Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[C:13]([O:22][CH3:23])[CH:12]=1.C([Li])CCC.[Cl:29]C(Cl)(Cl)C(Cl)(Cl)Cl>C(OCC)(=O)C.O>[Cl:29][C:18]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([CH:7]3[O:6][CH2:10][CH2:9][O:8]3)=[CH:12][C:13]=2[O:22][CH3:23])[CH:21]=[CH:20][N:19]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1cc(C2OCCO2)ccc1-n1ccnc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C2OCCO2)ccc1-n1ccnc1Cl
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a THF (50 mL) solution of 1-(4-[1,3]dioxolan-2-yl-2-methoxyphenyl)-1H-imidazole (3.85 g), n-butyllithium (1.6M hexane solution, 12 mL) was added dropwise under nitrogen atmosphere at −78° C., and the reaction solution was agitated for 30 minutes. THF (10 mL) solution of hexachloroethane (6.1 g) was added to the reaction solution and the reaction solution was agitated at room temperature for 1 hour after agitating for 30 minutes at −78° C. Water and ethyl acetate were added to the reaction mixture, 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 (elution solvent: hexane-ethyl acetate system), and 3.19 g of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33]>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCCC(Cc3cc(F)ccc3F)C2=O)sc1C(=O)NCc1ccccc1
Yield: 32 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 2-(bromomethyl)-1,4-difluorobenzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 32% yield: mp 144-145° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.37-7.22 (m, 5H), 7.02-6.81 (m, 3H), 6.01 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 4.32-4.20 (m, 1H), 4.03-3.94 (m, 1H), 3.47-3.37 (m, 1H), 2.90-2.73 (m, 2H), 2.63 (s, 3H), 2.12-1.98 (m, 1H), 1.96-1.75 (m, 2H), 1.64-1.45 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.5, 162.6, 160.2, 158.6, 157.3, 156.9, 152.2, 137.9, 128.8, 127.9, 127.5, 119.6, 117.7, 116.3, 114.7, 47.9, 44.1, 43.0, 30.6, 24.9, 21.3, 17.3; MS (ES+) m/z 456.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]#[N:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:16]([Cl:19])(=[O:18])[CH3:17]>C(O)C>[ClH:19].[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:12](=[NH:13])[O:18][CH2:16][CH3:17])[CH2:10][CH2:11]2)=[CH:7][CH:8]=1
Reactant: N#CC1(c2ccc(C(F)(F)F)cc2)CC1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=N)C1(c2ccc(C(F)(F)F)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.1 %

Procedure:
Into a 4 mL vial was added 1-(4-(trifluoromethyl)phenyl)cyclopropanecarbonitrile (21 mg, 0.1 mmol), ethanol (70 μL) and acetyl chloride (56 μL, 0.792 mmol). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure to afford the title compound as a white solid (30 mg). The material was used without further purification. 1H NMR (500 MHz, CD3OD) δ 1.45 (t, 3H), 1.61-1.66 (m, 2H), 1.95-2.00 (m, 2H), 4.44 (d, 2H), 7.70 (d, 2H), 7.75 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: OCCC(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2ccc(OCCC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
To a solution of 6-hydroxy-2,3-dihydro-1H-inden-1-one (3.0 g, 20.3 mmol) in THF (140 mL) were triphenylphosphine (7.97 g, 30.4 mmol) and 3,3,3-trifluoropropan-1-ol (1.963 mL, 22.27 mmol) added. Diisopropyl azodicarboxylate (5.98 mL, 30.4 mmol) was added dropwise and the mixture was left stirring at r.t. overnight. Since there was starting material remaining, 3,3,3-trifluoro-1-propanol (0.892 mL, 10.1 mmol) was added dropwise and stirring was continued. After 30 min the mixture was heated to 40° C. and after 1 h the mixture was concentrated. The crude product was purified by flash chromatography (0-12% EtOAc in heptane as eluent) to afford 1.08 g (22% yield) of the title compound (containing some diisopropyl azodicarboxylate): 1H NMR (500 MHz, CDCl3) δ 2.65 (qt, 2 H), 2.71-2.77 (m, 2 H), 3.05-3.13 (m, 2 H), 4.23 (t, 2 H), 7.17-7.23 (m, 2 H), 7.40 (d, 1 H); MS (ES+) m/z 245 [M+H]1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][NH:7][C:8](=[O:31])[C:9]=2[CH:10]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:11]=1[C:12]([O:14][CH2:15][CH2:16][C:17]#[N:18])=[O:13].C(OCC)(OCC)O[CH2:34][CH3:35]>S(=O)(=O)(O)O>[CH2:34]([O:31][C:8]1[N:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=1[O:27][C:26]([CH3:29])=[CH:25][C:24]3=[O:30])[C:11]([C:12]([O:14][CH2:15][CH2:16][C:17]#[N:18])=[O:13])=[C:2]([CH3:1])[NH:3]2)[CH3:35]
Reactant: CCOC(OCC)OCC
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc3c(=O)cc(C)oc23)c2c(cc[nH]c2=O)N1
Agent: O=S(=O)(O)O
Product: CCOc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)OCCC#N)=C(C)N2
Temperature: 130 °C
Reaction time: 8 h

