Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:3]1>CCCCCC.CCO>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: CC1CCCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)C1
Solvent: CCCCCC
Solvent: CCO
Product: C[C@@H]1CCCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)C1

Procedure:
1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea (50 mg, 0.12 mmol, Example 78) was separated by chiral HPLC (Chiraltech Chiralcel OJ 50×4.6 mm i.d.) using hexane/EtOH/DEA (90:10:0.2) to give a white solid. MS m/z: 409.3 (M+H). Calc'd for C21H24N6OS-408.52.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[CH:13][C:12]=2[C:30]2[N:31]([CH3:36])[N:32]=[CH:33][C:34]=2[Cl:35])[CH2:4][CH2:3]1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CC(N(C)C)=O>[Cl:35][C:34]1[CH:33]=[N:32][N:31]([CH3:36])[C:30]=1[C:12]1[CH:13]=[C:14]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:7][CH2:6]1
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCCN1CCC(N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCCN1CCC(NS(C)(=O)=O)CC1
Yield: 35.6 %

Procedure:
N-[4-[2-(4-Amino-piperidin-1-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide (0.038 g, 0.073 mmol) was dissolved in DMA (2.0 mL) in a vial with stir bar. Methanesulfonyl chloride (0.0085 g, 0.11 mmol) was added and the reaction was stirred at rt overnight. The reaction was concentrated, added to NaHCO3 (5 mL), and the solution was extracted with EtOAc (2×20 mL). The organic extracts were dried (Na2SO4), filtered, concd and purified by prep HPLC to afford the title compound (0.016 g, 0.026 mmol, 35%, TFA salt) as a white solid. LCMS m/z (%)=600 (M+H35Cl, 100), 602 (M+H37Cl, 36). 1H NMR (400 MHz, DMSO-d6) δ: 10.54 (s, 1H), 9.30 (s, 1H), 8.30 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.97 (m, 2H), 7.80 (m, 1H), 7.72 (d, J=2.6 Hz, 1H), 7.68 (s, 1H), 7.31 (m, 1H), 4.40 (m, 1H), 4.32 (m, 1H), 3.69 (s, 3H), 3.50-2.90 (m, 7H), 2.95 (s, 3H), 2.00-1.50 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[O-].[Li+].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].O>CN(C)C=O>[Br:1][C:2]1[C:3](/[CH:13]=[CH:19]/[N:20]([CH3:22])[CH3:21])=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: COc1ncc(Br)c(C)c1[N+](=O)[O-]
Agent: C[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(Br)c(/C=C/N(C)C)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
5-Bromo-2-methoxy-4-methyl-3-nitropyridine (15.0 g, 60.7 mmol) was dissolved in dimethylformamide (300 mL), and lithium methanolate (6.07 mL, 6.07 mmol, 1 M) was added. The reaction mixture was heated to 100° C. To this mixture was added 1,1-dimethoxy-N,N-dimethylmethanamine (64.5 mL, 486 mmol) over 10 minutes. The reaction mixture was stirred at 95° C. for 16 hours. The reaction mixture was cooled to room temperature and water was added carefully (300 mL, exothermic). The resulting precipitate was collected by vacuum filtration, washed with water, and dried to provide (E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine (13.9 g, 45.9 mmol, 76% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-])=O.CS(C)=[O:13]>CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:13])=[CH:6][CH:5]=1
Reactant: CS(C)=O
Reactant: Cc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: Nc1ccc(C=O)cc1

Procedure:
The procedure of Example 1 was followed except that 3.2 g (4.8% by weight of the p-nitrotoluene) of dimethylsulfoxide were substituted for the N,N-dimethylformamide, to obtain 38.3 g (0.317 mol) of p-aminobenzaldehyde and then 39.1 g (0.320 mol) of p-hydroxybenzaldehyde. Thus, the yield of the p-hydroxybenzaldehyde was 65.8%, based on the weight of p-nitrotoluene used.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16]([CH3:19])([CH3:18])[CH2:15][CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:13]=2[CH:26]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>ClCCl>[C:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16]([CH3:19])([CH3:18])[CH2:15][CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=3[O-:35])[C:13]=2[CH:26]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccccc3)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(=O)c3ccccc3)ccc2O1
Yield: 20.3 %

