Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.O.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2cnc(F)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cnc(F)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 468.7 %

Procedure:
A mixture of methyl 3-fluoroisoquinoline-6-carboxylate (0.257 g, 1.25 mmol) and lithium hydroxide, monohydrate (105 mg, 2.51 mmol) in THF:MeOH:H2O (3:2:1, 4 mL) was stirred at room temperature for 3 hours. The MeOH and THF were evaporated. 5% citric acid was added, and the mixture was further acidified to pH=4 with NaHSO4. The precipitate was recovered by filtration. The filtrate was extracted with chloroform-isopropanol. The organic extracts were washed with water, brine, dried over sodium sulfate and evaporated. The solids were combined to provide the product as a white solid (1.12 g, 100%). LCMS (API-ES) m/z: 192 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[N:17]1([C:23]2[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:24][CH:25]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:24][CH:25]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=C([O-])c1ccc(N2CCCCC2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCCCC4)cc3)cc2)cc1)c1ccc(N2CCCCC2)cc1

Procedure:
Compound 322 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-piperidinobenzoate. [M+H]+ calcd for C37H38N4O3: 587.30; found: 587.02.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:4]=1[F:13].[P:14](OCC)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15]>>[F:13][C:4]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([F:9])=[CH:8][C:3]=1[CH2:2][P:14](=[O:15])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: O=[N+]([O-])c1cc(F)c(CBr)cc1F
Reactant: CCOP(=O)(OCC)OCC
Product: CCOP(=O)(Cc1cc(F)c([N+](=O)[O-])cc1F)OCC
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1-(Bromomethyl)-2,5-difluoro-4-nitrobenzene (8.3 g, 32.9 mmol) and triethyl phosphate (12.03 mL) were heated in an oil bath for 2.5 hours at 140° C. Additional triethyl phosphate (5 mL) was added and the reaction was stirred at 140° C. for 1 hour. The reaction mixture was evaporated under reduced pressure and chromatographed on silica eluting with dichloromethane/methanol (1:0-1%) to give the title compound (11 g, 35.6 mmol). 1H NMR (CDCl3, 400 MHz): δ 7.82 (dd, 1H), 7.37 (ddd, 1H), 4.11 (m, 4H), 3.24 (d, 2H), 1.30 (m, 6H)
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.O>CN(C)P(N(C)C)(N(C)C)=O.C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]1([N:20]=[C:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=3)[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: O=C1c2ccccc2CCc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: c1ccc2c(c1)CCc1ccccc1C2=NC1CC1
Temperature: 25 °C

Procedure:
To a solution of 5 g of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one and 20 g of cyclopropylamine in 25 ml of hexamethylphosphoramide is added, with cooling, during 30 minutes, a solution of 1.7 ml of titanium tetrachloride in 10 ml of anhydrous benzene. After stirring at room temperature for 2 weeks, benzene (50 ml) and water (50 ml) are added, with cooling. The mixture is filtered, the layers of the filtrate are separated, and the aqueous phase is extracted with 50 ml of benzene. The combined aqueous phases are washed with 5% aqueous sodium bicarbonate solution (25ml) and water (3 × 25 ml) and dried with magnesium sulfate. The solvent is removed, and the residue is shortpath distilled at a bath temperature of 145°-150° (0.3 micron) to give N-cyclopropyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5-imine as a solid. Nmr spectrum (in CDCl3): multiplets at τ 2.3-3.0 (8H) 6.6-7.2 (5H) and 8.2-9.4 (4H).
Reaction SMILES: [C:1]1([C:15]([OH:16])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].NN1C=NN=C1.C[O-].[Na+].CO.[OH-:28].[Na+].[OH2:30]>CS(C)=O.C1(C)C=CC=CC=1>[N+:12]([C:11]1[C:10]([OH:28])=[C:6]([N+:7]([O-:9])=[O:8])[C:5]([OH:30])=[C:1]([N+:2]([O-:4])=[O:3])[C:15]=1[OH:16])([O-:14])=[O:13]
Reactant: O
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: C[O-]
Agent: Nn1cnnc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CO
Product: O=[N+]([O-])c1c(O)c([N+](=O)[O-])c(O)c([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
Picric acid (0.27 g, 1.20 mmol) and 4-amino-1,2,4-triazole (0.504 g, 6.00 mmol) are dissolved in a mixture of DMSO (3.6 ml) and toluene (4.8 ml) and treated with a 25 wt. % solution of sodium methoxide in methanol (3.00 ml, 13.1 mmol). The resulting suspension is stirred and heated from ambient temperature to 95° C. over a one hour period. The reaction suspension is cooled to ambient temperature prior to the addition of water (22.5 mL) and a 50% aqueous solution of sodium hydroxide (1.95 ml, 37.2 mmol). The brick-red suspension is stirred for 0.5 hour in a heated water bath (98–100° C.) and cooled in an ice bath for several hours. The resulting suspension is filtered and the resulting orange solid (trinitrophloroglucinol sodium salt) is collected and dissolved in hot 3N hydrochloric acid (16 ml). The resulting solution is cooled to ambient temperature prior to storage at 4° C. The crystalline product is collected, washed with cold 3N hydrochloric acid and dried to give trinitrophloroglucinol (0.211 g) in 67% overall yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O>[CH:15]1([CH2:14][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH2:17][CH2:16]1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(OCC3CC3)ccc21
Temperature: 80 °C
Yield: 86.5 %

