Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)(=[O:10])[CH:8]=[CH2:9].[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:49]=[CH:48][C:37]([C:38]([O:40][C:41]2[CH:46]=[CH:45][C:44](O)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1)(=[O:27])[CH:25]=[CH2:26].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([C:38]([O:40][C:41]2[CH:46]=[CH:45][C:44]([O:20][C:19](=[O:21])[C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][O:11][C:7](=[O:10])[CH:8]=[CH2:9])=[CH:23][CH:22]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:48][CH:49]=1)(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)OCCCCOc1ccc(C(=O)Oc2ccc(O)cc2)cc1
Reactant: C=CC(=O)OCCOc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: C=CC(=O)OCCCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OCCOC(=O)C=C)cc3)cc2)cc1
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
Oxalyl chloride (10 ml) is added at 0° C. to 4-(2'-acryloxyethoxy)-benzoic acid (4.3 g; 16.3 mmol), and the mixture is stirred until the evolution of gas subsides (30 min). The excess oxalyl chloride is removed by distillation in a water-pump vacuum, the acid chloride is taken up in toluene (10 ml), the toluene solution is added at 0° C. to a solution of (3) (5.8 g; 16.3 mmol) in pyridine (10 ml) and toluene (5 ml), and the mixture is subsequently stirred at room temperature for 13 hours. The reaction mixture is then transferred into water (200 ml), and the mixture is extracted twice with dichloromethane (50 ml each time). The organic extracts are dried using calcium chloride, hydroquinone (50 mg) is added to the filtrate, and the mixture is evaporated in a water-pump vacuum. The residue is chromatographed on silica gel (toluene/ethyl acetate (5:1), giving 7.8 g (83%) of (4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](C)[CH:7]=[CH:6][C:5]=1[OH:11].Br[CH2:14][CH2:15][Cl:16].[C:17](=O)([O-])[O-:18].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:18][CH3:17])=[CH:6][C:5]=1[O:11][CH2:14][CH2:15][Cl:16]
Reactant: O=C([O-])[O-]
Reactant: ClCCBr
Reactant: COC(=O)c1cc(C)ccc1O
Agent: [K+]
Product: COC(=O)c1ccc(OC)cc1OCCCl

Procedure:
This compound was prepared following the procedure described in Example 1 (part C) starting with 5 g (27.4 mmol) of 2-hydroxy-5-methyl-benzoic acid methyl ester, 9 mL (60.3 mmol) of 1-bromo-2-chloro-ethane and 5.9 g (42.8 mmol) of potassium carbonate. After the work-up and purification, 6.6 g (99% of yield) of the desired product was obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:17])(C)[C:8]=3[CH:7]=[C:6]([C:18]#[CH:19])[CH:5]=2)[CH2:3][CH2:2]1.[CH2:20]([O:22][C:23](=[O:34])/[C:24](/[CH3:33])=[CH:25]/[C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)[CH3:21].[CH2:35](N(CC)CC)C>[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>[CH2:20]([O:22][C:23](=[O:34])/[C:24](/[CH3:33])=[CH:25]/[C:26]1[CH:31]=[CH:30][C:29]([C:19]#[C:18][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:15]3[O:14][C:11]4([CH2:12][CH2:13]4)[C:10]([CH3:35])=[C:9]([CH3:17])[C:8]=3[CH:7]=2)=[CH:28][CH:27]=1)[CH3:21]
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC1(CC1)O2
Reactant: CCOC(=O)/C(C)=C/c1ccc(I)cc1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCOC(=O)/C(C)=C/c1ccc(C#Cc2cc3c(c(C4CC4)c2)OC2(CC2)C(C)=C3C)cc1

Procedure:
Following General Procedure B and using 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (0.077 g, 0.3 mmol), (E)-3-(4-iodo-phenyl)-2-methyl-acrylic acid ethyl ester (Reagent 7, 0.106 g, 0.23 mmol), triethyl amine (3 mL), copper(I)iodide (0.029 g, 0.15 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.064 g, 0.09 mmol) followed by flash column chromatography over silica gel (230-400 mesh), the title compound was obtained (0.06 g, 45%).
Reaction SMILES: [NH2:1][C:2]1([CH2:8]O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:1]2[C:2]3([CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)[CH2:8]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: NC1(CO)CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CC23CCOCC3)cc1
Reaction time: 18 h
Yield: 38.3 %

