Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([S:29][CH2:30][CH2:31][CH3:32])[C:12]2[O:21][CH:20]3[CH:15]([CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19]3)[C:13]=2[CH:14]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([S:29][CH2:30][CH2:31][CH3:32])[C:12]2[O:21][CH:20]3[CH:15]([CH2:16][NH:17][CH2:18][CH2:19]3)[C:13]=2[CH:14]=1
Reactant: CCCSc1cc(-c2ccc(Cl)cc2Cl)cc2c1OC1CCN(C(=O)OC(C)(C)C)CC21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCSc1cc(-c2ccc(Cl)cc2Cl)cc2c1OC1CCNCC21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 8-(2,4-dichlorophenyl)-6-(propylthio)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.090 g, 0.182 mmol) was dissolved in CH2Cl2 (5 mL). Trifluoracetic acid (0.3 mL, 0.182 mmol) was added and the reaction mixture was stirred at rt under N2 for 2.5 h when all the starting material was consumed. The reaction mixture was cooled to 0° C. and 5M NaOH (10 mL) was added. The reaction mixture was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography (first eluting with 3:1 Hexane:EtOAc, and then eluting with 2:6:92 conc. NH4OH:CH3OH:CH2Cl2 to elute the product). Example 252 (0.070 g) was obtained in 97% yield. HRMS (FAB) calcd for C20H21CL2NOS +H1 394.0799, found 394.0797.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[NH:10][C:9]2=[O:20])=[C:4]([F:21])[CH:3]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:16]([F:19])([F:17])[F:18])[N:10]([CH3:24])[C:9]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: Cc1c(C(F)(F)F)[nH]c(=O)n(-c2ccc(Br)cc2F)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1c(C(F)(F)F)n(C)c(=O)n(-c2ccc(Br)cc2F)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
3-(4-Bromo-2-fluorophenyl)-5-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (16.52 g), methyl iodide (7.99 g) and potassium carbonate (7.76 g) were suspended in DMF (90 ml), and the mixture was stirred at room temperature for about 8 hours. After the reaction, DMF was distilled off under reduced pressure, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off, and the resulting residue was crystallized from a mixed solvent of ethyl acetate and n-hexane (1:3 v/v) to obtain the objective 3-(4-bromo-2-fluoro-phenyl)-1,5-dimethyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (14.92 g).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[CH:15]=[N:16][C:17](Cl)=[C:18]([Cl:20])[CH:19]=2)(=[O:13])=[O:12])=[O:9])=[N:4][CH:3]=1.[CH3:22][CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[CH:15]=[N:16][C:17]([N:24]3[CH2:25][CH2:26][CH2:27][CH:23]3[CH3:22])=[C:18]([Cl:20])[CH:19]=2)(=[O:13])=[O:12])=[O:9])=[N:4][CH:3]=1
Reactant: CC1CCCN1
Reactant: O=C(Nc1ncc(Br)s1)NS(=O)(=O)c1cnc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CCCN1c1ncc(S(=O)(=O)NC(=O)Nc2ncc(Br)s2)cc1Cl

Procedure:
N-[(5-Bromo-1,3-thiazol-2-yl)carbamoyl]-5,6-dichloropyridine-3-sulfonamide (20 mg, 0.05 mmol) was dissolved in DMF (1 ml) and reacted with 2-methylpyrrolidine (0.10 ml, 1 mmol) at 50° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water, NaHCO3 (half sat. 3×), 5% KHSO4/10% K2SO4, NaCl sat., dried (MgSO4.2H2O), filtered and concentrated under reduced pressure. The crude was purified by preparative RP-HPLC: 6 mg, MS: m/e 477.9 (MH−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:13]=[CH:12][NH:11][C:10]1=[NH:14].[CH2:15](Br)[CH2:16]Br>Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:10]2=[N:14][CH2:15][CH2:16][N:11]2[CH:12]=[CH:13]1
Reactant: N=c1[nH]ccn1-c1c(Cl)cccc1Cl
Reactant: BrCCBr
Agent: Cl
Product: Clc1cccc(Cl)c1N1C=CN2CCN=C21
Temperature: 140 °C
Yield: 10.8 %

