Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:34](I)=[C:33]([CH:36]2[CH2:39][CH:38]([CH2:40][CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:37]2)[O:32][N:31]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:46]1(B2OC(C)(C)C(C)(C)O2)[CH2:48][CH2:47]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C(=O)C>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.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:34]([CH:46]2[CH2:48][CH2:47]2)=[C:33]([CH:36]2[CH2:39][CH:38]([CH2:40][CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:37]2)[O:32][N:31]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: CCC(CC)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2I)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCC(CC)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
tert-Butyl 5-(tert-butyldiphenylsilanyloxy)-3-{5-[3-(2-ethylbutyl)cyclobutyl]-4-iodoisoxazol-3-yl}valerate (4.96 g), 2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.68 g), tripotassium phosphate (5.66 g), PdCl2(PPh3)2 (468 mg) and N,N-dimethylacetamide (50 mL) were mixed. The mixture was stirred at 80° C. for 5 hr. To the reaction mixture were added ethyl acetate (50 mL) and Celite at RT, and the mixture was filtered. The collected solid was washed with ethyl acetate (50 mL×2). The filtrate was washed with water/brine=1/1 (100 mL×2) and brine (50 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/50→1/40→1/30→1/20) to give the title compound (2.86 g).
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].Br[CH2:11][CH2:12][CH2:13][CH2:14][N:15]([S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C(O)(=O)C>C(O)C.C(OCC)(=O)C>[C:2]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]([S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=1)(=[O:28])=[O:29])[C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)#[N:3]
Reactant: CCOC(=O)c1ccc(N(CCCCBr)S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1ccc(N(CCCCC(C#N)C(=O)OCC)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.506 g (0.0220 mol) of sodium in 10 mL of absolute ethanol under nitrogen was refluxed briefly, and a solution formed. After it had cooled to room temperature, to the solution was added dropwise over a 2-min period 2.74 g (0.0242 mol) of ethyl cyanoacetate. The mixture was refluxed for 10 min and was allowed to cool to room temperature. Then to it was added over a 6-min period 5.00 g (0.0110 mol) of ethyl 4-[(4-bromobutyl)tosylamino]benzoate and 15 mL of rinse absolute ethanol. The mixture was refluxed under nitrogen for 6 h, allowed to cool to room temperature, and stand overnight. It was neutralized with glacial acetic acid and concentrated under vacuum to a wet solid to which was added 50 mL of water and 50 mL of ether. The mixture was shaken in a separatory funnel, and the layers were separated. The aqueous layer was washed with 2×50 mL more ether, and the ether washes were combined, dried over magnesium sulfate for three days, filtered, and concentrated under high vacuum at 60° C. to a viscous, pink oil; yield, 5.97 g. The oil was purified by a flash chromatography column consisting of 400 g of Silica Gel 60 with 3:1 hexanes/ethyl acetate as the eluting solvent. Fractions containing clean product were combined and concentrated under vacuum to a colorless, viscous oil; yield, 2.76 g (50%): NMR (Me2SOd6) δ 1.19 (t, 3H), 1.29 (t, 3H), 1.3-1.5 (m, 4H), 1.65-1.85 (m, 2H), 2.37 (s, 3H), 3.5-3.7 (m, 2H), 4.14 (t, 1H), 4.15 (q, 2H), 4.29 (q, 2H), 7.22 (d, 2H), 7.3-7.5 (AA'BB', 4H), 7.90 (d, 2H), 0.15 mol of ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH2:17])[N:16]=2)[CH:13]=1)([O-:3])=[O:2].[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[N:16]=2)[CH:13]=1)([O-:3])=[O:2]
Reactant: Nc1cn2cc(Oc3cccc([N+](=O)[O-])c3)ccc2n1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cn2cc(Oc3cccc([N+](=O)[O-])c3)ccc2n1)C1CC1
Yield: 35.5 %

