Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[NH:19][C:18](=[O:20])[N:17]([C@H:21]([C:30]3[NH:31][C:32]([C:35]4[CH:40]=[CH:39][C:38]([C:41]#[CH:42])=[CH:37][C:36]=4[F:43])=[CH:33][N:34]=3)[C@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[C:16]2=[O:44])=[CH:11][CH:10]=1)(C)(C)C.ClCCl.C(#N)C.[I-].[Na+].Cl[Si](C)(C)C>C(OCC)(=O)C>[C:41]([C:38]1[CH:39]=[CH:40][C:35]([C:32]2[NH:31][C:30]([C@@H:21]([N:17]3[C:16](=[O:44])[C@@H:15]([C:12]4[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][OH:5])=[CH:14][CH:13]=4)[NH:19][C:18]3=[O:20])[C@H:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH3:23])=[N:34][CH:33]=2)=[C:36]([F:43])[CH:37]=1)#[CH:42]
Reactant: C#Cc1ccc(-c2cnc([C@H]([C@@H](C)c3ccccc3)N3C(=O)N[C@H](c4ccc(OCCOC(C)(C)C)cc4)C3=O)[nH]2)c(F)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C#Cc1ccc(-c2cnc([C@H]([C@@H](C)c3ccccc3)N3C(=O)N[C@H](c4ccc(OCCO)cc4)C3=O)[nH]2)c(F)c1
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
To a solution of (R)-5-[4-(2-tert-butoxy-ethoxy)-phenyl]-3-{(1S,2S)-1-[5-(4-ethynyl-2-fluoro-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-imidazolidine-2,4-dione (293 mg, 0.49 mmol) in 1:1 v/v dichloromethane/acetonitrile (10 mL) at 0° C. under an atmosphere of nitrogen was added sodium iodide (148 mg, 0.99 mmol) followed by chlorotrimethylsilane (184 μL, 1.45 mmol) and the resulting mixture was allowed to stir for 30 minutes. Additional sodium iodide (148 mg, 0.99 mmol) followed by chlorotrimethylsilane (184 μL, 1.45 mmol) was added and stirring continued for 45 minutes. The reaction was then poured into ethyl acetate (30 mL) and washed with 10% w/v aqueous sodium thiosulfate solution. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel eluted with 80 to 100% v/v ethyl acetate in hexanes to give (R)-3-{(1S,2S)-1-[5-(4-ethynyl-2-fluoro-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-5-[4-(2-hydroxy-ethoxy)-phenyl]-imidazolidine-2,4-dione (59 mg, 22%). HR-MS: calcd for C31H27FN4O4 [M+H+] 539.2089. Found 539.2086.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[N:14]1[C:18]2=[N:19][CH:20]=[N:21][C:22](O)=[C:17]2[CH:16]=[N:15]1>>[Cl:3][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([C:8]3[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=3[Cl:6])[N:15]=[CH:16][C:17]=12
Reactant: Oc1ncnc2c1cnn2-c1c(F)cccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Phosphorus oxychloride (17.54 mL, 188.18 mmol) was added to 1-(2-chloro-6-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate BH2) (2.49 g, 9.41 mmol). The resulting solution was stirred at 100° C. for 1 hour. The reaction mixture was evaporated. Ice/water (100 mL) and then EtOAc (100 mL) were added. The organic layer was separated and the aqueous layer re-extracted with EtOAc (100 mL). The combined organics were washed with water (100 mL), dried (MgSO4) and concentrated to give the crude product (2.48 g) which was used without further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:10]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:23][CH2:24][CH2:25][CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7][CH2:8][CH3:9].[C:33]([O-:36])(=O)C.[Na+].O.CN(C)[CH:41]=[O:42]>C(OCC)(=O)C>[CH2:6]([N:10]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[O:36])=[CH:29][CH:28]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:23][CH2:24][CH2:25][CH3:26])[C:17]1[CH:22]=[CH:21][C:20]([CH:41]=[O:42])=[CH:19][CH:18]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCN(CCCCCN(CCCC)c1ccccc1)c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCN(CCCCCN(CCCC)c1ccc(C=O)cc1)c1ccc(C=O)cc1
Yield: 90 %

