Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH:2]([CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[C:3]([OH:5])=[O:4].CCN(CC)CC>C(Cl)Cl.Cl>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([CH:6]=[CH:2][C:3]([OH:5])=[O:4])(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: COc1ccc(S(=O)(=O)CC(I)C(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
2-Iodo-3-(4-methoxyphenylsulfonyl)propionic acid (4.23 grams, 11.43 mmol) and Et3N (3.22 ml, 2.34 grams, 23.09 mmol) were combined in methylene chloride (150 ml) and stirred overnight at room temperature. The reaction mixture was diluted with 1N hydrochloric acid(aq) (100 ml). The separated aqueous layer was extracted with Et2O (2×). The dried (MgSO4) combined organics were then filtered and concentrated in vacuo to give 2.58 grams of crude product. This was filtered, the filtrate concentrated and the residue taken up in methanol, filtered and the filtrate concentrated to give 1.87 grams of crude product. This was taken up in hot methylene chloride. Fine crystals crashed out. Decanted filtrate. Washed crystals methylene chloride (2×1 ml) (decanted washings). Dried crystals on high vac to give 0.396 grams of 3-(4-Methoxyphenylsulfonyl)propenoic acid as a pale yellow solid (m.p.: 123°-128.5° C.). The filtrate was concentrated to give 1.42 grams of yellow solid which was flash chromatographed (60% EtOAc/hexane/2%/HOAc/0.5% methanol) to give 1.42 grams of 3-(4-Methoxyphenylsulfonyl)propenoic acid. A second chromatography (40% EtOAc/hexane/2%/HOAc/0.5% methanol) gave 0.568 grams of pure 3-(4-Methoxyphenylsulfonyl)propenoic acid.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][CH2:5][O:6][C:7](=[O:21])[CH2:8][N:9]([C:15]([S:17][CH2:18][C:19]#[CH:20])=[O:16])[CH2:10][P:11](Cl)(Cl)=[O:12].C(Cl)Cl.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(OCC)C>[CH3:1][CH2:2][O:3][CH2:4][CH2:5][O:6][C:7](=[O:21])[CH2:8][N:9]([C:15]([S:17][CH2:18][C:19]#[CH:20])=[O:16])[CH2:10][P:11]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:12]
Reactant: C#CCSC(=O)N(CC(=O)OCCOCC)CP(=O)(Cl)Cl
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: ClCCl
Product: C#CCSC(=O)N(CC(=O)OCCOCC)CP(=O)(N1CCOCC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2-Ethoxy)ethyl-N-[(propargylthio)carbonyl]-N-[dichlorophosphinylmethyl]glycinate (10.5 g.; 0.028 mol.) was dissolved in 50 ml. of diethyl ether and 50 ml. of methylene chloride. To the solution was added a solution of morpholine (9.7 g.; 0.11 mol.) in 100 ml. of diethyl ether. The resulting mixture was stirred for 16 hours at 25° C., then filtered. The filtrate was washed with 3% ammonium hydroxide, brine, 5% hydrochloric acid and again with brine. The ether layer was separated, dried and concentrated in vacuo. The residue was purified using a silica gel column with acetonitrile as the eluent to yield (2-ethoxy)ethyl-N-[(propargylthio)carbonyl]-N-[bis(morpholino)phosphinylmethyl]glycinate, dihydrate as an oil (nD25 =1.5200) having the following analysis:
Reaction SMILES: [O:1]=[S:2]1(=[O:37])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH3:28])=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])=[N:3]1.[Li+].[OH-].Cl.O>C1COCC1.CO.O>[O:1]=[S:2]1(=[O:37])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]([C:29]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[O:30])[CH3:28])=[CH:20][CH:19]=2)[C:13]([OH:15])=[O:14])=[N:3]1
Reactant: COC(=O)[C@H](Cc1ccc(OCCN(C)C(=O)C2CCCCC2)cc1)NC1=NS(=O)(=O)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(CCOc1ccc(C[C@H](NC2=NS(=O)(=O)c3ccccc32)C(=O)O)cc1)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
The crude product from Step A was dissolved in a THF/MeOH/H2O mixture (6:0.1:1; 2 ml). Aqueous 1M LiOH solution (1.6 ml) was added and the mixture was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated. The product was purified by chromatography (SiO2/ethyl acetate/hexane). The yield was 42%. MS (ES) 513 (M+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([OH:15])=O)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C@@H:31]([NH2:38])[C:32]3[O:36][N:35]=[C:34]([CH3:37])[N:33]=3)=[CH:26][CH:25]=2)[CH:20]=[CH:21][C:22]=1[F:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C@@H:31]([NH:38][C:13]([C:4]3[C:3]([O:2][CH3:1])=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=3)=[O:15])[C:32]3[O:36][N:35]=[C:34]([CH3:37])[N:33]=3)=[CH:26][CH:25]=2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Reactant: COc1cc2ccccc2cc1C(=O)O
Product: COc1cc2ccccc2cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Yield: 33.2 %

Procedure:
