Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[N+]([O-])(O)=O.[CH3:11][C:12]1[CH:16]=[C:15]([CH3:17])[N:14]([C:18](=[NH:20])[NH2:19])[N:13]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]=[S:23]>CS(C)=O>[CH3:11][C:12]1[CH:16]=[C:15]([CH3:17])[N:14]([C:18]([NH:19][C:22]([NH:21][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[S:23])=[NH:20])[N:13]=1
Reactant: CC(C)(C)OC(=O)NCCN=C=S
Reactant: Cc1cc(C)n(C(=N)N)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=[N+]([O-])O
Product: Cc1cc(C)n(C(=N)NC(=S)NCCNC(=O)OC(C)(C)C)n1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
554.7 mg (4.94 mmol) of potassium tert-butoxide are dissolved in 12 ml of DMSO while cooling slightly in ice, and then 596.8 mg (2.96 mmol) of 3,5-dimethyl-1H-pyrazole-1-carboximidamide nitrate are added. A clear solution is produced after stirring for about 5 minutes. Then 500 mg (2.47 mmol) of tert-butyl (2-isothiocyanatoethyl)carbamate are added, and the icebath is removed. The mixture is heated at 60° C. for a further 3 h and the solution obtained in this way is employed for the further subsequent reactions.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[Br:18][C:19]([CH3:24])([CH3:23])[C:20](Br)=[O:21]>ClCCl>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][O:5][CH2:6][CH2:7][O:8][C:20](=[O:21])[C:19]([Br:18])([CH3:24])[CH3:23]
Reactant: CC(C)(Br)C(=O)Br
Reactant: COC(COCCO)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(COCCOC(=O)C(C)(C)Br)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A solution of 2-(2,2-dimethoxy-ethoxy)-ethanol (11 g, 0.073 mol) and triethylamine (12 mL, 0.088 mol) in dichloromethane (150 mL) was cooled to 0° C. and a solution of 2-bromo-2-methyl propionyl bromide (8.5 mL, 0.069 mol) in 50 mL of dichloromethane was added dropwise in ca. 30 min. After stirring overnight at room temperature the resulting suspension was filtered and the yellow solution was washed with saturated NaHCO3 aqueous solution (2×100 mL) and dried with MgSO4. After filtration the solvent was removed under reduced pressure and the yellow oily residue was purified by distillation (b.p. 70° C./0.02 mbar) to give 14.0 g (0.061 mol, yield: 89%) of product as a colourless oil. 1H NMR (400.03 MHz, CDCl3, 298 K) δ=1.94 (s, 6H, (CH3)2CBr), 3.39 (s, 6H, OCH3), 3.56 (d, J=5.3 Hz, 2H, CHCH2), 3.76 (t, J=4.8 Hz, CH2OCH2), 4.33 (t, J=4.8 Hz, 2H, CH2OCO), 4.50 (t, 1H, CH(OCH3)2. 13C{1H} NMR (100.59 MHz, CDCl3, 298 K) δ=30.90 (2C, C(CH3)2), 54.13 (2C, CH3O), 55.79 (1C, BrC(CH3)2), 65.24 (1C, CH2OC(═O)), 69.21 (1C, CHCH2O), 71.18 (1C, OCH2CH2), 102.83 (1C, CH).
Reaction SMILES: O=C1[N:6]([S:7]([NH:10][C@@H:11]([CH2:22][C:23]2[O:24][C:25]([CH2:28][C:29]3[S:30][C:31]4[CH:37]=[C:36]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:35]=[CH:34][C:32]=4[N:33]=3)=[N:26][N:27]=2)[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])(=[O:9])=[O:8])[CH2:5][CH2:4]O1.[CH:44]1(N)CC1>C(#N)C>[CH:5]1([NH:6][S:7]([NH:10][C@@H:11]([CH2:22][C:23]2[O:24][C:25]([CH2:28][C:29]3[S:30][C:31]4[CH:37]=[C:36]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH:35]=[CH:34][C:32]=4[N:33]=3)=[N:26][N:27]=2)[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])(=[O:8])=[O:9])[CH2:4][CH2:44]1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)NS(=O)(=O)N1CCOC1=O
Reactant: NC1CC1
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)NS(=O)(=O)NC1CC1
Temperature: 70 °C
Yield: 46.4 %

