Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.CC(C)([O-])C.[K+].O1CCCC1.[C:24]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])#[N:25].C(O)(=O)C>>[C:30]([O:29][C:27](=[O:28])[CH:26]([C:24]#[N:25])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(C(C#N)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 50 %

Procedure:
Into a seal vessel, 4-Fluoro-2-methoxy-1-nitro-benzene (15.00 g, 87.65 mmol), 1.00 M of Potassium tert-Butoxide in Tetrahydrofuran (193 mL, 193 mmol), and t-Butyl cyanoacetate (24.7 g, 175 mmol) were added. The reaction mixture was heated at 80° C. for 4 hours. The reaction was cooled to room temperature. Acetic acid (10.96 mL, 192.8 mmol) was added. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc. The collected fractions afforded an orange collected fractions afforded Cyano-(3-methoxy-4-nitro-phenyl)-acetic acid tert-butyl ester as an orange solid (12.8 g, 49%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:8])([O-:3])=[O:2]
Reactant: Clc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
A mixture of m-nitrobenzoyl chloride 23.25 g (0.12 mol), chlorobenzene 25 ml (0.25 mol) and anhydrous aluminum chloride 17.5 g (0.13 mol) was stirred at 80°-100° C. for 4 hrs. After cooling, the reaction mixture was poured into ice-water with rapid stirring. The white precipitate obtained was collected by filtration and washed with water and then hexane. The white solid was recrystallized from hexane/CH2Cl2 to provide a solid with a melting point of 95°-96° C.; yield 76%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([CH2:38][CH3:39])=[N:29][N:30]3[CH:33]3[CH2:37][CH2:36][CH2:35]C3)=[CH:26][CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([CH2:38][CH3:39])=[N:29][N:30]3[CH:33]3[CH2:35][CH2:36][CH2:37]3)=[CH:26][CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCc1nn(C2CCCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Reactant: O=C(O)Cc1ncccn1
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4ncccn4)[C@@H](Cc4ccccc4)C3)ccc12

Procedure:
Prepared by the method outlined for Example 189 using pyrimidin-2-yl-acetic acid and 6-((S)-3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole (Example 56, Compound 144) as starting materials. Product as an oil. LC/MS (Method B) 2.46 min, [M+1]+ 495. Potency class C.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:27][C:28]1[N:32]2[N:33]=[C:34](Cl)[CH:35]=[CH:36][C:31]2=[N:30][C:29]=1[C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[Cl:27][C:28]1[N:32]2[N:33]=[C:34]([O:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:35]=[CH:36][C:31]2=[N:30][C:29]=1[C:38]([CH3:44])([CH3:45])[C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1nc2ccc(Cl)nn2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
334 mg of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 20 ml of N,N-dimethylformamide; 45 mg of a 60% dispersion of sodium hydride in mineral oil was added, followed by stirring at room temperature under reduced pressure for 35 minutes. 310:mg of ethyl 2-[3,6-dichloroimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate was then added, followed by stirring at 0° C. for 2 hours. Ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected; the crystal precipitated was dissolved in 5 ml of ethanol; 160 mg of fumaric acid was added, followed by concentration under reduced pressure. Ethyl acetate was added to the residue; the mixture was washed with aqueous sodium bicarbonate and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the residue to cause crystallization; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 168 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:8].[CH3:20][N:21](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:20]([C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:8])#[N:21]
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)cc1C(=O)Nc1ccc(Cl)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ccc(C#N)cc1C(=O)Nc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 64 %

