Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]([CH2:12][CH2:13][CH:14]=[C:15](C)[CH2:16][CH2:17][CH:18]=[C:19](C)C)[CH2:3][CH2:4][O:5]C1CCCCO1.[CH3:23]OCCOC.BrN1C(=O)CCC1=O>O>[CH3:23][CH:4]([OH:5])[CH2:3][CH2:2][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COCCOC
Reactant: CC(C)=CCCC(C)=CCCC(C)CCOC1CCCCO1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Product: CCCCCC=CCCCC(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 22.0 g (71 mmol) of tetrahydro-2-[(3,7,11-trimethyl-6,10-dodecadienyl)oxy]-2H-pyran, 80 ml of 1,2-dimethoxyethane and 16 ml of water is treated at -50° within 30 minutes with 13.5 g (76 mmol) of N-bromosuccinimide. The mixture is subsequently stirred at 0° for a further 2 hours and at room temperature for 30 minutes. The reaction mixture is then poured into ice-water, whereupon the mixture is extracted three times with ethyl acetate. The combined organic phases are washed firstly with saturated sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. There is obtained crude (E)-3-bromo-2,6,10-trimethyl-12-[(tetrahydro-2H)-pyran-2-yl)oxy]-6-dodecen-2-ol which is subsequently dissolved in 100 ml of methanol and treated at 0° with 14.0 g (0.1 mol) of potassium carbonate. After stirring at 0° for 15 hours the mixture is filtered over Hyflo, whereupon the filtrate is evaporated and the residue is taken up in 600 ml of ice-water and extracted three times with ether. The combined organic phases are washed with water, dried over sodium sulphate, filtered and evaporated. The residue is chromatographed on silica gel with hexane-ethyl acetate 4:1. There is obtained (E)-2-[(10,11-epoxy-3,7,11-trimethyl-6-dodecen-1-yl)oxy]tetrahydro-2H-pyran which is subsequently boiled under reflux for 18 hours together with 8.0 g (40 mmol) of aluminum isopropylate in 80 ml of toluene. The reaction mixture is then evaporated and the residue is taken up in 300 ml of 2N hydrochloric acid. After two-fold extraction with ether the combined organic phases are washed firstly with saturated sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. There is obtained (E)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6-dodecadien-3-ol which is dissolved in 130 ml of methanol and stirred at room temperature for 4 hours together with 13 g of strongly acidic ion-exchanger (Dowex 50 W X 8). After filtration and removal of the solvent in a rotary evaporator there remains behind a yellowish oil which is chromatographed on silica gel with hexane-ethyl acetate 2:1 with the addition of 0.1% triethylamine. There is obtained (E)-3,7,11-trimethyl-6,10-dodecadiene-1,10-diol in the form of a colourless oil. MS: 240 (M)+, 222 (M--H2O)+.
Reaction SMILES: [C:1]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[CH2:16]([OH:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:18]
Reactant: O=C1CCCCCCCCCCCCCCCO1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCCCCCCCCCCCCCCO
Reaction time: 1 h

