Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19].[C:20](OCC)(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>CCO.CC[O-].[Na+]>[CH2:24]([O:23][C:21](=[O:22])[C:20](=[O:26])[CH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19])[CH3:25]
Reactant: Cc1nc(-c2ncccc2C(F)(F)F)ccc1C#N
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1nc(-c2ncccc2C(F)(F)F)ccc1C#N
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Dissolve 6-methyl-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carbonitrile (150 mg, 0.570 mmol) and diethyl oxalate (150 mg, 1.03 mmol) in a solution of EtOH (2 mL) and 17% NaOEt in EtOH (0.6 mL, 1.71 mmol). Warm the mixture to 50° C. and stir overnight. Pour the mixture onto ice water (50 mL) and acidify with 3 N HCl. Extract with EtOAc (3×50 mL). Dry the combined organic extracts over Na2SO4 and remove the solvent under reduced pressure. Purify the crude product using silica gel chromatography eluting with EtOAc/hexane (1:1) to yield the title compound. MS 364.11 (M+1).
Reaction SMILES: C(C1C=CC=CC=1[C:10]1[C:11]([O:19]C(=O)C)=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O-:15])=[O:14])(=O)N.CC(OC1C=CC=CC=1C(O)=O)=O.[C:36]([NH2:45])(=[O:44])[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]>>[C:13]([OH:15])(=[O:14])[C:12]1[C:11](=[CH:10][CH:18]=[CH:17][CH:16]=1)[OH:19].[C:36]([NH2:45])(=[O:44])[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]
Reactant: CC(=O)Oc1c(C(=O)[O-])cccc1-c1ccccc1C(N)=O
Agent: CC(=O)Oc1ccccc1C(=O)O
Agent: NC(=O)c1ccccc1O
Product: O=C(O)c1ccccc1O

Procedure:
The following experiments illustrate (A) the reduced gastric toxicity of 2-(carbamoyl)phenyl-2-acetoxybenzoate relative to a physical mixture of aspirin and salicylamide and (B) the in vivo hydrolysis of 2-(carbamoyl)phenyl-2-acetoxybenzoate to give plasma concentrations of salicylic acid and salicylamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.Cl.CN.[C:12]([BH3-])#[N:13].[Na+].[OH-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH:13][CH3:12])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CNCc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
10.6 g of 4-bromothiophene-2-carbaldehyde are dissolved in 100 mL of acetonitrile, and 11.8 g of methylamine hydrochloride and 6.28 g of sodium cyanoborohydride are added. The reaction mixture is stirred overnight at room temperature. The reaction is stopped with 1M sodium hydroxide solution. After evaporating off the solvents, the residue is chromatographed on silica gel (7/3 heptane/ethyl acetate). 8.19 g of (4-bromothiophen-2-ylmethyl)methylamine are obtained. Yield=79%.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:7][N:6]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:18][C:13]1[CH:12]=[C:11]([C:9]2[C:8]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[N:10]=2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: COC(=O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 3.79 g 4-(3,4-dichloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic acid methyl ester in 28 mL tetrahydrofuran was added 13 mL of a 1M solution of lithium hydroxide in water and the mixture was stirred at room temperature for 1 h. The reaction mixture was acidified by addition of 1M hydrochloric acid. The precipitate was collected by filtration washed with water and dried to constant weight under high vacuum to yield 3.561 g (97.55%) of the title compound as white solid, MS 365.0 (M−H)−.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[ClH:9].Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(P(=O)(OCC)OCC)#N.Cl>C(OCC)(=O)C.C(OCC)C.C(OCC)(=O)C.O.CN(C)C=O.C(N(CC)CC)C>[ClH:9].[C:2]1([C:6]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][C:15]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:22][CH2:21]2)=[O:8])[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: O=C(O)c1cccs1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1cc(CN2CCN(C(=O)c3cccs3)CC2)cc(OC)c1OC
Yield: 50.4 %