Procedure:
While cooled and stirred, 5.4 g of phosphorus oxychloride were added dropwise to 11.0 g of dimethylformamide, and 3.7 g of N,N'-di-n-butyl-N,N'-diphenyl-1, 5-diaminopentane dissolved in dimethylformamide were added dropwise to the resulting solution, followed by heating and stirring at 85° C. for 2.5 hours. After the completion of the reaction, sodium acetate, water and ethyl acetate were added to the reaction solution to separate an ethyl acetate layer, which was in turn concentrated. The concentrate was purified through a column with a mixed solvent of ethyl acetate with n-hexane to obtain 3.8 g of N,N'-di-n-butyl-N,N'-bis-(4-formylphenyl)-1,5-diaminopentane in a 90% yield (which was found to have a melting point 51°-52° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([OH:16])=O)=[CH:10][C:9]=2[S:17][CH3:18])=[O:7])=[CH:4][CH:3]=1.C(Cl)(C(Cl)=O)=O.CN(C)C=O.[N+:32](=[CH2:34])=[N-:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([CH:34]=[N+:32]=[N-:33])=[O:16])=[CH:10][C:9]=2[S:17][CH3:18])=[O:7])=[CH:19][CH:20]=1
Reactant: CSc1cc(C(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: C=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1cc(C(=O)C=[N+]=[N-])n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of the crude 5-(p-chlorobenzoyl)-2-hydroxycarbonyl-4-methylthio-1-methylpyrrole in 3 ml of methylene chloride is added 100 μl of (COCl)2 followed by the addition of 0.5 μl of dimethylformamide (DMF). The resulting reaction mixture is stirred for about an hour and then concentrated to give a yellow solid. Subsequently freshly prepared diazomethane is added dropwise to a stirred solution of the yellow solid in 1 ml of methylene chloride at 0°. The reaction is allowed to warm up to room temperature over a period of one hour. After the excess amount of diazomethane is removed by bubbling nitrogen through the reaction mixture, the solvents are removed by evaporation under reduced pressure and a bright yellow solid is collected. This crude product, i.e., 5-(p-chlorobenzoyl)-2-diazomethylcarbonyl-4-methylthio-1-methylpyrrole, is used directly in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>ClCCCl.C(Cl)Cl>[C:10]([C:7]1[CH:8]=[C:9]2[C:4]([C:3]([CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:2][NH:1]2)=[CH:5][CH:6]=1)#[N:11]
Reactant: C=CC(=O)OCC
Reactant: N#Cc1ccc2cc[nH]c2c1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)CCc1c[nH]c2cc(C#N)ccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1H-indole-6-carbonitrile (D12) (3.2 g), ferric chloride (3.7 g) and ethyl acrylate (7.3 mL) in DCE (7 mL) was added to a sealed tube. The tube was sealed, and the reaction mixture was stirred at 120° C. for 2 hours. After cooling, the reaction mixture was diluted with DCM. The organic layer was washed with 0.5 M HCl, brine, dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (20% EtOAc in hexane) to afford ethyl 3-(6-cyano-1H-indol-3-yl)propanoate (D106) (3.1 g) as a yellow solid. δH (CDCl3, 400 MHz): 1.24 (3H, t), 2.71 (2H, t), 3.11 (2H, t), 4.14 (2H, q), 7.24 (1H, dd), 7.36 (1H, dd), 7.67 (1H, d), 7.70 (1H, dd), 8.36 (1H, br s). MS (ES): C14H14N2O2 requires 242. found 243.1 (M+H+).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](I)[CH:7]=1)[CH2:2][CH3:3].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1.C(Cl)Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)[CH2:2][CH3:3]
Reactant: C#Cc1ccccc1
Reactant: CCCNC(=O)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Solvent: ClCCl
Product: CCCNC(=O)c1cccc(C#Cc2ccccc2)c1
Temperature: 70 °C