Procedure:
A mixture consisting of 4.56 gm (0.02 mol) of 1-(2,6-dichloro-phenyl)-2-imino-4-imidazoline and 2.6 ml of ethylene bromide (about 150% of the stoichiometrically required amount) was heated to 140° C. while stirring and was maintained at that temperature for 15 minutes. After cooling, the glassy mass was dissolved in about 1 N hydrochloric acid, and the solution was friactionally extracted with ether at stepwisely increasing pH-values (addition of 2 N sodium hydroxide). Those fractions which contained the reaction product in substantially pure form, as determined by thin-layer chromatography, were combined, dried over anhydrous calcium sulfate and evaporated in vacuo. The residue was further purified by stirring it with acetone and collecting the crystallized product by suction filtration. 0.55 gm (10.8% of theory) of pure 7-(2,6-dichloro-phenyl)-2,3-dihydro-imidazo[1,2-α]imidazole, m.p. 184°-187° C. were obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[CH:15][C:16]=1[F:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=1[F:17])[O:18][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(F)c(Cl)c1
Product: O=Cc1ccc(Oc2ccc(F)c(Cl)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluorobenzaldehyde and 3-chloro-4-fluorophenol.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([OH:25])[CH:19]=2)=[O:15])=[O:6])#[N:2].[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34]O)[CH2:29][CH2:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([O:25][CH2:34][CH2:33][N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)[CH:19]=2)=[O:15])=[O:6])#[N:2]
Reactant: CN1CCN(CCO)CC1
Reactant: N#CCNC(=O)C1CCCCC1NC(=O)c1cc2ccc(O)cc2[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1CCN(CCOc2ccc3cc(C(=O)NC4CCCCC4C(=O)NCC#N)[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
To 85 mg (0.25 mM) 6-Hydroxy-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide in 5 ml dichloromethane at 0° C. was added 144 mg (1 mM) 2-(4-Methyl-piperazin-1-yl)-ethanol, 262 mg (1 mM) triphenylphosphine and 131 mg (0.75 mM) DEAD. After several hours the mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was purified directly on a preparative TLC plate and eluted with 10% methanol/dichloromethane. The product was then partitioned between 1 M HCl and ethyl acetate, the aqueous layer was neutralized and extracted with ethyl acetate, dried over magnesium sulfate and stripped to give 18.9 mg 6-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:20][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Temperature: 120 °C
Yield: 44.7 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (5 g), 4-nitrothiophenol (4.83 g) and potassium carbonate (7.8 g) in N,N-dimethylformamide (100 ml) was heated at 120° C. for hours with stirring. The reaction mixture was poured into ice-water. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 200 g) and eluted with a mixture of n-hexane and ethyl acetate (3:1). The fractions containing the objective compound were combined and concentrated under reduced pressure give 2-acetylamino-5-(4-nitrophenylthio)thiazole (3.74 g, yield: 50.2%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[CH3:46][C:47]1[C:51](B(O)O)=[C:50]([CH3:55])[O:49][N:48]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:51]2[C:47]([CH3:46])=[N:48][O:49][C:50]=2[CH3:55])=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2c(C)noc2C)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using compound 19 (95.1 mg, 0.139 mmol), 3,5-dimethylisoxazole-4-boronic acid (98.5 mg, 0.699 mmol), Pd(PPh)3Cl2 (4.84 mg, 0.0069 mmol), 2 M Na2CO3 (aq., 0.210 mL, 0.419 mmol), EtOH (0.4 mL) and DME (1.6 mL). Purification by RP-LC-MS (35 min gradient of 20-90% CH3CN in 0.05% aqueous formic acid) afforded the product (30.2 mg, 31%) as a white solid.
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[NH2:16][C:17]1[N:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][N:18]=1>>[S:15]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:20]1[CH:19]=[N:18][C:17]([NH2:16])=[N:22][CH:21]=1
Reactant: Brc1cc2c(s1)-c1ccccc1OCC2
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2cc3c(s2)-c2ccccc2OCC3)cn1