3-Methoxy-2-naphthoic acid 86 mg (0.43 mmol) and the 2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine 100 mg (0.35 mmol) were coupled using the general procedure A. to afford the 3-Methoxy-naphthalene-2-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide 60 mg.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:42][C@@H:43]([CH3:56])[CH2:44][O:45][Si:46]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])[CH:41]=1)[C:36]([OH:38])=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH2:57][C:58]1[CH:62]=[CH:61][N:60]([CH3:63])[N:59]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:42][C@@H:43]([CH3:56])[CH2:44][O:45][Si:46]([CH:53]([CH3:55])[CH3:54])([CH:47]([CH3:49])[CH3:48])[CH:50]([CH3:52])[CH3:51])[CH:41]=1)[C:36]([NH:57][C:58]1[CH:62]=[CH:61][N:60]([CH3:63])[N:59]=1)=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1ccc(N)n1
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1)(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
HATU (23.5 g, 61.8 mmol) was added to 3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoic acid (23.6 g, 51.5 mmol), followed by addition of DMF (140 mL), and cooled to 0° C. 3-Amino-1-methylpyrazole (6.00 g. 61.8 mmol) was added followed by DIPEA (21.3 mL) and the reaction was stirred under argon at 0° C. for 3 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (500 mL) and washed with citric acid solution (200 mL), sodium hydrogen carbonate solution (150 mL), and saturated brine solution (2×150 mL). The organic layer was separated and dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:4 to 1:1 ethyl acetate:hexanes, afforded the title compound as a colourless oil (21.7 g).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[N:19]([CH3:26])[N+:18]=3[O-:27])[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[N:19]([CH3:26])[N+:18]=3[O-:27])[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c2c(c(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)[n+]1[O-])CCCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c2c(c(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)[n+]1[O-])CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88167.1 %

Procedure:
To a pale yellow solution of 3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (43 mg, 86.2 μmol) in dichloromethane (2.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol51), the reaction mixture turned dark red and was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (added few drops MeOH and heating) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 10% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. Pure white solid product was sonicated with hexanes. The solid was separated by decantation and dried under high vacuum to give 3-(7-(tert-butylcarbamoyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (28 mg, 76.0 mmol, 88.1%) as a white solid. MS (M+H)+=369.1 (100% purity); 1H NMR (DMSO-d6) δ: 12.88 (br. s., 1H), 8.87 (s, 1H), 8.40 (s, 1H), 7.32 (s, 1H), 3.35 (s, 3H), 2.36-2.46 (m, 2H), 2.03 (br. s., 2H), 1.86-1.96 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[O:12])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[OH:30]>>[Cl:37][C:33]1[CH:32]=[C:31]([C@@H:29]([OH:30])[CH2:28][NH:27][CH:23]2[CH2:22][CH2:21][N:20]([C:17]3[CH:16]=[CH:15][C:14]([CH:13]=[C:9]4[S:8][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[N:11][C:10]4=[O:12])=[CH:19][CH:18]=3)[CH2:25][CH2:24]2)[CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCOCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)c3cccc(Cl)c3)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 28) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol (which was obtained in Intermediate 1) according to the procedure of Example 1 as a yellowish solid; mp>70° C. (dec.); 1 H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 2 H), 1.70-1.95 (m, 2 H), 2.60-2.90 (m, 7 H), 3.50-4.00(m, 8 H), 4.55-4.65(m, 1 H), 5.46 (brs, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.25-7.45 (m, 7 H), 7.54 (s, 1 H); MS (ES) m/z: 527.1(MH+, 100%); HRMS Calcd. for C27H32CIN4O3S (MH+): 527.1884. Found: 527.1863.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH3:16][C:17]1([CH3:23])[CH2:21][NH:20][C:19](=[S:22])[NH:18]1>CO>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:22][C:19]3=[N:18][C:17]([CH3:23])([CH3:16])[CH2:21][N:20]23)=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CC1(C)CNC(=S)N1
Solvent: CO
Product: Br
Product: CC1(C)CN2C(=N1)SCC2(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
3.1 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 1.3 g of 4,4-dimethyl-2-imidazolidine-thione were reacted as described in Example 12 in 15 ml of methanol, the reaction mixture was precipitated with 70 ml of diethyl ether and the oily precipitate was crystallized with ethyl acetate at 40° to 50° C. Colorless, crystalline solid body: melting point: 164° C (decomposition).
