Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O.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(O)C.C1(C)C=CC=CC=1>[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:25]=2)[N:7]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (50 mg, 0.21 mmol), 3-(trifluoromethyl)phenylboronic acid (Fluka) (55 mg, 0.287 mmol, 1.4 eq), tris(dibenzylideneacetone)dipalladium(0) (Aldrich Chemical Company) (4.7 mg, 0.0051 mmol, 0.025 eq) and triphenylphosphine (Aldrich Chemical Company) (10.8 mg, 0.041 mmol, 0.2 eq) in a mixed solvent (600 μL of toluene, 300 μL of 1.0 M Na2CO3, and 150 μL of ethanol) was heated at reflux under N2 for 19 h. Upon cooling to the room temperature, the reaction mixture was diluted with H2O (20 mL) and extracted with CHCl3 (3×20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated with a rotary evaporator. Mp: 206-208° C. 1H NMR (CDCl3, 400 MHz): δ 8.58 (s, 1), 8.28 (s, 1), 8.18 (d, 1, J=7.6), 7.82 (d, 1, J=7.8), 7.77-7.72 (m, 3), 7.53 (t, 2, J=7.4), 7.46 (t, 1, J=7.4), 6.98(d, 1, J=2.0), 2.89 (s, 3). MS m/z: 354 (M+1), 352 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CC(C)=O>[C:21]([O:20][C:18](=[O:19])[CH2:17][O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Br:1])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reaction time: 0.17 h
Yield: 95.4 %

Procedure:
A solution of 2-bromo-4-chlorophenol (Aldrich; 13.11 g; 63.2 mmol) in acetone (100 mL) was treated with potassium carbonate (9.61 g; 69.5 mmol), stirred for 10 minutes then treated with tert-butyl bromoacetate (Aldrich; 9.34 mL; 63.2 mmol). The reaction mixture was stirred at 65° C. for 18 hours, then the mixture was filtered, the solid was washed with acetone and the filtrate was concentrated to dryness under vacuum to give the title compound as a yellow sticky solid (19.4 g, 95%).
Reaction SMILES: C1COCC1.Cl.[CH3:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH2:13].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]#[CH:35])[C:26](Cl)=[O:27]>O>[CH3:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH:13][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]#[CH:35])=[C:23]([O:22][CH3:21])[CH:24]=1
Reactant: CC1CCCC1N
Reactant: C#CCOc1ccc(C(=O)Cl)cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C#CCOc1ccc(C(=O)NC2CCCC2C)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a mixture of 20 ml of THF, 0.50 g of 2-methylcyclopentylamine hydrochloride and 1.0 g of triethylamine was added 0.50 g of 3-methoxy-4-(2-propynyloxy)benzoyl chloride. The mixture obtained was stirred at room temperature for 3 hours. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 235 mg of N-(2-methylcyclopentyl)-3-methoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 18 of the present invention) represented by the formula:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CN(C)[CH:12]=[O:13].P(Cl)(Cl)(Cl)=O>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:12]=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)CCO2
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)CCO2
Temperature: 85 °C
Reaction time: 7.5 h
Yield: 94 %

Procedure:
To a solution of 2,3-dihydrobenzofuran (100.0 g, 832 mmols) in N,N-dimethylformamide (134.0 g, 1.83 mols) was added dropwise phosphorus oxychloride (255.1 g, 1.66 mols), then the mixture was stirred at 80-90° C. for 7.5 hours. The mixture was cooled to room temperature, poured into water (1 L) and stirred for 15 hours. The product was extracted with toluene (1.5 L). The extract was washed with water (500 mL) followed by a saturated aqueous solution of sodium bicarbonate (500 mL) and concentrated under reduced pressure to obtain 115.9 g (yield: 94%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)[CH2:12][OH:13].[OH-].[Na+].[Cl:29][CH2:30][C:31](Cl)=[O:32]>C(Cl)Cl.O>[Cl:29][CH2:30][C:31]([N:14]([CH:11]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10])[CH2:12][OH:13])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=1)=[O:32]
Reactant: COc1cccc(OC)c1C(CO)NCc1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cccc(OC)c1C(CO)N(Cc1ccc(OC(F)(F)F)cc1)C(=O)CCl
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A cooled (−10° C.) mixture of 2-(2,6-dimethoxyphenyl)-2-((4-(trifluoromethoxy)benzyl)-amino)ethanol (32 mg; 0.08 mmol) and NaOH (7 mg; 0.17 mmol) in DCM (1 ml) and water (0.5 ml) was treated with 2-chloroacetyl chloride (12 mg; 0.10 mmol). The resulting mixture was further stirred at −10° C., under nitrogen, for 15 min. Water and DCM were added, and the separated aq. layer was further extracted with DCM. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-chloro-N-(1-(2,6-dimethoxyphenyl)-2-hydroxyethyl)-N-(4-(trifluoromethoxy)benzyl)-acetamide as a yellow oil. LC-MS (conditions E): tR=0.75 min.; [M+H]+: 447.98 g/mol.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])C.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([C:41]([CH2:50][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=2)([CH2:45][CH:46]=[C:47]([CH3:49])[CH3:48])[C:42]([OH:44])=O)(=[O:40])=[O:39])=[CH:34][CH:33]=1.[OH-:57].[Na+]>CO>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([C:5]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)([CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[C:4]([OH:29])=[O:3])(=[O:20])=[O:19])=[CH:22][CH:23]=1.[OH:57][NH:14][C:42](=[O:44])[C:41]([S:38]([C:35]1[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:37][CH:36]=1)(=[O:40])=[O:39])([CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)[CH2:45][CH:46]=[C:47]([CH3:48])[CH3:49]
Reactant: [OH-]
Reactant: CCOC(=O)C(CC=C(C)C)(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: COc1ccc(S(=O)(=O)C(CC=C(C)C)(Cc2cccnc2)C(=O)O)cc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(CC=C(C)C)(Cc2cccnc2)C(=O)NO)cc1

