Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O.[C:10](O)(=[O:12])[CH3:11]>Br>[OH:2][C:1]1[CH:8]=[CH:7][C:6]([C:10](=[O:12])[CH3:11])=[C:4]([OH:5])[CH:3]=1
Reactant: CC(=O)O
Reactant: Oc1cccc(O)c1
Agent: Br
Solvent: O
Product: CC(=O)c1ccc(O)cc1O
Temperature: 80 °C
Yield: 53 %

Procedure:
Resorcinol (0.55 g, 5.0 mmol) was dissolved in 5% hydrobromic acid in glacial acetic acid (155 ml, made by bubbling hydrogen bromide gas through glacial acetic acid). The reaction mixture was heated to 80° C. for 4.5 hours. The reaction solution was cooled to room temperature, added to water (500 ml) and the aqueous solution was extracted with ether (500 ml, 2X). The ether phases combined and washed with brine (100 ml), dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The residue was recrystallized from an ether/hexane mixture to give 0.40 g, 53% of the title product:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([F:13])[CH:5]=1.C(Cl)(=O)C([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:18])=[O:9])=[C:6]([F:13])[CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)O)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Cl)c(F)c1

Procedure:
2-Fluoro-terephthalic acid 4-methyl ester (J. Med. Chem., 52(19), 5950-5966; 2009) (500 mg, 2.25 mmol) was suspended in DCM (10 ml). Then oxalyl chloride (5.08 ml, 58.0 mmol) and a drop of DMF were added. The resulting mixture was refluxed for 14 hrs. The solvents were removed in vacuo, and the resulting crude Intermediate 33 was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18]C)=O)[CH2:5]1.[NH2:20][NH2:21].O>CO>[NH:20]([C:16]([C@@H:6]1[CH2:5][C:4](=[N:3][O:2][CH3:1])[CH2:8][N:7]1[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[O:18])[NH2:21]
Reactant: NN
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Solvent: CO
Solvent: O
Product: CON=C1C[C@@H](C(=O)NN)N(C(=O)OC(C)(C)C)C1
Reaction time: 48 h

Procedure:
1-tert-butyl 2-methyl (2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate (1.95 mmoles; 530 mg) was dissolved in 4 mL of MeOH and a solution of 4 mL of MeOH and 1.5 mL (d=1.03; 30.86 mmoles) of 80% hydrazine.hydrate was added (final c(NH2NH2)=13%). The reaction mixture was agitated for 2 days. Solvents were evaporated in vacuo and the residue re-dissolved in MeOH and evaporated (3×). The desired compound, tert-butyl (2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate, was isolated as a yellow oil (500 mg; 94%).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH:10]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11]1>C(#N)C>[CH:10]1([NH:13][C:14]([N:6]2[CH2:7][CH2:8][C:9]3[NH:1][CH:2]=[N:3][C:4]=3[CH2:5]2)=[S:15])[CH2:12][CH2:11]1
Reactant: S=C=NC1CC1
Reactant: c1nc2c([nH]1)CCNC2
Solvent: CC#N
Product: S=C(NC1CC1)N1CCc2[nH]cnc2C1
Yield: 32 %

Procedure:
A solution of 2.462 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 2.97 g of cyclopropyl isothiocyanate in 20 ml of acetonitrile is refluxed for 7 h. After evaporation to dryness, the residue is chromatographed on silica gel (ethyl acetateethanol as eluant) to give 1.42 g of the pure title compound, m.p. 185°.
Reaction SMILES: [CH2:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.C1COCC1.C([Li:23])CCC>CCCCCC>[CH:10]1([Li:23])[C:11]2[CH2:12][C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)CC1=C2CCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]C1CCCC2=C1Cc1ccccc12
Temperature: -78 °C

