Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC([I:28])(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[I:28][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: C#Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: IC#Cc1ccccc1
Yield: 55.3 %

Procedure:
In a 10 mL round-bottom flask, 1.02 g of phenylacetylene (10 mmol), 4.46 g of perfluoro-n-hexyl iodide (10 mmol), and 300 mg of tetra-n-butylammonium fluoride trihydrate (0.948 mmol) were mixed at 24° C. for 1 h. Gas chromatographic analysis of the resulting mixture showed that it contained 1.26 g of 1-iodo-2phenylacetylene (55% yield) and 0.45 g of unconverted phenylacetylene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cccc(N)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COc1cccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and m-anisidine (60 mg, 0.39 mmol). The title compound was obtained as a solid (27 mg, 15% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.49 (1H, s), 9.01 (2H, s), 8.73 (1H, m), 7.31 (1H, m), 7.26 (2H, m), 6.70 (1H, m), 3.80 (3H, s). MS m/z: 454.09, 456.04 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:33])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]4C(=O)C5=CC=CC=C5C4=O)=[CH:14][CH:13]=3)[O:11][C:6]=2[C:5]([F:34])=[CH:4][CH:3]=1>CN(C)C=O.CO.O.NN>[NH2:1][C:2]1[C:7]2[C:8](=[O:33])[CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:16][CH:17]=3)[O:11][C:6]=2[C:5]([F:34])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)c2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)cc3)cc(=O)c12
Agent: NN
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: NCCCNc1ccc(-c2cc(=O)c3c(N)ccc(F)c3o2)cc1
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
4.22 g of Compound 19 was dissolved in 200 ml of a mixed solvent of dimethylformamide and methanol (1:1), 9.0 ml of hydrazine monohydrate was added and the mixture was stirred at 50-60° C. for 20 minutes. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:methanol:aqueous ammonia=9:1:1) to give Compound 20 which was dissolved in ethanol, a 5.5N hydrochloric acid-isopropylalcohol solution was added, and the precipitated crystals were collected by filtration to give 1.47 g (40%) of Compound 20.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][S:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C1C=CC=CC=1>[S:8]1[CH2:9][CH:7]=[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]12
Reactant: C1=C(C2CS2)CCCC1
Solvent: c1ccccc1
Product: C1=C2CCCCC2SC1
Yield: 35.7 %

Procedure:
A solution of 2-cyclohex-1-enyl-thiirane (100 mg, 0.7 mmol) and Cu(tfacac)2 (78 mg, 0.21 mmol) in benzene (21 mL) were heated to 100° C. for 24 h under N2. After cooling, concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography (n-pentane) to give 2,4,5,6,7,7a-Hexahydro-benzo[b]thiophene (35 mg, 35%) as a yellow oil.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)(=[O:11])[CH3:10].C(OC(C)C)(C)C>>[CH3:6][N:4]([CH3:5])[CH:3]=[CH:10][C:9]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)=[O:11]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cncnc1
Solvent: CC(C)OC(C)C
Product: CN(C)C=CC(=O)c1cncnc1
Yield: 68 %

Procedure:
6.01 g of N,N-dimethylformamide dimethylacetal was added to 1.54 g of 5-acetylpyrimidine (Khim. Geterotsikl. Soedim., 1981, (7), 958-962) and the mixture was heated at reflux for 15 hours. After the reaction solution was air-cooled, a small amount of diisopropyl ether was added and the deposited crystal was collected by filtration to obtain 1.52 g of the objective compound as reddish brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][N:13](S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:12][CH:11]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:10]=1.SCC(O)=O.O[Li].O>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][NH:13][CH2:12][CH:11]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC(c3cc(F)ccc3F)=CC(c3ccccc3)C2)cc1
Agent: O=C(O)CS
Agent: [Li]O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(F)c(C2=CC(c3ccccc3)CNC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2,5-difluorophenyl)-1-[(4-nitrophenyl)sulfonyl]-3-phenyl-1,2,3,6-tetrahydropyridine (1-6, 140 mg, 0.31 mmol) was dissolved in DMF (2 mL) and treated sequentially with mercaptoacetic acid (113 mg, 1.2 mmol) and LiOH hydrate (140 mg, 2.4 mmol). The reaction stirred at 25° C. for 2 h until completion. The reaction was then diluted with EtOAc (20 mL), washed with H2O (3×100 mL) and NaCl (sat. aq.). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified using reverse-phase column chromatography (5-95% MeOH—H2O w/0.1% TFA) to provide 5-(2,5-difluorophenyl)-3-phenyl-1,2,3,6-tetrahydropyridine (1-7) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.25 (m, 5H), 7.00 (m, 2H), 6.95 (m, 1H), 6.17 (s, 1H), 4.03 (br s, 1H), 3.77 (in, 3H), 3.41 (dd, J=12.9, 5.6 Hz, 1H), 2.85 (dd, J=12.7, 7.5 Hz, 1H); MS 272.33 found 272.3 (M+H+) required.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:13]3[CH:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.CCCCCC.C(O)C.C(NCC)C>>[CH3:1][C:2]1[O:3][C:4]2[C:13]3[C@H:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)NCCC1CCc2ccc3nc(C)oc3c21
Solvent: CCCCCC
Solvent: CCO
Solvent: CCNCC
Product: CC(=O)NCC[C@@H]1CCc2ccc3nc(C)oc3c21
Yield: 49.2 %

