Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[Li]CCCC.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([O:33][CH:34]([CH3:36])[CH3:35])[C:19]([F:32])=[C:20]([CH:31]=1)/[CH:21]=[N:22]/[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[CH3:14]>C1COCC1>[Br:7][C:5]1[N:6]=[C:2]([N:22]([CH2:21][C:20]2[CH:31]=[C:16]([O:15][CH2:13][CH3:14])[CH:17]=[C:18]([O:33][CH:34]([CH3:36])[CH3:35])[C:19]=2[F:32])[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[S:3][CH:4]=1
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1
Reactant: Brc1csc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2nc(Br)cs2)c(F)c(OC(C)C)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 19.3 %

Procedure:
To a solution of 2,4-dibromothiazole (100 mg, 0.412 mmol) in 2 mL THF was added BuLi (1.6 M in THF, 283 μL, 0.453 mmol). The mixture was stirred at −78° C. for 15 min, then a solution of Intermediate 7.3 (134 mg, 0.412 mmol) in 0.6 mL THF was added dropwise. The mixture was stirred at −78° C. for 30 min, was allowed to warm to rt, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) followed by preparative HPLC purification to afford 39 mg of Intermediate 16.1.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].CON(C)[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2)=[O:9]>C1COCC1>[NH:15]1[C:16]2[C:12](=[CH:11][C:10]([C:8](=[O:9])[CH2:2][CH3:1])=[CH:18][CH:17]=2)[CH:13]=[N:14]1
Reactant: CC[Mg+]
Reactant: CON(C)C(=O)c1ccc2[nH]ncc2c1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(=O)c1ccc2[nH]ncc2c1
Reaction time: 2 h
Yield: 95 %

Procedure:
EtMgBr (3 M, 2.0 eq, 6.5 mL) was added to a solution of N-methoxy-N-methyl-1H-indazole-5-carboxamide (2 g, 1.0 eq) in dry THF at 0° C. Once addition was complete, the mixture was stirred for 2 h, and extracted by EtOAc. The extract was dried, concentrated, and purified by column chromatography with petroleum ether:EtOAc=1:1 to give the desired product (1.8 g, 95%). 1H NMR (400 MHz, CDCl3) δ 11.20 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 3.08 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C@H:16]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)[CH:11]=[N:12][CH:13]=2)[CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[NH:18]1[CH2:19][CH2:20][C@H:16](/[CH:15]=[CH:14]/[C:10]2[CH:11]=[N:12][CH:13]=[C:8]([O:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:9]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](/C=C/c2cncc(OC3CCOCC3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(=C/[C@H]1CCNC1)\c1cncc(OC2CCOCC2)c1
Yield: 60.6 %

Procedure:
A solution of tert-butyl(R)-(E)-3-(2-(5-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl)vinyl)pyrrolidine-1-carboxylate (18 g, 48.13 mmol) in dichloromethane (40 mL) and trifluoroacetic acid (40 mL) was stirred at ambient temperature for 2 h. The reaction was concentrated on a rotary evaporator, and the residue was partitioned between saturated sodium chloride (50 mL) and chloroform (100 mL). The mixture was basified to pH 9 with 10% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer extracted with chloroform (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated on a rotary evaporator to give (R)-3-((E)-2-(pyrrolidin-3-yl)vinyl)-5-(tetrahydro-2H-pyran-4-yloxy)pyridine (8.0 g) as a gum. This was dissolved in