Procedure:
To a solution of 2-chloroethanol (0.10 mL, 1.3 mmol) in DCM (1 mL) at rt was added a solution of sulfurisocyanatidic chloride (180 mg, 1.3 mmol) in DCM (1 mL) and the reaction mixture was stirred for 6 h. The resulting mixture was added to a solution of Compound 181a (300 mg, 0.65 mmol, prepared as described in Example 45) and TEA (0.45 mL, 3.2 mmol) in DCM (4 mL) and the mixture stirred for 30 min then heated at 35° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 0-100% hexane/EtOAc to afford (S)-benzyl 2-(2-oxooxazolidine-3-sulfonamido)-3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)propanoate (230 mg, 57% yield) as a yellow foam. LCMS=1.2 min using analytical method (B), 620.2 (M+H). A portion of (S)-benzyl 2-(2-oxooxazolidine-3-sulfonamido)-3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)propanoate (93 mg, 0.15 mmol) was dissolved in ACN (3 mL) then TEA (0.031 mL, 0.23 mmol) was added followed by cyclopropanamine (0.053 mL, 0.75 mmol) and the reaction mixture heated at 70° C. for 16 h. The reaction mixture was allowed to cool to rt then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% hexane/EtOAc to give Compound 181b (41 mg, 46% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.13-7.97 (m, 2H), 7.72 (dd, J=8.5, 1.9 Hz, 1H), 7.67-7.59 (m, 2H), 7.51-7.44 (m, 2H), 7.42-7.38 (m, 1H), 7.34-7.31 (m, 3H), 7.30-7.27 (m, 2H), 5.53 (d, J=8.1 Hz, 1H), 5.23 (s, 1H), 5.18 (s, 2H), 4.68 (d, J=4.4 Hz, 2H), 3.43 (dd, J=5.7, 1.8 Hz, 2H), 2.51-2.35 (m, 1H), 0.65-0.43 (m, 4H). LCMS=1.2 min using analytical method (B), 590.2 (M+H)±.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=O)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:21][O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH3:21][O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:15](=[O:17])[C@@H:14]1[CH2:18][CH2:19][CH2:20][N:13]1[C:11](=[O:12])[CH2:10][CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CC1C=Cc2ccccc21
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC1C=Cc2ccccc21
Yield: 75 %

Procedure:
A colorless oil of 1-[1-(2-indenylacetyl)-L-prolyl]-L-proline methyl ester was prepared in the same manner as in Example 1, except that 1-(2-indenylacetyl)-L-proline and L-proline methyl ester were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 75%).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH2:12][CH2:13][NH2:14])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[C:1]1([C:7]2[S:8][C:9]([CH2:12][CH2:13][NH:14][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:32])([F:31])[F:15])[O:21][N:20]=4)[CH:23]=3)=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCc1cnc(-c2ccccc2)s1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1cnc(-c2ccccc2)s1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 27 %

