Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([OH:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([O:28][C:32]5[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: Cc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Product: Cc1cccnc1OC1CCCCC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)C1

Procedure:
As described for example 138, 4-(7-chloro-4-quinolinyl)-N-(3-hydroxycycloheptyl)-1-piperazinecarboxamide, NaH, and 2-bromo-3-picoline are reacted to give the product. LC-MS: 494 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.05 (s, 1H), 7.98 (d, 1H), 7.85 (m, 1H), 7.45 (d, 1H), 7.40 (m, 1H), 6.85 (d, 1H), 6.78 (m, 1H), 6.10 (d, 1H), 5.20 (m, 1H), 4.10 (m, 1H), 3.76 (m, 4H), 3.25 (m, 4H), 2.26 (m, 1H), 2.18 (s, 3H), 2.12 (m, 2H), 1.45–1.90 (m, 7H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=2)[C@@H:59]([C@H:69](O)[CH3:70])[CH2:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:63]=[CH:64][C:65]([F:68])=[CH:66][CH:67]=2)[C@@H:59]([C@@H:69]([O:27][C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=2)[CH3:70])[CH2:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)cc1
Reactant: Oc1ccc(Cl)cn1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (0.36 g, 1.1 mmol) in THF (40 mL) at 0° C. were added 5-chloro-pyridin-2-ol (97 mg, 0.75 mmol) and then DBAD (0.18 g, 0.80 mmol). After 5 minutes was added (R)-1-[(3R,4S)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (0.15 g, 0.50 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 0.15 g (73%) of the title compound as a colorless oil. ES-MS m/e: 411.2 (M+H+).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccccc4)cccc3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]-undec-7-ene (0.8 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) in acetonitrile (100 mL). The mixture was stirred for 30 minutes, and benzoyl chloride (0.4 g, 3.2 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was stirred with 2N HCl (30 mL) and CH2Cl2 (80 mL). The solid was collected to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide (0.5 g, 68%) as a white solid: mp 228-230° C.; 1H NMR (DMSO-d6) δ 2.01-2.05 (m, 1H), 2.33-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.48 (d, J=17.3 Hz, 1H), 4.53 (d, J=22.1 Hz, 1H), 4.55 (s, 2H), 5.12-5.19 (dd, J=5.0 and 13.2 Hz, 1H, CH), 7.44-7.65 (m, 6H, Ar), 7.87 (d, J=7.1 Hz, 2H, Ar), 9.11 (t, J=5.7 Hz, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.61, 31.20, 46.30, 51.60, 121.67, 127.25, 128.35, 130.67, 131.36, 131.63, 134.07, 134.74, 140.16, 166.37, 168.10, 171.04, 172.88; Anal. calcd. for C21H19N3O4: C, 66.83; H, 5.07; N, 11.13. Found: C, 66.58; H, 5.08; N, 11.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@H:20]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C@@H:19]([CH2:42][OH:43])[O:18][C@H:10]2[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[N:46]([C:49]1[CH:56]=[CH:55][C:52]([CH2:53]Br)=[CH:51][C:50]=1[Cl:57])=[N+:47]=[N-:48].[H-].[Na+].O>CN(C=O)C>[N:46]([C:49]1[CH:56]=[CH:55][C:52]([CH2:53][O:43][CH2:42][C@H:19]2[O:18][C@@H:10]([S:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:9]([O:8][CH2:7][C:6]3[CH:44]=[CH:45][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@@H:20]2[O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)=[CH:51][C:50]=1[Cl:57])=[N+:47]=[N-:48]
Reactant: [N-]=[N+]=Nc1ccc(CBr)cc1Cl
Reactant: COc1ccc(CO[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](Sc3ccccc3)O[C@H](CO)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CO[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](Sc3ccccc3)O[C@H](COCc3ccc(N=[N+]=[N-])c(Cl)c3)[C@H]2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
To a solution of phenyl 2,3,4-tri-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (8) (1.25 g, 1.98 mmol) and 4-azido-3-chlorobenzyl bromide (584 mg, 2.37 mmol) in DMF (10 ml) was added sodium hydride (60% in oil, 95 mg, 2.37 mmol), and the resulting mixture was stirred at room temperature for 3 hr. Cold water was added and the mixture was extracted twice with ether. The combined ether layers were washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to give phenyl 6-O-(4-azido-3-chlorobenzyl)-2,3,4-tri-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (9) as white crystals (1.25 g, yield 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=2)[CH:3]=1.Br[C:28]1[CH:29]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:19]=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH:3]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(B(O)O)c2)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)c1

