Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)=[C:2]=[O:3].Br.Br[CH2:22][CH2:23][CH:24]([NH2:26])[CH3:25].C(N(CC)CC)C.CC(C)([O-])C.[K+]>C(#N)C.C1COCC1>[CH3:25][CH:24]1[CH2:23][CH2:22][N:1]([CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]2)[C:2](=[O:3])[NH:26]1
Reactant: CC(N)CCBr
Reactant: O=C=NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of benzyl 4-isocyanatopiperidin-1-carboxylate (0.26 g) in acetonitrile (10 mL) was added to a solution of 4-bromobutan-2-amine hydrobromide (0.17 g) and triethylamine (0.10 g) in acetonitrile (10 mL), followed by stirring at room temperature for one hour. Potassium tert-butoxide (0.29 g) and THF (20 mL) were added thereto, and the mixture was further stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water, and extracted with ethyl acetate. The extract was washed with water and saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1) to obtain the title compound (0.15 g, 45%) as a light brown solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:9]C)(=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[C:11](#[N:13])[CH3:12]>O1CCCC1>[C:3]([CH2:12][C:11]#[N:13])(=[O:9])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC#N
Reactant: COC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC#N

Procedure:
In a 1 l. flask under an atmosphere of dry nitrogen there was placed 26.4 g. of a 50% oil dispersion of sodium hydride together with 240 ml. of dry tetrahydrofuran. While this mixture was refluxed there was added thereto dropwise over a period of about 1 hour a mixture of 40.6 g. of methyl pivalate and 22.6 g. of acetonitrile in 40 ml. of dry tetrahydrofuran. When addition was complete, the mixture was refluxed overnight. The reaction mixture was worked up by evaporating part of the tetrahydrofuran in vacuo and dissolving the remaining solution in about 300 ml. of water. This aqueous mixture was acidified to about pH 4 using concentrated aqueous hydrochloric acid. The remainder of the tetrahydrofuran was then removed using a rotovapor. The solid which was formed was filtered and slurried with 150 ml. of hexane to remove mineral oil. The crystals were filtered and dried. The crystals had a melting point of about 57°-59° C. and were identified as pivalyl acetonitrile. Yield: 36.3 g. (83%).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[CH:33](=O)[CH2:34][CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH2:33][CH2:34][CH3:35])=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: CCC=O
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 76.8 %

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained in Example (81e) (38 mg, 0.080 mmol), 1-propanal (7 μL, 0.097 mmol) and sodium (triacetoxy)borohydride (80 mg, 0.38 mmol), to obtain 31.9 mg of the title compound as a white solid (77%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:9]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[OH:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:27](O)(=O)[CH3:28].[CH:31](=O)[CH3:32].C(O[BH3-])(=O)C.[Na+]>CO>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH:11]([OH:12])[C:9]1[N:8]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:7]2[C:2]([N:1]([CH2:27][CH3:28])[CH2:31][CH3:32])=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: CC(=O)O
Reactant: CC=O
Reactant: COC(=O)CCn1c(C(O)c2ccc(Cl)cc2Cl)nc2cccc(N)c21
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCC(=O)OC)c12
Reaction time: 0.5 h

Procedure:
To a suspension of methyl 3-{7-amino-2-[(2,4-dichlorophenyl) (hydroxy)methyl]-1H-benzimidazol-1-yl}propanoate (6.00 g, 14.7 mmol) and acetic acid (7.4 mL) in methanol (147 mL) was added acetaldehyde (4.95 mL, 88.2 mmol) at 0° C. After 30 min, sodium acetoxyborohydride. (18.7 g, 88.2 mmol) was added. After 2 h, the reaction mixture was quenched with water, concentrated in vacuo, diluted with ethyl acetate, washed with aqueous sodium hydroxide (1 M) and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (6.30 g, 13.6 mmol, 92%).
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1[CH:16]=[CH:15][CH:14]=CC=1.C1([ClH]C(Cl)=O)CC1>ClCCl>[CH3:2][O:9][C:7](=[O:8])[CH2:6][C:4]([CH:14]1[CH2:15][CH2:16]1)=[O:5]
Reactant: c1ccncc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Product: COC(=O)CC(=O)C1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
48.6 g of meldrum's acid (337.4 mmol) were dissolved in 200 ml of dichloromethane at room temperature and the solution was cooled to 0° C. 40 g of pyridine (506.1 mmol) were added to said solution. 35.3 g of cyclopropyl carbonic acid chloride (337.4 mmol) were then added at 0° C. within 1 h. The reaction mixture was stirred overnight at room temperature, washed with 1 N HCl and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and stirred under reflux for 2 h. The reaction mixture was concentrated to dryness and the oily residue was purified by destillation at 90° C. bath temperature to yield 42.7 g (71.1%) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20][CH3:21].C1C=C(Cl)C=C(C(OO)=[O:31])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:22][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20]([CH3:21])=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SC)c1CC
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(C)=O)c1CC

