Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20].Cl>ClC1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([C:4](=[O:5])/[CH:3]=[CH:2]/[C:1]([OH:6])=[O:7])[CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1Cl
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: COc1ccc(C(=O)/C=C/C(=O)O)cc1Cl
Temperature: 10 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
Into a 500 ml four-neck flask were charged 66.9 g (0.682 mol) of maleic anhydride and 150 ml of chlorobenzene under a nitrogen atmosphere. Then, the whole was cooled to 10° C. or lower and 67.6 g (0.507 mol) of aluminum chloride was added thereto. While temperature was maintained at 10 to 15° C., 23.2 ml (0.195 mol) of 1-chloro-2-methoxybenzene was added dropwise, followed by 51 hours of reaction at 20 to 30° C. After termination of the reaction was confirmed by HPLC analysis, the reaction solution was added dropwise to 200 ml of a 1N hydrochloric acid aqueous solution cooled to 0° C. to decompose excess aluminum chloride. Extraction with 400 ml of ethyl acetate was conducted and the organic layer was washed twice with 200 ml of a 1N hydrochloric acid aqueous solution. Then, the organic layer was extracted three times with 200 ml of a saturated sodium hydrogen carbonate aqueous solution to extract (E)-4-(3-chloro-4-methoxyphenyl)-4-oxo-2-butenoic acid into the aqueous layer, followed by adjusting the aqueous layer to pH 2.0. After 24 hours of stirring at 5° C., filtration was carried out to obtain 28.4 g (yield 60.5%) of the aimed compound as light yellow crystals. As a result of HPLC analysis, the purity was found to be 96.3%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([OH:12])[CH2:9][CH2:8][CH2:7]2.ClCCl.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2
Reactant: OC1CCCc2cccc(Br)c21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCCc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 56.0 g (250 mmol) of 8-bromo-1,2,3,4-tetrahydronaphthalen-1-ol in 3500 ml of dichloromethane 265 g (1.23 mol) of PCC was added. The resulting mixture was stirred at room temperature for 5 h, then passed through a silica gel pad (500 ml), and evaporated to dryness. Yield 47.6 g (88%) of a colorless solid. Anal. Calc for C10H9BrO: C, 53.36; H, 4.03. Found: C, 53.44; H, 4.19. 1H NMR (CDCl3): δ 7.53 (m, 1H, 7-H); 7.18-7.22 (m, 2H, 5,6-H); 2.95 (t, J=6.1 Hz, 2H, 4,4′-H); 2.67 (t, J=6.6 Hz, 2H, 2,2′-H); 2.08 (qv, J=6.1 Hz, J=6.6 Hz, 2H, 3,3′-H).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH:34]([N:8]([CH2:6][C:5]1[CH:37]=[CH:38][C:2]([O:1][CH2:40][CH2:41][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:3][CH:4]=1)[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:18][CH2:19][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:25]=2[CH2:26]1)([CH3:36])[CH3:35]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: O=C(CCl)N1CCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCC3)cc2)C(C)C)c1
Yield: 80.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][C:5]=1[C:11]1[NH:15][N:14]=[CH:13][CH:12]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[NH2:1][C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][C:5]=1[C:11]1[CH:12]=[CH:13][NH:14][N:15]=1
Reactant: O=Cc1cc(-c2ccn[nH]2)c([N+](=O)[O-])s1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1sc(C=O)cc1-c1cc[nH]n1
Yield: 31.6 %