Procedure:
5.3 g (31.1 mmol) of the 1,2,3,4-tetrahydrofluorene (4HFluH) obtained in the item (C) of Example 1 was placed in a 500 mL four-neck flask, to which 100 mL of THF was added under a nitrogen atmosphere. 13 mL (2.6 mol/L) of a hexane solution of n-butyllithium was slowly added dropwise to the solution under stirring at −78° C., followed by stirring at room temperature for 2 hours. Thereafter, a precipitate was collected by filtering, and the solid matter was rinsed with hexane and dried to provide 4.4 g of 1,2,3,4-tetrahydrofluorenyllithium (4HFluHLi).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[O:35][CH3:36])=[CH:24][CH:23]=2)\[CH3:21])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>>[Cl:34][C:32]1[CH:31]=[CH:30][C:29]([O:35][CH3:36])=[C:28]([C:25]2[CH:26]=[CH:27][C:22](/[C:20](/[CH3:21])=[CH:19]/[CH2:18][O:17][C:14]3[CH:15]=[CH:16][C:11]([CH2:10][C@H:4]([O:3][CH2:1][CH3:2])[C:5]([OH:7])=[O:6])=[CH:12][CH:13]=3)=[CH:23][CH:24]=2)[CH:33]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Cl)ccc3OC)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Cl)ccc3OC)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (E)-(S)-ethyl 2-ethoxy-3-{4-[3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}propionate (example 56) (0.47 g, 0.92 mmol) and sodium hydroxide (1M, 1.8 ml, 1.8 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid as a colourless gum, which contained 0.2 mol equivalents of ethyl acetate; 0.43 g (98%).
Reaction SMILES: [BH4-].[Na+].[C:3]([CH2:7][C:8]([CH2:10][C:11]([F:14])([F:13])[F:12])=[O:9])([F:6])([F:5])[F:4]>O>[C:11]([CH2:10][CH:8]([CH2:7][C:3]([F:4])([F:5])[F:6])[OH:9])([F:14])([F:13])[F:12]
Reactant: O=C(CC(F)(F)F)CC(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: OC(CC(F)(F)F)CC(F)(F)F
Yield: 91 %

Procedure:
Sodium borohydride (0.8 g) was added to 15 ml water at 0 C. (ice bath). After the NaBH4 had dissolved, 9.7 g of CF3CH2C(O)CH2CF3 were added. The ketone froze. The ice bath was removed until the mixture was warm enough to melt the ketone, and the ice bath cooling was resumed. The reaction was quenched after 1 h with the addition of 5 ml 2N HCl and 10 ml brine. The lower layer (8.9 g) consisted of 95% pure CF3CH2CH(OH)CH2CF3 (91% yield). Distillation increased the purity to 97%; boiling point 65 C. at 95 mm Hg. 1H NMR: 4.4 (pentet, 1H), 2.9 (s, 1H), 2.4 (m, 4H) ppm. 19F NMR: -64.2 (t, J=10 Hz) ppm. FT-IR: 3415 (OH), 1264, 1154 cm-1. MS: 113 (64.8), 111 (18.6), 109 (10.8), 93 (91.4), 91 (14.2), 69(16.5), 65 (100), 64 (33.8), 49 (28.1), 29 (25.8). Anal. Calcd for C5H6F6O: C, 30.63; H, 3.08. Found: C, 30,61; H, 3.11.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7]C)=O)=[CH2:3].[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>CO>[CH3:11][O:10][C:1]([CH:2]1[CH2:4][C:5](=[O:7])[N:17]([CH2:16][C:15]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:14]=2[O:13][CH3:12])[CH2:3]1)=[O:9]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: C=C(CC(=O)OC)C(=O)OC
Solvent: CO
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1

Procedure:
A solution of dimethyl itaconate (4.08 g, 25.8 mmol) in MeOH (3.2 mL) was added to a solution of 2,4-dimethoxybenzylamine (4.32 g, 25.8 mmol) in MeOH (9.6 mL) via cannula at room temperature. After 18 h at room temperature the reaction was concentrated in vacuo to afford crude 1-(2,4-dimethoxybenzyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28]O)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[O:4][N:3]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: Oc1cc(-c2ccc(-c3ccccc3)cc2)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(-c3ccccc3)cc2)on1
Yield: 68.6 %

