Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:42]=[C:41]([N+:43]([O-])=O)[CH:40]=[CH:39][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:38]=[CH:37][C:17]([CH2:18][N:19]([CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][CH:15]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:43][C:41]1[CH:40]=[CH:39][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH:38]=[CH:37][C:17]([CH2:18][N:19]([CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:42]=1
Reactant: COCCOCCOCCN(Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1)C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COCCOCCOCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1)C(=O)OC(C)(C)C
Yield: 88.2 %

Procedure:
To a solution of 365 (0.49 g, 0.76 mmol) in MeOH (100 mL) was added iron dust (0.43 g, 7.6 mmol) and ammonium chloride (0.12 g, 2.3 mmol) in water (5 mL). The resulting mixture was heated to reflux for 4 h, then cooled, filtered through a celite pad and concentrated. The residue was partitioned between dichloromethane and water; the organic phase was collected, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluent 2% MeOH in EtOAc) to give 366 (0.41 g, 88% yield). LRMS (M+H): 612.6
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:11]=[CH:12][C:13]=1[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:29][C:30]([F:37])([F:36])[CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH2:1]([C:8]1[CH:9]=[C:10]([N:15]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[S:32]([CH2:31][C:30]([F:37])([F:36])[F:29])(=[O:34])=[O:33])[CH:11]=[CH:12][C:13]=1[Cl:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Clc1ccc(NCc2cccnc2)cc1Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1ccc(Cl)c(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-benzyl-4-chlorophenyl)pyrid-3-ylmethylamine (0.04 g, 0.13 mmol)and pyridine (1 ml) was dissolved in DCM. The reaction was cooled in an ice-bath to which was added dropwise 2,2,2-trifluoroethylsulfonyl chloride (0.59 g, 0.32 mmol). The mixture was stirred at room temperature overnight. After evaporation of solvent, the residue was dissolved in EtOAc and washed with cold NaHCO3 and brine, and evaporated to dryness. Chromatography gave the title compound. 1H NMR: 8.51 (d,1H,J=3.9 Hz), 8.27 (s,1H), 7.59 (d,1H,J=7.8 Hz), 7.34 (t,1H,J=8.3 Hz), 7.28 (d,2H,J=7.8 Hz), 7.21 (m,2H), 8.03 (m,3H), 6.89 (d,1H,J=2.4 Hz), 4.78 (s,2H), 4.01 (s,2H), 3.73 (q,2H,J=9.3 Hz). MS calcd 454.1; MS (M+1) 455.0.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:3][C:4]=1[O:10][CH3:11])=[O:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc(O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OCC(=O)OC(C)(C)C)ccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 218 %

Procedure:
A mixture of 4-hydroxy-2-methoxybenzaldehyde (5.23 g; 34.4 mmol), t-butyl bromoacetate (4.9 mL; 30.3 mmol) and K2CO3 (15.1 g; 108.9 mmol) in 50 mL of DMF was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, filtered, and partitioned between ethyl acetate and 1 N HCl. The organic phase was washed (sat. NaCl) and dried (MgSO4), and concentrated to give 17.59 g of t-butyl 4-formyl-3-methoxyphenoxyacetate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[F:28][C:24]1[CH:23]=[C:22]([C:20]2[CH:19]=[CH:18][C:14]([C:15]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:16])=[C:13]([CH3:12])[N:21]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nc(-c2cccc(F)c2)ccc1C(=O)O
Reactant: Nc1ccc2cccnc2c1
Product: Cc1nc(-c2cccc(F)c2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (28 mg, 0.20 mmol) and 6-(3-fluorophenyl)-2-methyl-nicotinic acid (D25) (50 mg, 0.33 mmol), as an off-white solid. MS(ES): MH+ 358, M-H+ 356.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:4]=[CH:5][C:6]([N+:15]([O-:17])=[O:16])=[C:7]2[C:12]=1[O:11][C:10]([CH3:13])=[CH:9][C:8]2=[O:14].C[N+]1([O-])CC[O:23]CC1>C(#N)C>[CH3:13][C:10]1[O:11][C:12]2[C:7]([C:8](=[O:14])[CH:9]=1)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=2[CH:2]=[O:23]
Reactant: Cc1cc(=O)c2c([N+](=O)[O-])ccc(C(Br)Br)c2o1
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: Cc1cc(=O)c2c([N+](=O)[O-])ccc(C=O)c2o1

