Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Li]CCCC.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:18]([Si:25]([CH3:27])([CH3:26])[CH3:24])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cn1c2c(c3ccc(F)cc31)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cn1c2c(c3ccc(F)cc31)C([Si](C)(C)C)c1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 2 %

Procedure:
Compound 31b (as a 2:1.1 mixture of regioisomers, 1.61 g, 6.79 mmol) was dissolved in anhydrous ether (46 mL) and the reaction mixture was immersed in a 25° C. water bath. n-BuLi (1.5M in hexanes, 5.25 mL, 7.87 mmol) was added dropwise via syringe pump over one hour. Following addition of base, the reaction mixture was stirred for one hour at 25° C. and then cooled to −78° C. TMSCl (1.81 mL, 14.25 mmol) was added rapidly via syringe and the resulting mixture was immediately warmed to 25° C. for 1.5 hours. The reaction mixture was diluted with 20 mL ether, filtered, and concentrated in vacuo to yield a dark green solid which was subsequently purified by multiple rounds of flash column chromatography (15:1 hexanes-ethyl acetate; 20:1 hexanes-ethyl acetate) to give the desired regioisomer in pure form and 2% yield. This low yield is a result of the similar polarities of regioisomers, which render separation a challenge. Spectral data are reported for the mixture that remained following purification of a small percentage of the desired regioisomer. As a result, product ratios do not represent those of the original product mixture. 1H NMR (600 MHz, CDCl3): δ 7.74 (d, 1H, J=7.8 Hz), 7.71 (d, 0.5H, J=7.2 Hz), 7.51-7.55 (m, 2.5H), 7.31-7.34 (m, 1.5H), 7.21-7.24 (td, 1H, J=7.2, 1.2 Hz), 7.18-7.21 (td, 0.5H, J=7.2, 1.2 Hz), 7.17 (d, 1H, J=7.8 Hz), 7.12-7.14 (m, 1H), 7.05-7.07 (dd, 0.5H, J=9.9, 2.4 Hz), 6.87-6.91 (m, 0.5H), 6.80-6.83 (ddd, 1H, J=10.2, 8.4, 1.2 Hz), 4.10 (s, 3H), 4.05 (s, 1.5H), 3.93 (s, 1H), 3.75 (s, 0.5H), −0.04 (s, 4.5H), −0.98 (d, 9H, J=0.6 Hz); 13C NMR (150 MHz, CDCl3): δ 159.3 (d, J=237.0 Hz), 156.0 (d, J=246 Hz), 150.4, 149.6, 144.3 (d, J=10.5 Hz), 143.6 (d, J=3.0 Hz), 143.0, 142.0 (d, J=12.0 Hz), 133.4, 132.7, 125.1, 124.9, 124.6, 124.6, 123.8, 123.52, 123.1, 121.3 (d, J=9.0 Hz), 120.6 (d, J=10.5 Hz), 120.3 (d, J=21.0 Hz), 117.6, 117.3, 113.0 (d, J=21.0 Hz), 107.4 (d, J=24.0 Hz), 105.6, 105.5, 104.4 (d, J=19.5 Hz), 96.2 (d, J=27.0 Hz), 37.3, 36.8, 31.5, 31.3, −2.42, −2.52 (d, J=3.0 Hz); 19F NMR (CD3CD, 376 MHz): δ −117.1 (d, J=6.8 Hz), −120.5-−120.1 (td, J=9.4, 3.8 Hz) FTIR: cm−1 3057, 2953, 1621, 1572, 1436, 1360, 1248, 1048, 839, 756, 727.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]2)[N:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1COCC1.[F:52][C:53]([F:62])([F:61])[C@H:54]1[CH2:59][CH2:58][C@H:57]([NH2:60])[CH2:56][CH2:55]1>O.CN(C=O)C>[F:52][C:53]([F:61])([F:62])[C@H:54]1[CH2:55][CH2:56][C@H:57]([NH:60][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:3]([NH:2][CH3:1])=[N:4][C:5]=2[N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:23])([F:24])[F:22])[CH2:17][CH2:16]2)[CH2:58][CH2:59]1
Reactant: N[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CNc1nc(N2CCC(C(F)(F)F)CC2)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNc1nc(N2CCC(C(F)(F)F)CC2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
A mixture of 6-methylamino-5-nitro-2-(4-trifluoromethyl-piperidinyl)-nicotinic acid (570 mg, 1.64 mmol), TBTU (540 mg, 1.68 mmol), TEA (1.00 mL, 7.2 mmol), THF (10 mL) and DMF (5 mL) are stirred for 5 min. Then trans-4-trifluoromethyl-cyclohexylamine (335 mg, 1.65 mmol) is added and it is stirred for 30 min. Water is added, the mixture is concentrated and the precipitate is filtered, washed with water and dried at 55° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].C(=O)=O.CC(C)=O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:15]([C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccsc1C
Reactant: BrCc1ccccc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1cc(Cc2ccccc2)sc1C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 77.1 %