Procedure:
2-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester using standard Suzuki coupling procedure. Purification on silica and triturating with diethyl ether gave 163. 1H NMR (400 MHz, CDCl3), 3.26 (2H, t, J=5.14), 4.37 (2H, t, J=5.18), 5.16 (2H, Broad s), 7.02-7.09 (3H, m), 7.16-7.22 (1H, m), 7.70 (1H, d, J=7.91), 8.56 (2H, s). MS: (ESI+) 396
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]2[CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1.CC1C=CC2C=CC3C=C[C:32](C)=[N:33]C=3C=2N=1.CN>CN(C=O)C.C1COCC1.[Cu]I>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]2[C:5]3[CH:6]=[CH:7][C:2]([NH:33][CH3:32])=[CH:3][C:4]=3[O:21][CH:9]2[CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(I)cc3OC2C1
Reactant: Cc1ccc2ccc3ccc(C)nc3c2n1
Agent: [Cu]I
Agent: CN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNc1ccc2c(c1)OC1CN(C(=O)OC(C)(C)C)CCC21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Anhydrous DMF was sparged with argon gas for 1 h before being used. Tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (1 g, 2.5 mmol) sodium tert-butoxide (723 mg, 7.5 mmol), neocuproine (52 mg, 0.25 mmol) and copper (I) iodide (290 mg, 1.5 mmol) were dissolved in anhydrous DMF (20 mL). To this mixture was added a 2M solution of methylamine in THF (6 mL) and the reaction shaken at 80° C. for 16 h. The solvent was evaporated and the residue dissolved in DCM and washed with H2O (3×). The solvent was evaporated and the crude residue used as such in the next reaction step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:13])[CH:10]=NO.S(=O)(=O)(O)[OH:15]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:9](=[O:13])[C:10]2=[O:15]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccccc1F
Product: O=C1Nc2c(F)cccc2C1=O
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
31.3 g of the product of Step A were added at 75°-77° C. over 65 minutes to 155 ml of concentrated sulfuric acid and the mixture was heated over 10 minutes to 90° C. and held there for 10 minutes and then cooled to 20° C. The mixture was poured into 750 g of ice and the mixture was stirred until the ice melted and was filtered. The filtrate was saturated with sodium chloride and was extracted several times with ethyl acetate. The combined organic phases were washed with aqueous saturated sodium chloride solution until the wash water was neutral, dried, filtered and evaporated to dryness under reduced pressure. The residue was dissolved in 350 ml of xylene at reflux and the hot solution was filtered and the filter was washed with 20 ml of boiling xylene. The filtrate was iced and vacuum filtered. The product was washed with xylene and dried under reduced pressure at 80° C. to obtain 12.85 g of 7-fluoro-1 H-indole-2,3-dione melting at 198° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[Sn].Cl.[H][H]>>[ClH:2].[NH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([Cl:2])[CH:10]=1
Reactant: [H][H]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: [Sn]
Product: N#Cc1ccc(N)cc1Cl