Procedure:
2.20 g (5.27 mmol) of the compound from Example 31A are suspended in 80 ml of triethyl orthoformate and heated to 130° C. Then, over a total period of 8 hours, 5 drops of concentrated sulfuric acid are added each hour to the reaction mixture. It is then stirred at the same temperature overnight. After cooling, excess orthoester is removed in a rotary evaporator, and the crude product is purified by column chromatography (silica gel; mobile phase: initially dichloromethane, then ethyl acetate, finally ethyl acetate/methanol 20:1). The product fractions are concentrated to a volume of about 5 ml. The precipitated product is filtered off and, after washing with ethyl acetate and diethyl ether, dried under high vacuum. 282 mg (12% of theory) of the title compound are obtained in the form of brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].[CH3:36][S:37]([CH2:40][C:41](O)=[O:42])(=[O:39])=[O:38].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([C:41](=[O:42])[CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:34][CH2:35]1)=[O:28]
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: CS(=O)(=O)CC(=O)O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(=O)NC2CCN(C(=O)CS(C)(=O)=O)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 24.1 %

Procedure:
To a solution of the compound of Example 77 (200 mg, 0.423 mmol), (methylsulfonyl)acetic acid (76.0 mg, 0.550 mmol) and HOBt (85.8 mg, 0.635 mmol) in DMF (4 mL) was added WSCD (122 mg, 0.635 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was combined, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate). Recrystallization of the obtained solid from ethyl acetate gave the title compound (60.3 mg, 24%) as white crystals.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17])[S:13][CH:14]=1)[C:5]([O:7]CC)=[O:6].O>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:21])[Cl:22])=[O:17])[S:13][CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Solvent: CCO
Solvent: O
Product: CON=C(C(=O)O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.1 g. of ethyl α-methoxyimino-[2-(β,β,β-trichloroethoxycarbonylamino)thiazol-4-yl]acetate in 50 ml. of ethanol is added a solution of 11.2 g. of KCH in a mixture of 30 ml. of water and 150 ml. of ethanol. The whole mixture is stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue is extracted with ethyl acetate. The water layer is made acidic with 10% aq. HCl and the separated solid is collected. Recrystallization of the solid from aq. methanol gives α-methoxyimino-[2-(β,β,β-trichloroethoxycarbonylamino)-thiazol-4-yl]acetic acid. 4.1 g. Melting point: 162°-163° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:12]3[CH:13]=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([CH:18]=3)[NH2:17])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Mn]([O-])(=O)(=O)=[O:23].[K+].[OH-:28].[Na+]>S(=O)(=O)(O)O.C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:12]3[CH:13]=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([CH:18]=3)[NH2:17])(=[O:23])=[O:28])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: [OH-]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Nc1cc(Sc2cccc3cnccc23)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1cc(S(=O)(=O)c2cccc3cnccc23)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
5-(5-Isoquinolylsulfanyl)-2-nitroaniline 300 mg (1.0 mmol) was dissolved in a mixture solution of 5% sulfuric acid 2 ml and acetic acid 6 ml, potassium permanganate 200 mg (1.3 mmol) was added in an ice bath, and the mixture was stirred for 3 hours at 0° C. After stirring at room temperature for 3 hours, the mixture was neutralized with 2N sodium hydroxide and extracted with ethyl acetate (70 ml×3). The organic layer was dried over potassium carbonate, and concentrated under reduced pressure. The resulting residue was recrystalized from methanol-water to give 5-(5-isoquinolylsulfonyl)-2-nitroaniline 59 mg (17.9%).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([CH2:63][CH2:64][CH2:65][CH2:66][C@H:67]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[C:68](OCC#N)=[O:69])=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([CH2:63][CH2:64][CH2:65][CH2:66][C@@H:67]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[C:68]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:69])=[N+:61]=[N-:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN=[N+]=[N-])C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCCN=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 27.8 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (78 mg, 0.122 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-azido-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk49) (152 mg, 0.488 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (18 mL), and the mixture was stirred at room temperature for 0.75 hour. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-azido-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk50) (30.2 mg, 28%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[O:5][C:4](=[O:13])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:10]=2)[O:5][C:4](=[O:13])[CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(=O)Oc2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)Oc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 25 °C

