Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:42]=[CH:41][C:18]([CH2:19][N:20]([C:24]2[S:25][C:26]([CH2:35][CH2:36][C:37]([O:39]C)=[O:38])=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)[CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.[ClH:51]>CO.O>[ClH:51].[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:42]=[CH:41][C:18]([CH2:19][N:20]([C:24]2[S:25][C:26]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)[CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=1
Reactant: CCCN(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1nc(-c2ccccc2)c(CCC(=O)OC)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCN(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1nc(-c2ccccc2)c(CCC(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A mixture of methyl 3-[2-[N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-N-(1-propyl)amino]-4-phenyl-5-thiazolyl]propionate (537 mg), lithium hydroxide hydrate (116 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (2.8 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. A mixture of the obtained colorless oil, 10% hydrochloric acid-methanol (3 ml) and diethyl ether (30 ml) was stirred at room temperature for 10 min. and concentrated to give 3-[2-[N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-N-(1-propyl)amino]-4-phenyl-5-thiazolyl]propionic acid hydrochloride (576 mg, yield 97%) as a colorless amorphous form.
Reaction SMILES: [NH2:1][C:2]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:14][C:15](=[CH2:18])[CH:16]=O>C(O)(=O)C>[CH3:18][C:15]1[CH:14]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:1][CH:16]=1
Reactant: CCOC(=O)C=C(N)C(=O)OCC
Reactant: C=C(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)cnc1C(=O)OCC
Temperature: 80 °C
Yield: 28.7 %

Procedure:
Ethyl β-amino-β-ethoxycarbonylacrylate 18.7 g (0.1 mol), 2-methyl-2-propenal 7.5 g (0.107 mol), and glacial acetic acid 50 g were placed in a 100 ml four neck distillation flask with a reflux condenser and the temperature of the mixture was raised to 80° C. on an oil bath over a period of 1 hour. Then, the mixture was reacted at 80° to 85° C. for 5 hours. After completion of the reaction, the reaction mixture was distilled to give 6.8 g of 5-methyl-2,3-diethoxycarbonylpyridine (bp3.5 : 160° to 161° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[OH:21].I[CH2:23][CH2:24][CH3:25]>CN(C)C=O>[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[O:21][CH2:23][CH2:24][CH3:25]
Reactant: COCOc1ccc(O)c(OCOC)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(OCOC)cc1OCOC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Potassium carbonate (322 mg, 2.33 mmol) was added to 3b (50 mg, 0.233 mmol) in N,N-dimethylformamide (2.33 mL) at room temperature. After 10 minutes, iodopropane (226 μL, 2.33 mmol) was added and the solution was heated to reflux for 12 hours. Upon cooling to room temperature, the solution was extracted with EtOAc (3×10 mL); combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (SiO2, 5:1 Hexane:EtOAc) to afford 4b as a yellow oil (36.4 mg, 61%): 1H NMR (CD2Cl2, 400 MHz) 6.87 (s, 1H), 6.84 (d, J=2.9 Hz, 1H), 6.68 (dd, J=11.7, 2.8 Hz, 1H), 5.19 (s, 2H), 5.12 (s, 2H), 3.93 (t, J=6.6 Hz, 2H), 3.53 (s, 3H), 3.49 (s, 3H), 1.86-1.78 (m, 2H), 1.06 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 150.6, 146.5, 143.8, 113.7, 108.5, 106.6, 94.7, 94.2, 70.3, 55.2, 54.9, 21.6, 9.5; IR (film) νmax 2961, 2826, 1595, 1506, 1400, 1261, 1154, 1013, 1076, 924, 800 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C13H20O5, 257.1389; found, 257.1410; [M+Na]+ calcd for C13H20O5, 279.1208; found, 279.1165.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26].O>C1COCC1>[CH3:26][CH:25]([CH3:27])[CH2:24][CH2:23][CH2:22][CH2:21][C:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CCCC1
Reactant: CC(C)CCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(CCCCC(C)C)CCCC1
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
To a solution of methyl cyclopentanecarboxylate (300 mg, 2.3 mmol) in THF (20 ml) at −78° C. was added LHMDS (4.6 mL, 4.6 mmol) and stirred for 30 min, and followed by 1-bromo-5-methylhexane (626 mg, 3.5 mmol). The mixture was stirred from −78° C. to rt over 16 hr, before 30 ml of H2O was added and then was extracted with CH2Cl2 (2×30 mL). The combined extracts were washed with water, dried over MgSO4, filtered and concentrated, then purified using flash chromatography to give an oil (110 mg, 21%). MS [M+H]+333.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].Cl>CCOCC>[CH2:13]([N:16]([CH2:17][CH2:18][CH3:19])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:14][CH3:15]
Reactant: CCCNCCC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCOCC
Product: CCCN(CCC)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
An amount of 37.1 gm (0.2 mol) of p-nitrobenzoyl chloride in 300 ml of ether were added dropwise, with agitation and at room temperature, into a solution of 50.6 gm (0.5 mol) of dipropylamine in 400 of ether. Then, the mixture was agitated for one hour at room temperature and one hour at boiling temperature, the reaction mixture was treated with dilute hydrochloric acid, and the ether phase washed with water and evaporated. An amount of 44.3 gm of p-nitrobenzoic acid dipropylamide in the form of a light-yellow, oily residue was obtained.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[CH2:5](O)[CH2:6][CH:7]([OH:9])[CH3:8]>>[CH:3]([CH:1]1[O:9][CH:7]([CH3:8])[CH2:6][CH2:5][O:2]1)=[CH2:4]
Reactant: CC(O)CCO
Reactant: C=CC=O
Product: C=CC1OCCC(C)O1

