Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[CH:7]=1>>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]([Cl:23])=[CH:14][C:15]([C:19]([F:22])([F:20])[F:21])=[CH:16][C:17]=2[Cl:18])[CH:9]=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1cc(Cl)c(-c2cccc(Cl)c2)c(Cl)c1
Product: O=[N+]([O-])c1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1Cl
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
To 50 ml of fuming nitric acid, 5.0 g (15.4 mmol) of 1-chloro-3-(2,6-dichloro-4-trifluoromethylphenyl)benzene was added dropwise at −30° C. After 15 minutes of stirring at the same temperature, the reaction mixture was warmed to 5° C., poured into about 200 ml of ice-cold water and extracted with 100 ml of diethyl ether twice. The diethyl ether layer was washed with 200 ml of water twice and dried over anhydrous magnesium sulfate, and the diethyl ether was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 3.0 g of 1-chloro-5-(2,6-dichloro-4-trifluoromethylphenyl)-2-nitrobenzene (yield 52.6%) as a pale yellow liquid (nD20 1.5744), which was used in Example 8 (2) as the starting material.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[N:8]=[C:7]2[NH:25][C:26]1[N:27](C(C)(C)C)[N:28]=[C:29]([CH3:31])[CH:30]=1)([O-:3])=[O:2]>C(O)=O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:9]2[N:8]=[C:7]([NH:25][C:26]3[NH:27][N:28]=[C:29]([CH3:31])[CH:30]=3)[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:10]2=[O:14])=[CH:16][CH:17]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc([N+](=O)[O-])cc23)n(C(C)(C)C)n1
Solvent: O=CO
Product: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc([N+](=O)[O-])cc23)[nH]n1
Yield: 47.3 %

Procedure:
12 mg 6-Nitro-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one (preparation see ZB-1) were deprotected by heating in formic acid as described for ZB-1. Evaporation of excess formic acid and chromatography of the residue on silica, eluting with DCM and then with DCM/MeOH 20:1 gave 5 mg of the title product. 1H-NMR: (400 MHz, D6-DMSO) 11.9 (1H, br s), 9.78 (1H, s), 9.52 (1H, s), 8.65-8.56 (2H, m), 7.65 (2H, d), 7.53 (2H, d), 6.26 (1H, s), 2.20 (3H, s), 1.35 (9H, s); MS (ESI+)=418.32 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([O:6][CH2:7][CH:8]1[CH2:12]OC(C)(C)[O:9]1)[CH:3]([F:5])[F:4].[Br:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])=[O:19].S(=O)(=O)(O)O>CC(C)=O>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1([CH2:17][Br:16])[O:9][CH:8]([CH2:7][O:6][C:2]([F:1])([F:15])[CH:3]([F:5])[F:4])[CH2:12][O:19]1
Reactant: CC1(C)OCC(COC(F)(F)C(F)F)O1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: FC(F)C(F)(F)OCC1COC(CBr)(c2ccc(Cl)cc2Cl)O1
Temperature: 120 °C

Procedure:
A mixture of 4-(1,1,2,2-tetrafluoroethoxy)methyl-2,2-dimethyl-1,3-dioxolane (6.8 g), 2-bromo-1-(2,4-dichlorophenyl)ethanone (6 g.), sulphuric acid (0.3 ml at 96%) is heated at 120° C. for 3 hours, the acetone being formed in the reaction being distilled off.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](Cl)=[O:5].[CH2:15]([SH:17])[CH3:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](=[O:5])[S:17][CH2:15][CH3:16]
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Reactant: CCS
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCSC(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
The compound of Example b (1.48 g, 0.006 mol), CH2Cl2 (50 mL), ethanethiol (0.44 g, 0.007 mol), and 4-(N,N-dimethylamino)pyridine (0.86 g, 0.007 mol) were allowed to stir at RT overnight. The mixture was washed with 10% HCl and three times with water, dried (MgSO4), and concentrated. The crude product was purified by RC, eluting with 1:3 ethyl acetate/hexanes. The title compound was obtained as a clear oil in 61% yield.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[N:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[OH:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[N:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]=1[CH3:32])=[O:7]
Reactant: CC(=O)OCC(=O)NCCc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccccc2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(CCNC(=O)CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccccc1
Temperature: 50 °C
Yield: 98 %

