Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:5].C(N(CC)CC)C.[CH2:22]([O:29][CH2:30][C:31](Cl)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:14])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:31](=[O:32])[CH2:30][O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(N)cc1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)Oc1ccc(NC(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To a mixture of 2-(4-aminophenoxy)-propionic acid methyl ester 10 (20 grams, 102.5 mmol) and triethylamine (23 ml, 165 mmol) in acetone (120 ml) at 0° C. was added dropwise benzyloxy acetyl chloride (28 g, 152 mmol) followed by stirring at room temp for 12 hours. The solids were filtered off, acetone distilled off, and water (100 ml) added. Crude 51 was extracted into chloroform, washed with 5% sodium bicarbonate (2×100 ml) and water (200 ml), then dried over sodium sulphate and distilled. Crude 51 was purified by column chromatography on silica gel using benzene as eluant to get pure 51 (21 g, 59.8%) as a light brown powder with an m.p. between 67-70° C.
Reaction SMILES: C(OC(=O)CC1C=CC(C#C[C:14]2[CH:23]=[CH:22][C:21]3[CH:20]([N:24]([CH:26]4CC4)C)CC[C:17]([CH3:30])([CH3:29])[C:16]=3[CH:15]=2)=CC=1F)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:39]1CCC[CH2:40]1>>[CH3:40][O:39][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][NH:24][CH2:26][C:17]2([CH3:29])[CH3:30]
Reactant: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1F
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc2c(c1)C(C)(C)CNC2
Yield: 100 %

Procedure:
A solution of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-1-one (Intermediate 17, 3.5 g, 17 mmol) in 100 mL of anhydrous tetrahydrofuran was treated with lithium aluminum hydride (1.3 g, 34.25 mmol) in small portions and the resulting suspension was refluxed for 3 hours under argon. The reaction mixture was then cooled in an ice bath and cautiously quenched with saturated aqueous sodium sulfate solution and the resulting slurry was filtered and the filter-cake washed well with ethyl acetate. The filtrate and washings were evaporated in vacuo to a brown oil which was dissolved in chloroform, the solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (3.2 g, ˜100%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[N:29]1([CH2:28][CH2:27][CH2:26][NH:25][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:23])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reactant: NCCCN1CCOCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NCCCN3CCOCC3)cc2n1
Yield: 76 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (96 mg, 0.3 mmol) was converted, using N-(3-aminopropyl)morpholine instead of aminomethylcyclopropane, to the title compound (102 mg, 76%) which was obtained as an off-white foam. MS: m/e=446.3 [M+H]+.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:11])=[C:3](/[CH2:9][CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(C(C)C)CC)(C)C.Cl[C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:22]([NH:1]/[C:2](/[CH3:11])=[C:3](/[CH2:9][CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:29])[CH3:28]
Reactant: CCOC(=O)/C(CC)=C(/C)N
Reactant: CCOC(=O)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)N/C(C)=C(/CC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A 100-mL round bottom flask was charged with ethyl (Z)-3-amino-2-ethyl-but-2-enoate (880 mg, 5.6 mmol, 1 eq.), diisopropylethylamine (750 mg, 5.8 mmol, 1.04 eq.) and THF (10 ml). To the mixture was added ethyl 3-chloro-3-oxo-propanoate (840 mg, 5.6 mmol, 1 eq.) dropwise by a syringe at 0° C. After the addition was complete, the resulting mixture was stirred at room temperature overnight and then added to aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layer was dried over anhydrous Na2SO4. Removal of solvent gave the crude product ethyl (Z)-3-[(3-ethoxy-3-oxo-propanoyl)amino]-2-ethyl-but-2-enoate as yellow oil (1.3 g, 86% yield).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]C)=[O:18])=[C:15]([O:21][CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[C:14]([CH2:32][CH3:33])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:34].[Li+]>O1CCOCC1.O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:21][CH2:22][CH2:23][NH:24][O:34][C:11]([CH3:16])([CH3:12])[CH3:10])[C:14]([CH2:32][CH3:33])=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1OCCNC(=O)OC(C)(C)C
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)O)c1OCCNOC(C)(C)C
Temperature: 130 °C
Yield: 131.6 %