Procedure:
A solution of 4-aminotetrahydro-2H-pyran-4-methanol (16 g, 122 mmol) in dichloromethane (700 mL) was treated with triethylamine (85 mL, 610 mmol), p-toluenesulfonyl chloride (69.8 g, 366 mmol) and DMAP (1490 mg, 12.2 mmol) under nitrogen. After approximately 18 hours at room temperature, the reaction was filtered through a pad of silica gel. The filtrate was concentrated in vacuo then purified by chromatography on silica gel (5-20% EtOAc/hexane) to afford intermediate the title compound (12.5 g) as a white solid.
Reaction SMILES: OC[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([N:6]1[CH2:5][CH2:4][CH2:3][CH2:8][CH2:7]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCC1CCNCC1
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc(CN2CCCCC2)cc1
Temperature: 57.5 °C
Yield: 98 %

Procedure:
To a stirred solution of 4-(hydroxymethyl)piperidine 38 (0.01 mol) and DIEA (0.02 mol) in anhydrous acetonitrile (20 ml) was added a solution of benzylbromide 39 (0.012 mol) in anhydrous acetonitrile (5 ml) at room temperature. The resulting mixture was heated at 55-60° C. for 12 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated on rotavapor and the residue was diluted with ethyl acetate (50 ml). The resulting ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate (Na2SO4) and evaporated the solvent. The residue was purified by silica gel column chromatography using a gradient of 0 to 100% ethyl acetate and hexane to get the title piperidine 40 in 98% yield (2.00 g) yield. 1H NMR (400 MHz, CDCl3): δ 1.26-1.33 (2H, m); 1.43-1.52 (1H, m); 1.70 (2H, broad d); 1.96 (2H, broad t); 2.90 (2H, broad d); 3.48 (2H, s); 3.49 (2H, s); 7.30 (5H, m). MS (ESI): m/z=206.20 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2([C:33]([F:36])([F:35])[F:34])[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4([F:32])[CH2:31][NH:30][CH2:29]4)=[CH:24][CH:23]=3)[O:18]2)[CH:12]=[C:13]([Cl:16])[C:14]=1[F:15].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:66][S:67]([CH2:70][C:71](O)=[O:72])(=[O:69])=[O:68]>CN(C=O)C>[Cl:16][C:13]1[CH:12]=[C:11]([C:17]2([C:33]([F:34])([F:35])[F:36])[O:21][N:20]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4([F:32])[CH2:31][N:30]([C:71](=[O:72])[CH2:70][S:67]([CH3:66])(=[O:69])=[O:68])[CH2:29]4)=[CH:26][CH:27]=3)[O:18]2)[CH:10]=[C:9]([Cl:8])[C:14]=1[F:15]
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)ON=C(c3ccc(C4(F)CNC4)cc3)O2)cc1Cl
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)O3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of trifluoroacetic acid salt of 5-(3,5-dichloro-4-fluoro-phenyl)-3-[4-(3-fluoro-azetidin-3-yl)-phenyl]-5-trifluoromethyl-[1,4,2]dioxazole (0.35 g, 0.77 mmol, 1 eq) in DMF (5 mL) was added triethyl amine (0.867 mL, 6.178 mmol, 8 eq.), followed by addition of EDC.HCl (0.22 g, 1.15 mmol, 1.5 eq), HOBt (0.104 g, 0.77 mmol, 1 eq) and methanesulfonyl-acetic acid (0.213 g, 1.54 mmol, 2 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (3×30 mL). Combined organic phase was washed with saturated solution of LiCl solution (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown thick oil (0.51 g, Crude). Crude was purified by combiflash using 40 g Redisep column. Desired compound was eluted in 47% ethyl acetate in hexane to afford title compound as off white solid (0.225 g, 50.82%). 1H NMR (400 MHz, CDCl3) δ: 3.17 (s, 3H), 3.87 (s, 2H), 4.37-4.45 (m, 1H), 4.52-4.60 (m, 1H), 4.80 (d, J=19.64 Hz, 2H), 7.61-7.65 (m, 4H), 7.91 (d, J=8.24 Hz, 2H), LC-MS (m/z): 571.0 (M−H), HPLC Purity: 93.59%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:32]#[N:33])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:8]=2)[CH:6]=1.C[Sn]([N:38]=[N+:39]=[N-:40])(C)C.[C:41]1([CH3:48])[C:42](C)=[CH:43][CH:44]=[CH:45][CH:46]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:32]2[N:38]([C:48]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:39]=[N:40][N:33]=2)[N:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][O:14][Si:15]([C:28]([CH3:29])([CH3:30])[CH3:31])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:11][CH:12]=2)[CH:6]=1
Reactant: CC(C)(C)[Si](OCc1ccc(-n2cc(Br)cc2C#N)cc1)(c1ccccc1)c1ccccc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cc1ccccc1C
Product: CC(C)(C)[Si](OCc1ccc(-n2cc(Br)cc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)(c1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 14 h