Procedure:
Racemic N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide (768 mg, 3.00 mmol) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIPALPAK AD (50 mmID×500 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=90/10/0.1, flow rate: 60 mL/min, column temperature: 30° C., sample concentration: 1.02 mg/mL, injection weight: 31 mg). A fraction containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated. The concentrate was re-dissolved in ethanol, and concentrated to dryness. Hexane was added again, and the mixture was concentrated to dryness to give the title compound (381 mg, 99.9% ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mmID×250 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=90/10/0.1, flow rate: 0.5 mL/min, column temperature: 30° C., sample concentration: 0.65 mg/mL (hexane/ethanol), injection volume: 10 μL).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:15]([O:14][C:12](=[O:13])[CH2:11][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(hydroxymethyl)-phenol (50 g, 0.4 mol) and t-butyl bromoacetate (86 g, 0.44 mol) in DMF (500 ml, anhydrous) at room temperature is added K2CO3 (122 g, 0.88 mol). The reaction mixture is stirred vigorously for 2 hrs, and the mixture is poured into ice-water (2.5 L) and extracted with ether (3×500 ml). The combined ether extracts are washed with water, dried over MgSO4 and evaporated in vacuo to provide t-butyl-3-(hydroxymethyl)-phenoxyacetate as a low melting, light yellow solid; mp: 52-56° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1ccnc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 64.2 %

Procedure:
A mixture of methyl thiosalicylate (1.15 g, 6.8 mmol), 2-cyano-4-methylpyridine (0.81 g, 6.8 mmol), triethylamine (1.50 ml, 10.8 mmol) and toluene (2.0 ml) was refluxed for 8 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (1.11 g, 64%).
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([CH2:60][C:61]([N:63]2[CH2:67][CH2:66][C@H:65]([NH:68][C:69]([O:71][CH2:72][C:73]3[CH:78]=[CH:77][C:76]([N+:79]([O-:81])=[O:80])=[CH:75][CH:74]=3)=[O:70])[CH2:64]2)=[O:62])[CH2:43]1>C(#N)C.C(N(C(C)C)CC)(C)C>[N+:57]([C:54]1[CH:55]=[CH:56][C:51]([CH2:50][O:49][C:47]([N:45]2[CH2:46][C@@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])[CH2:43][C@H:44]2[CH2:60][C:61]([N:63]2[CH2:67][CH2:66][C@H:65]([NH:68][C:69]([O:71][CH2:72][C:73]3[CH:74]=[CH:75][C:76]([N+:79]([O-:81])=[O:80])=[CH:77][CH:78]=3)=[O:70])[CH2:64]2)=[O:62])=[O:48])=[CH:52][CH:53]=1)([O-:59])=[O:58]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C(N[C@H]1CCN(C(=O)C[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CC(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@@H]12
Reaction time: 24 h
Yield: 94.6 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (478 mg) in anhydrous acetonitrile (5.5 ml), a solution of (2R,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonylmethyl]pyrrolidine (450 mg) in anhydrous acetonitrile (5.5 ml) and diisopropylethylamine (0.140 ml) were added under ice cooling. The resulting mixture was allowed to stand for one day at the same temperature. The reaction mixture was concentrated by evaporation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with water and saline, dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to chromatography on a silica gel column. From the fraction eluted with ethyl acetate-methanol (20:1), 4-nitrobenzyl (1R,5R,6S)-2-[(2R,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonylmethyl]pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (675 mg) was obtained as a powder.
Reaction SMILES: [I:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:17](Cl)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21].CC1NC=CN=1>>[I:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CCCCC(=O)Cl
Reactant: CC(C)[C@H](NCc1ccc(I)cc1)C(=O)O
Agent: Cc1ncc[nH]1
Product: CCCCC(=O)N(Cc1ccc(I)cc1)[C@H](C(=O)O)C(C)C
Yield: 63.4 %