Procedure:
A suspension of 25 g. 2-chloro-4-nitrobenzonitrile hydrochloride and 3 g. granular tin in 147 ml. concentrated hydrochloric acid was warmed to 50°C. and when vigorous hydrogen evolution started 56 g. tin was added in 3 to 5 g. portions with cooling to maintain reaction at 90 to 100°C. The mixture was heated at reflux for 45 minutes, the unreacted tin was separated by decantation, and the resulting solution was concentrated under reduced pressure till about 80 ml. of water was collected, the residual solution was made strongly alkaline with 130 ml. 35% sodium hydroxide solution, and the solids were collected by filtration, dissolved in ether and treated with ethereal hydrogen chloride to give, on filtration, 4-amino-2-chlorobenzonitrile hydrochloride; m.p. 170°-180°C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[N:10])=[C:4]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:3]=1.CO.Cl>CCO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH2:10])=[C:4]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:3]=1
Reactant: COC(=O)COc1cc(N)nc(C)c1C#N
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COC(=O)COc1cc(N)nc(C)c1CN
Reaction time: 48 h

Procedure:
Methyl 2-(6-amino-3-cyano-2-methylpyridin-4-yloxy)acetate (215 mg, 0.972 mmol) was dissolved in EtOH (16 ml), MeOH (8 ml) and HCl 1M (5 ml), then Palladium on carbon (310 mg, 0.292 mmol) was added and the reaction mixture was stirred at it under H2 pressure during 48 h. After filtration over celite, washing with MeOH and evaporation of the solvent, the title compound was obtained. MS (Method D): [M+H]+226.0/451.2.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17]I)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[OH:25][C:26]1[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[O:28][N:27]=1.CN(C=O)C>CCOCC>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][O:25][C:26]2[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[O:28][N:27]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCI)CC1
Reactant: COC(=O)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.2 %

Procedure:
A mixture of 4-3 (3.0 g, 8.1 mmol), Cs2CO3 (2.6 g, 8.1 mmol), methyl 3-hydroxy-5-isoxazolecarboxylate (Aldrich) (1.2 g, 8.1 mmol), and DMF (20 mL) was stirred at ambient temperature for 20 h. The reaction mixture was diluted with ether and then washed with H2O and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 3% acetone/CH2Cl2) gave 4-4 (2.7 g) as a colorless solid. Rf 0.17 (silica, 3% acetone/CH2Cl2).
Reaction SMILES: O[CH:2]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:4]=1.[ClH:29]>ClCCl.O.C(=O)(O)[O-].[Na+]>[Cl:29][CH:2]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:4]=1
Reactant: Cl
Reactant: N#Cc1cccc(C(O)c2cccc(/C=C/c3ccc4ccccc4n3)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#Cc1cccc(C(Cl)c2cccc(/C=C/c3ccc4ccccc4n3)c2)c1

Procedure:
A suspension of the 3-[α-hydroxy-3-{2(E)-(quinolin-2-yl)ethenyl}benzyl]benzonitrile (1.4 g, 3.87 mmol) in dichloromethane (75 ml) was stirred with concentrated hydrochloric acid (75 ml) for 3 hours, diluted with water and neutralised with saturated sodium bicarbonate solution. The aqueous layer was extracted with further dichloromethane and the combined solvent was dried and evaporated to a pale solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:11]1=[O:27])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:31](I)[CH2:32][CH3:33]>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:31][CH2:32][CH3:33])[C:11]1=[O:27])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCI
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(NC(=O)OCc2ccccc2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(C(=O)OCc1ccccc1)c1cccn([C@@H](CC)C(=O)OC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1283.5 %

Procedure:
To a solution of (S)-2-(3-Benzyloxycarbonylamino-2-oxo-2H-pyridin-1-yl)-butyric acid tert-butyl ester (100 mg, 0.26 mmol) in anhydrous DMF (3 mL) was added NaH (60% dispersion, 10 mg, 0.26 mmol) and the reaction was stirred at ambient temperature for 30 minutes. Propyliodide (30 μL, 0.31 mmol) was added dropwise and the reaction stirred at ambient temperature overnight. The mixture was concentrated in vacuo to a solid and partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (30% EtOAc/hexane) to afford the title compound as a pale green solid (1.43 g, 40%): 1H NMR (400 MHz, CDCl3) δ 0.85-0.95 (6H, m), 1.35 (9H, s), 1.55-1.65 (2H, m), 1.85-1.95 (1H, m), 2.20-2.27 (1H, m), 3.6-3.7 (2H, m), 5.15-5.2 (2H, m), 5.5-5.6 (1H, m), 6.25 (1H, t), 7.25-7.45 (7H, m); M+H 429.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[O:10]=[C:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2([OH:10])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)cc2)C1
Reaction time: 0.5 h