Procedure:
The title compound was prepared from 3-[4-methyl-6-(4-trifluoromethyl-phenyl)pyridin-2-yl]-benzeneboronic acid (example G.10) (0.407 g, 1.14 mmol) and commercially available 3-bromobenzenesulfonamide (177 mg, 1.14 mmol) according to the general procedure VI. Obtained as a white solid (0.052 g, 10%). MS (ISP) 469.4 [(M+H)+]; mp 200° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1.O1CCCC1>C1(C)C=CC=CC=1>[Cl:3][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH2:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[CH3:5])=[CH:20][CH:21]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A solution of thionyl chloride (1.5 mL) in toluene (5 mL) was added to a mixture of 4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyl alcohol (4.50 g), tetrahydrofuran (50 mL) and toluene (50 mL) under ice-cooling, which was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate, which was washed with saturated aqueous sodium bicarbonate solution, then with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and concentrated to obtain colorless crystals of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenylthiazole (4.50 g, yield 94%). Melting point: 100–101° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>[Ni].C(O)C>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nnc2c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2[nH]nnc2c1
Yield: 73.4 %

Procedure:
5-Nitrobenztriazole (10 g) was shaken with Raney nickel (3 spoons) and ethanol (200 ml) under hydrogen at atmospheric pressure until the uptake of hydrogen ceased. The Raney nickel was removed by filtration through Keiselguhr, and the dark ethanolic solution was evaporated to dryness. Crystallization from aqueous ethanol afforded 5-aminobenzotriazole (6 g, 75 percent).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[NH:10][CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[CH:15][CH:16]=1)=[O:4].[Cl:33][C:34]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>ClCCl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:36](=[O:37])[C:35]1[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:34]=1[Cl:33])[CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=2)=[CH:15][CH:16]=1)=[O:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NCc1ccc(-c2cccc(C(F)(F)F)c2)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(Cc1ccc(-c2cccc(C(F)(F)F)c2)o1)C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a stirred solution of 5-Phenyl-3-{[5-(3-trifluoromethyl-phenyl)-furan-2-ylmethyl]-amino}-thiophene-2-carboxylic acid methylester (65 mg 0.142 mmol) in dichloromethane (3 ml) and saturated NaHCO3 solution (3 ml) was added a solution of 2,4-dichloro-benzoyl chloride (36 mg, 1.2 eq.) in dichloromethane (0.9 ml). The reaction mixture was stirred vigorously at room temperature for overnight. The organic phase was collected and the aqueous phase was extracted twice with methylene chloride (2×15 ml). The organic layers were combined, washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed and residue was purified on silica gel using Hexane:EtOAc 9:1 as eluant to give the desired product in 78% yield (70 mg). The proton NMR indicated the presence of rotamers.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:8]2([C:6]3[CH:5]=[CH:4][N:3]=[CH:2][CH:7]=3)[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[NH:9]2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC1=CC(c2ccc(C(F)(F)F)cc2)=CC(c2ccncc2)(c2cccc(S(=O)(=O)NC(C)(C)C)c2)N1

