Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:26])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH:23]([CH3:25])[CH3:24])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35]>CN1C(=O)CCC1.CC#N>[F:26][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:32]4[CH2:33][CH2:34][NH:29][C:30](=[O:35])[CH2:31]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:21]([F:22])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH:23]([CH3:25])[CH3:24]
Reactant: CC(c1c(F)cc2c(cnn2C(C)C)c1F)c1cnc2ccc(Cl)nn12
Reactant: O=C1CNCCN1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: CC(c1c(F)cc2c(cnn2C(C)C)c1F)c1cnc2ccc(N3CCNC(=O)C3)nn12
Temperature: 180 °C
Reaction time: 3 h

Procedure:
(rac)-6-chloro-3-(1-(4,6-difluoro-1-isopropyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazine (Intermediate U, 56.4 mg, 0.15 mmol), KF (44.5 mg, 0.75 mmol) and piperazin-2-one (46.4 mg, 0.45 mmol) were suspended in NMP (0.5 mL). The RM was stirred at 180° C. for 3 h. The mixture was diluted with CH3CN and purified by reverse phase chromatography (Büchi MPLC: 5-28% CH3CN, 0.1% HCOOH). The fractions was combined, concentrated and neutralized with NaHCO3, extracted with EtOAc. The combined organics layers were tried over Na2SO4, filtered, concentrated, crystallized in EtOAc to afford the title compound as a white solid (tR 3.98 min (conditions 5), MH+=440.3, 1H-NMR in DMSO-d6: 8.09 (s, 1H); 7.80 (d, 1H); 7.53 (s, 1H); 7.41 (d, 1H); 7.05 (d, 1H), 4.86 (m, 2H); 4.03 (d, 1H); 3.74 (d, 1H); 3.54 (d, 2H); 3.17 (m, 2H); 1.79 (d, 3H); 1.41 (m, 6H)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[N:17]=[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=12.O.[O:30]=[CH:31][C@@H:32]([C@H:34]([C@H:36]([C@@H:38]([C:40]([OH:42])=[O:41])[OH:39])[OH:37])[OH:35])[OH:33]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.[O:30]=[CH:31][C@@H:32]([C@H:34]([C@H:36]([C@@H:38]([C:40]([O-:42])=[O:41])[OH:39])[OH:37])[OH:35])[OH:33]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(=O)O
Agent: COc1cc(NS(C)(=O)=O)ccc1Nc1c2ccccc2nc2ccccc12
Solvent: CCO
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(=O)[O-]
Reaction time: 16 h
Yield: 66.6 %

Procedure:
A solution of 3.93 gm of m-AMSA and 2.12 gm of D-galacturonic acid monohydrate in 325 ml of specially denatured 3A anhydrous ethanol at 70°-80° C. is filtered with suction. The filtrate is stirred and chilled to 0°-5° C., then stored at -20° C. for about 16 hours. The product is collected, washed with cold (about -20° C.) specially denatured 3A anhydrous ethanol, then with anhydrous diethyl ether and dried under reduced pressure at 50°-55° C. to give 3.9 gm of m-AMSA D-galacturonate. The salt obtained by this process retains a small amount about 3% of ethanol.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:10]([CH3:19])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:18][C:11]1([C:14]([F:17])([F:15])[F:16])[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH3:19]
Reactant: CC1CN(Cc2ccccc2)CCC1(O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CNCCC1(O)C(F)(F)F

Procedure:
A mixture of 1-benzyl-4-hydroxy-3-methyl-4-trifluoromethylpiperidine (5.1 g, 18.68 mmole) and 20% palladium hydroxide (1 g) in methanol (100 ml) was stirred in hydrogen atmosphere (1 atm.) for 12 hr at 35° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 4-hydroxy-3-methyl-4-trifluoromethyl-piperidine as oil. Yield 3.4 g (99%), C7H12F3NO, m/z 184 (M+1)
Reaction SMILES: FC(F)(F)C([NH:5]OC(=O)C(F)(F)F)=O.N1C=CC=CC=1.[CH2:21]([N:25]1[C:29](=[O:30])[CH:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=2)[NH:27][C:26]1=[O:40])[CH2:22][CH2:23][CH3:24]>C1C=CC=CC=1>[CH2:21]([N:25]1[C:29](=[O:30])[CH:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:5])=[CH:34][CH:33]=2)[NH:27][C:26]1=[O:40])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN1C(=O)NC(Cc2ccc(C=O)cc2)C1=O
Reactant: O=C(NOC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCN1C(=O)NC(Cc2ccc(C#N)cc2)C1=O