Procedure:
A solution of 2-(acetoxy)-N-[2-(1-phenyl-2-methyl-5-(4-methylsulphonylphenyl)-1H-pyrrol-3-yl)-ethyl]acetamide (0.95 g, 0.210 mmol) in methanol (10 mL) is treated with K2CO3 (0.58 g, 0.421 mmol) in water (10 mL). The reaction mixture is heated at 50° C. for 2 h, then it is concentrated and the residue is extracted with CH2Cl2. It is dried and concentrated, obtaining the product at yield of 98%. 1H NMR 400 MHz, CDCl3: δ 2.05 (s, 3H), 2.41 (s, 1H), 2.74 (t, J=4.00 Hz, 2H), 3.00 (s, 3H), 3.56-3.58 (m, 2H), 4.13 (s, 2H), 6.44 (s, 1H), 6.56 (s, 1H), 7.14-7.16 (m, 4H), 7.39-7.44 (m, 3H), 7.65 (d, J=8.00 Hz, 2H).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:41][CH:42]([CH3:44])[CH3:43])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([CH:31]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=4[F:40])[F:32])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[CH:31]([F:32])[CH:28]1[CH2:29][CH2:30][N:25]([C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]3=[N:18][C:19]=2[NH:41][CH:42]([CH3:44])[CH3:43])[CH2:26][CH2:27]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CCNC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (60 mg, 0.096 mmol) and Pd(OH)2 on carbon, (20 wt %, 6 mg, 8.54 μmol) in THF (960 μL) was stirred under an atmosphere of hydrogen gas (balloon) at rt. After 2 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (47.6 mg, 93%) as a yellow foam. 1H NMR (400 MHz, methanol-d4) δ ppm 1.23 (dd, J=6.4, 2.4 Hz, 6H), 1.41-1.49 (m, 1H), 1.52-1.74 (m, 2H), 1.98-2.14 (m, 2H), 2.68 (qd, J=12.6, 2.5 Hz, 2H), 2.96 (t, J=6.3 Hz, 2H), 3.40-3.51 (m, 2H), 3.52 (t, J=6.3 Hz, 2H), 4.10-4.16 (m, 1H), 4.16 (s, 2H), 5.53 (dd, J=46.5, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 420.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>>[N:21]1([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[CH:5]=[N:4][CH:3]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: Clc1cncc(Nc2ccc(N3CCOCC3)cc2)n1
Reactant: c1c[nH]cn1
Product: c1cn(-c2cncc(Nc3ccc(N4CCOCC4)cc3)n2)cn1
Yield: 33.8 %

Procedure:
In a procedure analogous to example 2, reaction of 6-chloro-N-(4-morpholin-4-ylphenyl)pyrazin-2-amine (100 mg, 0.34 mmol) and imidazole (126 mg, 0.38 mmol) furnished the product (37 mg, 34%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]=2[Cl:34])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:45])[CH2:43][CH3:44].O>ClCCl>[Si:17]([O:16][CH2:15][C:10]1[C:9]([Cl:34])=[C:8]([N:4]2[CH:5]=[CH:6][CH:7]=[C:3]2[CH2:2][NH:1][C:42](=[O:45])[CH2:43][CH3:44])[CH:13]=[CH:12][C:11]=1[Cl:14])([C:30]([CH3:31])([CH3:33])[CH3:32])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2CN)c1Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)NCc1cccn1-c1ccc(Cl)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a mixture of 2-aminomethyl-1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]pyrrole (167 mg) and triethylamine (39.8 mg) in dichloromethane (2 ml) was added propionyl chloride (33.4 mg) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature and for 3 hours at ambient temperature. The mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-(propionamidomethyl)pyrrole (185 mg) as oil.
Reaction SMILES: [C:1]([N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH2:11]([Li])[CH2:12][CH2:13]C.C(Br)C#C>C1COCC1>[C:1]([N:5]1[CH2:9][CH2:8][N:7]([CH2:13][C:12]#[CH:11])[C:6]1=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: CC(C)(C)N1CCNC1=O
Agent: C#CCBr
Solvent: C1CCOC1
Product: C#CCN1CCN(C(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve 1-tert-butyl-imidazolidin-2-one (2 g, 14 mmol) in anhydrous THF (60 mL) and cool at −78° C. Slowly add n-butyllithium (6.8 mL, 17 mmol, 2.5 M solution in hexanes). Stir the solution for 30 min. Rapidly add propargyl bromide (3.2 mL, 28.2 mmol, 80% solution in toluene). Warm the solution to room temperature while stirring overnight. Concentrate the reaction mixture in vacuo and filter the residue on a short pad of silica gel eluting with dichloromethane/diethyl ether (1:1) to give the title compound as a yellow oil that solidifies on standing (1.77 g, 70%). GC-MS m/z (%) 180 (M+, 7), 165 (100), 123 (12), 84 (17).
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)[Cl:21].C([O-])(O)=O.[Na+]>C(O)C>[Cl:21][CH2:20][CH:22]([OH:24])[CH2:23][N:17]1[CH2:16][CH2:15][N:14]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18]1
Reactant: ClCC1CO1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Diphenylmethylpiperazine (16.4 g, 0.065 mol) in ethanol (250 mL) was added dropwise to epichlorohydrin (5.1 mL, 0.065 mL) in ethanol (13 mL) with anhydrous NaHCO3 (0.065 mol, 5,46 g) at 0° C., over 45 min at room temperature under N2. After 17 h the NaHCO3 was removed by filtration via a sintered glass funnel and the ethanol removed from the filtrate in vacuo giving a white-yellow solid (21.5 g). This solid after triturating with Et2O (300 mL) gave a precipitate which was filtered and dried in vacuo to give the pure product (5.11 g, 22.8%) mp 114°-116° C. DCI/MS (M+1) 345. 400 MHz 1H NMR (CDCl3) δ: 7.2-7.4 (m, 10H), 4.2 (s, 1H), 3.9 (m, 1H), 3.55-3.7 (m, 2H), 2.7 (m, 2H), 2.45 (m, 8H).
Reaction SMILES: [OH:1][CH:2]([CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[C:3]([O:5][CH3:6])=[O:4].[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI.CN(C)C=O>O>[OH:1][CH:2]([CH2:7][N:8]([CH3:21])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(O)CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A mixture of methyl 2-hydroxy-3-{[(2-nitrophenyl)sulfonyl]amino}propanoate (1.1 g), cesium carbonate (1.4 g), methyl iodide (0.3 mL) and N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.1 g, 100%) as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:1][CH2:2][CH2:3][C:4]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[C:10]([O:15][CH3:16])[CH:11]=1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: COc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCCl)cc1OC

