Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[CH:22]1(O)[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:22]1([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=Cc1ccc(O)cc1
Reactant: OC1CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a tetrahydrofuran (250 mL) solution of diethylazodicarboxylate (16.1 mL, 40.9 mmol) were added 4-hydroxybenzaldehyde (5 g, 40.9 mmol), cyclopentanol (3.71 mL, 40.9 mmol) and triphenylphosphine (10.7 g, 40.9 mmol). This mixture was stirred for 30 minutes at room temperature. The mixture was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (4.36 g, 56%).
Reaction SMILES: [C:1](=O)([O:12][C@@H:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])[O:2]C1C=CC([N+]([O-])=O)=CC=1.[CH2:20]([N:27]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[CH2:20]([N:27]1[CH2:31][CH2:30][C@H:29]([NH:32][C:1](=[O:2])[O:12][C@@H:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C[C@H](OC(=O)N[C@H]1CCN(Cc2ccccc2)C1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate (2.20 g) in CHCl3 (30 ml) was added (3S)-1-benzylpyrrolidin-3-amine (1.39 g) at room temperature. The resulting mixture was refluxed for 2 hours and then cooled to room temperature. The mixture was purified with silica gel column chromatography (eluent:hexane/EtOAc=1/0˜0/1) to give (2S)-1,1,1-trifluoropropan-2-yl [(3S)-1-benzylpyrrolidin-3-yl]carbamate as a pale yellow oil.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[CH3:12]/[C:13](=[CH:17]\[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[C:14](O)=[O:15]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:14](=[O:15])/[C:13](/[CH3:12])=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4]2
Reactant: C/C(=C\c1ccccc1)C(=O)O
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: C/C(=C\c1ccccc1)C(=O)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-2-methyl-3-phenylpropenoic acid; MS (ES+) 271 (MH+).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:10]=1)(=O)=O.[I-:28].[Na+]>>[Si:21]([O:20][CH2:19][CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([CH2:8][CH2:7][CH2:6][I:28])=[CH:10]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(CCCOS(C)(=O)=O)c2ccccc21
Reactant: [I-]
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OCCn1cc(CCCI)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of 3-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-indol-3-yl]propyl methanesulfonate (Intermediate 42; 3.5 g, 8.5 mmol) in ketone (20 mL) was added sodium iodide (2.55 g, 17 mmol). The reaction mixture was stirred overnight at 50° C. The crude reaction was filtered and the solvent was removed under reduced pressure. The crude obtained was purified over silica gel eluting with hexane:ether (100/0 to 0/100) to obtain the title compound (2.7 g, 71%).
Reaction SMILES: [CH3:1][C:2](=[CH2:18])[CH2:3][C:4]1[C:5]([OH:17])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[NH:10][C:9](=[O:15])[C:8]([CH3:16])=[CH:7]2.[Br:19]N1C(=O)CCC1=O>>[Br:19][CH2:18][C:2]1([CH3:1])[O:17][C:5]2=[C:6]3[C:11](=[C:12]([CH3:14])[CH:13]=[C:4]2[CH2:3]1)[NH:10][C:9](=[O:15])[C:8]([CH3:16])=[CH:7]3
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)Cc1cc(C)c2[nH]c(=O)c(C)cc2c1O
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(C)(CBr)O3
Yield: 90.1 %

Procedure:
Reaction, past-process, and recrystallization (chloroform-methanol-ether) were performed in a manner similar to that described in Example 277 using 6-(2-methyl-2-propenyl)-5-hydroxy-3,8-dimethylcarbostyril (3.29 g, 13.54 mmol) and N-bromsuccinimide (2.41 g, 13.54 mmol). As a result, 3.93 g of the title compound was obtained as pale yellow prisms (90.1%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][Br:18]
Reactant: Cc1ccccc1-c1ccc2ccccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1-c1ccc2ccccc2c1