Procedure:
A mixture of 4-bromo-1-(4-tert-butyldiphenylsilyloxymethylphenyl)pyrrole-2-carbonitrile (2.02 g) and trimethyltin azide (2.42 g) in xylene (20 ml) was stirred at 120° C. for 14 hours. After cooled to ambient temperature, the reaction mixture was concentrated in vacuo. To the residue was added trityl chloride (42 mg), triethylamine (50 μl) and methylene chloride (1 ml), and the mixture was treated in a conventional manner to give 4-bromo-1-(4-tert-butyldiphenylsilyloxymethylphenyl)-2-(1-trityl-1H-tetrazol-5-yl)pyrrole (1.63 g)
Reaction SMILES: [C:1]([O:4][C:5]([CH3:7])=[CH2:6])(=[O:3])[CH3:2].[C:8]1([CH3:18])[CH:13]=C[C:11](S(O)(=O)=O)=[CH:10][CH:9]=1.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC>>[C:1]([O:4][C:5]([C:7]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:18])[CH:13]=1)=[CH2:6])(=[O:3])[CH3:2]
Reactant: C=C(C)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Product: C=C(OC(C)=O)c1cccc(C)c1
Yield: 60 %

Procedure:
Using a 15 cm Wiedmer distillation apparatus, a solution of 50 mmol of 3-methyl acetophenone in 15.02 g (150 mmol) of isopropenyl acetate was heated at 95° in the presence of 75 mg of para-toluene sulphonic acid. At a stabilised conversion (50–70% by GC, after 8 h at 95°), the mixture was cooled and 300 mg of trioctylamine were added. After extraction by means of ether, and usual workup, the product was distilled on a bulb-to-bulb apparatus and purified by preparative GC using a 1.2 m×6 mm column loaded with 10% SE-30 on Supelcoport® 80–100 mesh, vector gas: helium at 30 ml/min. The product was obtained in 60% yield
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]#[C:4][C:5]1[S:9][CH:8]=[C:7]([N:10]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:11]([C@@H:13]2[C@@H:18]([CH3:19])[CH2:17][C:16]([CH3:20])=[CH:15][CH2:14]2)=[O:12])[CH:6]=1.[BH4-].[Na+].Cl>CO>[CH3:28][C:2]([CH3:1])([CH3:29])[C:3]#[C:4][C:5]1[S:9][CH:8]=[C:7]([N:10]([C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[C:11]([C@@H:13]2[C@@H:18]([CH3:19])[CH2:17][C:16]([CH3:20])=[CH:15][CH2:14]2)=[O:12])[CH:6]=1
Reactant: CC1=CC[C@H](C(=O)N(c2csc(C#CC(C)(C)C)c2)C2CCC(=O)CC2)[C@@H](C)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1=CC[C@H](C(=O)N(c2csc(C#CC(C)(C)C)c2)[C@H]2CC[C@H](O)CC2)[C@@H](C)C1
Reaction time: 0.5 h