Procedure:
175 mg (0.47 mmol) of 8-(dibromomethyl)-2-methyl-5-nitro-4H-chromen-4-one are heated under reflux with 151 mg (1.29 mmol) of N-methylmorpholine N-oxide with the addition of molecular sieves in 15 ml of acetonitrile overnight. After filtration through kieselguhr, the solvent is removed in vacuo, and the residue is purified by preparative HPLC. 23 mg (24% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]([O:16]C(C)(C)C)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:28])[F:29])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]([OH:16])=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Oc1cc(C(=O)NC(C(=O)OC(C)(C)C)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Oc1cc(C(=O)NC(C(=O)O)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 105.4 %

Procedure:
To a solution of tert-butyl 2-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoate (example 199a, 0.485 g, 1.09 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (3.73 g, 2.52 ml, 32.8 mmol) and the reaction mixture was stirred at room temperature for 14 hours. Volatiles were removed in vacuo and the residue was dissolved in toluene followed by evaporation to dryness. The procedure was repeated twice to yield the title compound (446 mg) as a crude solid which was used without any purification. MS (ESI, m/z): 387.5 (M−H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:42])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([CH3:41])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:26]3[CH2:25][C:24](=[O:42])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:21])([F:22])[F:20])[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:39]=[C:38]([CH3:40])[N:37]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C(C)C)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from [2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(isopropyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M307) (0.43 g, 0.72 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (310 mg, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12]S[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[S:32]([O-:36])([O-])(=[O:34])=S.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][S:32](=[O:36])(=[O:34])[CH:10]([C:14]2[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCSC(c2ccc(Br)cc2)C1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCS(=O)(=O)C(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-bromo-phenyl)-thiomorpholine-4-carboxylic acid tert-butyl ester (3.60 g; 10.05 mmol) in CH2Cl2 (100 mL) was added 3-chloroperoxybenzoic acid (5.20 g; 30.14 mmol), at 0° C. The resulting mixture was stirred overnight at RT, and subsequently, a saturated aqueous sodium thiosulfate solution was added and the mixture stirred for another 30 min. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined EtOAc layers were washed twice with an aqueous Na2CO3 solution. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to afford 2-(4-bromo-phenyl)-1,1-dioxo-1λ6-thiomorpholine-4-carboxylic acid tert-butyl ester (4.06 g) which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26]([OH:28])=O)[C:5]2[C:10](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[N:9][N:8]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[C:6]=2[N:7]=1.[C:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C(=O)C.O1CCCC1>[C:32]([O:31][C:29]([N:36]1[CH2:41][CH2:40][N:39]([C:26]([C:4]2[C:5]3[C:10](/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=4)=[N:9][N:8]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[C:6]=3[N:7]=[C:2]([Cl:1])[CH:3]=2)=[O:28])[CH2:38][CH2:37]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(O)c1cc(Cl)nc2c1c(/C=C/c1ccc(Cl)cc1)nn2C1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)nc3c2c(/C=C/c2ccc(Cl)cc2)nn3C2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
To a solution of 6-chloro-3-[(E)-2-(4-chloro-phenyl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2 g, 4.79 mmol) in a mixture of anhydrous tetrahydrofuran (42 ml) and N,N-dimethylacetamide (10 ml) were added 1-boc-piperazine (0.98 g, 5.27 mmol), 1-hydroxybenzotriazole (0.06 g, 0.48 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.91 g, 4.79 mmol). The reaction mixture was stirred at room temperature for 4 hours, tetrahydrofuran was evaporated under reduced pressure, water and dichloromethane were then added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude residue was purified on a silica gel column chromatography using a gradient of ethyl acetate (0-45%) in cyclohexane to yield the title compound as a yellow foam (1.51 g, 54%).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:1]=1
Reactant: Cc1cccc(C)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1ccc(-c2nc(Cl)nc(Cl)n2)c(C)c1
Reaction time: 3 h