Procedure:
Prepared from product of Example 2 (5.8 g, 16.9 mmol) and MCPBA (3.43 g, of an 85% mixture with MCBA, 16.9 mmol) as described above. Recrystallization (ether/petroleum ether) afforded the product as a white solid (5.39 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[C:3]=1[F:12].Br[C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1>ClC1C=CC(C2N=CC(N)=NC=2)=C(F)C=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=2)=[C:4]([F:11])[C:3]=1[F:12]
Reactant: Nc1ncc(Br)cn1
Reactant: OB(O)c1ccc(Br)c(F)c1F
Agent: Nc1cnc(-c2ccc(Cl)cc2F)cn1
Product: Nc1ncc(-c2ccc(Br)c(F)c2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in 5-(4-chloro-2-fluorophenyl)pyrazin-2-amine using (4-bromo-2,3-difluorophenyl)boronic acid and 5-bromopyrimidin-2-amine. MS (ESI): mass calcd. for C10H6BrF2N3, 284.97; m/z found, 286.0 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]2[CH2:19][C@H:18]([S:20][C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][N:16]2[C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=2)=[O:41])[CH2:10]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.C(OCC)(=O)C>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]2[CH2:19][C@H:18]([S:20][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:17][N:16]2[C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=2)=[O:41])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N[C@H]1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
A solution of (2S,4S)-2-[(3S)-3-t-butoxycarbonylaminopyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (2.14 g) in a mixture of trifluoroacetic acid (10 ml) and anisole (1 ml) was stirred on ice-bath for 1 hour. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (50 ml) and saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo to give a residue of (2S,4S)-2-[(3S)-3-aminopyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine. To a solution of the residue in a mixture of ethyl acetate (40 ml) and water (20 ml) was dropwise added a soluiton of 4-nitrobenzyloxycarbonyl chloride (1.06 g) in tetrahydrofuran (10 ml) under ice-cooling, keeping the pH between 8 and 9 with 1N aqueous sodium hydroxide solution. The mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added ethyl acetate (50 ml). The solution was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-yl]methyl-4-(triphenylmethylthio)pyrrolidine (1.89 g).
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][CH:5]([O:8][CH3:9])[O:6][CH3:7].O[Li:12].O.O>C1COCC1>[Li+:12].[CH3:7][O:6][CH:5]([O:8][CH3:9])[CH2:4][C:3]([O-:10])=[O:2]
Reactant: COC(=O)CC(OC)OC
Reactant: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COC(CC(=O)[O-])OC
Product: [Li+]
Temperature: 25 °C
Yield: 98.7 %

Procedure:
(Related to methods described in Alabaster, C. T. et. al., J. Med. Chem. 1988, 31, 2048–2056.) 3,3-Dimethoxypropanoic acid methyl ester (14.25 g, 96.2 mmol) in THF (100 mL) was treated with LiOH.H2O (2.5 g, 106 mmol) and H2O (2 mL). The mixture was brought to reflux for 4 hours, cooled to room temperature and azeotropically dried from THF (4 times) to provide white solids (13.3 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:31]1[N:36]=[C:35]2[N:37]=[C:38]([CH3:40])[NH:39][C:34]2=[CH:33][CH:32]=1.CN(C)[CH:43]=[O:44].[CH3:46][OH:47]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH3:40][C:38]1[NH:39][C:34]2[C:35]([N:37]=1)=[N:36][C:31]([C:46]([O:44][CH3:43])=[O:47])=[CH:32][CH:33]=2
Reactant: CN(C)C=O
Reactant: Cc1nc2nc(Br)ccc2[nH]1
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2[nH]c(C)nc2n1
Temperature: 85 °C
Reaction time: 14 h

Procedure:
Palladium acetate (1.18 g), 1,3-bis(diphenylphosphino)propane (2.31 g) and 5-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (3.72 g) were placed in an autoclave, and N,N-dimethylformamide (18.6 ml), methanol (14.9 ml) and triethylamine (5.4 ml) were added thereto. The mixture was stirred at 85° C. for 14 hr at 10 atm under a carbon monoxide atmosphere. The reaction mixture was cooled and the solvent was evaporated. To the residue was added methanol (60 ml), and the mixture was heated. The insoluble matter was filtered off while the mixture was hot. The filtrate was concentrated to give the objective compound (2.95 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH:19]([P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])=[CH2:20]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:20][CH:19]([P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: C=CP(=O)(OCC)OCC
Reactant: ON=Cc1ccc(Cl)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C1CC(c2ccc(Cl)cc2)=NO1
Yield: 102.8 %