Procedure:
To a solution of 6-hydroxy-1-tetralone (2.0 g, 12.3 mmol) in ACN (30 mL) was added (bromomethyl)cyclopropane (2.0 g, 14.7 mmol) and K2CO3 (3.4 g, 24.6 mmol) at rt. The mixture was heated at 80° C. overnight. After the reaction was cooled to rt, it was diluted with EtOAc, filtered, and concentrated. The residue was purified by column chromatography (20:1 PE/EtOAc) to give 2.3 g (87%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 0.35-0.40 (2H, m), 0.65-0.71 (2H, m), 1.25-1.32 (1H, m), 2.08-2.16 (2H, m), 2.62 (2H, t, J=6.3 Hz), 2.93 (2H, t, J=6.0 Hz), 3.87 (2H, d, J=7.2 Hz), 6.71 (1H, s), 6.83 (1H, dd, J=2.1, 8.4 Hz), 8.01 (1H, d, J=8.4 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])[C:6]1=[O:18].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K].[I-].[K+]>CN(C)C=O>[O:24]=[C:22]1[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19](=[O:29])[N:23]1[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])[C:6]1=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)C(C(=O)O)N1CCCN(CCCCl)C1=O
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)O)N1CCCN(CCCN2C(=O)c3ccccc3C2=O)C1=O

Procedure:
As a further illustration, Scheme 28, Example 2 depicts the reaction of the chloro-propyl tetrahydropyrimidine derivative 28.13 with potassium phthalimide 28.16. Equimolar amounts of the reactants are combined in dimethylformamide at ca 80°, in the presence of a catalytic amount of potassium iodide, to afford 2-{3-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-2-oxo-tetrahydro-pyrimidin-1-yl}-3-methyl-butyric acid 28.17. The product is then reacted under reductive amination conditions, as described above (Scheme 10) with a dialkyl formylphenyl phosphonate 28.19 (Epsilon) to yield the phosphonate ester product 28.20.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:17]([Si:21](Cl)([CH2:24]C)[CH2:22]C)([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:11][CH2:12][CH:13]([O:16][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:22])[CH2:14][CH2:15]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(N)ccc1N1CCC(O)CC1
Reactant: CC[Si](Cl)(CC)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(c2ccc(N)cc2C#N)CC1
Yield: 75.5 %

Procedure:
5-Amino-2-(4-hydroxypiperidino)benzonitrile (4.0 g), tert-butyldiethylsilyl chloride (3.0 g) and imidazole (1.6 g) were stirred in dimethylformamide (20 ml) at room temperature for 1 h. The reaction mixture was treated with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was recrystallized from n-hexane to give the title compound (4.2 g), melting point: 88–90° C.
Reaction SMILES: C12(C3C=C[C:14]([O:15]CC(O)=O)=[CH:13]C=3)CC3CC(CC(C3)C1)C2.N[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27].O[N:32]1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:26]([C:25]1[CH:24]=[C:23]([CH2:13][C:14]([NH2:32])=[O:15])[CH:30]=[CH:29][CH:28]=1)#[N:27]
Reactant: N#Cc1cccc(N)c1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc(CC(N)=O)c1
Reaction time: 8 h
Yield: 198.7 %