methanol (100 mL) and galactaric acid (3.0 g, 14.6 mmol) was added and the mixture was heated to reflux. This hot solution was filtered, and filtrate was allowed to cool to ambient temperature. The crystallized product was filtered and solid was suspended in 10% water in ethanol (180 mL). The suspension was heated to reflux and hot solution was filtered. The filtrate was allowed to cool to ambient temperature. Crystallized product was filtered and dried on high vacuum pump to give (R)-3-((E)-2-pyrrolidin-3-ylvinyl)-5-(tetrahydro-2H-pyran-4-yloxy)pyridine hemigalactarate (4.5 g). MP: 179° C. 1H-NMR (CD3OD, 300 MHz): δ 8.04 (s, 1 H), 8.01 (d, J=2.2 Hz, 1 H), 7.36 (s, 1 H), 6.46 (d, J=16.0 Hz, 1 H), 6.21 (dd, J=16.0, 7.5 Hz, 1 H), 4.65-4.4.54 (m, 1 H), 4.12 (s, 1 H), 3.89-3.83 (m, 2 H), 4.80 (s, 1 H), 3.56-3.33 (m, 4 H), 3.27-3.18 (m, 1 H), 3.12-2.96 (m, 2 H), 2.23-2.14 (m, 1 H), 1.98-1.91 (m, 2 H), 1.88-1.78 (m, 1 H), 1.68-1.58 (m, 2 H); MS (m/z): 275 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[C:8]([C:11]2[N:15](C3CCCCO3)[N:14]=[CH:13][CH:12]=2)[CH:7]=[C:6]([F:22])[C:3]=1[C:4]#[N:5].Cl.CCO.C([O-])(O)=O.[Na+]>C(O)C>[Cl:1][C:2]1[C:9]([F:10])=[C:8]([C:11]2[NH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=[C:6]([F:22])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cc(-c2ccnn2C2CCCCO2)c(F)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(F)cc(-c2ccn[nH]2)c(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
2-Chloro-3,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-benzonitrile (0.853 mmol, 0.276 g) was stirred in ethanol. 10% HCl/EtOH solution (5 ml) was slowly added. The resulting mixture was stirred at RT overnight. The reaction mixture was neutralized with NaHCO3 and extracted twice with EtOAc. The combined organics were washed with water, dried, filtered and evaporated. 0.219 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 6.86 (bs, 1H), 7.88-8.10 (m, 2H), 13.57 (bs, 1H).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[C:27]([F:42])=[CH:28][C:29]([F:41])=[C:30]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[C:27]([F:42])=[CH:28][C:29]([F:41])=[C:30]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:39])[CH3:40])(=[O:34])=[O:33])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: CN(C)CCNS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (337 mg, 1.0 mmol) and 5-bromo-N-(2-dimethylamino-ethyl)-2,4-difluoro-benzenesulfonamide (example B.36) (446 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (300 mg, 50%). MS (ISP) 600.2 [(M+H)+]; mp 165-166° C.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1>Cl.O1CCCC1>[CH:3]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1)=[O:2]
Reactant: COC(=O)c1cc(C(OC)OC)cnc1C(=O)OC
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(C=O)cnc1C(=O)OC
Yield: 84.2 %

Procedure:
A solution of dimethyl 5-dimethoxymethylpyridine-2,3-dicarboxylate (6.57 g, 0.024 mol) in 2N HCl (15 mL) and tetrahydrofuran (25 mL) is stirred at reflux temperature for 2 hours. The tetrahydrofuran is removed in vacuo, the aqueous solution is diluted with water (to 30 mL) and extracted with methylene chloride. The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound (4.51 g, 82%) as a yellow solid, mp 75°-77° C., identified by IR and NMR spectral analyses.
