Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:34][C:35](=[O:37])[CH3:36])[C:10]2[N:11]=[CH:12][N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:14]=2)=[CH:5][C:4]=1[F:38])#[N:2].S(OC)(O[CH3:43])(=O)=O>CCOC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:34][C:35](=[O:37])[CH3:36])[C:10]2[N:11]([CH3:43])[CH:12]=[N:13][CH:14]=2)=[CH:5][C:4]=1[F:38])#[N:2]
Reactant: CC(=O)OC(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: CC(=O)OC(c1ccc(C#N)c(F)c1)c1cncn1C
Temperature: 60 °C

Procedure:
Acetic acid (4-cyano-3-fluoro-phenyl)-(1-trityl-1H-imidazol-4-yl)-methyl ester (4.60 g, 9.17 mmol) and dimethyl sulfate (0.83 mL, 8.81 mmol) were dissolved in EtOAc (20 mL) and heated at 60° C. overnight under Ar. The reaction was concentrated in vacuo, diluted with MeOH (30 mL), and refluxed for 1 h. Concentrated in vacuo and purified using SiO2 chromatography (0.5-4% MeOH/CH2Cl2 with NH4OH) to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:10][CH2:9][N:8]([C:11](=[O:26])[C@H:12]([NH:24][CH3:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:7][CH2:6]1)=[O:4].C(OC([NH:41][C:42]([CH3:50])([CH3:49])[CH2:43]/[CH:44]=[CH:45]/[C:46](O)=[O:47])=O)(C)(C)C>>[CH3:1][NH:2][C:3]([C:5]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:10][CH2:9][N:8]([C:11](=[O:26])[C@H:12]([N:24]([C:46](=[O:47])/[CH:45]=[CH:44]/[CH2:43][C:42]([NH2:41])([CH3:50])[CH3:49])[CH3:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)C1(Cc2ccccc2)CCN(C(=O)[C@@H](Cc2ccc3ccccc3c2)NC)CC1
Product: CNC(=O)C1(Cc2ccccc2)CCN(C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)/C=C/CC(C)(C)N)CC1

Procedure:
4-Benzyl-1-((2R)-2-methylamino-3-(2-naphthyl)propionyl)piperidine-4-carboxylic acid methylamide (360 mg; 0.82 mmole) was coupled to (2E)-5-(tert-butyloxycarbonylamino)-5-methyl-2-hexenoic acid using the same coupling procedure as in step D. Removal of the N-terminal Boc group was performed as in step D but at −10° C. The crude product was purified on a RP-18-Seppak® (5 g; Waters) using a gradient from 0.1% TFA in water/acetonitrile 100/0 to 0.1% TFA in 60/40 water/acetonitrile to afford 306 mg of the title compound as a trifluoroacetate.
Reaction SMILES: [Na].C(OP([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(OCC)=O)C.[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][C:19](=O)[CH2:18]1>C1(C)C=CC=CC=1>[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][C:19](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:18]1
Reactant: CC1CC(=O)CC(C)C1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CC(C)CC(C)C1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
85 g of dry toluene are added to a round flask which is fitted with a stirrer, thermometer, dropping funnel and reflux condenser. Under a nitrogen atmosphere there are now introduced 17.2 g of sodium in small portions and the mixture is heated to boiling. After dissolution of the sodium (after about 3 hours), the mixture is cooled to 20° C. and there is slowly added dropwise thereto (during about 11/2 hours) a mixture of 219 g of ethyl diethylphosphonoacetate, 95 g of 3,5-dimethyl-cyclohexanone and 220 g of dry toluene. The temperature is held between 25° and 30° C. The mixture is stirred at this temperature for a further 2 days and thereupon poured on to 400 g of ice, extracted with toluene, washed neutral and concentrated. The residue is distilled over a Widmer column and thus yields 110 g of ethyl 3,5-dimethyl-cyclohexylideneacetate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15](O)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CCCCCC.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[C:15]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCCCCCCCCC(=O)c1c(C(=O)OCC)[nH]c2ccccc12

