Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[N+:16]([C:4]1[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:5]=1[CH2:6][N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=1)([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CNCc1ccc(Br)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccc(Br)cc1[N+](=O)[O-])C(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
4.2 g (13.1 mmol) of ethyl (4-bromo-2-nitrobenzyl)aminoacetate was dissolved in 30 ml of dichloromethane. 2.2 ml (17.7 mmol) of 4-chlorobenzoyl chloride and 2.9 ml (19.6 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the crude product.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.[CH2:26](N)[CH2:27][C:28]1C=CC=C[CH:29]=1>>[NH2:20][C:8]([NH:4][CH2:5][CH2:6][C:2]1[CH:1]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Reactant: NCCc1ccccc1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=C(N)NCCc2ccccc2)cc1

Procedure:
The compound of Example 14 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of phenethylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 317.41; found mol. wt. (M+H) 318.3; 635.1 (Dimer)
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[NH:16][C:15](=[O:21])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:7][CH2:8][C@H:9]([C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]([C:38]1[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=1)[C:15](=[O:21])[CH:14]=[CH:13]2)[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2c(ccc(=O)n2-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reaction time: 120 h
Yield: 86.1 %

Procedure:
To the solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate (8J) (23 mg, 0.05 mmol) and 4-chlorophenylboronic acid (16 mg, 0.10 mmol) in dichloromethane (2 mL) was added copper (II) acetate (9 mg), followed by molecular sieve 4 Å and pyridine (82 μL). The mixture was stirred for 5 days, and filtered and washed with ethyl acetate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-(1,5-bis(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyethyl pivalate (25 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H36Cl2NO4: 580.2. Found: 580.0.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C>C(O)C.[OH-].[Pd+2].[OH-].[C]>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C@H:10]1[C@@H:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: O[C@H]1CCN(Cc2ccccc2)C[C@H]1COc1ccccc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O[C@H]1CCNC[C@H]1COc1ccccc1F
Temperature: 25 °C
Yield: 96.1 %

Procedure:
After dissolving 402 mg of cis-1-benzyl-3-(2-fluorophenoxymethyl)-4-hydroxypiperidine in 20 ml of ethanol, 0.2 g of 20% palladium hydroxide-carbon (hydrous) was added and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm). The mixture was further stirred for 5.5 hours, and then ethyl acetate was added thereto and the insoluble portion was filtered off. The filtrate was distilled off under reduced pressure to obtain the title compound (276 mg, 94% yield).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]([F:39])([F:38])[CH:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:35]([CH:32]3[CH2:31][CH2:30][CH:29]([C:28]([F:27])([F:38])[F:39])[CH2:34][CH2:33]3)=[O:36])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)C1CCC(C(F)(F)F)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CCC(C(F)(F)F)CC1

Procedure:
The title compound, white solid (42 mg, 33%), MS (ISP) m/z=505.3 [(M+H)+], mp 190° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-trifluoromethyl-cyclohexanecarboxylic acid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1.[CH:14]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>C(OCC)C>[Cl:13][C:9]1[CH:8]=[C:7]([C:25]2([OH:27])[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:26]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cccc(Br)c1
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(c2cccc(Cl)c2)c2ccccc2-c2ccccc21
Temperature: -40 °C

Procedure:
A 2.5M solution of butyllithium in hexanes (1.8 eq), (Aldrich) was added dropwise to a solution of 1-bromo-3-chlorobenzene (1.5 eq) in anhydrous diethyl ether with stirring under argon at -40° C. After stirring at room temperature for 0.5 h, a solution of 9-fluorenone (1 eq), (Aldrich) in anhydrous diethyl ether was added dropwise to the mixture with stirring and cooling at 0° C. The reaction mixture was stirred at room temperature for 1 h, poured into a saturated solution of ammonium chloride and extracted with dichloromethane. The combined dichloromethane extracts were washed with brine, dried (MgSO4), the solvent evaporated and the residue chromatographed on silica gel column with 10% ethyl acetate in hexanes to give the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][C:18](Br)([CH3:20])[CH3:19].C(=O)(O)[O-]>ClCCl>[C:18]([C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:10][CH:11]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: O=[N+]([O-])c1cnc2[nH]ccc2c1
Reactant: CC(C)(C)Br
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1c[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 4.1 %