Procedure:
Acrolein and 1,3-butanediol were condensed to produce 2-vinyl-4-methyl-1,3-dioxane in accordance with the procedure of Example I.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@@:10]2([CH2:12][OH:13])[C@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])[CH3:2].[H-].[Na+].IC.[C:25]([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@@:10]2([CH2:12][O:13][CH3:25])[C@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@]2(CO)C[C@@H]2N1C(=O)OC(C)(C)C
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@]2(COC)C[C@@H]2N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(1R,3S,5S) and (1S,3S,5R)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester as mixture of diastereoisomers (35:65 (1R,3S,5S)/(1S,3S,5R)) (840 mg, 2.94 mmol) were slowly added at 0° C. under Argon to a suspension of NaH (60% in mineral oil, 141 mg, 3.53 mmol) in THF (9 mL). The reaction mixture was stirred at 0° C. for 30 min and iodomethane (0.28 mL, 4.42 mmol) was added slowly at 0° C. The reaction mixture was further stirred at RT overnight. Saturated NaHCO3 and CH2Cl2 were added, the layers were separated and the aqueous one back-extracted twice with CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 2:8) to give the title compound as an unseparable mixture of diastereosisomers. TLC, Rf (c-hexane/EtOAc 1:1)=0.70; MS (UPLC/MS): 300.3 [M+H]+, 599.5 [2M+H]+; tR (HPLC conditions a): 3.45 min. The absolute stereochemistry of the diastereoisomers was tentatively assigned by NMR and based on the test results for the final compounds Example 214 and Example 184 in the biological assay.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[CH2:19][NH2:20]>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The compound was prepared as in Example 5 from 1-(4-carbomethoxymethoxyphenyl)propan-2-one (2.22 g) and 2-hydroxy-2-(3-trifluoromethylphenyl) ethanamine (2.05 g). The compound crystallised from hexane m.p. 70°-85° as a 1:1 mixture of diastereoisomers.
Reaction SMILES: C1C2C(CCCC2)CCC1.[CH3:11][S:12][C:13]1[C:14](C(O)=O)=[N:15][C:16]([S:19][CH3:20])=[CH:17][CH:18]=1.Cl>>[CH3:20][S:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][CH3:11])=[CH:14][N:15]=1
Reactant: CSc1ccc(SC)c(C(=O)O)n1
Agent: Cl
Solvent: C1CCC2CCCCC2C1
Product: CSc1ccc(SC)nc1
Temperature: 175 °C
Yield: 65.5 %

