Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[CH:7][C:6]2=[O:20].C([O-])(=[O:23])C.[K+].C([O-])([O-])=O.[K+].[K+].Cl>O1CCOCC1.CN(C=O)C.O.CO.C1COCC1>[OH:23][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[CH:7][C:6]2=[O:20]
Reactant: CC(=O)[O-]
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ccc(CBr)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: O=c1cc(-c2ccc(O)cc2)oc2ccc(CO)cc12
Temperature: 100 °C
Reaction time: 24 h
Yield: 39.6 %

Procedure:
To a solution of 6-bromomethyl-2-(4-hydroxyphenyl)chromen-4-one (250 mg, 0.754 mmol) in dioxane:DMF (10:2, 12 mL), was added potassium acetate (500 mg, 3.77 mmol). The mixture was heated at 100° C. for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give crude product (225 mg, 96%). To a solution of the crude product (220 mg, 0.711 mmol) in MeOH:THF (5 mL: 5 mL) was added K2CO3 (216 mg, 1.56 mmol) and the mixture was stirred for 24 h at rt. Then the reaction mixture was neutralized by dilute HCl and extracted by EtOAc, the combined organic layers were washed with water, brine, dried and concentrated to give a crude product, which was purified by column chromatography using 5% MeOH in dichloromethane, to afford 6-hydroxymethyl-2-(4-hydroxyphenyl)chromen-4-one (80 mg, 42%). MS (ES) m/z: 269.88 (M+1), 268.85 (M); Mp. 246-247° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:45]=[CH:46][CH:47]=2)/[CH:33]=[CH:34]/[C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:45]=[CH:46][CH:47]=3)/[CH:33]=[CH:34]/[C:35]3[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Reactant: COC(=O)c1ccc(/C=C/c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(/C=C/c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Yield: 37.3 %

Procedure:
To a stirred solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (150 mg, 0.46 mmol) and (E)-methyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)styryl)benzoate (200 mg, 0.55 mmol) in 25 mL of 1,4-dioxane were added Na2CO3 (100 mg, 0.94 mmol) and 3 mL of water at room temperature. Then the mixture was degassed with nitrogen for 15 minutes. Pd(PPh3)4 (40 mg, 0.035 mmol) was added in one portion and the reaction mixture was stirred at reflux for 18 hours under nitrogen. The solvent was evaporated and the residue was purified by silica gel chromatography (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate=1:1) to give (E)-methyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)styryl)benzoate (90 mg, 37%) as a yellow sold. LC-MS: 525 [M+H]+, tR=1.89 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][N:4]=1>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][N:4]=1)=[O:1]
Reactant: COC(=O)c1ccnc(CO)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COC(=O)c1ccnc(C=O)c1
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of methyl 2-(hydroxymethyl)pyridine-4-carboxylate (30 g, 179.64 mmol) in DCM (1 L) was added MnO2 (93.77 g. 1.0778 mol) at r.t. and stirred overnight. The reaction mixture was then filtered and concentrated to afford the title compound (21.3 g, 72%). [M+H] Calc'd for C8H7NO3, 166. Found, 166.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1.[CH:27]1C2C=CC3C=CC=CC=3NC=2C=C[CH:28]=1.[H-].[Na+].Br.NC1N=C(N)C2C(=NC=C(CBr)N=2)N=1>>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]3[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[CH:28]=[CH:27][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]3=4)[N:8]=2)[N:3]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: Br
Agent: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2nc(CN3c4ccccc4C=Cc4ccccc43)cnc2n1

Procedure:
N-[(2,4-Diaminopteridin-6-yl)methyl]dibenz[b,f]azepine (Formula I: Ar=2,4-diaminopteridin-6-yl; W=CH2; X=N; Z=CH═CH; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above, by using dibenz[b,f]azepine (154 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpteridine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[N:13]=2)[N:8]=[CH:7][C:6]=1Cl)=O.[NH2:18][C:19](=[S:30])[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:16][O:15][C:12]1[N:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:3]1[N:18]=[C:19]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[S:30][CH:2]=1
Reactant: COc1ccc2ncc(Cl)c(C(=O)CBr)c2n1
Reactant: CC(C)(C)OC(=O)NCCC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2nccc(-c3csc(CCNC(=O)OC(C)(C)C)n3)c2n1