Procedure:
A mixture of 3.8 g (20 mmol) of ethyl indole-2-carboxylate, 6.0 g (30 mmol) of octadecanoic acid, 1.0 g of polyphosphoric acid, 20 ml of absol. CH2Cl2 and 4.4 ml of trifluoroacetic anhydride is stirred at room temperature for 4 h. Then 1 M NaOH is added, and the mixture is extracted with ether. The ether phase is dried over Na2SO4 and the solvent is distilled off. The product precipitates after addition of petroleum ether.
Reaction SMILES: [CH3:1][C:2]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:41][CH2:42][C:43]1[N:48]([CH2:49][C:50](O)=[O:51])[C:47]2[N:53]=[CH:54][CH:55]=[CH:56][C:46]=2[C:45](=[O:57])[N:44]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:41][CH2:42][C:43]1[N:48]([CH2:49][C:50]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[CH:11]2[CH2:12][CH2:13][N:8]([C:2]([CH3:1])([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[CH2:9][CH2:10]2)=[O:51])[C:47]2[N:53]=[CH:54][CH:55]=[CH:56][C:46]=2[C:45](=[O:57])[N:44]=1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Reactant: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
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
Product: COC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.3 %

Procedure:
A mixture of methyl 2-methyl-2-{4-[({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-l piperidinyl}propanoate (Int. B6) (145 mg, 1 equiv), [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (122 mg, 1 equiv), DIPEA (0.084 ml, 1.5 equiv) and DMF (2.0 ml) was stirred at room temperature for 5 min. The HATU (160 mg, 1.3 equiv) was added in 1 portion and stirred an additional 1 hour under nitrogen. The crude reaction mixture was applied directly to reverse-phase HPLC (Preparative Method A) to obtain methyl 2-{4-[{[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}({4′-[(trifluoromethyl)oxy]-4-biphenylyl} methyl)amino]-1-piperidinyl}-2-methylpropanoate (116 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([Cl:12])=[C:9](Br)[CH:10]=1)=[O:4].[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[C:8]([Cl:12])=[N:7][CH:6]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Product: COC(=O)c1cnc(Cl)c(-c2ccc(F)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 5a, using 5-bromo-6-chloro-3-pyridinecarboxylic acid methyl ester and 4-fluorophenylboronic acid as starting materials, MS (ISP) 266.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH3:15])[C:12]1[CH2:11][CH2:10][C:9](=[CH:16][C:17]3[N:18]=[CH:19][NH:20][C:21]=3[CH3:22])[C:8](=[O:23])[C:7]2=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH3:15])[C:12]1[CH2:11][CH2:10][CH:9]([CH2:16][C:17]3[N:18]=[CH:19][NH:20][C:21]=3[CH3:22])[C:8](=[O:23])[C:7]2=1
Reactant: [H][H]
Reactant: Cc1[nH]cnc1C=C1CCc2c(c3cccc(F)c3n2C)C1=O
Agent: [Pd]
Solvent: CCO
Product: Cc1[nH]cnc1CC1CCc2c(c3cccc(F)c3n2C)C1=O
Yield: 99.4 %

Procedure:
8-Fluoro-1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl)methylene]-4H-carbazol-4-one (1.5 g) was dissolved in ethanol (50 ml) and added to a suspension of 5% palladium on charcoal (200 mg) in ethanol (ca. 50 ml), and the resulting mixture was hydrogenated at room temperature and atmospheric pressure until hydrogen uptake had ceased. The mixture was filtered, and the filtrate was evaporated in vacuo to give the title compound (1.5 g), m.p. 189°-191° (decomp.), t.l.c. (System A 100:8:1), Rf 0.43.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([OH:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(F)c(OCC(=O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(F)c(OC[C@@H](O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Reaction time: 0.25 h

