Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: COc1cccc(O)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2ccc(C=O)cc2)c1
Temperature: 90 °C
Yield: 100 %

Procedure:
To a solution of p-fluorobenzaldehyde (1.6 mmol, 0.2 g) in dimethylformamide (8 mLs) was added 3-methoxyphenol (3.52 mmol, 0.437 g) and cesium carbonate (3.52 mmol, 1.15 g). The reaction was heated to 90° C. for 3 hours at which time it was cooled to room temperature and filtered through a fritted funnel. The reaction mixture was diluted with 125 mL of ethyl acetate and extracted with eight 15 mL portions of water and one 10 mL portion of brine. The organic layer was dried with magnesium sulfate and evaporated to dryness. The crude oil was purified by flash chromatography to recover 0.365 g (1.6 mmol) of the title product. 1H NMR (300 MHz, CDCl3) δ 9.92 (s, 1H), 7.84 (d, J=8.7, 2H), 7.29 (dd, J=5.7, 13.9, 1H), 7.07 (d, J=8.7, 2H), 6.76 (d, J=8.3, 1H), 6.72-6.57 (m, 2H), 3.80 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 190.99, 163.25, 161.38, 156.42, 132.15, 130.76, 117.91, 112.63, 110.81, 106.59, 55.66.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Br:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(F)cc1Br
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4Br)nccc3c2)cc1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.053 g, 0.119 mmol) was added (2-bromo-4-fluorophenyl)boronic acid (Combi-Blocks, San Diego, Calif.) (0.042 g, 0.190 mmol), potassium carbonate (0.082 g, 0.594 mmol), dioxane (0.594 ml) and water (0.198 ml). The mixture was purged with argon prior to the addition of Pd(PPh3)4 (0.014 g, 0.012 mmol). The vessel was sealed and irradiated at 100° C. for 30 mins affording fairly clean conversion to desired product. The organic phase was decanted, the aqueous rinsed with EtOAc and the EtOAc decanted. The combined organics were dried under reduced pressure and purified with a 25 g HP silicycle column ramping EtOAc in heptane (0-45%, then isocratic at 45%) to provide product as an off-white foam 1-(2-bromo-4-fluorophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate KKK) (54 mg, 0.092 mmol, 78% yield) with minor impurities according to LC/MS and NMR (˜20% impurity). m/z (ESI) 582.2/584.2 (M+H)+.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[N:69]1[CH:74]=[CH:73][C:72]([N:75]2[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]2)=[CH:71][CH:70]=1>CN(C=O)C>[CH3:25][C:24]([CH3:27])([O:23][C:21]([NH:1][C@H:2]([C:18]([N:78]1[CH2:79][CH2:80][N:75]([C:72]2[CH:73]=[CH:74][N:69]=[CH:70][CH:71]=2)[CH2:76][CH2:77]1)=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:22])[CH3:26]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1

Procedure:
To a mixture of 18.8 g (0.0494 mol) of Boc-Lys(Z)-OH, 6.5 g (0.05 mol) of DIEA, 16 g (0.05 mol) of TBTU, 6.6 g (0.049 mol) of HOBt and 100 ml of dimethylformamide were added dropwise, with stirring, 8.1 g (0.0494 mol) of 1-(4-pyridinyl)piperazine, dissolved in 40 ml of DMF, and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate phase was then washed three times successively with 70 ml of saturated aqueous sodium hydrogen carbonate solution and once with 70 ml of saturated aqueous saline solution, dried over sodium sulphate and evaporated down in vacuo. 24.2 g (93.2% of theory) of a yellowish oil were obtained, which was used for the following reactions without further purification.
Reaction SMILES: [CH:1]1([O:11][C:4]2([CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]2)[O:3]1)[CH3:2].[CH:12]([C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:37]=[CH:36][CH:35]=[CH:34][C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:20])=[C:17](O)[CH:16]=1)([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOCC.CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:24](=[O:25])[C:23]2[CH:34]=[CH:35][CH:36]=[CH:37][C:22]=2[NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:39][C:38]=2[O:10][CH:7]2[CH2:8][CH2:9][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:5][CH2:6]2)=[N:28][CH:29]=1
Reactant: CC(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Reactant: CC1OC2(CCC(O)CC2)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCC3(CC2)OCCO3)c1
Reaction time: 1 h

