Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:23]4)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].Cl>C1COCC1.C(O)(C)C.O>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:23]4)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]c(CCC(=O)O)cc4c3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
Sodium hydroxide (61 mg) was added to a solution of ethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D114) (68 mg) in THF (5 mL), isopropanol (5 mL) and water (2.5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoic acid (E89) (6 mg). δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.69 (2H, t), 2.98 (2H, t), 4.97 (1H, m), 6.33 (1H, s), 7.44 (1H, d), 7.55 (1H, d), 7.75 (1H, dd), 8.21 (1H, s), 8.40 (1H, dd), 8.49 (1H, d), 11.34 (1H, s), 12.25 (1H, s); MS (ES): C23H20N4O4 requires 416; found 417.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][OH:13].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:9][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[O:13][CH2:12][CH2:11][O:10]1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc(N)cc2)OCCO1
Yield: 34.9 %

Procedure:
A mixture of 4′-aminoacetophenone (1.45 g, 10.7 mmol), ethylene glycol (2.00 g, 32.2 mmol), and p-TsOH.H2O (2.45 g, 12.9 mmol) in toluene (30 mL) were heated to reflux under a Dean-Stark trap for 3.5 h. Basic work-up and purification gave 4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamine as colourless crystals (0.67 g, 35%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:33])[C:27]([F:32])([F:31])[CH:28]([Cl:30])[F:29])[CH:20]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])C>C(O)(=O)C.Br.C(Cl)Cl>[Cl:30][CH:28]([F:29])[C:27]([F:31])([F:32])[C:26]([NH:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4]([OH:34])=[O:3])=[O:33]
Reactant: CCCCCCCCCCCCC(Oc1cccc(NC(=O)C(F)(F)C(F)Cl)c1)C(=O)OCC
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCCCCCCCCC(Oc1cccc(NC(=O)C(F)(F)C(F)Cl)c1)C(=O)O
Temperature: 100 °C

Procedure:
An amount of 76.2 g (0.15 mol) of 2-[m-(3-chloro-2,2,3-trifluoropropionamido)-phenoxy]-myristic acid ethyl ester is dissolved in a mixture of 300 ml of acetic acid and 37.5 ml of 40% aqueous hydrobromic acid. The reaction mixture is heated for 15 min at 100° C., next poured out in 500 ml of methylene chloride, and finally extracted with methylene chloride. The extract is rinsed with water until neutral, dried over magnesium sulphate, and heated to remove any remaining solvent by evaporation.
Reaction SMILES: [CH:1]1([C:5]([NH:7][C@H:8]([C:24]([NH:26][CH:27]([P:35](=[O:38])([OH:37])[OH:36])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:39]1([CH2:45][O:46][C:47]([NH:49][CH2:50][CH2:51][CH2:52][CH2:53][C@H:54](O)[C:55]([N:57]2[CH2:71][CH2:70][CH2:69][C@H:58]2[C:59]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:60])=[O:56])=[O:48])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:39]1([CH2:45][O:46][C:47]([NH:49][CH2:50][CH2:51][CH2:52][CH2:53][C@H:54]([O:38][P:35]([CH:27]([NH:26][C:24](=[O:25])[C@@H:8]([NH:7][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([OH:37])=[O:36])[C:55]([N:57]2[CH2:71][CH2:70][CH2:69][C@H:58]2[C:59]([O:61][CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)=[O:60])=[O:56])=[O:48])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(NCCCC[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=C(NCCCC[C@H](NC(=O)C1CCC1)C(=O)NC(Cc1ccccc1)P(=O)(O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: O=C(NCCCC[C@H](NC(=O)C1CCC1)C(=O)NC(Cc1ccccc1)P(=O)(O)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[1-[[N2 -(Cyclobutylcarbonyl)-N6 -[(phenylmethoxy) carbonyl]-L-lysyl]amino]-2-phenylethyl]phosphonic acid (500 mg., 0.91 mmole) is dissolved in pyridine (10 ml.) with 1-[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-hydroxy-1-oxohexyl]-L-proline, phenylmethyl ester (426 mg., 0.91 mmole). Dicyclohexylcarbodiimide (224 mg., 1.09 mmole) is added and the mixture is stirred at room temperature overnight. It is then concentrated in vacuo and partitioned between ethyl acetate and 5% potassium bisulfate after filtering to remove dicyclohexyl urea. The ethyl acetate layer is washed with brine, dried over sodium sulfate, and concentrated to give 1-[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-[[[1-[[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-[(cyclobutylcarbonyl)amino]-1-oxohexyl]amino]-2-phenylethyl]hydroxyphosphinyl]oxy]-1-oxohexyl]-L-proline, phenylmethyl ester as a crude oil. TLC (silica gel; dichloromethane:methanol:acetic acid, 20:1:1) Rf =0.33.