Procedure:
The title compound was prepared from 2′-chloro-6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl (example E.28) (0.200 g, 0.6 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.177 g, 0.7 mmol) according to the general procedure VI. Obtained as an off-white solid (0.286 g, 95%). MS (ISP) 526.2 [(M+H)+]; mp 189° C.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:24][CH2:25][O:26][CH2:27][CH3:28])=[C:16]([CH:18]=[CH:19][C:20]([O:22]C)=[O:21])[CH:17]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5].P([O-])([O-])([O-])=O>O1CCCC1.CO.O>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:24][CH2:25][O:26][CH2:27][CH3:28])=[C:16]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])[CH:17]=1)=[O:10])([CH3:6])([CH3:7])[CH3:5]
Reactant: CCOCOc1ccc(NC(=O)OC(C)(C)C)cc1C=CC(=O)OC
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOCOc1ccc(NC(=O)OC(C)(C)C)cc1C=CC(=O)O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
2.53 g (0.06 mol) of lithium hydroxide monohydrate was added at 0° C. to a solution of 6.3 g (0.018 mol) of methyl 3-(5-tert.butoxycarbonylamino-2-ethoxymethoxyphenyl)acrylate from step D in 50 mL of tetrahydrofuran, 15 mL of methanol and 30 mL of water. The mixture was allowed to agitate 24 hours at 60° C. The reaction mixture was then poured onto a phosphate buffer solution (pH 7.0) and extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous sodium chloride solution and then dried over sodium sulfate. The organic phase was partially evaporated to incipient formation of a precipitate, and hexane was then added. The precipitate was filtered off and washed with 50 mL of hexane. This gave 5.4 g (89% of the theoretical) of 3-(5-tert.butoxycarbonylamino-2-ethoxymethoxyphenyl)acrylic acid.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C.Cl.O1CCOCC1>>[ClH:29].[NH2:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reaction time: 0.5 h
Yield: 205.4 %

Procedure:
To (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(3′-chlorobiphenyl-4-yl)butanoate (Intermediate 9-1: 3.33 g, 7.97 mmol) is added a solution of 4 M HCl in 1,4-dioxane (19.9 mL, 18.0 mmol) at room temperature. After stirring for 0.5 hours, the reaction mixture is concentrated under reduced pressure to give (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (2.90 g). HPLC retention time=0.70 minutes (condition B); MS (m+1)=318.26; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19-1.24 (m, 3 H) 2.73-2.78 (m, 1 H) 2.84-2.91 (m, 1 H), 3.05-3.11 (m, 1 H) 3.50-3.54 (m, 1 H) 3.92 (br s, 1 H) 4.14-4.17 (m, 2 H) 7.29-7.53 (m, 8 H) 8.73 (br. s., 3 H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([NH2:25])=[N:22][C:21]=1[CH3:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)=[N:22][C:21]=1[CH3:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1cccnc1
Product: Cc1nc(NC(=O)c2cccnc2)sc1C(=O)NCc1ccccc1
Yield: 33 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use nicotinoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 33% yield. m.p. 224-226° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.17 (d, J=1.5 Hz, 1H), 8.76 (dd, J=1.5, 4.6 Hz, 1H), 8.63 (t, J=5.7 Hz, 1H), 8.40-8.36 (m, 1H), 7.55 (dd, J=4.6, 8.1 Hz, 1H), 7.33-7.19 (m, 5H), 4.38 (d, J=5.7 Hz, 2H), 2.51 (s, 3H); MS (ES+) m/z 353.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:27][CH:26]=3)=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.[Br:38]Br.O>CC(O)=O>[Br:38][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[O:10][C:9](=[O:13])[C:8]([C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=1)=[C:7]2[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:36])[CH3:35])=[CH:29][CH:30]=1
Reactant: BrBr
Reactant: COc1ccc2c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c2cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
A mixture of 2,2-dimethyl-propionic acid 4-(7-methoxy-2-oxo-3-(4-trifluoromethyl-phenyl)-2H-chromen-4-ylmethyl)-phenyl ester from step C (820 mg, 1.61 mmol) and Br2 (83 μL, 1.61 mmol) in AcOH (15 mL) was stirred at room temperature for 16 h. Another portion of Br2 (80 μL, 1.55 mmol) was added, and stirring was continued for 6 h. The mixture was poured into H2O, and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The residual orange solid was crystallized from CH2Cl2/hexane to afford the desired compound as a white solid (710 mg, 75%). 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.65 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 7.07–6.94 (m, 4H), 6.89 (s, 1H), 4.01 (s, 2H), 3.98 (s, 3H), 1.35 (s, 9H); MS (ESI) m/z 588.8 (M+H)+; HPLC tR 7.78 min.
Reaction SMILES: [F:1][C:2]([F:19])([C:5]([F:18])([F:17])[CH2:6][O:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][OH:4].C1(CCCCOCCC=O)C=CC=CC=1>>[F:1][C:2]([F:19])([C:5]([F:17])([F:18])[CH2:6][O:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:3]=[O:4]
Reactant: OCC(F)(F)C(F)(F)COC/C=C/c1ccccc1
Agent: O=CCCOCCCCc1ccccc1
Product: O=CC(F)(F)C(F)(F)COC/C=C/c1ccccc1

