Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25](Br)[CH:26]=O)[CH:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:19]2=[O:37])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:38]([NH2:40])=[S:39]>O1CCCC1.C(OCC)(=O)C>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:39][CH:38]=[N:40][CH:26]=1)[CH:20]([NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[C:19]2=[O:37])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CSC12
Reactant: NC=S
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cncs3)CSC12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (mixture of the epimeric bromoaldehydes) (2.34 g) and thioformamide (0.3 g) in dry tetrahydrofuran (23 cc) is stirred for 3 hours at 20° and then heated for 90 minutes at 50° C. The reaction mixture is diluted with ethyl acetate (160 cc) and washed with a saturated solution of sodium bicarbonate (100 cc) and then with a semi-saturated solution of sodium chloride (100 cc). After drying of the organic layer over magnesium sulphate and evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C., the residue obtained is subjected to chromatography on a column (height: 30 cm; diameter: 2.5 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.8 bar (80 kPa) with a 70/30 (by volume) mixture of cyclohexane and ethyl acetate, and 50 cc fractions being collected. Fractions 16 to 25, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C., and the residue is triturated in isopropyl ether (50 cc). After filtration and drying, 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(thiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.85 g) is obtained in the form of a cream-coloured solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]([C:25]([NH2:27])=[O:26])=[N:12][C:13]([CH:22]([CH3:24])[CH3:23])=[C:14]([O:16][C@@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[N:15]=2)[CH:6]=[N:5]1.C(N(C(C)C)CC)(C)C.[C:37](Cl)(=[O:40])[CH:38]=[CH2:39]>C(Cl)(Cl)Cl>[C:37]([N:19]1[CH2:20][CH2:21][C@@H:17]([O:16][C:14]2[N:15]=[C:10]([NH:9][C:7]3[CH:6]=[N:5][N:4]([CH2:3][CH2:2][OH:1])[CH:8]=3)[C:11]([C:25]([NH2:27])=[O:26])=[N:12][C:13]=2[CH:22]([CH3:23])[CH3:24])[CH2:18]1)(=[O:40])[CH:38]=[CH2:39]
Reactant: C=CC(=O)Cl
Reactant: CC(C)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1O[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C=CC(=O)N1CC[C@@H](Oc2nc(Nc3cnn(CCO)c3)c(C(N)=O)nc2C(C)C)C1
Reaction time: 1 h

Procedure:
To a mixture of 3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-isopropyl-5-[(3R)-pyrrolidin-3-yloxy]pyrazine-2-carboxamide (476 mg), chloroform (5 mL), and diisopropylethylamine (867 μL) was added acryloyl chloride (226 μL) at 0° C., followed by stirring at the same temperature for 1 hour. The solvent of the reactant was evaporated, and then to the obtained residue were added tetrahydrofuran (5 mL) and a 1 M aqueous sodium hydroxide solution (5 mL), followed by stirring at 50° C. for 4 hours. After leaving to be cooled, the mixture was extracted by the addition of chloroform, and the organic phase was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=980:18:2-90:9:1), and then washed with diisopropyl ether to obtain 5-{[(3R)-1-acryloylpyrrolidin-3-yl]oxy}-3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-isopropylpyrazine-2-carboxamide (343 mg) as a yellow solid.
Reaction SMILES: Cl.O1CCO[CH2:4][CH2:3]1.[Cl:8][C:9]1[C:17]2[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25](=O)[O:26]C(C)(C)C)[CH2:19]3)=[N:15][C:14]([NH:32][C:33]3[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=3)=[N:13][C:12]=2[NH:11][CH:10]=1.C(Cl)(=O)C=C>CO>[Cl:8][C:9]1[C:17]2[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:26])[CH:3]=[CH2:4])[CH2:19]3)=[N:15][C:14]([NH:32][C:33]3[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=3)=[N:13][C:12]=2[NH:11][CH:10]=1
Reactant: Cn1cc(Nc2nc(N3CCCC(NC(=O)OC(C)(C)C)C3)c3c(Cl)c[nH]c3n2)cn1
Reactant: C1COCCO1
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: CO
Product: C=CC(=O)N[C@@H]1CCCN(c2nc(Nc3cnn(C)c3)nc3[nH]cc(Cl)c23)C1
Reaction time: 24 h
Yield: 81.1 %