Procedure:
Under an argon atmosphere, 16-Hexadecanolide (4.860 g, 18.5 mmol) in THF (80 mL) was added with stirring to a suspension of lithium aluminium hydride (1.280 g, 33.7 mmol, 1.8 eq.) in THF (160 mL) at 0° C. Stirring was continued at this temperature for 1 h and for 3 more hours at r.t. Potassium sodium tartrate solution was carefully dropped to this mixture with stirring. The phases were separated and the aqueous phase was extracted with diethyl ether (3×100 mL). The combined organic layer was dried over MgSO4. After evaporation of the solvent, the product was isolated as a white solid, which was used for the next step without purification. Yield: 4.598 g (96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].[CH3:11][O:12][C:13]([CH:15]1[CH2:19][CH2:18][CH:17](OS(C)(=O)=O)[CH2:16]1)=[O:14]>C1COCC1>[CH3:11][O:12][C:13]([CH:15]1[CH2:19][CH2:18][CH:17]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:16]1)=[O:14]
Reactant: Sc1ccccc1Cl
Reactant: COC(=O)C1CCC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCC(Sc2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-chlorothiophenol (0.19 g, 1.5 eq) in THF (6.0 mL) was treated with NaH (60% dispersion in mineral oil, 0.05 g, 1.5 eq). The resulting solution was stirred at RT for 30 min. A solution of 3-methanesulfonyloxy-cyclopentanecarboxylic acid methyl ester (0.20 g, 1.0 eq) in THF (2.0 mL) was then added dropwise. The mixture was warmed at 50° C. and stirred for 3 h. The mixture was partitioned between 1N sodium bicarbonate and ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. The title compound was obtained as a colorless oil (0.24 g, 98%) and was used without further purification in the next step. MS (ESI): m/z=271.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]
Reactant: CCOC(=O)C=Cc1cccnc1
Reactant: COc1n[nH]c2cc(Br)ccc12
Product: CCOC(=O)C=C(c1cccnc1)c1ccc2c(OC)n[nH]c2c1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-3-pyridin-3yl-acrylic acid ethyl ester was prepared from 6-bromo-3-methoxy-1H-indazole and 3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl esterLVIII (Example 14).
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][OH:12].[H-].[Na+].[Na+].[I-]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:11][O:12][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 15.8 g of ethyl 4-chloroacetoacetate (96.2 mmol) and 3.39 g of methanol (106 mmol) in 10 mL of THF were added dropwise to a stirred suspension of 4.62 g of 60% NaH (in mineral oil), 1.60 g of NaI (9.62 mmol), and 3.10 g of tetrabutylammonium bromide (9.62 mmol) in 40 mL of THF at -30° C. over a period of 1.5 hrs. The reaction mixture was then warmed to room temperature and stirred for 4 days. The reaction mixture was cooled to -30° C., quenched with 5 mL of methanol, and warmed to room temperature. The reaction mixture was poured into 0.5 L of 10% HCl solution, extracted with 2×100 mL of EtOAc, dried (Na2 SO4), and the solvent was removed in vacuo. The crude product was distilled. The fraction boiling at 65°-70° C. (0.3 mm Hg) was collected and used in the next experiments after spectral characterization.
Reaction SMILES: [I-].[Na+].[CH2:3]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([O:13]C)[N:10]=[C:9]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:8]=1)[CH3:4].Cl[Si](C)(C)C>C(#N)C>[CH2:3]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([OH:13])[N:10]=[C:9]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:8]=1)[CH3:4]
Reactant: CCOC(=O)c1cc(N[C@@H](C)CC)nc(OC)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(O)nc(N[C@@H](C)CC)c1
Yield: 56.3 %

Procedure:
Treat sodium iodide (5.58 g, 36.7 mmol) and (S)-2-sec-butylamino-6-methoxy-isonicotinic acid ethyl ester (1.85 g, 7.3 mmol) in acetonitrile (30 mL) with chlorotrimethylsilane (4.66 mL, 36.7 mmol) and stir at reflux for 38 h. Quench with methanol (10 mL), stir for 24 h, and concentrate. Dissolve residue in ethyl acetate, wash with water, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 70:30 to 100:0 ethyl acetate:hexanes) to give the title compound (0.98 g, 56%).
Reaction SMILES: CS([Cl:5])(=O)=O.[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=1)[CH:7]=[CH2:8].C(N(CC)CC)C>ClCCl>[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Cl:5])=[CH:12][CH:11]=1)[CH:7]=[CH2:8]
Reactant: C=CCOc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.67 g (67.0 mmol) methanesulfonyl chloride were given at 0° C. to a solution of 10.0 g (60.9 mmol) (4-allyloxy-phenyl)-methanol and 9.34 ml (67.0 mmol) triethylamine in 35 ml dichloromethane and stirred at r.t. overnight. The mixture was poured in ice water, extracted with dichloromethane and the organic phase dried over Na2SO4. After removal of solvents the residue was purified by chromatography on silica gel (ethyl acetate/n-heptane 1:5) to yield 3.12 g (28%) pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]([CH3:18])([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH:21]=[CH2:22].P(OC1C=CC(C)=CC=1)(OC1C=CC(C)=CC=1)OC1C=CC(C)=CC=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:25]([O:24][C:20](=[O:23])[CH:21]=[CH:22][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])([CH3:18])[CH3:17])[CH:11]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(Cc1cccc(Br)c1)NC(=O)OC(C)(C)C
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(OP(Oc2ccc(C)cc2)Oc2ccc(C)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(Cc1cccc(C=CC(=O)OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Yield: 90 %