Procedure:
A mixture of methyl 6-(benzenesulphonylmethyl)-2-(2-t-butoxycarbonylaminoethoxy)-3-ethylbenzoate (Intermediate 108, 0.125 g), and lithium hydroxide (0.066 g) in dioxane (1.4 ml) and water (0.4 ml) was stirred and heated in the microwave at 130° C. for 45 minutes. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous layer was acidified with hydrochloric acid (1M) and extracted with ethyl acetate, washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 6-(benzenesulphonylmethyl)-2-(2-t-butoxyaminoethoxy)-3-ethylbenzoic acid (0.075 g) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([NH:13][CH2:14][CH2:15][CH2:16]O)=[N:6][CH:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([NH:13][CH2:14][CH2:15][CH2:16][Cl:26])=[N:6][CH:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(Cl)Cl
Reactant: CN1C(NCCCO)=NC(c2ccccc2)c2cc(Cl)ccc21
Solvent: ClC(Cl)Cl
Product: CN1C(NCCCCl)=NC(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A mixture of 3.3 g of 6-chloro-1,4-dihydro-2-(γ-hydroxypropylamino)-1-methyl-4-phenylquinazoline, 3.6 g of thionyl chloride and 50 ml of chloroform was stirred at room temperature overnight, and refluxed for an additional 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to give 3.5 g of 6-chloro-1,4-dihydro-2-(γ-chloropropylamino)-1-methyl-4-phenylquinazoline as a residue. To the residue were added 100 ml of dry ethanol and 2.8 g of potassium carbonate and the resulting mixture was heated under reflux for 5 hours. After cooling, insoluble material was filtered off and the filtrate was concentrated to dryness. The residue was chromatographed on activated alumina using chloroform as an eluent to give 8-chloro-11-methyl-6-phenyl-3,4,6,11-tetrahydro-2H-pyrimido[2,1-b]quinazoline.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si](C(C)(C)C)(C)C)=[CH:17][C:16]=2[O:29][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44](Cl)(=[O:47])[CH2:45][CH3:46]>ClC(Cl)C.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]([C@H:9]1[CH2:10][CH2:11][C@@H:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:29])[CH2:13][CH2:14]1)[C:44](=[O:47])[CH2:45][CH3:46])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)N(Cc1ccccc1)[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
cis-N-Benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl] amine (0.084 g) was dissolved in dichloroethane (7 ml), and triethylamine (0.045 ml) and 4-dimethylaminopyridine (catalytic) added. Propionyl chloride (0.028 ml) was then added, and the mixture stirred at room temperature for 60 hr. The reaction mixture was partitioned between dichloromethane (10 ml) and saturated aqueous sodium hydrogen carbonate (10 ml). The aqueous layer was extracted with dichloromethane (2×10 ml) and the combined organic extracts washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved with stirring in dichloroethane (16 ml) and heated with a mixture of water (10 ml), methanol (5 ml) and trifluoroacetic acid (10 ml) at 80° C. for 17 hr. Toluene (25 ml) was then added and the mixture concentrated in vacuo. Methanol (25 ml) was then added and the mixture again concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether) afforded the title compound (0.021 g, 37%) as a colourless solid. Rf 0.20 (ethyl acetate/petroleum ether, 1:1, v/v); m/s(ES+) 354.17 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.[F-].[Cs+].I[CH:36]([CH3:38])[CH3:37]>C(#N)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH:36]([CH3:38])[CH3:37])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:21]=2[C:22]([F:24])([F:25])[F:23])[O:11][N:10]=1
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1C(F)(F)F
Reactant: CC(C)I
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)OC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccccc2F)c1C(F)(F)F
Yield: 79.4 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid (30 mg, 0.064 mmol), cesium fluoride (12 mg, 0.077 mmol) and 2-iodopropane (0.008 mL, 0.077 mmol) were dissolved in dried acetonitrile (1 mL) and the mixture was refluxed for 20 h. The mixture was diluted with dichloromethane and washed with water. The organic phase was dried over Na2SO4, filtered and the solvent was solvent removed under reduced pressure. The product was purified by pTLC (PE/EE 9/1) to give 26 mg of a yellow oil (yield 79 To). Result of LC/MS [M+H]+: 511.8; 1H NMR (CDCl3): 1.02 (6H, d, 2×CH3), 5.02 (1H, m, CH-propyl), 7.18 (1H, t, CH-arom.), 7.28-7.61 (6H m, CH-arom.), 8.31 (1H, s, CH-pyraz.).