Procedure:
105 g (0.48 mol) of 13 and 90 g (0.5 mol) of N-bromosuccinimide were dissolved at room temperature in 2000 cm3 of carbon tetrachloride, admixed with 3 g of azobisisobutryronitrile and heated under reflux for 4 hours. The precipitated succinimide was filtered off, the solvent was removed under reduced pressure and the residue was purified by filtration through 1000 g of silica gel (hexane/methylene chloride 9:1). This gave 112 g (79%) of 14 as a colorless, lacrymatory oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)#[CH:15].C1COCC1>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.[Cu]I.O>[CH3:11][Si:10]([C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[CH:3][CH:4]=1)([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Reactant: C#Cc1ccc(N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C#Cc1ccc(C#Cc2ccc(N)cc2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
Following a general coupling procedure, (4-iodo-phenylethynyl)-trimethyl-silane (Maya et al., Chem. Mater., 2004, 16:2987-2997) (0.75 g, 2.50 mmol) was coupled to 4-ethynyl-phenylamine (Fan et al., J. Am. Chem. Soc., 2002, 124:5550) (0.35 g, 3.00 mmol) using PdCl2(PPh3)2 (0.09 g, 0.13 mmol), CuI (0.05 g, 0.25 mmol), TEA (3 mL), and THF (10 mL). The reaction was stirred at 40° C. overnight. The mixture was poured into H2O and extracted (3×) with CH2Cl2, dried using anhydrous MgSO4, and concentrated in vacuo. Column chromatography, silica gel (CH2Cl2) afforded 4-(4-trimethylsilanylethynyl-phenylethynyl)-phenylamine as a yellow solid (0.64 g). Following the general deprotection of TMS-protected alkynes, 4-(4-trimethylsilanylethynyl-phenylethynyl)-phenylamine (0.64 g, 2.21 mmol) was dissolved in a mixture of CH2Cl2 (15 mL), MeOH (15 mL), and K2CO3 (1.53 g, 11.05 mmol). The product 6, was afforded without additional purification as an orange solid (0.47 g, 87%, 2 steps). 1H NMR (400 MHz, (CD3)2CO) δ 7.45 (m, 4H), 7.25 (d, J=6.7 Hz, 2H), 6.68 (d, J=6.7 Hz, 2H), 5.09 (s, 2H), 3.77 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[N:38]=[C:39]=[O:40]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:39]([NH:38][C:32]3[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])=[O:40])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C=Nc1c(F)cccc1F
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1c(F)cccc1F

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2,6-difluorophenyl isocyanate according to the procedure of Example 65. HRMS: calcd for C30H18F5N3O2, 547.1319; found (ESI, [M+H]+), 548.1425.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:13]([Mg]Br)[CH3:14]>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:13][CH3:14])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-formyl-benzoic acid methyl ester (3.0 g, 18.3 mmol) in THF (10 mL) at 0° C. is added ethylmagnesium bromide (2M, 10 mL). After stirring at room temperature for 2 hours, it is quenched with saturated ammonium chloride, extracted with EtOAc. The organic is concentrated to give the titled compound as colorless oil: 2.2 g (62%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]([CH:25]([CH3:27])[CH3:26])[C:9](=[O:24])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]COC)[C:13]=2[CH:22]=[O:23])=[CH:6][CH:5]=[N:4]1)[CH3:2].Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:1]([N:3]1[C:7]([N:8]([CH:25]([CH3:26])[CH3:27])[C:9](=[O:24])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]=2[CH:22]=[O:23])=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1nccc1N(C(=O)COc1cccc(OCOC)c1C=O)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1nccc1N(C(=O)COc1cccc(O)c1C=O)C(C)C
Temperature: 40 °C
Yield: 53.5 %