Procedure:
2-(4Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4 enoic acid was prepared starting from 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid ethyl ester (4.0 g, 9.5 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 3.2 g, 87%; ivory solid; mp 117-119° C.; MS: 390 (M+H)+. Starting from 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid (2.1 g, 5.4 mmol) and following the procedure as outlined in Example 1, 1.82 g of 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid hydroxyamide was isolated as a colorless solid. Yield: 82%; mp 89-92° C.; MS: 405 (M+H)+; 1H NMR (300 MHz, CDCl3): δ1.63 (s, 3H), 1.76 (s, 3H), 2.62-2.78 (m, 2H), 3.3 (d, J=4.0 Hz, 1H), 3.63 (d, J=4.0 Hz, 1H), 3.82 (s, 3H), 5.26 (m, 1H), 7.12-7.88 (m, 6H), 8.27-8.33 (m. 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[C:23]([C:24]([OH:26])=O)=[CH:22][N:21]=[CH:20][CH:19]=3)[C:11]3[O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.[CH2:28]([N:30](CC)CC)C.CN.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[C:23]([C:24]([NH:30][CH3:28])=[O:26])=[CH:22][N:21]=[CH:20][CH:19]=3)[C:11]3[O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ylamino]-nicotinic acid (75 mg, 0.19 mmol, 1 eq) in DMF (2 ml) was added triethylamine (30 μl, 0.21 mmol, 1.1 eq) followed by methylamine (1.17 ml, 3.89 mmol, 2M solution in THF, 20 eq). To the suspension was added a solution of PyBrOP (100 mg, 0.21 mmol, 1.2 eq) in DMF (1 ml) dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and the residue was triturated with ether (2×20 ml). The crude residue was purified by flash column chromatography (5% MeOH in CHCl3) to afford 4-[2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ylamino]-N-methyl nicotinamide, 44 (20 mg, 26%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([S:13]([C:16]2[C:17]([CH2:27][CH3:28])=[N:18][N:19]3[C:24](Cl)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([CH2:27][CH3:28])=[N:18][N:19]3[C:24]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: CCc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CCc1nn2c(N3CCNCC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 27.7 %