Procedure:
94 mg of 6-benzoyl-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran and 52 mg of m-chloroperbenzoic acid were stirred in 15 ml of dichloromethane at room temperature until thin-layer chromatography indicated that the reaction was complete. The mixture was washed in succession with sodium bisulphite solution and sodium bicarbonate solution, then dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 10% (v/v) methanol/ethyl acetate for the elution. After trituration with diethyl ether there were obtained 20 mg of 2-(6-benzoyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 134°-136° C.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=2)[C@@H:7]([NH2:18])[CH2:6]1)[CH:2]=[CH2:3].FC(F)(F)C(N[C@@H:24]1[C:32]2C(=CC=C(OC(C)C)C=2)[C@H](O)[CH2:25]1)=O>>[CH2:1]([O:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:32]=[CH:24][CH:25]=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[CH:7]([NH2:18])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Reactant: CC(C)Oc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)C[C@H]2O
Product: C=CCOC1CC(N)c2cc(Oc3ccccc3)ccc21

Procedure:
Step BB (1). 3-(Allyloxy)-6-phenoxy-2,3-dihydro-1H-inden-1-amine was prepared using a series of procedures analogous to Steps AU (1-5), X (1) and U (2). 1H NMR (300 MHz, CDCl3) δ 1.6-1.8 (m, 1H) 2.7-2.9 (m, 1H) 4.0-4.2 (m, 3H) 4.7-4.8 (t, 1H) 5.1-5.4 (m, 2H) 5.8-6.0 (m, 1H) 6.8-7.1 (m, 5H) 7.2-7.4 (m, 3H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH2:12][N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[N+:22]([O-])=O)[C:14]1=[O:25].[Cl-].[NH4+]>CO.O.[Zn]>[NH2:22][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH2:21][N:13]([CH2:12][CH2:11][N:2]1[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]1)[C:14]2=[O:25]
Reactant: O=C1c2cccc([N+](=O)[O-])c2CN1CCN1CCc2ccccc2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Nc1cccc2c1CN(CCN1CCc3ccccc3C1)C2=O
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of 37 (0.38 g, 1.1 mmol) in methanol (6 mL) was added a solution of ammonium chloride (0.13 g, 2.42 mmol) in water (1.5 mL). Zinc powder (0.49 g, 7.4 mmol) was then added portionwise and the resulting mixture was stirred for 2 hours. The solids were filtered and washed with methanol, the filtrate was basified with saturated sodium bicarbonate (aq.), and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 38 (0.31 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:12][C:11]1([CH3:13])[C:4]2[C:3](=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[S:8][CH2:9][CH2:10]1
Reactant: CC(C)=CCSc1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CCSc2c(Br)cccc21

Procedure:
26.00 g (102.0 mmol) of 2-bromo-1-(3-methylbut-2-enylthio)benzene, 180 ml of toluene and 23.20 g (122.0 mmol) of para-toluenesulphonic acid are introduced into a three-necked flask. The reaction medium is refluxed for four hours and is then evaporated to dryness. The residue is taken up in aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate, and the organic phase is separated out after settling, dried over magnesium sulphate and evaporated The residue obtained is purified by chromatography on a column of silica and eluted with heptane. 20 g (76%) of the expected compound are collected in the form of an orange-coloured oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([N:23]1[C:24]2[C:29](=[CH:28][C:27]([N+:32]([O-:34])=[O:33])=[CH:26][CH:25]=2)[C:30](=[O:31])[N:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)[C:22]1=[O:35])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(Cc5ccccc5)c4=O)CC3)c2cc1OC
Yield: 80 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 200 mg (0.42 mmol) of Compound 24 was used and benzyl bromide was used in place of methyl iodide. As a result, 190.5 mg (yield: 80%) of Compound 8 was obtained as pale yellow crystals.
Reaction SMILES: C(O[C:4](=[O:19])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])=O)C.Cl.[C:21]([NH2:24])(=[NH:23])[CH3:22].C(O[K])(C)(C)C.Cl>C(O)C.O>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:23]=[C:21]([CH3:22])[NH:24][C:4](=[O:19])[CH:5]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(=O)c1ccccc1OCCOC
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COCCOc1ccccc1-c1cc(=O)[nH]c(C)n1
Yield: 66.6 %

