Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]5[CH2:28][CH2:27][CH2:26][C:25]5=[O:29])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=C[CH:34]=1.ClC(OC1C=CC=CC=1)=[O:41].C1(N)CC1>CN(C=O)C>[CH:38]1([NH:33][C:34]([NH:1][C:2]2[CH:31]=[CH:30][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]6[CH2:28][CH2:27][CH2:26][C:25]6=[O:29])=[CH:20][N:21]=5)[S:15][C:8]=34)=[C:4]([F:32])[CH:3]=2)=[O:41])[CH2:36][CH2:37]1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(CCN5CCCC5=O)cn4)sc23)c(F)c1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: c1ccncc1
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CCN5CCCC5=O)cn4)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
To a solution of 294 (0.33 g, 0.74 mmol) and pyridine (0.13 mL, 1.6 mmol) in DMF (15 mL) at 0° C. was added phenyl chloroformate (0.12 mL, 0.96 mmol). The reaction mixture was stirred for 15 min then cyclopropylamine (2.0 mL, 28 mmol) was added. The mixture was warmed to RT, stirred for an additional 18 h and partitioned between water and ethyl acetate. The organic phase was collected, washed with water, 1M NaOH, and brine, dried (anhydrous MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography (20% methanol/ethyl acetate) to afford title compound 295 (0.21 g, 54%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H); 8.52-8.50 (m, 2H); 8.31 (s, 1H); 8.20 (d, J=8.2, 1H): 7.82 (dd, J=8.2, 2.2, 1H); 7.73 (dd, J=13.5, 2.5, 1H); 7.38 (t, J=9.0, 1H); 7.22-7.18 (m, 1H); 6.64 (d, J=5.5, 1H); 6.59 (d, J=2.5, 1H); 3.48 (t, J=7.0, 2H); 3.35 (t?, obscured by water peak), 2.85 (t, J=6.8, 2H); 2.58-2.52 (m, 1H); 2.16 (t. J=7.8, 2H); 1.89 (quintet, J=7.4, 2H); 0.68-0.63 (m, 2H); 0.45-0.41 (m, 2H). MS: (calc.) 531.17 (found) 532.4 (MH)+
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18](OC(F)(F)F)=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[F:26][C:27]([F:47])([F:46])C1C=CC(N2C=NC(C3C=CC(N)=CC=3)=N2)=CC=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([C:27]([F:47])([F:46])[F:26])=[CH:19][CH:20]=3)[N:11]=2)=[CH:8][CH:9]=1)=[C:2]=[S:3]
Reactant: Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Yield: 94 %

Procedure:
Prepared according to the procedure reported in (WO 2011017513) for 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole from 4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)aniline and isolated as a white solid (10.6 g, 94%): 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.73-7.41 (m, 2H), 7.41-7.05 (m, 4H), 6.92-6.63 (m, 2H); ESIMS m/z 347 ([M+H]+).
Reaction SMILES: CCCCCC.[Li]CCCC.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.[I:21]I>C1COCC1>[Cl:12][C:13]1[CH:20]=[C:19]([I:21])[C:16]([C:17]#[N:18])=[CH:15][N:14]=1
Reactant: II
Reactant: N#Cc1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1cnc(Cl)cc1I
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
To a mixture of THF (100 mL) and hexane (40 mL) under nitrogen atmosphere was added DIPA (22.21 mL, 158.78 mmole, 1.1 eq). The mixture was cooled to −80° C. and to this was added n-BuLi (63.57 mL, 158.78 mmole, 1.1 eq) dropwise. After completion of addition the resulting mixture was allowed to warm and stirred at −10° C. for 15 min. The reaction mixture was again cooled to −80° C. and a solution of 6-chloro-nicotinonitrile (20 g, 144.35 mmol, 1 eq) in THF (100 mL) was added dropwise. The resulting mixture was stirred at −80° C. for 1 h. After 1 h a solution of iodine (43.96 g, 173.22 mmole, 1.2 eq) in THF (100 mL) was added in one portion. After completion of the reaction, the reaction was quenched with water (100 mL) and extracted with diethyl ether (6×100 mL). Combined organic layers were washed with saturated solution of sodium thiosulfate (2×100 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give crude product. Crude compound was purified by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate-hexane as the eluant to yield the title compound as a faintly yellow solid (15 g, 39%). 1H-NMR (400 MHz, DMSO-d6): δ 8.38 (s, 1H), 8.79 (s, 1H). LC-MS calculated for C6H2ClIN2 (M+H) 264.90. found 264.9.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][N:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:20]2[NH:21][C:22]([CH3:33])=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2cccc3c2CC(=O)N3)cn1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cnc(N)nc4)c32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
4-(2-Aminopyrimidin-5-yl)-1,3-dihydroindol-2-one (89 mg) was condensed with 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (98 mg) to give the title compound.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 30 °C
Yield: 80 %