Procedure:
To 75 ml of decahydronaphthalene was added portionwise while heating 59.5 g of 3,6-bis(methylthio)-2-pyridinecarboxylic acid. When the mixture reached 155° C., gas bubbles began to appear. The reaction was heated at 175° C. until no more bubbles appeared. Upon cooling the decahydronaphthalene solution was treated with 40 ml of 6 normal (N) HCl in three portions resulting in the formation of a solid which was collected. The solid was covered with water. The aqueous layer and solid were then made basic with 50% NaOH and extracted with ether. The ether solution was treated with charcoal, dried and the ether removed, which gave 31 g (66% yield) of a yellow oil. A portion of this oil was placed on a Kugelrohr distillation apparatus and the product, 2,5-bis(methylthio)pyridine recovered, at 90° C. at a pressure of 0.1 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[C:13](O)(=[O:15])[CH3:14].C(OC(=O)C)(=O)C>O>[C:13]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12])(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: COc1ccc([N+](=O)[O-])cc1N
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1NC(C)=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
504 g (3 mol) of 2-amino-4-nitro-1-methoxybenzene are introduced into 860 ml of acetic acid and 600 ml of water (or the combined main filtrate and first wash filtrate of a previous batch) and the mixture is heated to 80° C. 358 g (3.2 mol) of acetic anhydride are added dropwise in the course of 10 minutes. The mixture is subsequently stirred at 80° C. for 4 hours, and then cooled to room temperature, while stirring, by removing the heating bath and finally to 15° C. The pale yellow needles which have precipitated are filtered off with suction, washed with 300 ml of 60% strength acetic acid and 1500 ml of water in several portions and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1([CH:15](O)[CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: OC(CCN1CCN(c2ccccc2)CC1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OC(CCN2CCN(c3ccccc3)CC2)c2ccccc2)cc1
Reaction time: 48 h
Yield: 28.9 %

Procedure:
In a stirring solution of THF (10 mL) under N2, 2 equivalents of 4-fluorophenol (1.40 g, 12.4 mmol) was added to a solution of 1-Phenyl-3-(4-phenyl-piperazin-1-yl)-propan-1-ol (20) (1.84 g, 6.22 mmol) and allowed to dissolve. 1.5 equivalents of triphenylphosphine, PPh3, (2.49 g, 9.32 mmol) was then added and dissolved. After the reaction was allowed to equilibrate at a temperature between 10-15° C., 1.5 equivalents of diisopropyl azodicarboxylate, DLAD, (1.85 mL, 9.32 mmol) was added dropwise. The reaction was then allowed to return to room temperature and continued stirring for 48 hours. The solvent was then evaporated under reduced pressure and aspirated under vacuum for an extended period. Purification was performed by Flash Column Chromatography on silica gel by first washing with 500 mL of 10% EtOAc/hexanes and then extracting with 20% EtOAc/hexanes. Analytical thin-layer chromatography showed that the desired product had an Rf value of approximately 0.56 when developed in 30% EtOAc/hexanes. The fractions containing the desired product were combined, and the solvent was removed under reduced pressure. 0.70 g of the product 1a (1.795 mmol, 29%) was obtained as a yellow, clear oil. 1H-NMR (CDCl3): δ 7.29 (7H, m), 6.93 (2H, d, J=7.93 Hz), 6.86 (5H, m), 5.16 (1H, dd, J=5.00, 4.96 Hz), 3.21 (4H, t, J=4.85, 5.10 Hz), 2.60 (6H, m), 2.23 (1H, sextuplet, J=7.26, 6.75, 7.44, 6.91, 7.72 Hz), 2.02 (1H, m). 13C-NMR (CDCl3): δ 155.62, 154.34, 151.28, 141.61, 129.11, 128.63, 127.69, 126.02, 119.72, 117.15, 117.04, 116.09, 115.80, 115.50, 79.34, 54.62, 53.26, 49.15, 35.96. 19F-NMR(CDCl3): δ −123.77.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[CH3:9][C:10]([S:13]([NH2:15])=[O:14])([CH3:12])[CH3:11]>ClCCl>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1/[CH:7]=[N:15]/[S:13]([C:10]([CH3:12])([CH3:11])[CH3:9])=[O:14]
Reactant: Cn1ccnc1C=O
Reactant: CC(C)(C)S(N)=O
Solvent: ClCCl
Product: Cn1ccnc1/C=N/S(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.8 %