Procedure:
To a solution of 3-[2-(2-methoxy-ethoxy)-phenyl]-3-oxo-propionic acid ethyl ester (0.26 g, 0.98 mmol) in absolute ethanol (10 mL) was added acetamidine hydrochloride (0.3 g, 3.19 mmol) and tBuOK (0.5 g, 4.46 mmol). The reaction mixture refluxed 12 h. After cooling, a mixture poured into water (10 mL), adjusted to pH 3 with 10% HCl and extracted with CHCl3 (3×20 mL). Organic layers were combined, washed with water (10 mL), then dried over anhydrous sodium sulfate, concentrated and triturated with hexane to obtained 0.17 g (67%) 6-[2-(2-methoxy-ethoxy)-phenyl]-2-methyl-3H-pyrimidin-4-one as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:32])[CH3:6])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(C)c([N+](=O)[O-])cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)COc2cc(C)c([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A solution of 2-(7-methyl-6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.5 g crude, 48% pure, 0.81 mmol) and Lawesson's reagent (0.656 g, 1.62 mmol) in toluene (30 mL) was heated at 120° C. for 20 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo to give the crude product, which was purified by chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) and further purified by preparative TLC (eluting with 20% EtOAc in petroleum ether) to give 2-(7-methyl-6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.130 g, 50%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 7.64 (s, 1H), 6.90 (s, 1H), 6.61 (s, 1H), 4.90 (q, J=15.6 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 2.54 (s, 3H), 1.65 (d, J=7.2 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(S[CH:5]([CH2:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=O)C.C(Cl)(Cl)(Cl)Cl.[SH:30][CH2:31][C:32]([OH:34])=[O:33]>C(O)C>[C:17]([CH2:16][CH:5]([S:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)SC(CC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)CS
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CSC(CC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 72 h

Procedure:
To a suspension of 0.90 g. of 1-(3-benzoylacryloyl)-L-proline (prepared as described in Example 8) in 30 ml. of carbontetrachloride is added 0.28 ml. of mercaptoacetic acid. An additional 30 ml. of carbontetrachloride is added and the mixture stirred 3 days. The solvent is removed under vacuum. Carbontetrachloride (30 ml.) and 0.78 ml. of mercaptoacetic acid is added and the mixture stirred for 3 days. The solvent is removed and the residue chromatographed on a silica gel column with dichloromethane-methanol-acetic acid (90:10:2) as solvent. Fractions showing one spot by thin layer chromatography are combined to give 1.3 g. of clear gum. Placing the gum under high vacuum over night gives the product of the example as a glass, [α]D23° -31°±2(c, 0.534 ethanol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([O-])(=[O:16])C.[NH4+]>C(O)(=O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][NH:3][C:2]2=[O:16])=[CH:7][C:8]=1[F:13]
Reactant: Fc1cc2ccnc(Cl)c2cc1Cl
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1[nH]ccc2cc(F)c(Cl)cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
41.1 g 1,7-dichloro-6-fluoro-isoquinoline (59) were dissolved in 670 ml of acetic acid. After addition of 148.8 g of ammonium acetate, the solution was stirred at 100° C. After 3 h, the solvent was removed under reduced pressure and the residue was poured into water. The aqueous phase was extracted three times with dichloromethane, the combined organic layer was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated to dryness. The crude product was crystallized from ethyl acetate:heptane to yield 14.85 g of the desired product. Another 4.5 g could be obtained upon evaporation and silica gel chromatography of the mother liquor. The precipitate was filtered and dried to yield 9.91 g (83%) of the title compound. Rt=1.33 min (Method B). Detected mass: 198.0 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH3:12])[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=3)[C:7]=2[CH:35]=1)#[N:2].[OH-:36].[K+]>CC(O)(C)C>[CH2:11]([C:9]1[N:8]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=2)[C:7]2[CH:35]=[C:3]([C:1]([NH2:2])=[O:36])[CH:4]=[CH:5][C:6]=2[N:10]=1)[CH3:12]
Reactant: [OH-]
Reactant: CCc1nc2ccc(C#N)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCc1nc2ccc(C(N)=O)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 62.9 %