Procedure:
5-Nitro-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.92 mmol) was taken up in dry dichloromethane (9 mL) and was chilled to 0° C. Aluminum chloride (613 mg, 4.60 mmol, 5 eq.) was then added, and the mixture was allowed to stir at 0° C. for 15 minutes. 2-Methyl-2-bromopropane (107 μL, 0.919 mmol) was then added, and the mixture was allowed to gradually warm to room temperature over a 16 hour period. The mixture was then poured into cold saturated bicarbonate solution and extracted with dichloromethane (2×). The extracts were dried over sodium sulfate and concentrated. Prep plate purification (2×1.0 mm plates, 3:1 hexane:ethyl acetate) afforded 3-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (8.3 mg, 4%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 12.25 (br s, 1H), 9.07-9.09 (m, 1H), 8.84-8.86 (m, 1H), 7.48 (s, 1H), 1.42 (s, 9H); m/z (APCI-neg) M−1=218.3.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([OH:14])[C:8]=1[F:15])=O>C1COCC1>[F:15][C:8]1[C:7]([NH:6][CH2:4][C:3]2[CH:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:18]=[CH:19][C:2]=2[F:1])=[C:12]([CH3:13])[CH:11]=[CH:10][C:9]=1[OH:14]
Reactant: Cc1ccc(O)c(F)c1NC(=O)c1cc(-c2cccc(F)c2)ccc1F
Solvent: C1CCOC1
Product: Cc1ccc(O)c(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Temperature: 50 °C
Yield: 62.4 %

Procedure:
To a solution of 2-fluoro-N-(2-fluoro-3-hydroxy-6-methyl-phenyl)-5-(3-fluorophenyl)benzamide (500 mg, 1.4 mmol, 1 eq) in THF (10 mL) under N2 was added dropwise a solution of BH3 (1M in THF, 7 mL, 7.0 mmol, 5 eq). The reaction mixture was heated at 50° C. overnight. After cooling, the resulting mixture was quenched by addition of 1M HCl and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as an oil (300 mg, 42%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=1)=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CO>[CH3:3][C:2]([C:4]1[C:12]2[C:7]([NH:8][CH:9]=[N:10][C:11]=2[N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:18]2)=[N:6][CH:5]=1)=[CH2:1]
Reactant: C=C(C)c1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCC(NC(=O)c4ccccc4)CC3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)c1cnc2[nH]cnc(N3CCC(NC(=O)c4ccccc4)CC3)c1-2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-{1-[5-(1-methylethenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D8 (100 mg) and cesium carbonate (195 mg, 0.598 mmol) in THF (1.4 mL) and MeOH (0.7 mL) was stirred at room temperature for 4 hours. LCMS showed complete loss of starting material, but a few products were present. The mixture was partitioned between EtOAc (15 mL) and water (15 mL) and then the organic layer was washed with water (15 mL) and brine (15 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was purified by MDAP and the one clean fraction was concentrated in vacuo to give E19 (12 mg) as a white solid, 1H NMR (d6-DMSO) δ 11.88 (1H, s), 8.32 (1H, d), 8.27 (1H, s), 7.85 (2H, d), 7.51 (1H, t), 7.44 (2H, t), 7.31 (1H, s), 5.10 (2H, s), 4.10 (2H, d), 4.02 (1H, m), 2.97 (2H, t), 2.13 (3H, s), 1.83 (2H, d), 1.67 (2H, ddd), MS(ES+) 362 [M+H]+.
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[C:9]([C:10]([NH:12][OH:13])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.Cl>>[OH:11][C:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[N:5][C:4]=2[O:13][N:12]=1
Reactant: O=C(NO)c1cccnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1noc2ncccc12
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To 10% aqueous sodium hydroxide solution (26 ml) was added 2-chloropyridine-3-carbohydroxamic acid (2.60 g) and refluxed for 30 minutes. After pH was adjusted to 2.0 with 6N-hydrochloric acid under ice cooling, the reaction mixture was left to stand for 30 minutes at the same temperature. The title compound (1.68 g) was obtained by filtering the precipitated crystals and washing with water and then with a methanol-ether mixture (1:1).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:38])[CH:18]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])[CH:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:38])[CH:18]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:36])([F:37])[CH:33]([F:34])[F:35])[CH:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of zinc chloride (18.9 g, 139 mmol) in diethyl ether (500 ml) was added sodium borohydride (10.5 g, 278 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-[4-(benzyloxy)phenyl]-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (35.0 g, 69.4 mmol) in diethyl ether (200 ml) at 0° C., and the mixture was stirred for 30 min. 1N Hydrochloric acid was added to the reaction solution to stop the reaction. Then, water (500 ml) was added and the mixture was extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the objective substance (30.3 g, 86%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.N1CCNCC1.[CH:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O.C1(C)C=CC=CC=1>[CH3:8][C:3]1[CH:2]=[CH:1][C:6]2[O:7][CH:15]([OH:24])[CH2:16][CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=CC=Cc1ccccc1
Agent: C1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)C(c1ccccc1)CC(O)O2
Temperature: 80 °C