Procedure:
A solution of 4 M HCl in 1,4-dioxane (0.31 mL, 1.3 mmol) was added to a solution of tert-butyl (1-{5-chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}piperidin-3-yl)carbamate (56 mg, 0.12 mmol) in methanol (1.3 mL). After 24 hrs, the mixture was concentrated to dryness by rotary evaporation. The resulting residue was suspended in EtOAc (2.5 mL) and saturated aqueous sodium bicarcarbonate solution (1.3 mL). Acryloyl chloride (13 μL, 0.16 mmol) was added and the mixture was stirred for 1 hr. The organic layer was separated, dried over MgSO4 and evaporated to give the title compound (39 mg, 69% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.40 (br. s., 1H), 8.76 (s, 1H), 8.14 (d, J=7.82 Hz, 1H), 7.83 (s, 1H), 7.47 (s, 1H), 7.05 (d, J=2.45 Hz, 1H), 6.19-6.31 (m, 1H), 6.07-6.16 (m, 1H), 5.60 (dd, J=10.03, 2.45 Hz, 1H), 4.13 (d, J=12.23 Hz, 1H), 4.03 (d, J=12.72 Hz, 1H), 3.85-3.98 (m, 1H), 3.77 (s, 3H), 2.96 (t, J=11.25 Hz, 1H), 2.80 (t, J=11.13 Hz, 1H), 1.89-2.00 (m, 1H), 1.79-1.88 (m, 1H), 1.67-1.79 (m, 1H), 1.40-1.57 (m, 1H). m/z (APCI+) for C18H21ClN8O 401.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][C@H:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[N:12]1[C:18](Cl)=[O:19].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:18]([N:12]2[C@H:13]([CH3:17])[CH2:14][CH2:15][CH2:16][C@@H:11]2[CH3:10])=[O:19])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: C[C@@H]1CCC[C@H](C)N1C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1C(=O)NNc1ccc(F)cn1
Yield: 69.6 %

Procedure:
A solution of (5-fluoro-pyridine-2-yl)-hydrazine (21.7 g, 171 mmol), Intermediate 3a (31.5 g, 180 mmol) and DIPEA (44.7 mmol, 256 mmol) in DCM (350 mL) was stirred at RT for 4 days. Water (350 mL) was added, then the aqueous layer extracted with DCM (100 mL). The combined organic extracts were passed through a hydrophobic fit and concentrated under vacuum to leave a solid. Trituration with diethyl ether/pentane (1:4, 150 mL), and drying under vacuum at 50° C., gave Intermediate 3b (31.7 g, 70%, ˜90% purity). LCMS: Rt 2.58 min, m/z 289 [MH+]. 1H NMR (300 MHz, CDCl3): 1.29 (6H, d, J=7.0 Hz), 1.45-1.89 (6H, m), 4.26 (2H, apparent quin, J=6.5 Hz), 6.53 (1H, s), 6.65 (1H, br s), 6.77 (1H, dd, J=9.0, 3.6 Hz), 7.29-7.28 (1H, ddd, J=9.0, 8.0, 3.0), 8.02 (1H, d, J=2.9 Hz).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][N:13]3[C:18]([C:19]=2[CH3:20])=[C:17]([CH:21]2[CH2:23][CH2:22]2)[CH:16]=[C:15]([C:24]([O:26]CC)=[O:25])[C:14]3=[O:29])[CH:7]=[CH:8][CH:9]=1>CO>[NH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][N:13]3[C:18]([C:19]=2[CH3:20])=[C:17]([CH:21]2[CH2:23][CH2:22]2)[CH:16]=[C:15]([C:24]([OH:26])=[O:25])[C:14]3=[O:29])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(N)c3)ccn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(-c2cccc(N)c2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
2 ml of methanol and 0.5 ml of 1 N sodium hydroxide were added to 51 mg of ethyl 8-(3-aminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate, and they were stirred at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and then dissolved in 10 ml of water. The obtained solution was neutralized with 1 N hydrochloric acid. The crystals thus formed were taken by the filtration to obtain 36 mg of 8-(3-aminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][NH:30][N:29]=1)[CH3:26].O>CN(C)C=O>[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][N:30]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:16][C:17]=3[CH3:18])=[CH:7][CH:6]=2)[N:29]=1)[CH3:26]
Reactant: CCOC(=O)Cc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (551 mg), ethyl 3-ethoxy-1H-pyrazol-4-ylacetate (347 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-ylacetate (608 mg, yield: 73%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: O=C(CCl)N1CCCC1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCC3)c(F)c2)C(C)C)c1
Yield: 44.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.5 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH2:26]Br)[CH:7]=1)[CH3:2].[CH3:29][CH:30]([SH:32])[CH3:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH2:26][S:32][CH:30]([CH3:31])[CH3:29])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Oc2ccc([N+](=O)[O-])cc2CBr)cc(C(F)(F)F)c1
Reactant: CC(C)S
Product: CCOC(=O)Cc1cc(Oc2ccc([N+](=O)[O-])cc2CSC(C)C)cc(C(F)(F)F)c1