Procedure:
To 2-(4-Adamantan-1-yl-phenoxy)-acetic acid (200.0 mg, 0.70 mmol), 3-amino-benzonitrile (124.1 mg, 1.05 mmol), N-(3-dimethylaminopropyl)-N-ethyl carbodiimide HCl (EDC) (201.3 mg, 1.05 mmol) and 1-hydroxybenzotriazole (HOBt) (142.9 mg, 1.05 mmol) in DMF (10 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (131.5 mg, 0.18 ml, 1.05 mmol). The mixture was stirred overnight; and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:EtoAc:MeOH=6:3:1) to give 2-(4-Adamantyl-1-yl-phenoxyl)-N-(3-cyano-phenylacetamide as a yellow solid (222.8 mg, 82.6% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH2:14]O)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:18]>C(Cl)(Cl)Cl>[ClH:18].[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH2:14][Cl:18])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)ncn1Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1c(CCl)ncn1Cc1ccccc1
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of 1-benzyl-4-hydroxymethyl-5-methylimidazole (0.85 g, 0.0042 mol), prepared according to the method of Ueda et al., BioMed. Chem. Lett., 4:1623, 1994, in CHCl3 (20 ml) at 0° C. was added SOCl2 (0.421 ml, 0.0126 mol). The reaction was refluxed for 3 h, cooled to rt and the solvent removed in vacuo. The resulting solid was rinsed with Et2O (3×10 ml) and dried under vacuum to give 1-benzyl-4-chloromethyl-5-methylimidazole hydrochloride (13) as a white solid; mp 188° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:11][C:12]([F:15])([F:14])[F:13])=O)=[CH:4][C:3]=1[N:16]1[C:20](C=O)=[CH:19][C:18]([O:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[N:17]1.[C:32]([O-])(=O)C.[Na+].[Cl-].[OH:38][NH3+:39]>CO>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:11][C:12]([F:13])([F:15])[F:14])=[CH:4][C:3]=1[N:16]1[C:20](=[N:39][OH:38])[C:19](=[CH2:32])[C:18]([O:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[N:17]1
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C=O)cc1S(=O)CC(F)(F)F
Reactant: CC(=O)[O-]
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C=C1C(OCC(F)(F)C(F)(F)F)=NN(c2cc(SCC(F)(F)F)c(C)cc2F)C1=NO
Yield: 103.5 %

Procedure:
0.3 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-formyl-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 10 mL of methanol, and 79mg of sodium acetate and 67 mg of hydroxylammonium chloride were added, followed by stirring under reflux with heating for 2 hours. Then, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:3) to obtain 0.31 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-(hydroxyimino)methylene-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][S:26]([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27].CC(C)([O-])C.[K+].O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[C:19]([CH2:25][S:26]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
A solution of 1-benzyl-4-(4-nitrophenoxy)piperidine (3.00 g, 9.60 mmol) and 1-chloromethanesulfonyl-naphthalene (2.35 g, 9.76 mmol) in THF was chilled in an ice bath, treated dropwise with 1.0 M potassium tert-butoxide in THF (20 mL, 20 mmol), stirred at ambient temperature for 1 hour, 20 minutes under nitrogen, poured into water and extracted with ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 40-80% ethyl acetate in hexane to give 1-benzyl-4-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-piperidine as a brown gum/foam, 2.36 g (47.6% yield), Mass spectrum (+EI, [M+H]+) m/z 517. 1HNMR (500 MHz, DMSO-d6): δ8.44-8.47 (m, 1H), 8.28 (d, 1H, J=8.17 Hz), 8.06-8.09 (m, 1H), 7.91-7.96 (m, 2H), 7.59-7.68 (m, 3H), 7.20-7.32 (m, 5H), 7.03 (dd, 1H, J=9.15 Hz and 2.80 Hz), 6.62 (d, 1H, J=2.81 Hz), 5.24 (s, 2H), 4.07-4.10 (m, 1H), 3.44 (s, 2H), 2.49-2.53 (m, 2H), 2.05-2.09 (m, 2H), 1.65-1.69 (m, 2H), 1.38-1.46 ppm (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].CN(C=O)C.C(Cl)CCl>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Yield: 77.6 %

