Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][O:8][C:7]=1[Cl:11])=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:11][C:7]1[O:8][CH:9]=[CH:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccoc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccoc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
2-Trimethylsilyl-3-furancarboxylic acid (16.4 g) (synthesized in accordance with the method described in J. C. S. Perkin, 1, 1125 (1981)) was dissolved in N,N-dimethylformamide (50 ml), and potassium carbonate (12.3 g) and iodoethane (13.9 g) were added. The mixture was stirred at room temperature for 15 hours, poured into ice water and extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-trimethylsilyl-3-furancarboxylic acid ethyl ester (16.3 g) as oil. 2-Trimethylsilyl-3-furancarboxylic acid ethyl ester (16.3 g) was dissolved in acetonitrile (75 ml), and sulfuryl chloride (10.9 g) in acetonitrile (25 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour, poured into ice water and extracted with diethyl ether. The extract was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-chloro-3-furancarboxylic acid ethyl ester (3.5 g) as oil. 2-Chloro-3-furancarboxylic acid ethyl ester (3.5 g) was dissolved in ethanol (25 ml), and 1N aqueous sodium hydroxide (25 ml) was added. The mixture was stirred at room temperature for 1.5 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration and washed with diisopropyl ether-hexane to give 2-chloro-3-furancarboxylic acid (2.2 g) as crystals. mp 138°-141° C.
Reaction SMILES: [CH2:1]1COCC1.[CH:6]([C:8]1[CH:9]=[C:10](/[CH:19]=[CH:20]/[C:21]([NH:23][CH:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:22])[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:7].C[Mg]Br.O.[Cl-].[NH4+]>C(OCC)(=O)C>[OH:7][CH:6]([C:8]1[CH:9]=[C:10](/[CH:19]=[CH:20]/[C:21]([NH:23][CH:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:22])[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[CH3:1]
Reactant: C1CCOC1
Reactant: O=Cc1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1ccnc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)c1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1ccnc1
Reaction time: 1 h

Procedure:
To a THF (0.5 mL) solution of (E)-3-(3-formyl-4-(1H-imidazol-1-yl)phenyl)-N-indan-1-ylacrylamide (23 mg) obtained in Example 437, methyl magnesium bromide (3M ether solution, 0.04 mL) was added under nitrogen atmosphere under ice-cooling and the reaction mixture was agitated for 1 hour. A saturated ammonium chloride water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:methanol-ethyl acetate system), and 10 mg of the title compound was obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[CH3:14][O-:15].[Na+].O>CO>[I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:15][CH3:14])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(I)cc([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(I)cc([N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 52 h
Yield: 99 %

Procedure:
1-Iodo-3,5-dinitrobenzene (1.8 g, 6.1 mmol) are dissolved in methanol (12 ml) and treated with a solution of sodium methoxide in methanol (5.4M, 1.2 ml). The mixture is then stirred at 65° C. for 52 h. After cooling to ambient temperature, water (50 ml) is added and the mixture extracted three times with ethyl acetate (50 ml). The combined organic layers are extracted with brine (100 ml), dried and evaporated to dryness. Flash chromatography (silica, eluent ethyl acetate/cyclohexane 1:1) affords the product (1.7 g, 99%) as light yellow solid. MS: m/e=279 (M+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].O=C(C)C[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2>>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(=O)COc1cccc2cccnc12
Product: O=C(COc1cccc2cccnc12)c1ccccc1
Yield: 69 %