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH2:21])[C:12]1=[O:22])[CH2:7][CH:8]([CH3:10])[CH3:9])(=O)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([CH3:34])[C:31](O)=[O:32])=[CH:26][CH:25]=1.CN(C)C=O.C(=O)(O)[O-].[Na+].[OH-].[Na+]>CO>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C@@H:30]([CH3:34])[C:31]([NH:21][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18]=2[CH:19]=[CH:20][N:11]([C@@H:6]([CH2:5][OH:4])[CH2:7][CH:8]([CH3:9])[CH3:10])[C:12]3=[O:22])=[O:32])=[CH:28][CH:29]=1
Reactant: C[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: CC(=O)OC[C@@H](CC(C)C)n1ccc2c(N)cccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)C[C@H](CO)n1ccc2c(NC(=O)[C@H](C)c3ccc(Cl)cc3)cccc2c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 20 ml reaction vial reaction vial was combined (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-4-methylpentyl acetate (0.23 g, 0.00076 mol), (R)-2-(4-chlorophenyl)propanoic acid (0.175 g, 0.000949 mol) N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.58 g, 0.0015 mol) N,N-diisopropylethylamine (0.26 mL, 0.0015 mol), and N,N-dimethylformamide (4 mL, 0.06 mol). The mixture was heated at 50° C. for 3 hours and allowed to cool to room temperature. The mixture was poured on to saturated sodium bicarbonate (200 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were dried over sodium sulfate and reduced in vacuo to yield a light brown oil. The oil was taken up in methanol (10 ml) and 2N NaOH (10 ml) was added. The mixture was allowed to stir overnight. The volatiles were removed and the mixture was extracted with methylene chloride (2×20 ml). The combined extracts were reduced in vacuo and the mixture was purified by reversed phase prep HPLC using an acetonitrile: water gradient at pH 10. The combined pure fractions were reduced in vacuo to yield the title compound as yellow solid.
Reaction SMILES: I[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][CH:3]=1.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14]>C(N(CC)CC)C.Cl[Pd](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>[C:7]1([N:6]2[C:2]([C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:3][CH:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Ic1ccnn1-c1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccnn1-c1ccccc1
Temperature: 70 °C
Reaction time: 10 h
Yield: 86.5 %

Procedure:
To a solution of 5-iodo-1-phenyl-1H-pyrazole (2.00 g) (J. Org. Chem. 2008, 73, 1, 177-183) in triethylamine (40.0 mL) were added ethynyl(trimethyl)silane (0.80 g), CuT (0.141 g) and PdCl2(PPh3)2 (0.260 g) under an argon atmosphere, and the mixture was stirred at 70° C. for 10 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane) to give the title compound (1.54 g).
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:7])[C:3]([CH2:5]Cl)=[O:4].[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].O>CN(C=O)C>[CH3:1][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:7])[C:3]([CH2:5][O:22][C:19](=[O:21])[CH3:20])=[O:4]
Reactant: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC(=O)C(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1
Yield: 47.4 %

Procedure:
N-(1',1'-dimethyl-3'-chloroacetonyl)-3,5-dichlorobenzamide (20 gm, 0.065 m) was dissolved in 100 ml of dry DMF and 10.6 gm (0.128 m) of sodium acetate was added. The slurry was blanketed under a nitrogen atmosphere and then heated to 80°-90° C. for 4 days. The reaction mixture was cooled by adding 100 ml of water. The aqueous solution was extracted four times with 10 ml aliquots of methylene chloride. The combined organic extracts were washed with water (3×100 ml) and brine. The solvent was removed, the resulting white solid dried and then recrystallized from an acetone and hexane (about 1:4) mixture to yield 10.2 gm of the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[Br:11]
Reactant: OB(O)c1cccc(F)c1
Reactant: Oc1ccccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cccc(Oc2ccccc2Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.9 %

Procedure:
To a stirred solution of 3-fluorophenylboronic acid (2.10 g, 15 mmol), 2-bromophenol (1.77 g, 10 mmol) and Cu(OAc)2 (0.93 g, 5 mmol) in anhydrous CH2Cl2 (25 mL) was added activated 4 Å molecular sieves (˜0.1 g), followed by anhydrous Et3N (3.5 mL, 25 mmol). The resulting dark green solution was stirred at rt for 48 h. The mixture was evaporated under reduced pressure and the residue was washed several times with Et2O (˜150 mL). The Et2O solution was washed with sat'd aq NH4Cl, and 1 N aq HCl. The organic layer was evaporated and the crude product was purified by flash column chromatography to give 1-(3-fluorophenoxy)-2-bromobenzene (1.28 g, 48%) as clear oil.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:7]1([CH2:23][CH2:24][CH2:25][CH3:26])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][Si](C)(C)C)[CH:15]=2)[S:10][CH2:9][CH2:8]1)[CH2:4][CH2:5][CH3:6]>O.C(O)C>[CH2:3]([C:7]1([CH2:23][CH2:24][CH2:25][CH3:26])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[S:10][CH2:9][CH2:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1(CCCC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#Cc1ccc2c(c1)C(CCCC)(CCCC)CCS2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1.41 g (25 mmol) of potassium hydroxide in 1.4 mL of water and 10.0 mL of ethanol was added to 1.44 g (4.00 mmol) of (4,4-dibutylthiochroman-6-yl)(trimethylsilyl)acetylene (Compound 34) and the resulting mixture stirred at room temperature for 16 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with 5% aqueous H2SO4. The product was extracted with 2×50 mL of ether.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:19])[S:9][C:10]=1[C:11](=[O:16])N(OC)C.C(OCC)C.[C:31]1([Mg]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Cl-].[NH4+]>C1COCC1>[C:11]([C:10]1[S:9][C:8]([NH:17][C:18]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[O:19])=[N:7][C:6]=1[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:16])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