Procedure:
A solution of 4-fluorophenylmagnesium bromide (1M in THF, 11 mL, 11 mmol) was added gradually to a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1.85 g, 10 mmol) in diethyl ether (40 mL) during 5 min at ambient temperature. The mixture was stirred for 30 min and thereafter slowly quenched with NH3Cl (10 mL, 3M). The organic phase was isolated and evaporated. The residue was purified by flash chromatography (SiO2 2:1 heptane/EtOAc) to afford the title compound, which was used without further purification. MS (EI) 208 (M-tBuO)
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10]CC)=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[O:1]1[C:6]([C:7](=[N:13][O:14][CH3:15])[C:8]([OH:10])=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=NOC)C1=CSCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)C1=CSCCO1
Yield: 24.9 %

Procedure:
A mixture of ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetate (16 g.), methanol (160 ml.) and a 1N aqueous solution (85 ml.) of sodium hydroxide was stirred at room temperature for 25 minutes. The resultant solution was adjusted to pH 4.5 with 10% hydrochloric acid and concentrated at 40° C. in vacuo. To the residue was added ethyl acetate, and the solution was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate, and then shaken sufficiently. The organic layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate. The extract and the aqueous layer were combined together and adjusted to pH 1.0 with 10% hydrochloric acid. The solution was extracted with ethyl acetate, and the extract was washed with water and then dried over magnesium sulfate. After the solution was concentrated in vacuo, the residue was washed with diisopropyl ether to give 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (anti isomer, 3.5 g.), yellow crystals, mp. 108° to 110° C. (dec.).
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1>CCOCC>[Cl:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:3])=[O:10])=[CH:7][CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc(Cl)cc1
Solvent: CCOCC
Product: COC(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 71 %

Procedure:
An excess solution of diazomethane in ether was slowly added to an ice-cooled and stirred solution of p-chlorobenzoic acid (6.2 g, 39.6 mmol) in 50 ml of ether and the mixture was concentrated. The residue was recrystallized from 5 ml of MeOH to give a white crystalline product of methyl p-chlorobenzoate (4.8 g, 28.2 mmol, yield 71%). m.p. 42.0°-43.0° C. (recrystallized from methanol)
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C@H:7]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:9][N:8]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O)[CH3:3].B.C1COCC1.C1COCC1>CO>[CH3:3][CH:2]([NH:4][CH2:5][C@H:7]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:10][CH2:9][N:8]1[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH3:1]
Reactant: CC(C)NC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)NC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 40.5 %

Procedure:
A 500-mL round-bottomed flask was charged with di-tert-butyl (2R)-2-((1-methylethyl)carbamoyl)-1,4-piperazinedicarboxylate (1.77 g, 4.76 mmol, step 1), BH3.THF (1.0 M in THF, 15.0 mL, 15.0 mmol) and THF (60 mL). The mixture was heated at 50° C. for 12 h. After allowing the reaction to cool to room temperature, additional BH3.THF (1.0 M in THF, 5.0 mL, 5.0 mmol) was added. The mixture was then heated at 50° C. for 1.5 h. The reaction mixture was allowed to cool to room temperature and MeOH (20 mL) was slowly added. The solvent was removed in vacuo and the crude product was purified by column chromatography (100 g of silica gel, 0 to 10% iPrOH (with 10% NH4OH) in CHCl3) to afford di-tert-butyl (2S)-2-(((1-methylethyl)amino)methyl)-1,4-piperazinedicarboxylate (0.69 g) as a clear oil.