Procedure:
The compound is prepared in analogy to Example 1 from 23.34 g (0.15 mol) of 4-chlorobenzaldoxime, 22 g of N-chlorosuccinimide, 27.1 g of diethyl vinylphosphonate and 22.9 ml of triethylamine, resulting in 49 g of oily product.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][CH2:24][O:25]C)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>CO.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>[OH:25][CH2:24][CH2:23][O:22][C:3]1[C:2]([C:37]2[N:33]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][O:27]3)[N:34]=[CH:35][CH:36]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=2)=[O:8])=[CH:5][N:4]=1
Reactant: COCCOc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(OCCO)c(-c2ccnn2C2CCCCO2)c1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A mixture of 5-bromo-6-(2-methoxyethoxy)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 52.1, 100 mg, 0.237 mmol), 1-(tetrahydro-2h-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66 mg, 0.237 mmol), Pd(Ph3P)4 (27 mg, 0.024 mmol), K3PO4 (151 mg, 0.712 mmol) and toluene (1.5 mL) was stirred at 110° C. for 5 h under an argon atmosphere. The RM was diluted with MeOH, filtered through a cartridge of PL-Thiol MP-Resin, and the filtrate was evaporated to dryness under reduced pressure to afford 6-(2-hydroxyethoxy)-5-(1-(tetrahydro-2h-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, which was dissolved in DCM (0.4 mL), treated with TFA (0.25 mL, 3.24 mmol) and stirred overnight at RT. The mixture was treated with a solution of Na2CO3 (2 M) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product was purified by preparative SFC (Column DEAP; gradient 25% to 30% in 6 min.) and lyophilized to afford the title compound as a white powder. UPLC-MS (Condition 2) tR=0.92 min, m/z=409.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.82 (t, J=4.90 Hz, 2H) 4.48 (t, J=4.89 Hz, 2H) 6.98 (d, J=1.69 Hz, 1H) 7.37 (d, J=8.66 Hz, 2H) 7.75-7.83 (m, 1H) 7.88 (s, 2H) 8.70 (d, J=2.26 Hz, 2H) 8.79 (br. s, 1H) 10.54 (s, 1H) 12.86-13.40 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH2:15]([O:17][CH:18]([N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1)[CH3:19])[CH3:16].O>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:23]2[CH:22]=[N:21][N:20]([CH:18]([O:17][CH2:15][CH3:16])[CH3:19])[CH:24]=2)[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2OC)cn1
Temperature: 100 °C
Yield: 46.7 %

Procedure:
A biphasic solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.40 g, 1.4 mmol) and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.46 g, 1.7 mmol) in toluene (4 mL) and 10% sodium carbonate in water (3.0 mL, 2.9 mmol) was degassed under N2. Tetrakis(triphenylphosphine)palladium(0) (83 mg, 0.072 mmol) was added and the mixture was bubbled with N2 for 5 min and heated at 100° C. overnight. The resulting solution was cooled to room temperature and the organic layer was purified on silica gel (eluting with 0-40% of ethyl acetate in hexanes) to give the desired product (0.22 g, 45%). LCMS calculated for C17H22ClN2O3 (M+H)+: m/z=337.1. found: 337.1
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:22](I)[CH3:23].O(C1C=CC(C(C=CC(O)=O)=O)=CC=1)C1C=CC=CC=1.CI>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH:13]=[CH:14][C:15]([O:17][CH2:22][CH3:23])=[O:16])=[O:12])=[CH:9][CH:8]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Reactant: CCI
Agent: O=C(O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Solvent: CI
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccc(C)cc2)cc1
Yield: 76.4 %

Procedure:
The procedure in Example 12(1) was followed, except that 5.64 g of 3-[4-(4-methylphenoxy)benzoyl]acrylic acid and 5.98 g of ethyl iodide were used in place of 3-(4-phenoxybenzoyl)acrylic acid and methyl iodide, respectively, to give 4.74 g of ethyl 3-[4-(4-methylphenoxy)benzoyl]acrylate in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1CCCCC1.[CH3:15][S:16]SC.Cl>[Zr].O.C(O)CC>[CH3:15][S:16][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:8]
Reactant: CSSC
Reactant: Oc1ccc(Cl)cc1
Agent: [Zr]
Agent: Cl
Solvent: O
Solvent: C1CCCCC1
Solvent: CCCO
Product: CSc1cc(Cl)ccc1O
Temperature: 180 °C
Yield: 61.8 %