Procedure:
A mixture of bromomethylketone (b) (2.07 g, 9 mmol), 1,1-dimethylethyl (3-amino-3-thioxopropyl)carbamate (1.84 g, 9 mmol) and sodium bicarbonate (0.76 g, 9 mmol) in ethanol (120 mL) was heated to reflux for 1 hour under argon. The mixture was evaporated and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic extract was washed with brine, dried and evaporated. The residue was chromatographed on silica eluting with a gradient of 0–50% ethyl acetate in dichloromethane affording a yellow solid (0.93 g, 26%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:26](OC(=O)[C@@H](N)CCC1CCCCC1)[CH3:27].N1C2C(=CC=CC=2)C=C1C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:26]([O:11][C:10](=[O:12])[C@@H:9]([NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:27]
Reactant: O=C(N[C@@H](CCC1CCCCC1)C(=O)O)c1cc2ccccc2[nH]1
Reactant: CCOC(=O)[C@@H](N)CCC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CCC1CCCCC1)NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
The title compound was prepared following the procedures of Example 22, except that in step D it uses 4-cyclohexyl-(2S)-[(1H-indole-2-carbonyl)-amino]-butyric acid instead of Methyl-(2S)-(3-methyl-benzoylamino)-pentanoic acid. The final compound is isolated as a mixture of diastereomers in a 1.5:1 ratio. HPLC-MS calcd. for C29H38N4O3 (M+H+) 491.3, found 491.5. 1H NMR (CDCl3, 400 MHz) δ 0.55-1.38 (m, 16H), 1.53-1.71 (m, 2H), 2.89 (m, 2H), 3.49 (s, 3H), 4.03 (m, 1H), 4.41 (m, 1H), 6.35-7.17 (m, 9H), 7.40 (1H, m), 9.48 (s, 1H) 4-Cyclohexyl-(2S)-[(1H-indole-2-carbonyl)-amino]-butyric acid is made by the following procedure: (+)-Ethyl-(S)-2-amino-4-cyclohexylbutyrate hydrochloride (1.643 g, 6.577 mmol, 1.0 equiv.), 2-indolecarboxylic acid (1.166 g, 7.235 mmol, 1.1 equiv.), HATU (2.750 g, 7.232 mmol, 1.1 equiv.), and CH2Cl2 (80 mL) were combined in a 100 mL r.b. flask with a magnetic stir-bar. The resulting cloudy white solution reaction was allowed to stir at room temperature for 20 minutes, upon which DIPEA (5.8 mL, 33.29 mmol, 4.6 equiv.) was added via syringe. The reaction mixture turned dark yellow in color. The resulting solution was allowed to stir at rt for 3 h. When the reaction was complete by LC/MS, it was extracted with 100 mL water, washed the organic layer with 50 mL saturated NaCl and dried over MgSO4. After evaporation of solvent, the crude mixture was purified by ISCO normal phase separation to provide (2.161 g, 6.062 mmol, 92% yield) of 4-cyclohexyl-(2S)-[(1H-indole-2-carbonyl)-amino]-butyric acid ethyl ester as a clear liquid. HPLC-MS calcd. for C21H28N2O3 (M+H+) 357.5, found 357.5.
Reaction SMILES: C[Si](C)(C)CCOC(=O)[NH:7][CH:8]1[CH2:25][N:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:11]2[CH2:10][CH:9]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:30]([O:29][C:27](=[O:28])[NH:26][CH:9]1[CH:8]([NH2:7])[CH2:25][N:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:11]2[CH2:10]1)=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1cc2c(cc1OC)C1CC(NC(=O)OC(C)(C)C)C(NC(=O)OCC[Si](C)(C)C)CN1CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1cc2c(cc1OC)C1CC(NC(=O)OC(C)(C)C)C(N)CN1CC2
Temperature: 50 °C
Yield: 95.1 %

Procedure:
A suspension of (RS,RS,RS)-(2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-carbamic acid 2-trimethylsilanyl-ethyl ester (5.22 g, 10.0 mmol) in tetrabutylammonium fluoride solution (1 M in THF, 42 mL, 42 mmol) was heated 90 min at 50° C. The resultant solution was concentrated in vacuo and chromatographed (CH2Cl2/MeOH/NH4OH 95:5:0.25) to afford the title compound (3.59 g, 95%). Light yellow solid, MS (ISP) 378.4 (M+H)+; tR=7.2 and 18.9 min (Chiralpak® AD 25×0.03 cm, heptane/ethanol/triethylamine 70:30:0.3, flow rate 4 μL/min).
Reaction SMILES: C(OC([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]1=[O:22])=O)(C)(C)C.Cl>CO.C(OCC)(=O)C>[NH2:8][N:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[C:10]1=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(N)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A solution of (3S)-1,3-bis(tert-butoxycarbonylamino)-2-pyrrolidone (3.15 g) in methanol (10 ml) was combined with a 4N solution of hydrochloric acid in ethyl acetate (20 ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the resultant residue was combined with dichloromethane (30 ml) and triethylamine (6.06 g), and then with di-tert-butyl dicarbonate (2.62 g) at 0° C. and stirred at room temperature for 1 hour. The reaction mixture was combined with an aqueous solution of sodium carbonate, extracted with dichloromethane, dried and concentrated. The residue obtained was washed with hexane to obtain (3S)-1-amino-3-(tert-butoxycarbonylamino)-2-pyrrolidone (1.89 g) as a colorless solid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16]>>[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:3][CH2:2][C:1]#[N:4])[C:10](=[O:15])[C:9]2([OH:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reactant: C=CC#N
Product: N#CCCN1C(=O)C(O)(c2ccccc2)c2cc(Cl)ccc21

