Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:11][C:12]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Cc1ccc(F)cc1
Product: CC(=O)Cc1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred flask of chlorosulphonic acid (344 g, 2.96 mol) cooled to −10° C. is added dropwise 1-(4-fluoro-phenyl)-propan-2-one (10 g, 65 mmol). The reaction mixture is left stirring at room temperature overnight and then poured carefully onto ice. The resultant solution is extracted with ethyl acetate and the organic extracts combined, dried (MgSO4) and concentrated in vacuo to yield the titled compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[S:32][C:28]=3[CH:27]=2)=[O:25])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(#N)C.O>[CH3:36][C:34]1[C:29]2[NH:30][C:31](=[O:33])[S:32][C:28]=2[CH:27]=[C:26]([C:24]([C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:19]=2)=[O:25])[CH:35]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2sc(=O)[nH]c12
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2sc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.23 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 70.6 mg (0.23 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-4-methyl-3H-benzothiazol-2-one and 0.05 mL (0.27 mmol) DIPEA were combined in 2 mL DMF and shaken overnight at RT. The reaction mixture was taken up in acetonitrile/water and purified by preparative HPLC. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Li+].[OH-].[N+](C1C=CC(C([O:12][C@H:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([C:22]4[CH:47]=[CH:46][C:25]5[C:26]([CH:29]([C:39]6[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=6)[CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:27][S:28][C:24]=5[CH:23]=4)[C:16]=3[C@H:15]([CH3:48])[CH2:14]2)=O)=CC=1)([O-])=O>C1COCC1>[Cl:45][C:42]1[CH:41]=[CH:40][C:39]([CH:29]([C:26]2[C:25]3[CH:46]=[CH:47][C:22]([C:21]4[C:16]5[C@H:15]([CH3:48])[CH2:14][C@@H:13]([OH:12])[C:17]=5[N:18]=[CH:19][N:20]=4)=[CH:23][C:24]=3[S:28][N:27]=2)[CH2:30][NH:31][C:32](=[O:33])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:44][CH:43]=1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(-c3ccc4c(C(CNC(=O)OC(C)(C)C)c5ccc(Cl)cc5)nsc4c3)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc4c(C(CNC(=O)OC(C)(C)C)c5ccc(Cl)cc5)nsc4c3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
1 N LiOH aqueous solution (0.30 mL, 0.30 mmol) was added to a stirred solution of (5R,7R)-4-(3-(2-(tert-butoxycarbonylamino)-1-(4-chlorophenyl)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (102 mg, 0.149 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The resulting residue was purified by column chromatography (DCM:MeOH, 60:1) to give tert-butyl 2-(4-chlorophenyl)-2-(6-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzo[d]isothiazol-3-yl)ethylcarbamate (62 mg, 78%) as an oil. LCMS (APCI+) m/z 537, 539 [M+H]+; Rt=3.99 min.
Reaction SMILES: F[C:2]1C(F)=C(F)C(F)=C(F)N=1.F[C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[N+:14]=1[O-:23].C[Mg]I.[Cl-].[NH4+]>C(OCC)C>[CH3:2][C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[N+:14]=1[O-:23]
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: [O-][n+]1c(F)c(F)c(F)c(F)c1F
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1c(F)c(F)c(F)c(F)[n+]1[O-]