Procedure:
N-(1-Ethyl-1H-pyrazol-5-yl)-2-(2-formyl-3-(methoxymethoxy)phenoxy)-N-isopropylacetamide (0.38 g, 1.01 mmol) was dissolved in THF (10 ml), purged with N2 gas and stirred in an ice bath. HCl (concentrated, 0.34 ml, 4.05 mmol) was slowly added and the solution stirred to 25° C. More HCl (0.3 ml) was added over 4 h with warming (40° C.) to reach completion of reaction. 10% Sodium bicarbonate solution (20 ml) was added and the mixture was extracted with ethyl acetate (3×75 ml). The combined organic phases were washed with a saturated aqueous sodium chloride solution (50 ml) and dried over sodium sulfate. After evaporation the resulting solid was purified by silica gel chromatography (5-80% ethyl acetate/hexanes) to give 0.179 g (53%) of N-(1-ethyl-1H-pyrazol-5-yl)-2-(2-formyl-3-hydroxyphenoxy)-N-isopropylacetamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 11.90 (s, 1H), 10.35 (s, 1H), 7.50 (s, 1H), 7.43 (t, J=8.43 Hz, 1H), 6.67 (d, J=8.53 Hz, 1H), 6.39 (d, J=8.27 Hz, 1H), 6.32-6.27 (m, 1H), 6.12 (d, J=7.30 Hz, 1H), 5.65 (s, 1H), 4.25-4.13 (m, 3H), 1.46 (t, J=7.23 Hz, 3H), 1.22 (d, J=6.54 Hz, 3H), 1.14 (d, J=6.51 Hz, 3H). MS (ESI) m/z 332 [M+H]+. MP 179-182° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].CO>O1CCCC1>[Br:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CBr)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: O[C@H](CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
(S)-2-amino-2-cyclohexyl-1,1-bis-(4-methoxyphenyl)ethanol (71.2 mg, 0.2 mmol), dry tetrahydrofuran (2 mL) and borane dimethylsulfide complex (1 00 μL, 1.0 mmol) were added to a dry flask under at atmosphere of nitrogen. The mixture was stirred at room temperature for 1.5 hours to form (R)-4-cyclohexyl-5,5-bis-(4-methoxy)phenyl-1,3,2-oxazaborolidine. A solution of bromoacetophenone (199 mg, 1.0 mmol) in dry tetrahydrofuran (4 mL) was added to the borane/(R)-4-cyclohexyl-5,5-bis-(4-methoxy)phenyl-1,3,2-oxazaborolidine complex at the rate of 9 mL/hr by means of a syringe pump. The resulting mixture was stirred at room temperature for an additional 1.5 hours. Methanol was added to quench the reaction and then the solvent was removed by evaporation. The resulting residue was chromatographed on silica gel (hexane/ethyl acetate, 25:1) and combination of the like fractions followed by removal of the solvent gave (S)-2-bromo-1-phenylethanol (170 mg, 96.6% ee). The enantiomeric excess was measured by HPLC (Chiralcel OD-H column, mobile phase, hexane/2-propanol 9:1, flow rate=0.7 mL/min).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([C:14]#[N:15])([CH3:13])[CH2:8][CH2:9][C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])=O>C1C=CC=CC=1>[C:1]([N:5]=[N:6][C:7]([C:14]#[N:15])([CH3:13])[CH2:8][CH2:9][C:10]([Cl:18])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=NC(C)(C#N)CCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)N=NC(C)(C#N)CCC(=O)Cl
Reaction time: 4 h
Yield: 98.8 %

Procedure:
Into a 25 ml round bottom flask was weighed 5 grams (.0237 mole) of 4-t-butylazo-4-cyanovaleric acid and then 15 ml of benzene and 2 ml of thionyl chloride were added. The acid dissolved and the solution was stirred for 4 hours at 25° ±2° C (protected from the atmosphere by a CaCl2 tube). At the end of the stirring period the benzene and excess leaving 5.35 grams (98.8% yield) of 4-t- butylazo-4-cyanovaleryl chloride.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:11][C:12]1[N:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH:8]([CH3:10])[CH3:9].[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1F)[C:23]#[N:24]>CS(C)=O.O>[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:18][C:15]1[CH:16]=[N:17][C:12]([O:11][CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:13][CH:14]=1)[C:23]#[N:24]
Reactant: CC(C)COc1ccc(O)cn1
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)COc1ccc(Oc2ccc(C#N)cc2Br)cn1
Temperature: 80 °C
Yield: 97.5 %

Procedure:
Potassium carbonate (0.622, 4.50 mmol) and 6-isobutoxypyridin-3-ol (Preparation 7, 0.251 g, 1.50 mmol) were added to a solution of 3-bromo-4-fluorobenzonitrile (0.300 g, 1.50 mmol) in DMSO (7 mL). The reaction was heated at 80° C. for a total of 4 hours and then allowed to cool to room temperature. The mixture was diluted with water (50 mL) and extracted with DCM (3×30 mL). The combined organics were washed with brine (2×50 mL), filtered and concentrated in vacuo to yield the title compound as a solid (0.508 g).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6](OC(C(OCC)=O)=CC=[N+](C)C)[CH3:7].[CH3:20][N:21]([CH3:33])[CH:22]=[CH:23][C:24](=[O:32])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].F[B-](F)(F)F.C([O+](CC)CC)C>ClCCl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O:32][C:24]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])=[CH:23][CH:22]=[N+:21]([CH3:20])[CH3:33])[CH3:7]
Reactant: CN(C)C=CC(=O)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(=CC=[N+](C)C)OCC
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=CC=[N+](C)C)C(=O)OC(C)(C)C