Procedure:
To a solution of p-cresol (25 g, 0.231 mol, 1 equiv), piperazine (11.94 g, 0.139 mol, 0.6 equiv) and toluene (250 ml, 10 ml/g) at reflux under Dean & Stark conditions was added cinnamaldehyde (45.83 g, 44 ml, 0.347 mol, 1.5 equiv) over a 2 hour period and reaction mixture monitored by HPLC for the presence of p-cresol. Upon completion (2 to 3 hours), the mixture was cooled to 80° C. and a solution of c.HCl (25 ml, 0.301 mol, 1.3 equiv) in water (100 ml, 5 ml/g) was slowly added and heated at 80-90° C. for at least 5 hours. The resulting solution was allowed to cool to room temperature and the phases separated. The toluene solution was washed with 1M HCl (125 ml, 5 ml/g), then water (3×125 ml). The resulting organic layer was taken into the reductive amination step (Step B) as a crude mixture.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:3]=1.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:28]([N:35]1[CH2:36][CH2:37][N:38]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH:8]3[N:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]3)[CH:3]=2)[CH2:39][CH2:40]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(Br)ccn2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 94.4 %

Procedure:
5-(4-Bromo-pyridin-2-yl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (300.0 mg, 0.66 mmol) prepared in Step 4 of Preparation 11, 1-BOC-piperazine (184.0 mg, 0.99 mmol), Pd2(dba)3 (30.2 mg, cat.), BINAP (41.1 mg, cat.) and sodium t-butoxide (114.0 mg, 1.19 mmol) were added to toluene (10.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 350.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8].P(Br)(Br)[Br:17].O.C(OCC)(=O)C>COCCOC>[Br:17][CH2:14][C:11]1[CH:12]=[CH:13][C:2]([Cl:1])=[C:3]([CH:10]=1)[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8]
Reactant: BrP(Br)Br
Reactant: COC(=O)NCc1cc(CO)ccc1Cl
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)NCc1cc(CBr)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 209 %

Procedure:
6.2 g of methyl N-(2-chloro-5-hydroxymethylbenzyl)carbamate was dissolved in 50 ml of ethylene glycol dimethyl ether, and 2.7 g of phosphorus tribromide was dropwise added to this solution at −20° C., followed by stirring at room temperature for 1 hour. After completion of the reaction, water was added to the reaction solution, extraction with ethyl acetate was carried out, followed by washing with an aqueous sodium hydrogencarbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.1 g of methyl N-(5-bromomethyl-2-chlorobenzyl)carbamate as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[C:18]1[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH2:38][C:39]1[CH:49]=[CH:48][C:42]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])=[CH:41][CH:40]=1>C(O)(C)(C)C.[Pd].C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]3[CH:15]=[C:14]([NH:38][C:39]4[CH:40]=[CH:41][C:42]([C:43](=[O:44])[N:45]([CH3:46])[CH3:47])=[CH:48][CH:49]=4)[N:13]=[CH:12][C:11]=3[CH:10]=2)[CH:19]=[N:20]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CN(C)C(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Cl)cc3n2C(=O)OC(C)(C)C)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CN(C)C(=O)c1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 35.3 %