Procedure:
The formyl compound (4.3 g., 0.01 mole), N,O-bis (trifluoroacetyl)hydroxylamine (3.6 g., 0.016 mole) and dry pyridine (2.6 ml. 0.032 mole) were mixed in benzene (75 ml) and heated under reflux for 2 hours. After cooling the benzene solution was washed with water (2×50 ml), dried over magnesium sulphate monohydrate and evaporated in vacuo to give an oil which slowly crystallised. This product was further purified by silica gel chromatography and recrystallisation from a small volume of ethyl acetate to give the title compound, yield 2.5 g., m.p. 136° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[C:11]([F:36])=[C:12]([N:16]2[C:23](=[O:24])[C:22]3[CH:21]=[CH:20][N:19]([CH:25]([CH3:27])[CH3:26])[C:18]=3[CH:17]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[CH3:35])[CH:13]=[CH:14][CH:15]=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:8][C:20]1[N:19]([CH:25]([CH3:27])[CH3:26])[C:18]2[CH:17]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[CH3:35])[N:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[C:11]=3[F:36])[C:23](=[O:24])[C:22]=2[CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)ccc1C1c2c(ccn2C(C)C)C(=O)N1c1cccc(Cl)c1F
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Cl)ccc1C1c2c(cc(Br)n2C(C)C)C(=O)N1c1cccc(Cl)c1F
Reaction time: 1.5 h

Procedure:
NBS (1.926 mmol) was added to a mixture of 5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Step A1) (1.965 mmol) in CCl4 (65 mL). After 1.5 h, the reaction mixture was diluted with EtOAc and successively washed with a saturated aqueous solution of NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 5.69 min (HPLC 1); ESI-MS: tR=1.39 min, [M+H]+ 495/497/499 (LC-MS 1); TLC: Rf=0.12 (CH2Cl2).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH:27]=[CH2:28])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-:29].[Na+].OO>C1COCC1.C(OCC)C>[Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:17])([CH3:18])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Reaction time: 5 h
Yield: 72 %

Procedure:
A solution of (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (26 g, 63 mmol) in THF (200 mL) was cooled in an ice-bath, followed by dropwise addition of 10 M BH3SMe2 (6.3 mL). After stirring for 5 hr, 10% NaOH solution (32 mL) followed by 30% H2O2 (32 mL) were added carefully. The reaction mixture was stirred at rt for 16 hr. The reaction mixture was diluted with diethyl ether (500 mL) and the aqueous layer was extracted with diethyl ether (3×250 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to afford (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxypentyl)-2,2-dimethyloxazolidine-3-carboxylate (19.6 g, 72%).
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].N1C=CC=CC=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@H:4]1[C@H:6]([C:7]([Cl:24])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.1 %

Procedure:
To a stirred solution of 4.1 g (0.0173 mole) of (+)-trans-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid in 40 ml of toluene at ambient temperature was added 1.7 g (0.022 mole) of pyridine, then 2.6 g (0.022 mole) of thionyl chloride in 25 ml of toluene. Upon complete addition the reaction mixture was stirred at ambient temperature for 17 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure to give 3.8 g of (+)-trans-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=O)[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O.CN(C=O)C>O1CCOCC1>[Cl:16][C:8]1[C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1NS(=O)(=O)c2cccc(F)c21
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=S1(=O)N=C(Cl)c2c(F)cccc21
Yield: 93.3 %

Procedure:
1.1 g of 4-fluoro-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (EP291851 A2 19881123), 2 g of thionyl chloride and a catalytic amount of DMF in 6 ml of dioxane are heated under reflux for 18 hours. Then additional 2 g of thionyl chloride are added and the mixture is heated for 8 hours. The mixture is concentrated and 1.12 g of a crude solid is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[O:17]1[CH2:18][CH2:19][N:14]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=2[N+:11]([O-:13])=[O:12])[CH2:15][CH2:16]1
Reactant: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-nitrobenzonitrile (7.12 g, 29.55 mmol) and morpholine (3.09 g, 35.45 mmol) in CH2Cl2 (98 mL) was added triethylamine (8.97 g, 88.64 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 1.5 h and evaporated to dryness under reduced pressure. The residue was diluted with water (40 mL) and extracted with CH2Cl2 (3×100 mL). The CH2Cl2 solution was washed with water (50 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 4-(morpholinomethyl)-3-nitrobenzonitrile (5.84 g, 80%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.83 (br s, 2H), 3.84 (s, 2H), 3.67 (t, 4H, J=4.6 Hz), 2.45 (t, 4H, J=4.6 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:20][CH2:21][CH2:22][N:23]1[CH:28]=[C:27]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]1=[O:42])(=O)=O.O>CN(C=O)C>[C:30]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:27]2[CH:26]=[CH:25][C:24](=[O:42])[N:23]([CH2:22][CH2:21][CH2:20][S:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)[CH:28]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Oc1cccc(S)c1
Reactant: CS(=O)(=O)OCCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCCSc1cccc(O)c1
Reaction time: 7 h
Yield: 81.1 %