Procedure:
5-Bromo-N-(4-chlorophenyl)-2-methoxybenzamide (9.0 g) obtained in step C, and 7.8 g of zinc cyanide were dissolved in 100 mL of N,N-dimethylformamide. The N,N-dimethylformamide was degassed under reduced pressure, and then the interior of the reactor was purged with nitrogen. After 2.3 g of tetrakistriphenylphosphine palladium was added, the N,N-dimethylformamide was degassed again under reduced pressure, and then the interior of the reactor was purged with argon. This solution was stirred for 2 hours and a half at 100° C., whereafter the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The insolubles were removed by filtration, and washed with ethyl acetate. The filtrate and the washings were combined, 100 mL of water was added, and then the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. After the respective organic layers were combined, the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and then washed with ethyl acetate. The filtrate and the washings were combined, and ethyl acetate was distilled off under reduced pressure. The resulting residue was washed with methanol. The resulting solid was dried under reduced pressure to obtain 4.9 g (64%) of 5-cyano-N-(4-chlorophenyl)-2-methoxybenzamide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]#[N:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6]([CH2:11][CH2:12][NH2:13])=[CH:7][NH:8]2
Reactant: N#CCc1c[nH]c2cc(F)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCc1c[nH]c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Combine 2-(6-fluoro-1H-indol-3-yl)acetonitrile (165 g, 0.925 mol) and THF (1.32 L). Slowly add 1M solution of BH3 (2.042 L, 1,832 Kg, 0.131 mol) in THF over about 40 minutes. When the addition is complete, heat to reflux within 1 hour. After 1 hour at reflux, cool to room temperature and the reaction mixture, over about 25 minutes, to a well-stirred 15% aqueous solution of NaOH (1.9 L, 9.5 mol). After addition, slowly and gradually heat to 50° C. After 1 hour, heat 60° C. After 30 minutes, heat to reflux for 1 hour. Cool to room temperature and stir overnight, decant the alkaline aqueous layer and replace by water. Heat to 30° C. under a pressure of 200 mbars in order to distill the THF until about 2.5 kg of distilate is removed. Extract the mixture with dichloromethane. Slowly add to the combined organic layers over a 25 minutes a mixture of 37% aqueous HCl (143 g) and water (220 g) and stir to give a solid. After 1 hour, collect the solid by filtration, wash with of dichloromethane, and dry overnight to afford of the hydrochloride salt of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([N:8]=[C:9]([CH3:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([NH:8][CH:9]([CH3:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N=C(C)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)c1ccc(NC(C)c2ccccc2)cc1

Procedure:
p-Acetyl-N-(α-methylbenzylidene) aniline (XXIII) (30 g) prepared by the procedure described in Example XXIXA was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent. p-Acetyl-N-(α-methyl benzyl) aniline (XXIV) was obtained by fractional distillation. XXIV had a boiling point of 165° C. at 0.1 millimeter.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([O:13]CC)=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4].[OH-].[K+]>O.C1COCC1>[NH:1]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4]
Reactant: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Boc-Gly-Nleu-OEt (28.8 g, 0.094 mol.) was dissolved in a mixture of 150 ml H2O and 150 ml THF. KOH (11.9 g, 0.18 mol.) dissolved in 50 ml H2O was added while stirring the solution. After one hour, The THF was removed under reduced pressure. The aqueous solution was chilled to 0° C. and acidified to about pH=2 by addition of concentrated HCl (swirling the solution vigorously at the same time). The product was extracted from the aqueous layer by ethyl acetate 3×100 ml. The organic layers were combined, washed by brine and dried by Na2SO4. The ethyl acetate was removed under reduced pressure to get the crude product. Column chromatography (elution solvents: E/H, 1:1. This solvent system was used to remove the impurities and the pure product was washed out from the column by a mixture of methanol and ethyl acetate) was carried out to obtain the pure product (white oil, 20 g, 74%). TLC Rf=0.2 (developing solvents: E/H, 3:1). FAB-MS, observed (M+H)+ =289. 1H-NMR (360 MHz, DMSO-d6) d 6.72 (m, Gly-NH), 6.62 (m, Gly-NH), 4.03 (s, Nleu-α), 3.87 (s, Nleu-α), 3.78 (d, Gly-α), 3.68 (d, Gly-α), 3.06 (m, Nleu-β), 1.82 (m, 1H, Nleu-γ), 1.32 (s, 9H, Boc-CH3), 0.85 (d, Nleu-δ), 0.76 (d, Nleu-δ).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[C:25]([F:44])=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[C:25]([F:44])=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OC/C=C/C[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Yield: 100 %