Procedure:
2,3,4,5,6-Pentafluoropyridine (commercially available from Aldich Chemical Co.) is oxidized to the corresponding N-oxide following the procedures described in Step 6 of Example 66. The 2,3,4,5,6-pentafluoropyridine N-oxide is treated at ambient temperature with one equivalent of methylmagnesium iodide in diethyl ether as described by F. Binns and H. Suschitsky in Chemical Communications, 750-751 (1970) and J Chem Soc (C), 1223-1231 (1771). The reaction mixture is treated with aqueous ammonium chloride and extracted with diethyl ether. The ether solution is dried over anhydrous magnesium sulfate, filtered and concentated under reduced pressure and the crude product is chromatographed on silica gel to afford 2-methyl-3,4,5,6-tetrafluoropyridine N-oxide (3,4,5,6-tetrafluoro-2-picoline). The N-oxide is then reduced to afford the title compound by the procedures described in Step 8 of Example 66.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[I-].[Na+].[CH3:39][NH:40][CH3:41]>CN(C=O)C>[CH3:39][N:40]([CH3:41])[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6]
Reactant: CNC
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1
Yield: 46.8 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indazole-7-carboxamide (Example 48a) (0.076 mmol) in DMF (4 mL) was reacted with K2CO3 (22 mg, 0.16 mmol), sodium iodide (2 mg) and dimethyl amine (0.2 mL, 0.4 mmol) to afford the title compound (16.9 mg, 47%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)=[CH:11][CH:10]=1.[CH2:26]([O:33][C:34]([C@@H:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C:41](O)=[O:42])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CCO.Cl.CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O.[Pd]>[CH2:26]([O:33][C:34]([C@@H:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C:41](=[O:42])[NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:10][CH:11]=2)[CH:18]=1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Reactant: O=C(O)[C@@H]1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(Nc1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1)[C@@H]1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A mixture of 2,4-difluoro-4′-(3-nitro-benzyloxy)-biphenyl (26.3 mg, 0.077 mmol) and 10% Pd/C (5.3 mg) in EtOH (3 mL) containing 2 drops 2N HCl was hydrogenated at 50 psi for 2 hrs. The reaction mixture was filtered and evaporated. The crude product was dissolved in DMF (1 mL) with rac-(trans)-cyclopentane-1,2-dicarboxylic acid monobenzyl ester (19.5 mg, 0.77 mmol), triethylamine (32 uL, 0.231 mmol) and BOP (33 mg, 0.077 mmol). The mixture was stirred for 1 hr at RT. DMAP (1 mg) was added and stirring continued overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with 2.5% KHSO4 (3×10 mL), 50% saturated NaHCO3 (10 mL), saturated NaCl (10 mL), dried over MgSO4, filtered and evaporated. The crude ester was purified by flash chromatography with a 0-20% gradient of ethyl acetate in hexanes to yield 18.3 mg of (trans)-2-[3-(2′,4′-difluoro-biphenyl-4-yloxymethyl)-phenylcarbamoyl]-cyclopentanecarboxylic acid benzyl ester as a clear oil. This material was dissolved in EtOH (3 mL) with 10% Pd/C (4 mg) and hydrogenated at 50 psi for 1 hr. The reaction mixture was filtered through Celite and evaporated to give (trans)-2-[3-(2′,4′-difluoro-biphenyl-4-yloxymethyl)-phenylcarbamoyl]-cyclopentanecarboxylic acid as a white solid (16.4 mg, 47%). LC-MS (ES) calculated for C26H23F2NO4, 451.47; found m/z 450.2 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([CH:14]3[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:25][CH3:26])[C:3]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.[CH2:38]([Mg]Br)[CH3:39]>C1COCC1>[C:21]([O:20][C:18]([N:16]1[CH2:17][CH:14]([C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:25][CH3:26])[C:3]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][CH:29]=2)=[C:2]3[Cl:1])([OH:13])[CH2:38][CH3:39])[CH2:15]1)=[O:19])([CH3:22])([CH3:24])[CH3:23]
Reactant: CC[Mg]Br
Reactant: COc1nc2ccc(C(=O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CCC(O)(c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1)C1CN(C(=O)OC(C)(C)C)C1

Procedure:
To a flask containing tert-butyl-3-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-6-carbonyl)azetidine-1-carboxylate (250 mg, 0.47 mmol, Intermediate 13: step b) was added THF (8 mL) to give a homogeneous solution. The solution was cooled in an ice-water bath and ethylmagnesium bromide (3 M in Et2O, 0.3 mL, 0.9 mmol) was introduced. After 35 minutes the reaction mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc, (4×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness to afford a colorless gum. Chromatography on silica gel (5% EtOAc-DCM increasing to 1% MeOH-DCM) provided the title compound as a white amorphous solid. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=2.0 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.60 (dd, J=8.7, 2.1 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 4.35 (s, 2H), 4.16-4.08 (m, 1H), 4.07 (s, 3H), 4.00 (t, J=8.5 Hz, 1H), 3.71-3.53 (m, 2H), 3.20-3.07 (m, 1H), 2.13 (s, 1H), 1.97-1.74 (m, 2H), 1.41 (s, 9H), 0.73 (t, J=7.4 Hz, 3H); MS (ESI): mass calcd. for C29H32ClF3N2O4, 564.2, m/z found 565.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH2:39][CH3:40]>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]([CH2:39][CH3:40])[C:27](=[O:31])[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(=O)n2CC)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 16 h
Yield: 16.8 %