Procedure:
5-Nitro-4-(1H-pyrazol-5-yl)thiophene-2-carbaldehyde (40 mg, 0.18 mmol) was dissolved in absolute ethanol (4 mL). A saturated solution of sodium hydrosulfite in water was added dropwise until complete consumption of the starting material (10 minutes). Water (30 mL) added, the aqueous layer extracted with ethyl acetate (3×10 mL), and the resulting organics were dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography, eluting with ethyl acetate in hexanes, to yield 5-amino-4-(1H-pyrazol-3-yl)thiophene-2-carbaldehyde as a powder (11 mg, 42%). 1H NMR (400 MHZ, DMSO-d6) δ 6.60 (d, J 2.3 Hz, 1H), 7.80 (d, J 2.3 Hz, 1H), 8.02 (s, 1H), 9.49 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[OH:10].[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[Cl:25]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:26]([C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)(=[O:28])=[O:27])=[C:3]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[OH:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Cl)cc1C(O)c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Cl)cc1C(O)c1ccccc1Cl)c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To 0.9 g of (2-amino-5-chlorophenyl)(2-chlorophenyl)methanol dissolved in 4 ml of pyridine is added 0.822 g of 3,4-dichlorobenzenesulfonyl chloride, and the mixture is left for 30 minutes at room temperature. The reaction medium is taken up in ethyl acetate and washed with water, and then with 1M hydrochloric acid solution. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane, to give 0.601 g of the expected product.
Reaction SMILES: B.[CH2:2]([CH:4]([CH2:18][CH3:19])[CH2:5][O:6][C:7]1[N:12]=[C:11]([C:13](=[O:17])[CH2:14][C:15]#[N:16])[CH:10]=[CH:9][CH:8]=1)[CH3:3].N.CO.C(Cl)Cl>>[NH2:16][CH2:15][CH2:14][C@H:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH:4]([CH2:18][CH3:19])[CH2:2][CH3:3])[N:12]=1)[OH:17]
Reactant: CCC(CC)COc1cccc(C(=O)CC#N)n1
Agent: B
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCC(CC)COc1cccc([C@H](O)CCN)n1

Procedure:
Borane reduction of 3-(6-(2-ethylbutoxy)pyridin-2-yl)-3-oxopropanenitrile following the method described in Example 6 gave after flash chromatography purification (25%-30% 7N NH3/MeOH—CH2Cl2 gradient) Example 30 as a colorless oil. Yield (0.11 g, 25%); 1H NMR (400 MHz, DMSO-d6) δ 7.61 (t, J=7.6 Hz, 1H), 7.0 (d, J=7.6 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 4.57-4.50 (m, 1H), 4.15-4.06 (m, 2H), 2.70-2.58 (m, 2H), 1.84-1.76 (m, 1H), 1.64-1.52 (m, 2H), 1.42-1.28 (m, 4H), 0.85 (t, J=7.2 Hz, 6H); RP-HPLC tR=8.51 min; ESI-MS m/z 253.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(=O)(O)[O-].[Na+].[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=1>CN(C)C=O.O1CCCC1>[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:38][CH:39]=1
Reactant: Oc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccc(O)cc23)CC1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7 g), sodium bicarbonate (4.2 g) and 4-(5-hydroxy-3-indolyl)-1,2,3,6-tetrahydropyridine (5.3 g) in dimethylformamide (50 cc) and tetrahydrofuran (50 cc). The mixture is heated for 5 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 7 hours at this temperature. After purification by crystallization from water (100 cc), then recrystallization from a boiling acetoneethanol mixture (50-50 vol) (80 cc), 2-(3-[4-(5-hydroxy 3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.1 ) is obtained, m.p. 214° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:29])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[C:14]([O:27][CH3:28])[CH:13]=2)[CH2:4][CH2:3]1.[OH-].[K+]>CO>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:29])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:14]([O:27][CH3:28])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)CCCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCC(=O)O

Procedure:
Using 1.6 g of N-(trans-4-methylcyclohexyl)-4-[3(ethoxycarbonyl)propoxy]-3-methoxycinnamamide (Example 174), 20 ml of 2 M aqueous potassium hydroxide solution, and 80 ml of methanol, a reaction similar to that conducted in Example 169 was carried out. As a result, 1.36 g of N-(trans-4-methylcyclohexyl)-4-(3-carboxypropoxy) -3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([NH:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH:17]([NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:18]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Cc1ccnc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(N2CCC(NC(=O)OC(C)(C)C)C2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
A suspension of 2-fluoro-4-methylpyridine (1.11 g), 3-(tert-butoxycarbonylamino)pyrrolidine (1.68 g) and potassium carbonate (1.49 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 16 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water five times and brine, dried over sodium sulfate and evaporated under reduced pressure to give 1-(4-methylpyridin-2-yl)-3-(tert-butoxycarbonylamino)pyrrolidine (1.36 g).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8](OCC)[O:9]CC)=[CH:4][C:3]1=[O:15].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]1=[O:15]
Reactant: CCOC(OCC)c1ccn(C)c(=O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc(C=O)cc1=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 93.7 %