Procedure:
The procedure is as in Example 2 for the preparation of N-(3-ethoxy-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate, starting with t-butyl 4-dimethylamino-2-oxo-3-butenoate (3.3 g) and triethyloxonium tetrafluoroborate (3.62 g) in dichloromethane (20 cc). The solution of N-(3-ethoxy-3-t-butyloxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate in methylene chloride thereby obtained is stored under an argon atmosphere and used immediately in the subsequent syntheses.
Reaction SMILES: [O:1]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:1][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1
Reactant: CC(C)(C)[Si](OCc1cccc(-c2ccccc2)n1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
To a solution of 2-(tert-butyldiphenylsiloxy)methyl-6-phenylpyridine (1.2 g) in THF (20 mL) was added Bu4NF (3.3 mL of a 1M solution in THF). After 1 h, NH4OAc buffer was added and the mixture extracted with EtOAc. The organics were dried (MgSO4), concentrated and chromatographed (silica gel; hexane/EtOAc acetate (3:2)) to provide the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC1C=CC=CC=1)=[O:12])=[O:5])[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)COCCCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)COCCCC(=O)O

Procedure:
45 g (0.16 mol) of benzyl 4-ethoxycarbonylmethoxybutyrate 58 g are dissolved in 450 ml of tetrahydrofuran and the solution is hydrogenated under normal pressure at room temperature by addition of 4.5 g of 5% Pd/C. Upon cessation of hydrogenation, the catalyst is removed by filtration and the filtrate is concentrated by evaporation giving 4-ethoxycarbonylmethoxybutyric acid which is further reacted without purification.
Reaction SMILES: [C:1](Cl)(=[O:15])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[NH:20][CH2:19][CH2:18]2>>[N:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[N:20]([C:1]([O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])[CH2:19][CH2:18]2
Reactant: C1CN2CCC(CC2)N1
Reactant: O=C(Cl)Oc1ccccc1-c1ccccc1
Product: O=C(Oc1ccccc1-c1ccccc1)N1CCN2CCC1CC2
Yield: 14.7 %

Procedure:
Biphenyl-2-yl carbonochloridate (83.0 mg, 0.358 mmol) was treated with 1,4-diazabicyclo[3.2.2] nonane (113 mg, 0.896 mmol) using the same procedure reported in example 46 to afford the title compound as an off-white solid (17 mg, 15%). Purity: >99% UPLCMS (210 nm); retention time 0.75 min; (M+1) 323.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:9]([OH:17])=[C:10]([CH2:14][CH:15]=O)[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)[CH2:21][C:22]([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:9]([OH:17])=[C:10]([CH2:14][CH:15]=[CH:21][C:22]([OH:24])=[O:23])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=CCc1cccc(C(=O)c2ccc(Cl)cc2)c1O
Product: O=C(O)C=CCc1cccc(C(=O)c2ccc(Cl)cc2)c1O

