Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([S@@]([NH:6][C@@H:7]([C:9]1[N:10]([S:21]([C:24]2[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:11]=[CH:12][C:13]=1[C:14](OC(C)(C)C)=[O:15])[CH3:8])=O)C.Cl.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C>O1CCOCC1.CN(C=O)C.C(Cl)Cl>[CH3:8][C@@H:7]1[C:9]2[N:10]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:11]=[CH:12][C:13]=2[C:14](=[O:15])[NH:6]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)OC(C)(C)C)c2[C@@H](C)N[S@@](=O)C(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2[C@@H](C)NC3=O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To tert-butyl 2-((R)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)-1-tosyl-1H-pyrrole-3-carboxylate (287b, 0.55 g, 1.17 mmol) in 4 mL of dioxane under N2 was added hydrogen chloride (Aldrich, St. Louis, Mo.; 4.40 ml of 4.0 M solution in 1,4-dioxane, 17.60 mmol). The homogeneous reaction was sealed and allowed to stir overnight. The reaction was concentrated in vacuo to give a foam. This material was treated with 3 mL DCM and TFA (Aldrich, St. Louis, Mo.; 2.62 mL, 35.2 mmol) and fitted with a drying tube. After 5 h, the stir bar was removed and the reaction was concentrated in vacuo and placed on hood pump overnight, to give a light yellow solid. The solid was treated with 5 mL DCM and 5 mL DMF and cooled to 0° C. DIEA (Aldrich, 1.23 mL, 7.04 mmol) was added dropwise via syringe to give a solution, and PyBoP (Aldrich, 0.73 g, 1.41 mmol) was added in one portion. The ice bath was removed and the reaction warmed to RT. After 1 h, the reaction was treated with ice and saturated aq. NaHCO3. The reaction was partitioned between saturated aq. NaHCO3 and Et2O (slightly cloudy). The aq. layer was extracted 1× Et2O, and the combined organic layers were washed with water 2 times, saturated aq. NaCl once, and the organics (rinsed some undissolved solid into organics from sep funnel with DCM) were dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (40 g ISCO gold column) using 0-100% EtOAc/hexanes. The product-containing fractions were concentrated to afford (R)-6-methyl-1-tosyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (287c; 0.194 g, 0.67 mmol, 57% yield) as a white foam. 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.2 Hz), 7.16 (1H, d, J=3.1 Hz), 6.48 (1H, d, J=3.1 Hz), 5.76 (1H, br. s.), 4.68 (1H, q, J=6.6 Hz), 2.45 (3H, s), 1.62 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 291.0 (M+H)+.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[C:4]1([CH:3]=[CH:2][CH:1]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[N+]([O-])=CC=Cc1ccccc1
Temperature: 5 °C
Reaction time: 144 h