Procedure:
In a 25 mL vial, cupric sulfate (1.96 g, 12.3 mmol), 1-methyl-1H-imidazole-2-carbaldehyde (450 mg, 4.09 mmol) and 2-methylpropane-2-sulfinamide (594 mg, 4.9 mmol) were combined with dichloromethane (2 ml) to give a light blue suspension. The reaction mixture was stirred at 25° C. for 15 h then filtered through Celite. The reaction mixture was filtered again through silica gel eluting with ethyl acetate. The crude reaction mixture was concentrated in vacuo to provide 670 mg (76%) of 2-methyl-propane-2-sulfinic acid 1-(1-methyl-1H-imidazol-2-yl)-meth-(E)-ylideneamide as an oil. 1H NMR (300 MHz, CDCl3): δ 8.62 (s, 1H), 7.27 (bs, 1H), 7.08 (bs, 1H), 4.02 (s, 1H), 1.26 (s, 9H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[NH:9][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>CN(C)C(=O)C.O>[CH2:23]([N:12]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:9]=[C:8]1[CH3:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1nc(C)[nH]c1C(=O)OCC
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1nc(C)n(Cc2ccccc2)c1C(=O)OCC
Reaction time: 0.5 h

Procedure:
5.21 g of potassium t-butoxide were added to a solution of 10.0 g of diethyl 2-methylimidazole-4,5-dicarboxylate in 100 ml of N,N-dimethylacetamide, whilst ice-cooling and under a nitrogen atmosphere. The mixture was stirred for 30 minutes, until a homogeneous solution was obtained, and then 5.78 ml of benzyl bromide were added dropwise to this solution, whilst ice-cooling. The resulting mixture was stirred at room temperature for 1 hour, after which it was mixed with ethyl acetate and water and shaken. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 12.38 g of the title compound as a syrup.
Reaction SMILES: [CH:1]1[C:2]([C:10]([O:12][CH3:13])=[O:11])=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[C:14]([O-])(=[O:16])[CH3:15].[Na+]>C(OC(=O)C)(=O)C>[C:14]([C:3]1[N:4]2[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]2)=[CH:1][C:2]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cc2ccccn2c1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2ccccn2c1C(C)=O
Yield: 99.2 %

Procedure:
A stirred solution of 2-indolizinecarboxylic acid, methyl ester (91.42 g, 0.522 mole) and anhydrous sodium acetate (42.53 g, 0.52 mole) in acetic anhydride (1.1 L) was refluxed, under anhydrous conditions, for 48 hours. After cooling most of the acetic anhydride was evaporated in vacuo. The resulting residue (150 ml) was cooled in an ice water bath and methanol (140 ml) was added to destroy the remaining acetic anhydride. The resulting mixture was poured into water (1.1 L) and the product was extracted with diethyl ether, three times. The ethereal layer was washed with saturated sodium bicarbonate solution, three times, with water, two times, and was dried over magnesium sulfate. Evaporation of solvent yielded 112 g of crude 3-acetyl-2-indolizinecarboxylic acid, methyl ester which was chromatographed on silica gel (3 kg) using 10% acetone in benzene as eluant, to afford the pure compound (85.5 g). For analysis, the product was recrystallized from a mixture of diethyl ether and petroleum ether.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][C:2]1([CH3:1])[CH2:7][CH2:6][CH:5]([NH:17][NH:16][C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][CH2:3]1)[CH3:14]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)CC1(C)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)CC1(C)CCC(NNC(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 72.3 %