Procedure:
A mixture of 4-chlorophenol (15.0 g, 0.12 moles) and cyclohexane (8 ml) was distilled to remove cyclohexane and water. To the dry p-chlorophenol was added 3.3 g of zirconium n-propoxide in n-propanol consisting of 21.6% zirconium (0.008 mole) and 10.8% free propanol. The mixture was distilled at atmospheric pressure under nitrogen removing 1.0 g of n-propanol. To the resultant mixture was added methyl disulfide (7.1 g, 0.075 moles). The mixture was heated under nitrogen at reflux for 43 hours during which the temperature increased to 180° C. The mixture was cooled, hydrolyzed by addition of water, treated with concentrated HCl to dissolve solids, and extracted with ether. The ether extracts were dried over magnesium sulfate, filtered, and concentrated on a rotary flash evaporator. GC analysis of the concentrate indicated only two major components, 5.9 g of 4-chlorophenol and 8.1 g of 2-methylthio-4-chlorophenol (62% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[C:7]([OH:9])=O.[NH2:10][CH:11]1[CH2:15]CC[CH:12]1C(O)=O>>[CH:11]([NH:10][C:7]([C@H:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[NH2:1])=[O:9])([CH3:15])[CH3:12]
Reactant: N[C@@H]1CCC[C@@H]1C(=O)O
Reactant: NC1CCCC1C(=O)O
Product: CC(C)NC(=O)[C@H]1CCC[C@H]1N

Procedure:
The chiral compound (1S,2R)-2-aminocyclopentane-carboxylic acid isopropylamide is prepared analogously to this procedure using (1S,2R)-2-aminocyclopentanecarboxylic acid. In addition, a number of amides are prepared in this way starting from 2-aminocyclopentanecarboxylic acid (racemic or chiral).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2.C(N(CC)CC)C.C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 92.3 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g), triethylamine (9.42 g), acetic acid (0.75 g) and 1,2-dichloroethane (24 g) was heated under reflux for 8 hours. The reaction mixture was washed with water (24 g). The organic layer was separated and treated as in Example 4 to give the compound (I) (16.2 g).
Reaction SMILES: C1C=C(SSC2N=CC=CC=2)N=CC=1.C(N(CC)CC)C.[SH:22][CH2:23][C:24]([OH:26])=[O:25].[CH2:27]([SH:31])[CH:28]([CH3:30])[CH3:29]>O1CCCC1.CCOCC>[CH2:27]([S:31][S:22][CH2:23][C:24]([OH:26])=[O:25])[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)CS
Reactant: O=C(O)CS
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CSSCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 11 g (50 mmol) of 2-,2′-dipyridyl disulfide and 10.5 mL (75 mmol) of triethyl amine in 100 mL of tetrahydrofuran at 0° C. as added 3.5 mL (50 mmol) of mercaptoacetic acid in 5 mL of tetrahydrofuran. The ice bath was removed and after one hour 5.5 mL (50 mmol) iso-butyl thiol was added. The reaction was allowed to stir overnight at ambient temperature before diluting with ether and washing three times with 1N aqueous HCl. The product was then extracted into 10% aqueous NaOH. The aqueous phase was washed twice with ether and then acidified with HCl to pH ˜3.5. The product was extracted with ether, dried with Na2SO4, filtered and evaporated under reduced pressure to give a crude product. This material was distilled by Kugelrohr distillation to give 3.0 g (17 mmol, 33%) of partially purified product. This material was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([CH3:12])[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(O)C(=O)Nc2cc(Br)ccc21
Solvent: C1CCOC1
Product: Cc1c[nH]c2cc(Br)ccc12
Temperature: 60 °C

Procedure:
A mixture of 6-bromo-3-hydroxy-3-methyl-1,3-dihydro-2H-indol-2-one (0.25 g, 1.0 mmol) and BH3—S(CH3)2 (5.16 mL. 1.0 M, 5.16 mmol) in THF (20 mL) was heated at 60° C. The reaction was quenched with MeOH. Volatiles were removed. Chromatography over silica eluting with 4:1 hexane:EtOAc afforded the title compound. LC-MS: calculated for C9H8BrN 210.07, observed m/e 211.0 (M+H)+ (Rt 1.14 min).