Reaction SMILES: C(N([CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29](O)=[C:28]([F:33])[CH:27]=3)[N:18]=2)[CH:14]=[CH:15][CH:16]=1)C1CCNCC1)C.FC1[CH:36]=[C:37]([CH2:41][CH2:42][NH2:43])[CH:38]=[CH:39]C=1>>[F:33][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][CH2:36][CH:37]4[CH2:41][CH2:42][NH:43][CH2:39][CH2:38]4)[CH:12]=3)[CH:22]=[CH:21][N:20]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: NCCc1cccc(F)c1
Reactant: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(F)c3)n2)c1)C1CCNCC1
Product: Fc1cccc(CCNc2nccc(-c3cccc(CCC4CCNCC4)c3)n2)c1

Procedure:
Intermediate 92 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 406. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.27 (d, 1H), 8.04 (s, 1H), 7.96 (m, 1H), 7.47 (d, 2H), 7.25 (m, 2H), 7.09 (d, 1H), 7.04 (d, 1H), 6.89 (t, 1H), 3.80 (m, 2H), 3.36 (m, 2H), 2.91 (m, 4H), 2.77 (t, 2H), 2.00 (d, 2H), 1.67 (m, 3H), 1.36 (m, 2H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:32][CH:33]=2)[C:28]([Sn](CCCC)(CCCC)CCCC)=[N:27]1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:29]4[C:34](=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:37])([F:39])[F:38])[CH:30]=4)[N:26]([CH3:25])[N:27]=3)[N:3]=2)[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:12])([CH3:16])[CH3:15]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(OC(F)(F)F)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(OC(F)(F)F)cc34)nc12
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 79.8 %

Procedure:
In a 25 mL round-bottomed flask, 2-bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (107 mg, 258 μmol) and 1-methyl-3-(tributylstannyl)-5-(trifluoromethoxy)-1H-indazole (209 mg, 413 μmol) were dissolved in DMF (2.5 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (14.9 mg, 12.9 μmol) and CuI (9.83 mg, 51.6 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (40 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 30 min) to give N-isopropyl-2-(1-methyl-5-(trifluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (113 mg, 206 μmol, 80%) as a light yellow solid. MS (M+H)+=549; 1H NMR (CDCl3) δ: 9.23 (s, 1H), 8.35 (s, 2H), 8.01 (d, J=7.9 Hz, 1H), 7.44-7.53 (m, 1H), 7.34-7.43 (m, 1H), 5.70 (s, 2H), 4.38-4.56 (m, 1H), 4.19 (s, 3H), 3.52-3.64 (m, 2H), 1.42 (d, J=6.4 Hz, 6H), 0.84-1.00 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][C:28]1[CH:35]=[C:34](F)[CH:33]=[C:32]([CH3:37])[C:29]=1[C:30]#[N:31]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:34]5[CH:33]=[C:32]([CH3:37])[C:29]([C:30]#[N:31])=[C:28]([CH3:27])[CH:35]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cc1cc(F)cc(C)c1C#N
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cc(C)c(C#N)c(C)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,6-dimethyl-4-fluoro-benzonitrile following a procedure analogous to that described for Intermediate 12.
Reaction SMILES: I[C:2]1[NH:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:6]=1.[S:13]1[C:17](B(O)O)=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].N#N>O.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:9]1[S:8][C:7]([C:5]2[N:6]=[C:2]([C:14]3[S:13][C:17]([C:2]4[NH:3][CH:4]=[C:5]([C:7]5[S:8][C:9]([CH3:12])=[CH:10][CH:11]=5)[N:6]=4)=[CH:16][CH:15]=3)[NH:3][CH:4]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2c[nH]c(I)n2)s1
Reactant: OB(O)c1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2c[nH]c(-c3ccc(-c4nc(-c5ccc(C)s5)c[nH]4)s3)n2)s1
Temperature: 25 °C
Yield: 276.6 %

Procedure:
