Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(N(CC)CC)C>ClCCl>[O:11]=[C:12]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: COC(=O)CCC(O)C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)CCC(=O)C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
To a solution of 0.39 ml of oxalyl chloride in 12 ml of dichloromethane was added under nitrogen atmosphere at -70° C. while stirring a solution of 0.60 ml of dimethyl sulfoxide in 4 ml of dichloromethane. To the mixture was added a solution of 0.95 g of 1-t-butyl 5-methyl 2-hydoxyglutarate obtained as above in 3.5 ml of dichloromethane. The whole mixture was stirred for 15 minutes at -70° C., to which was added 3.0 ml of triethylamine. The temperature of the reaction mixture was raised to -40° C., and the reaction mixture was poured into ice-water, followed by extraction with dichloromethane. The extract was wahsed with water, dilute acetic acid and water, in sequence, which was then dried (Na2SO4.), followed by distilling off the solvent. The residue was subjected to a silica gel column chromatography, eluting with hexane-ethyl acetate (5:1), followed by combining fractions containing the end product. Thus combined eluate was concentrated under reduced pressure to give 0.60 g of 1-t-butyl 5-methyl 2-oxoglutarate as a colorless oily substance.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([F:28])[CH:22]=1>CN(C=O)C>[ClH:2].[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[C:23]([F:28])[CH:22]=1
Reactant: COCCOc1cc2nccc(Cl)c2cc1OC
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1OC
Temperature: 150 °C
Yield: 50.6 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (3 g, 9.8 mmol), (prepared as described for the starting material in Example 5), and 4-chloro-2-fluoroaniline (2.2 ml, 19.6 mmol) in DMF (50 ml) was heated at 150° C. for 30 minutes. After dilution with isopropanol (50 ml), the precipitate was collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (2.05 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:49])C=1.OS([O-])=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16]([CH3:17])=[O:49])[CH:7]=1
Reactant: COC(=O)N(Cc1cc(SC)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(S(C)=O)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: -78 °C

Procedure:
Methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-(methylthio)-5-(trifluoromethyl)benzyl]carbamate (21.7 mg, 0.037 mmol) (Example 129) in CH2Cl2 (1 mL) was cooled to −78° C. Next, m-CPBA (8.3 mg, 0.037 mmol) was added. The reaction was stirred at −78° C. for fifteen minutes, then was warmed to 45° C., and after five minutes at −45° C. was poured into NaHSO3 (10 mL). The mixture was extracted with EtOAc (50 mL), and the organic extracts were washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 50% EtOAc/hexanes afforded methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-(methylsulfinyl)-5-(trifluoromethyl)benzyl]carbamate. Rf=0.20 (50% EtOAc/hexanes). LCMS=602.2 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.63 (broad singlet, 1H), 7.54 (broad singlet, 1H), 7.48 (broad singlet, 1H), 7.33 (s, 1H), 7.32 (s, 1H), 7.07-7.05 (m, 2H), 6.89 (s, 1H), 6.62 (d, J=8.0 Hz, 1H), 4.41 (broad singlet, 2H), 4.04 (broad singlet, 2H), 3.37 (s, 3H), 3.30 (s, 3H), 2.75 (m, 1H), 1.93 (s, 3H), 1.16 (d, J=6.5 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.BrC1C=CN=C(N)C=1.[CH3:19][N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:19][N:20]1[C:24]([C:2]2[CH:7]=[CH:6][N:5]3[CH:8]=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:23][CH:22]=[N:21]1
Reactant: Brc1ccn2ccnc2c1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Nc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1nccc1-c1ccn2ccnc2c1
Temperature: 75 °C
Yield: 70 %