Procedure:
Reaction of acrylonitrile with 5-chloro-3-phenyl-3-hydroxyindolin-2-one by a process analogous to that of Example 1 gives 5-chloro-1-(cyanoethyl)-3-hydroxy-3-phenylindolin-2-one. Hydrogenation of the 5-chloro-1-(2-cyanoethyl)-3-hydroxy-3-phenylindolin-2-one by a procedure analogous to that of Example 2 gives 1-(3-aminopropyl)-5-chloro-3-hydroxy-3-phenylindolin-2-one. Cyclodehydration of the 1-(3-aminopropyl)-5-chloro-3-hydroxy-3-phenylindolin-2-one by a procedure analogous to that of Example 3 gives 8-chloro-2,3,4,10-tetrahydro-10-phenylpyrimido [1,2-a] indol-10 -ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([CH2:20][F:21])=[CH:18][C:17]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])=[N:16]1.ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:12])([F:13])[F:14])=[O:41])=[CH:4][C:3]=1[N:15]1[C:19]([CH2:20][F:21])=[CH:18][C:17]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:28])([F:29])[F:27])=[N:16]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2CF)cc1SCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2CF)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 68.4 %

Procedure:
0.17 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-fluoromethyl-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 78 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.12 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-fluoromethyl-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)([O-:3])=[O:2].Cl.CN(C)CCCN=C=NCC.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCl>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:13]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][CH:6]=[CH:5][C:4]=3[N+:1]([O-:3])=[O:2])=[O:15])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc3cccc([N+](=O)[O-])c3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A mixture of 7-nitroindole-2-carboxylic acid (4.38 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.89 g) in dichloromethane (50 mL) was treated with piperazine-1-carboxylic acid tert-butyl ester (1.63 g) and stirred at ambient temperature for 16 h. The reaction mixture was poured into in dichloromethane (20 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-5% methanol/dichloromethane) to give 4-(7-Nitro-1H-indole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (2.17 g). This material (1.69 g) was dissolved in CH3OH (50 mL). At room temperature, ammonium formate (2.85 g) was added, followed by 10% palladium on carbon (0.47 g). The reaction mixture was heated to reflux for forty min, cooled and filtered through celite pad. The filtrate was concentrated and the residue was purified via silica gel chromatography (0-10% methanol/dichloromethane) to give 4-(7-Amino-1H-indole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (1.34 g). This material (1.3 g) was treated with 20% trifluoroacetic acid/dichloromethane (50 mL) and stirred at ambient temperature for 1 h. The solvent was removed under reduced pressure to afford (7-Amino-1H-indol-2-yl)-piperazin-1-yl-methanone trifluoroacetate salt. This intermediate was dissolved in dichloromethane (100 mL), washed with saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% 2M ammonia in methanol/dichloromethane) to give the title compound (0.824 g). 1H NMR (400 MHz, CDCl3/CD3OD): δ 7.09 (d, J=7.83 Hz, 1H), 6.95 (t, J=7.63 Hz, 1H), 6.72 (s, 1H), 6.60 (d, J=7.63 Hz, 1H), 4.20 (br s, 4H), 3.88 (br s, 4H), 2.94 (t, J=5.09 Hz, 3H). MS (electrospray): exact mass calculated for C13H16N4O, 244.13; m/z found, 245.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:28])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:14][C:15]([C:18]3[S:19][C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:21][CH:22]=3)=[N:16][N:17]=2)=[CH:8][C:7]=1[CH3:27].CCN(C(C)C)C(C)C.[C:38](O)(=[O:41])[CH2:39][OH:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[OH:41][CH2:38][C:39]([NH:1][CH2:2][CH:3]([OH:28])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:14][C:15]([C:18]3[S:19][C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:21][CH:22]=3)=[N:16][N:17]=2)=[CH:8][C:7]=1[CH3:27])=[O:40]
Reactant: O=C(O)CO
Reactant: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1OCC(O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To a solution of 1-amino-3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (109 mg, 271 μmol) in DCM (10 mL), DIPEA (140 mg, 1.086 mmol) and glycolic acid (41 mg, 543 μmol) followed by TBTU (102 mg, 319 μmol) is added at 0° C. The mixture is stirred at rt for 1 h before it is diluted with EA and washed with water. The water phase is separated and extracted once more with EA. The combined org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with DCM containing 4% of 7 N NH3 in methanol to give 2-hydroxy-N-(2-hydroxy-3-{4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propyl)-acetamide (31 mg) as a white solid; LC-MS: tR=0.94 min, [M+1]+=460.51.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)[CH:17]=1)[NH2:14].CS(O)(=O)=O>O1CCOCC1.C(OCC)(=O)C>[CH2:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:14][C:13]2[CH:15]=[C:16]([B:18]3[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:26])([CH3:25])[O:19]3)[CH:17]=[C:11]([CH3:10])[CH:12]=2)[N:7]=1)[CH3:9]
Reactant: CCc1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1ccnc(Nc2cc(C)cc(B3OC(C)(C)C(C)(C)O3)c2)n1
Temperature: 110 °C