Procedure:
At -78° C., to a stirred solution of 2,3-dimethylthiophene (5.00 g, 44.6 mmol) in THF (89.3 mL) was added dropwise 2.5M BuLi/hexanes (17.9 mL, 44.6 mmol). After the addition was complete, the dry ice/acetone bath was replaced with a water ice bath and the reaction was stirred for 0.75 h. At -78° C., to the reaction was added a solution of benzyl bromide (5.30 mL, 44.6 mmol) in THF (44.6 mL) that had been previously cooled to -78° C. After the addition was complete, the reaction was stirred for 18 h eventually warming to ambient temerature. The reaction was filtered through a silica gel pad eluting with 1% EtOAc/pet ether and the filtrate was concentrated. Purification on Biotage KP-Sil eluting with 1% EtOAc/pet ether gave 6.960 g (77%) of the title compound as an oil. 1H NMR (DMSO-d6) δ 2.01 (s, 3 H), 2.21 (s, 3 H), 3.98 (s, 2 H), 6.58 (s, 1 H), 7.18-7.37 (m, 5 H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.P(Br)(Br)[Br:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:27][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1
Reactant: O=c1cc(CCc2ccccc2)ccn1CCc1ccc(CO)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(CCc2ccccc2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 150 mg (0.45 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-phenethyl-1H-pyridin-2-one (example 18.1a) in 2.0 mL of DCM is added at 0° C. 21 μL (0.23 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and is then added to aqueous 5% NaHCO3-solution. The layers are separated, the aqueous phase is extracted with DCM. The combined organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:5]=2[S:6][C:7]=1[C:8](O)=O.COC1C2C=CC=CC=2SC=1C[C:27]([O:29][CH3:30])=[O:28]>>[CH3:1][O:2][C:3]1[C:4]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:5]=2[S:6][C:7]=1[CH2:8][C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)Cc1sc2ccccc2c1OC
Reactant: COc1c(C(=O)O)sc2ccc(C(F)(F)F)cc12
Product: COC(=O)Cc1sc2ccc(C(F)(F)F)cc2c1OC

Procedure:
When 3-methoxy-5-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid was used in place of the starting benzthiophene of Example C-1, and carried through the same sequence of reactions, methyl 3-methoxy-5-(trifluoromethyl)benzo[b]thiophene-2-acetate is obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][C:2]1=[O:10].C1([NH:17][C:18](=O)[O-:19])C=CC=CC=1.[H-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[OH:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]=1[C:18]([NH2:17])=[O:19]
Reactant: O=C([O-])Nc1ccccc1
Reactant: O=C1Cc2ccccc2S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: NC(=O)c1c(O)sc2ccccc12