Procedure:
As described for Example 21, [3-(2-bromomethyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester and 2-propanethiol were reacted to provide [3-(2-isopropylsulfanylmethyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester. Reduction to amine and then treatment of the amine with pivaloyl chloride was carried out to provide {3-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided the acid.
Reaction SMILES: O.[CH2:2]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)[CH2:11][C:12]([O:14]C)=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:2]([NH:9][C@H:10]([C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)[CH2:11][C:12]([OH:14])=[O:13])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC(NCc1ccccc1)c1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C[C@H](NCc1ccccc1)c1ccc2c(c1)OCO2
Temperature: 30 °C
Reaction time: 20 h

Procedure:
To 4 mL of water were added 400 mg (1.28 mmol) of methyl (±)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate and 107 mg (1.28 mmol) of sodium hydrogen carbonate, and the mixture was maintained to 30° C. To the resulting mixture was added 2 mg of lipase (CAL; available from Roche, CHIRAZYME L-2 (trade name)) originated from Candida antarctica at the same temperature, and the mixture was reacted at 30° C. while stirring. After 20 hours, at the time when the conversion rate of the starting materials reached 46.2%, 8 ml of ethyl acetate and 112 mg of sodium hydrogen carbonate were added to the reaction mixture and the aqueous layer was extracted. The resulting aqueous layer was adjusted to an inner pH of 2.0 with 2 mol/L of hydrochloric acid aqueous solution, and 8 ml of ethyl acetate and 500 mg of sodium chloride were added to the mixture to extract the organic layer. The resulting organic layer was dried over magnesium sulfate, filtered and concentrated to obtain 135 mg (Isolated yield based on methyl (±)-3-benzylamino-3-(4-fluorophenyl)propionate=35.3%) of (R) or (S)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionic acid as white crystal.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.[S:20](Cl)([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21].CCOC(C)=O>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[S:20]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[O:1][CH:5]=[N:4][N:3]=2)=[CH:7][CH:8]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: Oc1ccc(-c2nnco2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccc(-c2nnco2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
A solution of 4-(1,3,4-oxadiazol-2-yl)phenol (1.05 g, 6.48 mmol) and triethylamine (1.82 mL, 13.0 mmol) in CH2Cl2 (12 mL) was cooled to 0° C. and treated with triflic chloride (0.83 mL, 7.77 mmol). The resultant orange-colored reaction was stirred 30 min at 0° C. and 30 min at RT. The reaction was poured into EtOAc (50 mL), washed with water (20 mL), satd aq NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4) and concentrated in vacuo to provide 4-(1,3,4-Oxadiazol-2-yl)phenyl trifluoromethanesulfonate (1.94 g, 102% yield) as a beige-colored solid. 1H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1 H), 8.22 (d, J=8.6 Hz, 2 H), 7.78 (d, J=8.6 Hz, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]([CH3:35])([OH:34])[CH3:33]>C(#N)C.O>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:23][N:22]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[CH2:21][CH2:20][C:6]1=2
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(CC(C)(C)O)C1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of 2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (200 mg, 0.651 mmol) in acetonitrile (4 mL), potassium carbonate (270 mg, 1.95 mmol) and 1-chloro-2-methyl-propan-2-ol (105 mg, 0.977 mmol) were added and the reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Neutral alumina, 1% MeOH-DCM), to yield 1-[5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-2-methyl-propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.6 (d, 2H), 7.27 (m, 2H), 7.2 (m, 2H), 7.0 (d, 1H), 5.08 (t, 1H), 4.19 (m, 2H), 3.9 (bs, 2H), 3.0-3.1 (m, 2H), 2.9 (m, 1H), 2.6 (s, 2H), 2.56 (m, 1H), 2.21 (s, 3H), 1.21 (s, 6H). Separation by chiral HPLC provides enantiomers II-84a-b.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]([N:18]1[CH:22]=[C:21]([CH3:23])[C:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:19]1[C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:11]([N:18]1[C:19]([C:31]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[O:32])=[C:20]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:21]([CH3:23])=[C:22]1[CH:4]=[O:5])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C=O
Reactant: Cc1cn(Cc2ccccc2)c(C(=O)N2CCOCC2)c1-c1ccc(Cl)cc1
Agent: On1nnc2cccnc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCOCC2)n(Cc2ccccc2)c1C=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
To an ice-cold solution of DMF (0.441 mL, 5.70 mmol) in DCM (5 mL) was added POCl3 (0.425 mL, 4.56 mmol). After stirring the reaction mixture at 0° C. for 15 min, a solution of (1-benzyl-3-(4-chlorophenyl)-4-methyl-1H-pyrrol-2-yl)(morpholino)methanone [obtained via standard EDI/HOAt coupling of ACI-02 with morpholine] (900 mg, 2.28 mmol) in DCM (1 mL) was dropwise added. The reaction was stirred for 30 min, then the ice-bath was removed and stirring was continued at room temperature for 1 h. The reaction mixture was cooled to 0° C., then saturated aqueous NaHCO3 was added while vigorously stirring, until the mixture was neutralised. The mixture was extracted with DCM, washed with brine and concentrated. The residue was dissolved in i-PrOH and precipitated with H2O. The precipitate was filtered, washed with i-PrOH/H2O (1:1, 2×) and MeOH (2×) and dried on for a couple of hours to give the desired product (761 mg, 79%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[N:20][CH:21]=1)#[CH:15].C(N(CC)C(C)C)(C)C>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>[C:23]([NH:22][C:19]1[N:20]=[CH:21][C:16]([C:14]#[C:15][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=2[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:17][CH:18]=1)(=[O:25])[CH3:24]
Reactant: CCOC(=O)c1ccc(C)c(I)c1
Reactant: C#Cc1ccc(NC(C)=O)nc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C)c(C#Cc2ccc(NC(C)=O)nc2)c1
Temperature: 25 °C