Procedure:
(1S,6S)-4,6-Dimethyl-cyclohex-3-ene-carboxylic acid [5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(4-oxo-cyclohexyl)-amide (2.0 g, 4.9 mmol) in MeOH (100 mL) was treated with sodium borohydride (230 mg, 6.0 mmol) at 0° C. After stirring for 30 min, 4M HCl (6 mL) was added and the reaction mixture was twice extracted with ethyl acetate. The combined organic layers washed with saturated NaHCO3(aq)), brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography (20-60% ethyl acetate/hexanes) gave the desired (1S,6S)-4,6-dimethyl-cyclohex-3-ene-carboxylic acid [5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(trans-4-hydroxy-cyclohexyl)-amide (1.74 g, 4.2 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC.CCOC(C)=O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:14]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[CH2:15]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cccc(CC(=O)OCC)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a mixture of ethyl 2-(3-bromophenyl)acetate (1.5 g, 6.1 mmol) in anhydrous DMF (15 mL) was added tributyl(vinyl)stannane (2.1 mL, 7.4 mmol) and tetrakis (triphenylphosphine) palladium (400 mg, 0.5 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 110° C. for 8 hours. Followed a standard aqueous/EtOAc workup. Purified by silica gel column chromatography (petroleum: ether/ethyl acetate=15:1) (640 mg, yield 54%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5](ON=O)(C)(C)C.CN[C:14]1[C:15](=[C:19]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:21][CH:22]=1)[C:16]([OH:18])=[O:17]>C(#N)C>[CH2:1]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:15]=1[C:16]([O:18][CH3:5])=[O:17])[CH:2]=[CH2:3]
Reactant: CC(C)(C)ON=O
Reactant: C=CCBr
Reactant: CNc1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CC#N
Product: C=CCc1cccc([N+](=O)[O-])c1C(=O)OC
Reaction time: 1 h
Yield: 62 %

Procedure:
To a stirred solution of allyl bromide (39.7 ml, 459.18 mmol) and tert-butylnitrite (5.5 ml, 45.91 mmol) in acetonitrile (30 ml) was added methyl 6-nitroanthranilic acid (6.0 g, 30.61 mmol) portion-wise at room temperature and the mixture was further stirred for 1 h. The volatile components were evaporated under reduced pressure and the residue was diluted with water. The mixture was extracted with ethyl acetate (2×50 ml) and the combined organic extracts were washed with water and dried over anhydrous sodium sulfate. The residue obtained after evaporation of the solvent was purified by silica gel column chromatography using 5% ethyl acetate in petroleum ether as eluent to give 4.2 g of the product as a yellow oil; 1H NMR (δ ppm, CDCl3, 300 MHz): 7.99 (d, J=7.8, 1H); 7.58-7.46 (m, 2H); 5.93-5.80 (m, 1H), 5.15-5.03 (m, 2H); 3.93 (s, 3H); 3.46 (d, J=6.0, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=C(O)C=CC=1.[C:24]1([CH:30]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[O:40])[C:32]2=[O:41])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:33]2([OH:40])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:31]([CH:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:32]2=[O:41])=[C:11]([OH:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(OCc2ccccc2)cc1O

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 3-(benzyloxy)phenol to replace 3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one was obtained (75%): MS (ES+) m/z 496.0 (M−17).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[CH2:26]([O:33][C:34]1[C:43]2[C:38](=[C:39]([CH2:44][CH2:45][NH2:46])[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(Cl)Cl.O.C(Cl)CCl>[CH2:26]([O:33][C:34]1[C:43]2[C:38](=[C:39]([CH2:44][CH2:45][NH:46][C:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:10])[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NCCc1cccc2c(OCc3ccccc3)cccc12
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: O=C(NCCc1cccc2c(OCc3ccccc3)cccc12)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a solution of diphenylacetic acid (0.171 g) in methylene chloride (10 ml), dimethylaminopyridine (0.01 g) and 1-benzyloxy-5-(2-aminoethyl)naphthalene (0.196 g) were added at room temperature. After 10 minutes, EDC. HCl (0.154 g) was added to the mixture solution. The mixture was stirred overnight at room temperature for 1 night. After termination of reaction, water and methylene chloride were added to the reaction mixture. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, dried over and concentrated under reduced pressure. The residue was purified on silica gel chromatography to give the title compound (0.172 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O)[C:7](=O)[CH3:8])=[O:5])[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:14])[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]=1[CH3:8])=[O:5])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1C(=O)O
Product: CCOC(=O)c1c(C)n(-c2ccccc2)c(=O)c2ccccc12
Temperature: 150 °C
Yield: 93.1 %

