Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[B:11]([OH:13])[OH:12])=O.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].Cl>O.CCOC(C)=O>[N+:14]([CH:17]([CH:3]1[O:13][B:11]([OH:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]1=2)[CH3:18])([O-:16])=[O:15]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C1OB(O)c2ccccc21)[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
A solution of NaOH (1.6 g, 41 mmol) in H2O (20 mL) was added to 2-formyl phenylboronic acid (5.1 g, 34 mmol) at rt. The mixture was stirred for 15 min then nitroethane (2.9 mL, 41 mmol) was added dropwise. The mixture was stirred for 30 min and then the clear reaction solution was acidified with 2 N HCl and EtOAc was added. The organic layer was separated, washed with H2O then brine, dried (Na2SO4), and concentrated in vacuo. Purification by flash chromatography (2:1 hexane/EtOAc) gave the title compound as a colorless oil: yield 6.72 g (quantitative).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])=O)(C)(C)C>ClCCl>[N:15]1([C:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCCC1
Solvent: ClCCl
Product: O=C([C@@H]1CCCN1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 132.1 %

Procedure:
(S)-2-(Pyrrolidin-1-ylcarbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (5.90 g, 22 mmol) was dissolved in dichloromethane (50 ml) Trifluoroacetic acid (30 ml) was added. The reaction mixture was stirred for 50 min at room temperature. The solvent was removed in vacuo. The residue was dissolved in a saturated aqueous solution of potassium carbonate (200 ml). It was extracted with dichloromethane (3×100 ml). The aqueous phase was saturated with sodium chloride and extracted with dichloromethane (3×200 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo to give 4.89 g of the crude (pyrrolidin-1-yl)-((S)-pyrrolidin-2-yl)methanone, which was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=2)[CH2:16][CH2:15]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1C[C@@H]1C1CCN(c2ccc(CO)cn2)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COCc1ccc(N2CCC([C@H]3C[C@H]3CCO[Si](C)(C)C(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the (6-{4-[(1R,2S)-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyridin-3-yl)methanol (0.3 g, 0.768 mmol) in THF (1.920 ml) was cooled at ice-bath temperature. A solution of NaHMDS (0.922 ml, 0.922 mmol) was added followed by addition of methyl iodide (0.067 ml, 1.075 mmol). The bath was removed and the resulting mixture stirred at room temperature for 2 hours. The mixture was diluted with 1N NaOH (50 ml), extracted with EtOAc (3×30 ml), the organic fractions combined, washed with brine, dried over sodium sulfate, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel, Biotage 25 g, using a gradient eluant of 0-30% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 405 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)/C=C(\C)c1ccc(I)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
The colourless solid (E)-ethyl 3-(4′-fluoro-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91a) and 4-fluorobenzene boronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:42])[CH2:38][CH2:39][CH:40]=[CH2:41]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:42])[CH2:38][CH2:39][CH:40]=[CH2:41]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: C=CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 100 mg (1 mmole) of 4-pentenoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 155 mg (Yield: 42%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])=[O:9]
Reactant: COc1ccc(-c2ccccc2)cc1N
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: COc1ccc(-c2ccccc2)cc1NC(=O)c1cc(Cl)ccc1O
Yield: 37 %

Procedure:
Using 5-chlorosalicylic acid and 3-amino-4-methoxybiphenyl as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [NH2:1]/[C:2](=[C:5](\[N:8]=[CH:9][O:10][CH3:11])/[C:6]#[N:7])/[C:3]#[N:4].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(#N)C>[CH3:11][O:10][C:9]1[NH:8][C:5]([C:6]#[N:7])=[C:2]([C:3]#[N:4])[N:1]=1
Reactant: COC=N/C(C#N)=C(\N)C#N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Product: COc1nc(C#N)c(C#N)[nH]1