Procedure:
4-Hydroxycyclohexanone-1,1-ethylene ketal (0.63 g, 4 mmol), 2-[4-isopropyl-2-hydroxybenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (1.64 g, 4 mmol), triphenyl-phosphine (1.05 g, 4 mmol), and dry DMF (2 mL) were sonicated for 5 min at room temperature. DIAD (0.8 mL, 4 mmol) was added and sonication was continued for 1 h. Ether (40 mL) was added and the solution was chilled overnight in the freezer to crystallize triphenylphosphine oxide. The crystals were filtered, washed with a little ether, and the combined filtrates were evaporated to dryness to give a yellow oil.
Reaction SMILES: C(O)(=O)C.C[Si](N[Si](C)(C)C)(C)C.[I:14][C:15]1[S:19][C:18]([C:20](=O)[CH3:21])=[CH:17][C:16]=1[CH3:23].[C:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])#[N:25]>CCOC(C)=O>[CH2:30]([O:29][C:27](=[O:28])[C:26]([C:24]#[N:25])=[C:20]([C:18]1[S:19][C:15]([I:14])=[C:16]([CH3:23])[CH:17]=1)[CH3:21])[CH3:31]
Reactant: CC(=O)c1cc(C)c(I)s1
Reactant: CCOC(=O)CC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)c1cc(C)c(I)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
Acetic acid (9.4 ml) was placed in a flask at rt and HMDS (3.0 ml, 14.1 mmol) was added dropwise. After the exotherm subsided, 1-(5-Iodo-4-methyl-thiophen-2-yl)-ethanone (2.5 g, 9.4 mmol) was added as a solid followed by ethyl cyanoacetate (2.0 ml, 18.8 mmol). The reaction was stirred at 80° C. for 8 h, cooled to rt and concentrated by rotary evaporation to give a brown residue. The residue was taken up in EtOAc, washed with NaHCO3 (aq, sat.) and then with H2O. The organics were dried (NaSO4), filtered and concentrated to give a brown solid. The solid was triturated with EtOH and filtered to give 2-Cyano-3-(5-iodo-4-methyl-thiophen-2-yl)-but-2-enoic acid ethyl ester (2.0 g, 5.5 mmol, 58%) as a light yellow solid. MS (ESI) m/z 362.0 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.27 (t, 1H) 2.21 (s, 1H) 2.66 (s, 1H) 4.26 (q, 1H) 7.67 (s, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:21]=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>ClCCl>[CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([N:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:42](=[O:44])[CH3:43])[CH:21]=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(F)c(Cn2nc(-c3nccc(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(F)c(Cn2nc(-c3nccc(N(C(C)=O)c4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-N-(pyridin-4-yl)-pyrimidin-4-amine (5-1-1, 0.218 mmol, 1. eq.) was dissolved in 2 ml of dry dichloromethane. First 94 μl of dry N,N-diethylethanamine (0.676 mmol, 3.1 eq.) and then 23 μl of acetyl chloride (0.327 mmol, 1.5 eq,) were added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 hours. Then the mixture was partitioned between water and dichloromethane. The phases were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over a silicon filter and concentrated in vacuo. The residue was purified by flash chromatography and preparative TLC to yield 29.8 mg (0.06 mmol, 26.8%) of the analytically pure target compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])(=[O:3])[CH3:2].S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O.[N+:30]([O-])([OH:32])=[O:31]>>[C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][C:15]=1[N+:30]([O-:32])=[O:31])[NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1cccc(NC(=O)C(C)C)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CC(=O)c1cc(NC(=O)C(C)C)ccc1[N+](=O)[O-]
Temperature: -8 °C
Reaction time: 0.67 h