Procedure:
Another modification of the process comprises reacting 3-bromo-1-propene with methyl 2-hydroxybenzoate to obtain methyl 2'-(3-oxy-1-propene)-benzoate, hydrolyzing the latter to form the free acid, reacting the latter with a chlorinating agent such as thionyl chloride to form the corresponding acid chloride, condensing the latter with cadmium chlorophenyl to form 3-(2'-p-chlorobenzoyl-phenyl)oxy-1-propene, heating the latter to form 3-(3'-p-chlorobenzoyl-2'-hydroxy-phenyl)-1-propene, reacting the latter with an oxidizing agent to form 2-(3'-p-chlorobenzoyl-2'-hydroxyphenyl)-1-oxo-ethane, condensing the latter with malonic acid, decarboxylating the resulting dicarboxylic acid to form 4-(3'-p-chlorobenzoyl-2'-hydroxy-phenyl)-2-butenoic acid and hydrogenating the latter in the presence of palladium to obtain 4-(3'-p-chlorobenzoyl-2'-hydroxyphenyl)-butyric acid and finally with an oxidizing agent to form 4-(3'-p-chlorobenzoyl-2',5'-dihydroxy-phenyl)-butyric acid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[NH2:16][C:17]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][NH:19][N:18]=1>CC(O)=O>[C:7]1([CH:5]2[CH2:4][CH:3]([C:2]([F:15])([F:14])[F:1])[N:18]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]3[NH:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c1NC(c1ccccc1)CC2C(F)(F)F
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A mixture of 4,4,4-trifluoro-1-phenyl-1,3-butanedione 1 (6.97 g, 32.24 mmol) and ethyl 3-aminopyrazole-4-carboxylate 2 (5.0 g, 32.22 mmol) in AcOH (100 mL) was refluxed for 4 h. The mixture was cooled to room temperature and concentrated and precipitated crystals were collected by filtration to give 8.63 g (79%) of the title compound as yellow crystals. 1H NMR (CDCl3, 200 MHz): 1.47 (3H, t, J=7.0 Hz), 4.47 (2H, q, J=7.0 Hz), 7.54-7.61 (3H, m), 7.80 (1H, s), 8.23-8.28 (2H, m), 8.68 (1H, s)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC(Cl)(Cl)[C:13]([N:15]=C=O)=[O:14].[OH-].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:13]([NH2:15])=[O:14])[C:5]2=[N:6][CH:7]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: Brc1cnc2c(c1)CCN2
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)N1CCc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a cooled (0° C.) solution of 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2.5 g, 12.6 mmol) in DCM (30 mL) is added a trichloroacetyl isocyanate (1.6 mL, 13.2 mmol). After stirring for 1 h at 0° C., a solution of methanolic KOH (1M, 10 mL) is added. The resulting mixture is allowed to warm and stir at room temperature for 16 h. The reaction is concentrated and purified by silica gel column (0-100% EtOAc in heptane) to afford the title compound (2.6 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[N:32]=[C:31]2[S:33][C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])=[N:35][C:30]2=[CH:29][CH:28]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[S:33][C:31]3[C:30]([N:35]=2)=[CH:29][CH:28]=[C:27]([O:26][C:25]2[CH:24]=[C:23]([NH:22][C:8]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[O:10])[CH:44]=[CH:43][CH:42]=2)[N:32]=3)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Reactant: Cc1cccnc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Yield: 76.8 %

Procedure:
In the same manner as in Example 18-4 and using 3-methylpyridine-2-carboxylic acid (132 mg, 0.965 mmol), tetrahydrofuran (8 mL), oxalyl chloride (169 μL, 1.93 mmol), N-[5-(3-aminophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (210 mg, 0.643 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (220 mg, 77%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[S:9](=O)(=[O:12])([OH:11])[OH:10]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:8]=[C:7]([S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccccc1Cl
Reactant: O=S(=O)(O)O
Solvent: Clc1ccccc1Cl
Product: Nc1ccc(S(=O)(=O)O)cc1Cl
Reaction time: 4.3 h

Procedure:
Starting from 293.5 g of 2-chloroaniline, 460 ml of o-dichlorobenzene and 225.5 g of monohydrate, the reaction was performed as in Example 4. After 4.3 hours at 200° C., the mixture was cooled, filtered off with suction and dried. The isolated solid weighed 489.3 g and contained 51.1% of 2-chloroaniline-4-sulphonic acid, based on the use of 2-chloroaniline, with a selectivity of 100%.
Reaction SMILES: O/[C:2](/[C:10]1([CH3:13])[CH2:12][CH2:11]1)=[CH:3]\[C:4](=[O:9])/[CH:5]=[CH:6]/[O:7]C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:13][C:10]1([C:2]2[O:7][CH:6]=[CH:5][C:4](=[O:9])[CH:3]=2)[CH2:11][CH2:12]1
Reactant: CO/C=C/C(=O)/C=C(\O)C1(C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(c2cc(=O)cco2)CC1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
A mixture of (1Z,4E)-1-hydroxy-5-methoxy-1-(1-methyl-cyclopropyl)-penta-1,4-dien-3-one one (Step 1.7) (111 mmol) and TFA (221 mmol) in toluene (175 mL) was stirred for 15.5 h at rt and then concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. LC-MS: tR=1.48 min, [M+H]+ 151; TLC: Rf=0.26 (EtOAc).