Procedure:
1-Methyl-4-(diethoxymethyl)-2(1H)-pyridone (1.20 g, 5.58 mmol) was dissolved in tetrahydrofuran (10.0 mL). To this, 1 mol/L hydrochloric acid (10.0 mL) was added under a nitrogen atmosphere at room temperature and the mixture was stirred at 50° C. for 6 hours. By addition of a saturated aqueous sodium bicarbonate solution to neutralize the reaction mixture, the reaction was stopped. Then, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=9/1) to give 1-methyl-4-formyl-2(1H)-pyridone (717 mg, yield: 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-])=O)[CH:16]=2)=[CH:10][CH:9]=1)([O-])=O.[H][H]>CN(C)C=O>[NH2:25][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=1)[O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=[C:4]([NH2:1])[CH:5]=2)=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cc(Oc2ccc(Oc3cc([N+](=O)[O-])cc(C(F)(F)F)c3)cc2)cc(C(F)(F)F)c1
Reactant: [H][H]
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(Oc3cc(N)cc(C(F)(F)F)c3)cc2)cc(C(F)(F)F)c1
Yield: 70.5 %

Procedure:
To a reducing apparatus equipped with a thermometer, reflux condenser and stirrer, 36.5 g (0.0747 mol) of 1,4-bis(3-nitro-5-trifluoromethylphenoxy)benzene, 250 ml of N,N-dimethylformamide and 1.8 g Pd-alumina were charged and reacted in a hydrogen atmosphere at 50° C. for 6 hours. After finishing the reaction, the catalyst was filtered and the filtrate was concentrated under reduced pressure to obtain 1,4-bis(3-amino-5-trifluoromethylphenoxy)benzene as colorless crystals. The product was 36.5 g (70.5% yield) and had a melting point of 157.4~158.0° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]1([CH3:36])[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[CH:29][CH:28]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:36][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[S:35])=[CH:29][CH:28]=1
Reactant: Cc1ccc(N=C=S)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: S=C=Nc1ccc(CBr)cc1
Yield: 63.2 %

Procedure:
N-bromosuccinimide (6.26 g) (supplied from Tokyo Chemical Industry) and 1.13 g of 70% benzoyl peroxide (supplied from Aldrich) were added to a solution of 5.02 g of p-tolyl isothiocyanate (supplied from Tokyo Chemical Industry) in 100 mL of carbon tetrachloride, and stirred with heating reflux for 19 hours. The reaction suspension was filtrated and the filtrate was concentrated. The residue was applied onto the silica gel column and eluted with hexane, to yield 4.85 g of the title compound.
Reaction SMILES: [CH:1]1[NH:2][C:3]2[N:9]=[C:8]([NH2:10])[N:7]=[C:6](Cl)[C:4]=2[N:5]=1.C(N(CC)CC)C.C[O:20]C1C=C(C)C(S)=CC=1.O>CO>[NH:7]1[C:6](=[O:20])[C:4]2[NH:5][CH:1]=[N:2][C:3]=2[N:9]=[C:8]1[NH2:10]
Reactant: COc1ccc(S)c(C)c1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: Nc1nc2nc[nH]c2c(=O)[nH]1

Procedure:
6-Chloroguanine derivative prepared in Preparation 6 (4.86 g) was dissolved in 85 Ml of methanol and 1.4 g of triethylamine and 2.9 g of 4-methoxythiocresol were added. The reaction mixture was reacted under reflux condition for 24 hours. The reaction was stopped by adding 20 ml of water, and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichloromethane and purified by silica gel column to give a compound wherein 6-position of guanine was substituted by 4-methoxyphenylthio group.
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][CH2:10][CH:9]1[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.OS(O)(=O)=O>C(#N)C>[CH2:1]([N:8]1[CH2:11][CH2:10][CH:9]1[C:12]([O:14][CH2:15][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)C1CCN1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)C1CCN1Cc1ccccc1
Temperature: 20 °C
Yield: 87 %