Procedure:
A mixture of 2-(1-ethoxycarbonyl-2-oxo-propyl)-benzoic acid (7.6 g, 30.4 mmol) and aniline (10 ml, 108 mmol) was flushed with argon, sealed in the Emrys process vial and heated at 150° C. for 15 min under microwave irradiation. The volatiles were removed in vacuo and the obtained residue was partitioned between ethyl acetate (100 ml) and 2M HCl (100 ml). The organic layer was washed with brine (2×20 ml), dried (Na2SO4) and evaporated to give 8.7 g of brown oil that solidified. The obtained crude product was of ca. 90% purity according to 1H NMR and can be used in the next step without further purification. Alternatively, the crude product was dissolved in hot ethyl acetate (20 ml), precipitated with heptane (60 ml), allowed to cool, filtered and washed with diethyl ether to give 4.2 g of a pale-brown crystalline solid, yield 45%. LC-MS (m/z) 308.2 (MH+); tR=1.43. 1H NMR (500 MHz, DMSO-d6): 1.34 (t, 3H), 1.97 (s, 3H), 4.41 (q, 2H), 7.38 (d, 2H), 7.51 (t, 1H), 7.56 (t (overlapping m), 3H), 7.62 (d, 1H), 7.8 (t, 1H), 8.22 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:43]4[CH2:42][CH2:41][N:40]([C:37]5[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=5)[CH2:45][CH2:44]4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(C(=O)c3ccc(-c4cnc5c(c4)N(Cc4cc(Cl)ccc4C(F)(F)F)CCN5)cc3)CC2)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=622.01 (M+H+); retention time=0.92 minutes.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:42])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[O:31])=[C:25]([O:40][CH3:41])[CH:24]=1)[CH2:16][CH2:15][CH2:14]2)[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.O>[C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:42])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[O:31])=[C:25]([O:40][CH3:41])[CH:24]=1)[CH2:16][CH2:15][CH2:14]2)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)CCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1)NC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(CC(=O)N2CCCc3cc(CC(NC(C)=O)C(=O)O)ccc32)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
A solution of methyl (S) 2-acetylamino-3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinolin-6-yl)-propionate [220 mg, Reference Example 4(1)] in dioxane (3 ml) was treated with a solution of lithium hydroxide hydrate (50 mg) in water (1 ml). The mixture was stirred at room temperature for 3 hours, then treated with water (5 ml), then acidified to pH 1-2 by the addition of dilute hydrochloric acid (with ice cooling). The resulting precipitate was extracted three times with ethyl acetate and the combined extracts were washed with water, then with brine, then dried and then evaporated. The residue was recrystallised from ethyl acetate to give the title compound (21 mg)as a white powder. LC-MS: RT=2.77 minutes (100% total area by ELS); MS (ES+) 581 (MNa+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:12])[CH3:11])([CH3:3])[CH3:2].B(F)(F)F>F>[C:4]1([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:10]([C:5]1[CH:4]=[C:9]([CH:1]([CH3:3])[CH3:2])[CH:8]=[C:7]([CH:4]([CH3:9])[CH3:5])[CH:6]=1)([CH3:11])[CH3:12]
Reactant: CC(C)c1ccccc1C(C)C
Agent: F
Agent: FB(F)F
Product: CC(C)c1cc(C(C)C)cc(C(C)C)c1
Product: CC(C)c1ccccc1
Reaction time: 0.5 h

Procedure:
A commercial mixture of 16 g (0.1 mol) diisopropylbenzene containing about 60% of the para and 40% of the ortho isomer, is dissolved in 150 ml of anhydrous hydrogen fluoride. The reaction mixture is cooled to -20 to 0° and saturated, while stirred, with boron trifluoride. After stirring at this temperature for 30 min., the temperature is raised and HF and BF3 is distilled off, (which can be reused). After washing, neutralization and drying, the organic layer is separated, distilled and analyzed by gas liquid chromatography. The diisopropylbenzene fraction consists of 99% meta-diisopropylbenzene and 1% para-diisopropylbenzene. Cumene and 1,3,5-triisopropylbenzene are also formed, as products of disproportionation, amounting to about 20%.