Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].C([Li])CCC.[C:26](OC)(=[O:29])[CH2:27][CH3:28].O>O1CCCC1>[C:1]([C:3]1[C:7]([C:26](=[O:29])[CH2:27][CH3:28])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: CCC(=O)OC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: -72 °C

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (7.2 g) in tetrahydrofuran (80 ml) at -78° C. under an atmosphere of nitrogen was added, at such a rate that the temperature of the reaction mixture did not exceed -71° C., n-butyllithium (8 ml of a 2.5M solution in hexanes). A solution of methyl propionate (3.2 ml) in tetrahydrofuran (10 ml) was then added at such a rate that the temperature of the reaction mixture did not exceed -72° C. Upon completion of the addition the mixture was stirred at -72° C. and then allowed to warm to room temperature over a period of 1.5 hours. After stirring overnight at room temperature water (100 ml) was added and the mixture extracted twice with ethyl acetate (200 ml). The combined organic layers were dried (Na2SO4) and evaporated to give a brown gum which was purified by column chromatography on silica gel (500 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave a brown solid which was further purified by column chromatography on silica gel (60 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a pale yellow solid, m.p. 143° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:17](=O)[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:20][O:21][C:22]([NH2:24])=[NH:23].OS(O)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[CH3:20][O:21][C:22]1[NH:24][C:17]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:23]=1
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 61.6 %

Procedure:
A mixture of 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, ethyl ester (16.46 g, 62.6 mmol), o-methylisourea hydrogen sulfate (14.00 g, 81.4 mmol), and sodium bicarbonate (15.8 g, 18.8 mmol) in dimethylformamide (9.4 ml) was heated at 70° C. (oil bath) under argon overnight. The cooled reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed several times with water, washed with saturated sodium chloride, dried (potassium carbonate) and evaporated. The residue was passed through a pad of silica gel, crystallized from isopropyl ether/hexanes and then triturated with 60% isopropyl ether hexanes (50 ml) to give 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester as light yellow crystals (12.32 g), melting point 101°-103° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.[C:10]([S@@:14]([NH2:16])=[O:15])([CH3:13])([CH3:12])[CH3:11]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[N:16]/[S:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:15])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C/c1ccc(Br)cn1
Temperature: 73 °C
Reaction time: 2.5 h
Yield: 77 %

Procedure:
To a solution of 5-bromo-2-formyl-pyridine (3.0 g, 16.1 mmol) in dry THF (95 mL), (S)-tert-butylsulfinamide (2.05 g, 16.9 mmol) was added at RT under argon. Then titanium tetra-isopropoxyide (7 mL, 33.9 mmol) was added drop wise. The reaction mixture was stirred at 73° C. (external temperature) for 2.5 h, and was allowed to cool down. The reaction mixture was slowly poured into a vigorously stirring mixture of ca. 200 mL of brine and ice. The slurry was filtered and washed with DCM. The organic layer was separated and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered, evaporated to give a brown solid. The product was triturated in cold ether and successive filtered solids were combined to give the title intermediate (3.66 g, 12.4 mmol, 77%). HPLC: EtRet=4.987 min; LC-MS: m/z 291.0 [M+H]+.
Reaction SMILES: [CH2:1](S)[CH3:2].[H-].[Na+].[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([CH2:14][C:15]2[CH:20]=[C:19]([O:21]C)[C:18]([C:23]([CH3:25])=[CH2:24])=[C:17]([O:26][CH3:27])[CH:16]=2)=[CH:9][N:8]=1>CN(C)C=O>[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([CH2:14][C:15]2[CH:16]=[C:17]([O:26][CH3:27])[C:18]([C:23]([CH3:25])=[CH2:24])=[C:19]([O:21][CH2:1][CH3:2])[CH:20]=2)=[CH:9][N:8]=1
Reactant: C=C(C)c1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)c1c(OC)cc(Cc2cnc(N)nc2N)cc1OCC