Procedure:
To 68.3 g of methyl N-benzylazetidine-2-carboxylate (see Example 4 above; purity 89.8 area % ), acetonitrile (127 mL), K2CO3(s) (23.3 g) and benzyl alcohol (75.6 g) were added. The stirred reaction slurry was heated to between 75 and 80° C., and a modest vacuum (p>700 mbar) was applied. Methanol and acetonitrile were distilled off and, as the reaction slurry became highly concentrated, more acetonitrile was added and the distillation was continued. This procedure was repeated until a conversion of 97% was attained. The concentrated reaction mixture was cooled to 20° C. and diluted with acetonitrile (70 mL). The solid salts were filtered off and the filter cake was washed with acetonitrile (3×50 mL). The solvent was evaporated off at 40° C. To the remaining high-boiling liquid, heptane (1.5 L) and 5% (w/w) NaCl(aq.) (700 mL) were added, giving a mixture of three phases. 2 M H2SO4 (5 mL) was added to give a pH of about 8. After two more extractions of the organic phase with 5% (w/w) NaCl (aq), and water at pH 8, almost all of the third phase (benzyl alcohol) was successfully dissolved. Water (550 mL) was added to the organic phase and the pH was adjusted to 2.6 with 2M H2SO4 (38 mL). After separation, the organic phase was extracted with two more portions of acidified water (150 mL H2O at pH 2.2, followed by 50 mL H2O at pH 2.6). The organic phase was discarded. To the combined aqueous phases (pH 2.5), heptane (1.25 L) was added and pH was adjusted to 4.5 with K2CO3(s). The organic phase was separated off and washed with 10% (w/w) NaCl (aq.) and water. The obtained organic phase was evaporated at 40° C., until a bright yellow to brownish liquid remained (65.1 g, according to titration 94.0% (w/w) product, 4.3% (w/w) benzyl alcohol, purity(GC) 99.5 area % ). A second crop of product was isolated as above by extracting the remaining water phase (pH 4.5) with three more portions of heptane (0.25/0.1/0.1 L heptane at pH 5.8/5.2/4.9). Yield 7.8 g of a slightly more coloured product (assay 90% (w/w) according to titr., purity(GC) 97.9 area %), resulting in a total yield of 87% (68.2 g, 0.242 mol).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][N:5]=[C:4]([S:23][CH3:24])[N:3]=1.[CH:25]([Mg]Br)([CH3:27])[CH3:26]>C1COCC1.CN1C(=O)CCC1>[CH:25]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][N:5]=[C:4]([S:23][CH3:24])[N:3]=1)([CH3:27])[CH3:26]
Reactant: CC(C)[Mg]Br
Reactant: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(Cl)n1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
4-(4′-Chloro-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile (35) (125 mg, 0.352 mmol) and ferric acetylacetonate (12.44 mg, 0.035 mmol) were dissolved in THF (1791 μl) and NMP (134 μl), then isopropylmagnesium bromide (528 μl, 0.528 mmol) was added dropwise. According to LC/MS, approximately 40% conversion was observed. Additional isopropylmagnesium bromide (528 μl, 0.528 mmol) was added, and the reaction was stirred at rt for an additional 1 hour. The reaction was quenched with 1N HCl, then was extract with EtOAc. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was dry-loaded onto silica gel, then was purified by Biotage™ silica gel chromatgraphy [25 g SNAP column, 30% EtOAc/heptane to 100% EtOAc] to obtain the desired product (51.1 mg, 40%). MS (ES+): m/z=363.3 [M+1] (100). HPLC: tR=1.70 minutes over 3 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([N:17]([CH2:20][CH:21]([OH:23])[CH3:22])C=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([NH:17][CH2:20][CH:21]([OH:23])[CH3:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)CN(C=O)c1cc(OCc2ccccc2)ccc1C=O
Solvent: O
Product: CC(O)CNc1cc(OCc2ccccc2)ccc1C=O

