8, 131.2, 130.0, 113.1, 77.8, 70.5, 69.4, 54.9, 52.8, 46.3, 44.6, 32.0, 26.7, 26.6, 25.6, 23.9.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][NH2:18])[N:13]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28](N(CC)C(C)C)(C)C.CO[C:39](=[O:52])[C:40]1[CH:45]=[CH:44][C:43](C)=[C:42]([O:47][CH2:48][O:49][CH3:50])[C:41]=1Br>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][N:18]3[CH2:28][C:41]4[C:40](=[CH:45][CH:44]=[CH:43][C:42]=4[O:47][CH2:48][O:49][CH3:50])[C:39]3=[O:52])[N:13]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCOc1c(C)ccc(C(=O)OC)c1Br
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN
Solvent: CC#N
Product: COCOc1cccc2c1CN(C[C@@H]1Cc3c(sc(N)c3C(=O)OC(C)(C)C)CN1[C@@H](C)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 109.7 %

Procedure:
To a stirred mixture of 2-amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.24 g, 0.67 mmol) in acetonitrile (30 ml) was added N,N-diisopropylethylamine (0.16 ml, 0.93 mmol) under nitrogen. 2-Bromo-methyl-3-methoxymethoxy-benzoic acid methyl ester (0.16 g, 0.55 mmol) dissolved in acetonitrile, was added via syringe pump at a rate of 0.3 ml/hour. Once the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. Tlc analysis (1:1 ethyl acetate/hexanes) indicated the reaction to be complete. The volatiles were removed in vacuo and the resultant oil dissolved in ethyl acetate/water. The layers were separated and the aqueous layer extracted with ethyl acetate (3×). The organic layers were combined, dried (MgSO4), filtered and the solvebt evaporated in vacuo, which afforded 0.34 g (100%) of 2-amino-5-(S)-(4-methoxymethoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester, which was used without further purification in the next step.