Procedure:
This compound was synthesized from 2-(2-phenylthiazol-5-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (35 mg, yield 27%) as an off white solid. 1H NMR (400 MHz, MeOD) δ 8.61 (t, J=1.5 Hz, 1H), 8.32-8.29 (dt, J=7.8 Hz, 1.3 Hz, 1H), 8.09-8.06 (dt, J=7.8 Hz, 1.5 Hz, 1H), 7.90-7.88 (m, 2H), 7.73-7.69 (t, J=7.9 Hz, 1H), 7.66 (s, 1H), 7.47-7.45 (m, 3H), 3.75-3.71 (t, J=6.8 Hz, 2H), 3.28-3.25 (t, J=6.8 Hz, 2H). MS (ESI) m/z: Calculated for C21H15F3N4O2S: 444.09. found: 445.0 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[C:16]1([CH3:24])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1.Cl>ClCCCl>[CH3:24][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5]([OH:10])=[O:15])=[O:9]
Reactant: Cc1cc(C)cc(C)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1cc(C)c(C(=O)c2ccccc2C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (60 g, 0.45 mol) was added in portions to a solution of phthalic anhydride (30 g, 0.20 mol) and mesitylene (40 mL) in 150 mL of 1,2-dichloroethane at 0 ° 5C. the reaction mixture was stirred at room temperature for 2 hours, then poured into ice-water. The mixture was acidified with 37% hydrochloric acid and extracted with ether. The ether extract was washed with 1 N hydrochloric acid, water, dried and concentrated to give 59 g of the title compound as white solids which was used in the next reaction without further purification.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.COP([CH2:19][C:20]1[N:21]([CH3:36])[C:22]2[C:27]([N:28]=1)=[C:26]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[N:25]=[C:24]([Cl:35])[N:23]=2)(=O)OC.[C:37]([O:41][C:42]([N:44]1[CH2:47][C:46](=O)[CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[C:37]([O:41][C:42]([N:44]1[CH2:47][C:46](=[CH:19][C:20]2[N:21]([CH3:36])[C:22]3[C:27]([N:28]=2)=[C:26]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[N:25]=[C:24]([Cl:35])[N:23]=3)[CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: COP(=O)(Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1c(C=C2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
To a solution of diisopropylamine (1.4 mL, 9.8 mmol) in THF (3 mL) at −78° C. was added n-BuLi (3.9 mL, 9.8 mmol, 2.5 M in hexanes) and the resulting mixture allowed to stir for 20 min. The resulting solution was added to a pale green solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)phosphonic acid dimethyl ester (3.36 g, 8.9 mmol) in THF (80 mL) at −78° C. The resulting mixture was warmed to r.t. before a solution of 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (1.76 g, 10.2 mmol) in THF (10 mL) was added. The resulting pink mixture was stirred for 16 h then quenched with H2O. The mixture was concentrated in vacuo and the residue was partitioned between DCM and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-70%) affording the title compound as a green powder (3.46 g, 92%). 1H NMR (CDCl3, 400 MHz): δ 6.33-6.32 (1 H, m), 4.91-4.90 (2 H, m), 4.71-4.70 (2 H, m), 4.28 (4 H, brd s), 3.81 (4 H, t, J=4.74 Hz), 3.71 (3 H, s), 1.48 (9 H, s).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]([C:12]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)c1cc(F)c2cccnc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cc(F)c2cccnc2c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of 5-fluoro-8-hydroxyquinoline-7-carboxylic acid (0.311 g) of reparation 4 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirred overnight. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried. The crude product is recrystallized from EtOAc/hexanes to yield 0.207 g of the title product as an off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[CH3:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:24]C1C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[N:24]1[CH2:2][C:3]2[C:4](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])[C:5]1=[O:7]
Reactant: Cc1cccc(Nc2ccccc2)c1C
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(N2Cc3c(cccc3[N+](=O)[O-])C2=O)c1C

Procedure:
A solution of 6 (0.140 g), 2,3 - dimethylphenyl aniline (0.065 mL), and triethyl-amine (0.142 mL) in acetonitrile (10 mL) was refluxed 18 h. The solution was concentrated in vacuo and the residue was partitioned between methylene chloride and 2% potassium hydrogen sulfate. The methylene chloride was washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to afford the the product as a solid. NMR (300 MHz, CDCl3) δ 8.46 (1H, d, J=8 Hz), 8.30 (1H, d, J=8 Hz), 7.77 (1H, t, J=8 Hz), 7.24 (1H, s ), 7.22 (1H, d, J=2 Hz), 7.12 (1H, m), 5.18 (2H, s), 2.35 (3H, s), 2.14(3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(O)Cc2ccccc2)ccc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of 20 g (82.64 mmol) of O-benzylvanillin in 200 mL of dry tetrahydrofuran was slowly added to a stirred solution of benzyl magnesium chloride (103.30 mmol) in 150 mL of diethylether at 10° C. over 20 min, and the reaction mixture was then boiled for 10 min, cooled, quenched with a mixture of ice and dilute hydrochloric acid and evaporated at reduced pressure. The residue was dissolved in dichloromethane, the solution washed with brine, dried with sodium sulphate and the solvent was evaporated under reduced pressure leaving a crystalline residue that was recrystallised from diethylether and petroleum ether. 1-(4-Benzyloxy-3-methoxyphenyl)-2-phenyl-1-ethanol was obtained as white crystals, m.p. 97 to 98° C.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[C:13]([C:14]#[N:15])=[C:12]([NH2:16])[N:11]([CH3:17])[N:10]=1.Cl>N1C=CC=CC=1>[NH2:16][C:12]1[N:11]([CH3:17])[N:10]=[C:9]([NH:8][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:13]=1[C:14]#[N:15]
Reactant: Cn1nc(N)c(C#N)c1N
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: Cn1nc(NC(=O)C(C)(C)C)c(C#N)c1N
Temperature: 0 °C
Yield: 59 %