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[C:24]([C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=1.[OH-].[K+]>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[C:24]([C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1
Reactant: COc1cccc(OC)c1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(=O)N4CCOCC4)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(OC)c1-c1c[nH]c2ncc(-c3cccc(C(=O)N4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Methanol (1 mL) was added to erode (3-(3-(2,6-dimethoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone from step 1 and potassium hydroxide (50% w/v, 0.038 mL, 0.34 mmol) was added to the resulting solution. The mixture was stirred for 30 minutes at room temperature before being diluted with water and extracted with ethyl, acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography afforded (3-(3-(2,6-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (7) (31% yield from (3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone) as light yellow solids. 1H NMR (500 MHz, CD2OD) δ 3.65 (m, br, 8H), 3.75 (s, 6H), 6.77 (d, J=8.5 Hz, 2H), 7.31 (t, J=8.5 Hz, 1H), 7.39 (m, 1H), 7.46 (s, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.67 (m, 1H), 7.74 (m, 1H), 7.91 (d, J=2.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H). MS; m/z 444.1 (M+H+).
Reaction SMILES: [N:1]([N:3]([CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)C(N)=O)=O.[OH-].[Na+]>CCOCC.CCCCC>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][CH2:8][CH:7]=[N+:3]=[N-:1]
Reactant: NC(=O)N(CCOC1CCCCO1)N=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCC
Product: [N-]=[N+]=CCOC1CCCCO1
Reaction time: 0.5 h

Procedure:
A solution of 41.8 g of N-nitroso-N-[2-(tetrahydropyran-2-yloxy)ethyl]urea in 200 ml of ether and 100 ml of pentane is added to 450 ml of 1N sodium hydroxide solution at 1°-4°C over a 25 minute period. The solution is stirred for an additional 30 minutes and the layers are separated. The organic layer is dried over sodium hydroxide pellets at 20°C for 5 minutes, and then filtered.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20]#N)=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:31].[K+].Cl.C(Cl)Cl.C[OH:38]>C(O)C1C=CC=CC=1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20]([OH:38])=[O:31])=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: [OH-]
Reactant: COc1cc2c(cc1C#N)C(Cc1ccc(Cl)c(Cl)c1)N(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: OCc1ccccc1
Product: COc1cc2c(cc1C(=O)O)C(Cc1ccc(Cl)c(Cl)c1)N(C(=O)OC(C)(C)C)CC2
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-cyano-1-(3,4-dichloro-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (3.60 g, 8.06 mmol) in benzyl alcohol (10 mL) is added KOH (3.00 g), and the reaction mixture is stirred at 160° C. for 0.5 h. The reaction mixture is allowed to cool to rt and is acidified with 2 M aqueous HCl. The reaction mixture is partitioned with EtOAc (3×20 mL). The combined organic phases are washed with brine, dried over MgSO4, filtered, and evaporated to yield a yellow oil. Chromatography over silica gel with CH2Cl2:MeOH 19:1 and then with MeOH provides the title compound as yellow solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([N:10]=[C:11]([O:18][CH3:19])[C:12]([O:16][CH3:17])=[N:13]2)=[C:8]([CH2:20]Br)[CH:7]=1.O>CN(C)C=O>[N:1]([CH2:20][C:8]1[CH:7]=[C:6]([Br:5])[CH:15]=[C:14]2[C:9]=1[NH:10][CH:11]([O:18][CH3:19])[CH:12]([O:16][CH3:17])[NH:13]2)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1Nc2cc(Br)cc(CN=[N+]=[N-])c2NC1OC
Reaction time: 3 h

Procedure:
743 mg (2 equiv.) of sodium azide are added at 20° C. to 2.07 g (5.72 mmol) of 7-bromo-5-bromomethyl-2,3-dimethoxy-quinoxaline in 25 ml of dimethylformamide. After 3 hours, the mixture is poured into water, extracted with diethyl ether, washed with water and brine and dried with magnesium sulfate. The solvent is concentrated by evaporation.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:55][C:56]1[S:57][C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=1>C(Cl)Cl>[S:57]1[C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=[C:56]1[NH:55][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1
Yield: 65.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (50 mg, 0.17 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (119 mg, 0.27 mmol), triethylamine (70 μL, 0.51 mmol), and 2-aminobenzthiazole (41 mg, 0.27 mmol) in methylene chloride (5 mL) was stirred at 25° C. under nitrogen for 2.33 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was sequentially washed with a 1N aqueous hydrochloric acid solution (1×10 mL), water (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide (48 mg, 66%) as a white solid: mp 206-209° C.; EI-HRMS m/e calcd for C22H24N2O3S2(M+) 428.1228, found 428.1233.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:14]#[C:15][Si](C)(C)C.[NH2:20][C@@H:21]([CH3:26])[C:22]([CH3:25])([OH:24])[CH3:23].CCN(C(C)C)C(C)C.NC1C=CC=CC=1.N1C2C(=CC=CC=2)C=C1.CC([O-])(C)C.[K+]>CN1C(=O)CCC1>[OH:24][C:22]([CH3:25])([CH3:23])[C@@H:21]([N:20]1[C:2]2[C:3](=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([C:6]#[N:7])=[CH:8][CH:9]=2)[CH:14]=[CH:15]1)[CH3:26]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C(F)(F)F