Procedure:
Pd2(dba)3 (11.32 mg, 0.012 mmol) was added to a mixture of tert-butyl 2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-6-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (17) (37 mg, 0.088 mmol), potassium phosphate (62.1 mg, 0.29 mmol), 4-amino-N,N-dimethylbenzamide (16.68 mg, 0.10 mmol) and di-tBuX-Phos (15.75 mg, 0.037 mmol) in tert-BuOH containing 3% water (1.0 mL). The reaction mixture was heated at 80° C. for 1 h under microwave irradiation. More palladium catalyst (10.0 mg) and di-tBuX-Phos (8.0 mg) were added and the reaction mixture was heated at 80° C. for an additional 70 min under microwave irradiation. A final portion of palladium catalyst (4.0 mg) was added and the reaction mixture was heated at 80° C. for 70 min under microwave irradiation; it was then diluted with ethyl acetate (40 mL), washed with water (2×10 mL), dried (Na2SO4), and concentrated in vacuo. The residue was absorbed on silica gel (0.7 g), the free-running powder was placed on a 10 g isolute silica column. Elution with 60%, 70%, 80%, 90% ethyl acetate in hexane afforded the title compound (0.017 g) that was contaminated with the aniline starting material (4-amino-N,N-dimethylbenzamide) in a ratio of 1:1. 1H-NMR (500 MHz, CDCl3) 1.53 (s, 9H), 1.69 (s, 9H), 3.10 (s, 6H), 6.60 (d, J=0.6 Hz), 6.73 (br s, 1H), 7.39 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.70 (s, 1H), 7.83 (d, J=0.7 Hz, 1H), 8.23 (d, J=0.6 Hz, 1H), 8.50 (d, J=0.8 Hz, 1H). Also present were the following peaks consistent with the structure of the starting material, 4-amino-N,N-dimethylbenzamide: 3.06 (s, 6H), 3.84 (br s, 2H), 6.66 (d, J=8.6 Hz, 2H), 7.30 (d, J=8.6 Hz, 2H).
Reaction SMILES: [CH2:1]1[C:12]2[C:4](=[CH:5][C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:3]1[C:4]2[C:12](=[C:11]([C:13](=[O:15])[CH3:14])[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[CH2:1][CH2:2]1
Reactant: CC(=O)Cl
Reactant: c1c2c(cc3c1CCC3)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(=O)c1c2c(cc3c1CCC3)CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1,2,3,5,6,7-hexahydro-s-indacene (30 grams) and acetyl chloride (14.2 mL) in 120 mL of benzene at 0° C. was added 30 grams of aluminum chloride over a period of 1 hour. The cooling bath was removed and the solution was warmed to room temperature and stirred for 4 hours. The deep red mixture was then poured onto a mixture of 270 grams of ice and 50 mL of concentrated hydrochloric acid. The layers were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford an orange solid which was recrystallized from hexane to give 34 grams of the title compound, m.p. 69.1-76.1° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C:5]2[C:7]([S:11]([NH:14][C:15](NC)=[O:16])(=[O:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.C(Cl)(Cl)=O>ClC1C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[O:6][C:5]2[C:7]([S:11]([N:14]=[C:15]=[O:16])(=[O:12])=[O:13])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1
Reactant: CNC(=O)NS(=O)(=O)c1cccc2c1OC(C)(C)C2
Agent: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: CC1(C)Cc2cccc(S(=O)(=O)N=C=O)c2O1

Procedure:
8 g of N-(2,3-dihydro-2,2-dimethylbenzo[b]furan-7-ylsulfonyl)-N'-methylurea are dispersed in 400 ml of absolute chlorobenzene and the dispersion is saturated with phosgene at about 130° C., whereupon a clear solution forms. The solvent is then destilled off in vacuo, with the exclusion of moisture, to give 2,3-dihydro-2,2-dimethylbenzo[b]furan-7-ylsulfonylisocyanate in the form of an oil, which can be used without further purification for obtaining the fused N-phenylsulfonyl-N'-pyrimidinylureas and N-phenylsulfonyl-N'-triazinylureas of the formula I.