Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH:21]([CH3:23])[CH3:22])[C:9](=[O:20])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](OC)[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].IC1C=C(C=CC=1)[C:29]#[N:30]>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH:21]([CH3:22])[CH3:23])[C:9](=[O:20])/[CH:10]=[CH:11]\[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:29]#[N:30])[CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(/C=C/C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)c1
Reactant: N#Cc1cccc(I)c1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)/C=C\c1cccc(C#N)c1
Yield: 90 %

Procedure:
Following the procedure described for [(R)-(E)-1-isopropyl-4-(3-methoxy-phenyl)-2-oxo-but-3-enyl]-carbamic acid tert-butyl ester with 3-iodobenzonitrile (5.50 g, 24.0 mmol, 1 equiv) afforded the title compound as a yellow solid (7.4 g of ˜90% purity material). ESMS [M+H]+: 329.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH2:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH3:36])[C:33](O)=[O:34])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH3:36])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(Nc2cc(F)ccc2N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc(F)cc1NC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(2-amino-5-fluorophenylamino)azetidine-1-carboxylic acid tert-butyl ester (15.5 mmol), (S)-2-benzyloxycarbonylaminopropionic acid (3.81 g, 17.1 mmol), HOAt (2.32 g, 17.1 mmol), 4-methylmorpholine (3.75 mL, 34.1 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.27 g, 17.1 mmol) in DCM (53 mL) was stirred at RT for 2 h. The reaction mixture was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc (×3) and the combined organic fractions were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow oil (quantitative). LCMS (Method B): RT 3.63 min [M+H]+ 487.3.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].CO[CH:7](OC)[CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH3:25]>C(O)C>[CH3:3][O:2][N:4]=[CH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH3:25]
Reactant: CON
Reactant: COC(CCCn1c(C)nc2c(N)nc3ccccc3c21)OC
Agent: Cl
Solvent: CCO
Product: CON=CCCCn1c(C)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methoxylamine hydrochloride (22.8 g, 272 mmol) was added to a solution of 1-(4,4-dimethoxybutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (36.6 g, 136 mmol) in ethanol (200 mL). The reaction mixture was stirred at room temperature for two hours, then was concentrated under reduced pressure. The residue was diluted with water and brought to pH 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with 5% methanol/dichloromethane. The organic layers were combined, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, elution with 5% methanol in dichloromethane) followed by recrystallization from ethyl acetate to yield 4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butanal O-methyloxime as an off-white powder, mp 153-155° C.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[Br:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Br:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: Nc1ccccc1Br
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2ccccc2Br)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-bromo-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.06 (br, 1H), 7.76 (br, 1H), 7.69 (2H), 7.41 (t, 1H), 7.16 (t, 1H), 7.05-6.95 (2H), 6.47 (br, 1H), 3.96 (t, 2H), 3.84 (s, 3H) and 2.96 (t, 2H); MS (ESI) (M+H)+ 398, 400.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][C:3]=1[CH:4]=O.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH2:25][CH2:26][C:27]#[N:28]>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH2:25][C:26]1[C:27]([NH2:28])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][C:7]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[CH:8][CH:9]=2
Reactant: Nc1ccc(N2CCOCC2)cc1C=O
Reactant: COc1cccc(F)c1CCC#N
Product: COc1cccc(F)c1Cc1cc2cc(N3CCOCC3)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-morpholin-4-ylbenzaldehyde and 3-(2-methoxy-6-fluorophenyl)propionitrile.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>CN(C=O)C>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([OH:25])[N:12]2[CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[O:23])=[CH:20][CH:21]=2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(Cc3ccc(C(=O)O)cc3)c2n1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(O)n(Cc3ccc(C(=O)OCc4cccnc4)cc3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
After 2-butoxy-9-(4-carboxybenzyl)-8-methoxyadenine (0.05 g, 0.13 mmol) prepared in accordance with the method of Reference example 5 and potassium carbonate (0.03 g, 0.22 mmol) were added to DMF (10 ml), 3-chloromethylpyridine hydrochloride (0.03 g, 0.18 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hours. After removing the solvent, the residue was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=300/1˜30/1) and the resulting solid was added to methanol (10 ml) and concentrated hydrochloric acid (10 ml). The mixture was stirred at room temperature for 18 hours. After being neutralized with saturated sodium hydrogencarbonate, the solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated and washed with methanol to give the captioned compound (0.03 g, 0.07 mmol, yield: 52%) as a white solid.
Reaction SMILES: [OH-].[Na+].[Br:3]Br.[C:5]1([C:11]#[CH:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.C(COC)OC>[C:5]1([C:11]#[C:12][Br:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C#Cc1ccccc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: BrC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of sodium hydroxide (31.4 g) in water (160 ml) was cooled to 6° C. and bromine (18 ml) was added dropwise, the temperature being kept below 20° C. Phenylacetylene (20 g) in dimethoxyethane (80 ml) was added over 15 minutes and the mixture was stirred at room temperature for 5 hours. Water (200 ml) was added, and the mixture was extracted with ether (4×60 ml), dried (MgSO4) and the solvents removed at room temperature to yield phenylbromoacetylene.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH3:6][CH:7]([CH:13]([CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][OH:15])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:6][CH:7]([CH:13]([CH2:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:14][O:15][P:1]([Cl:5])([Cl:3])=[O:2])[CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(CCC(CO)C(C)CC(C)(C)C)CC(C)(C)C
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(CCC(COP(=O)(Cl)Cl)C(C)CC(C)(C)C)CC(C)(C)C
Temperature: -10 °C
Yield: 34.7 %

