Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16]C3C(=O)[N:13]([CH2:18][C:19]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][NH:28][CH3:29])=[CH:23][CH:22]=4)=[O:20])[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)CC)C.[O:41]1CC[CH2:43][CH2:42]1>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:31]3[C:30](=[O:32])[N:13]([CH2:18][C:19]([C:21]4[CH:22]=[CH:23][C:24]([CH2:27][N:28]([CH3:29])[C:42](=[O:41])[CH3:43])=[CH:25][CH:26]=4)=[O:20])[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CNCc1ccc(C(=O)Cn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: C1CCOC1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N(C)Cc1ccc(C(=O)Cn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the compound (50 mg) obtained in Example 13, acetyl chloride (10 mg), triethylamine (18 mg) and tetrahydrofuran (1 ml) was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and water, and the precipitate was collected by filtration to give the title compound (39 mg) as a colorless powder.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([PH:12](=[O:16])[O:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH3:11].[CH3:17][Si:18]([CH3:21])([CH3:20])Cl.[O:22]1[CH2:36][CH:23]1[CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>O1CCCC1.ClCCl.[Cl-].[Zn+2].[Cl-]>[C:26]1(=[O:35])[N:25]([CH2:24][CH:23]([O:22][Si:18]([CH3:21])([CH3:20])[CH3:17])[CH2:36][P:12]([CH2:8][CH2:9][CH2:10][CH3:11])(=[O:16])[O:13][CH2:14][CH3:15])[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: C[Si](C)(C)Cl
Reactant: CCCC[PH](=O)OCC
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCP(=O)(CC(CN1C(=O)c2ccccc2C1=O)O[Si](C)(C)C)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3.79 g of anhydrous triethylamine and 4.5 g ethyl n-butylphosphinate in 100 ml of anhydrous tetrahydrofuran under an inert atmosphere is treated with 4.07 g of trimethylchlorosilane. The resulting suspension is stirred for 20 hours at room temperature and the solid removed by filtration. Concentration in vacuo affords a cloudy, colourless oil which is treated with 6.09 g of anhydrous N-(2,3-epoxypropyl)-phthalimide and 0.5 g of anhydrous zinc chloride. The mixture is heated to 66° C. under an inert atmosphere for 3 hours, cooled to 20° and diluted with dichloromethane. The organic solution is washed with 100 ml 10% of aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulphate. Removal of the solvent and chromatography on silica gel affords ethyl 3-phthalimido-2-trimethylsilyloxy-propyl(n-butyl)phosphinate as a viscous oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[N+]([O-])([O-])=O.[NH4+].[Sc:12]>>[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[Sc+3:12].[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[Sc+3:12]
Reactant: O=C(O)C(=O)O
Reactant: [Sc]
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Product: O=C([O-])C(=O)[O-]
Product: [Sc+3]

Procedure:
adding oxalic acid to the collected ammonium nitrate solution containing scandium to form a precipitate of scandium oxalate; and
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.C(OC(=O)[NH:27][C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:30]3[CH2:31][CH2:32][C@H:28]([NH2:27])[CH2:29]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Solvent: CN1CCOCC1
Product: N[C@H]1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)C1
Temperature: 60 °C
Yield: 21.6 %

Procedure:
The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (700 mg, 2.65 mmol) obtained in Step 6 of Example 1, (S)-(pyrrolidin-3-yl)carbamic acid tert-butyl ester (740 g, 3.98 mmol), 1-hydroxybenzotriazole monohydrate (470 mg, 3.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (710 mg, 3.72 mmol) and N-methylmorpholine (0.608 mL, 5.32 mmol) in a similar manner to Example 5, was dissolved in methanol (1.5 mL) and the solution was added with 4 moL/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 60 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was added with saturated aqueous sodium hydrogencarbonate solution and ethyl acetate, followed by extraction. The crude product was crystallized from acetone to obtain Compound 159 (190 mg, 22%).
Reaction SMILES: [OH-].[K+].Cl[C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]1([F:17])[CH2:16][CH2:15][CH2:14]1.[CH:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1>CS(C)=O>[CH:18]1([CH2:21][O:22][C:4]2[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=2[C:13]2([F:17])[CH2:16][CH2:15][CH2:14]2)[CH2:20][CH2:19]1
Reactant: OCC1CC1
Reactant: O=C(O)c1ccc(C2(F)CCC2)c(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(C2(F)CCC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.3 %