Procedure:
Cyanuric chloride (1.84 g) was allowed to react with 1.9 eq of m-xylene and 2.5 eq (3.35 g) of AlCl3 in 25 mL of chlorobenzene at 5° C. for 0.5 h and then at room temperature for 3 h. Analysis by HPLC, after 2.5 h, showed that less than 8% of cyanuric chloride had reacted to form only 2,4-dichloro-6-(2,4-dimethylphenyl)-1,3,5-triazine, no 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine or 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine were present. The reaction was allowed to continue at room temperature. After 24 hours, HPLC analysis showed about 51% cyanuric chloride conversion and formation of 2,4 dichloro-6-(2,4-dimethylphenyl)-1,3,5-triazine and 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine in the ratio of 95:5, respectively No 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine was detected.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([C:24]3[N:25]=[C:26]4[C:32]([C:33](O)=[O:34])=[CH:31][N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:27]4=[N:28][CH:29]=3)=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:44]([NH2:48])([CH3:47])([CH3:46])[CH3:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:44]([NH:48][C:33]([C:32]1[C:26]2[C:27](=[N:28][CH:29]=[C:24]([C:16]3[C:17]4[C:22](=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[N:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]4)[N:15]=3)[N:25]=2)[N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:31]=1)=[O:34])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)CC1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CCN(C(=O)OC(C)(C)C)CC4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
In a 10 ml round-bottomed flask, 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (85 mg, 0.14 mmol) was dissolved in DMF (1.5 ml) and tert-butylamine (0.06 ml, 0.57 mmol) and HATU (59 mg, 0.155 mmol) were added. The light yellow suspension was stirred at room temperature overnight then water and petroleum ether were added. The resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum. The residue was chromatographed over 8 g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 47 mg (51%) of 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[S:16]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])(=[O:19])(=[O:18])[NH2:17]>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([S:16](=[O:19])(=[O:18])[NH2:17])[CH:21]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2cccc(S(N)(=O)=O)c2)C(=O)OC1=O

Procedure:
To a hot solution of 2.12 g. (0.01 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 40 ml. of methanol is added 1.72 g. (0.01 mol) of m-sulfamylaniline and the mixture is refluxed for one hour. The solid is filtered from the reaction mixture to obtain 5-acetyl-4-hydroxy-3-[1-(3-sulfamylphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 237° C.
Reaction SMILES: [N:1]([CH2:4][CH:5]([N:7]([C:22]([CH:24]1[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])[C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:10][C:9]=1[C:19]([OH:21])=[O:20])[CH3:6])=[N+]=[N-]>CCO.[Pd]>[NH2:1][CH2:4][CH:5]([N:7]([C:22]([CH:24]1[CH2:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH2:29]1)=[O:23])[C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:10][C:9]=1[C:19]([OH:21])=[O:20])[CH3:6]
Reactant: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C(C)CN=[N+]=[N-])CC1
Agent: [Pd]
Solvent: CCO
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C(C)CN)CC1
Reaction time: 1.5 h

Procedure:
A solution of 3-[(2-Azido-1-methyl-ethyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (8 mg, 0.19 mmol) in EtOH (0.2 ml) at 21°, was treated with 10% Pd/C (4 mg, 50% w/w) and stirred under an atmosphere of H2 for 1.5 h. The reaction mixture was filtered through a pad of celite with hot EtOAc and the combined filtrate and washings dried and evaporated to a glass to provide 3-[(2-Amino-1-methyl-ethyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 36). (7 mg, %); 1H NMR (300 MHz, Acetone-d6) 0.43-0.65 and 0.75-0.90 (m, 4H), 1.17-1.64 (m, 6H), 1.81-1.90 and 2.01-2.40 (m, 3H), 2.54 (bs, 1H), 3.00 (bs, 1H), 3.50 and 3.70 (bs, 1H), 7.20 (s, 1H), 7.22-7.25 and 7.29-7.34 (m, 3H), 7.58-7.62 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17]O)[CH2:3][CH2:2]1.P(Br)(Br)[Br:20].C(=O)(O)[O-].[Na+]>ClCCl>[Br:20][CH2:17][C:5]1[C:6]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
Alternate procedure: Cool a solution of (5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-yl)-methanol (100 g, 0.35 mol) in dichloromethane (1200 mL) to −10° C. Add phosphorous tribromide (105 g, 0.39 mol) dropwise while maintaining the internal temperature between −5° C. and 0° C. Stir at −5° C. to 0° C. for 30 min. Allow to warm to between 20° C. and 25° C. and stir at 20° C. to 35° C. for 2 h. Cool the reaction mixture to 0° C. to 5° C. Add an aqueous solution of sodium bicarbonate (775 mL) dropwise. Separate the phases. Extract the aqueous phase with dichloromethane (2×350 mL). Wash the combined organic phases with water (3×500 mL). Concentrate the organic phase to afford 115 g (94%) of the title compound as a solid.
Reaction SMILES: [S:1]1[CH2:6][CH2:5]C(=O)[CH2:3][CH2:2]1.[CH:8](OC)([O:11][CH3:12])[O:9][CH3:10]>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>[CH3:10][O:9][C:8]1([O:11][CH3:12])[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1
Reactant: COC(OC)OC
Reactant: O=C1CCSCC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1(OC)CCSCC1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A mixture of tetrahydro-(4H)-thiopyran-4-one (15.0 g, 129 mmol), trimethyl orthoformate (28.3 mL, 258 mmol) and para-toluenesulfonic acid monohydrate (67 mg, 0.35 mmol) in methanol (40 mL) was refluxed for 1 hour. The reaction mixture was cooled to room temperature, 1 M NaOMe (0.35 mL, 0.35 mmol) was added and excess methanol and trimethyl orthoformate was removed by distillation (atmospheric pressure). Further distillation under reduced pressure afforded 4,4-dimethoxytetrahydro-(4H)-thiopyran (20.7 g, 99%). 1H NMR (DMSO) δ 3.07 (s, 6H), 2.56 (m, 4H), 1.84 (m, 4H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[I:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: Nc1ccc(C(F)(F)F)cc1I
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C(F)(F)F)cc1I
Temperature: 105 °C
Yield: 32.3 %