Procedure:
Obtained from Intermediate 37 (1.80 g, 6.47 mmol) by the procedure described in Intermediate 13. 2,2,3,3-Tetrafluoro-4-{[(2E)-3-phenylprop-2-en-1-yl]oxy}butanal was obtained (1.37 g, 77%) as oil.
Reaction SMILES: [C:1]([C:4]1[N:5]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([NH2:13])=[CH:8][CH:7]=2)(=[O:3])[CH3:2].[CH3:21][N:22]([CH3:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=1>>[C:1]([C:4]1[N:5]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([N:22]([CH3:32])[CH3:21])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([NH:13][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([N:22]([CH3:21])[CH3:32])=[CH:31][CH:30]=1)=[CH:8][CH:7]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2cc(N)ccc2n1-c1ccc(N)cc1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Product: CC(=O)c1cc2cc(NC(=O)c3ccc(N(C)C)cc3)ccc2n1-c1ccc(NC(=O)c2ccc(N(C)C)cc2)cc1

Procedure:
Compound 372 was prepared according to the procedure described in Scheme IV from 2-acetyl-5-amino-1-(4-aminophenyl)indole and 4-dimethylaminobenzoate. [M+H]+ calcd for C34H33N5O3: 560.26; found: 560.02.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:32]>C(Cl)Cl.CCOC(C)=O>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[C:31]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:32]
Reactant: OC(c1ccccc1)c1cc(F)ccc1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(F)ccc1Br
Yield: 92.4 %

Procedure:
A mixture of Dess-Martin periodinane (0.931 g, 2.20 mmol) and the product of example 35A (0.561 g, 2.00 mmol) was stirred in CH2Cl2 (10 mL) for 1 hour, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The residue was chromatographed on SiO2 (eluted with 4% Et2O/hexanes) to give 515.6 mg of the title compound as a clear gum. 1H NMR (300 MHz, DMSO) δ 7.81 (dd, 1H), 7.69-7.76 (m, 3H), 7.54-7.61 (m, 2H), 7.50 (dd, 1H), 7.39 (ddd, 1H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Br:12][C:13]1[N:18]=[CH:17][C:16]2[CH:19]=[C:20]([C:26]3[CH:27]=[N:28][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:30]=3)[N:21](S(C)(=O)=O)[C:15]=2[CH:14]=1.C(O)(C)(C)C>C1COCC1.O>[Br:12][C:13]1[N:18]=[CH:17][C:16]2[CH:19]=[C:20]([C:26]3[CH:27]=[N:28][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:30]=3)[NH:21][C:15]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2S(C)(=O)=O)cn1
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
DBU (0.193 mL, 1.289 mmol) was added to a solution of tert-butyl 4-(6-bromo-1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)-1H-pyrazole-1-carboxylate (9) (0.517 g, 1.172 mmol) and tert-butanol (0.224 mL, 2.343 mmol) in THF (11.7 mL). The reaction mixture was stirred at 40° C. for 1 hr. It was then diluted with water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was adsorbed on silica and purified via Biotage (DCM/EtOAc, 95/5 to 85/15, 25+M column) to afford the title compound as a white solid (271 mg, 58%). 1H NMR (500 MHz, CDCl3) 1.71 (s, 9H), 6.75 (s, 1H), 7.50 (s, 1H), 8.02 (s, 1H), 8.38 (s, 1H), 8.50 (s, 1H), 8.66 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=2)[O:22][CH2:23][C:24]([O:26]CC)=[O:25])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O1CCCC1>O>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=2)[O:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2C2=CCCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(OCC(=O)O)c2)c1)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
Ethyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(cyclohex-1-en-1-yl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 8a (97 mg, 0.18 mmol) and lithium hydroxide (100 mg, 4.2 mmol) were added to 25 mL of a mixed solvent of tetrahydrofuran and water (V:V=1:1), and then the reaction solution was stirred for 1 h. The reaction solution was extracted with dichloromethane (50 mL×3), and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(cyclohex-1-en-1-yl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetic acid 8b (69 mg, a colorless oil) in 75% yield.