Procedure:
With nitrogen substitution, 540 ml of toluene and 138.0 grams (0.9 moles) of phosphorus oxychloride were added and cooled to −10 degrees C. To this mixture, a solution of 243.5 grams (0.9 moles; 1.0 in molar ratio) of 2-(1,3,3-trimethyl-n-butyl)-5,7,7-trimethyl-n-octanol and 91.1 grams (0.9 moles) of triethylamine was dripped, and the mixture was reacted for 12 hours at 0 degrees C. The mixture was then heated to 25 degrees C., and a triethylamine hydrochloride was removed by filtering to obtain 1003.9 grams of a toluene solution of [2-(1,3,3-trimethyl-n-butyl)-5,7,7-trimethyl-n-octyl]dichlorophosphate (34.7% in concentration).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][C:32]1[NH:33][CH:34]=[CH:35][N:36]=1)([CH3:23])[CH3:22]>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:21]([CH3:23])[CH3:22])[CH2:31][C:32]2[NH:36][CH:35]=[CH:34][N:33]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Reactant: CC(C)c1ccccc1NCc1ncc[nH]1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2ccccc2C(C)C)[C@@H]1O
Yield: 19.9 %

Procedure:
The title compound (140 mg, 20%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (400 mg, 1.42 mmol) and 2-isopropylphenyl-1H-imidazol-2-ylmethylamine (306 mg, 1.42 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23](I)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.[Cl:30][C:31]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:32]=1[OH:39]>>[CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:39][C:32]4[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:31]=4[Cl:30])[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1
Reactant: COc1cccc(O)c1Cl
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(I)cc1=O
Product: COc1cccc(Oc2cnn(C(CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)c1Cl

Procedure:
Using the method described in Example 126, Step 1,2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Intermediate 94) and 2-chloro-3-methoxy-phenol afforded 2-[4-(2-chloro-3-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white solid as a mixture of diastereomers (42 mg, 77%); ES+-HRMS m/e calcd for C26H32N5O6Cl [M+H+] 546.2114 found 546.2114. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.78-0.97 (m, 6H), 1.24 (s, 3H), 1.30 (2×s, 3H), 1.45 (br. s., 1H), 1.69-1.87 (m, 1H), 2.05-2.25 (m, 1H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 3.92 (s, 3H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.04-4.19 (m, 2H), 4.35 (quin, J=5.8 Hz, 1H), 5.51 (dd, J=11.0, 4.1 Hz, 1H), 5.71 (d, J=2.7 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.45 (t, J=8.2 Hz, 1H), 7.59 (s, 1H), 8.19 (d, J=2.7 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:17]1([C:23]2[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:15][N:4]1[C:3](=[O:16])[C:2]([NH:29][C:26]2[CH:27]=[N:28][C:23]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:24][CH:25]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13]
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CN1C(=O)C(Nc2ccc(N3CCOCC3)nc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 6-morpholin-4-ylpyridin-3-amine in a similar manner as described for Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 3.20 (s, 3H), 3.26-3.30 (m, 4H), 3.65-3.70 (m, 4H), 6.31 (d, 1H), 6.94-6.99 (m, 1H), 7.11-7.22 (m, 4H), 7.25-7.30 (m, 1H), 7.58 (bs, 1H), 7.71 (d, 1H); Mass Spectrum: M−H+ 399.
Reaction SMILES: Cl.O.[C:3]([O:9][C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[C:19]1([NH:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37][CH3:38])[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[N+:29]([O-])=O)[C:20]1=[O:32])(=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7]>C(O)C.[Fe]>[C:3]([O:9][C:10]1[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[CH:13]=[CH:12][C:11]=1[C:19]1([NH:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37][CH3:38])[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[NH2:29])[C:20]1=[O:32])(=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCC)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCC)C(=O)c2cccc(N)c2C1=O
Yield: 57.5 %