Procedure:
A solution of the above 2-amino-3-(methoxymethylenamino) maleonitrile (20 g; 0. 11 mol) and 2,3-dichloro-5,6-dicyanobenzoquinone (25.5 g; 0.11 mol) in acetonitrile (750 mL) was heated at reflux for 4 days. Silica gel (100 g) was added and the acetonitrile was removed in vacuo. The silica gel was extracted with dichloromethane. The dichloromethane solution was concentrated to dryness in vacuo, the yellow residue was suspended in dichloromethane (150 mL) and the mixture was stirred. The mixture was filtered and the filtrate was concentrated in vacuo to yield a light yellow solid that was crystallized from water to give 2-methoxy-4,5-imidazoledicarbonitrile (mp 137°-138° C.).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([CH:25]([CH3:27])[CH3:26])=[N:23][CH:24]=[C:18]2[CH:17]1[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)Cl.C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([CH:25]([CH3:27])[CH3:26])=[N:23][C:24]([Cl:1])=[C:18]2[CH:17]1[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=1)=[O:15])([CH3:11])([CH3:12])[CH3:10]
Reactant: CC(C)c1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 70 °C

Procedure:
To a solution of N-chlorosuccinimide (87.3 mg; 0.628 mmol) in chloroform (1 ml) was added a solution of 3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (229 mg; 0.523 mmol) in chloroform (2 ml) and the resulting solution was heated to 70° C. for 5 h30. The reaction mixture was allowed to cool to rt, diluted with DCM (20 ml) and washed with water (3×10 ml). The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC gave the pure product 1-chloro-3-isopropyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (97 mg; 39%). LC-MS: tR=1.04 min.; [M+H]+=472.51 g/mol.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[O:15])[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CCOC(C)=O>[CH2:8]([C:9]1[CH:10]=[C:11]([CH:14]=[O:15])[S:12][CH:13]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc(C#Cc2ccccc2)cs1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=Cc1cc(CCc2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Under a N2 atmosphere, 4-(phenylethynyl)thiophene-2-carbaldehyde (386 mg, 1.8 mmol) was dissolved EtOAc (6 mL), and palladium on carbon (Pd/C) (44 mg) was added. The flask was evacuated and flushed with H2 (3×). The reaction stirred at rt overnight with a balloon of H2. The mixture was filtered through a plug of Celite® and the filtrate was concentrated to give 4-phenethylthiophene-2-carbaldehyde (373 mg, 95%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.87 (d, 1H), 7.56 (d, 1H), 7.33 (m, 1H), 7.29 (m, 2H), 7.23 (m, 1H), 7.16 (m, 2H), 2.97 (m, 4H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][O:8][C:9](=[O:41])[CH2:10][C@H:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][C@H:21]3[C:29]4[C:24](=[C:25]([CH2:34][N:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)[C:26]([C:30]([F:33])([F:32])[F:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)=[CH:19][C:14]=2[O:13][CH2:12]1>>[CH3:7][O:8][C:9](=[O:41])[CH2:10][C@H:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][C@H:21]3[C:29]4[C:24](=[C:25]([CH2:34][N:35]5[CH2:36][CH2:37][N:38]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:39][CH2:40]5)[C:26]([C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCNCC3)ccc21
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCN(Cc2c(C(F)(F)F)ccc3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)OC)CC1

Procedure:
The title compound is prepared from ethyl chloroformate and {(S)-6-[(R)-4-piperazin-1-ylmethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Intermediate 27. LC (method 4): tR=1.02 min; Mass spectrum (ESI+): m/z=563 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][O:38][N:39]([CH3:49])[C:40](=[O:48])[CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][C:40]([N:39]([O:38][CH3:37])[CH3:49])=[O:48])[CH2:47][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)OC)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-methoxy-N-methyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 16b) in an analogous manner as described in example 25. LR-MS: 691.3 [(M+H)+]
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[CH2:28]([O:30][CH2:31][C:32](O)=[O:33])[CH3:29]>>[CH2:28]([O:30][CH2:31][C:32]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:8]3[C:7]4[CH:6]=[CH:5][O:4][C:12]=4[CH:11]=[CH:10][N:9]=3)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1)=[O:33])[CH3:29]
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Reactant: CCOCC(=O)O
Agent: Cl
Product: CCOCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1