Procedure:
400 mL dry THF, 93 mL of 1M (S)-CBS reagent in toluene, and 30.3 g borane-diethylaniline complex were stirred together 10 min at rt. 3-{2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-ethoxy}-4-fluoro-benzonitrile (40 g) in 1.2 L dry THF was then added through an addition funnel at rt over 10 min. The mixture stirred for 15 min, then was quenched by slow addition of 100 mL MeOH. After gas evolution ceased the mixture was evaporated to a yellow oil. The oil was dissolved in 200 mL diethyl ether, precipitated with 1.2 L of hexanes and stored 18 h at −20° C. The desired product was collected by filtration and dried under vacuum to give 28.9 g. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.38 (m, 2H), 7.3-7.15 (m, 4H), 6.97 (m, 2H), 5.13 (m, 1H), 5.03 (s, 2H), 4.10 (m, 2H), 2.63 (d, 1H).
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([CH2:10][O:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])[C:6]=2[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:37]=[C:36]4[C:31]([CH:32]=[C:33]([C:38]([O:40]C)=[O:39])[N:34]=[CH:35]4)=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([CH2:10][O:11][C:12]3[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[C:6]=2[CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:37]=[C:36]4[C:31]([CH:32]=[C:33]([C:38]([OH:40])=[O:39])[N:34]=[CH:35]4)=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2ccc(-c3ccc(OCc4c(COc5c(C)cccc5C)noc4C4CCC4)cc3)cc2cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(C)c1OCc1noc(C2CCC2)c1COc1ccc(-c2ccc3cc(C(=O)O)ncc3c2)cc1
Temperature: 100 °C
Yield: 84.3 %

Procedure:
To a solution of methyl 7-(4-{[(5-cyclobutyl-3-{[(2,6-dimethylphenyl)oxy]methyl}-4-isoxazolyl)methyl]oxy}phenyl)-3-isoquinolinecarboxylate (50 mg, 0.091 mmol) in 2:1 tetrahydrofuran:methanol (3 mL) was added 1 N sodium hydroxide (0.14 mL, 0.14 mmol). The solution was heated in a microwave reactor at 100° C. for 500 seconds. Then 1 N hydrochloric acid (0.14 mL, 0.14 mmol) was added and the mixture was concentrated. The residue was taken up with ethyl acetate and water. The layers were separated and the organic layer was washed with water, dried over magnesium sulfate and concentrated to afford 7-(4-{[(5-cyclobutyl-3-{[(2,6-dimethylphenyl)oxy]methyl}-4-isoxazolyl)methyl]oxy}phenyl)-3-isoquinolinecarboxylic acid (41 mg, 84%). 1H-NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.61 (s, 1H), 8.49 (s, 1H), 8.24-8.18 (m, 2H), 7.85 (d, J=9 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 7.00-6.90 (m, 3H), 5.06 (s, 2H), 4.90 (s, 2H), 4.01-3.90 (m, 1H), 2.39-2.30 (m, 4H), 2.14 (s, 6H), 2.10-2.00 (m, 1H), 1.90-1.89 (m, 1H). HRMS (ESI) C33H30N2O5 calculated: 535.2228 (M+H)+, found: 535.2228 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9]Br>O.C(O)C>[C:11]1([CH:8]([CH3:9])[CH2:7][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CNCCN1
Reactant: CC(CBr)c1ccccc1
Solvent: O
Solvent: CCO
Product: CC(CN1CCNCC1)c1ccccc1

