Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1.O1CCOCC1.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]>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Fc1ccccc1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-bromopyridine (3.37 mL, 5.53 g, 35 mmol), 2-fluorobenzeneboronic acid (6.12 g, 43.8 mmol) and potassium fluoride (6.71 g, 116 mmol) in THF (50 mL) was degassed with nitrogen for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (0.64 g, 0.70 mmol) and tri(tert-butyl)phosphine (7 mL of a 0.2 M solution in dioxane, 1.4 mmol) were added. A solid precipitated, giving a thick slurry which was stirred under nitrogen for 15 min, then at 50° C. for 30 min. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium chloride solution, then was dried over magnesium sulfate and pre-adsorbed on to silica gel. Purification by flash chromatography on silica gel eluting with isohexane (+0.5% methanol +0.5% triethylamine) on a gradient of 20% to 40% ethyl acetate afforded 3-(2-fluorophenyl)pyridine as a pale yellow oil, which crystallised upon standing. δH (360 MHz, DMSO) 7.33-7.40 (2H, m), 7.46-7.55 (2H, m), 7.61 (1H, ddd, J 8, 8 and 2), 7.96-8.01 (1H, m), 8.61 (1H, dd, J 5 and 2), 8.77 (1H, s).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:37])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH2:35][NH:34][CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:20][CH2:19]1.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[F:37][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH2:35][N:34]([C:40]([N:39]([CH3:43])[CH3:38])=[O:41])[CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:22][CH2:23]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CCNC4)CC2)c(F)c1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N1CCc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2C1
Reaction time: 8 h

Procedure:
A solution of N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (15 mg, 0.028 mmol) in DCM (278 μL) at room temperature was treated with dimethylcarbamic chloride (3.0 mg, 0.028 mmol) and DIPEA (4.9 μL, 0.028 mmol), and the resulting reaction mixture was stirred overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 nm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (7 mg) as a white solid. 1H NMR (400 MHz, methanol-d4) 6 ppm 1.92-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.81-2.86 (m, 2H), 2.90 (s, 6H), 2.96-3.04 (m, 2H), 3.34-3.42 (m, 2H), 3.54 (t, J=5.9 Hz, 2H), 3.74-3.84 (m, 2H), 4.28 (s, 2H), 4.46 (tt, J=7.7, 3.9 Hz, 1H), 5.90-6.22 (m, 1H), 6.88 (dddd, J=9.1, 8.1, 3.2, 1.9 Hz, 1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 497.4.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH2:17]([O:20][C:21]1[CH:31]=[CH:30][C:24]([CH:25]=[CH:26][C:27](O)=O)=[CH:23][CH:22]=1)[CH2:18][CH3:19]>>[CH2:17]([O:20][C:21]1[CH:22]=[CH:23][C:24](/[CH:25]=[CH:26]/[C:27]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[CH:30][CH:31]=1)[CH2:18][CH3:19]
Reactant: CCCOc1ccc(C=CC(=O)O)cc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCOc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(CCC)c(=O)n3CCC)cc1
Yield: 32.4 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.01 g (14.6 mmol) of 4-propoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.71 g (yield 33%) of Compound 50 as pale brown needles.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C1COCC1>[CH3:15][S:16]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])(=[O:18])=[O:17]
Reactant: CSCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSCCCCOS(C)(=O)=O

Procedure:
The 4-(methylthio)-1-butanol (Aldrich, 0.15 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[CH2:8][CH2:7][CH2:6][C:5]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[C:4]=2[N:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:12][C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][C:5]4([CH2:13][CH2:14][CH2:15][CH2:16]4)[C:4]=3[N:3]=[C:2]([NH2:1])[N:11]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Nc1nc(O)c2c(n1)C1(CCCC1)CCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC32CCCC2)cc1
Reaction time: 3 h
Yield: 15.1 %