Procedure:
To a solution of 3-hydroxythiophenol (222 mg) in DMF (15 mL) were added K2CO3 (243 mg) and 3-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]propyl methanesulfonate (700 mg) at ambient temperature and the mixture was stirred for 7 hours. Water was added to the mixture at ambient temperature and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=1:1) to afford 5-(diphenylmethyl)-1-{3-[(3-hydroxyphenyl)sulfanyl]propyl}pyridin-2(1H)-one (610 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH3:2].[CH3:16][Li].O>CCOCC>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:16])=[CH:7][CH:6]=1)[CH3:15]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Product: CCOC(OCC)c1ccc(C(C)O)cc1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
4-(Diethoxymethyl)benzaldehyde (104 g, 0.5 mol) was dissolved in 300 ml of ether and the resulting solution cooled to -75° C. in an acetone-dry ice bath. With vigorous stirring, methyllithium (390 mL of 1.4M in ether, 0.55 mol) was added at a rate which maintained the temperature at less than -60° C. The reaction mixture was allowed to warm to room temperature, stirred for two hours at that temperature, poured into 500 mL of ice and water, stirred 10 minutes and the layers separated. The aqueous layer was extracted with 500 mL ether. The organic layers were combined, washed with 500 mL each of H2O and then brine dried (MgSO4) and stripped in vacuo to yield 110-111.5 (98-100%) of present title product as a viscous, light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[C@H:14]([OH:26])[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:58]([OH:61])(=[S:60])[CH3:59]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:60][C:58](=[O:61])[CH3:59])[CH2:10][C@H:9]1[C@H:14]([OH:26])[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH3:18])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(CC[C@@H](O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@@H]1C[C@@H]([C@H](O)CCN(C)C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Reaction time: 0.17 h
Yield: 680.3 %

Procedure:
To a solution of (2S,4R)-N-tert-butoxycarbonyl-2-[(R)-3-(N-tert-butoxycarbonyl-N-methylamino)-1-hydroxypropyl]-4-hydroxypyrrolidine (1.0 g, 2.67 mmol, intermediate prepared in REFERENCE EXAMPLE 27-2) in tetrahydrofuran (10 ml) were successively added triphenylphosphine (842 mg, 3.21 mmol) and diethyl azodicarboxylate (0.505 ml, 3.21 mmol) under a nitrogen atmosphere under cooling with ice. The mixture was stirred at the same temperature for 10 minutes, and then thioacetic acid (0.25 ml, 0.35 mmol) was dropwise added thereto. The reaction solution was stirred at the same temperature for 2.5 h and then concentrated in vacuo. A mixture (10 ml) of hexane-ethyl acetate (5:1) was added to the residue. The precipitate was filtered off, and the filtrate was concentrated in vacuo. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, hexane-ethyl acetate=5:1) to give (2S,4R)-N-tert-butoxycarbonyl-4-acetylthio-2-[(R)-3-(N-tert-butoxycarbonyl-N-methylamino)-1-hydroxypropyl]pyrrolidine (1.03 g, yield: 89.2%). The data of this compound agreed with those of the compound prepared in REFERENCE EXAMPLE 27-2. ##STR411##
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:31]#[N:32])=[C:14]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=1>CN(C=O)C>[Cl:1][C:11]1[C:10]([Cl:9])=[CH:15][C:14]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[C:13]([C:31]#[N:32])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1Nc1cc(Cl)ccc1C#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1Nc1cc(Cl)c(Cl)cc1C#N
Temperature: 80 °C
Reaction time: 5 h

Procedure:
1-Chloro-2,5-pyrrolidinedione (NCS) was added at room temperature to a DMF solution of tert-butyl {(1R,2R)-2-[(5-chloro-2-cyanophenyl)amino]cyclohexyl}carbamate, followed by stirring at 80° C. for 5 hours. By post-treating the reaction liquid, tert-butyl {(1R,2R)-2-[(4,5-dichloro-2-cyanophenyl)amino]cyclohexyl}carbamate was obtained.
Reaction SMILES: O=[C:2]([CH2:18][CH3:19])[CH2:3][NH:4][C:5]([C:7]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:9]=2[CH:8]=1)=[O:6].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.O>C1COCC1>[CH2:18]([C:2]1[O:6][C:5]([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:9]=3[CH:8]=2)=[N:4][CH:3]=1)[CH3:19]
Reactant: CCC(=O)CNC(=O)c1cc2c(OC)cccc2o1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: O
Solvent: C1CCOC1
Product: CCc1cnc(-c2cc3c(OC)cccc3o2)o1
Yield: 83.8 %