Procedure:
A solution of piperazine (344 g), β-bromoisopropylbenzene (199 g) in water (1 liter) and ethanol (0.35 liter) is refluxed for 24 hours. After cooling, the resulting amine is extracted with 3×0.5 liter methylene chloride. After washing with water and evaporation of the solvent in vacuo, the resulting 2-phenylpropyl piperazine is distilled; b.p.=163°-165° C./15 mm Hg.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1.CCOC(C)=O>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[C:20]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(Cl)cc1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2C2CCCCC2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (10 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-chloro-2-cyclohexylphenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (80 ml), washed with H2O (2×40 ml) and brine (60 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-chloro-2-cyclohexylphenoxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: [O:1]=[S:2]1(=[O:9])[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.Cl>[O:1]=[S:2]1(=[O:9])[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:3]1
Reactant: O=S1(=O)CCC(CO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC2CCS(=O)(=O)C2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
A mixture of (1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-yl)-methanol (3.59 g), 4-toluenesulfonyl chloride (9.11 g) and pyridine 5.8 mL) in chloroform (50 mL) was heated to 60° C. and stirred overnight. The reaction mixture was cooled and diluted with 100 mL 1N HCl and extracted with methylene chloride. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (60% EtOAc in hexanes) to give 4.012 g of toluene-4-sulfonic acid 1,1-dioxo-tetrahydro-1lambda*6*-thiophen-3-ylmethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: COc1c(C)cc(F)cc1C(C)O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: CCOCC
Product: COc1c(C)cc(F)cc1C(C)=O
Reaction time: 3 h
Yield: 92.4 %

Procedure:
To a solution of 1-(5-Fluoro-2-methoxy-3-methylphenyl)ethanol (1.3 g 7.13 mmol) in acetone (15 mL) at room temperature was added pyridinium chlorochromate (3.8 g, 17.64 mmol). The reaction was stirred for 3 hours, diethyl ether was added (30 mL). The resultant sludge was filtered through celite. The organic phase was dried over Na2SO4, filtered over silica gel, and concentrated to the crude compound which was purified by silica gel column (20% ethyl acetate in hexanes) to afford 1-(5-fluoro-2-methoxy-3-methylphenyl)ethanone (1.2 g, 98%): 1H NMR (400 MHz, CDCl3): δ 7.18 (dd, 1H), 7.05 (dd, 1H), 3.63 (s, 3H), 2.61 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]>CCOCC>[NH:1]([C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[NH2:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NN
Solvent: CCOCC
Product: NNC(=O)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of hydrazine (0.83 mL, 26 mmol) in ether was added phenyl chloroformate (0.92 mL, 7.4 mmol) at −20° C. The solution was stirred for 1 h, removed solid by filtration, and filtrate was concentrated to give phenyl hydrazinecarboxylate. To phenyl hydrazinecarboxylate was added compound 2b (1.2 g, 5.2 mmol), THF (20 mL), and DIPEA (1.5 mL) and the solution was stirred for 1 h. Partitioned reaction between sat. aq. NaHCO3 and CH2Cl2, dried (MgSO4), filtered, and concentrated to yield compound 81a (400 mg, 22%).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][C:8](N(OC)C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH:14]([Mg]Br)=[CH2:15]>C1COCC1>[C:1]([N:5]1[CH2:15][CH2:14][C:8](=[O:9])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)CCNC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)N1CCC(=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
3-(t-Butyl-amino)-N-methoxy-N-methyl-propanamide (5 g, 26.6 mmol, 1.0 equiv) was dissolved in dry THF (50 mL) under Ar. The solution was cooled to −78° C. and a 1 M solution of vinylmagnesium bromide (66.5 mL, 66.5 mmol, 2.5 equiv) was added dropwise over a 20 min period. The reaction was then stirred at −78° C. for 30 min and at 0° C. for 30 min at which time the reaction solution was transferred via a double-ended cannula into ice-cold saturated sodium bicarbonate solution under Ar. The mixture was stirred for 10 min and the crude product was extracted 2×150 mL EtOAc. The organic extracts were combined and concentrated in vacuo to a red oil. Purification was done by flash chromatography on silica using 100% CH2Cl2 through 4, 8, and 16% MeOH in CH2Cl2. The product was isolated as an orange oil (1.3 g, 32%); MS, m/z 156=M+1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+]([O-])=O)=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([Br:20])=[C:17]([Cl:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:24][S-:25].[Na+].C(O)(=O)C>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:25][CH3:24])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([Br:20])=[C:17]([Cl:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: C[S-]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Br)c(Cl)c2)c([N+](=O)[O-])s1
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(Br)c(Cl)c2)c(SC)s1
Yield: 22.9 %