Procedure:
To a solution of 6-(3-nitrophenoxy)imidazo[1,2-a]pyridin-2-amine (1.40 g, 5.18 mmol) in pyridine (6 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (706 μL, 7.77 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol (50 mL). Sodium carbonate (1.00 g) and water (5 mL) were added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate) to give the title compound (622 mg, 35%) as a white solid.
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@H:7]([C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[C:32]1(C)C=CC=C[C:33]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC.C=C>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@H:7]([C:14]1[CH:19]=[C:18]([CH:32]=[CH2:33])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: CC(C)N(CC[C@@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: C=Cc1ccc(OCc2ccccc2)c([C@@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (prepared as described in WO 94/11337, Example 1) (8 g, 12.7 mmol), Pd(OAc)2 (28 mg, 0.12 mmol), tri-o-tolyl-phosphine (74 mg, 0.14 mmol) and tributylamine (5.9 mL, 24.5 mmol) in dimethylacetamide (50 mL) was heated to 60° C. under nitrogen atmosphere. Ethene (g) was then added to 8 bars pressure. After stirring overnight the reaction mixture was allowed to cool to room temperature. Nitrogen was flushed through the reaction vessel, and toluene and water were added. The aqueous layer was extracted with toluene and the combined organic layers were dried (MgSO4) and concentrated. The residue was treated with sodium hydroxide (1 M) and extracted with diethyl ether and toluene. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica (gradient ethyl acetate-methanol 90:10 up to 0.06% NH3 in ethyl acetate-methanol 90:10) Yield 1 g (18%); 1H NMR (CDCl3) δ0.94 (d, 12H), 2.20 (br, 2H), 2.37 (br, 2H), 3.0 (br, 2H), 4.38 (t, 1H), 5.0 (s, 2H), 5.11 (d, 1H), 5.61 (d, 1H), 6.60-6.70 (m, 1H), 6.80 (d, 1H), 7.12-7.19 (m, 12H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([C:21]3[O:22][C:23]([C:26]4[N:31]=[C:30]([C:32]([O:34]C)=[O:33])[CH:29]=[CH:28][CH:27]=4)=[CH:24][N:25]=3)=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3].[Li+].[OH-].Cl>C1COCC1.O.C(Cl)Cl>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([C:21]3[O:22][C:23]([C:26]4[N:31]=[C:30]([C:32]([OH:34])=[O:33])[CH:29]=[CH:28][CH:27]=4)=[CH:24][N:25]=3)=[O:20])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN(C)C)cc4)cc3)o2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CN(C)Cc1ccc(-c2ccc(CCC(=O)c3ncc(-c4cccc(C(=O)O)n4)o3)cc2)cc1

Procedure:
Methyl 6-(2-(3-(4′-((Dimethylamino)methyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate was dissolved in THF/H2O (3:2, 2 mL) and LiOH was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 25 min before the addition of aqueous 1 N HCl to pH 4. The reaction solution was diluted with CH2Cl2 and the organic and aqueous layers were separated. The aqueous layer was made basic to pH 8 with the addition of saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by tritration in ether to provide 6-{2-[3-(4′-Dimethylaminomethyl-biphenyl-4-yl)-propionyl]oxazol-5-yl}-pyridine-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH:9]=[CH:8][CH2:7][C@H:6]1[C:11]([OH:13])=O)=[O:4].S(Cl)(Cl)=O.[CH:18]1C=CC=CC=1>>[C:11]([C@@H:6]1[CH2:7][CH:8]=[CH:9][CH2:10][C@@H:5]1[C:3]([O:2][CH3:1])=[O:4])(=[O:13])[CH3:18]
Reactant: COC(=O)[C@H]1CC=CC[C@H]1C(=O)O
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC=CC[C@H]1C(C)=O
Temperature: -5 °C
Reaction time: 1 h

Procedure:
25 g of (1R, 2S)-2-methoxycarbonylcyclohex-4-ene-1-carboxylic acid and 40 ml of thionyl chloride were dissolved in 200 ml of dry benzene, and the mixture was refluxed for two hours. The solvent was distilled off under a reduced pressure, and to the residue was added ml of dried tetrahydrofuran. Further, 1.29 g of copper (I) iodide was added to the solution, which was cooled to -5° C, 182 ml of tetrahydrofuran solution of methylmagnesium bromide (0.82M) was added dropwise to the solution over a period of 1.5 hours. The solution was further stirred for one hour at the same temperature, and then 1N-hydrochloric acid was added. After the organic layer was separated, the water layer was extracted with ether. The organic layer was successively washed with 5% sodium thiosulfate solution, saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane=15:85) to be purified, and thus 18.27 g of the titled compound was obtained.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][CH:20]1[CH2:25][N:24]([CH2:17][CH2:16][CH2:15][C:9]2[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:23][CH2:22][N:21]1[C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3)C(C)C2)nn1-c1ccccc1