Procedure:
3-Hydroxy-5-(4-phenylphenyl)isoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.15 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.22 g, 69%) as a colorless powder.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C>C(Cl)Cl>[C:4]([NH:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[CH2:17][CH2:18]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])[CH:3]=[CH2:2]
Reactant: O=C(CCCl)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
0.5 g of 1-[4-(3-chloropropionylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine and 0.4 g of triethylamine are dissolved in 20 ml of methylene chloride, and the solution is boiled under reflux for 4 hours and then concentrated by evaporation, yielding 1-(4-acryloylaminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 163°-165°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[C:34]([N:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH2:19][N:20]2[C:11]([C:9]([NH:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:10])=[CH:12][CH:13]=[C:14]2[CH2:15]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 80.2 %

Procedure:
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Step C (300 mg, 0.942 mmol) in dry tetrahydrofuran (15 mL) at room temperature under nitrogen was added N,N-diisopropylethylamine (0.26 mL, 1.508 mmol) followed by benzoyl chloride (0.165 mL, 1.41 mmol) and the reaction mixture stirred at room temperature for 21 hours. The reaction was quenched by the addition of 2 M sodium hydroxide (5 mL) and then the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane gave a white foam that was crystallized from diethyl ether/hexane to give the title compound (0.319 g, 80%) as a white crystalline solid, m.p. 197° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:2].C(N(CC)CC)C.C(=O)([O-])O.[Na+].C([N-]C(C)C)(C)C.[Li+].O1CCCC1.Cl[Si:38]([CH3:41])([CH3:40])[CH3:39]>C1(C)C=CC=CC=1.Cl[Si](C)(C)C.O.CCCCCC>[CH2:1]([O:3][C:4]([O:11][Si:38]([CH3:41])([CH3:40])[CH3:39])=[CH:5][C:6]([O:10][Si:38]([CH3:41])([CH3:40])[CH3:39])=[CH:7][CH2:8][CH3:9])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC=C(C=C(OCC)O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 193.6 %

Procedure:
3-Oxohexanoic acid ethyl ester (20 mL, 0.13 mol) was dissolved in toluene (100 mL), and the obtained solution was added with triethylamine (28 mL, 0.20 mol) and chlorotrimethylsilane (24 mL, 0.19 mmol), followed by stirring at a room temperature for 4 hours. The reaction mixture was added with hexane (200 mL) and 0.5 mol/L aqueous sodium hydrogencarbonate solution and then, extracted with hexane 3 times. The organic layers were combined, sequentially washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL) and cooled to −78° C. The obtained solution was added with 2.0 mol/L lithiumdiisopropylamide-tetrahydrofuran solution (78 mL, 0.16 mol) followed by stirring at −78° C. for 1 hour. Then, chlorotrimethylsilane (18 mL, 0.14 mol) was added and the reaction mixture was stirred at −78° C. for 8 hours. The reaction mixture was further added with hexane (200 mL) and water and extracted with hexane 3 times. The organic layers were combined, sequentially washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to obtain 1-ethoxy-1,3-bis(trimethylsiloxy)hexa-1,3-diene (41 g, 100%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:27][CH2:28][CH3:29]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:27][CH2:28][CH3:29])[CH2:18]1
Reactant: CCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(CCC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and 1-iodopropane.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH3:13])(=O)=O)=CC=1.[CH2:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH:12]([CH3:13])[CH2:11][N:39]2[CH2:40][CH2:41][N:36]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:37][CH2:38]2)=[CH:19][CH:18]=1)(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)c2ccc(C(=O)c3ccccc3)cc2)cc1
Solvent: CC#N
Product: CC(CN1CCN(Cc2ccccc2)CC1)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
Reaction of 2-(4-benzoylphenyl)propyl p-toluenesulfonate with 1-benzylpiperazine in acetonitrile and isolation of the product in the form of the free base affords 1-[2-(4-benzoylphenyl)propyl]-4-benzylpiperazine. Conversion of the latter to the ethylene glycol ketal, catalytic reduction of the latter over palladium-on-charcoal at a hydrogen pressure of 50 p.s.i. in order to effect catalytic debenzylation thereof using the manipulative procedure described in Example 10 above, cleavage of the ketal with aqueous hydrochloric acid, and isolation of the product in the form of the dihydrochloric salt affords 1-[2-(4-benzoylphenyl)propyl]piperazine dihydrochloride m.p. 243°-245° C. (from ethanol).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH2:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl.CN(C1C=CN=CC=1)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.7 %