Procedure:
To a solution of N-(2-oxobutyl)-4-methoxybenzo(b)furan-2-carboxamide (2.00 g) in THF (60 ml) was added Burgess reagent (7.30 g), and the mixture was stirred with refluxing. Water (200 ml) was added to the reaction mixture and the mixture was extracted with ether. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.56 g) as colorless crystals, melting point 88–87° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]([C:14]1[C:18]2[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=2[O:16][N:15]=1)=[O:13])[CH3:10].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:9]([O:11][C:12]([C:14]1[C:18]2[CH:19]=[CH:20][C:21]([O:23][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:22][C:17]=2[O:16][N:15]=1)=[O:13])[CH3:10]
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOC(=O)c1noc2cc(O)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1noc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A suspension of 2.7 g (18.1 mMol) 2,4-dichloropyrimidine, 4.12 g (19.9 mMol) 6-hydroxy-benzo[d]isoxazole-3-carboxylic acid ethyl ester [preparation see: J. Am. Chem. Soc. 97 (1974), 7305] and 8.45 g (39.8 mMol) K3PO4 in 90 ml NMP is stirred for 22 h at rt. Then the mixture is diluted with 0.5 l CH2Cl2 and 0.9 l of a 5% citric acid solution. The organic phase is separated off, washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2) gives the title compound: MS: [M+1]+=320; TLC(CH2Cl2/EtOAc 49:1): Rf=0.42.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.S=[C:7]1[CH2:11][S:10][C:9](=[O:12])[NH:8]1>C(O)C>[CH:1]1([CH2:4][NH:5][C:7]2[CH2:11][S:10][C:9](=[O:12])[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1NC(=S)CS1
Reactant: NCC1CC1
Solvent: CCO
Product: O=C1N=C(NCC2CC2)CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of 1-cyclopropylmethanamine (2.34 g) in ethanol (100 mL) was added 4-thioxo-1,3-thiazolidin-2-one (2.92 g), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and washed with ethanol to give the title compound (1.60 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-].C1CCCCC=1>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: [O-][n+]1ccccc1NCCCO
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: OCCCNc1ccccn1
Reaction time: 48 h
Yield: 88.1 %

Procedure:
A mixture of 2-(3-hydroxypropyl)aminopyridine N-oxide (3.0 g, 17.9 mmol), as prepared in the preceding step, cyclohexene (10 ML, 100 mmol), and 10% palladium(0) on carbon (300 mg) in ethanol (50 mL) was heated to reflux. After two days, the reaction mixture was cooled. The catalyst was removed by filtration through Celite and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 5% methanol in methylene chloride) to give the title compound as a colorless oil (2.4 g, 88%). 1H-NMR (400 MHz, CDCl3) δ 8.02 (d, J=5.0 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 6.54 (d, J=6.0 Hz, 1H), 6.39 (t, J=8.0 Hz, 1H), 4.69 (br s, 2H), 3.65 (t, J=5.5 Hz, 2H), 3.53 (q, J=5.9 Hz, 2H), 1.77 (t, J=5.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:13])=[N:10][S:11][N:12]=2)=[CH:4][CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:13][CH3:14])=[N:10][S:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1nsnc1-c1ccc(Cl)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1nsnc1-c1ccc(Cl)cc1
Yield: 86.3 %

Procedure:
By the method of L. Weinstock, et al., supra, 0.5 g (0.0023 mole) 4-(4-chlorophenyl)-3-hydroxy-1,2,5-thiadiazole, 0.36 g (0.0026 mole) of potassium carbonate and 0.37 g (0.0026 mole) of iodomethane in 15 ml of N,N-dimethylformamide were reacted to produce 0.45 g of 4-(4-chlorophenyl)-3-methoxy-1,2,5-thiadiazole, Compound 25 of Table I. Compounds 22-24, 26-29, 31, 35, 37, and 39-41 were also prepared by this method, except that, in some cases sodium carbonate was used in place of potassium carbonate and/or an appropriate bromide or chloride was used in place of methyl iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]2)[C:7]1=[O:21].P(Cl)(Cl)(Cl)=O.O.CN(C)[CH:34]=[O:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]2[CH:34]=[O:35])[C:7]1=[O:21]
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CN1C(=O)NC(=O)C12C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
1'-(3,4-Dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.8 g.) was added to a solution of phosphorus oxychloride (0.55 ml.) in N,N-dimethylformamide (20 ml.) and the mixture was stirred at 60° C. for 90 minutes. The solution obtained was then poured into water (150 ml.). The solid which formed was collected by filtration, washed with water, air-dried and then recrystallised twice from ethyl acetate/petrol 60-80 to give 1'-(3,4-dichlorobenzyl)-3-formyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (0.6 g.), m.p. 244°-46° C.