Procedure:
To a solution of 6-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (Example 85, 162 mg, 0.33 mmol) in 2-methyl-2-propanol (10 mL) was added powdered KOH (66 mg, 1.0 mmol). The resulting mixture was heated at reflux temperature for 3 h. After removal of solvent, the reaction mixture was partitioned between dichloromethane (50 mL) and phosphate buffer (50 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic phases were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residual solids were recrystallized from ethyl acetate to afford 105 mg (63%) of the title compound as white solids: 1H-NMR (CDCl3) δ: 7.79 (2H, d, J=8.4 Hz), 7.75 (1H, d, J=8.8 Hz), 7.71-7.63 (2H, m), 7.35-7.25 (4H, m), 7.16 (2H, d, J=8.4 Hz), 6.75 (2H, br.s), 6.55 (1H, br.s), 3.54 (2H, t, J=6.4 Hz), 2.88 (2H, t, J=6.4 Hz), 2.79 (2H, q, J=7.5 Hz), 2.40 (3H, s), 1.34 (3H, t, J=7.5 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[C:12]([O:16][C:17](=[O:20])[C:18]#[CH:19])([CH3:15])([CH3:14])[CH3:13].CN1CCOCC1>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]/[CH:19]=[CH:18]\[C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:20])=[CH:7][CH:6]=1
Reactant: COCCc1ccc(O)cc1
Reactant: C#CC(=O)OC(C)(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COCCc1ccc(O/C=C\C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
a mixture of 4-(2-methoxy ethyl)phenol (1.547 g, 10.3 mmol), propiolic acid tert-butyl ester (1.367 g, 10.8 mmol) and N-methyl morpholine (1.18 mL, 10.8 mmol) in CH2Cl2 (15 mL) was stirred at room temperature for 24 hours. The mixture was absorbed on SiO2 (20 g) and purified by column chromatography using a mixture of methylene chloride/hexane. The product was obtained as a two to one mixture of (E)/(Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate isomers (2.0 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:16]1([CH2:22][CH2:23][CH2:24]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[C:16]1([CH2:22][CH2:23][CH2:24][S:15][C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[NH:3][CH:2]=[N:1][C:5]=4[CH:6]=3)=[N:11][N:12]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCc1ccccc1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Solvent: CCO
Product: c1ccc(CCCSc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol), and phenylpropylbromide (0.228 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:37][C:38]([NH:41][S:42]([C:45]1[S:49][C:48](Br)=[CH:47][CH:46]=1)(=[O:44])=[O:43])([CH3:40])[CH3:39].CCCCCC>C1(C)C=CC=CC=1>[C:38]([NH:41][S:42]([C:45]1[S:49][C:48]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:12]=3)[CH:23]=2)=[CH:47][CH:46]=1)(=[O:43])=[O:44])([CH3:40])([CH3:37])[CH3:39]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.6) (0.46 g, 0.71 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.23 g, 0.78 mmol), tetrakis(triphenyl-phosphine)palladium (0.049 g, 0.042 mmol) in toluene (8 mL) was heated under reflux conditions for 15 h, hexane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.34 g) as a white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9](B(O)O)[CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:9]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCB(O)O
Reactant: O=Cc1ccc(Br)s1
Product: CCCCCc1ccc(C=O)s1
Yield: 67.4 %

Procedure:
The compound was synthesized as in Example 3.1 using 5-bromothiophene-2-carbaldehyde (250 mg, 1.31 mmol) in place of 5-bromo-2-formylfuran and pentylboronic acid (250 mg, 2.16 mmol) in place of hexylboronic acid to give 5-pentylthiophene-2-carbaldehyde (161 mg, 67%). Used without further characterization.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([CH:30]=O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc2ccccc12
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc2ccccc12

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 1-naphthaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 376.17 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5](O)=[CH:4][C:3]=1[NH:10][C:11]([CH3:13])=[O:12].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>[OH-].[K+].C(O)C>[C:11]([NH:10][C:3]1[CH:4]=[C:5]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:12])[CH3:13]
Reactant: CC(=O)Nc1cc(O)c(Cl)cc1Cl
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCc1cc(NC(C)=O)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 74.8 %

Procedure:
In a solution of 5.6 g of potassium hydroxide in 200 ml of ethanol was dissolved 22 g of 4,6-dichloro-3-acetaminophenol (which was synthesized using the method described in Beilstein, 13, I, 135). To the solution was added 30.5 g of hexadecyl bromide. After the mixture was stirred for an hour at room temperature (about 20-30° C.), the mixture was heated at reflux for 8 hours. The reaction mixture was poured into water. The resulting precipitate was recovered by filtration and washed with methanol to obtain 32 g of the desired product. The melting point thereof was 92 to 93.5° C.