Procedure:
A mixture of [2-(3-bromophenyl)-1,1-dimethylethyl]carbamic acid tert-butyl ester (preparation 32), (2 g, 6.09 mmol), benzyl acrylate (2 g, 12.19), palladium (II) acetate (204 mg, 0.91 mmol), tri-p-tolyl phosphite (556 mg, 1.83 mmol) and triethylamine (2.12 mL, 15.22 mmol) in acetonitrile (100 mL) was heated under reflux for 48 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate:pentane to afford the title compound as a pale yellow oil in 90% yield, 2.23 g.
Reaction SMILES: [Cl-].C([Al+]CC)C.[Br:7][C:8]1[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]([CH:16]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[F:32])[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[C:10]([C:33]([O:35]C)=O)[CH:9]=1>>[Br:7][C:8]1[N:12]([CH:13]([CH3:14])[CH3:15])[C:11]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=3)[N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=3[F:32])[C:33](=[O:35])[C:10]=2[CH:9]=1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(Nc1cccc(Cl)c1F)c1ccc(Cl)cn1
Agent: CC[Al+]CC
Agent: [Cl-]
Product: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cn1)N(c1cccc(Cl)c1F)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Step H1, but diethylaluminium chloride (1.8M in toluene) was used instead of trimethylaluminium chloride, and methyl 5-bromo-2-(((3-chloro-2-fluorophenyl)amino)(5-chloropyridin-2-yl)methyl)-1-isopropyl-1H-pyrrole-3-carboxylate (Step BT1) was used instead of 2-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester to afford the title compound as a green solid. ESI-MS: tR=1.27 min, [M+H]+ 482/484/486 (LC-MS 1).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:24][O:25][C:26]1[N:31]=[C:30]2[S:32][C:33]([NH2:35])=[N:34][C:29]2=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:35][C:33]3[S:32][C:30]4[C:29]([N:34]=3)=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[N:31]=4)=[O:16])=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: COc1ccc2nc(N)sc2n1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2n1
Yield: 42.1 %

Procedure:
The compound of example A80 was obtained by similar method described in example A75 using (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.5 g,1.32 mmol), 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (0.286 g, 1.59 mmol), HOBt (0.267 g, 1.98 mmol), and EDCI (0.378 g,1.98 mmol), N-methyl morpholine (0.4 g, 3.97 mmol) in DMF (10 mL) to provide the title compound (0.280 g).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@H:8]([S:10]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][C@H:6]1[CH2:30][OH:31])(=[O:4])=[O:3].Br[CH2:33][CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[CH3:1][S:2]([N:5]1[C@H:6]([CH2:30][O:31][CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:7][C@@H:8]([SH:10])[CH2:9]1)(=[O:3])=[O:4]
Reactant: BrCC=Cc1ccccc1
Reactant: CS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1C[C@H](S)C[C@H]1COCCCc1ccccc1