Procedure:
0.64 g (7.4 mmol) of piperazine in 10 ml of DMF was added to a solution of 1.0 g (3 mmol) of 3-benzenesulphonyl-7-chloro-2-ethyl-5-methyl-pyrazolo[1,5-a]pyrimidine in 10 ml of DMF and stirred at 60° for 2 hrs. The DMF was evaporated in a high vacuum, the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with 50 ml of CH2Cl2 and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 9:1) and crystallization from EtOH yielded 0.32 g (27%) of 3-benzenesulphonyl-2-ethyl-5-methyl-7-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 150-150.8°.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C:14]1[C:15]([C:20]([F:23])([F:22])[F:21])=[N:16][N:17]([CH3:19])[CH:18]=1)=[O:13].I[CH:25]([CH3:27])[CH3:26].O>CN(C)C=O.CO>[CH:25]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C:14]1[C:15]([C:20]([F:23])([F:22])[F:21])=[N:16][N:17]([CH3:19])[CH:18]=1)=[O:13])([CH3:27])[CH3:26]
Reactant: Cn1cc(C(=O)Nc2ccccc2CO)c(C(F)(F)F)n1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC(C)OCc1ccccc1NC(=O)c1cn(C)nc1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
156.0 mg (3.9 mmol) of 60% sodium hydride in oil are added to a solution of 897.8 mg (3.0 mmol) N-[2-(hydroxymethyl)phenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (IV-1) in 2 ml dimethyl formamide at room temperature. After 30 minutes, 0.6 ml (6.0 mmol) 2-iodopropane are added. The reaction mixture is stirred for 6 hours at 100° C. and thereafter for 16 hours at room temperature. Afterward, the mixture is diluted with 1 ml methanol, added to water and extracted with ethyl acetate; the organic phase is dried over magnesium sulfate, the drying agent filtered off and the material concentrated under vacuum. Column chromatography (3:1 cyclohexane/ethyl acetate) yielded 100.0 mg (9.7% of the theoretical yield) of N-[2-(isopropoxymethyl)phenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-carboxamide [logP (pH 2.3)=2.85].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]([Si:34]([CH3:53])([CH3:52])[O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](O)([C:47]([F:50])([F:49])[F:48])[C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=1)([CH3:33])([CH3:32])[CH3:31].CC(OC(/N=N/C(OC(C)C)=O)=O)C.[NH4+].[Cl-]>C1COCC1>[C:30]([Si:34]([CH3:53])([CH3:52])[O:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:47]([F:50])([F:48])[F:49])[C:43]([F:46])([F:44])[F:45])=[CH:40][CH:41]=1)([CH3:32])([CH3:31])[CH3:33]
Reactant: COc1ccc(CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(COC(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 4.1 g (29.6 mmol) of 4-methoxybenzyl alcohol in 100 mL of THF was added 7.76 g (29.6 mmol) of triphenylphosphine and 8.53 g (22.8 mmol) of 2-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol at room temperature. The reaction mixture was cooled to 0° C. and 5.7 mL (29.6 mmol) of diisopropylazo dicarboxylate were added. The solution was stirred at room temperature overnight, a solution of NH4Cl was added and the inorganic layer was extracted with ethyl acetate. The combined layers were washed with brine, and dried (Na2SO4), filtered and evaporated. Column chromatography with ethyl acetate/n-heptane 1:99 as eluent yielded 8.39 g (74%) of tert-butyl-dimethyl-{4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-silane as a light yellow liquid, MS: 494 (M)+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[NH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH2:2][CH2:3][N:4]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]=[C:5]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23]2)=[CH:28]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=c1c2ccccc2nc(-c2ccccc2)n1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=c1c2ccccc2nc(-c2ccccc2)n1CCN1CCC(c2c[nH]c3ccccc23)CC1

Procedure:
A mixture of 5.5 parts of 3-(2-chloroethyl)-2-phenyl-4(3H)-quinazolinone, 3.2 parts of 3-(4-piperidinyl)-1H-indole, 7 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 22 hours. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. The residue is purified by column-chromatography over silic gel using a mixture of trichloromethane and methanol (92:8 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of ethanol and 1,1'-oxybisethane, yielding 5 parts of 3-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2-phenyl-4(3H)-quinazolinone; mp. 191.3° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([OH:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([O:12][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)c1c(O)ccc(Br)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(OCCOC2CCCCO2)ccc(Br)c1C
Temperature: 55 °C
Yield: 71.6 %