Procedure:
Pivaloyl chloride (2,2-dimethylpropionyl chloride) (3.6 g) was added cautiously to a suspension of 3,5-diamino-4-cyano-1-methylpyrazole (4.1 g) in pyridine (25 ml). The temperature of the mixture rose to about 60°. The mixture was left to cool overnight and was then poured into a mixture of ice (60 g) and concentrated HCl (40 ml). The precipitate was filtered off, washed and dried, to give 3.9 g of crude 5-amino-4-cyano-3-(2,2-dimethylpropanoylamino)-1-methylpyrazole. Recrystallisation from a 70:30 ethanol/water mixture gave 3.1 g of pure product, mp 245°-247° C.
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]=2[S:5][C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[C:22](#[N:25])[CH:23]=[CH2:24]>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:4]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:5][C:6]3([CH:23]([C:22]#[N:25])[CH2:24]2)[N:7]1[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=13
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccccc1-2
Reactant: C=CC#N
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#CC1CC2(c3ccccc3)SC13c1ccccc1CCN3C2=O

Procedure:
4.08 g of 5,6-dihydro-3-hydroxy-2-phenylthiazolo[2,3-a]isoquinolinium hydroxide (internal salt) and 1.95 ml of acrylonitrile were heated together under reflux overnight in 250 ml of toluene. After evaporation of the solvent in vacuo, the residue was recrystallized from acetonitrile. There was obtained 1,2,3,4,6,7-hexahydro-4-oxo-3-phenyl-3,11b-epithio-11bH -benzo[a]quinolizine-1carbonitrile of m.p. 225°-226°.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7](=O)[NH:8][N:9]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:7]1[N:8]=[N:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(=O)[nH]n1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)c1ccc(Cl)nn1

Procedure:
6-Isopropyl-3(2H)-pyridazinone (3.30 g) and phosphorus oxychloride (15.0 ml) were heated for 1 hour under reflux. After an excess of phosphorus oxychloride was distilled away, ice-water (200 ml) was added to the residues which were then adjusted to pH 6 with 20% aqueous sodium hydroxide solution. The reaction solution was extracted 3 times with ethyl acetate, and the extracts were combined, dried over anhydrous magnesium sulfate and concentrated. The residues were purified by silica gel column chromatography (ethyl acetate:chloroform=1:2) to give the title compound as pale red crystals. The yield was 1.60 g (40.8% based on 5-methyl-4-oxohexanoic acid).
Reaction SMILES: [CH2:1]([N:9]1[C:13](=[O:14])[CH:12]=[CH:11][S:10]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:16][C:17]([C:19]([CH3:21])=[CH2:20])=[CH2:18]>C(Cl)CCl>[CH3:16][C:17]1[CH2:18][CH:12]2[C:13](=[O:14])[N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[S:10](=[O:15])[CH:11]2[CH2:20][C:19]=1[CH3:21]
Reactant: C=C(C)C(=C)C
Reactant: CCCCCCCCN1C(=O)C=CS1=O
Solvent: ClCCCl
Product: CCCCCCCCN1C(=O)C2CC(C)=C(C)CC2S1=O
Temperature: 60 °C
Yield: 50.7 %

Procedure:
To a solution of 2.2 g (0.01 mole) of 2-n-octyl-4-isothiazolin-3-one 1-oxide in 15 ml of ethylene dichloride is added 1.1 g (0.012 mole) of 2,3-dimethyl-1,3-butadiene. The solution is stirred and maintained at 60° C. overnight. The mixture is concentrated to give a dark, thick oil. The oil is further purified by column chromatography (90% benzene, 10% acetone, silica) to yield 1.58 g (51%) of product as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:1]([O:3][C:4]([CH:6]1[C:14]2[N:13]=[CH:12][N:11]([C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCc2[nH]cnc21
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 4,5,6,7-tetrahydro-1H-benzimidazole-4-carboxylic acid ethyl ester (18.9 g, 97 mmol, J. Am. Chem. Soc., 1996, 98, 984) in acetonitrile (250 ml) were added triethylamine (27 ml, 194 mmol) and a solution of trityl chloride (40.6 g, 146 mmol) in acetonitrile (500 ml). The resulting mixture was stirred at 20° C. overnight. The mixture was concentrated under reduced pressure and the residue was redissolved in ethyl acetate, washed with water (2×) and brine (1×), and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/heptane, to yield 20.8 g (49%) of 1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole-4-carboxylic acid ethyl ester as a colourless solid. From the mother liquor more product (10.3 g, 24%) was isolated by column chromatography (silica gel, gradient elution with heptane/ethyl acetate 9:1 to 1:1).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3][CH:2]1O.C1(P(=[CH:32][C:33]([O:35][CH3:36])=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(O)C.[C].[Pd]>[OH:3][CH2:4][CH2:5][C:6]1([CH2:1][CH2:2][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1CC2(CCCCC2)CCO1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CCCC1(CCO)CCCCC1
Yield: 34 %