A portion of 2-iodo-4-(5-methylthiophen-2-yl)-1H-imidazole 3 (940 mg, 3.25 mmol), thiophene-2,5-diboronic acid (250 mg, 1.46 mmol), Na2CO3 (780 mg, 7.40 mmol) in H2O (5 mL) and DMF (40 mL) was degassed (N2 bubbling). Pd(PPh3)4 (85 mg) was added and the mixture was heated to reflux for 3 h. The mixture was allowed to cool to room temperature and concentrated. The mixture was diluted with EtOAc and H2O and the organic phase was separated. The aqueous phase was re-extracted (EtOAc) and the combined organics were washed (saturated aqueous NaCl), dried (MgSO4), filtered and concentrated to give a residue. The residue was purified by flash chromatography (EtOAc/hexanes 35:65 then 50:50 then 75:25) to give 2,5-bis(4-(5-methylthiophen-2-yl)-1H-imidazol-2-yl)thiophene 4 (1.65 g, 27%) as a pale brown solid. 1H NMR [(CD3)2SO, 400 MHz] δ2.44 (s, 6H), 6.75 (s, 2H), 7.11 (d, J=3.0 Hz, 2H), 7.51 (br s, 4H), 12.65-12.85 (br s, 2H); HRMS (EI) m/z 408.0539 C20H16N4S3 [M]+. requires 408.0532.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH3:17])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:9]1[C:25]([N:27]1[CH2:32][CH2:31]S[CH2:29][CH2:28]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[O:34][S:35]([O-:37])=O.[K+]>CO.O>[CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:11]([CH3:17])[C:10]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:9]1[C:25]([N:27]1[CH2:28][CH2:29][S:35](=[O:37])(=[O:34])[CH2:31][CH2:32]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCSCC2)n(Cc2ccccc2)c1C(F)(F)F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCS(=O)(=O)CC2)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (1-benzyl-3-(4-chlorophenyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(thiomorpholino)methanone (162 mg, 0.34 mmol) in MeOH (4 mL) and H2O (1 mL) was added oxone (624 mg, 1.015 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O and extracted with DCM (60 mL). The organic layer was washed with brine, dried (Na2SO4) and purified by flash column chromategraphy (silica, heptane/EtOAc, 4:1→3:2) to give SC-26 (66 mg, 38%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]1=[O:20].[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22].C(Cl)Cl>>[OH:27][C:21]([C:23]([F:26])([F:25])[F:24])=[O:22].[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]1=[O:20]
Reactant: CN1C(=O)N(c2ccccn2)CC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(c2ccccn2)CC1C(=O)O

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 2 mmol) (prepared as described in step (iii) of Example 13) and 2-bromopyridine (316 mg, 2 mmol) in 1,4-dioxane (10 ml) was treated with cesium carbonate (977 mg, 3 mmol), Xantphos™ (87 mg, 0.15 mmol) and tris(dibenzylideneacetone)dipalladium(0) (45.8 mg, 0.05 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane (2 columns required) to give 1,1-dimethylethyl 3-methyl-2-oxo-1-(2-pyridinyl)-4-imidazolidinecarboxylate (198 mg, 36%). LC/MS [M+H]+=278. (ii) A solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-(2-pyridinyl)-4-imidazolidinecarboxylate (198 mg, 0.71 mmol) in TFA/DCM (1:2, 4.5 ml) was stirred at room temperature for 8 hours. The solution was evaporated and the residue was dried to give 3-methyl-2-oxo-1-(2-pyridinyl)-4-imidazolidinecarboxylic acid TFA salt (assume ˜0.71 mmol)) which was used in the next step. LC/MS [M+H]+=222.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:15])([F:14])[F:13])[C:9]([C:16]([OH:18])=[O:17])=[CH:8][C:7]=2[CH:19]=1)=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:14])([F:15])[F:13])[C:9]([C:16]([OH:18])=[O:17])=[CH:8][C:7]=2[CH:19]=1