Procedure:
68 mg (45%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg, 0.330 mmol), 2-methyl-1-m-tolylpiperazine (63 mg, 0.330 mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)3 (210 mg, 0.990 mmol).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])N.[ClH:19]>C(#N)C>[Cl:19][C:2]([CH3:4])([CH2:3][C:14]1[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[C:16]([O:17][CH3:18])[CH:15]=1)[C:1]([O:6][CH3:7])=[O:5]
Reactant: Cl
Reactant: C=C(C)C(=O)OC
Reactant: COc1ccc(N)cc1OC
Solvent: CC#N
Product: COC(=O)C(C)(Cl)Cc1ccc(OC)c(OC)c1
Yield: 39.2 %

Procedure:
Following the general procedure of Example I, 280 mmols of distilled methyl methacrylate were reacted with 25 mmols of 3,4-dimethoxyaniline in 30 mL of acetonitrile and in the presence of 42 mmols of concentrated HCl and 2.5 mmols of cuprous oxide. The process resulted in a 39.2% yield of methyl 2-chloro-2-methyl-3-(3,4-dimethoxyphenyl)propionate.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:28]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[CH2:29][CH2:30][CH3:31]>C1COCC1>[CH2:28]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:35][CH:34]=1)[CH2:29][CH2:30][CH3:31]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCOc1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCOc1ccc(C=CCCCC(=O)O)cc1
Yield: 72.8 %

Procedure:
This compound was synthesized from 4-carboxybutyltriphenylphosphonium bromide (8.86 g, 20 mmol) and p-butoxybenzaldehyde (3.56 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (3.82 g, 73%) as white crystals (mp: 56-57° C.). IR: 3350-2500, 1700 cm-1 ; 1H-NMR: 1.00 (t, 3 H), 1.50 (m, 2 H), 1.80 (m, 4 H), 2.40 (m, 4 H), 3.90 (t, 2 H), 5.50+6.00 (m, 1 H), 6.38 (q, 1 H), 7.05 (q, 4 H), 11.00 (bs, 1 H). Anal. Calcd. for C16H22O3 : C, 73.25, H, 8.45%; Found: C, 73.32, H, 8.46%. Z:E=37:63.
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[S:19][CH2:20][CH2:21][OH:22])=CC=2)C=CC=1)=O)C.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40]Br)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24].SCCO.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][S:19][CH2:20][CH2:21][OH:22])[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Reactant: CCOC(=O)c1cccc(-c2ccccc2CBr)c1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2ccccc2CSCCO)c1

Procedure:
2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester was synthesized as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 2′-Bromomethyl-biphenyl-3-carboxylic acid ethyl ester (10.3 g, 32.27 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol (3.03 g, 38.72 mmol, 1.2 eq.) and potassium carbonate (13.38 g, 96.81 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a yellow/orange oil.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>O>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[CH:14][C:13]2[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=2)[C:26]([OH:28])=[O:27])=[CH:23][CH:24]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CSc1ccc(C=C(C(=O)O)c2ccc(Br)cc2)cc1
Temperature: 90 °C
Yield: 44.4 %