Procedure:
To a stirred mixture of benzthiophene-2-one (1.50 g, 0.01 m), phenylcarbamate (1.4 g, 0.01 m), and hexamethylphosphorictriamide (2.2 ml) at 5° C. is added sodium hydride (0.24 g, from 0.4 g 60% mineral oil dispersion), and the resultant mixture stirred at ambient temperatures for 5 hours. The volatiles are removed under high vacuum, and the residue triturated well with hexane and then with water to yield 2-hydroxybenzo(b)thiophene-3-carboxamide.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:30])[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[H-].[Na+].[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]=[O:41])[C:35]=1[NH:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45]>O1CCCC1>[F:33][C:34]1[C:35]([NH:42][C:43](=[O:48])[C:44]([CH3:46])([CH3:45])[CH3:47])=[C:36]([CH:40]([OH:41])[CH:16]([CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]2)[C:15]([O:14][CH3:13])=[O:30])[CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)C(=O)Nc1c(F)cccc1C=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cccc(F)c1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
Diisopropylamine (3.40 mL, 24.2 mmol) was dissolved in tetrahydrofuran (70 mL). The mixture was cooled to −78° C. Butyllithium (2 M in cyclohexane, 12.2 μL, 24.4 mmol) was added dropwise to the reaction. The mixture was held at −78° C. with stirring and held for 20 minutes. A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (5.20 g, 20.2 mmol) in tetrahydrofuran (15 mL) was added to the mixture dropwise. The mixture was held at −78° C. with stirring and held for 45 min. In a separate flask, sodium hydride (60% in mineral oil, 970 mg, 24.3 mmol) was washed with hexanes then suspended in tetrahydrofuran (50 mL). The mixture was cooled to 0° C. A solution of N-(2-Fluoro-6-formylphenyl)pivalamide (4.50 g, 20.2 mmol) in tetrahydrofuran (20 mL) was added to the mixture dropwise. The mixture was held at 0° C. with stirring and held for 1 h. The above prepared aldehyde mixture was added to the ester mixture dropwise over 1.25 h. The mixture was held at −78° C. with stirring and held for 1 h. The reaction was quenched with aqueous ammonium chloride, warmed to room temperature, and diluted with water. The mixture was extracted ethyl acetate (2×) and the aqueous phase was discarded. The material was dried (magnesium sulfate), filtered, and concentrated to dryness. Silica gel chromatography gave the title compound as white foam in 81% yield. Mass spec.: 381.2 (M-C4H8O2+H)+.
Reaction SMILES: CN(P(N(C)C)N(C)C)C.[CH3:11][O:12][CH:13]([O:22][CH3:23])[CH2:14][C@@H:15]1[C:17]([CH3:19])([CH3:18])[C@@H:16]1[CH:20]=O.[C:24](Cl)(Cl)([Cl:26])[Cl:25].O>CCCCC>[CH3:11][O:12][CH:13]([O:22][CH3:23])[CH2:14][C@H:15]1[C:17]([CH3:19])([CH3:18])[C@H:16]1[CH:20]=[C:24]([Cl:26])[Cl:25]
Reactant: COC(C[C@H]1[C@@H](C=O)C1(C)C)OC
Reactant: ClC(Cl)(Cl)Cl
Agent: CN(C)P(N(C)C)N(C)C
Solvent: CCCCC
Solvent: O
Product: COC(C[C@@H]1[C@H](C=C(Cl)Cl)C1(C)C)OC
Temperature: 14 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
Tri(dimethylamino)phosphine (163.2 mmol) was added with stirring at 0° C. to a solution of (1R,cis)-2-(2,2-dimethoxyethyl)-3,3-dimethylcyclopropanecarbaldehyde (65.5 mmol) and carbon tetrachloride (163.2 mmol) in n-pentane (350 ml) kept under nitrogen in a 1-l flask. After 15 minutes stirring, the mixture was warmed up to 14° C. and kept at this temperature for 15 minutes. Then, water (75 ml) was added at 14° C. and--after removal of the aqueous phase--the organic phase was washed with two 35-ml portions of water. The washed organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried solution to give a residue (15.7 g) containing 32.1 mmol of 2-[2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropyl]ethanal dimethyl acetal (100% (1R,cis), purity 51.7%, yield 49%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([C:26]([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]C)=[O:23])[CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([C:26]([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2cccc(C(=O)OC)c2)C(=O)Nc2ccc3ccccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)C(Cc2cccc(C(=O)O)c2)C(=O)Nc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of 2-[(1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(3-(methoxycarbonyl)phenyl)ethyl)carbonyl]aminonaphthalene (110 mg, 0.2 mmol) in THF (8 mL) was added a solution of LiOH (27 mg, 0.6 mmol) in water (6 mL). The reaction mixture was stirred at ambient temperature. After 5 hours, the reaction mixture was acidified to pH 2-3 by 2N NaHSO4,then extracted with ethyl acetate (3×10 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo to afford 2-[(1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(3-carboxyphenyl)ethyl)carbonyl]aminonaphthalene (90 mg, 0.18 mmol); NMR (DMSO-d6) 1.25 (t, 3), 3.10-3.30 (m, 6), 3.40-3.60 (m, 4), 3.97 (q, 2), 4.14 (t, 1), 7.35-7.55 (m, 5), 7.70-7.87 (m, 5), 8.14 (s, 1), 10.12 (s, 1) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH:8]=O)=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH2:21][NH2:22].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH2:8][NH:22][CH2:21][C:14]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=2[O:12][CH3:11])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C=O
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CNCc2ncc(Br)cc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 5-bromo-3-methylpicolinaldehyde 81-1 (1.0 g, 5 mmol), (2,4-dimethoxyphenyl)methanamine 81-2 (0.83 g, 5 mmol), acetic acid (0.9 g, 15 mmol) in DMF (10 mL) was added Na(OAc)3BH (2.46 g, 15 mmol) at room temperature. The reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with aqueous Na2CO3 and brine. The organic phase was dried to give crude 1-(5-bromo-3-methylpyridin-2-yl)-N-(2,4-dimethoxybenzyl)methanamine 81-3. MS m/z 351.2 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[N:7]([CH3:25])[N:6]=1)=[O:4].C[O:27][C:28]([C:30]1[CH:34]=C(OCC2C(C3C=CC=CN=3)=NOC=2C)N(C)[N:31]=1)=O>>[OH:27][CH2:28][C@@H:30]([NH:31][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[N:7]([CH3:25])[N:6]=1)=[O:4])[CH3:34]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)n(C)n1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n(C)n1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)N[C@@H](C)CO)nn1C
Yield: 59 %