Procedure:
To a suspension of cinnamaldehyde (769.8 mg, 5.82 mmol), 1,1-dimethylnitroethane (1.20 g, 11.6 mmol) and zinc (1.14 g, 17.4 mmol) in ethanol (30 ml) was added acetic acid (2.10 g, 35.0 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 3 hours and let stand for 6 days. After cooling the mixture to 5° C., zinc acetate was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=1/1-0/1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH:23][CH2:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH3:22][N:23]([CH2:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=1)[C:18]([CH:16]1[CH2:15][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:17]1)=[O:19]
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: CNCc1ncccc1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cccnc1CN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added methyl-(3-methyl-pyridin-2-ylmethyl)-amine (176 mg, 1.29 mmol) and T3P (50% solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound 127 mg, 46% yield). Rf=0.30 (15% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C24H30Cl N3 O2, 427.9, found, 428.2 (M+1) APCI; 400 MHz 1H NMR (CDCl3) 2:1 mixture of rotomers, diagnostic peaks, δ 4.72, 4.53 (s, 2H), 3.72 & 3.70 (s, 2H), 2.97, 2.93 (s, 3H), 1.76-1.74 (m, 4H); 100 MHz 13C NMR (CDCl3) 2:1 mixture of rotomers, diagnostic peaks δ 177.6, 175.7, 154.7, 153.6, 146.8, 146.6, 126.5, 126.4, 122.8, 122.7, 73.4, 73.2, 56.7, 56.6, 54.3, 54.2, 51.1, 41.4, 40.9, 35.6, 35.4, 28.9, 28.7, 23.7, 23.6, 18.3, 18.2.
Reaction SMILES: C([O:4][C:5]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][CH:6]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[OH:4][C:5]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][CH:6]=1
Reactant: CC(=O)Oc1coc(-c2ccccc2)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=c1cc(-c2ccccc2)occ1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-oxo-6-phenyl-4H-pyran-3-yl acetate (100 mg, 0.4 mmol) in MeOH (10.9 mL) is added K2CO3 (180 mg, 1.3 mmol) and the reaction was stirred for 15 min at room temperature. The reaction mixture was concentrated under reduced pressure to provide 5-hydroxy-2-phenyl-4H-pyran-4-one which was used in the subsequent step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([O-])=O.O.NN>CO>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a solution of tert-butyl (2-nitro-4-(thiophen-2-yl)phenyl)carbamate (1.6 g, 4.99 mmol, 1 eq.) in methanol (20 mL) was added hydrazine hydrate (14 mL) and ferric chloride (0.05 g, 0.3 mmol, 0.06 eq.). The resulting mixture was warmed to 60° C. and stirred for 2 h. The reaction was then filtered through Celite, the solids were washed with MeOH. The filtrate was concentrated under reduced pressure. Water was added to the residue and the suspension was stirred for 1 h. The obtained solid was filtered, washed with hexanes then dried to yield tert-butyl (2-amino-4-(thiophen-2-yl)phenyl)carbamate (1.2 g, 83% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][C:20](OC)=[O:21])=[CH:11][CH:10]=1.O.[H-]>CCOCC>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][CH2:20][OH:21])=[CH:11][CH:10]=1
Reactant: COC(=O)Cc1cccc2ccc(OC)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc2cccc(CCO)c2c1

Procedure:
3.34 g of lithium aluminum hydride are placed in a 250-cm3 flask, and ether is added gently with stirring. Using a dropping funnel, 5 g of methyl (7-methoxy-1-naphthyl)acetate previously dissolved in 50 cm3 of ether are added slowly. The reaction medium is left stirring for 30 minutes. It is poured very slowly into a mixture of water and ice so as to hydrolyze the excess unreacted hydride. The reaction medium is filtered. The aqueous phase is extracted with 3 times 50 cm3 of ether, and the ether phases are dried over magnesium sulfate and evaporated. The white solid obtained is recrystallized.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7]P(=O)(OCC)OCC)=[CH:5][CH:4]=1.[C:18]1([CH3:40])[CH:23]=[CH:22][C:21]([N:24]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[CH:20][CH:19]=1.C(O[K])(C)(C)C.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:39][C:36]2[CH:35]=[CH:34][C:33]([N:24]([C:25]3[CH:32]=[CH:31][C:28]([CH3:29])=[CH:27][CH:26]=3)[C:21]3[CH:22]=[CH:23][C:18]([CH3:40])=[CH:19][CH:20]=3)=[CH:38][CH:37]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=O)cc2)cc1
Reactant: CCOP(=O)(Cc1ccc(OC)cc1)OCC
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=Cc2ccc(N(c3ccc(C)cc3)c3ccc(C)cc3)cc2)cc1