Procedure:
Powdered potassium hydroxide (240 mg, 4.28 mmol) was added to a solution of 6-chloro-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid (Example 130 e, 393 mg, 1.71 mmol) in DMSO (7.86 mL). The mixture was stirred at ambient temperature for 15 minutes. Cyclopropylmethanol (136 mg, 153 μL, 1.88 mmol) was added and stirring was continued for 5 h at 60° C. Additional cyclopropylmethanol (68 mg, 76 μL, 94 mmol) was added, the mixture was stirred for 14 h at ambient temperature, poured onto ice/brine (100 mL) and extracted with TBME (2×100 mL). The aqueous layer was acidified with 1 N HCl and extracted with EtOAc (2×150 mL). The combined organic layers were washed with ice/brine (50 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash-chromatography (20 g SiO2, dichloromethane/MeOH 0-3% in 75 min) to give the title compound (65 mg, 31%) as colorless oil, MS (ESI) m/e=264.5 [M−H−].
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:16][C:15]([N:17](C)[C:18](=O)OC(C)(C)C)=[N:14][CH:13]=1)=[O:11])[CH2:2]2.[ClH:26].O1CCOCC1>CO>[ClH:26].[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][CH3:18])=[N:14][CH:13]=1)=[O:11])[CH2:2]2
Reactant: CN(C(=O)OC(C)(C)C)c1ncc(C(=O)N[C@H]2CN3CCC2CC3)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNc1ncc(C(=O)N[C@H]2CN3CCC2CC3)s1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63 %

Procedure:
A flask is charged with tert-butyl 5-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1,3-thiazol-2-yl(methyl)carbamate (72 mg, 0.18 mmol) in MeOH (5 mL). To this suspension is added a solution of 4.0 N HCl/dioxane (10 mL) and the reaction mixture is stirred at room temperature for 3.5 hours. The solvents are removed in vacuo and the residue crystallized from IPA/ether. Yield 63%. MS (ESI) for C12H18N4OS m/z 267.2 (M+H)+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:24]([C@H:25]2[C@H:30]([OH:31])[C@@H:29]([OH:32])[C@H:28]([OH:33])[C@@H:27]([CH2:34][OH:35])[O:26]2)=[CH:23][CH:22]=[CH:21][C:5]=1[CH2:6][C:7]1[CH:16]=[C:15]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14]2)[C:8]=1C(OC)=O.C(OCC)(=O)C.Cl>CO>[CH:8]1[C:9]2[C:15]([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:16][C:7]=1[CH2:6][C:5]1[C:4]([F:3])=[C:24]([C@@H:25]2[O:26][C@H:27]([CH2:34][OH:35])[C@@H:28]([OH:33])[C@H:29]([OH:32])[C@H:30]2[OH:31])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1c(Cc2cccc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2F)cc2cccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3)c2F)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 60.3 %

Procedure:
10% aqueous solution of sodium hydroxide (2 ml) was added to a solution of methyl 2-[2-fluoro-3-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]benzyl]azulene-1-carboxylate (19 mg) in methanol (2 ml). The mixture was refluxed with heating for 2 hours. The reaction mixture was neutralized by adding a 4 M ethyl acetate solution of hydrochloric acid and the solvent was evaporated under reduced pressure. Acetonitrile (5 ml) and a 4 M ethyl acetate solution of hydrochloric acid (1 ml) were added to the resulting residue and the mixture was refluxed with heating for 30 minutes. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[3-(azulen-2-ylmethyl)-2-fluorophenyl]-D-glucitol (10 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1(=O)[O:10][CH2:9][CH2:8][CH2:7]1>>[OH:5][CH2:4][CH2:3][CH2:2][N:1]1[CH2:6][CH2:7][CH2:8][C:9]1=[O:10]
Reactant: O=C1CCCO1
Reactant: NCCCO
Product: O=C1CCCN1CCCO
Yield: 78.6 %