Reaction SMILES: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]1O.C1CC[CH:31]([NH:34]C2CCCCC2)CC1.[C:41]([O:45][C:46]([N:48]([C@H:50]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=1)[C:51](O)=[O:52])[CH3:49])=[O:47])([CH3:44])([CH3:43])[CH3:42].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:41]([O:45][C:46](=[O:47])[N:48]([C@@H:50]([C:51](=[O:52])[NH:34][CH3:31])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=1)[CH3:49])([CH3:44])([CH3:43])[CH3:42]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(F)cc1)C(=O)O
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dicyclohexylammoniumsalt of (R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(4-fluorophenyl)propionic acid (3.00 g; 10.1 mmol) was dissolved in methylene chloride (30 mL) and washed with an aqueous solution of sodium hydrogen sulfate (10%; 30 mL). The organic phase was dried (magnesium sulfate) and filtered. 1-Hydroxybenzotriazole (1.40 g; 10.1 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.0 g; 10.6 mmol) were added to the filtrate and the reaction mixture was stirred for 15 min at room temperature. Methylamine (40% in methanol; 0.75 g; 9.17 mmol) and diisopropylethylamine (1.7 mL; 10.1 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogen carbonate (sat; 50 mL) and an is aqueous solution of sodium hydrogen sulfate (10%; 50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (3×40 cm) using ethyl acetate/heptane (2:1) as eluent to afford 1.06 g of ((1R)-2-(4-fluorophenyl)-1-(methylcarbamoyl)ethyl)-methylcarbamic acid tert-butylester.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:32][CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:40])C.[OH-].[Na+].Cl>C(O)C>[CH:34]1([CH2:33][O:32][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:41])=[O:3])=[C:8]([CH3:40])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=3)[CH:17]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCC3CCCCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCC3CCCCC3)c2)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
{4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (120 mg; 0.202 mmol) was dissolved in ethanol (50 mL), and aqueous 1 N sodium hydroxide (2 mL) was added. The reaction mixture was stirred for 30 min, acidified with 1 N aqueous hydrochloric acid and extracted with dichloromethane. The organic phase was dried and evaporated to dryness. Yield: 90 mg. HPLC-MS: m/z: 565.3 (M+H)+; Rt: 2.81 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]([I:12])=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Cl:1][C:2]1[C:11]([I:12])=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH2:14][C:15]([O:17][CH3:18])=[O:16])[NH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)CBr
Reactant: S=c1[nH]c2cc(Cl)c(I)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)CSc1nc2cc(I)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 6-chloro-5-iodo-2-thio-1H-benzo[d]imidazole (Intermediate 7; 4.00 g, 12.9 mmol), methyl bromoacetate (1.2 mL, 12.9 mmol), and Cs2CO3 (8.41 g, 25.8 mmol) in 65 mL of THF was stirred for 2.5 h at rt. The volume of the solvent was reduced by rotary evaporation to about 20 mL, the mixture was diluted with 200 mL of EtOAc and washed with brine, dried (MgSO4) and evaporated. The resulting residue was subjected to chromatography on an 80 g column of SiO2 eluting with 14% EtOAc in hexanes, followed by 20% to provide the title compound as an amorphous solid, which exists as a tautomer mixture in DMSO according to 1H NMR: 1H NMR (500 MHz, DMSO-d6): δ 3.66, 3.72, 3.73 (s each, 3H), 4.24, 4.25, 4.26 (s each, 2H), 7.71, 7.95 (s each, 1H), 7.99, 8.11, 8.22 (s each, 1H), 12.91 (br s, 1H); LC-MS: calculated for C10H8ClIN2O2S 382.6, observed m/e 382.9/384.9 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[O:24][C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:10][N:9]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH:7]2[O:24][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][N:9]([CH2:25][C:26]([F:28])([F:29])[F:27])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)(F)F)CC(c1ccccc1)O2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)CN1CC(c2ccccc2)OC2(CCNCC2)C1