Procedure:
Add portion-wise 16.4 g. of m-acetyl-isobutyranilide to a solution of 44 milliliters of concentrated sulfuric acid and 62 milliliters of oleum (30-33%) while maintaining the internal temperature at 0°-5° C. Cool the mixture to -8° C. and add drop-wise 65 milliliters of 90% nitric acid. Stir the reaction mixture at 0°-5° C. for an additional 40 minutes and precipitate the product as described in Example 1 to obtain 3'-acetyl-4'-nitro-isobutyranilide.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](O)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.CCCCCC.S(Cl)([Cl:28])=O>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([Cl:28])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 5.0 g of 4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid in 5.0 ml of thionyl chloride is heated on a steam bath under Argon for 1 hour and hexane added. The resulting solid is collected and dried to give 5.36 g of the desired product as a colorless oil. M+ =280 as methyl ester.
Reaction SMILES: CS(C)=O.[OH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1.[NH2:27][OH:28]>O>[OH:28][N:27]=[C:23]([NH2:24])[C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][OH:5])[CH2:14][CH2:13]2)=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(OCCCC2CCN(CCCO)CC2)cc1
Reactant: NO
Solvent: CS(C)=O
Solvent: O
Product: NC(=NO)c1ccc(OCCCC2CCN(CCCO)CC2)cc1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a dimethylsulfoxide (43 mL) suspension of 4.27 g of 4-{3-[1-(3-hydroxypropyl)-4-piperidinyl]propoxy}benzonitrile was added 4.32 mL of a 50% hydroxylamine aqueous solution at room temperature, which was then stirred at 40 to 50° C. for 3 hours and 30 minutes. The reaction mixture was cooled down to room temperature, to which 50 mL of water was then added dropwise over a period of 10 minutes, followed by stirring at room temperature for 30 minutes. The precipitate was collected by filtration and washed with water to provide 4.59 g of N′-hydroxy-4-{3-[1-(3-hydroxypropyl)-4-piperidinyl]propoxy}benzamidine as white solid form.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][O:14][C:41]3[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCS2
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCS2
Yield: 76.8 %

Procedure:
0.25 g of (RS)-2-(4,4-dimethyl-thiochroman-6-yl)-heptanol dissolved in 15 ml THF were treated with 250 mg of triphenylphosphine, 150 mg of methyl 4-hydroxybenzoate and 0.15 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 50 ml of ether and washed with two portions of 15 ml of water and one portion of 15 ml of sat. aq. sodium chloride solution. The organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes), giving 280 mg of (RS)-methyl 4-[2-(4,4-dimethyl-thiochroman-6-yl)-heptyloxy]-benzoate as a pale yellow oil. 1H NMR (CDCl3): 7.95 (d, J=8.9 Hz, 2H), 7.21 (d, J=1.9 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.91 (dd, J=8.1, 1.9 Hz, 1H), 6.87 (d, J=8.9 Hz, 2H), 4.10-4.00 (m, 2H), 3.87 (s, 3H), 3.05-2.90 (m, 3H), 2.00-1.80 (m, 3H), 1.70-1.60 (m, 1H), 1.32 (s, 3H), 1.31 (s, 3H), 1.35-1.15 (m, 6H), 0.90-0.80 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[C:11]([O-])([O-])=O.[Cs+].[Cs+].CI>CC(C)=O>[OH:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: OCCc1ccccc1O
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccccc1CCO
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 10 g of 2-(2-hydroxyphenyl)-ethanol in 200 ml of acetone there are added 35.3 g of Cs2CO3 and then a solution of 6.5 ml of methyl iodide in 40 ml of acetone. The reaction mixture is stirred for 50 minutes at room temperature, is filtered and is concentrated by evaporation. The residue is partitioned between diethyl ether and water. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (dichloromethane/diethyl ether=97:3), yielding the title compound: Rf (dichloromethane/diethyl ether=97:3)=0.34; HPLC Rt =9.31 minutes.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[NH2:12][C:13]1[N:17]([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[N:16]=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:14]=1.N1C=CN=C1>CN(C=O)C>[C:25]([C:15]1[CH:14]=[C:13]([NH2:12])[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[CH:19]=2)[N:16]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(O)c2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Triisopropylsilylchloride (1.02 mL, 3.96 mmol) was added to a solution of 3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (915 mg, 3.96 mmol) and imidazole (646 mg, 9.50 mmol) in DMF (15 mL) at 0° C. The reaction was stirred at RT over the weekend then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-40% EtOAc in cyclohexane, to give the title compound (1.53 g, 99%). LCMS (Method 4): Rt 4.78 min, m/z 388 [MH+].
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[CH2:13](Br)[CH2:14][CH2:15][CH3:16]>CCOCC>[CH2:13]([N:3]1[C:2]([CH3:12])([CH3:1])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]1([CH3:11])[CH3:10])[CH2:14][CH2:15][CH3:16]
Reactant: CC1(C)CS(=O)(=O)CC(C)(C)N1
Reactant: CCCCBr
Solvent: CCOCC
Product: CCCCN1C(C)(C)CS(=O)(=O)CC1(C)C