Procedure:
To a solution of 3oxaspiro[5.5]undecan-2-ol (460 mg) in dichloromethane (15 mL) was added methyl triphenylphosphoranylideneacetate (1.36 g). After stirring the solution under reflux for 3 hours, methyl triphenylphosphoranylideneacetate (1.36 g) was further added thereto. The solution was stirred under reflux for 14 hours. The solution was concentrated under reduced pressure, and the resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=1:1) to give a mixture of an unsaturated ester derivative and 3-oxaspiro[5.5]undecan-2-ol (520 mg) To a solution of the resulting mixture in ethanol (30 mL) was added 10% palladium-carbon (60 mg). The mixture was stirred at room temperature under hydrogen atmosphere for 63 hours. The catalyst was filtered off, concentrated under reduced pressure and the resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=1:1) to give the title compound (210 mg) 1HNMR (CDCl3) δ: 1.23-1.48 (m, 12H), 1.52-1.68 (m, 4H), 2.29 (t, 2H, J=7.2 Hz), 3.62-3.71 (m, 2H), 3.67 (s, 3H).
Reaction SMILES: C(OP([CH2:9][P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.C([Li])CCC.C(OC([N:28]1[CH2:32][CH2:31][C:30](=O)[CH:29]1[C:34]([O:36]CC)=[O:35])=O)C>O1CCCC1>[CH2:16]([O:15][P:10]([CH2:9][O:36][C:34]([CH:29]1[CH:30]=[CH:31][CH2:32][NH:28]1)=[O:35])([O:12][CH2:13][CH3:14])=[O:11])[CH3:17]
Reactant: CCOC(=O)C1C(=O)CCN1C(=O)OCC
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(COC(=O)C1C=CCN1)OCC
Temperature: 25 °C

Procedure:
A stirred solution of 5.3 ml of bis-(diethylphosphono)methane in 30 ml of anhydrous tetrahydrofuran (THF) under nitrogen is cooled to -78° and 8.5 ml of 2.5M butyl lithium is added dropwise. After stirring 5 minutes a solution of 4.64 g of ethyl 1-ethoxycarbonyl-3-oxo-pyrrolidine-2-carboxylate [J. Am. Chem. Soc. 86, 5297 (1964)] in 30 ml dry THF is added dropwise rapidly. The solution is heated at reflux for 18 hours, cooled to room temperature and concentrated; 40 ml of 1N hydrochloric acid is added and the mixture is extracted with 100 ml of methylene chloride. The organic fraction is washed with 25 ml water, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography using ethyl acetate as solvent yields ethyl 1-ethoxycarbonyl-3-(diethylphosphonomethyl-2,5-dihydropyrrole-2-carboxylate.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1.[C-]#N.[Na+]>CN(C)C=O.O>[CH:1]1([O:6][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: Brc1ccsc1
Agent: [C-]#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(OC2CCCC2)cs1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
To a solution of cyclopentanol (8.75 ml, 95.8 mmol) in N,N-dimethylformamide (250 mL) was added sodium hydride (60% dispersion in mineral oil, 3.84 g, 95.8 mmol) at 0–5° C. under nitrogen. After 10 minutes, the mixture was allowed to reach room temperature and stirred for 40 minutes. 3-Bromothiophene (3.59 mL, 38.3 mmol) was added followed by cuprous iodide (14.63 g, 76.8 mmol). The mixture was heated at 120° C. for 22 hours. After cooling to about 10° C., a solution of sodium cyanide (12.1 g, 0.25 mol) in water (200 mL) was added under vigorous stirring. The mixture was stirred for additional 10 minutes then filtered. The filtrate was extracted with hexane. The extract was washed with water, dried (Na2SO4) and concentrated to dryness. Distillation (100° C., 8 mm Hg) gave 3-cyclopentyloxythiopene (4.52 g, 70%) as a slightly pale yellow oil; 1H NMR (300 Mz, CDCl3) δ 7.15 (dd, J=5.2, 3.1 Hz, 1H), 6.72 (dd, J=5.2, 15 Hz, 1H) 6.19 (dd, J=3.1, 1.5 Hz, 1H), 4.65 (quintet, J=4.2 Hz, 1H), 1.55–1.95 (m, 8H). MS m/e (%): 168 (M+; 17).