Procedure:
To a mixture of thiophene-2-carboxylic acid (0.4 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.1 g), triethylamine (1.2 g) and dimethylformamide (20 ml) is added dropwise, while stirring, diethyl cyanophosphonate (1.2 ml), followed by stirring for one hour. To the reaction mixture are added water (100 ml) and ethyl acetate (100 ml), followed by extraction. The extract is washed with water, dried and concentrated under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane:acetone=2:1) to give an oily product, which is led to its hydrochloride in a mixture of ethyl acetate - ethyl ether to yield 1-(2-thenoyl)-4(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.65 g) as colorless needles, m.p. 205°-209° C. (decomp.).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2CCC(c3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a suspension of 4-phenylpiperidine (5.0 g) in acetonitrile (100 ml) was added triethylamine (8.64 ml) and then was added dropwise at 0° C. a solution of p-toluenesulfonyl chloride (6.50 g) in acetonitrile (30 ml). The mixture was stirred at 0° C. for 2 hours. Under reduced pressure, the solvent was evaporated, and to the residue was water. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the resulting crystals were collected by filtration, which were washed with hexane to give colorless crystals of 1-(4-methylphenylsulfonyl)-4-phenylpiperidine (8.93 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(N(CC)CC)C>[CH2:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]=[O:15])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1csc(NCc2ccccc2)n1
Solvent: CCN(CC)CC
Product: O=Cc1csc(NCc2ccccc2)n1

Procedure:
The reaction described in Preparation 44 was repeated, but using 1.21 g of 2-benzylaminothiazol-4-ylmethanol, 2.6 g of pyridine sulfur trioxide complex, 3 ml of triethylamine and 30 ml of dimethyl sulfoxlde, giving the title compound as pale brown crystals.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH:5]([C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1)[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:15][CH:14]=2)[N:7]=1.O.[OH-].[Li+:38]>C1COCC1.O>[Li+:38].[F:33][C:31]1[CH:32]=[C:27]([CH:5]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[CH:17][CH:18]=3)[N:7]=2)[CH2:4][C:3]([O-:35])=[O:2])[CH:28]=[C:29]([F:34])[CH:30]=1
Reactant: COC(=O)CC(c1cc(F)cc(F)c1)c1ccnc(Oc2ccc(CNc3ccccn3)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])CC(c1cc(F)cc(F)c1)c1ccnc(Oc2ccc(CNc3ccccn3)cc2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The compound of Example 4 (40 mg, 0.088 mmol) in THF (10 ml) and water (5 ml) was stirred at room temperature and lithium hydroxide monohydrate (37 mg, 0.88 mmol) added. The solution was stirred at room temperature for 72 h, then the solvents were removed in vacuo, and the crude white solid partitioned between ethyl acetate (10 ml) and water (10 ml). The water layer was freeze dried and the title compound was obtained as a white solid. 1H NMR (d6 DMSO) δ 8.29 (1H, d, J 5.1 Hz), 7.81 (1H, d, J 5.1 Hz), 7.21 (4H, m), 7.09 (1H, d, J 5.1 Hz), 6.80 (4H, m), .6.52 (1H, t, J 10.0 Hz), 6.42 (1H, t, J 5.8 Hz), 6.39 (1H, d, J 8.6 Hz), 4.42 (1H, t, J 7.9 Hz), 4.34 (2H, s), 2.98 (1H, dd, J 15.6, 8.4 Hz) and 2.77 (1H, dd, J 15.2, 7.5 Hz). MS (ES) m/e 463 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[O:10][C:9]2[C:5](=[C:6]([Br:16])[S:7][C:8]=2[C:11]([O:13]CC)=[O:12])[O:4]1>CO>[CH2:3]1[O:10][C:9]2[C:5](=[C:6]([Br:16])[S:7][C:8]=2[C:11]([OH:13])=[O:12])[O:4]1
Reactant: CCOC(=O)c1sc(Br)c2c1OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1sc(Br)c2c1OCO2
Reaction time: 2 h

Procedure:
NaOH (10%) and MeOH were mixed in the proportion 1:1 (80 mL) and added to 3,4-methylenedioxy-2-bromo-5-ethoxycarbonyl thiophene (1.91 g, 7.00 mmol (Example 77)), and the reaction mixture was heated to 60°-70° C. and kept there for 2 h. After cooling, the reaction mixture was filtered and the MeOH of the filtrate was evaporated and water was added. Acidification with 10% HCl precipitated the free acid 3,4-methylenedioxy-2-bromo-5-carboxy thiophene, which was filtered and dried in a desiccator (P2O5), yielding 1.41 g (82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]=O)[CH:6]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(O)(=O)C.CO>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:6]=1
Reactant: C1COCCN1
Reactant: O=CCC(c1ccccc1)n1cc(Br)cn1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Brc1cnn(C(CCN2CCOCC2)c2ccccc2)c1