Procedure:
Further, Patent Document 2 discloses that 3-chloropropionyl chloride was reacted with 1,2-dimethoxybenzene in the presence of aluminum chloride to produce 3-chloro-3′,4′-dimethoxypropiophenone in situ. To the reaction mixture concentrated sulfuric acid was added and the reaction was allowed to proceed at 70° C. The resulting product was then purified by silica gel column chromatography to give 5,6-dimethoxy-1-indanone with a yield of 40%. However, silica gel chromatography as used in the above method is a cumbersome method, and further, a problem of the above method is low yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2/[C:30](=[CH:35]\[O:36][CH3:37])/[C:31]([O:33][CH3:34])=[O:32])[CH:18]=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:17]1[N:22]=[CH:21][N:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2/[C:30](=[CH:35]\[O:36][CH3:37])/[C:31]([O:33][CH3:34])=[O:32])[CH:18]=1)#[N:2]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 105 °C

Procedure:
A mixture of 2-cyanophenol (39.7 g), potassium carbonate (62.2 g), polyethylene glycol 400 (60.0 g), (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (98.3 g) and toluene (130 g) was heated at 105° C. for 16 hours. (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate was produced (89.5 area %).
Reaction SMILES: C(C1C=CC([C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[N:14]=[C:13]([C:27]3[CH:32]=[C:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:30]([OH:39])=[CH:29][C:28]=3[OH:40])[N:12]=2)=CC=1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52]>CC(C)=O>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15]2[NH:14][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)([C:27]3[CH:32]=[C:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:30]([O:39][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:29][C:28]=3[OH:40])[N:12]=[CH:11][N:16]=2)=[CH:22][CH:21]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CCCCCCc1cc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)c(O)cc1O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCc1cc(C2(c3ccc(C(C)(C)C)cc3)N=CN=C(c3ccc(C(C)(C)C)cc3)N2)c(O)cc1OCC(=O)OCC
Temperature: 25 °C
Yield: 171.8 %

Procedure:
To a stirred mixture of 10 g of 2,4-bis(4-tert-butylphenyl)-6-(2,4-dihydroxy-5-hexylphenyl)-1,3,5-triazine, 7.4 g of anhydrous potassium carbonate, 0.5 g of potassium iodide, and 80 mL of acetone was added 2.2 mL (2.5 g) of ethyl chloroacetate. The mixture was stirred at reflux for 2.5 h and then allowed to cool to room temperature. The solids were removed by filtration and washed with methylene chloride. The combined filtrates were concentrated under reduced pressure to a volume of 75 mL and diluted with 50 mL of methanol. The resulting solid was collected by filtration and washed with methanol. After drying in vacuo, 10 g of 2,6-bis(4-tert-butylphenyl)-6-(2-hydroxy-4-ethoxycarbonylmethoxy-5-hexylphenyl)-1,3,5-triazine was obtained. The structure was verified by 1HNMR spectroscopy.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11]N[C:9]1=[O:13])(=[O:4])=[O:3].O[CH2:15]CN1CCCC1=O>>[CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:15][C:9]1=[O:13])(=[O:4])=[O:3]
Reactant: O=C1CCCN1CCO
Reactant: CS(=O)(=O)OCCN1CCNC1=O
Product: CS(=O)(=O)OCCN1CCCC1=O
Yield: 50 %