Reaction time: 0.67 h
Yield: 100.1 %

Procedure:
To tert-butyl 10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (779 mg, 1.86 mmol) in dichloromethane (5 mL) was added 2,2,2-trifluoroacetic acid (5 mL, 64.90 mmol) at room temperature. The reaction mixture was stirred for 40 minutes, then diluted with dichloromethane (75 mL) and the organic solution was washed with saturated sodium bicarbonate (twice) and then brine. The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to give 10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane as an amber oil (585 mg, 99%). ESI-MS m/z calc. 314.2. found 315.3 (M+1)+; Retention time: 1.29 minutes (3 min run). 1H NMR (400 MHz, CD3CN) δ 7.44-7.25 (m, 5H), 4.82 (dd, J=10.6, 2.8 Hz, 1H), 3.74 (br s, 1H), 3.06 (q, J=9.8 Hz, 2H), 3.02-2.91 (m, 2H), 2.88 (dd, J=11.2, 1.5 Hz, 1H), 2.85-2.74 (m, 3H), 2.34 (d, J=14.8 Hz, 1H), 2.28 (dt, J=10.9, 5.3 Hz, 2H), 1.76-1.64 (m, J=16.0, 8.7, 5.3 Hz, 1H), 1.64-1.52 (m, 2H).
Reaction SMILES: CN(C)C=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1.[O-][CH2:18][CH3:19].C(I)C>C(OCC)C>[CH2:18]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1)[CH3:19]
Reactant: CC[O-]
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CCI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCn1cc(C=O)c2ccccc21
Temperature: 55 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
To a 500 milliliter reaction vessel equipped with a magnetic stirrer is added 100 milliliters anhydrous dimethylformamide and 80 milliliters anhydrous ethylether. The reaction vessel is now partially immersed in an oil bath and 14.2 grams (0.098 moles) indole-3-carboxaldehyde (purified) introduced into the reaction vessel followed by the addition of 24.9 grams (0.1 moles) thallous ethoxide. The reaction mixture is then heated to a temperature in the range of about 35° - 40° C with constant stirring for a period of about 20 minutes. At the end of this period, about 15.6 grams (0.1 moles) ethyliodide is introduced into the reaction vessel and the oil bath temperature raised to about 55° C. Subsequent to the addition of the above material and prior to increase in the temperature, the reaction vessel is equipped with a reflux condenser. Heating at the above temperature is allowed to proceed for about 60 minutes. A large amount of orange/yellow precipitate is formed during this period. The reaction mixture is allowed to cool to room temperature, filtered and the filtrate poured into one liter of water. The ether layer is saved and the water layer extracted with chloroform. The chloroform extracts are combined with the ether portion and the combined solution reextracted several times with water to remove residual traces of dimethylformamide. The chloroform layer is then dried over anhydrous magnesium sulfate, filtered and flash evaporated. An oily residue which remains is crystallized from cyclohexanone. Yield: 50 - 60 percent of white platelett crystals, m. p. 103° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.CN1CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:24])[CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(O)c2ccc(F)cc2)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A mixture of 500 mg (1.5 mmol) of 