Procedure:
In a suspension of 26.6 g of KOH in 200 ml of dimethylformamide, 20.1 g of solid 5-bromoindole was incorporated while being stirred. The mixture was stirred for 50 minutes at room temperature, and 25.4 g of benzyl chloride was dropwise added to the mixture over a period of 16 minutes at a temperature of not higher than 30° C. The reaction mixture was maintained at 30° C. in an oil bath for 5 hours with stirring. After completion of the reaction, 200 ml of water was added and the thus-formed aqueous phase was extracted with 120 ml of ether three times. The thus-obtained organic phase was washed with water and dried over sodium sulfate overnight. The dried product was concentrated to dryness and then recrystallized from isopropyl ether to give 23.5 g of N-benzyl-5-bromoindole. The yield was 80% by mole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:33]=[CH:32][C:31]3[C:30]4[C:25](=[CH:26][C:27]([C:34]5[CH:60]=[CH:59][C:37]6[N:38]=[C:39]([CH:41]7[CH:46]8[CH2:47][CH:43]([CH2:44][CH2:45]8)[N:42]7[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])[NH:40][C:36]=6[CH:35]=5)=[CH:28][CH:29]=4)[C:24](F)(F)[C:23]=3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[OH2:64]>CC#N.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:33]=[CH:32][C:31]3[C:30]4[C:25](=[CH:26][C:27]([C:34]5[CH:60]=[CH:59][C:37]6[N:38]=[C:39]([CH:41]7[CH:46]8[CH2:47][CH:43]([CH2:44][CH2:45]8)[N:42]7[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])[NH:40][C:36]=6[CH:35]=5)=[CH:28][CH:29]=4)[C:24](=[O:64])[C:23]=3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: O
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(=O)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C

Procedure:
(1-{2-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (10 mg) is dissolve in MeCN (1 mL) and water (1 mL). 1 drop of TFA was added. The mixture was treated with long wavelength UV light at room temperature for 2 hours. The reaction crude was concentrated down and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA). Product was lyophilized to give (1-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9-oxo-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DL) (3.7 mg).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19](Cl)=O)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].Br[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[C:25]([F:31])[CH:24]=1>>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[C:25]([F:31])[CH:24]=3)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](CC(=O)Cl)CC2)CC1
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](CCc3cc(F)c(F)c(F)c3)CC2)CC1