Procedure:
A solution of Example 1C (2.91 g, 13.27 mmol), p-toluenesulfonyl chloride (3.79 g, 19.91 mmol), and DMAP (324 mg, 2.65 mmol) in CH2Cl2 (60 mL) was treated with TEA (3.7 ml, 4.40 mmol) at ambient temperature, and the resulting solution was stirred for 3 hours. It was then diluted with CH2Cl2 (100 mL) and H2O (50 mL), and the layers were separated. The organic layer was dried with MgSO4 and concentrated under reduced pressure, then the residue was chromatographed on silica gel (1:2:2 EtOAc/CH2Cl2/hexane, eluant) to provide the title product (750 mg). 1H NMR (300 MHz, CD3OD) δ 7.95 (d, 2 H), 7.44 (d, 2 H), 2.45-2.47 (m, 3 H), 2.40-2.45 (m, 2 H), 1.99-2.10 (m, 2 H), 1.79-1.90 (m, 2 H), 1.65-1.75 (m, 6 H), 1.52-1.62 (m, 2 H). MS (DCI+) m/z 374 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:44]1([O:54][CH3:55])[C:45](=[CH:47][CH:48]=[C:49]([CH:53]=1)[CH2:50][CH:51]=[CH2:52])O>ClCCl.CN(C1C=CN=CC=1)C>[CH2:50]([C:49]1[CH:48]=[CH:47][C:45]([O:9][C:8](=[O:10])[CH2:7][CH:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)=[C:44]([O:54][CH3:55])[CH:53]=1)[CH:51]=[CH2:52]
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCc1ccc(OC(=O)CC2OC(C)(C)OC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.8 %

Procedure:
To a solution of ((S)-2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-yl)-acetic acid (2.1 g, 12.0 mmol) in dichloromethane were added N-ethyldiisopropyl amine (10.3 mL), EDCI. HCl (6.9 g, 36.0 mmol), HOBt (1.8 g, 12.0 mmol), DMAP (0.14 g, 1.2 mmol) at ice temperature (0° C.) and the reaction mixture was stirred at same temperature over a period of 15 min. Then eugenol (2.18 g, 13.2 mmol) was added to the reaction mixture at same temperature and the mixture was stirred at room temperature (25° C.) over a period of 12 h. The resulting mixture was diluted with dichloromethane (200 mL), washed with water (4×100 mL), dried (Na2SO4) and concentrated. The crude product obtained was further purified by column chromatography to obtain colourless solid (2.3 g, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:27](=[O:36])[N:28]([CH3:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C=1>>[CH3:19][C:6]1[C:5]2[C:10](=[CH:11][C:2]([O:1][C:27](=[O:36])[N:28]([CH3:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:3][CH:4]=2)[O:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1c(-c2ccccc2)c(=O)oc2cc(O)ccc12
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: Cc1c(-c2ccccc2)c(=O)oc2cc(OC(=O)N(C)c3ccccc3)ccc12
Yield: 62.3 %

Procedure:
The title compound (120 mg, 52% yield, white solid) was prepared from 7-hydroxy-4-methyl-3-phenyl-chromen-2-one (126 mg, 0.50 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (175 mg, 0.51 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:22][O:21][C:17](=[O:20])/[CH:18]=[CH:19]/[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([F:16])[CH:11]=1
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Reactant: C=CC(=O)OC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc(OCc2ccccc2)c(F)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 22 %