Procedure:
A mixture of 2-iodo-4-(trifluoromethyl)benzenamine (11.0 g, 0.0382 mol), pyridine (40 ml), methanesulfonylchloride (5.3 g, 0.046 mol) and DMAP (0.46 g, 0.0038 mol) in a 100 ml RB flask was heated slowly to 105° C. and maintained the same temperature for over night. The reaction mixture was concentrated to remove the pyridine. The crude product obtained was purified by column chromatography using 10% ethyl acetate in pet ether as eluent to get N-(2-iodo-4-(trifluoromethyl)phenyl)methanesulfonamide (4.5 g, 32%) as white solid. 1H NMR (400 MHz, CDCl3) δ 3.08 (s, 3H), 6.88 (bs, 1H), 7.65 (d, 1H), 7.75 (d, 1H), 8.07 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:7]([S:8][C:9]([F:12])([F:11])[F:10])=[C:6]([CH:13]=[O:14])[N:5]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:4]=1)#[N:2].[F:27][C:28]([Si](C)(C)C)([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[C:1]([C:3]1[C:7]([S:8][C:9]([F:11])([F:10])[F:12])=[C:6]([CH:13]([OH:14])[C:28]([F:30])([F:29])[F:27])[N:5]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:24])([F:25])[F:23])=[CH:17][C:16]=2[Cl:26])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C=O)c1SC(F)(F)F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C(O)C(F)(F)F)c1SC(F)(F)F
Temperature: 0 °C
Reaction time: 21 h
Yield: 46.6 %

Procedure:
The product of Example 3 (2.0 g, 0.0046 mol) was dissolved in anhydrous tetrahydrofuran (10 mL). Trifluoromethyltrimethylsilane (0.8 mL, 0.0055 mol) was added and the reaction cooled to 0° C. Tetrabutylammoniumfluoride (TBAF, 50 μL, cat.) was added. After intervals of 20 minutes, 1.5 hours, and 18 hours, aliquots of TBAF (50 μL) were added at 0° C. followed by warming to room temperature. After 21 hours, more trifluoromethyltrimethylsilane (0.8 mL, 0.0055 mol) was added and the reaction stirred for 5 days. This was poured into 10% hydrochloric acid (100 mL) and washed with diethyl ether (3×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to an oil. This was purified by silica gel chromatography using an ethyl acetate in hexanes gradient to provide the title compound (1.08 g) as a white solid, m.p. about 106° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(Cl)Cl>O>[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[C:20]([C:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:21]
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Solvent: O
Solvent: ClCCl
Product: COc1c(C)cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (ice bath) mixture of 10.5 g. (0.054 mol.) of 2-phenylbenzofuran and 11.5 g (0.058 mol.) of 3,5-dimethyl-4-methoxybenzoyl chloride in 100 ml. of methylene chloride is added dropwise 28.7 g. (0.11 mol.) of stannic chloride. The reaction mixture is allowed to warm to ambient temperature, then stirred for two hours. Water is slowly added to the mixture and it is stirred an additional 30 minutes. The layers are separated and the organic phase is washed with water until the washings are neutral, dried (MgSO4) and concentrated to give 3-(3,5-dimethyl-4-methoxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)(Cl)Cl>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)NCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21

Procedure:
Using the general method of Example 242, except that chloroform was used in place of dichloromethane, 1-(3-aminopropyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.32 mmol) was reacted with methanesulfonyl chloride (3+ g) to provide 1.38 g of N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide as a solid, m.p. 176-178° C. Analysis: Calculated for C23H27N5O3S: % C, 60.91; % H, 6.00; % N, 15.44; Found: % C, 60.71; % H, 5.98; % N, 15.45.