Procedure:
Compound 3 is reacted with a base or an acid in the presence of water and an organic solvent, to yield (±)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzaldehyde (6). Preferably, base is used and the preferred base is sodium hydroxide or potassium hydroxide and the preferred solvent is tetrahydrofuran and the temperature is 0 to 35° C., preferably 20 to 25° C. Preferably, an inert atmosphere, e.g., nitrogen or argon, is maintained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[N-:12]=[N+]=[N-].[Na+].[OH-].[Na+]>ClCCl.CS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:12][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1NCCc2cc(F)ccc21
Reaction time: 3 h
Yield: 55.7 %

Procedure:
To a stirred solution of 5-fluoro-2,3-dihydro-1H-inden-1-one (433 mg, 2.9 mmol) in dichloromethane (2.5 ml) and methanesulfonic acid (2.5 ml) was added sodium azide (378 mg, 5.8 mmol) portionwise at room temperature. Gas evolution was seen immediately and after 3 hours, complete conversion was observed by TLC. The reaction mixture was added dropwise to a rapidly stirred 5M NaOH solution (8 ml) in ice maintaining the internal temperature below 15° C. On complete addition, the aqueous phase (pH 14) was extracted with dichloromethane (3×25 ml). The organics were combined and washed with water (2×25 ml), dried (MgSO4), filtered and concentrated in vacuo. NMR showed a 7:3 mixture of regioisomers that were separated by FCC (using a gradient of eluents 1:1 Hexane/EtOAc to EtOAc) providing the title compound as white solid (267 mg, 58%).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17][NH2:18])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](OC(OCC)OCC)C>>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][N:18]=[CH:19][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1nnc(-c2ccccc2)c2ccccc12
Product: c1ccc(-c2nn3cnnc3c3ccccc23)cc1

Procedure:
A mixture of 4-phenyl-1-hydrazinophthalazine (30 g) and triethylorthoformate (200 ml) is refluxed for 3 hours, then the excess of the orthoformate is evaporated off and the residue is crystallized from ethanol yielding 26 g of the compound of the title. M.p. 198°-99° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH2:14][O:15][CH3:16])=[CH:5][C:4]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH3:2].II.FC(F)(F)C(O[I:29](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH2:14][O:15][CH3:16])=[C:5]([I:29])[C:4]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH3:2]
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CCc1c(CC(=O)OC)cc(OCOC)cc1OCOC
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1c(OCOC)cc(OCOC)c(I)c1CC(=O)OC
Temperature: -30 °C
Yield: 54.2 %

Procedure:
Methyl 2-ethyl-3,5-bis(methoxymethoxy)phenylacetate (300 mg, 1.0 mmol) was dissolved in chloroform (9.0 mL), and with stirring at −30° C., iodine (260 mg, 1.0 mmol) and [bis(trifluoroacetoxy)iodo]benzene (440 mg, 1.0 mmol) were added thereto in order, and stirred at the same temperature for 1 hour. Aqueous saturated sodium thiosulfate solution and aqueous saturated sodium hydroxide solution were added to the reaction mixture, then heated up to room temperature, and stirred further for 2 hours. The reaction mixture was subjected to liquid-liquid separation, and the aqueous layer was washed twice with ethyl acetate. The organic layers were combined and washed with aqueous saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/n-hexane=1/9 to 1/4) to obtain methyl 2-ethyl-6-iodo-3,5-bis(methoxymethoxy)phenylacetate (230 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([N:15]=C(C2C=CC=CC=2)C2C=CC=CC=2)[C:13]#[N:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1>ClCCl.Cl>[ClH:1].[NH2:15][CH:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][N:4]=1)[C:13]#[N:14]
Reactant: N#CC(N=C(c1ccccc1)c1ccccc1)c1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: ClCCl
Product: N#CC(N)c1ncc(C(F)(F)F)cc1Cl

Procedure:
15.0 g of [3-chloro-5-(trifluoromethyl)-2-pyridinyl][(diphenylmethylene)amino]acetonitrile (0.037 mol) are stirred at room temperature for 3 h in a mixture of dichloromethane (15 mL) and hydrochloric acid 10% (15 mL). Phases are separated and the organic phase is washed with 15 mL of hydrochloric acid 10%.