Procedure:
To N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (11 mg, 0.027 mmol; prepared as in Example 17, Step A) in DMF (2 mL) was added K2CO3 (7.4 mg, 0.053 mmol) and iodoethane (21 mg, 0.13 mmol). The reaction mixture was stirred for 16 hours and then concentrated under reduced pressure to remove DMF. Silica gel chromatography (DCM/MeOH 10:1) gave the final product (2 mg). MS (ES+APCI) m/z=441 (M+H). The O-alkylated product was also isolated (See Example 27).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH:35]([OH:39])[CH2:36][NH:37][CH3:38])=[CH:34][C:29]=2[O:28][CH2:27]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH:35]([OH:39])[CH2:36][N:37]([CH2:20][C:18]3[S:19][C:12]4[C:11](=[O:23])[C:10]([C:8]([NH:7][CH2:6][C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=5)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=4[C:17]=3[CH3:22])[CH3:38])=[CH:34][C:29]=2[O:28][CH2:27]1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccc2c(c1)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccc3c(c2)OCO3)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 7 h
Yield: 72.9 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-(1,3-benzodioxol-5-yl)-2-(methylamino)ethanol (Journal of Organometallic Chemistry, 1998, 339, 267-75) (74 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (101 mg) as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[C:18]1([C:24]2[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[S:26][N:25]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:28]=2)[CH2:30][CH2:31]1)=[O:9])([CH3:2])[CH3:3]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 69 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 3-phenyl-5-piperazino-1,2,4-thiadiazole. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white crystalline solid (yield 69%). MS (m/e): 487.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](=[O:14])[CH3:13])=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:15].C(=O)CC.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](=[O:14])[CH:13]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:15]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc2c(c1)SCC(=O)N2C
Solvent: CCC=O
Product: CN1C(=O)CSc2cc(C(=O)C=Cc3ccccc3)ccc21

Procedure:
Using the procedure described in Preparation 3, but replacing 3-methyl-6-acetylbenzoxazolin-3-one by 4-methyl-7-acetyl-2,3-dihydro-4H-1,4-benzothiazin-3-one and propionaldehyde by benzaldehyde, the product of the title is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CCCCCCCCCC(=O)NCCN=[N+]=[N-]
Product: CCCCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.114 g, 0.412 mmol) was reacted with N-(2-azidoethyl)decanamide (0.099 g, 0.412 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-decanamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), δ 6.57 (s, 1H), δ 6.43 (s, 1H), δ 6.09 (s, 2H), δ 4.38 (s, 2H), δ 3.67 (s, 2H), δ 2.61 (t, 2H), δ 2.08 (s, 2H), δ 2.08 (t, 2H), δ 1.42 (m, 15H), δ 1.17 (m, 14H), δ 0.79 (t, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.2, 149.7, 148.4, 138.8, 121.9, 106.6, 84.9, 49.5, 39.5, 36.7, 32.1, 31.3, 30.6, 29.9, 29.7, 29.6, 29.5, 29.5, 29.3, 29.0, 28.3, 28.2, 25.9, 25.6, 25.5, 22.9, 14.3 ppm; HRMS (ESI) calcd for C27H47N7O3(M+) 517.3740. Found 517.3736, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)decanamide hydrochloride (0.137 g, 73% yield). 1H NMR (300 MHz, CD3OD) δ 8.55 (s, 1H), δ 6.53 (s, 1H), 4.72 (s, 2H), δ 3.75 (s, 2H), 2.89 (s, 2H), δ 2.54 (t, 2H), δ 2.16 (t, 2H), δ 1.81 (s, 2H), δ 1.69 (s, 2H), δ 1.49 (m, 4H), δ 1.28 (s, 12H), δ 0.89 (t, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 175.7, 147.3, 128.5, 127.6, 125.1, 120.8, 108.6, 108.4, 105.6, 63.1, 59.3, 52.5, 48.6, 48.3, 48.1, 47.9, 47.7, 47.5, 57.3, 38.7, 336.6, 35.8, 36.6, 35.8, 31.8, 30.6, 29.4, 29.3, 29.3, 29.2, 28.0, 27.8, 27.7, 25.8, 24.1, 23.9, 23.3, 22.6 ppm; HRMS (ESI) calcd for C22H39N7O (M+) 417.3216. Found 417.3209.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:11]=[C:12]([CH:19]3[CH2:21][CH2:20]3)[C:13]=2[O:14][C:15]([F:18])([F:17])[F:16])[C:7](OC)=[O:8])[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=[C:12]([CH:19]3[CH2:21][CH2:20]3)[C:13]=2[O:14][C:15]([F:17])([F:18])[F:16])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(C2CC2)c(OC(F)(F)F)c(C2CC2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCc1cc(C2CC2)c(OC(F)(F)F)c(C2CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
Methyl 3,5-dicyclopropyl-4-(trifluoromethoxy)benzoate (259 mg, 0.863 mmol) was dissolved in DCM (8.6 mL) and the mixture was cooled to 0° C. DIBAL in toluene (1.73 mL, 1.73 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with the addition of 3N HCl and water. The mixture was stirred vigorously for 30 minutes and extracted with DCM. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/hexanes) to yield the title compound as a clear oil (190 mg).
Reaction SMILES: [OH-:1].[Na+].Cl[CH2:4][C:5]1[C:14]2[C:9](=[C:10]([CH3:16])[C:11]([OH:15])=[CH:12][CH:13]=2)[O:8][C:7](=[O:17])[CH:6]=1.Cl>>[OH:15][C:11]1[CH:12]=[CH:13][C:14]2[C:5]([CH2:6][C:7]([OH:17])=[O:1])=[CH:4][O:8][C:9]=2[C:10]=1[CH3:16]
Reactant: Cc1c(O)ccc2c(CCl)cc(=O)oc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1c(O)ccc2c(CC(=O)O)coc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 1M NaOH (89 mL) and 4-(chloromethyl)-7-hydroxy-8-methyl-2H-chromen-2-one (4.0 g) was stirred at 100° C. for 1 h. After cooling, the reaction mixture was acidified with 6N HCl. The precipitate was collected by filtration, and washed with water and hexane to give the title compound (2.62 g). The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The solid was washed with hexane to give the title compound (831.4 mg). Total yield: 3.45 g.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH:28]=5)[CH:20]=[CH:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1>[Pd].C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]5)[CH:20]=[CH:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(C3=CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Temperature: 40 °C