Procedure:
Boc-Pro-OH (50.0 g, 0.23 mol) was dissolved in dichloromethane (500 mL), and EDCI (89.1 g, 0.46 mol), DMAP (5.7 g, 0.05 mol), DIPEA (162 mL, 0.93 mol) and benzyl alcohol (48 mL, 0.46 mol) were added dropwise. The mixture was stirred at room temperature for 12 hours. The mixture was washed several times with an aqueous solution of 5% citric acid. The organic layer was dried over sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound as yellow oil (70.0 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14](Cl)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[C:9]([C:21]([O:23][CH3:24])=[O:22])=[C:8]([CH3:25])[NH:7][C:6]=1[CH3:26])=[O:4].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28]>CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[C:9]([C:21]([O:23][CH3:24])=[O:22])=[C:8]([CH3:25])[NH:7][C:6]=1[CH3:26])=[O:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN(CC)CCN
Solvent: CCOCC
Product: CCN(CC)CCNc1ccc(C2C(C(=O)OC)=C(C)NC(C)=C2C(=O)OC)cc1[N+](=O)[O-]
Yield: 80 %

Procedure:
Ten grams of 2,6-dimethyl-4-(3-nitro-4-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester and 8 g of 2-(diethylamino)ethylamine are heated to 100° (external temperature) overnight. After cooling, ether is added and the product collected by filtration to yield orange crystals of melting point 161°C after recrystallization from 80 ml of methanol. Yield: 80% of theory.
Reaction SMILES: [CH2:1]([S:8][CH:9]1[NH:12][C:11](=[O:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]OS(C(F)(F)F)(=O)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:12]2[CH:9]([S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:10][C:11]2=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(OCCCCCCCCCc1ccccc1)C(F)(F)F
Reactant: O=C1CC(SCc2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(SCc2ccccc2)N1CCCCCCCCCc1ccccc1
Yield: 68 %

Procedure:
Treatment of 4-benzylthio-2-oxo-azetidine (1.35 g) in THF with NaH (0.18 g) followed by 9-phenylnonyltriflate (2.8 g) gave the title compound as a colourless oil, 1.9 g, 68% yield. 1H NMR δ (CDCl3) 1.2-1.7 (14H, m, 7×CH2), 2.60 (2H, t, J=8 Hz, CH2Ar), 2.8, 3.2 (each 2H, m, H3 +NCH2), 3.76 (2H, s, SCH2), 4.59 (1H, m, H4), 7.15-7.35 (10H, m, Ph--H)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])=[CH:4][C:3]=1[S:18]([CH3:21])(=[O:20])=[O:19].[Cl:22]C1C=CC(CC(=O)C)=CC=1>>[Cl:22][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])=[CH:4][C:3]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(F)c(S(C)(=O)=O)c2)s1
Reactant: CC(=O)Cc1ccc(Cl)cc1
Product: CC(=O)Nc1nc(C)c(-c2ccc(Cl)c(S(C)(=O)=O)c2)s1