Procedure:
Prepared in 100% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S,24E)-19-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the same procedure as methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 8.10 (d, J=7.0 Hz, 1H), 8.00 (s, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.36 (br. s., 1H), 7.22-7.18 (m, 1H), 7.11-7.05 (m, 2H), 6.10 (br. s., 1H), 4.99 (dt, J=12.5, 6.3 Hz, 1H), 4.38 (br. s., 1H), 4.07 (t, J=10.5 Hz, 1H), 3.70 (s, 3H), 3.56-3.42 (m, 2H), 3.04 (d, J=10.5 Hz, 1H), 2.76 (d, J=8.5 Hz, 1H), 2.47 (s, 3H), 2.04-1.58 (m, 10H), 1.29 (s, 3H), 1.26 (s, 9H), 0.84 (d, J=6.0 Hz, 3H); LCMS (ESI, M+1): 658.20.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C)=[CH:27][CH:26]=3)=[O:23])=[CH:18][CH:17]=2)=[C:12]([F:40])[C:11]=1[F:41])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OC1C=CC(C2C=CC(C(OC3C=CC(CCCCCCCC)=C(F)C=3)=O)=CC=2)=C(F)C=1F)CCCCCCC.C(OC1C=CC(C2C=CC(C(OC3C=CC(CCCCCCCC)=CC=3F)=O)=CC=2)=C(F)C=1F)CCCCCCC.C(OC1C=CC(C2C=CC(C(OC3C=CC(OCCCCCCCC)=CC=3F)=O)=CC=2)=C(F)C=1F)CCCCCCC.C(OC1C=CC(C2C=CC(C(O[C@H]3CC[C@H](CCCCC)CC3)=O)=CC=2)=C(F)C=1F)CCCCCCC.C(OC1C=CC(C2C=CC(C(OC3C=CC(CCCCCCC)=C(F)C=3)=O)=CC=2)=C(F)C=1F)CCCCCCC.C(OC1C=CC(C2C=CC(C(OC3C=CC(OCCCCCCCC)=C(F)C=3)=O)=CC=2)=C(F)C=1F)CCCCCCC>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:27][CH:26]=3)=[O:23])=[CH:18][CH:17]=2)=[C:12]([F:40])[C:11]=1[F:41])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(OC(=O)c2ccc(-c3ccc(OCCCCCCCC)c(F)c3F)cc2)cc1
Agent: CCCCCCCCOc1ccc(-c2ccc(C(=O)O[C@H]3CC[C@H](CCCCC)CC3)cc2)c(F)c1F
Agent: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(CCCCCCC)c(F)c3)cc2)c(F)c1F
Agent: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(CCCCCCCC)c(F)c3)cc2)c(F)c1F
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(OCCCCCCC)cc3)cc2)c(F)c1F