Procedure:
As described for example 114d, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.29 mmol), instead of 1-methyl-5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-1H-pyrazole-3-carboxylic acid methyl ester, was converted, to the title compound (66 mg, 59%) which was obtained as a colorless oil. MS: m/e=390.1 [M+H]+.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][CH:27]=4)=[CH:22][C:21]3=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)=[CH:22][C:21]2=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc3ccccc23)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc3ccccc23)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A solution of (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.43 g, 0.83 mmol) in methanol (8.38 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (24 mg, 0.12 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2.5-4% methanol/dichloromethane) afforded (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.32 g, 80%) as an off-white solid: HR-ES-MS m/z calculated for C26H30N4O5 [M+H]+ 479.2289, observed 479.2287; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.3 Hz, 3H), 0.96 (d, J=6.3 Hz, 3H), 1.43-1.67 (m, 2H), 1.71-1.84 (m, 1H), 3.20-3.32 (m, 2H), 3.70-3.82 (m, 1H), 3.87 (dd, J=13.5, 7.5 Hz, 1H), 4.09 (dd, J=13.5, 3.8 Hz, 1H), 4.39 (d, J=18.1 Hz, 1H), 4.66-4.77 (m, 3H), 4.89 (dd, J=10.4, 5.0 Hz, 1H), 4.95 (d, J=5.4 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.48-7.66 (m, 5H), 7.91 (d, J=8.2 Hz, 1H), 7.99-8.09 (m, 2H), 10.77 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[S:7]([CH3:18])([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)=[O:8])=[O:5])[CH3:2].[OH-].[Na+].O.C(OCC)(=O)C>C1COCC1.Cl>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:7]([CH3:18])(=[N:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:8])=[CH:10][CH:11]=1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of 8.70 g (32.0 mmol) (RS)—N-(ethoxycarbonyl)-S-methyl-S-(4-nitro-phenyl)sulfoximide in 650 ml THF is slowly treated at room temperature with 435 ml of a 10% solution of Ti(III)Cl in approximately 10% hydrochloric acid (Aldrich). The mixture is stirred at room temperature for 4 hours and then cooled to 0° C. 450 ml of a 32% NaOH solution are added dropwise. During this, the reaction mixture is periodically diluted by the addition of water and ethyl acetate. It is treated with 500 ml ethyl acetate and the organic phase is separated. The mushy aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with dilute NaCl solution, dried (Na2SO4), filtered and concentrated. 8.05 g (ca. 32.0 mmol) of the product is obtained, which is used without further purification.
Reaction SMILES: C(N=C(SC)SC)#N.CC1[CH:14]=[C:13]([CH2:15][N:16](C)C)OC=1CSCCN.[C:24]([NH:26][C:27](=[N:30][CH2:31][CH2:32][S:33][CH2:34][C:35]1[O:36][C:37]([CH2:41][N:42]([CH3:44])[CH3:43])=[CH:38][C:39]=1[CH3:40])SC)#[N:25].C(N)C#C>>[C:24]([NH:26][C:27]([NH:16][CH2:15][C:13]#[CH:14])=[N:30][CH2:31][CH2:32][S:33][CH2:34][C:35]1[O:36][C:37]([CH2:41][N:42]([CH3:44])[CH3:43])=[CH:38][C:39]=1[CH3:40])#[N:25]
Reactant: Cc1cc(CN(C)C)oc1CSCCN
Reactant: CSC(=NCCSCc1oc(CN(C)C)cc1C)NC#N
Agent: C#CCN
Agent: CSC(=NC#N)SC
Product: C#CCNC(=NCCSCc1oc(CN(C)C)cc1C)NC#N