Procedure:
1-Benzyloxy-4-bromo-2-fluoro-benzene (1.62 g, 5.7 mmol) obtained in Step A was added with methyl acrylate (1 mL), 1,4-dioxane (19 mL), Pd2(dba)3(0.1 g, 0.11 mmol), TEA (1.6 mL, 11.4 mmol) and tri-t-butylphosphine tetrafluoroborate (0.16 g, 0.57 mmol), and the mixture was stirred at 100° C. for 6 hours. The reactant was filtered by using celite, and the filtrate was washed with EtOAc and purified by column chromatography to obtain the title compound (0.37 g, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:27][O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>>[CH3:27][O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[CH:34][CH:33]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: COC(=O)COc1ccc(CBr)cc1
Product: COC(=O)COc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and (4-bromomethyl-phenoxy)-acetic acid methyl ester (CAS Reg. No. 104508-23-8). Brown sticky solid (55%). MS (Turbo Spray): m/z=555.2 (M+H).
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH3:18])[CH3:17])[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)[C:37]=1[C:38](O)=[O:39].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:18][N:16]([CH3:17])[C:11]1[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:38]([C:37]4[C:41]([N:45]5[N:49]=[CH:48][CH:47]=[N:46]5)=[CH:42][CH:43]=[CH:44][C:36]=4[F:35])=[O:39])[CH2:2]3)[CH2:7]2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(N(C)C)n1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-n4nccn4)C[C@@H]32)nc(N(C)C)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[4-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-6-methyl-pyrimidin-2-yl]-dimethyl-amine (Intermediate L) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C22H25FN8O, 436.492; m/z found 437.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.19-7.72 (m, 2M), 7.55-7.29 (m, 2H), 7.21-6.81 (m, 1H), 5.52-5.08 (m, 1H), 4.70-4.26 (m, 1H), 4.13-3.44 (m, 5H), 3.23-3.03 (m, 2H), 2.95-2.70 (m, 5H), 2.30-1.68 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1C(OC)=O.CN1CCNCC1.CN1C(=O)CCC1.C(O[CH:28]=[C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])C>CC#N>[S:4]1[CH:5]=[CH:6][C:2]([NH:1][CH:28]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:3]1
Reactant: COC(=O)c1sccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: CCOC(=O)C(=CNc1ccsc1)C(=O)OCC
Temperature: 25 °C

Procedure:
A mixture of methyl 3-aminothiophene-2-carboxylate 1 (5.0 g, 32 mmol, 1.0 eq), N-methyl piperazine (6.5 g, 64 mmol, 2.0 eq) and NMP (30 mL) was heated to reflux for 16 hours. After the decarboxylation was complete, the reaction mixture was allowed to cool to room temperature and diethyl 2-(ethoxymethylene)-malonate (7.0 g, 32 mmol, 2.0 eq) was added. The reaction mixture was heated to reflux for 4 h. The product was purified using SiO2 column chromatography (Hex/EtOAc; 100:0 to 80:20%) to obtain a light yellow powder, 5.0 g (31%). LC/MS (10-99% CH3CN/0.05% TFA gradient over 5 min): m/z 270.2, retention time 1.52 minutes. 1H NMR (DMSO-d6) δ: 10.80 (d, 1.0H, J=13.87 Hz, NH), 8.30 (d, 1.0H, J=13.94 Hz), 7.60 (dd, 1.0H, J=3.0 Hz, J′=2.0 Hz), 7.40 (dd, 1.0H, J=1.5 Hz, J′=3.13 Hz), 7.28 (dd, 1.0H, J=1.5 Hz, J′=5.2 Hz), 4.20 (q, 2H, J=7.0 Hz), 4.10 (q, 2H, J=7.0 Hz), 1.30 (m, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[S:15][CH:16]=[C:17]([C:18]4[NH:22][N:21]=[C:20]([NH:23][C:24]5[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=5)[CH:19]=4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.OC1C=C(C2C3SC=C(C4NN=C(NC5C=CC(S(N)(=O)=O)=CC=5)C=4)C=3C=CC=2)C=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:14]3[S:15][CH:16]=[C:17]([C:18]4[NH:22][N:21]=[C:20]([NH:23][C:24]5[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=5)[CH:19]=4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cccc3c(-c4cc(Nc5ccc(S(N)(=O)=O)cc5)n[nH]4)csc23)cc1
Agent: NS(=O)(=O)c1ccc(Nc2cc(-c3csc4c(-c5cccc(O)c5)cccc34)[nH]n2)cc1
Product: NS(=O)(=O)c1ccc(Nc2cc(-c3csc4c(-c5ccc(O)cc5)cccc34)[nH]n2)cc1
Yield: 63 %