Procedure:
A solution of 7-Bromo-imidazol[1,2-a]pyridine (0.5 g, 2.54 mmol, 1 equivalent, made according to general procedure A1 using 4-bromo-pyridin-2-ylamine instead of 4-chloro-pyridin-2-ylamine), 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 5.08 mmol, 2 equivalents), bis(tri-t-butylphosphine)palladium(0) (66 mg, 0.13 mmol, 0.05 equivalents) and potassium carbonate (2.1 g, 15.24 mmol, 6 equivalents) in ethanol (10 ml), toluene (10 ml) and water (10 ml) was heated at 75° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was then washed with a saturated brine solution, dried (MgSO4), filtered and the solvent removed by evaporation in vacuo. The residue was purified by column chromatography (Biotage SP4, 25S, flow rate 25 ml/min, gradient 0% to 20% methanol in ethyl acetate) to give 7-(2-methyl-2H-pyrazol-3-yl)-imidazo[1,2,a]pyridine as a colourless oil (350 mg, 70%). MS: [M+H]30 199.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1([CH3:18])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]([CH3:16])[C:6]1=[O:17].[OH-].[Na+]>CO>[CH3:16][N:7]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([CH3:18])([CH2:4][C:3]([OH:19])=[O:2])[C:6]1=[O:17]
Reactant: COC(=O)CC1(C)C(=O)N(C)c2ccc(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)C(C)(CC(=O)O)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Methyl ester 3 (8 g) was dissolved in methanol (200 ml) containing sodium hydroxide (10 g), and the reaction mixture was stirred at r.t. (room temperature) for 2 h. The solvent was evaporated, the residue rendered acidic with 3N HCl, then extracted with ethyl acetate, the extract dried (MgSO4) and evaporated, to give colorless crystals of 1,3-dimethyl-5-methoxyoxindole-3-acetic acid (4, 7.1 g, 94%) of m.p. 120°-121° degrees C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].C(Cl)Cl.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.N1C=CC=CC=1>O>[O:18]=[C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:19])[N:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCCCN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 24 h

Procedure:
783 mg of 2-(7-hydroxyheptyl)isoindol-1,3-dione was added to 40 mL of DCM, and 800 mg of p-toluenesulfonyl chloride was added. Pyridine was then added dropwise with stirring, and the mixture was stirred overnight. After 24 h, 100 mL of water was added to the reaction system, which was then violently vibrated and isolated. The water layer was extracted with 50 mL of DCM. The organic layers were combined, successively washed with 100 mL of 5% citric acid aqueous solution, 100 mL of saturated sodium carbonate aqueous solution, and 100 mL of saturated sodium chloride aqueous solution, dried over 5 g of MgSO4 for 30 min, and concentrated via a rotary evaporator to obtain an oily liquid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.Cl.[NH:31]1[CH2:34][CH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32]1>ClCCl>[C:19]([C:7]1[C:5]2[N:6]=[C:2]([N:31]3[CH2:34][CH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32]3)[O:3][C:4]=2[C:10]([F:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:18])#[N:20]
Reactant: CCOC(=O)C1CNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)C1

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.45 g, 1.57 mmol) was dissolved in dichloromethane (15 ml), then diisopropylethylamine (0.6 ml, 3.53 mmol) and ethyl azetidine-3-carboxylate hydrochloride (I-147) (0.55 g) were added. After heated under reflux for 3 hours, this was diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=70:1) to obtain a brown oil (0.60 g, quant).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][OH:32])[CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:32][CH2:31][CH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:25][CH2:26]1
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(Cl)n2n1
Reactant: OCCC1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cc2nc(NC(=O)C3CC3c3ccccc3)cc(N3CCC(CCO)CC3)n2n1
Temperature: 25 °C
Yield: 3.5 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropanecarboxamide (8C, 200 mg, 0.612 mmol) and 2-(piperidin-4-yl)ethanol (158 mg, 1.2 mmol) in NMP (1.85 mL) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 40-50% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (9 mg, 4%). 1H NMR (METHANOL-d4) δ: 7.25-7.31 (m, 2H), 7.14-7.23 (m, 4H), 6.07 (s, 1H), 4.41 (d, J=12.1 Hz, 2H), 3.67 (t, J=6.6 Hz, 2H), 2.98 (td, J=12.4, 2.4 Hz, 2H), 2.51 (ddd, J=9.2, 6.4, 4.3 Hz, 1H), 2.40 (s, 3H), 2.15-2.23 (m, 1H), 1.85 (br. s., 2H), 1.29-1.69 (m, 7H). ESI-MS: m/z 420.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[OH:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:35]5[CH:34]=[C:29]([CH:28]=[C:27]([OH:26])[CH:36]=5)[C:30]([O:32][CH3:33])=[O:31])[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COC(=O)c1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cc(O)cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c1
Temperature: 120 °C
Yield: 97.9 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (130 mg, 0.36 mmol) was dissolved in 1,2-dimethoxyethane (3.6 mL) in a reaction tube. Methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (150 mg, 0.55 mmol), aqueous 2 M sodium carbonate (0.37 mL), and (Ph3P)4Pd (21 mg, 0.018 mmol) were added and the reaction mixture was heated at 120° C. for 30 minutes in the microwave. The resulting material was cooled to room temperature, filtered, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield methyl 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclo-propanecarboxamido)-3-methylpyridin-2-yl)-5-hydroxybenzoate (170 mg, 99%) as a white solid. ESI-MS m/z calc. 482.1. found 483.53 (M+1)+. Retention time 1.83 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.Cl.[C:9](=[NH:20])(SCCC)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[CH3:7][C:5]1[O:4][N:3]=[C:2]([NH:1][C:9](=[NH:20])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1
Reactant: CCCSC(=N)c1ccccc1
Reactant: Cc1cc(N)no1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(NC(=N)c2ccccc2)no1
Reaction time: 8 h
Yield: 55.7 %