Procedure:
In a manner similar to Example 5 and starting from 800 mg (2.40 mmol) of N-(4-iodobenzyl)-L-Valine, 0.47 mL (3.84 mmol) of valeryl chloride and 296 mg (3.60 mmol) of 2-methylimidazole, 635 mg (64%) of N-(4-iodobenzyl)-N-valeryl-L-Valine is obtained. The solid is recrystallised from a mixture of EtOH:H2O 1:1.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([N:13]3[CH2:17][C@H:16]([C:18]([O:20]C)=O)[O:15][C:14]3=[O:22])=[CH:12][C:7]=2[S:6][C:5]1=[O:23])([CH3:3])[CH3:2].[CH3:24][NH2:25]>CO>[CH3:24][NH:25][C:18]([C@@H:16]1[O:15][C:14](=[O:22])[N:13]([C:11]2[CH:10]=[CH:9][C:8]3[N:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:23])[S:6][C:7]=3[CH:12]=2)[CH2:17]1)=[O:20]
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C(C)C)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The methyl (5R)-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 31, Step 3, 2.89 g, 8.59 mmol) is treated with 2N methylamine in MeOH (8.2 mL), and the mixture is stirred at ambient temperature for 45 mins and then filtered to give the title compound, mp 172–173.5° C.; MS (ESI+) for C15H17N3O4S m/z 336 (M+H)+; [α]25D−43 (c 0.98, DMSO).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=O)[O:25]C(C)(C)C)[CH3:22])[CH:15]=4)=[N:11][C:10]=3[CH:31]=2)[CH2:3][CH2:2]1.Cl.[C:33](OCC)(=O)C>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:25])[CH3:33])[CH3:22])[CH:15]=4)=[N:11][C:10]=3[CH:31]=2)[CH2:2][CH2:3]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1cc(-c2nc3cc(OCC4CC4)ccc3o2)on1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc(-c2nc3cc(OCC4CC4)ccc3o2)on1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl [(1S)-2-({5-[5-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]isoxazol-3-yl}oxy)-1-methylethyl]carbamate (510 mg) in ethyl acetate (11 mL) was added 4M hydrogen chloride/ethyl acetate (12 mL), and the mixture was stirred at room temperature for 5 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in pyridine (1.5 ml). Acetic anhydride (1.5 mL) was added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol), and recrystallized (hexane/ethyl acetate) to give the title compound (182 mg).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=1)(C(C)(C)C)(C)C.S(=O)(=O)(O)O>C(O)C>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C#N)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: N#Cc1cc(CO)ccn1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
In ethanol, 4-(tert-butyldimethylsilyloxymethyl)pyridine-2-carbonitrile (260 mg, 1.1 mmol) synthesized in Production Example 86 was dissolved, and concentrated sulfuric acid (123 μL, 2.3 mmol) was added thereto. The mixture was refluxed overnight. After the completion of the reaction was confirmed by HPLC, the reaction mixture was allowed to cool down to a room temperature, and the solvent was distilled off. The resulting residue was dissolved in ethyl acetate and washed with water and a saturated saline solution in order. Thereafter, the organic layer was dried over magnesium sulfate, and the solvent was distilled off. Thus the title compound (111 mg, 78.8%) was obtained as a yellowish white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[C:13](#[N:16])[CH:14]=[CH2:15].CC(C)([O-])C.[K+]>>[C:13]([CH2:14][CH2:15][O:1][CH2:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)#[N:16]
Reactant: C=CC#N
Reactant: Cc1cccc(CO)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1cccc(COCCC#N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A mixture of 10 grams (g) [60 millimoles (mMol)] of 3-hydroxymethyl-2-nitrotoluene (1) (Aldrich Chemical Co., Milwaukee, WI) and 7.9 milliliters (ml) of acrylonitrile was stirred under argon at room temperature. Potassium tert-butoxide [10 milligrams (mg)] was added, followed 90 minutes later by an additional 10 mg portion. After a total of 3 hours, the reaction was quenched by the addition of 0.2 ml of acetic acid. Volatile material was removed under reduced pressure, and the residue chromatographed on 300 g of silica gel eluting with methylene chloride (CH2Cl2). Fractions of approximately 17 ml were collected. Fractions 155-200 were combined and the solvent evaporated to give 12.5 grams (g) (90% yield) of 3-(2-cyanoethoxymethyl)-2-nitrotoluene (2) as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[C:18](=[O:23])[C:19]([Cl:22])([Cl:21])[Cl:20])[CH2:11][C:10](=[O:12])[NH:9][C:7]1=[O:8])=[O:5])[CH3:2].S(Cl)([Cl:27])(=O)=O.O>C(Cl)(Cl)Cl>[Cl:27][C:16]1[CH:15]=[C:14]([C:18](=[O:23])[C:19]([Cl:22])([Cl:20])[Cl:21])[N:13]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][C:10](=[O:12])[NH:9][C:7]2=[O:8])[CH:17]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C1(n2cccc2C(=O)C(Cl)(Cl)Cl)CC(=O)NC1=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(n2cc(Cl)cc2C(=O)C(Cl)(Cl)Cl)CC(=O)NC1=O