Procedure:
Prepared in 63% yield from 4-{5-[7-(4-methoxy-phenyl)-benzo[b]thiophen-3-yl]-1H-pyrazol-3-ylamino]-benzenesulfonamide analogous to the procedure for 4-{5-[7-(3-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-1H-pyrazol-3-ylamino]-benzenesulfonamide [Example 3(c)]. 1H NMR (300 MHz, DMSO-d6) δ12.66 (s, 1H), 9.74 (s, 1H), 9.13 (s, 1H), 8.02 (s, 1H), 7.98 (d, 1H, J=7.8 Hz). 7.65 (d, 2H, J=8.7 Hz), 7.41-7.60 (m, 6H), 7.06 (s, 2H), 6.93 (d, 2H, J=8.7 Hz), 6.33 (s, 1H). Anal. (C23H18N4O3S2) C, H, N, S. Calculated C=60.49; H=4.23; N=11.76; S=13.45; found C=60.27; H=4.27; N=11.79; S=13.39.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=2)[CH:3]=1.[CH:23]1([CH:26]=O)[CH2:25][CH2:24]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH:23]1([CH2:26][NH:1][C:2]2[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]3[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=3)[CH:3]=2)[CH2:25][CH2:24]1
Reactant: O=CC1CC1
Reactant: COc1ccc(-c2cc(N)c(=O)n(C)c2)cc1NS(C)(=O)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(-c2cc(NCC3CC3)c(=O)n(C)c2)cc1NS(C)(=O)=O
Temperature: 30 °C
Yield: 13.2 %

Procedure:
To a solution of compound from Example 109 (64.6 mg, 0.2 mmol) in MeOH (3 mL) and AcOH (0.3 mL) was added cyclopropanecarbaldehyde (14.0 mg, 0.2 mmol) dropwise with stirring at 30° C. NaBH3CN (24.5 mg, 0.4 mol) was added in portions at 30° C. The reaction mixture was stirred for 2 h at 30° C. It was then quenched with saturated aqueous NH4Cl (5 mL), extracted with EtOAc (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give the title compound (10.0 mg, 13.2%) as a light green solid. 1H NMR (Methanol-d4 400 MHz): δ 7.55 (d, J=2.4 Hz, 1H), 7.36 (dd, J=8.4, 2.4 Hz, 1H), 7.16-7.07 (m, 2H), 6.61 (d, J=2.4 Hz, 1H), 3.94 (s, 3H), 3.66 (s, 3H), 3.05 (s, 2H), 2.95 (s, 3H), 1.21-1.14 (m, 1H), 0.64-0.56 (m, 2H), 0.35-0.28 (m, 2H). LCMS (M+H)+ 378.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:21]([CH3:23])[CH3:22])[C:7]([N:9]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10]1)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:49][CH2:50][C:51]([C:53]1[CH:58]=[CH:57][C:56]([Br:59])=[CH:55][CH:54]=1)=[O:52].CCN(C(C)C)C(C)C>[Cl-].[Na+].O.CN(C=O)C>[Br:59][C:56]1[CH:55]=[CH:54][C:53]([C:51](=[O:52])[CH2:50][NH:49][C:18]([C@@H:17]2[CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][N:9]2[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:21]([CH3:22])[CH3:23])=[O:19])=[CH:58][CH:57]=1
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)O)OCCO2)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1)OCCO2)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.8 %

Procedure:
In a 50 mL flask, (S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylic acid (110 mg, 333 μmol) was combined with DMF (5.00 ml) to give a colorless solution. HATU (127 mg, 333 μmol) was added and stirred at room temperature for 10 min followed by addition of 2-amino-1-(4-bromophenyl)ethanone HCl (83.3 mg, 333 μmol, Eq: 1.00). DIPEA (129 mg, 174 μl, 999 μmol) was then added dropwise and the suspension became a yellow solution once the DIPEA was added. It was stirred at room temperature for 1 hr then poured into brine solution (80 ml). The precipitate was filtered and washed with H2O then dissolved in CH2Cl2 (50 ml), It was dried with MgSO4, filtered and concentrated in vacuo to afford methyl(S)-1-((S)-8-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a yellow solid (75 mg, 42.8%). ESI-LRMS m/e calcd for C22H28BrN3O7 [M+] 526. found 527 [M+H+].
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[C:8](OC(=O)C)(=[O:10])[CH3:9]>>[N:2]([CH2:3][CH2:4][CH2:5][O:6][C:8]([CH3:9])=[O:10])([CH3:7])[CH3:1]
Reactant: CN(C)CCCO
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCCN(C)C