Procedure:
The procedure used is substantially in accordance with (Journal of Organic Chemistry, Vol. 46, No. 11, (1981) p 2280-81). To a solution of 2.5 g (9.8 mmol) of 4,4-dimethyl-6-bromo-2-oxo-chroman and 0.087 g (0.3317 mmol) of triphenylphosphine in 36 ml of triethylamine under argon was added 1.74 g (2.5 ml, 17.7 mmol) of trimethylsilylacetylene and 0.027 g (0.12 mmol) of palladium(II) acetate. The mixture was refluxed for 20 hours then cooled to room temperature and filtered. The solvent removed in-vacuo and the resulting residue was purified using flash chromatography (SiO2 ; 5% ethyl acetate in hexanes) to give the title compound as a yellow oil.
Reaction SMILES: [SH2]=N.[CH2:3]([NH:5][C:6](C1C=CC=CC=1C(O)=O)=[O:7])[CH3:4].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>CC(C)=O>[C:18]1([NH:17][C:6]([NH:5][CH2:3][CH3:4])=[O:7])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: CCNC(=O)c1ccccc1C(=O)O
Agent: N=[SH2]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCNC(=O)Nc1ccccc1
Yield: 79 %

Procedure:
5.08 g ethylcarbamoyl-benzoic acid sulfimide was reacted with 1.86 g aniline and 2.8 ml triethylamine in 20 ml of a 1:1 mixture of water and acetone, as described in example 1. 2.59 g 1-phenyl-3-ethylurea was obtained, melting at 99°-100° C.
Reaction SMILES: [NH2:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.[C:8](OC(=O)C)(=[O:10])[CH3:9].CO>O1CCCC1>[C:8]([NH:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nn1nnnc1S
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nn1nnnc1S
Reaction time: 0.33 h
Yield: 82.9 %

Procedure:
1-Amino-5-mercapto-1H-tetrazole (4.18 g) was dissolved in tetrahydrofuran (30 ml), and acetic anhydride (4.01 g) was added thereto. The mixture was refluxed for 6 hours and then condensed under reduced pressure to remove solvent. Methanol (4 ml) was added to the residue thus obtained, and the methanol solution was allowed to stand at room temperature for 20 minutes. The mixture was evaporated to remove solvent. Hot isopropanol was added to the residue thus obtained, and the solution was allowed to stand at room temperature. Crystalline precipitates were collected by filtration. 4.71 g of 1-acetamido-5-mercapto-1H-tetrazole were obtained as colorless needles. mp 147°-148° C. (decomp.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([C:44]#[N:45])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([C:44]#[N:45])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example J31) (256 mg, 0.75 mmol) and 3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K24) (242 mg, 0.75 mmol) according to the general procedure M. Obtained as a colorless solid (249 mg, 53%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[CH2:16][CH2:15][C:6]2=[C:7]([C:12]([OH:14])=O)[S:8][C:9]([S:10][CH3:11])=[C:5]2[CH2:4]1)[CH3:2].[CH3:19][Li]>C(OCC)C>[CH2:17]([C:3]1([CH2:1][CH3:2])[CH2:16][CH2:15][C:6]2=[C:7]([C:12](=[O:14])[CH3:19])[S:8][C:9]([S:10][CH3:11])=[C:5]2[CH2:4]1)[CH3:18]
Reactant: [Li]C
Reactant: CCC1(CC)CCc2c(C(=O)O)sc(SC)c2C1
Solvent: CCOCC
Product: CCC1(CC)CCc2c(C(C)=O)sc(SC)c2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5,5-diethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (669 mg, 2.35 mmol) in diethyl ether (20 mL), a solution of methyllithium (2.6 mL, 1.6 M in diethyl ether) is added at rt. The reaction mixture is stirred at rt for 4 h, diluted with diethyl ether, washed with 1 N aq. K2HPO4 solution followed by 1 N aq. NaOH, dried over Na2SO4 and evaporated to give 1-(5,5-diethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (458 mg) as a yellow oil, LC-MS: tR=1.15 min, [M+1]=283.1; 1H NMR (CDCl3): δ 2.96 (t, J=7.0 Hz, 2H), 2.53 (s, 3H), 2.45 (s, 3H), 2.32 (s, 2H), 1.56 (t, J=7.0 Hz, 2H), 1.35-1.20 (m, 4H), 0.83 (t, J=7.6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])=[CH:5][CH:4]=1.[C:21](Cl)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:21](=[O:23])[CH3:22])[CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16]([CH:18]2[CH2:19][CH2:20]2)=[O:17])=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2cccc(CCNC(=O)C3CC3)c2c1
Product: COc1ccc2cc(C(C)=O)cc(CCNC(=O)C3CC3)c2c1
Yield: 31 %