Procedure:
A solution of 16.1 ml. of ethylmercaptan in 130 ml. of dimethylformamide was added dropwise while stirring and gassing with nitrogen to a suspension of 10.4 g. of sodium hydride (50%) in 130 ml. of dimethylformamide. After the evolution of gas had ceased, the mixture was stirred at room temperature for an additional 15 minutes and treated with a solution 13 g. of 2,4-diamino-5-(4-isopropenyl-3,5-dimethoxybenzyl)-pyrimidine in 260 ml. of dimethylformamide. The mixture was stirred at 120° C. for 6 hours. The solvent was removed under a high vacuum. The solid residue was dissolved in water, filtered and the filtrate was adjusted to pH 4 with 1-N hydrochloric acid. The acid solution was then adjusted to pH 8 with ammonia and the solid crude product was isolated in a yield of 98%. Recrystallization from methanol yielded pure 2,4-diamino-5-(3-hydroxy-4-isopropenyl-5-methoxybenzyl)-pyrimidine, having a melting point of 218°-219° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C1COCC1.CC([O-])(C)C.[K+].C1(S([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)(=[O:39])=[O:38])=[CH:33][N:32]=2)(=O)=O)CCCCC1>O>[CH:40]1([S:37]([C:34]2[CH:35]=[CH:36][C:31]([O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=3)=[N:32][CH:33]=2)(=[O:39])=[O:38])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=S(=O)(c1ccc(S(=O)(=O)C2CCCCC2)nc1)C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Oc2ccc(S(=O)(=O)C3CCCCC3)cn2)cc1
Yield: 31 %

Procedure:
To 3.68 g of p-hydroxyacetophenone in a 25 ml THF/25 ml DMSO mixture was added 3.2 g of t-BuOK and then 10.03 g of 2,5-bis(cyclohexylsulfonyl)pyridine, and the resulting mixture was heated at 62° C. for 11/2 hrs. The reaction mixture was cooled overnight, then added to 4 volumes of water and the crude product which formed recovered by filtration. Recrystallization of the crude product from CH2Cl2 /ethanol gave the product, 1-(4-((5-(cyclohexylsulfonyl)-2-pyridinyl)oxy)phenyl)ethanone, (31% yield), as light yellow prisms, m.p. 116°-118° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([OH:20])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:20][CH:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15]1)[CH3:29]
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ol (1.2 g, 4.16 mmol) was dissolved in 60 mL of dry DMF, and the reaction mixture was cooled in an ice bath. Sodium hydride (0.2 g of 60% solid in oil, washed with hexanes) was added, and the reaction mixture was stirred under nitrogen for 20 minutes. Ethyl bromoacetate (0.55 mL) was added dropwise, and stirring was continued for three hours, during which time the reaction mixture was allowed to warm to room temperature. Water (250 mL) was added to the reaction mixture, and the aqueous mixture was extracted twice with 150 mL of EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4, and the solvent was removed under reduced pressure to yield an oil which was eluted through silica gel under medium pressure with 4:1 EtOAc/hexanes. Removal of solvent under reduced pressure afforded 0.75 g (2.0 mmol, 48%) of (6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yloxy)-acetic acid ethyl ester as an oil. MS: 375 (M+H)+.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH3:6])([O-:3])=[O:2].CO[CH:9]([O:15]C)[CH2:10][CH2:11][CH2:12][CH:13]=O>CCOC(C)=O.CCCCCC>[N+:1](/[C:4](/[CH2:5][CH3:6])=[CH:13]/[CH2:12][CH2:11][CH2:10][CH:9]=[O:15])([O-:3])=[O:2]
Reactant: CCC[N+](=O)[O-]
Reactant: COC(CCCC=O)OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC/C(=C\CCCC=O)[N+](=O)[O-]
Yield: 55.1 %