Procedure:
14.4 g of 3-dimethylamino-1-propanol and 14.3 g of acetic anhydride are reacted and worked up as described in Example 7. Yield: 14.9 g (73.1%) of analytically pure product (analysis by gas chromatography) with a boiling point of 53° C./12 torr.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[O:11][N:10]=2)[CH:5]=[C:6](O)[CH:7]=1.[OH:19]C1C=CC(O)=CC=1C1N=C(CCC(O)=O)ON=1.OC1C=CC=C(O)C=1C1N=C(CCC(O)=O)ON=1.OC1C(C2N=C(CCC(O)=O)ON=2)=C(C)C=C(OC)N=1>>[OH:19][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[O:11][N:10]=1
Reactant: O=C(O)CCc1nc(-c2cc(O)ccc2O)no1
Reactant: O=C(O)CCc1nc(-c2cc(O)cc(O)c2)no1
Agent: COc1cc(C)c(-c2noc(CCC(=O)O)n2)c(O)n1
Agent: O=C(O)CCc1nc(-c2c(O)cccc2O)no1
Product: O=C(O)CCc1nc(-c2cccc(O)c2O)no1

Procedure:
3-[3-(3,5-Dihydroxyphenyl)-1,2,4-oxadiazol-5-yl]propionic acid; 3-[3-(2,5-Dihydroxyphenyl)-1,2,4-oxadiazol-5-yl]propionic acid; 3-[3-(2,6-Dihydroxyphenyl)-1,2,4-oxadiazol-5-yl]propionic acid; and 3-[3-(2-Hydroxy-6-methoxy-4-methylpyridin-3-yl)-1,2,4-oxadiazol-5-yl]propionic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([C:26]#[N:27])[CH2:25][CH2:24]4)[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.O>N1C=CC=CC=1>[C:26]([C:23]1([C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][S:36]([C:33]4[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=4)(=[O:38])=[O:37])=[CH:3][CH:4]=3)[CH:10]=2)=[O:28])[CH2:24][CH2:25]1)#[N:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc(N)nc4)c3)c2)CC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)cn2)cc1
Temperature: 80 °C
Yield: 92.1 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (2.0 g, 5.4 mmol) in pyridine (60 mL) was added 4-methylbenzenesulfonyl chloride (1.13 g, 5.94 mmol) under ice-cooling, and the mixture was stirred with heating at 80° C. for 2 days. The reaction mixture was cooled to room temperature, water (200 mL) was added thereto, and the mixture was extracted with ethyl acetate (400 mL). The organic layer was washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate and diisopropyl ether to give the title compound (2.61 g, 92%) as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([C:12]2[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])=[CH:8][CH:7]=1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>C(O)C>[CH2:29]([N:31]([CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([C:12]2[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])=[CH:8][CH:7]=1)[CH3:30]
Reactant: O=C(c1ccc(OCCCBr)cc1)c1oc2ccccc2c1-c1ccccc1
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CCCOc1ccc(C(=O)c2oc3ccccc3c2-c2ccccc2)cc1

Procedure:
2-[4-(3-Bromopropoxy)benzoyl]-3-phenylbenzofuran (2.5 g., 5.7 mmol.) is refluxed for 6 hours in 50 ml. of ethanol containing 20 ml. of diethylamine. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in chloroform. The chloroform solution is washed with water, saturated aqueous sodium chloride solution and water, dried (MgSO4) and concentrated to give the title compound.