Procedure:
Same mol of the diethyl 4-methoxybenzylphosphonate and 4-(di-para-tolylamino)benzaldehyde were dissolved in N.N-dimethylformamide, and tert-butoxy kalium was gradually added to the solution while water-cooled and stirred. After stirred for 5 hrs at a room temperature, water was added thereto to acidize the solution and a crude product is separated out. The crude product was further column-refined with silica gel to prepare 4-methoxy-4′-(di-para-tolylamino)stilbene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O1CCCC1.CN(C)C1C=CN=CC=1>[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[N:34]([C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)CCc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 3-methoxy-4-[3-o-tolyl-ureido]phenylacetic acid (0.282 g, prepared as described in Example 52B of International Patent Application Publication No. WO 96/22966) in anhydrous tetrahydrofuran (5 ml), under an atmosphere of argon and at 25° C., was treated with powdered molecular sieves 4 Å (0.5 g), 7-(2-ethoxycarbonyl-ethyl)-1,2,3,4-tetrahydro-quinoxaline-1-carboxylic acid tert-butyl ester (0.2 g, Reference Example 3), triethylamine (0,336 ml), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.273 g) and 4-dimethylaminopyridine (7 mg). After stirring at 25° C. for 3 hours the reaction mixture was filtered through a pad of celite and the filter pad was washed three times with ethyl acetate (10 ml). The combined filtrate and washings were washed twice with an aqueous saturated solution of ammonium chloride (20 ml), then with water (20 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting white foamy solid (0.483 g) was subjected to flash chromatography on silica (0,040-0,063 mm) eluting with a mixture of cyclohexane and ethyl acetate (1:1, v/v) to give the title compound (0.3 g) as a white foamy solid. 1H NMR, 400 Hz, (CD3)2SO: δ1.2 (t, 3H); 1.5 (s, 9H); 2.3 (s, 3H); 2.65 (t, 2H); 2.9 (t, 2H); 3.65 (t, 2H); 3.85 (m, 7H); 4.1 (q, 2H); 6.7 (very broad s, 2H); 7.2 (m, 2H); 7.5 (very broad s, 1H); 7.65 (broad s, 1H); 7.8 (d, J=8 Hz, 1H); 8.05 (broad d, J=8 Hz, 1H); 8.5 (s, 1H); 8.6 (broad s, 1H). MS (CI, NH3): MNH4+ 648, MH+ 631.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[N:20][C:15]=2[NH:14][CH:13]=1.C(=C/C(/C=C/C1C=CC=CC=1)=O)\C1C=CC=CC=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N.O.C(O)(C(F)(F)F)=O>C1(C)C(C)=CC=CC=1.[OH-].[Na+]>[N:12]1[C:16]2[C:15](=[N:20][CH:19]=[CH:18][CH:17]=2)[N:14]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)[CH:13]=1
Reactant: c1cnc2[nH]cnc2c1
Reactant: O=C(O)Cc1ccc(I)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Temperature: 125 °C
Reaction time: 80 h

Procedure:
A mixture of 400 mg of 4-iodophenylacetic acid, 273 mg of 4-azabenzimidazole, 17.9 mg of trans,trans-dibenzylideneacetone, 303 mg of 1,10-phenanthroline, 19.2 mg of copper (I) trifluoromethanesulfonate benzene complex and 547 mg of Cs2CO3 in 1.5 ml of xylene is stirred for 80 hours at 125° C. The mixture obtained is allowed to cool to rt and concentrated in vacuo. The concentration residue obtained is dissolved in aqueous 1N NaOH solution and extracted with EtOAc. To the aqueous layer aqueous 1N HCl is added in order to obtain an acidic pH and the mixture obtained is extracted with CH2Cl2. The organic phase obtained is dried (Na2SO4), filtered and concentrated. The concentration residue obtained is subjected to reversed phase MPLC(CH3CN/H2O/TFA). (4-Imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17](O)([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[O:10][C:3]=12.[CH3:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:31][C:30]3[C:22]([CH3:21])=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)[CH:8]=2)=[CH:12][CH:13]=1)([CH3:19])=[CH2:18]
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: CC(C)(O)c1ccc(-c2cc3nccc(Cl)c3o2)cc1
Product: C=C(C)c1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)cc1