Procedure:
A solution of methyl 3-bromo-6-hydroxy-2-methylbenzoate (Cpd GG, 1.94 g, 7.90 mmol) in DMF (25 mL) was treated with cesium carbonate (3.45 g, 10.0 mmol) and then 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.06 g, 9.84 mmol). The reaction mixture was heated at 55° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water (2×) and brine. The organic layer was concentrated under vacuum to give a brown oil which was purified by column chromatography (0-25%, ethyl acetate/heptane) to give the title compound (Cpd HH, 2.11 g, 67% yield) as a clear oil. 1H NMR (400 MHz, chloroform-d) δ 7.50 (d, J=8.80 Hz, 1H), 6.72 (d, J=8.80 Hz, 1H), 4.68 (t, J=3.36 Hz, 1H), 4.13-4.18 (m, 2H), 4.00 (td, J=4.77, 11.37 Hz, 1H), 3.91 (s, 3H), 3.86 (ddd, J=3.06, 8.59, 11.34 Hz, 1H), 3.74-3.80 (m, 1H), 3.49-3.56 (m, 1H), 2.32 (s, 3H), 1.78-1.89 (m, 1H), 1.67-1.77 (m, 1H), 1.58-1.66 (m, 2H), 1.49-1.55 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18]O.C([O-])=O.[Na+]>C(O)=O.O>[C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)c1cc(C=O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CC(C)(C)c1cc(C#N)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
The above aldehyde (1.4 g, 6.3 mmol), hydroxylamine hydrochloride (0.438 g, 6.3 mmol), and sodium formate (0.771 g, 11.3 mmol) in formic acid (20 mL) were heated overnight, at reflux, then cooled to room temperature. The reaction was diluted with water, and the resulting precipitate was filtered. The solid was taken up in ether, dried over Na2SO4, filtered and concentrated in vacuo to yield 5-tert-butyl-2-hydroxyl-3-nitro-benzonitrile (1.21 g, 87%) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:10]=[C:9](F)[CH:8]=[C:7]2[C:3]=1[C:4]([S:12][CH2:13][C:14]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1)=[O:15])=[CH:5][NH:6]2.[OH:23]O>C(O)(C(F)(F)F)C(F)(F)F>[NH:6]1[C:7]2[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=2)[C:4]([S:12]([CH2:13][C:14]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[O:15])=[O:23])=[CH:5]1
Reactant: OO
Reactant: Cc1cc(NC(=O)CSc2c[nH]c3cc(F)cc(F)c23)no1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: Cc1cc(NC(=O)CS(=O)c2c[nH]c3ccccc23)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
2-((4,6-difluoro-1H-indol-3-yl)thio)-N-(5-methylisoxazol-3-yl)acetamide (100 mg, 0.348 mmol) from Step C was dissolved in hexafluoro-2-propanol (500 μL) and hydrogen peroxide (30% by weight, 88.0 μL, 0.696 mmol). The mixture was stirred at ambient temperature for 2 hours. The reaction was quenched with saturated aqueous sodium sulfite (500 μL) and extracted with ethyl acetate (3×1 mL). The organics were combined, dried over magnesium sulfate, and concentrated in vacuo to give a residue which was purified on a silica gel column (0-100% ethyl acetate:hexanes over 19 min) to yield the desired product (79.0 mg, 0.174 mmol, 75% yield). LCMS>99% at 220 nm, RT=1.00 min, m/z=304 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([F:14])[CH:3]=1.[CH2:15]([Mg]Br)[CH3:16]>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:15][CH3:16])=[C:4]([F:14])[CH:3]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Br)cc1F
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 1000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide (60 g, 229.01 mmol, 1.00 equiv) in tetrahydrofuran (200 mL). To the resulting mixture was then added ethylmagnesium bromide (2M) (185 mL, 1.60 equiv) dropwise with stirring at −20° C. The resulting solution was stirred for 2 h at room temperature, then cooled to 0° C. with a water/ice bath. The reaction was then quenched by the addition of NH4Cl/H2O (500 mL). The resulting solution was extracted with ethyl acetate (3×300 mL) and the organic layers combined. The resulting mixture was washed with water (1×300 mL) and brine (1×300 mL), then dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20) to yield 1-(4-bromo-2-fluorophenyl)propan-1-one as a white solid.
Reaction SMILES: [OH-].[K+].O.O.[Cl:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[C:7]=1[S:16]([OH:19])(=O)=[O:17].P(Cl)(Cl)(Cl)(Cl)[Cl:21].O=P(Cl)(Cl)Cl>CO>[Cl:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[C:7]=1[S:16]([Cl:21])(=[O:19])=[O:17]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.9 %

Procedure:
Potassium hydroxide (11.54 g, 0.206 mol) was added to a solution of 2,6-dichloro-3-nitrobenzenesulfonic acid dihydrate (37.38 g, 0.137 mol) in MeOH (500 mL) and the reaction was allowed to stir at room temperature for 14 hr. The reaction mixture was concentrated and the resulting solid was dried in vacuo overnight. To this was added PCl5 (29.60 g, 0.142 mol) followed by POCl3 (400 mL) and the mixture was refluxed overnight. The reaction was then cooled to room temperature and concentrated. The resulting mixture was taken up in EtOAc and chilled in an ice bath. Ice chunks were slowly added to the reaction mixture to quench any leftover PCl5. When bubbling ceased, water was added and the reaction mix was extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to yield 2,6-Dichloro-3-nitrobenzenesulfonyl chloride (31.4 g, 79%).
Reaction SMILES: [C:1](=[O:17])([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([N+:14]([O-])=O)[CH:7]=1)[O:2][CH2:3][CH3:4].C(O)(=O)C>CCOC(C)=O.[Pd]>[C:1](=[O:17])([O:2][CH2:3][CH3:4])[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH2:14])[CH:7]=1
Reactant: CCOC(=O)Oc1ccc(OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)Oc1ccc(OC)c(N)c1
Reaction time: 2 h
Yield: 95 %

Procedure:
Ethyl 4-methoxy-3-nitrophenyl carbonate (0.720 g, 2.99 mmol) was dissolved in EtOAc (20 ml), and glacial acetic acid (0.200 ml, 3.49 mmol) was added followed by 10% palladium on carbon (0.100 g, 0.094 mmol). The mixture was stirred in a Parr apparatus under hydrogen atmosphere (25 psi) for 2 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The resulting crude 3-amino-4-methoxyphenyl ethyl carbonate (0.600 g, 2.84 mmol, 95% yield, MS/ESI+ 212.3 [MH]+), was used for the next step without any further purification.