Procedure:
When an alcohol solution of dimethyl cyanodithioimidocarbonate is reacted with 2-[(3-methyl-5-dimethylaminomethyl-2-furyl)methylthio]ethylamine, and the resultant N-cyano-N'-{2-[(3-methyl-5-dimethylaminomethyl-2-furyl)methylthio]ethyl}-S-methylisothiourea is treated with propargylamine according to the general procedure of Example 3, the title compound is produced.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH3:15])=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#N.[OH-:16].[K+].[OH2:18]>>[CH3:1][C:2]1[C:3]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH3:15])=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]([OH:18])=[O:16]
Reactant: [OH-]
Reactant: O
Reactant: Cc1cc(C#N)cnc1N1CCCC1C
Agent: [K+]
Product: Cc1cc(C(=O)O)cnc1N1CCCC1C

Procedure:
A solution of 5-methyl-6-(2-methylpyrrolidin-1-yl)nicotinonitrile obtained in step 1 (591 mg; 2.94 mmol) in water (15 mL) and KOH (823 mg; 14.68 mmol) was heated at reflux for 16 hours. Reaction mixture was basified to pH 6 and extracted with EtOAc to give the title compound as a white solid. 1H NMR (DMSO-d6) δ 12.43 (s, 1H), 8.48 (d, J=2.2 Hz, 1H), 7.74-7.73 (m, 1H), 4.41-4.32 (m, 1H), 3.81-3.73 (m, 1H), 3.49-3.42 (m, 1H), 2.29 (s, 3H), 2.10-2.04 (m, 1H), 1.94-1.88 (m, 1H), 1.74-1.68 (m, 1H), 1.59-1.52 (m, 1H), 1.25 (d, J=6 Hz, 3H). HPLC (Method A) Rt 1.45 min (Purity: 99.8%). LC/MS (Method B): 221.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].[CH:18](OCC)=[O:19]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[N:10]([CH:18]=[O:19])[CH3:11]
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Reactant: CCOC=O
Product: Cc1ccsc1C(Cc1ccccc1N)N(C)C=O

Procedure:
A stirred solution of 5.00 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 235 ml of ethyl formate was refluxed for 8 hours. Volatile components were removed at 60° C. on a rotary evaporator. Thin layer chromatography (silica gel, ethyl acetate as the eluent) of the resultant oil indicated a multi-component mixture. HPLC of the mixture (Water's Associates Prep LC/System 500, silica gel, elution with ethyl acetate) permitted component separation. The faster eluting fractions were concentrated to an oil which crystallized upon standing. Recrystallization from methanol-water afforded 1.2 g of 2-amino-N-formyl-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, mp 111°-112° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1.Cl[CH:14]([NH:20][OH:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C1COCC1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[O:21][N:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(Cl)NO
Reactant: C=Cc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1=NOC(c2ccc(C(F)(F)F)cc2)C1
Reaction time: 8 h

Procedure:
To a mixture of 1-(trifluoromethyl)-4-vinylbenzene (2.0 g, 11.27 mmol), a compound of formula (20) and ethyl 2-chloro-2-(hydroxyamino)acetate (2.11 g, 13.52 mmol), a compound of formula (21), in anhydrous THF was added a solution of triethylamine (3.0 ml) in tetrahydrofuran was added dropwise at room temperature. The mixture was stirred overnight under N2. The white precipitate thus formed was filtered off, and washed twice with tetrahydrofuran (10 ml). The solvent was removed from the filtrate under reduced pressure, and the residue partitioned between water/ethyl acetate (20 ml:20 ml v/v), extracting three times with 20 ml of ethyl acetate. The combined organic layers were washed with aqueous ammonium chloride, and dried over MgSO4, to provide ethyl 5-[4-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-3-carboxylate, a compound of formula (22).