Procedure:
A mixture of N-n-propyl-3-iodobenzamide, phenylacetylene (1.5 eq.) and Pd(PPh3)2Cl2 (5 mol %) in piperidine (3 eq.) was heated at 70° C. for 30 minutes in a sealed tube. The solidified residue was dissolved with CH2Cl2 and water and poured onto HCl 2N. The acidic phase was extracted three times with CH2Cl2. The combined organic layers were washed once with HC 2N, twice with saturated NaHCO3, once with water and once with brine. The organic layer was then dried over MgSO4 and concentrated. The resulting residue was purified using SiO2 with CH2Cl2/petroleum ether 80:20 to CH2Cl2 100% to give N-n-propyl-3-phenylethynyl-benzamide as a yellow solid (Quantitative yield). NMR 1H (ppm, CDCl3): 7.88 (s, 1H), 7.74-7.68 (m, 1H), 7.63-7.60 (m, 1H), 7.53-7.50 (m, 2H), 7.42-7.33 (m, 4H), 6.22 (br. s., 1H), 3.44-3.38 (m, 2H), 1.64 (sext., J3=7.3 Hz, 2H), 0.98 (t, J3=7.3 Hz, 3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CN=CC=1.[CH2:17]([O:19][N:20]=[C:21]([C:25]1[C:26](=[O:39])[CH2:27][CH:28]([C:32]2[S:33][C:34]([CH3:38])=[C:35]([CH3:37])[N:36]=2)[CH2:29][C:30]=1[OH:31])[CH2:22][CH2:23][CH3:24])[CH3:18]>ClCCl>[CH2:17]([O:19][N:20]=[C:21]([C:25]1[C:26](=[O:39])[CH2:27][CH:28]([C:32]2[S:33][C:34]([CH3:38])=[C:35]([CH3:37])[N:36]=2)[CH2:29][C:30]=1[O:31][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:22][CH2:23][CH3:24])[CH3:18]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC(=NOCC)C1=C(O)CC(c2nc(C)c(C)s2)CC1=O
Solvent: Cc1ccncc1
Solvent: ClCCl
Product: CCCC(=NOCC)C1=C(OC(=O)c2ccccc2)CC(c2nc(C)c(C)s2)CC1=O
Yield: 79.2 %

Procedure:
Benzoyl chloride (0.12 g) and 4-methylpyridine (0.08 g) were added dropwise with stirring to a solution of 2-[1-(ethoxyimino)butyl]-5-(4,5-dimethyl-2-thiazolyl)-3-hydroxycyclohex-2-en-1-one (2) (0.27 g) in dichloromethane (40 ml) at ambient temperature. After 1 hour the solution was washed with cold dilute aqueous sodium hydroxide, followed by cold dilute hydrochloric acid and then dried over magnesium sulphate and evaporated to give 2-[1-(ethoxyimino)butyl]-3-benzoyloxy-5-(4,5-dimethyl-2-thiazolyl)cyclohex-2-en-1-one (0.28 g, 80%) as an orange oil. The product was characterized by proton nuclear magnetic resonance spectroscopy and appropriate physical data are recorded in Example 5 Table 6.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[S:12])[N:8]([CH3:13])[C:7]2=[O:14].[C:15]([O-])([O-])=O.[K+].[K+].CI>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:15])[N:8]([CH3:13])[C:7]2=[O:14]
Reactant: Cn1c(=S)[nH]c2c(I)cccc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nc2c(I)cccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
At RT, to a mixture of 8-iodo-3-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (11.2 g g, 35.3 mmol) and K2CO3 (9.76 g, 70.6 mmol) in THF (100 mL) was added MeI (6.58 mL, 106 mmol). The reaction was heated to reflux for 6 h, and then cooled to RT. The mixture was poured into ice/water (300 mL) and stirred for 10 min. The suspension was filtered and the solid was washed with cold water (20 mL) followed by cold ether (20 mL). The solid was dried to give 8-iodo-3-methyl-2-(methylthio)quinazolin-4(3H)-one (700a; 11.4 g, 97% yield) as an off-white solid. Crude material was used in the next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (1H, dd, J=7.6, 1.4 Hz), 8.08 (1H, dd, J=7.8, 1.4 Hz), 7.19 (1H, t, J=7.7 Hz), 3.51 (3H, s), 2.73 (3H, s). m/z (ES, +ve) 332.9 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O-:14])=[O:13].CCN(CC)CC.N#N>C1COCC1>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:11][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)(=[O:23])=[O:22])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC1CCCc2cccnc21
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCc2cccnc21
Yield: 93 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-quinolin-8-ylamine (1.73 g, 12.0 mmol) dissolved in THF (80 mL) was added 2-nitrobenzenesulfonyl chloride (2.92 g, 13.0 mmol) and Et3N (2.4 mL, 18.0 mmol). The mixture was stirred for 16 hours at room temperature under a positive pressure of N2. The reaction mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford 2-nitro-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-benzenesulfonamide as a dark brown solid (3.72 g, 94%). 1H NMR (CDCl3) δ 1.59 (m, 1H), 1.89 (m, 2H), 2.50 (m, 1H), 2.76 (m, 2H), 4.35 (m, 1H), 6.86 (m, 1H), 7.04 (m, 1H), 7.35 (m, 1H), 7.74 (m, 2H), 7.99 (m, 1H), 8.12 (m, 1H), 8.26 (m, 1H).
Reaction SMILES: [ClH:1].[CH2:2]([O:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:7]1)[CH:3]=[CH2:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1>>[ClH:1].[CH2:2]([O:5][CH:6]1[CH2:11][CH2:10][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)([OH:12])[CH:8]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:7]1)[CH:3]=[CH2:4]
Reactant: COc1cccc(Br)c1
Reactant: C=CCOC1CCC(=O)C(CN(C)C)C1
Agent: Cl
Product: C=CCOC1CCC(O)(c2cccc(OC)c2)C(CN(C)C)C1
Yield: 37 %