Procedure:
By working as in Example 1, using N-[2-(7-methoxynaphth-1-yl)ethyl]cyclopropylcarboxamide and acetyl chloride as starting materials, the compound of Example 50 is obtained.
Reaction SMILES: N1C=CC=CC=1.C(OC(=O)C)(=O)C.[C:14]([N:17]1[CH2:21][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:19]([O:28][C@H:29]([C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=2)[CH3:30])[CH2:18]1)(=[O:16])[CH3:15]>C(Cl)Cl>[C:14]([N:17]1[CH2:21][C@H:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:19]([O:28][C@@H:29]([C:31]2[CH:32]=[C:33]([C:41]([F:42])([F:43])[F:44])[CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=2)[CH3:30])[CH2:18]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1C[C@H](O[C@@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccccc2)C1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1C[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 200 mg intermediate step E (0.47 mmol) in 3 mL dry methylene chloride at 0° C. was added 0.097 mL pyridine (1.18 mmol) followed by 0.089 mL acetic anhydride (0.94 mmol). The reaction mixture was stirred for 6 hr at ambient temperature then the volatiles were removed under vacuum. The residue was partitioned between 2N aq. NaOH (5 mL) and methylene chloride (10 mL). The layers were separated and the aqueous layer extracted with methylene chloride (2×5 mL). The combined organic extracts were dried over sodium sulfate, filtered and solvent evaporated under vacuum. The resulting material was purified by preparative TLC eluting with methylene chloride/methanol (9/1). The resulting material was further purified by prep HPLC on Chiralpak AD column eluting with heptanes/ethanol (97/3) to afford a minor faster moving isomer A (3R,4S)-1-acetyl-3-({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-phenylpyrrolidine and the title compound. 1H-NMR (CDCl3) rotamers: δ: 1.45 (t, 3H, 6.5 Hz), 2.15 (2s, 3H) 3.38-3.63 (m, 3H), 3.85-4.03 (m, 3H), 4.58 (m, 1H), 7.1 (m, 2H), 7.25 (m, 3H), 7.61 (s, 2H), 7.78 (s, 1H)ppm. MS: 446 (MH)+ observed.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]([C:19]([OH:21])=[O:20])[CH2:16][C:15]=3[CH:22]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:23](O)[CH3:24]>S(=O)(=O)(O)O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]([C:19]([O:21][CH2:23][CH3:24])=[O:20])[CH2:16][C:15]=3[CH:22]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)Nc1ccc(-c2ccc3c(c2)CC(C(=O)O)O3)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1Cc2cc(-c3ccc(NC(C)=O)cc3)ccc2O1
Reaction time: 4 h

Procedure:
5 drops of concentrated sulfuric acid was added to a mixture of 3.2 g of 7C and 150 ml of ethanol. The mixture was heated under reflux, using a Soxhlet extractor filled with molecular sieve (3A). After 4 hours, the solvent was evaporated under reduced pressure, and the residue was dissolved in chloroform. The solution was washed with saturated sodium bicarbonate solution, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dry column chromatographed over silica gel, using chloroform as eluent. The product was extracted with tetrahydrofuran and the solvent was evaporated under reduced pressure. The residue was stirred in ether. The solid was collected and refluxed in ether. The solid was collected and dried under reduced pressure to give ethyl 5-(4-(acetylamino)phenyl)-2,3-dihydro-2-benzofurancarboxylate (7D), mp: 164°-166° C.