Procedure:
Prepared according to the general procedure A from 1-nitropropane 112c (80 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.51 g, 55% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH:8]([CH3:10])[CH3:9].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[CH3:11][C:12]1[N:17]=[C:16]([S:18][CH2:2][C:3]2[S:7][CH:6]=[N:5][C:4]=2[CH:8]([CH3:10])[CH3:9])[N:15]=[C:14]([OH:19])[CH:13]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CC(C)c1ncsc1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2scnc2C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A mixture of 5-(bromomethyl)-4-(propan-2-yl)-1,3-thiazole (5.1 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (510 mg, 3.6 mmol), and triethylamine (2.2 mL, 15.8 mmol) in absolute ethanol (30 mL) was stirred at room temperature overnight. The mixture was evaporated to dryness and then co-evaporated with EtOAc (20 mL). The residue was treated with water (100 mL). The solid material was recovered by filtration and washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL). The solid material was dried in vacuo, affording the title compound (565 mg, 56% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.20 (d, 6H, J=6.8 Hz), 2.24 (s, 3H), 3.27 (m, 1H), 4.61 (s, 2H), 6.03 (s, 1H), 8.84 (s, 1H); M+ 282.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]1[C:21]([Cl:22])=[C:20]([F:23])[C:19]([Cl:24])=[CH:18][C:16]=1[NH2:17]>C1(C)C=CC=CC=1>[F:14][C:15]1[C:21]([Cl:22])=[C:20]([F:23])[C:19]([Cl:24])=[CH:18][C:16]=1[NH:17][C:7]([NH:6][C:4](=[O:5])[C:3]1[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=1[F:13])=[O:8]
Reactant: Nc1cc(Cl)c(F)c(Cl)c1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Three grams (0.016 mol) of 2,6-difluoro-benzoyl isocyanate were added to a solution of 2.95 gm (0.015 mol) of 2,4-difluoro-3,5-dichloroaniline in 50 ml of toluene. The solution thus obtained was stirred for 15 hours at room temperature. Thereafter, the product which precipitated during that time was removed by suction filtration and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:28]([O:30][CH3:31])=[O:29])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(F)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Methyl 2-(4-fluorophenyl)piperidine-4-carboxylate (7.4 g, 31.19 mmol) was dissolved in DCM (100 mL) and DIPEA (6.52 mL, 37.43 mmol) added followed by methyl chloroformate (2.95 mL, 37.43 mmol) at 0° C. The solution was stirred at room temperature for 1 h. The reaction mixture washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(4-fluorophenyl)piperidine-1,4-dicarboxylate (8.07 g, 97%) as a brown oil. MS m/z 296 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16]CCCC(C)(C#N)C)[C:12]([CH2:25][CH3:26])=[CH:11][C:10]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][CH2:39][CH2:40]Br)#[N:35]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:40][CH2:39][CH2:38][CH2:37][C:36]([CH3:43])([C:34]#[N:35])[CH3:42])[C:12]([CH2:25][CH3:26])=[CH:11][C:10]=1[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCC(C)(C)C#N
Reactant: CC(C)(C#N)CCCCBr
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N

Procedure:
1-(Benzyloxy)-4-ethyl-2-(4-fluorophenyl)-5-[(6-methyl-6-cyanoheptyl)oxy]-benzene was prepared as described in Example 1 for the synthesis of 1-(benzyloxy)-4-ethyl-2-(4-fluorophenyl)-5-[(5-methyl-5-cyanohexyl)oxy]-benzene substituting 6-cyano-6-methyl-1-bromoheptane for 5-cyano-5-methyl1-bromohexane.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]2[C:12](=[O:24])[N:13]([CH2:22][CH3:23])[C:14]3[C:19]([CH:20]=2)=[CH:18][N:17]=[C:16](Cl)[CH:15]=3)[CH:3]=1.[CH3:25][NH2:26]>>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]2[C:12](=[O:24])[N:13]([CH2:22][CH3:23])[C:14]3[C:19]([CH:20]=2)=[CH:18][N:17]=[C:16]([NH:26][CH3:25])[CH:15]=3)[CH:3]=1
Reactant: CN
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C#N)cc2cnc(Cl)cc21
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2C#N)cc2cnc(NC)cc21
Temperature: 120 °C
Yield: 61 %