Procedure:
Base (13) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with 1:4 ether/diisopropyl ether via a silica gel column and was taken up in 1:1 2-butanone/ether. After adding trimethylchlorosilane/water, compound (10) was obtained in a yield of 37% theoretical.
Reaction SMILES: C[Mg]Br.[CH2:4]([N:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.[CH2:18](OCC)C>O1CCCC1>[CH2:4]([N:11]1[CH2:15][CH2:14][C:13]([CH3:18])([OH:16])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)C1

Procedure:
Methylmagnesium bromide (4 ml of 3M solution in diethyl ether) was added dropwise to a solution of 1-benzylpyrrolidin-3-one (1.75 g) in tetrahydrofuran (50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour before water and diethyl ether were added and the layers separated. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (SiO2, 5% methanol/dichloromethane as eluent) to afford the subtitle compound as a pale brown oil (0.8 g).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>CN(C)C1C=CN=CC=1.O1CCCC1>[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][N:26]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:25][CH2:24]1
Reactant: CCC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 53 %

Procedure:
Propionyl chloride (0.620 g, 4.88 mmol), triethylamine (0.747 ml, 5.32 mmol) and 4-dimethylaminopyridine (0.0542 g, 0.444 mmol) were added to a solution of 1-(2-fluoro-4-nitrophenyl)piperazine (compound of Reference Example 52; 1.00 g, 4.44 mmol) in anhydrous tetrahydrofuran (9 ml) under ice cooling, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (0.662 g, 53%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:4][N:3]=1.[CH3:19][S-:20].[Na+].C(OCC)C>CN(C)C=O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:20][CH3:19])=[N:3][CH:4]=1)=[O:18]
Reactant: O=C(Cc1ccc(F)cc1F)c1ccc(Cl)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CSc1ccc(C(=O)Cc2ccc(F)cc2F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
A solution of the product of part (ii) (23.9 g, 89 mmol) in N,N-dimethylformamide (DMF) (105 ml) was treated with sodium methanethiolate (6.6 g, 94 mmol) and the resulting suspension was stirred for 2 hours at room temperature. The mixture was poured into diethyl ether (1000 ml) and the suspension was washed with water (2×500 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was triturated with diethyl ether to afford the title compound as a yellow solid, (3.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([N:18]([C:20]4[CH:25]=[CH:24][N:23]=[C:22](Cl)[N:21]=4)[CH3:19])=[CH:17][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:29][NH:30][S:31]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)(=[O:33])=[O:32]>>[ClH:1].[CH3:29][NH:30][S:31]([CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:22]2[N:21]=[C:20]([N:18]([C:16]3[CH:15]=[CH:14][C:11]4[N:12]([CH3:13])[C:8]([NH:7][CH2:6][C:5]5[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=5)=[N:9][C:10]=4[CH:17]=3)[CH3:19])[CH:25]=[CH:24][N:23]=2)=[CH:40][CH:41]=1)(=[O:32])=[O:33]
Reactant: CN(c1ccc2c(c1)nc(NCc1ccc(Cl)cc1)n2C)c1ccnc(Cl)n1
Reactant: CNS(=O)(=O)CCc1ccc(N)cc1
Product: CNS(=O)(=O)CCc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCc3ccc(Cl)cc3)n4C)n2)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N2-(4-Chloro-benzyl)-N5-(2-chloro-pyrimidin-4-yl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (103 mg, 0.25 mmol) and 2-(4-amino-phenyl)-ethanesulfonic acid methylamide (54 mg, 0.25 mmol) as a white solid (96 mg, 64%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 10.27 (br s, 1H), 9.34 (br s, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.49-7.54 (m, 4H), 7.38-7.44 (m, 3H), 7.20-7.26 (m, 3H), 6.99 (q, J=5.1 Hz, 1H), 5.83 (br s, 1H), 4.72 (d, J=5.7 Hz, 2H), 3.71 (s, 3H), 3.48 (s, 3H), 3.22-3.28 (M, 2H), 2.87-2.93 (m, 2H), 2.58 (d, J=4.8 Hz, 3H). MS (ESI) m/z=562 [M+H]+.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[N:9]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=O)=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1>C1COCC1.O.CS(C)=O>[N:9]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=[N:7][OH:8])=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: O=Cc1ccc(-n2cncn2)c2ccccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: ON=Cc1ccc(-n2cncn2)c2ccccc12
Reaction time: 5 h