Procedure:
3-aminopropanol reacted in similar manner to Example 2 with butyrolactone furnished a 78.6% yield of N-(3-hydroxypropyl)-2-pyrrolidinone, b.p. 160° C./3 torr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][C:19]([NH2:21])=O)[CH:14]=3)[C:9]2=[O:22])=[CH:5][CH:4]=1.N1C(Cl)=NC(Cl)=NC=1Cl>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][C:19]#[N:21])[CH:14]=3)[C:9]2=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2CCc3cc(CC(N)=O)ccc3C2=O)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCc3cc(CC#N)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To a suspension of 1.3 g of 2-[2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-acetamide in 5 mL of THF and 10 mL of DMF was added 370 mg of cyanuric chloride and after stirring at room temperature for 0.5 hour, the reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with 5% sodium bicarbonate, followed by brine and then dried over sodium sulfate. Purification by flash chromatograpy on silica gel column using 75% ethyl acetate in hexane as eluent afforded 1.2 g of [2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(=O)C(Cl)=O.C[N:22](C=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH2:22])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CC(N)=O)cc1OC
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of 35.31 g (0.18 mole) of (3,4-dimethoxyphenyl)acetic acid in 345 ml of dry toluene and 34.5 ml of dry DMF at 0° C. under argon was added 16.8 ml (0.19 mole) of freshly distilled oxalyl chloride over 40 minutes. The reaction was stirred an additional 35 minutes at 0° C. and then at room temperature for 17 hours. The reaction mixture was again cooled to 0° C. and gaseous ammonia slowly bubbled through it for 1 hour. The reaction mixture was warmed to room temperature and stirred for 4 hours after which the solid was filtered off and partitioned between chloroform and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo giving 20.84 g of the title compound as an off-white solid, mp 142°-144° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13]1.[CH3:36][NH2:37]>O.O1CCOCC1>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:12]4([C:6]5[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:37][CH3:36])[CH2:14][CH2:13]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3cc(F)ccc3OCCCl)CC2)c1=O
Solvent: O
Solvent: C1COCCO1
Product: CNCCOc1ccc(F)cc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CC1

Procedure:
3-[3-[[1-[2-(2-chloroethoxy)-5-fluorophenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 278e, 0.25 g) and 40% methylamine in water (1 mL) were stirred together at 100° C. in dioxane (8 mL) in a sealed tube for 24 h. Purification of the cooled solution by preparative HPLC (Xbridge column—acetonitrile/0.2% ammonia mobile phase) gave the title compound (110 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:21])(=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:6]=1)=[O:4].[CH3:22][NH:23][C:24]([NH:26][CH3:27])=[S:25]>>[ClH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:25][C:24](=[N:23][CH3:22])[N:26]2[CH3:27])=[CH:6][C:7]=1[S:12](=[O:21])(=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16]
Reactant: CCCN(CCC)S(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Reactant: CNC(=S)NC
Product: CCCN(CCC)S(=O)(=O)c1cc(C2(O)CSC(=NC)N2C)ccc1Cl
Product: Cl