Procedure:
A mixture of 4-amino-2-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-5-fluorobenzonitrile (420 mg, 1.23 mmol) and methylamine (25%, 50 mL) was heated at 120° C. in a pressure vessel for 1 day. The mixture was cooled to RT, the solid collected via filtration and purified via silica gel chromatography (EtOAc/pet ether) to afford 4-amino-2-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-5-fluorobenzonitrile (250 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.42 (s, 1H), 7.81 (s, 1H), 7.72 (s, 1H), 7.53 (d, J=11.6 Hz, 1H), 7.09-7.08 (m, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.23 (s, 2H), 4.16-4.11 (q, J=6.8 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H), 1.22-1.18 (t, J=6.8 Hz, 3H).
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:21][O:22][CH2:23][O:24][CH3:25])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@H:12]([CH2:21][O:22][CH2:23][O:24][CH3:25])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15]
Reactant: COCOC[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCOC[C@@H](N)CC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 83.5 %

Procedure:
To a solution of tert-butyl(3S)-3-{[(benzyloxy)carbonyl]amino}-4-(methoxymethoxy)butanoate (16.3 g, 53 mmol) in methanol (150 ml) was added 10% Pd—C (3.3 g) and the mixture was stirred for 6 hours at a hydrogen atmosphere. Additional 10% Pd—C (0.75 g) was added thereto and the mixture was stirred for 1.5 hours. After removal of catalyst by filtration, the solvent was removed in vacuo to give tert-butyl(3S)-3-amino-4-(methoxymethoxy)butanoate (9.7 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[C:15]1([CH2:21][N:22]2[CH:27]3[CH2:28][CH2:29][CH:23]2[CH2:24][NH:25][CH2:26]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O.O>[OH:13][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:25]1[CH2:26][CH:27]2[N:22]([CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:23]([CH2:29][CH2:28]2)[CH2:24]1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: c1ccc(CN2C3CCC2CNC3)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C(O)CN2CC3CCC(C2)N3Cc2ccccc2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (1.0 g, 3.7 mmol) and 8-(phenylmethyl)-3,8-diazabicyclo[3.2.1]octane (748 mg, 3.68 mmol) in 2 mL DMSO was heated under microwave condition (150° C.) for 1 hr. After cooling to rt., the mixture was diluted with water (50 mL), extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated. The residue was purified by TLC (MeOH/DCM=1:15) to obtain 5-{1-hydroxy-2-[8-(phenylmethyl)-3,8-diazabicyclo [3.2.1]oct-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one. The two isomers were separated by SFC chiral chromatography to obtain two single isomers, isomer A and isomer B with the same MS m/z 393 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]=[O:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]1[O:31][C:30]2[C:25](=[CH:26][CH:27]=[C-:28][CH:29]=2)[O:24]1.[Mg+2].[Br-].C1(C)C=CC=CC=1.O1CCCC1>O1CCCC1>[O:24]1[C:25]2[CH:26]=[CH:27][C:28]([CH:21]([OH:22])[CH2:20][C:10]3[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[N:17]4)=[C:12]([Cl:19])[CH:11]=3)=[CH:29][C:30]=2[O:31][CH2:23]1
Reactant: O=CCc1cc(Cl)c2cccnc2c1OCc1ccccc1
Reactant: [c-]1ccc2c(c1)OCO2
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a stirring solution of [8-(benzyloxy)-5-chloroquinolin-7-yl]acetaldehyde (0.380 mmol) in tetrahydrofuran (4 mL) at −78° C. was dropwise added a 1M solution of 3,4-(methylenedioxy)phenylmagnesium bromide in 1:1 toluene/tetrahydrofuran (0.380 mmol, 1.0 eq.) and stirring at −78° C. was continued for 10 min. The reaction mixture was then allowed to warm to room temperature and was stirred 1 h then quenched with saturated aqueous sodium bicarbonate solution (2 mL). After stirring 15 min the reaction mixture was extracted with ethyl acetate (3×5 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated to give a brown oil that was purified by column chromatography using 30% ethyl acetate/hexanes to give the final product as a white foam (0.126 mmol, 33%). MS (ESI) m/z 434.2; HRMS: calcd for C25H20ClNO4+H+, 434.11536; found (ESI, [M+H]+ Obs'd), 434.1150.