Procedure:
A suspension of EXAMPLE 77C (150 mg), morpholine (0.117 mL), acetic acid (0.062 mL) and solid-supported MP-CNBH3 (Argonaut Technologies, 885 mg, 2.63 mmol/g) in dichloromethane (4 mL) and methanol (2 mL) was shaken at room temperature for 18 hours. The reaction mixture was filtered, concentrated and purified by RP HPLC (30-100% CH3CN/water/0.1% TFA) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([C:12]1[C:13](=[O:23])[O:14][C:15]([OH:22])=[C:16]([C:19](=O)[CH3:20])[C:17]=1[OH:18])(=[O:11])[CH3:10]>CO>[C:9]([C:12]1[C:13](=[O:23])[O:14][C:15](=[O:22])[C:16](=[C:19]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:20])[C:17]=1[OH:18])(=[O:11])[CH3:10]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: Nc1ccc(F)cc1
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(F)cc2)C(=O)OC1=O

Procedure:
p-Fluoroaniline (2.2 g., 0.02 m.) is added to a hot solution of 4.24 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of methanol. The mixture is refluxed overnight and filtered to give 5-acetyl-3-[1-(p-fluorophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6-(3H)-dione, m.p. 199°-201° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[CH3:8].CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:63](=[NH:76])([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:10][O:9][C:6]1[C:7]([CH3:8])=[C:2]([N:76]=[C:63]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:3]=[N:4][CH:5]=1
Reactant: COc1cncc(Br)c1C
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cncc(N=C(c2ccccc2)c2ccccc2)c1C
Temperature: 150 °C

Procedure:
3-Bromo-5-methoxy-4-methylpridine (0.76 g) was placed in a single neck round bottom flask with NaOtBu (1.4 eq), BINAP (0.8 eq), Pd2(dba)3 (0.25 eq), and benzhydrylideneamine (1 eq) in toluene 20 ml, and refluxed at 150° C. for 4 h. The reaction was partitioned between water and EtOAc, and the EtOAc layer dried over Na2SO4. The product was purified by SGC (EtOAc/ Hexane) affording 5-methoxy-4-methyl-N-(diphenymethylene)pyridine-3-amine. MS (ESI+) for m/z 302 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[N:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:7][C:3]([CH2:2][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:4][N:5]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(-c2ncc(CBr)o2)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ncc(CN3CCCCC3)o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
5-(Bromomethyl)-2-(4-nitrophenyl)oxazole (800 mg, 2.82 mmol) was heated with piperidine (10 mL) in a sealed tube at 100-110° C. for 12 h. The resulting mixture was allowed to cool ambient temperature and then poured into water (30 0 mL) and stirred for 30 min. The resultant solid was filtered and washed with water to remove excess piperidine. The residue was dried to give 2-(4-nitrophenyl)-5-(1-piperidylmethyl)oxazole (700 mg, 86%) as light orange colour solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30][S:31]([CH2:34][CH2:35]O)(=[O:33])=[O:32]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CS(=O)(=O)CCO
Product: CS(=O)(=O)CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(methylsulfonyl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 2-(methylsulfonyl)ethyl alcohol following General Procedure J.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:18]=1)[C:9]([O:11]CC(C)C)=[O:10])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>CO.O>[CH2:20]([O:19][C:17]1[CH:16]=[C:8]([CH:7]=[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:18]=1)[C:9]([OH:11])=[O:10])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)COC(=O)c1cc(OCC(C)C)cc(OCC(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)COc1cc(OCC(C)C)cc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
In 13 ml of methanol is dissolved 2.5 g of isobutyl 3,5-diisobutoxybenzoate, to which is then added 2.3 ml of 5 mol/L sodium hydroxide solution. The mixture thus obtained is stirred at 50° C. for 3 hours. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 1.8 g of 3,5-diisobutoxybenzoic acid is obtained as a white solid product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC=CC=1>[C:8]([C:2]1[NH:1][CH:5]=[C:4]([CH:6]=[O:7])[N:3]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
Imidazole 4-carboxaldehyde, 96 mg (1 mmole), is treated with 278.5 mg (1 mmole) of trityl chloride in 25 ml of DMF containing 139 μl of triethylamine (1 mmole) overnight. The DMF is pumped off in vacuo and the residue, taken up in benzene, is washed with dilute aqueous NaHCO3 three times, then brine, then dried with K2CO3, filtered and evaporated to afford compound 3.I.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1
Reactant: COC(=O)c1cncn1C1c2ccccc2C(=O)NC1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)NC(=O)c2ccccc2C1n1cncc1CO
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester (200 mg, 0.67 mmol) (Example 33c) in THF (20 mL) at −10° C. is added lithium aluminum hydride (56 mg, 1.47 mmol). After stirring for 5 min the reaction is placed at room temperature for 1 h, at which time the reaction is cooled to 0° C. and quenched by the consecutive addition of 9:1 THF/H2O (0.8 mL), 2M aqueous NaOH (0.92 mL), and H2O (0.6 mL). The reaction is then warmed to room temperature and diluted with THF (6 mL). After the addition of MgSO4 (900 mg), the heterogeneous mixture is stirred for 15 min and then filtered through a pad of Celite®. The pad of Celite® is washed with ethyl acetate and the combined filtrate is concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-hexanes-ethanol, 6.5:2.5:1 to 9:0.5:1.2) to furnish 4-(5-hydroxymethyl-imidazol-1-yl)-3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1-one; MS (ESI) m/z 272.0 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.11 (s, 3 H), 1.42 (s, 3 H), 2.25 (br. s., 1 H), 4.61-4.93 (m, 2 H), 5.40 (s, 1 H), 5.73 (br. s., 1 H), 6.96 (s, 1 H), 7.32-7.37 (m, 1 H), 7.38 (s, 1 H), 7.46-7.56 (m, 2 H), 8.15-8.26 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1(O)[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH2:6]1.C([Li])CCC.CN([CH:26]=[O:27])C>CCOCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[C:6]=1[CH:26]=[O:27]
Reactant: COCOC1(O)C=C(OC)C(OC)=C(OC)C1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COCOc1cc(OC)c(OC)c(OC)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30.4 g of 1-methoxymethyloxy-3,4,5-trimethoxyphenol prepared in Referential Example 10 was dissolved in 250 ml of anhydrous ether, and 100 ml of n-butyllithium (1.6 M n-hexane solution) was dropwise added thereto at -20° C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hr, and 14.6 ml of DMF was added thereto. 100 ml of ice water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent; n-hexane ethyl acetate=6 : 4) to prepare 25.5 g of the product compound as a light yellow oleaginous substance.
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]=[C:13]([CH2:36][O:37][CH3:38])[C:14]2[C:19]([C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:18][CH:17]=[C:16]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:15]=2)=[O:10])C1C=CC=CC=1.[OH-].[K+]>CCO>[CH2:22]([O:21][C:20]1[C:19]2[C:14](=[CH:15][C:16]([O:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:17][CH:18]=2)[C:13]([CH2:36][O:37][CH3:38])=[N:12][C:11]=1[C:9]([OH:10])=[O:8])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COCc1nc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccc(Oc3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCc1nc(C(=O)O)c(OCc2ccccc2)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.9 %