Procedure:
8-(2-Oxo-2-phenylethoxy)quinoline (8a) was prepared from 2-bromoacetophenone by the same procedure as 7a in 69% yield. mp: 124°-125° C.; 1H-NMR (CDCl3): δ5.65 (s, 2H, OCH2), 6.95-8.97 (m, 11H, Ar--H).
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=O)#[N:2].[OH-].[K+].C(Cl)(=O)C(Cl)=O.[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>C1C=CC=CC=1.C(OCC)C>[CH:22]([N:25]([CH:26]([CH3:28])[CH3:27])[C:5](=[O:7])[CH2:4][CH:3]([C:1]#[N:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:24])[CH3:23]
Reactant: N#CC(CC(=O)O)c1ccccc1
Reactant: CC(C)NC(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(C)N(C(=O)CC(C#N)c1ccccc1)C(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3-Cyano-3-phenylpropanoic acid (67.7 g, 0.389 mol) was dissolved in 2-PrOH. To the filtered acid solution was carefully added KOH (18.4 g, 0.33 mol) dissolved in 2-PrOH (200 mL), diethyl ether (100 mL) was added and the precipitate was filtered off. The dried acid salt (51.9 g, 0.24 mol) was suspended in benzene (400 mL) and oxalyl chloride was carefully added. The reaction mixture was stirred at 80° C. for 2 hours. The solvent was evaporated and the residue was co-evaporated twice with benzene. The brown oil was dissolved in benzene (200 mL) and cooled in an ice-bath. A solution of diisopropylamine (82 g, 0.81 mol) in benzene (200 mL) was added to the stirred reaction mixture during 45 min. The mixture was left to slowly warm up to room temperature overnight. The solvent was evaporated and the residue was taken up in diethyl ether and 1 M HCl. The organic phase was washed once with water, once with 1 M NaOH, again with water, dried (Na2SO4) and the solvent evaporated to afford the title compound as a dark brown oil, 41.7 g (41%): 1H NMR (CDCl3) δ1.07 (d, 3H), 1.17 (d, 3H), 1.36 (m, 6H), 2.77 (m, 1H), 2.97 (m, 1H), 3,51 (br, 1H), 3.81 (m, 1H), 4.50 (dd, 1H), 7.39 (m, 5H).
Reaction SMILES: CC[CH:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=1)[CH2:4][CH3:5].[CH3:16]C(C)CC(Cl)=O>>[CH2:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1)[CH:4]([CH3:5])[CH3:16]
Reactant: CCOC(=O)c1csc(C(CC)CC)n1
Reactant: CC(C)CC(=O)Cl
Product: CC(C)Cc1nc(C(=O)O)cs1

Procedure:
Prepared by the method of Carboxylic Acid 3, using 3-methylbutanoyl chloride (10 mL) in place of 2-ethylbutanoyl chloride in step a. Yield 3.8 g.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH3:36])[N:31]1[CH2:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1>>[CH3:36][CH:32]1[CH2:33][CH2:34][CH2:35][CH:30]([CH3:29])[N:31]1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([NH:42]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:43][CH:44]=1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CC1CCCC(C)N1Cc1ccc(N)cc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2C(C)CCCC2C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-aniline Rf value: 0.6 (silica gel, methylene chloride/ethanol=5:1) C32H35N3O3
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]1[CH:6]=[C:7]([C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)[CH2:8]Cl>CS(C)=O>[F:4][C:5]1[CH:6]=[C:7]([CH2:8][C:1]#[N:2])[C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1
Reactant: [C-]#N
Reactant: Fc1ccc(Sc2ccccc2)c(CCl)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1cc(F)ccc1Sc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
18.6 g of sodium cyanide in 222 ml of dimethyl sulphoxide are treated at 50° C with 74 g of 3-fluoro-6-(phenylthio)-benzyl chloride in 75 ml of dimethyl sulphoxide in one portion. The resulting dark solution is stirred at 45°-50° C for 1 hour, subsequently poured on to 1500 ml of ice-water and extracted with ether. The organic phase is washed three times with 500 ml of water each time, dried over sodium sulphate and evaporated. There is obtained 3-fluoro-6-(phenylthio)-phenylacetonitrile as a reddish oil.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[OH:13][C:14]1[CH:22]=[CH:21][C:17]2[CH:18]=[CH:19][O:20][C:16]=2[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[O:20]1[C:16]2[CH:15]=[C:14]([O:13][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:22]=[CH:21][C:17]=2[CH:18]=[CH:19]1
Reactant: Oc1ccc2ccoc2c1
Reactant: OC(CCl)CCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OC(CCc1cccnc1)COc1ccc2ccoc2c1
Temperature: 120 °C
Yield: 24.9 %

Procedure:
##STR16## (±)-α-(Chloromethyl)-3-pyridinepropanol (0.339 g, Example 2a)) was dissolved in anhydrous N,N-dimethylformamide (5 ml) and added to a suspension of 6-hydroxybenzofuran (0.245 g, Bull. Soc. Chim. Fr., 1973, 2355) and cesium carbonate (0.596 g) in anhydrous N,N-dimethylformamide (5 ml) which had been heated previously for one hour at 120° C. The mixture was then heated at 120° C. for 7 hours before being cooled to room temperature. The mixture was then poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:ethanol (19:1) and recrystallised from ethyl acetate:hexane to give the title compound (0.129 g).
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].C([O-])(O)=O.[Na+].[CH3:27][C:28](OC(C)=O)=[O:29]>C1(C)C=CC=CC=1.CC#N>[C:28]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)(=[O:29])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)C1(O)CC=C2C[C@@H]3[C@@H]4C=C[C@H](O)[C@@H]5OC1=C2[C@]45CCN3C
Yield: 98.8 %