Procedure:
To a 1 L round-bottom flask, were added 4-acetamidobenzoic acid (21.7 g, 122 mmol), tert-butyl (2-aminophenyl)carbamate (23.0 g, 111 mmol), and DMF (90 mL). The mixture was stirred to dissolve under N2, before EDC (27.6 g, 144 mmol) was added in one portion. The reaction mixture was stirred for 2 h, and water (270 mL) was added and stirred for 2 h. The precipitates were filtered, washed with water (2×45 mL) and heptane (2×45 mL). The filter cake was dried at 40° C. in vacuo for 16 h to afford tert-butyl (2-(4-acetamidobenzamido) phenyl)carbamate (31.8 g, 78% yield, 90.6% HPLC purity) as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[C:11]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH:9][CH:8]=2)CCCC[CH2:2]1.C([Li])CCC.[CH3:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[CH3:29][N:30](CCO)[CH3:31].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[CH:25]1([C:8]2[CH:9]=[CH:10][C:11]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[C:7]=2[CH2:1][CH2:2][N:30]([CH3:31])[CH3:29])[CH2:24][CH2:23][CH2:28][CH2:27][CH2:26]1
Reactant: CN(C)CCO
Reactant: CC(C)C1(C(C)C)C=CC=C1C1CCCCC1
Reactant: CCCCCC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)C1(C(C)C)C=CC(C2CCCCC2)=C1CCN(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 91.4 %

Procedure:
In a Schlenk vessel, to a solution of cyclohexyldiisopropylcyclopentadiene (9.28 g; 40.0 mmol) in dry THF (150 mL) at room temperature, a solution of n-butyllithium in hexane (25.0 mL; 1.6 mol/L; 40.0 mmol) was added dropwise. Then, in another Schlenk vessel, a solution of n-butyllithium in hexane (25.0 mL; 1.6 mol/L; 40.0 mmol) was added dropwise to a cold (-78° C.) solution of dimethylaminoethanol (3.56 g; 40.0 mmol) in THF (100 mL). After an hour and a half's stirring at room temperature, the mixture was again cooled to -78° C. and the solid tosyl chloride (8.10 g; 40.0 mmol) was added slowly. The mixture was brought to 0° C., being stirred for 5 minutes in the process, again cooled to -78° C., and the mixture from the first Schlenk vessel then added at once. After 16 hours' stirring at room temperature the conversion was 100%. After column chromatography 11.1 g of cyclohexyl(dimethylaminoethyl)-di-(2-propyl)cyclopentadiene were obtained.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:16])[C:6]1[CH:11]=[C:10]([C:12]#[CH:13])[CH:9]=[C:8]([C:14]#[CH:15])[CH:7]=1)([CH3:3])[CH3:2].[C:17]([O:20][CH2:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=1[F:32])(=[O:19])[CH3:18].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[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>[CH:1]([O:4][C:5](=[O:16])[C:6]1[CH:11]=[C:10]([C:12]#[CH:13])[CH:9]=[C:8]([C:14]#[C:15][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][C:23]([O:22][CH2:21][O:20][C:17](=[O:19])[CH3:18])=[O:33])=[C:26]([F:32])[CH:27]=2)[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OCOC(=O)Cc1ccc(I)cc1F
Reactant: C#Cc1cc(C#C)cc(C(=O)OC(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C#Cc1cc(C#Cc2ccc(CC(=O)OCOC(C)=O)c(F)c2)cc(C(=O)OC(C)C)c1