Procedure:
p-octyloxyphenyl 4-octyloxy-2,3-difluorobiphenyl-4'-ylcarboxylate, C 83.8° SC 151.7° SA 154.9° N 165.4° I 4-octyl-3-fluorophenyl 4-octyloxy-2,3-difluorobiphenyl-4'-ylcarboxylate, 4-octyl-2-fluorophenyl 4-octyloxy-2,3-difluorobiphenyl-4'-ylcarboxylate, C 45.2°SC 84.3° N 120.7° I 4-octyloxy-2-fluorophenyl 4-octyloxy-2,3-difluorobiphenyl-4'-ylcarboxylate, C 56.7° SC 103° N 141.6° I 4-heptyl-2-fluorophenyl heptyl-2,3-difluorophenyl-4'-yl-carboxylate, C<20° N 83.4° I trans-4-pentylcyclohexyl 4-octyloxy-2,3-difluorobiphenyl-4'-ylcarboxylate C (67.8°Sc) 81.6° SA 97.5° N 132.4° I 4-heptyl-3-fluorophenyl 4-octyloxy-2,3-difluorobiphenyl-4'-ylcarboxylate, C 44.7° SC (41°) SA 146° I 4-octyloxy-3-fluorophenyl 4-octyloxy-2,3-difluorobiphenyl-4'-ylcarboxylate, C 83.6° SC 116° SA 162.9° I.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:31])/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])[NH2:3].C1C=CC2[N:40]([OH:41])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>CN(C=O)C>[OH:41][NH:40][C:28](/[CH:27]=[CH:26]/[C:23]1[CH:24]=[CH:25][C:20](/[CH:19]=[CH:18]/[C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:8]3[CH2:9][CH2:10][N:5]([C:2]([NH2:3])=[O:4])[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)=[O:31])=[CH:21][CH:22]=1)=[O:29]
Reactant: NC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: NOC1CCCCO1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)NO)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.2 %

Procedure:
(E)-3-(4-{(E)-3-[4-(4-Carbamoyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride (316 mg, 0.716 mmol) was suspended in DMF (5 ml). HOBT (193 mg, 1.43 mmol), EDC (273 mg, 1.43 mmol), TEA (0.200 ml, 1.43 mmol) and NH2OTHP (100 mg, 0.86 mmol) were added. The mixture was stirred at room temperature for 72 h and then partitioned between water and hot AcOEt. The organic extract was dried over Na2SO4, evaporated in vacuo and the crude product was crystallized from DCM/Et2O. The resulting solid was suspended in DCM and treated with HCl/Et2O for 1 h. The precipitate was filtered off, giving 103 mg of 4-(4-{(E)-3-[4-((E)-2-hydroxycarbamoyl-vinyl)-phenyl]-acryloyl}-phenyl)-piperazine-1-carboxylic acid amide as its hydrochloride salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH:10]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(O)C(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
(RS)-3-(4-Benzyloxy-benzenesulfonyl)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (13.4 mg, 0.031 mmol) was dissolved in MeOH (0.5 ml), cooled to 0° C. and treated with NaBH4 (1.64 mg, 0.043 mmol). After 0.5 hour stirring at 0° C., the reaction mixture was acidified to pH 1 with 1N HCl. The aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with H2O, dried over Na2SO4, filtered and the solvent was evaporated to provide (3RS,4SR)-3-(4-benzyloxy-benzenesulfonyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (12.3 mg, 92%) as a white solid, MS: m/e=434.4 (M+H+).
Reaction SMILES: [BH4-].[Li+].[O:3]=[C:4]([CH3:29])[CH2:5][N:6]1[C:15](=[O:16])[C:14]2[NH:13][C:12]([C:17]34[CH2:24][CH:23]5[CH2:25][CH:19]([CH2:20][CH:21]3[CH2:22]5)[CH2:18]4)=[N:11][C:10]=2[N:9]([CH2:26][CH2:27][CH3:28])[C:7]1=[O:8].Cl>>[OH:3][CH:4]([CH3:29])[CH2:5][N:6]1[C:15](=[O:16])[C:14]2[NH:13][C:12]([C:17]34[CH2:18][CH:19]5[CH2:25][CH:23]([CH2:22][CH:21]3[CH2:20]5)[CH2:24]4)=[N:11][C:10]=2[N:9]([CH2:26][CH2:27][CH3:28])[C:7]1=[O:8]
Reactant: CCCn1c(=O)n(CC(C)=O)c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Product: CCCn1c(=O)n(CC(C)O)c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
Lithium borohydride (102 mg, 4.22 mmol) was added under ice-cooling to 22 ml of a ethanolic solution of 780 mg (2.11 mmol) of Compound C obtained in Reference Example 1, followed by stirring at room temperature for 1.5 hours. The reaction solution was adjusted to pH 3 with 1N hydrochloric acid, and then extracted three times with chloroform. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from acetonitrile to give 440 mg (yield 56%) of Compound D as white prisms.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:25])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:14][CH:15]=2)=[O:9])[CH:7]=1.NC(C)(C)C#C>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:25])=[C:6]([CH:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:14][CH:15]=2)[OH:9])[CH:7]=1
Reactant: O=C(c1ccc(Nc2ccc(F)cc2F)nc1)c1cc(Br)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CC(C)(C)N
Solvent: CCN(CC)CC
Product: OC(c1ccc(Nc2ccc(F)cc2F)nc1)c1cc(Br)ccc1Cl
Reaction time: 2.5 h