Procedure:
Iron powder (0.03 g, 0.6 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 5-isopropyl-2-(4-nitro-1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)phenyl pentanoate (43 mg, 0.08 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. The reaction mixture was hot filtered off, the filtrate was concentrated in a vacuum and purified by column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (22 mg, 55%).
Reaction SMILES: [C:1]([CH:4]([C:14](=O)[CH3:15])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])(=O)[CH3:2].O.[NH2:18][NH2:19].O>C(O)(=O)C>[CH3:2][C:1]1[C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[C:14]([CH3:15])[NH:19][N:18]=1
Reactant: CC(=O)C(C(C)=O)C(=O)Nc1ccccc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Cc1n[nH]c(C)c1C(=O)Nc1ccccc1
Yield: 88 %

Procedure:
The foregoing diacetyl acetanilide (2.2 g) in glacial acetic acid (30 ml) was treated with hydrazine hydrate (1.5 g) and the mixture boiled under reflux for 30 min. The mixture was then poured into water and the product collected and crystallised from ethanol. 3,5-dimethyl-N-phenyl-4-pyrazolecarboxamide (1.9 g, 86%) was obtained as colourless plates, m.p. 244-5° C (Found: C, 66.8 H, 6.0 N, 19.3 C12H13N3O requires C, 66.9; H, 6.1; N, 19.5%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH2:17]O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:1]([O:9][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccccc1
Reactant: O=C(O)c1ccccc1
Product: O=C(OCCc1ccccc1)c1ccccc1
Temperature: 180 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
A 2-L, 4-neck round bottom flask, fitted with a thermometer, mechanical stirrer, nitrogen inlet tube and Liebig condenser/receiving flask, was charged with 671.7 g (5.50 mol, 1.00 equiv) of benzoic acid, 806.3 g (6.60 mol, 1.20 equiv) of 2-phenylethyl alcohol, and 1.25 g (0.1% w/w) of Fascat 2001®. The system was heated gently with slow stirring (<50 rpm) until the benzoic acid dissolved. The air was removed with three cycles of evacuation/nitrogen fill using a mechanical vacuum pump (50–100 torr). The rate of stirring was increased to ca. 200 rpm, the nitrogen sparge was set at 0.2 scfh, and the reaction mixture was heated to 180° C. After a 1 -h hold, the temperature was increased to 190° C. for 1 h and then to 200° C. for 1 h. The temperature was increased to 210° C. and the nitrogen sparge was increased to 0.5 scfh. After a 1-h hold, the temperature was further increased to 220° C. for 1 h. The total amount of distillate was 159.2 g, from which 94.4 g of water (theor. 99.1 g) was separated as the top layer. The reaction mixture was cooled to room temperature and sampled for analysis. The acid number was 1.10 mg KOH/g (99.7% conversion) and the APHA color was 115. The excess 2-phenylethyl alcohol (5.5% by GLC) was removed by vacuum distillation. Thus, after 1 h at 180–190° C. and 20 torr (0.5 scfh nitrogen sweep), the residual 2-phenylethyl alcohol was <0.05% by GLC and the APHA color was 222. Activated carbon (37.3 g, 3% w/w) was added, and the mixture was heated at 75–80° C. under vacuum (50–70 torr) for 1 h. After cooling to room temperature, filtration through Celite® gave 1100 g (90%) of 2-phenylethyl benzoate. The APHA color was 20, the acid number was 0.14 mg KOH/g, the saponification number was 246 mg KOH/g (theor. 248), and the residual tin was <10 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1)(=[O:18])[CH3:17]
Reactant: CCOC(=O)c1cn2cc(N)ccc2n1
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn2cc(NC(C)=O)ccc2n1