Procedure:
The title compound, white crystals (86 mg, 60%), MS (ISP) m/z=415.3 [(M+H)+], was prepared in analogy to example 4 starting from trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate A) (150 mg, 0.34 mmol) and ethoxyacetic acid (43 mg, 0.41 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH3:21])[CH:5]=[CH:6][CH:7]=1.[C:40](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:40][O:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[CH3:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(O)c3)c(=O)c12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(-n2c(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)nc3cccc(C)c3c2=O)c1
Reaction time: 0.08 h
Yield: 82 %

Procedure:
A 100-mL, one-neck, round bottomed flask equipped with a magnetic stirrer was charged with compound 126 (370 mg, 0.68 mmol), potassium carbonate (235 mg, 1.70 mmol), and DMF (4 mL). The resulting mixture was stirred for 5 min, and methyl iodide (435 mg, 3.10 mmol) was then added. After stirring for a further 1 h at ambient temperature, the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give an 82% yield of compound 127 as a light yellow oil. 1H NMR (CD3OD) δ (ppm) 8.20 (m, 2H), 6.99-7.66 (m, 7H), 5.58 (s, 2H), 5.15 (bs, 1H), 3.62 (dt, 2H, J=1.8, 8.0 Hz), 3.32 (s, 3H), 2.78 (s, 3H), 1.55 (m, 3H), 0.88 (m, 2H), −0.07 (s 9H); m/z=558 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](=O)[CH3:17])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:19]=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:8]([C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:16]=1[CH3:17])=[O:28])[CH3:12]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc([N+](=O)[O-])cc2)c1C
Temperature: 2.5 °C

Procedure:
p-Nitroaniline (5 mmol, 0.7 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.25 g), and tosic acid were combined in ethanol, then heated under reflux. The reaction mixture was cooled on ice (0-5° C.), and the precipitate filtered from the reaction mixture. 1H-NMR analysis confirmed that the precipitate was the named product, (CDCl3, ppm); 1.38 t (3H), 2.45 s (3H), 4.20 q (2H), 6.80 s (1H), 6.97-7.35 bm (7H), 8.25 d (2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[CH3:27][N:28]=[C:29]=[O:30]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29]([NH:28][CH3:27])=[O:30])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN=C=O
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(N)cc1OCC2)c1ccccc1Cl
Product: CNC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following the procedures of Example 76, 8-amino-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide and methyl isocyanate gave 167. MS: (ESI+) 442.1
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=1.CCN(CC)CC>C(#N)C>[CH3:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:17]([F:18])([F:20])[F:19])[CH:9]=2)[CH2:3]1
Reactant: C[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1CCN(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of (R)-3-methylpyrrolidine (1.000 g, 8.226 mmol), 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (1.72 g, 8.226 mmol) and Et3N (2.080 g, 2.865 mL, 20.56 mmol) in ACN was heated at 80° C. for 5 hours. The reaction was cooled to RT, quenched with water, the layers separated and the aqueous layer was extracted with DCM. The combined organic layer was washed with 1M HCl to remove the unreacted amine. The organic layer was dried over Na2SO4, filtered and concentrated to give (S)-3-methyl-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (1.97 g, 7.184 mmol) MS 275.0 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[O:18]1[C:22]2[CH:23]=[C:24](O)[CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][C:24]2[CH:25]=[CH:26][C:21]3[CH2:20][CH2:19][O:18][C:22]=3[CH:23]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Oc1ccc2c(c1)OCC2
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc3c(c2)OCC3)CN1C(=O)OC(C)(C)C
Yield: 41.6 %

Procedure:
The title compound was prepared from (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl-ester 2-methyl ester and 2,3-dihydro-benzofuran-6-ol by the method of Preparation 14 in 41.6% yield as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].[CH2:11]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]=[CH:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl>C(OCC)C>[OH:22][C:19]1([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH2:20][CH2:21][CH:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:17]=[CH:18]1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CCCCCC1C=CC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC1C=CC(O)(c2cc(F)cc(F)c2)CC1