Procedure:
Sodium acetate (262 mg) is added to a solution of hydroxylamine hydrochloride (193 mg) and 4-[1,2,4]triazol-1-yl-naphthalene-1-carbaldehyde (455 mg) in THF (16 ml), water (2 ml) and DMSO (2 ml). After 5 hours at room temperature, the reaction is quenched with water and ethyl acetate. The organic phase is separated and the water phase is extracted with ethyl acetate. The combined organic phases are extracted with water and with a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo to yield 4-[1,2,4]triazol-1-yl-naphthalene-1-carbaldehyde oxime. The crude product obtained (390 mg, beige crystals) is used without further purification. MS (HPLC/MS): 239 (MH+). Retention time 2.76 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[C:12]([NH2:15])[C:11]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:36](Cl)(=[O:38])[CH3:37].CCN(CC)CC.Cl>CC#N>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:34])[CH3:35])=[CH:28][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[C:12]([NH:15][C:36](=[O:38])[CH3:37])[C:11]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][CH:21]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(N)c(-c3ccc(OC(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc2c(NC(C)=O)c(-c3ccc(OC(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104 %

Procedure:
A mixture of 4-amino-1,5-bis(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (160 mg, 0.34 mmol; see Example 5(a)), acetyl chloride (50 mg, 0.63 mmol), Et3N (63 mg, 0.63 mmol) and MeCN (10 mL) was stirred at room temperature for 30 minutes, then poured into HCl (1M) and extracted with EtOAc. The combined extracts were washed with water and brine, and dried over Na2SO4. Concentration and purification by chromatography gave the sub-title compound (182 mg, 84%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[N:10]([O-])=O.[Na+]>C(O)(=O)C.O>[C:6]([N:7]=[N+:8]=[N-:10])(=[O:9])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N=[N+]=[N-]
Reaction time: 0.5 h

Procedure:
25 g (0.19 mol) of t-butylcarbazate was dissolved in 80 mL of acetic acid and 160 mL of water, and 15 g (0.22 mol) of sodium nitrite was added in small portions under cooling with ice. The reaction solution was stirred for 30 minutes under cooling with ice and extracted with 250 ml of diisopropyl ether. The organic layer was washed with 200 mL of saturated aqueous sodium hydrogen carbonate twice and with 100 mL of saturated aqueous sodium chloride once successively, dried over anhydrous sodium sulfate and filtered to give a solution of t-butyl carbonazidate in diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.Cl.CN.O[N:34]1[C:38]2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:34][CH3:38])=[O:18])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (105 mg, 0.25 mmol) in methylene chloride (3 ml), methylamine hydrochloride (19 mg, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0.061 ml, 0.55 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol) were added at room temperature. After stirring for 2 hours at room temperature, water was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=7:3 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and hexane and then collected by filtration, to obtain the title compound (73 mg, 0.17 mmol, 67%) as a white solid.