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a stirred solution of 2-ethoxycarbonyl-2-(2-trichloroacetylpyrrol-1-yl)succinimide (6.0 g) in chloroform (50 ml) was added dropwise a solution of sulfuryl chloride (4.8 g) in chloroform (5 ml) under ice cooling. The resulting mixture was stirred under ice cooling for 30 minutes, poured into water, and extracted with chloroform. The extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using n-hexane/ethyl acetate (2:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (2.5 g, 41.7%) as colorless crystals, mp 182°-185° C.
Reaction SMILES: [CH3:1][CH:2]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[CH:4]=[C:3]1[CH3:10].CC1C2C=CSC=2CC=1C.[Li]CCCC.[Cl:26][Si:27](Cl)([CH3:29])[CH3:28]>C1COCC1>[Cl:26][Si:27]([CH:4]1[C:5]2[S:6][CH:7]=[CH:8][C:9]=2[C:2]([CH3:1])=[C:3]1[CH3:10])([CH3:29])[CH3:28]
Reactant: CC1=Cc2sccc2C1C
Reactant: C[Si](C)(Cl)Cl
Agent: CC1=C(C)c2ccsc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Cl)c2sccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere, to a solution of 10.0 g (66.6 mmol) of a mixture of 4,5-dimethyl-4H-cyclopenta[b]thiophene and 4,5-dimethyl-6H-cyclopenta[b]thiophene in 150 ml of THF, 26.6 ml of 2.5 M (66.6 mmol) nBuLi in hexanes was added dropwise over 30 minutes at −60° C. This mixture was additionally stirred for 2 hours at room temperature and then added dropwise for 3 hours to a solution of 23.7 ml (25.2 g, 200 mmol) of dichlorodimethylsilane in 50 ml of THF. The resulting mixture was stirred for 12 hours at ambient temperature and then evaporated to dryness. Fractional distillation gave yellowish liquid, by 83-85° C./0.2 mm Hg. Yield 10.7 g (66%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]1([NH:52][CH3:53])[CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:52]([CH:47]4[CH2:51][CH2:50][CH2:49][CH2:48]4)[CH3:53])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNC1CCCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)C2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with cyclopentyl-methyl-amine (Oakwood) to give the title product. LC-MS (ES+) 746 [(M+H)+].
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].[H-].[Na+].[I:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[O:27][CH2:28][CH2:29][CH3:30].[Cl-].[NH4+]>O1CCCC1>[I:18][C:19]1[CH:26]=[CH:25][C:22](/[CH:23]=[C:6](\[CH3:7])/[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:21][C:20]=1[O:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCOc1cc(C=O)ccc1I
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCOc1cc(/C=C(\C)C(=O)OCC)ccc1I
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
A solution of 1.8 g (7.7 mmol) of triethyl 2-phosphonopropionate in 25 mL of tetrahydrofuran is added to a suspension of 310 mg (7.7 mmol) of 60% sodium hydride in oil, precooled to 0° C. After stirring at 0° C. for 15 minutes, a solution of 1.5 g (5.2 mmol) of 4-iodo-3-propoxybenzaldehyde in 10 mL of tetrahydrofuran is added. The reaction medium is stirred at room temperature for 12 hours. Saturated ammonium chloride solution is added and the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 1.6 g (84%) of ethyl (E)-3-(4-iodo-3-propoxyphenyl)-2-methylacrylate are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)#[N:15]>O1CCCC1.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(Cc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.6 %

Procedure:
Under the argon atmosphere, 4-methylpiperazine (2.00 g, 20.0 mmole) and potassium carbonate (3.41 g, 24.7 mole ) were added to a solution of 4-cyanobenzyl bromide (3.20 g, 16.3 mole) in tetrahydrofuran (30 ml). After stirring at room temperature for 18 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated aqueous saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4(4-methyl-1-piperazinylmethyl)benzonitrile as a colorless crystalline powder (1.49 g, 42.4%).