Procedure:
(2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-yl)-methanol with 3-bromo-1-phenyl-1-propene, followed by hydrogenation (17 h) and TFA/triethylsilane deprotection (Method 3) gave (3R,5S)-1-methanesulfonyl-5-(3-phenyl-propoxymethyl)-pyrrolidine-3-thiol, MS: 329 (M).
Reaction SMILES: [CH:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[C:24]([C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][NH:32][CH2:33]4)=[CH:28][CH:27]=3)[N:23]=[C:22]([NH2:36])[N:21]=2)[CH2:16][CH2:15]1>>[CH:1]1([CH:7]([CH3:11])[C:8]([N:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][C:26]([C:24]4[CH:25]=[C:20]([N:17]5[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]5)[N:21]=[C:22]([NH2:36])[N:23]=4)=[CH:27][CH:28]=3)[CH2:33]2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CC(C(=O)O)C1CCCCC1
Agent: Cl
Product: CC(C(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1)C1CCCCC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from 2-cyclohexylpropanoic acid and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=463.3.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]=[C:3]1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:24]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7]([CH3:8])=[O:24])=[N:5][N:4]=[C:3]1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: CSc1nnc(-c2ccc3ccccc3c2)n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(-c2ccc3ccccc3c2)nnc1S(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, 0° C., solution of 4-methyl-5-methylthio3-(2-naphthyl)-4H-1,2,4-triazole (4.00 g, 1.57×10-2 mole) and CH2Cl2 (110 ml) was added portionwise m-chloroperoxybenzoic acid (3.38 g, 1.57×10-2 mole). After stirring overnight at room temperature the reaction was diluted with CH2Cl2 (200 ml), washed two times with saturated aqueous NaHCO3 and one time with saturated aqueous NaCl, and dried over anhydrous N2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an off-white solid which was purified by flash chromatography (4% CH3OH/CH2Cl2). Crystallization from toluene afforded small colorless plates: 2.5 g (59%), mp 224°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, to the solution of 2-chloro-4-fluoro-5-nitro-benzoic acid (1.0 g, 4.56 mmol in 40 mL of DCM at 0° C. are added thionyl chloride (1.0 mL, 13.68 mmol) and 0.1 mL of DMF sequentially. The reaction mixture was warmed gradually to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo to afford 2-chloro-4-fluoro-5-nitrobenzoyl chloride. The crude was dissolved in 40 mL of DCM, and 1-boc-4-aminopiperidine (910 mg, 4.56 mmol) and triethylamine (1.29 mL, 9.12 mmol) were added to the solution sequentially. After stirring at room temperature 1 h, the reaction mixture was washed with 20 mL of water. The organic extract was dried (Na2SO4), followed by concentration in vacuo to afford tert-Butyl 4-(2-chloro-4-fluoro-5-nitrobenzamido)piperidine-1-carboxylate; ESMS m/z 402.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[C:9]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[O:33]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)C(O)=O>C(Cl)Cl.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.CN(C=O)C.O>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[C:8]([C:43]3[CH:44]=[CH:45][C:40]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:41][CH:42]=3)[C:9]=2[CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(-c2c(C3CCN(C(=O)OC(C)(C)C)CC3)c(Br)c3c(N)ncnn23)c1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2c(C3CCNCC3)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnn23)c1
Temperature: 100 °C
Yield: 32.5 %

Procedure:
The compound (25 mg, 0.050 mmol) prepared in Example 24, 4-phenoxyphenylboronic acid (10.65 mg, 0.050 mmol), potassium phosphate (10.56 mg, 0.050 mmol) and Pd(PPh3)4 (11.50 mg, 0.01 mmol) were added to a small pressure tube and DMF/water (1 mL/0.5 mL) was added. The reaction mixture was flushed with argon for 5 minutes then sealed. The reaction was heated to 100° C. for 24 hours. The DMF was removed under vacuum and the product was isolated by prep-HPLC. The product was then treated with trifluoroacetic acid (TFA) in DCM for 2 hours. The solvent (DCM/TFA) was removed under vacuum and the residue taken up in ethyl acetate/1N sodium hydroxide. The organic layer was separated and aqueous layer extracted with ethyl acetate, dried over sodium sulfate, filtered and solvent removed. Solid was dried under vacuum to obtain the title compound (8 mg) having the following physical data.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11](OS(C(F)(F)F)(=O)=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN1C(=O)CCC1>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3c(OC(C)C)n2)n[nH]1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2cc3cc(N4CCN(C)CC4)ccc3c(OC(C)C)n2)n[nH]1
Temperature: 200 °C

Procedure:
A 2.0˜5.0 mL process vial was charged with Trifluoro-methanesulfonic acid 1-isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl ester (100 mg) in 2 mL NMP. Excess 1-Methyl-piperazine was added to the mixture. The vial was heated at 200° C. for 2 h under microwave irradiation. After cooling, the reaction mixture was sent to prep-HPLC to give 5 mg of [1-Isopropoxy-6-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 381 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:27][C:28]1([CH3:44])[O:33][CH:32]([C:34]([NH:36][CH2:37][CH2:38][C:39](O)=[O:40])=[O:35])[C:31]([CH3:43])([CH3:42])[CH2:30][O:29]1>>[C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:39](=[O:40])[CH2:38][CH2:37][NH:36][C:34]([CH:32]1[C:31]([CH3:42])([CH3:43])[CH2:30][O:29][C:28]([CH3:44])([CH3:27])[O:33]1)=[O:35])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCCCN
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCCCNC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 60 %

Procedure:
N-(5-Aminopentyl)oleamide (3.66 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 3.64 g of the title compound (yield: 60%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:32])=[CH:26][CH:25]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCO)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOC(=O)Cc3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(3-hydroxypropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and (4-fluorophenyl)acetyl chloride: ESMS m/e: 441.3 (M+H)+.