Procedure:
A solution of 2-chloro-4-ethyl pyrimidine (0.98 g, 7.00 mmol), the product of Step 1 (1.794 g, 7.70 mmol), and methanesulfonic acid (0.50 mL, 7.70 mmol) in 1,4-dioxane (30 mL) was sealed in a 100 mL screw-top pressure flask and heated at 110° C. for 15 hours. The flask was cooled, an additional portion of 2-chloro-4-ethyl pyrimidine (0.145 g, 1.05 mmol) was added, and the flask was resealed and heated for another 6.5 hours. The reaction mixture was cooled, diluted with ethyl acetate (70 mL), washed with saturated aqueous sodium bicarbonate solution (25 mL) and brine (25 mL), dried over sodium sulfate, filtered, and concentrated. The resulting reddish brown solid 4-ethyl-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (3.44 g as a 80:20 w/w mixture with 1,4-dioxane) was used without further purification. MS ESI: [M+H]+ m/z 340.1
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:4][CH2:3][CH2:2][Br:1]
Reactant: C1=COCCC1
Reactant: OCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: BrCCOC1CCCCO1
Reaction time: 2.5 h

Procedure:
Combine 2-bromoethanol (14.2 mL, 200 mmol) and dihydropyrane (18.25 mL, 200 mmol) in dichloromethane (20 mL). Add pyridinium p-toluenesulfonic acid (5 g, 20 mmol). After 2.5 hours, dilute the reaction mixture with diethyl ether and extract with water, 1/1 water/brine, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Distill the residue to give the title compound: bp; 80-90° C. at 15-20 mm Hg.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[CH:11][C:10]=2[CH3:18])=[CH:5][CH:4]=1)=O.[CH2:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22].[BH4-].[Na+]>CO>[CH3:18][C:10]1[CH:11]=[C:12]([C:15]([NH2:17])=[O:16])[CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:1][NH:24][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:4][CH:5]=1
Reactant: Cc1cc(C(N)=O)ccc1-c1ccc(C=O)cc1
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(N)=O)ccc1-c1ccc(CNCCC(C)C)cc1
Reaction time: 12 h

Procedure:
4′-Formyl-2-methylbiphenyl-4-carboxamide (I-4a: 4.3 g, 18.0 mmol) and isoamylamine (36.2 mg, 0.425 mmol) were combined in methanol (100 ml). After 12 hours, the reaction mixture was treated with sodium borohydride (2.10 g, 53.9 mmol). After 1 hour, the reaction mixture was treated with concentrated (37%) aqueous hydrochloric acid solution and the volatiles were removed under reduced pressure. The residue was taken up in 2N sodium hydroxide and extracted with ethyl acetate (2 times). The combined organic phases were washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound (E4-01).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]([OH:13])([CH3:12])[CH3:11]>>[C:1]1([NH:7][C:8](=[O:9])[O:13][CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)O
Product: CC(C)OC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.1 %

Procedure:
A liquid mixture of 50 g (0.42 mol) of phenyl isocyanate and 6.43 ml (0.084 mol) of isopropanol was stirred at room temperature for 20 minutes and thereafter an unreacted raw material was distilled away under a reduced pressure to obtain 16.1% of isopropyl N-phenylcarbamate.