Procedure:
4.8 g of 2,4'-dichloro-3'-dipropylsulfamoylacetophenone and 1.5 g of 1,3-dimethylthiourea were reacted as prescribed in Example 23 and worked up. Colorless crystals, melting point: 166° C (decomposition).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[C:29]([Si:31]([CH3:34])([CH3:33])[CH3:32])#[CH:30].O>CN(C=O)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>[CH3:32][Si:31]([C:29]#[C:30][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1)([CH3:34])[CH3:33]
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)cnc43)cc2s1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a stirred suspension of (1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (152 mg, 0.30 mmol) from Step 2 of this Example in DMF (3 mL) were added CuI (6 mg, 0.032 mmol) and PdCl2(PPh3)2 (11 mg, 0.015 mmol). The mixture was purged with argon while ethynyltrimethylsilane (85 μL, 0.60 mmol) and TEA (127 μL, 0.90 mmol) were added sequentially. The resulting mixture was stirred at rt for 1 h. LCMS analysis showed that the reaction was complete. Water (30 mL) was added and the resulting dark brown solid was collected by filtration and dried to give crude (1R,2R)-2-((6-((6-((trimethylsilyl)ethynyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 70%). LCMS (ESI) m/z 476 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15]>O>[OH:5][C:6]1[C:13]([N+:1]([O-:4])=[O:2])=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=[N+]([O-])O
Solvent: O
Product: COc1cc(C=O)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of concentrated nitric acid (900 ml) and water (900 ml) was added 4-hydroxy-3-methoxybenzaldehyde (300 g) at a temperature under 10° C. After stirring 1 hour at 0° C. the precipitate was filtered and washed with water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[C:10]([O:14][C:15]([NH:17][C:18](=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]>N1CCCCC1.C(OCC)(=O)C>[C:10]([O:14][C:15]([NH:17][CH:18]([CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)[S:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:16])([CH3:12])([CH3:13])[CH3:11]
Reactant: COc1cccc(S)c1
Reactant: COC(=O)C(=Cc1cccc(OC)c1)NC(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: COC(=O)C(NC(=O)OC(C)(C)C)C(Sc1cccc(OC)c1)c1cccc(OC)c1
Temperature: 60 °C

Procedure:
A solution of 0.091 g (0.65 mmol) of 3-methoxy-benzenethiol in 4 drops of piperidine is stirred at room temperature for 5 minutes. A quantity of 0.200 g (0.65 mmol) of 2-tert-butoxycarbonylamino-3-(3-methoxyphenyl)acrylic acid, methyl ester of Example 30 is added and the solution is heated at 60° C. for 24 hours. Ethyl acetate (120 mL) is added and the solution is washed with 3×80 mL of 1N sodium hydroxide and brine (80 mL). After drying (magnesium sulfate), the solution is evaporated and the residue is purified by silica gel chromatography, eluting with 20% ethyl acetate-hexane to give the product as an inseparable mixture of diastereomers; wt 0.26 g (89%);
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14]([NH:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(OCC)C>[CH2:14]([N:18]([CH2:19][CH3:20])[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CCCCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1C=O
Temperature: 25 °C
Yield: 91.9 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzaldehyde (5.0 g) and butyl-ethyl-amine (3.95 g) are dissolved in toluene (50 ml) and thereto is added potassium carbonate (10.78 g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added water and diethyl ether, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give 2-(butyl-ethyl-amino)-5-trifluoromethyl-benzaldehyde (6.54 g). MS (m/z): 274 [M+H]+
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3].S(=O)(=O)(O)O.II.[I:21](O)(=O)(=O)=O>C(O)(=O)C.O>[I:21][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)NCCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)NCCc1ccc(I)cc1
Temperature: 72.5 °C
Reaction time: 8 h
Yield: 300.1 %