Procedure:
In a 1 liter flask provided with a condenser, a thermometer and a stirring device are added 250 ml acetonitrile, 24.5 g 3-amino-5-methyl-isoxazole. This gives a solution to which are added 54 g propyl thiobenzimidate hydrochloride, and the resulting suspension is then refluxed. Dissolution is found to occur. Refluxing is maintained 2 hours. The material crystallizes and is left aside overnight, after which it is filtered, suction filtered and dried. Crystallization from isopropanol and reconversion to the base by addition of the suitable amount of sodium hydroxide solution give 28 g N-(5-methyl-isoxazol-3-yl)-benzamidine. (Yield: 56%). M.p. (capillary tube): 127°-129° C.
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([NH:38][C:39]([NH:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[O:40])[CH:35]=[CH:36][CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[F:44][C:43]([F:45])([F:46])[CH2:42][NH:41][C:39]([NH:38][C:34]1[CH:35]=[C:36]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=4)=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:37]=[CH:32][CH:33]=1)=[O:40]
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Reactant: CCOC(=O)C(C)c1ccc(-c2cnn3c(I)cnc3c2)cc1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (12 mg, 0.017 mmol) was added to a mixture of ethyl 2-[4-(3-iodoimidazo[1,2-b]pyridazin-7-yl)phenyl]propanoate (0.24 g, 0.58 mmol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (240 mg, 0.70 mmol), sodium carbonate (130 mg, 1.2 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) and then the reaction was vacuumed and refilled with nitrogen for 3 times. The reaction was stirred at 95° C. overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in methylene chloride (0-10%) to afford the desired product. LCMS (M+H)+: m/z=512.1
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)=[CH:4][CH:3]=1.[C:18]([O:24][CH3:25])(=[O:23])[CH2:19][C:20]([CH3:22])=[O:21].N1CCCCC1.C(O)(=O)C>C(O)(C)C>[C:20]([C:19](=[CH:10][C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[O:7][CH2:6][C:5]1[CH:16]=[CH:17][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:18]([O:24][CH3:25])=[O:23])(=[O:21])[CH3:22]
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ccc(COc2ccccc2C=O)cc1
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1ccccc1OCc1ccc(C)cc1)C(C)=O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
25 g (110.6 millimols) of 2-(4-methylbenzyloxy)-benzaldehyde were stirred with 11.9 ml (110.6 millimols) of methyl acetoacetate in 66 ml of isopropanol, and a freshly prepared solution of 0.64 ml of piperidine and 0.38 ml of glacial acetic acid in 5.5 ml of isopropanol was added. The mixture was stirred for 1 hour at 60° C. and for 4 hours at 40° C., and was cooled and concentrated. The residue from evaporation was dissolved in ether, and the solution was washed successively with approx. 100 ml of 1N hydrochloric acid, with two portions of water, with saturated sodium bicarbonate solution and again with two portions of water. The ether phase was dried, filtered and concentrated. 35.3 g (98.51% of theory) of a dark yellow oil were obtained, and the oil was reacted further in the crude form.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[CH:28]1([C:34]2[C:35]3[CH:36]=[CH:37][C:38]([C:57]([O:59]C)=[O:58])=[CH:39][C:40]=3[N:41]3[C:48]=2[C:47]2[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=2[O:45][CH2:44][C:43]([CH2:55]O)([CH2:53]O)[CH2:42]3)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CC[N:63](C(C)C)[CH:64]([CH3:66])[CH3:65].C(N)(C)C>CO.C1COCC1.CC#N.CCOC(C)=O>[CH:28]1([C:34]2[C:35]3[CH:36]=[CH:37][C:38]([C:57]([OH:59])=[O:58])=[CH:39][C:40]=3[N:41]3[C:48]=2[C:47]2[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=2[O:45][CH2:44][C:43]2([CH2:53][N:63]([CH:64]([CH3:66])[CH3:65])[CH2:55]2)[CH2:42]3)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)(CO)COc1ccccc1-3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)N
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)N1CC2(COc3ccccc3-c3c(C4CCCCC4)c4ccc(C(=O)O)cc4n3C2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 4 %