Procedure:
Using trans-4-[2-(trans-4-propylcyclohexyl)ethyl]-cyclohexylacetyl chloride and a Grignard reagent prepared from 1-bromo-3,4,5-trifluorobenzene, as starting raw materials, 1-[trans-4-{2-(trans-4-propylcyclohexyl)ethyl}-cyclohexyl]-2-(3,4,5-trifluorophenyl)ethane was obtained in the same manner as in Example 2.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23]C(=O)OC(C)(C)C)=[CH:19][C:18]=2[F:31])[N:10]=3)=[O:5])[CH2:3][CH2:2]1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:11]2[N:10]=[C:9]3[S:8][C:7]([NH:6][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])=[N:15][C:14]3=[CH:13][CH:12]=2)=[C:18]([F:31])[CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of tert-butyl [4-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-3-fluorophenyl]carbamate (0.50 g, 1.12 mmol) in trifluoroacetic acid (10 mL) was added anisole (0.5 mL), and the mixture was stirred at 0° C. for 2 hr. Trifluoroacetic acid was evaporated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→1/9) to give the title compound (294 mg, 76%) as a white solid.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:3]=1.[C:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:7]1[C:6]2[C:2]([C:25]3[CH:26]=[CH:27][C:22]([CH2:21][C:19]#[N:20])=[CH:23][CH:24]=3)=[CH:3][N:4]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: COc1nccc2c1c(I)cn2C1CCOCC1
Reactant: N#CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1ccc(CC#N)cc1)cn2C1CCOCC1
Temperature: 130 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-c]pyridine (20.0 mg) obtained in Step A of Example 16 in DMF (2 mL)/water (0.20 mL) were added (4-(cyanomethyl)phenyl)boronic acid (13.5 mg), tetrakis(triphenylphosphine)palladium(0) (6.45 mg) and potassium carbonate (15.4 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 2/1) to give the title compound (12.0 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=C[CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:18]([CH3:26])([CH2:20][CH2:21][C:22](Cl)([CH3:24])[CH3:23])[CH3:19].[C:27](=S)=S>>[CH3:19][C:18]1([CH3:26])[C:10]2[C:23](=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=2)[C:22]([CH3:27])([CH3:24])[CH2:21][CH2:20]1
Reactant: CCCCCCc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: S=C=S
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
83 ml of hexylbenzene were treated with 1.8 g of aluminum chloride while cooling with ice. After brief stirring a solution of 40 g of 2,5-dichloro-2,5-dimethyl-hexane in 300 ml of carbon disulphide was added dropwise and the mixture was stirred at 0° C. for a further 2 hours. The reaction mixture was poured into ice/6N hydrochloric acid, extracted with ethyl acetate, dried over sodium sulphate and evaporated. The crude product was distilled in a high vacuum. There were obtained 25.5 g of 1,1,4,4-tetramethyl-6-hexyl-1,2,3,4-tetrahydro-naphthalene as a colourless oil, boiling point 141°-152° C./0.8 mm.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.BrCCC1C=CC=CC=1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][C:35]=1[F:46])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CS(O[CH2:52][CH2:53][CH2:54][CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1)(=O)=O>>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][N:43]([CH2:52][CH2:53][CH2:54][CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)[CH2:42][CH2:41]2)=[CH:36][C:35]=1[F:46])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)OCCCC1CCCCC1
Agent: BrCCc1ccccc1
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: Fc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Yield: 99.4 %

Procedure:
Production Example 1 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and (2-bromoethyl)-benzene were replaced with 1-(4-benzyloxy-3-fluorophenyl)piperazine (1.33 g) and 3-cyclohexylpropyl methanesulfonate (1.02 g), respectively, to provide crude 1-(4-benzyloxy-3-fluorophenyl)-4-(3-cyclohexylpropyl)piperazine (1.89 g).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](Cl)=[CH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-:18].[K+].[K+].[NH:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C=O)C>[CH3:10][S:7]([OH:8])(=[O:9])=[O:18].[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N:23]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Cl)cn1
Reactant: C1CNCCNC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)O
Product: O=S(=O)(c1ccccc1)c1ccc(N2CCCNCC2)cn1
Temperature: 85 °C
Yield: 11.1 %