Procedure:
Ethyl 2-(1-methyl-4-oxocyclohexyl)acetate (1.5 g, 7.57 mmol) and tert-butyl carbazate (1.100 g, 8.32 mmol) were dissolved in chloroform (30 mL), and AcOH (1.0 mL) and NaBH(OAc)3 (5.65 g) were added under ice-cooling. The mixture was allowed to gradually return to room temperature, and the mixture was stirred for 4 h. The reaction mixture was poured into saturated aqueous NaHCO3 solution, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:EtOAc, 100%-35%) to give tert-butyl 2-(4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)hydrazinecarboxylate (1.72 g, 5.47 mmol, 72.3% yield) as a mixture of isomers (colorless oil). LCMS=315.4 (M+H)+.
Reaction SMILES: [CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18](B5OC(C)(C)C(C)(C)O5)=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:32]([NH2:34])=[O:33])=[CH:12][N:11]=2)[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1.CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].[I-:51].[Na+]>C1COCC1.O.CCOC(C)=O>[CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([I:51])=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:32]([NH2:34])=[O:33])=[CH:12][N:11]=2)[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1
Reactant: [I-]
Reactant: CC1(C)OB(c2ccc3c(c2)[nH]c2c(C(N)=O)cnc(N[C@H](C4CC4)C(F)(F)F)c23)OC1(C)C
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(I)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[4,3-b]indole-4-carboxamide (0.17 g, 0.35 mmol) in THF (0.88 mL) and water (0.88 mL) were added chloramine T trihydrate (0.11 g, 0.39 mmol) and sodium iodide (0.079 g, 0.53 mmol). The reaction mixture was left to stir at room temperature for 2 h, diluted with EtOAc, and washed with water and brine. The organic layer was dried (sodium sulfate), concentrated, and purified by prep-HPLC to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].BrC1SC(C)=CC=1C(O)=O.S(Cl)(Cl)=O.[NH2:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[OH:33].C(OC(C)C)(C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.N1C=CC=CC=1>[OH:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([CH3:32])[C:26]=1[NH:25][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[S:3][C:2]=1[Br:1])=[O:8]
Reactant: Cc1cc(C(=O)Cl)c(Br)s1
Reactant: Cc1cccc(O)c1N
Agent: Cc1cc(C(=O)O)c(Br)s1
Solvent: CC(C)OC(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2c(C)cccc2O)c(Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
2-Bromo-5-methyl-3-thiophenecarbonyl chloride (2.6 g), prepared in the same manner as above from 2-bromo-5-methyl-3-thiophenecarboxylic acid and thionyl chloride, was suspended in toluene (20 ml). This toluene solution was added dropwise to a solution of 2-amino-3-methylphenol (1.4 g) in pyridine (30 ml) at 0° C. The mixture was stirred at room temperature for 3 hours and diisopropyl ether-ethyl acetate was added. The solvent was evaporated under reduced pressure. The precipitated crystals were collected by filtration, and washed with diluted hydrochloric acid and diisopropyl ether to give N-(2-hydroxy-6-methylphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide (3.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:5](COCC[Si](C)(C)C)[CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>COCCOC.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:5][CH:6]=1
Reactant: CCOC(=O)/C=C/c1cc(Br)cn1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)/C=C/c1cc(Br)c[nH]1
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 78.2 %

Procedure:
A mixture of ethyl (2E)-3-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)acrylate (200 mg) obtained in Step C of Example 7 and tetra-n-butylammonium fluoride (698 mg) in DME (2 mL) was stirred at 85° C. for 2.5 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (102 mg).