Reactant: O=Cc1ccc2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C1=Cc2cc(CO)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To a chilled (ice bath), stirred solution of 6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example 75, Step 2) (0.133 g, 0.489 mmol) in THE (1 mL) and ethanol (1 mL) in a 10 mL round bottom flask was added NaBH4 (0.020 g, 0.528 mmol) in two portions. The reaction was allowed to warm to room temperature and more NaBH4 (0.050 g, 1.322 mmol) was added. The total reaction time was 3 hours. The reaction was quenched with aqueous HCl (1 N solution) and was extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated in vacuo yielding a foam. This crude product was purified by flash chromatography (silica gel 60, eluant 1:1, hexane-ethyl Acetate with 2% acetic acid). The product collected from the chromatography was recrystallized from hexanes and ethyl acetate, and collected by vacuum filtration yielding the title compound (0.042 g, 31%) as a very pale yellow powder: mp 177.5-180.8° C. 1H NMR (acetone-d6/300 MHz) 7.89 (s, 1H), 7.44 (s, 1H), 7.41 (d, 1H, J=8.3 Hz), 6.99 (d, 1H, J=8.3 Hz), 5.80 (q, 1H, J=7.3 Hz), 4.59 (s, 2H). FABLRMS m/z 275 (M+H). EIHRMS m/z 274.0417 (M+, Calc'd 274.0453). Anal. Calc'd for C12H9F3O4: C, 52.57; H, 3.31. Found: C, 52.43; H, 3.34.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N:20]=[C:19]([NH:30][CH2:31][CH2:32][N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[N:18]=1)[CH2:27][CH2:26][CH2:25]3.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N+:20]([O-:4])=[C:19]([NH:30][CH2:31][CH2:32][N:33]([CH2:34][CH2:35][CH3:36])[CH2:37][CH2:38][CH3:39])[N:18]=1)[CH2:27][CH2:26][CH2:25]3
Reactant: CCCN(CCC)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
H2O2 (70%, 0.39 mL, ca. 7.7 mmol) was added dropwise to a stirred solution of TFAA (1.1 mL, 7.7 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 28 (253 mg, 0.8 mmol) and TFA (0.30 mL, 3.8 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 5° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 29 (134 mg, 50%) as a red solid: mp (MeOH/EtOAc) 142-145° C.; 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.46 (br s, 1H, NH), 3.54-3.60 (m, 2H, CH2N), 3.03-3.11 (m, 4H, H-6, H-8), 2.74 (dd, J=6.1, 5.9 Hz, 2H, CH2N), 2.43-2.47 (m, 4H, 2×CH2N), 2.16-2.24 (m, 2H, H-7), 1.45-1.54 (m, 4H, 2×CH2), 0.91 (t, J=7.4 Hz, 6H, 2×CH3); 13C NMR δ 155.5, 149.5, 145.7, 138.0, 129.6, 115.7, 111.6, 56.0 (2), 52.5, 39.1, 33.4, 32.4, 25.6, 20.4 (2), 11.8 (2). Anal. calcd for C18H27N5O2: C, 62.6; H, 7.9; N, 20.3. Found: C, 62.3; H, 8.0; N, 20.2%.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C@H:11]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.[NH:32]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C@H:33]([C:41](O)=[O:42])[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:40])[NH2:39].Cl.N1C=CC=CC=1.C(Cl)(=O)C(C)(C)C>CC(N(C)C)=O>[NH:32]([C:44]([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45])[C@H:33]([C:41]([NH:10][C@H:11]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:42])[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:40]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
DMA, 1.00 equivalent of DIPEA and 1.00 equivalent of H-Trp-Pro-OH (Mw=301.3; purity=94.0%) were mixed at room temperature for at least 30 min until a solution was obtained and then the solution was cooled to 10±5° (solution No. 1). 1.00 equivalent of Z-Arg-OH.HCl (Mw=344.8) were added to DMA at room temperature until a clear solution was obtained (solution No. 2). While cooling solution No. 2 to −15±5° C., 1.05 equivalents pyridine (Mw=79.1; purity=99.0%) and 1.00 equivalent of DIPEA were added. Once this temperature was reached, 1.00 equivalent of pivaloyl chloride (PivCl) (Mw=120.58) was poured into the reaction mixture (solution No. 2) which was further activated for about 5 minutes. Finally, solution No. 1 was added to the activated solution No. 2 and the reaction mixture was further stirred for at least 1 hour while cooling was stopped and the reaction mixture allowed to warm up to room temperature.