Procedure:
To a mixture of 5-chloro-2-pyridinyl phenyl sulfone (2.0 g, 7.9 mmol) in DMF (50 mL) was added potassium carbonate (2.5 g, 18 mmol) and homopiperazine (1.7 g, 17 mmol). The mixture was heated at 85° C. for 72 h. The mixture then was removed from heat and partitioned between water and ethyl acetate. The layers were separated and the organic layer washed twice with water (2×100 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. Column chromatography (silica gel, 75 mL) using 5% CH3OH in CH2Cl2 with 0.7% NH4OH and conversion to the methanesulfonate salt gave 0.182 g of the title compound; IR (drift) 1570, 1304, 1240, 1223, 1207, 1196, 1178, 1145, 1112, 1059, 1052, 785, 715, 688, 645 cm−1. 1H NMR (DMSO-d6) δ2.0, 3.1, 3.2, 3.38, 3.56, 3.78, 7.26, 7.64, 7.88, 8.21, 8.67.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22].O>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([Cl:17])[CH:19]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1cc(Cl)ccc1Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ccc1Br)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 2-bromo-5-chloroaniline (0.380 g, 1.84 mmol) and triethylamine (0.768 mL, 5.52 mmol) in dichloromethane (15 mL) is added 3-chlorobenzoyl chloride (0.353 mL, 2.76 mmol) in a dropwise fashion. The resulting mixture is allowed to stir at room temperature for 2 h. Water (30 mL) is added and extracted with the mixture is extracted with dichloromethane 3×. The organic layer is combined, washed with brine 1×, dried (Na2SO4) and concentrated under vacuum to give 0.630 g of N-(2-bromo-5-chloro-phenyl)-3-chloro-benzamide in 99% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C1C[O:32][CH2:31]C1.[NH2:34][CH:35]1[CH2:39][CH2:38]C[CH:36]1[OH:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:31]4[O:32][CH:39]5[CH2:38][O:40][CH2:36][CH:35]5[N:34]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: NC1CCCC1O
Reactant: C1CCOC1
Reactant: Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Solvent: ClCCl
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccc(NC5=NC6COCC6O5)cc34)cc2Cl)c1
Reaction time: 3 h
Yield: 65 %

Procedure:
N4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine is prepared by adding thioCDI (27 mg, 0.152 mmol) to a stirred solution of N4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine (60 mg, 0.152 mmol) in 1:1 THF:DCM (8 mL). After 3 hours, 2-amino-cyclopentanol (30 mg, 0.30 mmol) is added and the reaction mixture stirred for 4 hours. Solvent is removed under reduced pressure and the resulting thiourea is triturated with diethyl ether. The crude thiourea is suspended in THF (10 mL) and 1 M NaOH in water (0.38 mL) is added followed by addition of a 1 M TsCl solution in THF (0.17 mL). After 1 hour, the reaction mixture is diluted with EtOAc and water, and the phases separated. The aqueous phase is extracted with EtOAc and the combined organic extracts are dried (Na2SO4) and concentrated. Purification by column chromatography (10:5:1 EtOAc:Hexanes:MeOH) provides the desired product (50 mg, 65%). MS APCI (+) m/z 506, 508 (M+1, Cl pattern) detected; 1H NMR (400 mHz, CD3CN) δ 8.49 (s, 1H), 8.23 (bs, 1H), 7.94 (s, 1H), 7.73 (m, 2H), 7.59 (m, 2H), 7.45 (m, 1H), 7.35 (d, 1H), 7.29 (d, 1H), 7.19-7.10 (m, 3H), 5.23 (s, 2H), 5.18 (m, 1H), 4.66 (m, 1H), 4.11 (d, 1H), 3.96 (d, 1H), 3.56 (dd, 2H).
Reaction SMILES: [CH:1]1[S:5][CH:4]=[C:3]2[C:6](=[O:14])[C:7]3[C:8]([C:12](=[O:13])[C:2]=12)=[CH:9][S:10][CH:11]=3.S(=O)(=O)(O)O.[N-:20]=[N+]=[N-].[Na+]>C(Cl)Cl>[CH:1]1[S:5][CH:4]=[C:3]2[C:2]=1[C:12](=[O:13])[C:8]1=[CH:9][S:10][CH:11]=[C:7]1[C:6](=[O:14])[NH:20]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2cscc2C(=O)c2cscc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]c2cscc2c(=O)c2cscc12
Temperature: 0 °C