Reactant: C[C@H](N)C(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc2[nH]ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: Nc1ccccc1
Product: C[C@H](n1ccc2c(C(F)(F)F)c(C#N)ccc21)C(C)(C)O
Temperature: 90 °C

Procedure:
4-Fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (0.063 g, 0.221 mmol), (S)-3-amino-2-methylbutan-2-ol (0.060 g, 0.582 mmol) and DIEA (0.077 mL, 0.442 mmol) were combined in NMP (0.5 mL) and heated to 90° C. LCMS after heating for 9 h showed good conversion to the aniline intermediate and some desired indole formation. The mixture was cooled to rt and then treated with KOtBu (1.98 mL, 1 M in THF). The base did not afford conversion to the desired indole despite heating. The mixture was quenched with sat. aqueous NH4Cl, and then extracted with EtOAc. The combined organic fractions were concentrated to a yellow oil and then diluted with NMP (1 mL). Addition of more KOtBu (1.98 mL, 1 M in THF) afforded a dark brown solution that was heated to 50° C. LCMS after 0.5 h showed conversion to the desired indole. The reaction was again quenched with sat. aqueous NH4Cl and then extracted with EtOAc. The combined organic portions were concentrated to a yellow oil and then chromatographed (ISCO, std grad, hex/EtOAc, 24 g silica) to afford the desired product. The mixture was next subjected to reverse phase semiprep (Agilent, 230 nm detection) to afford the desired product as a colorless gum: MS (ESI): m/z 297 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[O:12])=[CH:9][C:8]=2[N+:23]([O-:25])=[O:24])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36]>ClCCl>[Cl:40][C:39]([Cl:42])([Cl:41])[CH2:38][O:37][C:35](=[O:36])[NH:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:22]=[CH:21][C:10]([C:11](=[O:12])[NH:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[CH:9][C:8]=2[N+:23]([O-:25])=[O:24])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
To the product from Example 268A (4.2 g, 9.8 mmol) dissolved in dichloromethane (100 mL) was added pyridine (1.62 mL, 20 mmol) followed by the dropwise addition of 2,2,2-trichloroethyl chloroformate (2.29 g, 10.8 mmol). The resultant solution was stirred for 4 hours and then concentrated under vacuum. The mixture was then poured into water (200 mL), the pH of the solution adjusted to 5 with 1N aqueous hydrochloric acid, the resultant solution stirred for 30 minutes and the resultant solid collected and dried to provide the title compound (6.0 g, 100%).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][N:14]=1>C1COCC1>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[CH2:8][O:18]2)=[CH:15][N:14]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccc(C2CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 137.9 %

Procedure:
The title compound was prepared by following general procedure 3. DMSO (4 mL) was added to NaH 60% dispersion in oil (0.314 g, 7.8 mmol, 1.3 equiv.) and heated to 65° C. for 1 h. THF (10 mL) was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1.2 g, 5.9 mmol, 1 equiv.) was added and stirred for 10 min. and then a solution of 6-methylnicotinaldehyde (0.720 g, 5.9 mmol, 1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h, the product was detected by LCMS. The reaction mixture was poured into ice water and the product was extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to get the crude product 2-methyl-5-(oxiran-2-yl)pyridine (1.1 g crude).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]2=[O:31])=[CH:21][C:20]=1[F:32].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.C(N(CC)CC)C>C(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15](=[O:17])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]2=[O:31])=[CH:21][C:20]=1[F:32])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccc(N2CCCCC2=O)cc1F
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CO[C@@H]1C[C@H](C(=O)Nc2ccc(N3CCCCC3=O)cc2F)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
Into a solution of 6 (0.250 g, 1.02 mmol) in CHCl3 (10 mL) was added 7 (0.212 g, 1.02 mmol), EEDQ (0.302 g, 1.22 mmol), and triethylamine (0.213 mL, 1.53 mmol). The solution was stirred at reflux for 19 h before cooling to RT and adding EtOAc. The solution was washed sequentially with 10% aq. citric acid, 1N NaOH, water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was purified by flash chromatography to reveal 8 (0.329 g, 74%) as a tan foam. MS: APCI (AP+): 436.1 (M)+, (AP−): 434.1 (M)−.