4-(3-(4-fluorophenyl)-3-(RS)-hydroxypropyl)-1-(t-butoxycarbonyl) piperidine (from EXAMPLE 188, Step B), 351 mg (3.0 mmol) of 4-(methyl)morpholine and 800 mg of 4 A molecular sieves in 10 _mL of CH2Cl2 at 0° C. was treated with 35 mg (0.1 mmol) of tetrapropylammonium perruthenate. The cooling bath was removed and the mixture was stirred at rt for 1 h. The mixture was filtered and the filtrate was concentrated. Flash chromatography on 15 g of silica gel using 3:1 v/v hexanes/ether afforded 386 mg (78%) of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.10-1.19 (m, 2H), 1.43-1.49 (m, 1H), 1.45 (s, 9H), 1.58-1.70 (4H), 2.65-2.70 (m, 2H), 2.70 (t, J=7.5, 2H), 4.054.1 1 (m, 2H), 7.11-7.15 (m, 21), 7.97-8.00 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:14](=[O:17])([O-])[O-].[K+].[K+].Cl>CN(C=O)C.[Cu].C[C@H]1O[C@H]2[C@H](O)[C@@H](O)[C@H](OC3C4C(=CC5OCOC=5C=4)[C@@H](C4C=C(OC)C(O)=C(OC)C=4)[C@@H]4[C@@H]3COC4=O)O[C@@H]2CO1.C1COP(NCCCl)(=O)N(CCCl)C1.[NH2-].[NH2-].Cl[Pt+2]Cl>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[C:3]3[C:2]([O:17][C:14]=2[CH:10]=1)=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=3
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C([O-])[O-]
Agent: Cl[Pt+2]Cl
Agent: [Cu]
Agent: COc1cc([C@@H]2c3cc4c(cc3C(O[C@@H]3O[C@@H]5CO[C@@H](C)O[C@H]5[C@H](O)[C@H]3O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Solvent: CN(C)C=O
Product: Nc1ccc2c(=O)c3ccc([N+](=O)[O-])cc3oc2c1
Temperature: 130 °C
Yield: 162.6 %

Procedure:
To a solution of 2-chloro-4-nitrobenzoic acid (3 g, 14.88 mmol) in DMF (40 mL) was added 3-3′-acetamidolphenol (2.47 g, 16.38 mmol), potassium carbonate (3.08 g, 16.38 mmol), and copper powder (102 mg, 1.61 mmol). After heating at 130° C. overnight, the reaction mixture was cooled to room temperature and poured to ice—1 N HCl solution (300 mL) slowly. The solution was stirred until the brown solid was formed. The solid was filtered off and washed with cold water to yield a brown solid (3.1 g). A crude solid was dissolved in conc. sulfuric acid (20 mL) and heated at 80° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured to ice (350 mL volume) and stirred for 1 hour. The precipitated solid was filtered off and re-suspended in 2.5% aq. sodium carbonate solution. The solid was filtered and washed with cold water and dried under vacuum. The solid was further recrystallized in pyridine or pyridine/water to yield 1.23 g of S3 (Y═O) (60%, two steps) as a yellowish-brown solid. 1H-NMR (DMSO-d6) δ 8.37 (d, J=2.0, 1H), 8.32 (d, J=8.4, 1H), 8.15 (dd, J=2.0, 8.4, 1H), 7.88 (d, J=8.8, 1H), 6.75 (bs, 2H), 6.72 (dd, J=2.0, 8.8, 1H), 6.56 (d, J=2.0, 1H). ESI-MS m/z (H+H) calc'd: 257.2. found 257.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[N:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[N:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1ccc2nccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2nccnc2c1
Reaction time: 0.08 h
Yield: 87 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (147 mg, 0.651 mmol) in dichloromethane (4 mL) was added pyridine (125 μL, 1.55 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-aminoquinoxaline (90 mg, 0.62 mmol) was added. The resulting mixture was stirred for 5 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale yellow solid (180 mg, 87%), single spot at Rf 0.60 (ethyl acetate). mp 166.5-166.9° C., HPLC purity 99+% (tR 2.15 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.77 (1H, d, J=1.7 Hz), 8.74 (1H, d, J=1.7 Hz), 8.06 (1H, d, J=8.2 Hz), 8.00 (1H, d, J=9.2 Hz), 7.66 (1H, d, J=2.5 Hz), 7.56 (1H, d, J=7.9 Hz), 7.50 (1H, dd, J=9.1, 2.6 Hz), 7.28-7.22 (1H, obscured under CHCl3), 2.76 (3H, s). LCMS: 332.24 (M−). FAB-MS (MH+, C15H12ClN3O2S): calcd 334.0417, found 334.0433.