Procedure:
The title compound was prepared by procedure E using 2-[4-(7-chlorofuro[3,2-b]pyridin-2-yl)phenyl]propan-2-ol (29.50 mg; 0.10 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (15.74 mg; 0.11 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (26 mg, 66%). (HPLC (method F): 93%, RT: 4.44 min); 1H NMR (500 MHz, DMSO-d6) δ[ppm] 11.14 (s, 1H), 8.57 (s, 1H), 7.99-7.90 (m, 3H), 7.62 (d, J=8.5, 2H), 7.44 (s, 1H), 7.38 (t, J=2.7, 1H), 7.31 (d, J=8.4, 1H), 7.01 (d, J=8.4, 1H), 6.52 (s, 1H), 6.09 (d, J=5.5, 1H), 5.55 (s, 1H), 5.18 (s, 1H), 2.36 (s, 3H), 2.16 (s, 3H); MS (m/z) 380 [M+H]+, RT: 4.4 min.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)([Cl:22])=O>>[CH2:4]([O:3][C:1]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([Cl:22])=[O:19])[CH2:13][CH2:12]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Piperidine-1,4-dicarboxylic acid monobenzyl ester (VI) (5.0 g, 19 mmol) was suspended in thionyl chloride (10 ml) and stirred at room temperature for one hour. Excess thionyl chloride was distilled out and the obtained crude 4-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (VII) was used for the next reaction immediately.
Reaction SMILES: [CH3:1][NH2:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1>CC(C)=O>[CH3:1][NH:2][CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNCc1cc([N+](=O)[O-])nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a stirred solution of MeNH2 (30% wt in water) (2.5 g, 20 mmol) in acetone (10 mL) at 0° C. (ice bath) was added K2CO3 (415 mg, 3 mmol), followed by the dropwise addition of a solution of 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (220 mg, 1 mmol) in acetone (5 mL). The reaction mixture was then warmed to room temperature and stirred for 3 h. The solvent was removed and the residue was extracted with methylene chloride (3×15 mL), dried over Na2SO4 and concentrated to afford 302a as a yellow oil (170 mg, 99%), which was used in the next step without additional purification. LCMS: (M+H)+ 171
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6](=[O:14])[C:5]2[N:15]([CH3:18])[N:16]=[CH:17][C:4]1=2)[CH3:2].CS(OC1C[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:18][N:15]1[C:5]2[C:6](=[O:14])[C:7]3[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][C:12]=3[N:3]([CH:1]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:2]3)[C:4]=2[CH:17]=[N:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2C1CCNCC1
Temperature: 85 °C
Yield: 35.2 %

Procedure:
A mixture of 1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 47, step 2, 0.1 g, 0.47 mmol), tert-butyl 4-[(methylsulfonyl)oxy]-1-piperidinecarboxylate ((Leeson et al., Bioorg. Med. Chem. Lett., 1999, 9, 1285), 0.66 g, 2.4 mmol) and potassium carbonate (0.13 g, 0.94 mmol) in dimethylsulfoxide (15 ml) was heated at 85° C. for 46.5 h. The reaction mixture was diluted with toluene/ethyl acetate (1:3, 30 ml), washed with water (30 ml), and dried over sodium sulfate. Removal of solvent gave a residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:1) to afford 49 mg (26%) of the title compound as a pale brown solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:33][CH2:34][NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:38]([O:37][C:36](=[O:45])[NH:35][CH2:34][CH2:33][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: Oc1ccc(-n2cccn2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCOc1ccc(-n2cccn2)cc1)OCc1ccccc1
Temperature: 0 °C

Procedure:
A round-bottomed flask was charged with 4-pyrazole-1-yl-phenol (175 mg, 1.09 mmol), and 3.6 ml of toluene, triphenylphosphine (430 mg, 1.64 mmol), and benzyl N-(2-hydroxyethyl)carbamate (320 mg, 1.64 mmol) were then added. The solution was cooled to 0° C. and 1,1′-(azodicarbonyl)-dipiperidine (414 mg, 1.64 mmol) was added. The mixture was allowed to stir for about ten minutes at about 0° C. and was then allowed to warm to room temperature. An additional 3.6 ml of toluene and 3.6 ml of tetrahydrofuran were added to the viscous solution. The reaction mixture was stirred for about forty-eight hours, and the precipitated solids were filtered off and washed with a minimum volume of 1:1 toluene/tetrahydrofuran. The filtrate was concentrated in vacuo to afford the intermediate [2-(4-pyrazole-1-yl-phenoxy)-ethyl]-carbamic acid benzyl ester as an oil which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@H]1CCNC1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Temperature: 140 °C