Procedure:
A mixture of 4-Benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid benzyl ester (480 mg, 0.95 mmol), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at ambient temperature for 48 h before the solvent was evaporated in vacuo. To the residue was added water (10 ml), the mixture was acidified by the addition of aqueous 6N HCl and extracted with EtOAc (2×25 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (355 mg); MS-(−)-ion: M−1=414.1.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:25]=[C:26]([N:30]([CH3:39])[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=O)[CH:27]=[CH:28][CH:29]=1>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([N:30]([CH3:39])[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[S:10])[CH:27]=[CH:28][CH:29]=1
Reactant: CN(C(=O)c1ccccn1)c1cccc(F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CN(C(=S)c1ccccn1)c1cccc(F)c1
Yield: 87.4 %

Procedure:
Lawesson's reagent (3.20 g, 7.9 mmol) and N-(3-fluorophenyl)-N-methyl-2-pyridinecarboxamide (3.51 g, 15.2 mmol) were heated to reflux in toluene (45 mL) under nitrogen for 2 hours. The residue, after evaporation of the solvent, was dissolved in dichloromethane, preadsorbed onto silica gel, and flash chromatographed (250 g of silica gel eluted with 10% ethyl acetate in petroleum ether) to yield N-(3-fluorophenyl)-N-methyl-2-pyridinecarbothioamide as a yellow solid (1.70 g, 45%), m.p. 100°-103° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.N1CCC1.Cl>CN(C=O)C.O>[N:48]1([C:29]([C:26]2[CH:25]=[C:24]([C:20]3[CH:19]=[C:18]([O:17][C:16]4[CH:32]=[CH:33][C:13]([NH:12][C:10]([NH:9][C:3]5[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=5[F:1])=[O:11])=[CH:14][CH:15]=4)[CH:23]=[CH:22][N:21]=3)[NH:28][CH:27]=2)=[O:30])[CH2:47][CH2:46][CH2:43]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: C1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N5CCC5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100 mg, 0.22 mmol), HATU (99 mg, 0.26 mmol) and N,N-diisopropylethylamine (62 mg, 0.48 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of azetidine (20 mg, 0.35 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=4˜5. The precipitates were filtered, washed with water and dried in vacuo to give 1-[4-({2-[4-(azetidin-1-ylcarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]-3-(2-fluoro-5-methylphenyl)urea as light brown solid. Yield: 95 mg, 87%.