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([NH2:19])[CH:13]=[C:12](Cl)[N:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>O1CCOCC1.CCOC(C)=O.O>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([NH2:19])[CH:13]=[C:12]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([F:35])([F:34])[F:23])[N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCCOc1nc(Cl)cc(N)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1nc(-c2ccccc2C(F)(F)F)cc(N)c1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-chloro-3-nitro-pyridin-4-ylamine (1.20 g, 3.45 mmol, prepared as described in the previous step), 2-trifluoromethyl-phenyl-boronic acid (786 mg, 4.14 mmol), Cs2CO3 (2.81 g, 8.62 mmol) and Pd(dppf)2.DCM (282 mg, 0.345 mmol) in 1,4-dioxane (12 mL) was added water (5 mL). The resulting mixture was stirred at 110° C. under microwave irradiation for 2 h and then cooled to room temperature. The resulting mixture was treated with of EtOAc (50 mL), then washed with H2O and brine and was dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5:95-40:60 EtOAc-hexanes) yielded 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine as a light brown solid. 1H-NMR (400 MHz, CDCl3) δ: 7.76 (d, J=7.8 Hz, 1H), 7.51-7.65 (m, 2H), 7.46 (d, J=7.3 Hz, 1H), 6.41 (s, 1H), 6.08 (br. s., 2H), 4.50 (t, J=5.3 Hz, 2H), 3.95 (t, J=5.3 Hz, 2H), 0.89 (s, 9H), 0.07 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calculated For C20H26F3N3O4Si: 458.1 (M+H), Measured: 458.0.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:9][C:8]=1[CH3:18])(=O)=O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C]=O.[C:59]([O:62]CC)(=[O:61])C>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][C:8]1[CH:9]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[C:12]([CH3:13])[C:7]=1[C:59]([OH:62])=[O:61]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cc(C)c(OS(=O)(=O)C(F)(F)F)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)c(C(=O)O)c(C)c1
Temperature: 80 °C

Procedure:
To a solution of trifluoromethanesulfonic acid, 4-(methoxycarbonyl)-2,6-dimethylphenyl ester (3.12 g, 10 mmol) in acetonitrile (80 mL) and water (10 mL) at 25° C. is added palladium (II) acetate (224.5 mg, 1.0 mmol), 1,3-bis(diphenylphosphino)propane (412.5 mg, 10 mmol), followed by triethylamine (2.79 mL, 20 mmol). The reaction is then pressurized to 40 psi with carbon monoxide and heated to 80° C. for 4 h. The mixture is diluted with ethyl acetate (500 mL) and is washed with water (250 mL) containing 5 mL of triethylamine. The separated aqueous layer is re-extracted with ethyl acetate (2×250 mL) and the combined organic layers are discarded. The aqueous phase is then adjusted with 1N hydrochloric acid solution to pH 2 and is extracted with ethyl acetate (500 mL). The organic extract is washed with water (250 mL) and brine (250 mL), then is dried (MgSO4), filtered and evaporated in vacuo to yield 2,6-dimethyl-4-(methoxycarbonyl)benzoic acid.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=O)=[CH:11][CH:10]=1.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[N:1]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(N)CO
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2=NC(C)(C)CO2)cc1
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A solution of 2-amino-2-methyl-propan-1-ol (104.5 g, 1.17 moles) in CH2Cl2 (400 ml) under N2 was dropwise added in 30 minutes with a solution of 4-methoxybenzoyl chloride (100 g, 0.59 moles) in CH2Cl2 (500 ml), keeping the temperature at about 18° C. with water/ice. After 3 hours under stirring the precipitate was filtered over celite and washed with CH2Cl2. The organic phase was stirred under N2 at 2° C. and dropwise added with thionyl chloride (123 ml, 1.77 moles), keeping the temperature below 10° C. At the end of the dropping the reaction mixture was stirred overnight, then concentrated under vacuum. The residue was taken up in 5% HCl and twice extracted with ethyl ether. The extracts were in turn extracted with 5% HCl. The aqueous phase was alkalinised with concentrated NaOH and extracted three times with ethyl ether, then anhydrified and concentrated under vacuum. The crude was distilled at 95-98° C. (30 Pascal) to give 106.43 g of the title compound (yield: 87.6%).