Procedure:
A mixture of acetic anhydride (100 mL), 4-(methylthio)benzaldehyde (12.61 g, 82.8 mmol), 4-bromophenylacetic acid (17.79 g, 82.7 mmol), and triethylamine (8.48 g, 83.8 mmol) was heated to reflux for 4.25 hours. The reaction was cooled to 90° C., and water (100 mL) was added through an addition funnel. A yellow solid separated from the solution and was isolated by filtration and air dried and recrystallized from a mixture of ethyl acetate and isooctane to afford the acid (12.83 g, 44%): mp 187°-190° C. 1H NMR (acetone d6) 300 MHz 7.83 (s,1H), 7.57 (d, J=8.5Hz, 1H), 7.20 (d, J=8.5Hz, 2H), 7.10 (d, J=8.1Hz, 2H), 7.08 (d, J=8.1Hz, 1H), 2.46 (s, 3H). Mass spectrum M+ +H=350.
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl[CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][C:50]1=[O:54]>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][C:50]1=[O:54])[CH2:23][CH2:22]2
Reactant: O=C1CCCN1CCCl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 1-(2-chloroethyl)pyrrolidin-2-one as the alkylating reagent in Step 1. The product was isolated as a white solid (19 mg, 62%). LCMS: m/e 641.57 (M+H)+, 2.58 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.55 Hz, 2H), 5.37 (d, J=4.88 Hz, 1H), 4.91 (s, 1H), 4.76 (s, 1H), 3.89-3.73 (m, 2H), 3.72-3.56 (m, 3H), 3.55-3.45 (m, 1H), 2.93-2.80 (m, 1H), 2.57 (td, J=8.24, 3.97 Hz, 2H), 2.34-1.19 (m, 24H), 1.78 (s, 3H), 1.23 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1.CCN(CC)CC.[Cl:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:26][CH2:27][CH2:28][CH2:29][C:30]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1)=[O:31]
Reactant: N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCl)N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a stirred slurry of benzyl N-[(1S,3R)-3-aminocyclohexyl]carbamate, 18e, (0.97 g, 3.41 mmol) in CH2Cl2 (34 mL), was added Et3N (1.00 mL, 7.15 mmol), followed by 4-chlorobutanoyl chloride (0.40 mL, 3.58 mmol). After stirring at room temperature, the mixture was diluted with CH2Cl2, washed with 1N HCl (2×), 1N NaOH (2×), and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 1.07 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[NH:4][C:3]1=[O:14].Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1.C(Cl)Cl>CCCCCC.CCOC(C)=O>[NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([CH2:23][C:24]2[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[CH:26][CH:25]=2)[C:3]1=[O:14]
Reactant: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2Cc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 64.7 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 93 from 1 g of 3-amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one and 0.984 g of tert-butyl 4-bromomethylbenzoate. Chromatography on silica using DCM and then a DCM/AcOEt mixture (70/30; v/v) as the eluent gives 1.053 g of the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH3:16])\[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH3:16])\[CH2:7][Br:18])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1ccccc1SC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccccc1SC
Yield: 37.7 %

Procedure:
To a stirred mixture of (E)-3-(2-methylsulfanyl-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.004 mol) in carbon tetrachloride (15 mL) under a nitrogen atmosphere was added N-bromosuccinimide (1.00 g, 0.006 mol) and benzoyl peroxide (0.13 g, 0.001 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2-methylsulfanyl-phenoxy)-but-2-enoic acid ethyl ester (0.50 g, 38%) as a yellow oil: LR-ES-MS m/z calculated for C13H15BrO3S [M]+ 330, observed 333.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([NH:16]C(=O)OC(C)(C)C)=[CH:10]1>ClCCl>[NH3:9].[NH2:16][C:11]1[CH:12]=[CH:13][C:14](=[O:15])[N:9]([CH3:8])[CH:10]=1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)ccc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(N)ccc1=O
Product: N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trifluoroacetic acid (10 mL) was added dropwise to an ice-cooled solution of tert-butyl (1-methyl-6-oxo-1,6-dihydropyridin-3-yl)carbamate (Heterocycles 1995; 40; 2; 831-836) (2.87 g, 12.8 mmol) in dichloromethane (80 mL), and the reaction then stirred at room temperature for 18 hours. The mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:1) as eluant to afford the title compound as a red/brown solid, 1.90 g.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](B(O)O)=[N:2]1.Br[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])=[C:12]([F:28])[CH:11]=1.Br[C:30]1[CH:31]=C2C(=C[CH:38]=1)CN(C(NC1C=CC(C(=O)NCCC)=CC=1)=O)C2>>[F:28][C:12]1[CH:11]=[C:10]([C:4]2[CH:3]=[N:2][N:1]([CH2:38][CH2:30][CH3:31])[CH:5]=2)[CH:15]=[CH:14][C:13]=1[NH:16][C:17]([N:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18]
Reactant: O=C(Nc1ccc(Br)cc1F)N1Cc2ccccc2C1
Reactant: OB(O)c1cc[nH]n1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Product: CCCn1cc(-c2ccc(NC(=O)N3Cc4ccccc4C3)c(F)c2)cn1

Procedure:
The title compound was prepared as described in Example 280, substituting 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1H-pyrazol-3-ylboronic acid and N-(4-bromo-2-fluorophenyl)isoindoline-2-carboxamide for 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.19 (s, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.57 (t, J=8.4 Hz, 1H), 7.46 (dd, J=12.1, 1.9 Hz, 1H), 7.24-7.39 (m, 5H), 4.76-4.78 (bs, 4H), 4.06 (t, J=6.9 Hz, 2H), 1.75-1.88 (m, 2H), 0.86 (t, J=7.3 Hz, 3H); MS (ESI(+)) m/e 365 (M+H)+.