Procedure:
5-Bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 185.2, 206 mg, 0.5 mmol) and (S)-pyrrolidin-3-ol (52.3 mg, 0.6 mmol) were dissolved in iPrOH (0.5 mL). DIPEA (192 μL, 1.1 mmol) was added and the RM mixture was heated at 140° C. for 1 h in a pressure safe vial. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give residue that was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 20% to 100% EtOAc). Trituration with n-heptane, filtered and dried afforded the title compound as a white crystalline powder. HPLC (Condition 4) tR=5.89 min, UPLC-MS (Condition 3) tR=1.20 min, m/z=464.1 [M+H]+.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]=1[CH2:7][OH:8].[CH:13]([C:15]1[O:16][C:17](B(O)O)=[CH:18][CH:19]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+].N#N>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O.CC(N(C)C)=O>[CH:13]([C:15]1[O:16][C:17]([C:2]2[O:3][C:4]3[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=3[C:6]=2[CH2:7][OH:8])=[CH:18][CH:19]=1)=[O:14]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: OCc1c(Br)oc2ccccc12
Agent: [Pd]
Agent: N#N
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1ccc(-c2oc3ccccc3c2CO)o1
Temperature: 120 °C

Procedure:
To the bromo-benzofuran derivative from Step B (0.1 mmol), 2-formylfuran-5-boronic acid (1.5 equiv.), potassium carbonate (1.5 equiv.), palladium dibenzylidene acetone (0.03 eq.) and degassed dimethylacetamide (1 ml) was added. The mixture was blanketed with N2 and heated in a microwave reactor at 120° C. for 10 mins (initial power 50 W). Water (2 mL) was added, the mixture extracted with ether (4×10 mL), the crude extract adsorbed on silica gel, and purified by MPLC (hexanes/ethyl acetate gradient). MS (m/e): 242 (M+), 225, 213, 196, 185, 168, 157, 139, 128, 102, 77. 1H-NMR (acetone-D6): 5.15 (s, 2H), 7.19 (d, 1H, J=4 Hz), 7.35 (dd, 1H, J=8 Hz, 1 Hz), 7.44 (dd, 1H, J=8 Hz, 1 Hz), 7.56-7.65 (m, 2H), 7.93 (d, 1H, J=8 Hz), 9.76 (s, 1H). 13C-NMR (acetone-D6).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.O.NN>>[NH2:3][O:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(ON)CC1
Yield: 85 %

Procedure:
The title compound was prepared from tert-butyl 4-(1,3-dioxoisoindolin-2-yloxy)piperidine-1-carboxylate and hydrazine monohydrate in 85% yield using the same procedure as described in the synthesis of intermediate G
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:14](=[O:15])[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][S:11][CH2:10]2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[S:26][CH2:27][CH2:28][N:29]=1>CC(C)=O>[S:26]1[CH2:27][CH2:28][N:29]=[C:25]1[NH:24][C:14]1([OH:15])[C:9](=[CH:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH2:10][S:11][CH2:12][C:13]1=[CH:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1
Reactant: NC1=NCCS1
Reactant: Cc1ccc(C=C2CSCC(=Cc3ccc(C)cc3)C2=O)cc1
Solvent: CC(C)=O
Product: Cc1ccc(C=C2CSCC(=Cc3ccc(C)cc3)C2(O)NC2=NCCS2)cc1

Procedure:
To a stirred suspension of tetrahydro-3,5-bis-(4-methylphenylmethylene)-4H-thiopyran-4-one (5 gm; 15.6 mmole) in acetone (150 ml) is added a freshly filtered solution of 2-amino-2-thiazoline (1.9 gm, 18.6 mmole) in acetone (100 ml).