Procedure:
A suspension of 0.2 g of ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate (Heterocycles, 38(7), 1527 (1994)) in 1 ml of acetic anhydride is heated at reflux for 45 minutes. The reaction mixture is concentrated under reduced pressure; the residue is taken up in water and basified by addition of a 1N sodium hydroxide solution. The solid is filtered off and dried to give 150 mg of ethyl 6-acetamidoimidazo[1,2-a]pyridine-2-carboxylate in the form of an ecru solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH:21]([O:20][CH3:19])[CH:13]([C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:17][CH3:18])[CH:11]=1)[OH:14]
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: COCC(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(OC)C(O)c1ccc(OCc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
A solution of 4-benzyloxy-3-methoxy-benzaldehyde (0.44 g, 1.92 mmol) and methyl methoxyacetate (0.19 mL, 1.92 mmol) in THF (10 mL) at −78° C. was added dropwise to sodium bis(trimethylsilyl)amide (20 mL, 2.11 mmol, 1N in THF) at −78° C. The reaction mixture was stirred for 3 h and quenched with 1N HCl (5 mL). The mixture was allowed to warm to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography (silica gel, hexanes/ethyl acetate, 1:1) to produce 3-(4-benzyloxy-3-methoxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methyl ester as an oil (350 mg, 52%); 1H-NMR (200.15 MHz, CDCl3): δ 7.45–7.20 (m, 5H), 6.9 (s, 1H), 6.8 (b, 2H), 5.1 (s, 2H), 4.90–4.80 (m, 1H), 4.10 (m, 1H), 3.90 (s, 3H), 3.65 (s, 3H), 3.31 (s, 3H), 3.10–2.96 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=O)=[CH:4][C:3]=1[Cl:18].C(OP([CH2:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])(OCC)=O)C.CC(C)([O-])C.[K+]>CN(C)C=O>[NH2:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])=[CH:4][C:3]=1[Cl:18]
Reactant: CCOP(=O)(CC(=O)N1CCOCC1)OCC
Reactant: Nc1c(Cl)cc(C(=O)c2ccc(Cl)cc2)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1Cl

Procedure:
This compound was prepared from 4-amino-3,4',5-trichlorobenzophenone, diethylphosphonoacetic acid morpholide and potassium tert.butoxide in dimethylformamide analogous to Example 4.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:18])[CH2:4][CH2:3]1.[N+:19]([O-])([OH:21])=[O:20]>OS(O)(=O)=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:18])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])O
Reactant: CN1CCC(N2C(=O)CCc3ccccc32)CC1
Agent: O=S(=O)(O)O
Product: CN1CCC(N2C(=O)CCc3cc([N+](=O)[O-])ccc32)CC1
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A solution of 1-(1-methylpiperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (305 mg, 1.25 mmol) in conc. H2SO4 (4 mL) was treated with fuming HNO3 (53 μL, 1.25 mmol) at −5 to −10° C. (ice/MeOH) and the resulting solution was stirred for 30 min. at the same temperature. The reaction was quenched with the addition of crushed ice, and then basified with 1 N NaOH, and the product was extracted into CH2Cl2 (2×50 mL). The combined CH2Cl2 layer was dried (Na2SO4), filtered, and the solvent was evaporated. The crude was triturated with hexanes to afford the title compound (320 mg, 88.4%) as a solid. 1H-NMR (CDCl3) δ 8.10-8.05 (m, 2H), 7.33 (d, J=8.7 Hz, 1H), 4.50-4.39 (m, 1H), 3.01-2.90 (m, 4H), 2.67-2.54 (m, 4H), 2.33 (s, 3H), 2.15-2.08 (m, 2H), 1.74-1.70 (m, 2H). MS (ESI): 290.2 (M+1, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10]([NH2:12])=[O:11].C(O)=O>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:12][CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NC=O
Solvent: O=CO
Solvent: O
Product: O=CNCc1ccc(O)cc1
Temperature: 189 °C
Yield: 77.4 %

Procedure:
4-hydroxybenzaldehyde (1.22 g or 10 mmol), formamide (22.72 g or 20.03 mL) and formic acid (2.43 g or 2 mL) were placed into a 50 mL round bottom flask equipped with a thermometer, a reflux condenser, a magnetic stirrer and a heating mantle. The reaction mixture was heated to 189° C. The heating was immediately turned off; the reaction flask was quickly raised from the heating mantle and allowed to cool to room temperature. The TLC conducted on the cold reaction mixture confirmed that the reaction was complete. The reaction mixture was diluted with 50 ml of water and extracted with ethyl acetate. The extract was dried with sodium sulfate and the solvent was evaporated to produce 1.17 g (77.1%) of 4-hydroxybenzylformamide (IV).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[F:15][C:16]1[CH:26]=[C:25]([NH2:27])[CH:24]=[C:23]([F:28])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[F:15][C:16]1[CH:26]=[C:25]([NH:27][C:12]([C:6]2[O:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:24]=[C:23]([F:28])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Reactant: CCOC(=O)c1c(F)cc(N)cc1F
Product: CCOC(=O)c1c(F)cc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1F
Yield: 67.8 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylfuran-2-carboxylic acid (80 mg, 0.408 mmol) and ethyl 2,6-difluoro-4-aminobenzoate (148 mg, 0.736 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [n-hexane-ethyl acetate (40:1)] to obtain ethyl 2,6-difluoro-4-[(4,5-diisopropylfuran-2-carbonyl)amino]benzoate (105 mg, 68%).