Procedure:
30.4 g (138 mmoles) of 4,8-dihydro-benzo[1,2-c:4,5-c']dithiophene-4,8-dione are suspended in 200 ml of methylene chloride; 280 ml of concentrated sulfuric acid are then added dropwise, with ice-cooling and stirring. A total of 13.0 g (200 mmoles) of sodium azide is then introduced a little at a time into the well stirred reaction mixture at 0° C. over a period of 2 hours. The mixture is then stirred at room temperature for 8 to 10 hours. The reaction mixture is poured carefully into 3 l of ice-water, with thorough stirring, and the solid which precipitates after a short time is filtered off with suction. The crude product is washed with a large amount of water until it gives a neutral reaction, and is dried at 50° C. under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10](SC)=[N:9]2)=[CH:4][CH:3]=1.O[O:19][S:20]([O-:22])=O.[K+].[C:24](#N)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([S:20]([CH3:24])(=[O:22])=[O:19])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: O=S([O-])OO
Reactant: CSc1cc(C(=O)O)n(-c2ccc(F)cc2)n1
Agent: [K+]
Product: CS(=O)(=O)c1cc(C(=O)O)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(4-fluorophenyl)-3-(methylthio)-1H-pyrazole-5-carboxylic acid (120 mg, 0.48 mmol) was dissolved in acetonitrile (5 mL) at RT. Oxone™ (440 mg, 1.4 mmol) was added. The mixture was stirred at RT for 30 min and then heated at 50° C. for 3 h. The mixture was cooled to RT and most volatiles were removed under vacuum. The residue was partitioned between DCM/brine. The DCM layer was dried over Na2SO4 and filtered. Concentration of the filtrate afforded the crude 1-(4-fluorophenyl)-3-(methylsulfonyl)-1H-pyrazole-5-carboxylic acid (−140 mg), which was used without further purification. LC-MS [M+H] 285.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([OH:12])[C:3]=1[S:13][C:14]#[N:15]>CN(C)C=O.C(OCC)(=O)C>[NH2:15][C:14]1[S:13][C:3]2[C:4]([OH:12])=[N:5][C:6]([C:8]([F:10])([F:11])[F:9])=[N:7][C:2]=2[N:1]=1
Reactant: N#CSc1c(N)nc(C(F)(F)F)nc1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc2nc(C(F)(F)F)nc(O)c2s1
Yield: 78.8 %

Procedure:
A solution of the compound (4.25 g) obtained in Step 5 in N,N-dimethylformamide (128 ml) was stirred at 130° C. for 14 hr. The reaction mixture was concentrated under reduced pressure, xylene was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained crude crystals were suspended in ethyl acetate, collected by filtration and dried to give the title compound (3.35 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH:13]=[O:14]>C1COCC1>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH:13]([OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1
Reactant: Fc1cccc(Br)c1
Reactant: COc1ccc(C=O)cc1F
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cccc(F)c2)cc1F
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A mixture of Mg0 turnings (2.45 g, 101 mmol), 1-bromo-3-fluorobenzene (17.6 g, 100 mmol), and dry THF (200 mL) was carefully heated to reflux for 30 min. While still refluxing, 3-fluoro-p-anisaldehyde (15.3 g, 99.3 mmol) in THF (100 mL) was added over a period of 5 min. The reaction temperature was maintained for 30 min, cooled to room temperature, and then the reaction was quenched with satd. aq. NH4Cl (200 mL). The organic layer was separated, washed with satd. aq. NaCl (2×200 mL), dried (anh. Na2SO4), and rotary evaporated to yield 23.5 g (94.4%) of product as an orange-brown oil.