Reaction SMILES: [Cl-].[Li+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.C1CCN2C(=NCCC2)CC1.[CH:25]1([N:28]([CH2:36][C:37]2[CH:42]=[C:41]([CH2:43][CH:44]=O)[CH:40]=[C:39]([Cl:46])[C:38]=2[Cl:47])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]1>C1COCC1>[CH:25]1([N:28]([CH2:36][C:37]2[CH:42]=[C:41]([CH2:43]/[CH:44]=[CH:11]/[C:12]#[N:13])[CH:40]=[C:39]([Cl:46])[C:38]=2[Cl:47])[C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CC=O)cc(Cl)c1Cl)C1CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cc(C/C=C/C#N)cc(Cl)c1Cl)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a THF (0.1 M) suspension of anhydrous lithium chloride (1.2 eq.) was added sequentially diethyl(cyanomethyl)phosphonate (1.2 eq.) and DBU (1 eq.). The resulting suspension was stirred at RT for 15 min before 1,1-dimethylethyl cyclopropyl{[2,3-dichloro-5-(2-oxoethyl)phenyl]methyl}carbamate (1 eq.) from the previous step was added dropwise as a THF (0.1 M) solution. The resulting pink suspension was allowed to stir at RT for 12 h before it was carefully quenched with 1 N aq. HCl and then extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[NH:3]1[CH:4]=[C:5]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH:8][C:19](=[O:21])[CH3:20])[N:1]=[CH:2]1
Reactant: Nc1ccccc1-c1cnc[nH]1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1-c1c[nH]cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
To a solution of 2-(1H-imidazol-5-yl)aniline (18 mg, 0.113 mmol) in dichloromethane (3 mL) was added pyridine (47 μL, 0.339 mmol) and acetyl chloride (19 μL, 0.271 mmol). The reaction was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The crude product was dissolved in methanol (4 mL) and refluxed for 2 h. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 5%-30% MeOH/DCM as eluent) to afford the desired product as a white solid (10 mg, 0.050 mmol, 44%). 1H NMR (MeOH-d4): 2.17 (s, 3H), 7.05-7.26 (m, 2H), 7.46 (s, 1H), 7.62 (d, 1H, J=7.8 Hz), 7.78 (s, 1H), 8.18 (s, 1H).
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)([CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2].Cl[C:22]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:6]([CH:5]1[CH2:4][C:3]([C:1]#[N:2])([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:9][CH2:10][C:11]1=[O:13])([O:8][CH3:22])=[O:7]
Reactant: Cc1ccc(C(C#N)(CCC(=O)O)CCC(=O)O)cc1
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(c2ccc(C)cc2)CCC1=O
Yield: 99 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 42.44 gm. (0.14 mole) of the dimethyl ester of 4-cyano-4-(p-tolyl)pimelic acid (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 900 ml. of the tetrahydrofuran, 31.5 gm. (0.28 mole) of the potassium tert-butoxide, and 225 ml. of the 2.5 N aqueous acetic acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 39.3 gm. (99% yield) of 2-carbomethoxy-4-cyano-4-(p-tolyl)cyclohexanone as a gum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[N:16]2[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[N:16]2[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C2(O)c3ccccc3C(=O)N2CCc2ccccn2)ccc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2c3ccccc3C(=O)N2CCc2ccccn2)ccc1OCc1ccccc1
Reaction time: 6 h
Yield: 80.9 %

Procedure:
To a solution of 6 (0.50 g, 1.07 mmol), in CH2Cl2 (5 mL) at room temperature, trifluoroacetic acid (1.0 mL) was added and the reaction mixture was stirred for 6 h. Et3SiH (0.34 mL, 2.14 mmol) was added to the reaction mixture and the resulting pink solution was stirred overnight at room temperature. Solvent was evaporated under reduced pressure and the residue was neutralized with aqueous NaHCO3 solution and extracted with CH2Cl2 (2×10 mL). The combined organic layer was washed with H2O (5 mL), brine (5 mL) and then dried over anhydrous Na2SO4. Solvent was evaporated under reduced pressure and the residual light yellow syrup was purified by column chromatography using 20% acetone/hexane as the eluent to afford the title compound 8 (0.39 g, 81%) as a white solid.