Procedure:
(5-Bromo-2-chloro-phenyl)-[6-(2,4-difluoro-phenylamino)-pyridin-3-yl]-methanone (1.5 g; 3.5 mmol) is dissolved in NEt3 (110 ml), 3-amino-3-methyl-1-butyne (1.7 ml; 15.9 mmol), CuI (200 mg; 1 mmol), PdCl2(PPh3)2 (250 mg; 0.35 mmol) added and refluxed for 45 min. Since only small amount of product is formed, more PdCl2(PPh3)2 (500 mg; 0.7 mmol), CuI (500 mg; 2.5 mmol) and 3-amino-3-methyl-1-butyne (2 ml; 18.7 mmol) is added and refluxing continued for 2.5 hours. The reaction mixture is decanted, the solvent evaporated and the residue purified by chromatography (SiO2; toluene/ethanol/NH3conc 95/5/0.2) to yield the title compound as slightly colored foam (730 mg; 48%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(=O)c2ccc(F)cc2Cl)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-piperazinone (4.00 g, 40 mmol, commercially available e.g. from Sigma-Aldrich) was dissolved in Dichloromethane (DCM) (125 mL) and to this was added triethylamine (6.69 mL, 48.0 mmol). This solution was then cooled with ice water. 2-Chloro-4-fluorobenzoyl chloride (8.49 g, 44.0 mmol, commercially available e.g. from Maybridge, Alfa Aesar or ABCR) was then diluted down with Dichloromethane (DCM) (25 mL), before being added via a pressure-equalizing dropping funnel. The solution was allowed to stir at room temperature overnight, and was then washed with sodium bicarbonate (100 ml), the solid was removed, and the remaining solution was washed again with sodium bicarbonate (100 ml) and brine (100 ml), before being dried over magnesium sulphate. The solvent was then removed in vacuo to afford crude product which was triturated with hexane then stirred in ethyl acetate at 80° C., before being filtered and air-dried to give 4-[(2-chloro-4-fluorophenyl)carbonyl]-2-piperazinone (5.179 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][CH:11]=2)[OH:9])=[C:5]([CH3:7])[N:6]=1.[Al]>O=[Mn]=O.O1CCOCC1>[CH3:1][C:2]1[S:3][C:4]([C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][CH:11]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(O)c2cnnn2C)s1
Agent: O=[Mn]=O
Agent: [Al]
Solvent: C1COCCO1
Product: Cc1nc(C)c(C(=O)c2cnnn2C)s1
Reaction time: 1.5 h

Procedure:
To a 500 ml flask containing (2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (10.5 g, 46.8 mmol, Intermediate 48: step a) was added 1,4-dioxane (400 mL) and the contents were warmed to form a homogeneous solution. Activated MnO2 (18 g, 207 mmol) was added and the dark brownish mixture was heated to reflux in an aluminum heating mantle under an atmosphere of N2. After 1.5 hours, the contents were filtered while still hot through Celite® and rinsed with warm THF. The resulting light orange solution was concentrated and passed through a silica gel column (25% acetone-DCM) to give the title compound as a light orange solid.