Procedure:
A mixture of morphine (23.63 g, 83 mmol), NaHCO3 (28.2 g, 336 mmol), Ac2O (8.69 g, 85 mmol) in toluene (500 ml) and CH3CN (900 ml) was heated at reflux for 21 hrs. The reaction mixture was evaporated to dryness in vacuo. To the residue was added water (80 ml) and extracted with chloroform (500 ml). The extracts were dried, combined and evaporated to dryness in vacuo to obtain a residue, which was chromatographed on silica gel (column: d=6 cm, I=8 cm, packed with 141 g of silica gel; solvent system: 5-10% MeOH in CH2Cl2) to yield 3-acetylmorphine (27 g, 100% yield). IR (KBr)(ν, cm-1): 3500 (m, sharp, --OH), 1750 (s, sharp, AcO); NMR (δH)(CDCl3): 6.73 (1, d, J, 8.1, 2-H), 6.57 (1, d, J, 8.1, 1-H), 5.74 (1, dm, J, 10.1, 7-H), 5.25 (1, dm, J, 9.9, 8-H), 4.91 (1, d, J, 6.9, 5-H), 4.25-4.10 (1, m, 6-H), 3.50-3.35 (1, m, 9-H), 3.05(1, d, J, 19.1, 10-Hβ), 2.8-2.7 (1, m, 14-H), 2.85-2.60 (1, m, 16-He), 2.50-2.25 (1, m, 16-Ha), 2.45 (3, s, NCH3), 2.5-2.2 (1, m, 10-Hα), 2.28 (3, s, AcO), 2.06 (1, td, 12.1 & 5.0, 15-Ha), 2.0-1.85 (1, m, 15-He).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:21][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)CNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 1.00 g of Boc-Pro-OH, 0.58 ml of neopentylamine, 0.71 g of HOBt and 1.06 g of EDC hydrochloride were added and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 30 (Process 3) to give 605 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[N:12]=[C:11](S(C)(=O)=O)[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1.[CH3:36][NH:37][CH3:38]>>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[N:12]=[C:11]([N:37]([CH3:38])[CH3:36])[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CNC
Product: CN(C)c1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2-(3,4-Difluorobenzyloxy)-4-(methylsulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-pyrimidine (Reference Example 7) (29 mg, 0.05 mmol) was reacted with 2 equivalents of dimethylamine by the same general procedure described in Example 103 to afford the title compound: HPLC/MS: m/e=520 (M++1); Rt=3.68 min. 1H-NMR 400 MHz (CDCl3): δ 2.80 (s, 6H), 5.28-5.42 (m, 2H), 6.90 (d, J=9 Hz, 1H), 7.01-7.21 (m, 8H), 7.35-7.40 (m, 1H).
Reaction SMILES: [C:1]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][NH2:15])=[CH:13][C:8]=2[CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]([CH3:21])=O>>[C:1]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][N:15]=[C:19]([CH3:21])[CH3:18])=[CH:13][C:8]=2[CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)=O
Reactant: CCCC(=O)N1CCc2nnc(NN)cc2C1
Product: CCCC(=O)N1CCc2nnc(NN=C(C)C)cc2C1

Procedure:
A solution of 3.5 g of crude oily 6-butyryl-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 20 cc of acetone is heated to the boil at reflux on a water bath for 20 minutes. The title compound has a M.P. of 152°-154° (decomp., from acetone).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C1C(S(Cl)(=O)=O)=CC=C([I:23])C=1>>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([I:23])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CCS(=O)(=O)c1ccc(F)cc1
Product: CCS(=O)(=O)c1ccc(I)cc1
Yield: 20 %

Procedure:
Compound 5e was prepared in analogy to Compound 5a, starting from pipsyl chloride (10 mmol, 3.02 g). A white solid was crystallized from ethyl acetate and hexane. HPLC indicated 100% purity, mp 78-79° C., (0.60 g, 20% yield). 1H NMR (CDCl3): 1.28 (t, 3H, CH3), 3.12 (q, 2H, CH2), 7.63 (d, 2H, Ar—H), 7.96 (d, 2H, Ar—H); MS: 296 M+. Elemental Analysis (C, H, I, S) for C8H9IO2S.0.2C6H14-0.1H2O; calculated C, 35.06; H, 3.83; I, 40.26; S, 10.17. found C, 35.04; H, 3.41; I, 40.32; S, 9.74.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=O)[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[NH:6]1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9](=[S:24])[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1[nH]c(C(F)(F)F)cc1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCCCn1[nH]c(C(F)(F)F)cc1=S
Reaction time: 6 h
Yield: 99.6 %