Procedure:
A mixture of tert-butyl 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (125 mg, 0.266 mmol) and palladium on activated carbon, reduced 10% (28 mg, 0.0266 mmol) in ethanol 10.0 mL was stirred under H2 balloon at 40° C. 18 h. The reaction was filtered through celite and wash with MeOH. The crude product was carried to next step.
Reaction SMILES: C[O:2][C:3](=[O:48])[CH2:4][C@H:5]([C:25]1[S:26][C:27]([C:30]2[C:38]3[C:33](=[N:34][CH:35]=[CH:36][CH:37]=3)[N:32](S(C3C=CC=CC=3)(=O)=O)[CH:31]=2)=[CH:28][CH:29]=1)[NH:6][C:7]([C:9]1[C:10](=[O:24])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)=[O:8].C(Cl)Cl>C[O-].[Na+].CO>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[CH2:15][N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]([NH:6][C@@H:5]([C:25]2[S:26][C:27]([C:30]3[C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:32][CH:31]=3)=[CH:28][CH:29]=2)[CH2:4][C:3]([OH:48])=[O:2])=[O:8])[C:10]1=[O:24]
Reactant: COC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)s1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1

Procedure:
(R)-3-[5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-yl]-3-{[1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-propionic acid methyl ester (0.050 g, 0.000072 mol;) was dissolved in 0.5 M of Sodium methoxide in methanol (3 mL) and Methylene chloride (3 g, 0.04 mol;). The reaction was heated at 75 C for 1 hour. LC-MS showed the disappearance of starting material and the appearance of product at 1.25 535.55. Some methyl ester and acid were seen but by the time it was injected on gilson only acid was present. The reaction was concentrated and dissolved in DMSO and methanol 1:1 for purification by Gilson Preparative HPLC. Pure fractions were combined and concentrated. ES (+) MS m/e=535.55; NMR (400 MHz, DMSO-d6) δ ppm 2.98 (d, 2H, J=7 Hz), 5.22 (s, 2H,), 5.66 (m, 1H), 6.66 (t, 1H, J=8 Hz), 7.03 (d, 1H, J=3 Hz), 7.14-7.20 (m, 2H), 7.22 (d, 1H, J=4 Hz), 7.38-7.49 (m, 2H), 7.81 (m, 1H), 8.2-8.25 (m, 2H), 8.29 (m, 1H), 8.4 (dd. 1H), 10.27 (d, 1H)
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[CH:3][C:4]#[N:5].[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28](=O)[CH2:29][C:30](OCC)=[O:31])=[CH:24][CH:23]=1)([O-:21])=[O:20]>CN(C)C(=O)C>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[NH:1][C:2]([C:6]3[CH:11]=[CH:10][C:9]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:8][CH:7]=3)=[C:3]([C:4]#[N:5])[C:30](=[O:31])[CH:29]=2)=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: N#CC=C(N)c1ccc(Oc2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)[nH]c(-c2ccc([N+](=O)[O-])cc2)cc1=O
Temperature: 25 °C
Yield: 120.7 %

Procedure:
A mixture of 3-amino-3-(4-phenoxyphenyl)acrylonitrile (101 mg, 0.427 mmol) and ethyl 3-(4-nitrophenyl)-3-oxopropanoate (312.8 mg, 1.319 mmol) in N,N-dimethylacetamide (1 mL) was microwaved at 230° C. for 20 min, cooled to room temperature, and concentrated. Silica gel chromatography, eluting with 0-5% methanol in dichloromethane, gave 6-(4-nitrophenyl)-4-oxo-2-(4-phenoxyphenyl)-1,4-dihydropyridine-3-carbonitrile as brown solid (211 mg, 100% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (2H, δ, J=8.78 Hz), 8.19 (2H, br. s), 7.96 (2H, br. s), 7.39 (2H, t, J=7.91 Hz), 7.18 (1H, t, J=7.40 Hz), 7.06-7.13 (3H, m); MS (ES+) m/z: 410 (M+H); LC retention time: 4.275 min (analytical HPLC Method A).