Procedure:
Following the general method as outlined in Intermediate 31, starting from 1-(2-hydroxyethyl)pyrrolidin-2-one (500 mg; 3.87 mmol), 400 mg (50%) of the title compound as a yellow oil, which was used directly without further purification.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].Br[C:19]1[S:20][CH:21]=[CH:22][N:23]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Reactant: Brc1nccs1
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nccs3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 123 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 2-bromo-1,3-thiazole (commercially available).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][O:12][C:5]=2[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:7]2[CH2:8][N:2]([CH3:1])[CH2:3][CH2:4][C:5]3[O:12][CH:11]=[CH:10][C:6]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CN1CCc2occc2C(O)C1
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: CN1CCc2occc2C(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-d]azepin-4-ol (Reference Example 27) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:19]([NH2:21])[CH3:20]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:21][CH2:19][CH3:20])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCN
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: CCNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and ethylamine in DME. EI-MS m/e (%): 229 (M+, 100), 228 ([M—H]+, 76), 214 ([M—CH3]+, 84), 201 (50), 44 (61).
Reaction SMILES: [Cl:1][C:2]([Cl:18])=[CH:3][C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.ClC1C=CC=C(C(OO)=[O:27])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Cl:18][C:2]([Cl:1])=[CH:3][C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])(=[O:27])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CS(=O)c1ccc(-c2ccc(C=C(Cl)Cl)s2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc(C=C(Cl)Cl)s2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
A mixture of 2-(2,2-dichloroethenyl)-5-(4-methylsulfinylphenyl)thiophene (0.8 g, 0.0025 mole) and m-chloroperbenzoic acid (2.0 g, 0.005 mole) in methylene chloride (50 mL) was stirred at room temperature for two days. The mixture was poured into a 0.5N aqueous sodium thiosulfate solution. The resultant mixture was extracted with diethyl ether. The extract was washed first with an aqueous 10% sodium hydroxide solution, followed by an aqueous 10% hydrochloric acid solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, leaving a solid residue. This residue was purified by column chromatography on alumina, eluting with n-hexane:ethyl acetate (50:50), yielding 0.4 g of 2-(2,2-dichloroethenyl)-5-(4-methylsulfonylphenyl)thiophene as a solid (mp 143°-145° C.).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[N:11]=[C:10]([CH:37]=[O:38])[N:9]=1)(=[O:3])[CH3:2].C1CC2[O:45]CCOCCOC3C(OCCOCCOC2CC1)CCCC3.[Mn]([O-])(=O)(=O)=O.[K+]>C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:12]([NH:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([CH3:34])([CH3:36])[CH3:35])=[CH:31][CH:32]=2)(=[O:25])=[O:26])[N:11]=[C:10]([C:37]([OH:45])=[O:38])[N:9]=1)(=[O:3])[CH3:2]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C=O)nc2OCCOC(C)=O)c1
Reactant: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C(=O)O)nc2OCCOC(C)=O)c1
Yield: 32.4 %

Procedure:
0.27 g of 2-[6-(4-tert.butyl-phenylsulphonylamino)-2-formyl-5-(3-methoxy-phenoxy)-pyrimidin-4-yloxy]-ethyl acetate and 0.19 g of dicyclohexyl-18-crown-6 in 15 ml of benzene were stirred with 0.078 g of potassium permanganate at 2000 for 16 hours. The reaction mixture was partitioned between toluene and water. The organic phase was dried and evaporated, and the residue was purified over silica gel with chloroform-methanol. 0.09 g of 4-(2-acetoxy-ethoxy)-6-(4-tert.butyl-phenylsulphonylamino)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid was obtained as a foam, MS: (M-H)- 558.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=1.[Cl:17][C:18]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:27])([F:28])[F:29])[C:18]=2[Cl:17])[CH:6]=1
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: COC(=O)Cc1cccc(OCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1cccc(OCCCNCc2cccc(C(F)(F)F)c2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A solution of [3-(3-bromo-propoxy)-phenyl]-acetic acid methyl ester (1.5 g, 5.26 mmol) and 2-chloro-3-trifluoromethyl-benzylamine (1 g, 4.77 mmol) in acetonitrile (300 ml) was treated with solid potassium carbonate (0.79 g, 5.74 mmol). The reaction was heated to reflux and stirred overnight. Upon cooling to room temperature, the reaction was filtered through a pad of celite, washed with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatograph (EtOAc:Hexane/30:90) to give the title compound as an oil (1.5 g, 50%). MS m/e 402.2 (M+H)+.