Procedure:
The procedure described in Example 27: step a was followed using 4-(6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (63 mg, 0.14 mmol, Example 123: step b) and sodium thiomethoxide (0.5 M in EtOH, 0.18 mmol, 360 μL). The reaction was quenched with acetic acid (10 uL, 0.18 mol) followed by concentration in vacuo. The residue was then dissolved into EtOAc and washed with saturated NaHCO3 and brine solutions. The organic layers were dried (Na2SO4) and removal of the solvents in vacuo was followed by purification by preparative SiO2 TLC (30% EtOAc in hexanes) that yielded the title compound (14.2 mg, 23%) as a yellow solid. ESI-MS (m/z): Calcd. for C12H9BrClNO4S3: 441.9 (M+1) found: 442.0.
Reaction SMILES: [CH2:1]([CH2:16][C:17](=O)[CH3:18])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[C:20]([CH:22]([CH:17]([CH3:18])[CH2:16][CH2:1]/[CH:2]=[C:3](\[CH3:4])/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:9])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)C(C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
In 200 ml of benzene was dissolved 50 g of farnesylacetone, and 28 g of ethyl cyanoacetate, 5 g of ammonium acetate and 5 g of acetic acid were added to the solution. The mixture was refluxed for 8 hours while removing the water formed by the reaction. The liquid reaction mixture was washed with water and dried and a solution of 4.3 g of sodium borohydride in 50 ml of ethanol was added dropwise to the reaction mixture under agitation at 10° to 20° C. The resulting mixture was stirred for 1 hour. To the liquid reaction mixture was added 50 ml of 10% acetic acid, and the mixture was washed with water and dried. The solvent was removed by distillation and the residue was purified by column chromatography using silica gel to obtain 50.5 g of the intended compound in the form of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].[H-].[Na+].Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[Na+].[Cl-]>CN(C)C=O.C(O)(=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][C:7]=1[O:12][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: Clc1cnccn1
Reactant: CCOC(=O)c1ccc(F)c(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(F)c(Oc2cnccn2)c1
Temperature: 80 °C
Yield: 49.5 %

Procedure:
To a solution of 4-fluoro-3-hydroxy-benzoic acid ethyl ester (2.2 g, 11.95 mmol) in N,N-dimethylformamide (50 ml) was added 60% NaH in mineral oil (0.72 g, 17.93 mmol) and chloropyrazine (1.64 g, 14.34 mmol) and heated at 80° C. for overnight. One more equivalent of chloropyrazine was added and heated at the same temperature for 10 h. The reaction mixture was poured into a flask containing 150 ml of aqueous saturated NaCl solution and 0.6 ml of acetic acid. The mixture was extracted with ethyl acetate (3×100 ml), the combined organic extracts were washed with sat NaCl (150 ml), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography using dichloromethane to yield 1.55 g (50%) of product. MS (ESI+) m/z 263 (M+H)+;
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:30]([CH2:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH3:29]>>[C:34]([O:33][C:31]([N:30]([CH2:38][C:39]1[CH:45]=[CH:44][C:42]([NH:43]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:41][CH:40]=1)[CH2:28][CH3:29])=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Product: CCN(Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-ethyl-N-tert.butoxycarbonyl-aminomethyl)-aniline Rf value: 0.6 (silica gel, methylene chloride/methanol=10:1) C31H33N3O5
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:12].Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[OH:12]
Reactant: Brc1ccccc1
Reactant: COc1ccc(C(=O)C(CCOC2CCCCO2)c2ccccc2)cc1
Product: COc1ccc(C(O)(c2ccccc2)C(CCOC2CCCCO2)c2ccccc2)cc1

Procedure:
The (RS,SR)-isomers are prepared from the evaporation residue obtained in step (a) and 23.6 g of bromobenzene in the same manner as (RR,SS)-isomers above.