Compound 98 (354 mg, 0.989 mmol) was dissolved in THF (5 mL), and a diethyl ether solution of 3 mol/L phenylmagnesium bromide (1.32 mL, 3.96 mmol) was added thereto under ice-cooling, followed by stirring at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was reslurried with ethanol to afford the entitled Compound 99 (220 mg, 59%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@H:9]2[CH2:13][NH:12][C@H:11]([C:14]([NH:16][C:17]3([C:20]#[N:21])[CH2:19][CH2:18]3)=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:36][CH2:35][CH:34]2[C:37]([O-])=[O:38])[CH2:29][CH2:28]1)=[O:26])[CH3:23].[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@H:9]2[CH2:13][N:12]([C:37]([CH:34]3[CH2:35][CH2:36][N:33]3[CH:30]3[CH2:29][CH2:28][N:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:32][CH2:31]3)=[O:38])[C@H:11]([C:14](=[O:15])[NH:16][C:17]3([C:20]#[N:21])[CH2:19][CH2:18]3)[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](Sc3ccc(Cl)cc3)CN2)CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](Sc3ccc(Cl)cc3)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(4-chlorophenylthio)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 12G and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-4-(4-chlorophenylthio)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (70%). MS ISP (m/e): 560.3/562.1 (100/62) [(M+H)]+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[N:5][N:4]=1)[CH3:2].C([Li])CCC.[F:14][C:15]1[CH:29]=[CH:28][C:18]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>O1CCCC1.CCCCCC>[F:14][C:15]1[CH:29]=[CH:28][C:18]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([OH:20])[CH:1]([C:3]2[N:7]([CH3:8])[N:6]=[N:5][N:4]=2)[CH3:2])=[CH:17][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCc1nnnn1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(c1nnnn1C)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a solution of 5-ethyl-1-methyl-1H-tetrazole (5.6 g, 0.05 mole) [prepared in Step A] in 60 mL of dry tetrahydrofuran was added 2.5M n-butyllithium (20 mL, 0.05 mole) in hexane over 5 minutes at -78° C. (bath temperature) under an inert atmosphere. The mixture was stirred for 30 minutes and a solution of 4,4'-difluorobenzophenone (10.8 g, 0.5 mole) in 25 mL of dry tetrahydrofuran was added over 5 minutes. This mixture was stirred for an additional 2 hours while the bath temperature was slowly warmed to -20° C. The reaction was quenched with 1N HCl and extracted with ethyl acetate (3×50 mL) and chloroform (3×50 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a white solid. The solid was purified by crystallization from ethanol-hexane to give 10.8 g (65%) of the title compound; m.p.=160°-161° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[O:3][CH2:4][C:5]#[CH:6].C([Li])CCC.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[CH3:1][Si:2]([CH3:8])([CH3:7])[O:3][CH2:4][C:5]#[C:6][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C#CCO[Si](C)(C)C
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CCO[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of trimethyl(prop-2-ynyloxy)silane (15 ml) in tetrahydrofuran (100 ml) was added butyllithium (2.6 M in hexane, 38 ml) at −78° C. The resulting mixture was stirred at the same temperature for 0.5 hour, and ethyl chloroformate (10 ml) was added thereto. The resulting mixture was stirred at −78° C. for 1.5 hours, and poured into ice water. The resulting materials were extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution successively. The extract was dried over anhydrous sodium sulfate, and the solvents were evaporated in vacuo to afford ethyl 4-(trimethylsilyloxy)but-2-ynoate (16.5 g).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[ClH:1].[ClH:1].[NH2:23]/[C:22](=[N:25]\[OH:26])/[C:20]1[CH:19]=[CH:18][C:16]2[CH:17]=[C:13]([C:11]([NH:10][C@@H:4]3[CH:5]4[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]4)[CH2:3]3)=[O:12])[S:14][C:15]=2[CH:21]=1
Reactant: NO
Reactant: N#Cc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N/C(=N\O)c1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1

Procedure:
800 mg (2.0 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1-benzothiophene-2-carboxamide hydrochloride (Example 26A), 278.1 mg (4.0 mmol) of hydroxylamine hydrochloride and 829.5 mg (6.0 mmol) of potassium carbonate are heated in 8 ml of an 8:1 mixture of water and ethanol at 80° C. for 3 h. The mixture is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol/25% ammonia solution 100:20:4). The product fractions are combined, concentrated, mixed with methanol and 4 M hydrogen chloride in dioxane, then again concentrated and dried under high vacuum. 447.3 mg (53.6% of theory) of the title compound are obtained.