Procedure:
A mixture of ethyl 3-iodo-4-methylbenzoate (845 mg, 2.9 mmol, 0.8 eq), N-(5-ethynylpyridin-2-yl)acetamide (3.5 mmol, 1.0 eq). Pd(PPh3)4 (51 mg, 0.044 mmol), CuI (20.4 mg, 0.11 mmol), and N,N-diisopropylethylamine (0.8 ml, 4.4 mmol) in 2 ml of DMF is heated at 55° C. (oil bath) for 1 hr under nitrogen. After cooling to r.t., the solvent is evaporated and DCM is added to dissolve the residue. The solution is washed with water and brine, dried and evaporated and the crude material is chromatographed with CombiFlash (DCM/MeOH).
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH:25]1(N=C=NC2CCCCC2)CCCC[CH2:26]1>C(Cl)Cl.CN(C=O)C>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:24]([NH-:19])[C:23]1[CH:26]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccncc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [NH-]Cc1ccccc1

Procedure:
When 5 is stirred with Z-Val-OH and pyridine in methylene chloride (24 hours, 20° C.), the carbonyl band at 1,888 cm-1 disappears and the polymeric activated ester 6a forms. A resin which has an identical IR spectrum can also be obtained by reacting 4 with Z-Val-OH and dicyclohexylcarbodiimide (DCC) in DMF. The dicyclohexylurea is removed by eluting with methanol. In order to determine the content of activated aminoacid ester, the resin 6a was reacted with benzylamine. From the amount of Z-L-Val-benzylamide formed, the proportion of active groups introduced is 0.15 mmole of Z-Val/g of resin. If the resin is reacted with Val-OMe in methylene chloride for 130 minutes at 20° C., the Z-dipeptide ester is again formed in a yield of 0.15 mmole/g of resin.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:18])[C:8](=O)[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[C:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[NH:3][N:2]=1)=[O:18])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)C1CCCCCC1=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1n[nH]c2c1CCCCC2
Yield: 72.3 %

Procedure:
Hydrazine hydrate (0.142 mL, 2.94 mmol) was added to a stirring room temperature solution of 13 (0.6229 g, 2.94 mmol) in EtOH (2.9 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC (4.5 h): The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 70:30:2 Hexanes:CH2Cl2:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 0.4428 g (72.3%) of 14. 1H (CDCl3, 400 MHz): δ 8.56 (1H, broad s), 4.30 (2H, q, J=7.1 Hz), 2.92-2.86 (2H, m), 2.73-2.78 (2H, m), 1.84-1.76 (2H, m), 1.65-1.57 (4H, m), 1.30 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 162.11, 150.70, 134.97, 124.58, 60.85, 32.33, 28.63, 28.32, 27.39, 24.42, 14.47 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 14.47; CH2 carbons: 60.85, 32.33, 28.63, 28.32, 27.39, 24.42; ppm. HPLC: 9.19 min.