Procedure:
The title compound is prepared following the same route as N-[5-(4-Fluoro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 47) by replacing 4-fluorophenyl acetone with 4-chlorophenyl acetone.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[C:15]([O:14][C:12]([N:5]1[CH2:6][CH2:7][CH2:8][CH:9]([OH:10])[CH:4]1[CH2:3][OH:2])=[O:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: OCc1ncccc1O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(O)C1CO
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.7 %

Procedure:
A suspension of 5 g (31.00 mmol) of 2-hydroxymethyl-pyridin-3-ol hydrochlorid and 2.50 g 5% Rh/Alox in 100 ml AcOEt was stirred under hydrogen atmosphere 20 h at 25° C. and 8 bar. The suspension was filtered and evaporated to give an yellow oil. The crude product was treated with 8.78 g (40.00 mmol) BOC2O and 12 ml (93.00 mmol) Hunig's base in 30 ml DMF under ice cooling for 25 h. An extraction (water/brine/AcOEt) and two crystallizations (AcOEt, MeCN/CH2Cl2) gave 1.77 g (25%) of the title compound as a white solid. MS: 232.0 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4](C)C.N[C@H](C(O)=O)[C@H](CC)C.N[C@H](C(O)=O)C(C)C.N[C@H](C(O)=O)[CH2:29][SH:30]>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:30][CH3:29]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)[C@H](N)C(=O)O
Agent: CC[C@H](C)[C@H](N)C(=O)O
Product: CSCC[C@H](N)C(=O)O

Procedure:
Leu, Ile, Val, Cys
Reaction SMILES: [N:1]([CH:4]1[CH2:8][N:7]([C:9](=[O:24])[CH2:10][P:11]([OH:23])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[C@H:6]([C:25]([O:27]C)=[O:26])[CH2:5]1)=[N+:2]=[N-:3].[OH-].[Na+].Cl>>[N:1]([CH:4]1[CH2:8][N:7]([C:9](=[O:24])[CH2:10][P:11]([OH:23])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[C@H:6]([C:25]([OH:27])=[O:26])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@@H]1CC(N=[N+]=[N-])CN1C(=O)CP(=O)(O)CCCCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: [N-]=[N+]=NC1C[C@@H](C(=O)O)N(C(=O)CP(=O)(O)CCCCc2ccccc2)C1
Yield: 88.4 %

Procedure:
(S)-4-Azido-1-[[hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline, methyl ester (1.30 g) and 1 N sodium hydroxide (about 15 ml) is stirred for 30 minutes. The reaction mixture is acidified with concentrated hydrochloric acid, extracted with ethyl acetate, washed with water, washed with brine, dried over sodium sulfate, and the solvent is stripped yielding 1.11 g of the title compound having an optical rotation [α]D =-22.3° (c=10 mg/ml, methanol). The product contains 1/2 mole of water.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:24][C:25]1[CH:29]=[CH:28][NH:27][C:26]=1[C:30](O)=[O:31].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[CH:29]=[CH:28][NH:27][C:26]=1[C:30]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:23])=[O:31]
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1[nH]ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]ccc3Cl)c2F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (71.0 mg, 0.206 mmol), 3-chloro-1H-pyrrole-2-carboxylic acid (30.0 mg, 0.206 mmol) and diisopropylethyl amine (0.036 ml, 0.206 mmol) in DMF (3.0 ml) was added HATU (78 mg, 0.206 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and the solvent was removed. The crude material was purified via reverse phase HPLC to give 3-chloro-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-pyrrole-2-carboxamide (83 mg, 0.176 mmol, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.78 (t, 1H), 8.11 (s, 1H), 7.95 (t, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.46-7.57 (m, 1H), 7.37 (t, 1H), 6.92 (t, 1H), 6.18 (t, 1H), 4.54 (d, 2H). LC-MS (ES+) m/z 472.12, [M+H].