Procedure:
38.2 g (0.2 mole) of 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is heated with 13.7 g of n-butylbromide for 120 hours at 95°-100° C. After cooling, the contents of the flask are taken up in 300 ml of ether. The difficultly soluble hydrobromide of 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is separated by filtration, and the ether solution extracted twice with 100 ml of water each time, in order to remove the last traces of starting product or its hydrobromide. The ether solution is dried over sodium sulphate and then fully concentrated by evaporation. The residue is crystallised from ligroin to obtain 1-butyl-2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide, M.P. 180° C (3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O.[C:25](=[O:28])([O-])[OH:26].[Na+]>C(#N)C.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:15]([O:26][C:25]([N:21]1[CH2:22][CH2:23][CH:18]([CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1)=[O:28])([CH3:18])([CH3:16])[CH3:14]
Reactant: COc1cc(N2CCC(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: [Zr+4]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a suspension of 1-(3-methoxy-4-nitro-phenyl)-[4,4′]bipiperidinyl (1.75 g, 5.48 mmol), di-tert-butyl-dicarboxylate (1.20 g, 5.48 mmol) in acetonitrile (55 mL), zirconium tetrachloride (128 mg, 0.55 mmol) is added and the mixture is stirred at ambient temperature for 30 min. After water and aqueous sodium hydrogen carbonate are added, the mixture is filtrated and dried to give 1′-(3-Methoxy-4-nitro-phenyl)-[4,4′]bipiperidinyl-1-carboxylic acid tert-butyl ester (5.11 g, 92% yield) as yellow solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:7][C:6]2=[O:16].[CH3:17][CH:18](O)[CH:19]=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:17]([CH:7]1[C:6](=[O:16])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]21[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:18]=[CH:19][CH3:20]
Reactant: C=CC(C)O
Reactant: COc1ccc2c(c1)C(=O)CC21CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1C(=O)c2cc(OC)ccc2C12CCCC2
Yield: 51 %

Procedure:
A solution of 9.73 g of 5'-methoxy-2',3'-dihydro-spiro[cyclo-pentane-1,1'-[1H]indene]-3'-one, 9.3 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxy-propane was boiled under reflux for 90 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 7:1). In addition to 4.0 g of educt, there were obtained 6.24 g (51%) of (RS)-2'-(2-buten-1-yl)-5'-methoxy-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([O:13][CH3:14])=[O:12])=[C:6](B(O)O)[CH:7]=1.[C:15]1([S:21]N2C(=O)C3C(=CC=CC=3)C2=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1.OC1C(C(C)C)=CC(C(C)C)=CC=1C(O[Cu])=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([O:13][CH3:14])=[O:12])=[C:6]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Sc1ccccc1
Reactant: COC(=O)c1ccc(F)cc1B(O)O
Agent: CC(C)c1cc(C(=O)O[Cu])c(O)c(C(C)C)c1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)cc1Sc1ccccc1

Procedure:
5-Fluoro-2-(methoxycarbonyl)phenylboronic acid (1.00 g), 2-(phenylthio)isoindoline-1,3-dione (0.86 g), and (2-hydroxy-3,5-diisopropylbenzoyloxy)copper (0.29 g) were stirred in dioxane (15 mL) at 50° C. for 24 hours. The reaction mixture was chromatographed on silica gel with 5% ethyl acetate/hexanes.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C@H:9]([CH3:12])[CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][C:15]=1[C:29]1[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=1>>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:15]2[CH:16]=[CH:17][C:18]([C:2]3[C:3]([O:8][C@H:9]([CH3:12])[CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:19][C:14]=2[F:13])=[CH:30][N:31]=1
Reactant: C[C@H](CO)Oc1ncccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: C[C@H](CO)Oc1ncccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (R)-2-((3-bromopyridin-2-yl)oxy)propan-1-ol and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C18H17FN4O2, 340.13; m/z found, 340.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=1.4, 2H), 8.17 (dd, J=4.9, 1.9, 1H), 7.85 (dd, J=7.4, 1.9, 1H), 7.67-7.54 (m, 3H), 7.09 (dd, J=7.4, 4.9, 1H), 6.89 (s, 2H), 5.35-5.23 (m, 1H), 4.86 (t, J=5.4, 1H), 3.62-3.51 (m, 2H), 1.25 (d, J=6.3, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:12]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH:9]([Br:12])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCC(=O)c1cccc(Cl)c1
Product: CC(Br)C(=O)c1cccc(Cl)c1
Reaction time: 5.5 h

Procedure:
To 1 mole of m-chloropropiophenone was heated to 70±5° C., bromine was added dropwise under stirring. The reaction temperature was kept at 70±5° C. during the addition of bromine and kept for 5.5 hours after the addition. m-chloro-α-bromopropiophenone (compound of formula (II)) was obtained.