Procedure:
A solution of 30.1 g of 3,5-difluorobromobenzene in 90 ml of anhydrous diethyl ether was added dropwise under stirring at 15°-20° C. to 4.5 g of magnesium metal powder, followed by reaction at room temperature for one hour so that 3,5-difluoromagnesium bromobenzene (a Grignard reagent) was formed. After 20 g of 4-pentylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was gradually added dropwise to the reaction mixture, followed by extraction with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The resultant mixture was filtered and the solvent was distilled off from the filtrate under reduced pressure, whereby 1-(1-hydroxy-4-pentylcyclohexenyl)-3,5-difluorobenzene was obtained as a crude reaction product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[CH:15][C:10]=2[N:9]=[CH:8]1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(C5CCN(C(=O)OC(C)(C)C)CC5)ccc43)cc2OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C5CCNCC5)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
To a stirred and cooled (5° C.) solution of tert-butyl 4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (0.28 g, 0.51 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was allowed to warm room temperature and stir. After 2 h, the mixture was treated with 1 N sodium hydroxide solution to achieve a pH −10 and was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over sodium sulfate, concentrated. The residue was purified by prep-HPLC to afford 0.018 g (8%) of the product as a white solid: 1H NMR (500 MHz, MeOD-d4) δ 8.25 (s, 1H), 8.16 (d, J=2.5 Hz, 1H), 7.76 (dd, J=8.5, 2.5 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.20 (dd, J=8.5, 1.0 Hz, 1H), 7.00-6.97 (m, 2H), 6.82-6.79 (m, 2H), 5.41 (s, 2H), 5.01 (s, 2H), 3.91 (s, 3H), 3.79 (s, 3H), 3.24-3.21 (m, 2H), 2.86-2.81 (m, 3H), 1.93-1.90 (m, 2H), 1.78-1.75 (m, 2H) ppm; (M+1)=459.
Reaction SMILES: [Na:1].[C:2]([C:5]1([O:11][CH2:10]1)[CH2:6][C:7]([O-:9])=[O:8])(=[O:4])[NH2:3].[C-:12]#[N:13].[Na+]>>[Na:1].[C:2]([C:5]([OH:11])([CH2:10][C:12]#[N:13])[CH2:6][C:7]([O-:9])=[O:8])(=[O:4])[NH2:3]
Reactant: [C-]#N
Reactant: NC(=O)C1(CC(=O)[O-])CO1
Agent: [Na+]
Agent: [Na]
Product: N#CCC(O)(CC(=O)[O-])C(N)=O
Reaction time: 4 h

Procedure:
To this solution of sodium-3-carbamoyl-3,4-epoxybutyrate was added a 5 molal aqueous solution of NaCN in proportions of 3 mols per mol of sodium-3-carbamoyl-3,4-epoxybutyrate. The system was agitated for about 4 hours at 35°-40°C. The yield to sodium-3-carbamoyl-3-hydroxy-4-cyanobutyrate was virtually quantitative as determined by NMR.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=[O:4].S(Cl)([Cl:21])=O>C(Cl)Cl>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([Cl:21])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
A mixture of Z-L-Pro-OH E-1 (10.0 g, 40.1 mmol, 1 equiv.) and thionyl chloride (30 mL, 401.2 mmol, 10 equiv.) in DCM (200 mL) is heated to reflux under nitrogen for 20 minutes and concentrated in vacuo. The residual oil is coevaporated with toluene 3×, and concentrated to give Z-L-Pro-Cl as an opaque oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1)(=[O:24])=[O:23]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: COC(=O)Cc1nc(N)sc1C
Product: COC(=O)Cc1nc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)sc1C

Procedure:
The title compound was prepared from methyl 2-(2-amino-5-methyl-1,3-thiazol-4-yl)acetate and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (27.2 mg) with purity >80%. MS (pos) m/z 409.0, 411.0.