Procedure:
To a stirring room temperature solution of (methylsulfonyl)(2-phenylethyl)amine (205 g, 1.03 moles), water (200 mL), 95% sulfuric acid (111 g, 1.08 moles) in acetic acid (1 L), was added iodine (111 g, 0.438 mol) and periodic acid (H5lO6, 45.6 g, 0.206 mol). The reaction mixture was warmed to 70-75° C. for 3 h. The heat was removed and the dark violet reaction mixture was allowed to proceed overnight at room temperature. Potassium hydroxide pellets (85%, 143 g, 2.16 moles) were added to neutralized the sulfuric acid and then enough saturated aqueous sodium sulfite was added to decolorize the mixture to afford a white suspension. The suspension was cooled to 15° C. and filtered. The filter cake was triturated thoroughly with water and was then dissolved in CH2Cl2 (1 L) and extracted with additional water (2×200 mL). The organic phase was concentrated under reduced pressure to provide the intermediate title compound, [2-(4-iodophenyl)ethyl](methylsulfonyl)amine, (201 g, 60.2%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Cl)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[CH:16]1(B(O)O)[CH2:18][CH2:17]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH:16]2[CH2:18][CH2:17]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1cc2ccccc2c(Cl)n1
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccccc2c(C2CC2)n1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 481 mg (2.17 mmol) 1-chloro-isoquinoline-3-carboxylic acid methyl ester, 235 mg (2.74 mmol) cyclopropylboronic acid, 100 mg (0.137 mmol) 1,1′-bis(diphenyl-phosphino)ferrocenedichloropalladium(II) and 950 mg (4.47 mmol) potassium phosphate in 20 mL dioxane was stirred at 110° C. for 12 h. The mixture was diluted with EtOAc, filtered over Celite and activated carbon and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=3/1).
Reaction SMILES: [C:1](=[O:24])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:7]([CH3:16])[N:6]=[C:5]([CH3:17])[C:4]=1I.[Cl-].[Li+].[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>O1CCOCC1.C(Cl)(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>[C:1](=[O:24])([O:2][C:3]1[C:4]([CH:27]=[CH2:28])=[C:5]([CH3:17])[N:6]=[C:7]([CH3:16])[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCCCCCCc1c(C)nc(C)c(I)c1OC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: C=Cc1c(C)nc(C)c(CCCCCCC)c1OC(=O)OC(C)(C)C
Yield: 10 %

Procedure:
To a solution of 7 (60 mg, 0.864 mmol) in 1,4-dioxane (4 ml) were added lithium chloride (73.2 mg, 1.73 mmol), tetrakis(triphenylphosphine)palladium (99.8 mg, 10 mol %) and tributyl(vinyl)tin (0.327 ml, 1.12 mmol). The mixture was heated at reflux for 3 h then cooled and diluted with CHCl3. The mixture was washed with brine, dried over Na2SO4, filtered, and concentrated in under diminished pressure. The residue was purified by column chromatography on silica gel [AcOEt/MeOH (20:1)] to afford tert-butyl 3-heptyl-2,6-dimethyl-5-vinylpyridin-4-yl carbonate (9) (30 mg, 64%). 1H NMR (CDCl3) δ 0.85-0.88 (m, 3H), 1.27-1.32 (m, 10H), 1.47 (s, 9H), 2.40 (s, 3H), 2.43 (s, 3H), 2.47-2.50 (m, 2H), 5.50 (dd, 2H, J=18 Hz, 11.2 Hz) and 6.45 (dd, 1H, J=11.6 Hz, 11.6 Hz).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[C:18]3[O:17][CH2:16][C:15](=[O:19])[C:14]=3[CH:13]=[CH:12][C:11]=2[OH:20])[CH2:3]1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[N:22]1.N1CCCCC1>CO>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](/[CH:30]=[C:16]2\[O:17][C:18]3[C:10]([CH2:9][N:4]4[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]4)=[C:11]([OH:20])[CH:12]=[CH:13][C:14]=3[C:15]\2=[O:19])=[N:22]1
Reactant: C[C@@H]1CN(Cc2c(O)ccc3c2OCC3=O)C[C@H](C)N1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: C[C@@H]1CN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)C[C@H](C)N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of 7-[(cis-3,5-dimethylpiperazin-1-yl)methyl]-6-hydroxybenzofuran-3(2H)-one (0.166 g, 0.601 mmol) in methanol (2.4 mL) was added with 1H-indazole-3-carbaldehyde (0.0878 g, 0.601 mmol), and piperidine (0.00512 g, 0.0601 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, then added with methanol (8 mL), suspended in methanol, and thereby washed to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-7-[(cis-3,5-dimethylpiperazin-1-yl)methyl]-6-hydroxybenzofuran-3(2H)-one (0.197 g, 81%).