Procedure:
A catalytic amount of para-toluenesulfonic acid monohydrate was added to a suspension of methyl 14′-cyclohexyl-2,2-dimethylspiro[1,3-dioxane-5,7′-indolo[1,2e][1,5]benzoxazocine]-11′-carboxylate in MeOH/THF 1:2 (0.03 M), and the solution was stirred for 3 h at RT. Filtration over a pad of neutral alumina with EtOAc afforded after evaporation of the solvent in vacuo, methyl 14-cyclohexyl-7,7-bis(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (quant). Triflic anhydride (2.8 eq) was added at 0° C. to a solution of methyl 14-cyclohexyl-7,7-bis(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in dry MeCN (0.05M), DIPEA (3.0 eq) was added and the mixture was stirred for 15 min at 0° C., then further 3.0 eq of DIPEA were added, followed by iPrNH2 (2 eq). The mixture was transferred into a closed vessel and stirring was continued at 70° C. for 4 h. EtOAc was added, the organic phase was washed with water and brine, dried over Na2SO4 and the solvent was removed in vacuo. The residue was hydrolysed with aqueous 1N KOH in dioxane (65° C., overnight); evaporation to dryness gave a residue that was purified by RP-HPLC to afford the title compound (4%). 1H NMR (300 MHz, DMSO-d6, 330 K) δ 8.50 (s, 1H), 7.87 (d, 1H, J 8.3), 7.70 (d, 1H, J 8.3), 7.51-7.46 (m, 1H), 7.24-7.15 (m, 3H), 5.16 (b.d, 1H, J 15.9), 4.28 (d, 1H, J 12.7), 4.20 (d, 1H, J 12.7), 4.1-3.5 (m, 6H), 2.75-2.66 (m, 1H), 2.01-1.58 (m, 7H), 1.39-1.17 (m, 9H); MS (ES+) m/z 459 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O.[OH-].[K+]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:16])([F:17])[F:15])[C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(F)cc(C(F)(F)F)c2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])c(C(F)(F)F)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.8 %

Procedure:
To a solution of 7-fluoro-5-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (60 mg, 0.24 mmol) in concentrated H2SO4 (1 mL) at 0° C. was added KNO3 (27 mg, 0.26 mmol, Baker). The mixture was stirred at 90°-100° C. for 14 h, then cooled to room temperature and poured into ice water (2 g). The precipitate was collected by filtration, affording 64 mg (90%) of crude title compound. It was dissolved in 1N KOH (2 mL) and filtered. The filtrate was acidified to pH=2 with 4N HCl to give a yellow precipitate, which was collected by filtration, then was dried in the air at 50° C. for 4 h, affording pure title compound (54 mg, 76%) as a yellow powder. Mp: 305°-307° C.; IR (KBr, cm-1): 3418, 3124, 2971, 1717, 1624, 1556; 1H NMR (DMSO-d6): δ 7.422 (d, 1H, J=10.2 Hz), 11.765 (br, 1H), 12.532 (s, 1H). HRMS: calcd for C9H3F4N3O4 (M+) m/z: 293.0086, found: 293.0071.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[N+:17]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].O.[S-2].[Na+].[Na+]>CO>[CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cc([N+](=O)[O-])ccc1NC1CCCCC1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 2.2 g (8,3 mmol) N-cyclohexyl-2,4-dinitroaniline, 1.95 g (36.4 mmol) ammonium chloride, 7.85 g (32.7 mmol) sodium sulfide hydrate and 100 ml methanol was refluxed for 1 h. After cooling to 25° C. the mixture was filtered and evaporated The product was stirred with water to give 1.6 g (82%) N-cyclohexyl-2-amino-4-nitroaniline. 1H-NMR (CDCl3 ): 7.9-7.4 (2H, m), 6.5 (1H, d), 4.4 (1H, broad s), 3.4 (2H, broad s), 2.3-0.8 (11H, m).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:25])=[CH:6][C:7]2[O:11][CH:10]=[C:9]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[C:8]=2[CH:24]=1)[CH:2]=[CH2:3]>C(O)(=O)C.[Pd]>[OH:25][C:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[CH:24][C:8]2[CH:9]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[CH2:10][O:11][C:7]=2[CH:6]=1
Reactant: C=CCc1cc2c(-c3cc(OC)c(OC)c(OC)c3)coc2cc1O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCc1cc2c(cc1O)OCC2c1cc(OC)c(OC)c(OC)c1
Reaction time: 2.5 h
Yield: 68.4 %

Procedure:
A solution of 5-allyl-6-hydroxy-3-(3,4,5-trimethoxyphenyl)benzofuran (130 mg) in glacial acetic acid (1 ml) containing 10% palladium-on-charcoal (50 mg) was hydrogenated for 2.5 h. The mixture was filtered and the filtrate was evaporated to give 6-hydroxy-3-(3,4,5-trimethoxyphenyl)-5-propyl-2,3-dihydrobenzofuran (90 mg).