Procedure:
Following General Procedure B and using 3,5-diethynyl-benzoic acid isopropyl ester (Intermediate 206, 0.27 g, 1.27 mmol), (2-fluoro-4-iodo-phenyl)-acetic acid acetoxymethyl ester (0.224 g, 0.64 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 2.5-20% ethyl acetate in hexane as the eluent, the title compound was obtained as an orange solid (0.09 g, 32%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:19].O>C(OCC)C>[Br:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCCCCCCCCCCc1ccccc1
Solvent: CCOCC
Solvent: O
Product: BrCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In diethylether (200 mL), 10-phenyl-1-decanol (10 g) was dissolved, phosphorus tribromide (4.0 mL) was carefully added thereto, at 0° C., followed by stirring at room temperature for 6 hours. Water was added carefully to the reaction solution, followed by extraction with tert-buthylmethylether. The organic layer was washed with water, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (7.0 g) having the following physical property values.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:6]=12.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([CH:11]([Br:20])[CH3:12])=[CH:7][C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccn2ncc(Br)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccn2ncc(Br)c2c1
Temperature: 77 °C
Reaction time: 2 h
Yield: 28697.2 %

Procedure:
To a stirred solution of 3-bromo-5-ethylpyrazolo[1,5-a]pyridine (I-17, 2.1 g, 0.0094 mmol) in CCl4 (20 mL) at rt was added NBS (2 g, 0.01 mmol) followed by benzoyl peroxide (1.1 g, 0.004 mmol). The resulting reaction mixture was heated to 77° C. After 2 h, the reaction mixture was allowed to cool to rt and subsequently water (20 mL) was added followed by extraction with dichloromethane (2×20 mL). The combined organic layers were washed with water (1×20 mL), sat NaHCO3 solution (1×10 mL), brine (1×10 mL), dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography over silica gel (petroleum ether/EtOAc, 0-5% EtOAc) to afford 820 mg (29%) of 3-bromo-5-(1-bromoethyl)pyrazolo[1,5-a]pyridine (I-18) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=7.91 Hz, 1H), 7.93 (s, 1H), 7.46 (d, J=1.32 Hz, 1H), 6.90-6.92 (dd, J=1.76, 5.71 Hz, 1H), 5.19-5.24 (m, 2H), 2.08 (d, J=7.04 Hz, 3H); ESI-LC/MS (m/z): [M+H]+ 302.9, [(M+2)+H]+ 304.9, [(M+4)+H]+ 306.9, RT 2.65 min
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]2[N:31]=[N:32][N:33]([CH2:35][CH2:36][OH:37])[CH:34]=2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]3[N:31]=[N:32][N:33]([CH2:35][CH2:36][OH:37])[CH:34]=3)=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1-c1cn(CCO)nn1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1-c1cn(CCO)nn1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.32 mmol) and 2-[4-(6-chloro-2-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl]ethanol (76 mg, 0.32 mmol) as starting materials.
Reaction SMILES: [CH2:1](O)[C:2]#[CH:3].[Cl:5][C:6]1[S:7][CH:8]=[C:9]([CH:12]=[CH:13][C:14](Cl)=[O:15])[C:10]=1[Cl:11].C([O:19]CC)C>N1C=CC=CC=1>[Cl:5][C:6]1[S:7][CH:8]=[C:9]([CH:12]=[CH:13][C:14]([O:15][CH2:3][C:2]#[CH:1])=[O:19])[C:10]=1[Cl:11]
Reactant: C#CCO
Reactant: CCOCC
Reactant: O=C(Cl)C=Cc1csc(Cl)c1Cl
Solvent: c1ccncc1
Product: C#CCOC(=O)C=Cc1csc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4.7 g of propargyl alcohol was dissolved in 50 ml of absolute pyridine. At 0° C. at most, 18.4 g of 3-(2,3-dichlorothiophen-4-yl)-propenoyl chloride was added and the reaction batch was stirred for 12 hours at room temperature. 50 ml of diethyl ether was added, the precipitated pyridine hydrochloride was filtered off and the filtrate concentrated under reduced pressure. The residue was taken up in 150 ml of ethyl acetate, the mixture was shaken with water and the organic phase was dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was recrystallized from methanol. There was obtained 7.6 g of propargyl 3-(2,3-dichlorothiophen-4-yl)-propenoate of melting point 84° to 86° C.