Procedure:
5.00 g of 1-butyl-3-(trifluoromethyl)pyrazol-5-one (8-3), and 7.88 g of Lawesson's reagent were suspended in 300 ml of anhydrous toluene. The suspension was heated under reflux with stirring for 6 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to produce 4.35 g of 1-butyl-3-(trifluoromethyl)pyrazol-5-thione (8-6).
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)=[O:7])(=O)C.O>C(OCC)C>[OH:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)=[O:7]
Reactant: CC(=O)OCC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Solvent: CCOCC
Solvent: O
Product: O=C(CO)N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Yield: 99.1 %

Procedure:
Using essentially the technique of Example 74, starting from 3-(4-((3S)-3-acetoxyacetylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one (140 mg, 0.3 mmol) gave the desired product (125 mg) after trituration with water, diethyl ether and drying.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:7]=1)CCC.Br[C:29]1[N:30]=[C:31]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH3:46])[CH2:41][CH2:40]2)[C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:45]([N:42]1[CH2:41][CH2:40][N:39]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:38]=[C:29]([C:6]3[CH:7]=[CH:8][C:9]([CH:12]([CH3:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:11]=3)[N:30]=2)[CH2:44][CH2:43]1)[CH3:46]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(C)CC(=O)OCC)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCOC(=O)CC(C)c1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Yield: 74.8 %

Procedure:
Ethyl 3-(4-Tributylstannylphenyl)butyrate (5.46 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.33 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.19 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted in ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(1-ethoxycarbonylpropan-2-yl)phenyl]isoquinoline (1.34 g) as a pale yellow viscous oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)#[CH:18]>>[NH2:23][C:22]1[CH:24]=[CH:25][C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:21]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: Nc1ccc(C#Cc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Yield: 85.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 4-ethynylaniline (76 mg, 0.65 mmol) to provide 261 (115 mg, 85% yield) as a brown solid. LC-MS (M+H=312 obsd.=312).
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([C:27]1[S:31][C:30]([S:32][CH3:33])=[N:29][CH:28]=1)=[C:7]2[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][C:40](Cl)=[O:41].C(N(CC)CC)C>O1CCCC1>[CH:14]([O:13][C:11]([C:7]1[N:8]2[CH:3]([S:4][CH2:5][C:6]=1[C:27]1[S:31][C:30]([S:32][CH3:33])=[N:29][CH:28]=1)[CH:2]([NH:1][C:40](=[O:41])[CH2:39][C:35]1[S:34][CH:38]=[CH:37][CH:36]=1)[C:9]2=[O:10])=[O:12])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CSc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1

Procedure:
Crude 7-amino-2-benzhydryloxycarbonyl-3-(2-methylthiothiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.3 g) is dissolved in tetrahydrofuran (30 cc) and is then acylated with (thien-2-yl)-acetyl chloride (0.83 cc) in the presence of triethylamine (0.94 cc) in accordance with the working method described in Example 1. The crude product obtained is chromatographed on a column (height: 30 cm; diameter: 4 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 1 bar (100 kPa), with a 70:30 (by volume) mixture of cyclohexane and ethyl acetate, and 50 cc fractions being collected. Fractions 16 to 27, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C., and the residue is triturated with isopropyl ether (30 cc). 2-Benzhydryloxycarbonyl-3-(2-methylthio-thiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia- 1-azabicyclo[4.2.0]oct-2-ene (1.6 g) is obtained in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]=[C:10]([CH:21]3[CH2:26][C:25]([CH3:28])([CH3:27])[O:24][C:23]([CH3:30])([CH3:29])[CH2:22]3)[CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:38])C(=O)C1>C(Cl)Cl>[Br:38][C:9]1[C:10]([CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[O:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)=[N:11][N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)c(Br)c1-c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
To a solution of 5-(4-chlorophenyl)-1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazole (80 mg, 0.19 mmol)(Example 1) in 2 mL of DCM was added NBS (33 mg, 0.19 mmol) and the mixture stirred for 30 mins at Rt. The crude product was purified by silica gel chromatography (Thomson Scientific 12-g cartridge, 2-20% EtOAc/heptane) to give 40 mg (40%) of the title compound.