Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[I:19]I>C(Cl)(Cl)Cl.C(#N)C.FC(F)(F)C([O-])=O.[Ag+]>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:19]
Reactant: CC(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reaction time: 18 h
Yield: 106.8 %

Procedure:
Acetic acid (5R)-3-(3-fluoro-phenyl)-1,3-oxazolidin-2-one-5-ylmethyl ester (15.2 g, 60 mM) was dissolved in a mixture of chloroform (100 mL) and acetonitrile (100 mL) under nitrogen, and silver trifluoroacetate (16.96 g, 77 mM) added. Iodine (18.07 g, 71 mM) was added in portions over 30 minutes to the vigorously stirred solution, and stirring continued at ambient temperature for 18 hours. As reaction was not complete, a further portion of silver trifluoroacetate (2.64 g, 12 mM) was added and stirring continued for 18 hours. After filtration, the mixture was added to sodium thiosulfate solution (3%, 200 mL) and dichloromethane (200 mL), and the organic phase separated, washed with sodium thiosulfate (200 mL), saturated aqueous sodium bicarbonate (200 mL), brine (200 mL), dried (magnesium sulfate), filtered and evaporated. The crude product was suspended in isohexane (100 mL), and sufficient diethyl ether added to dissolve out the brown impurity while stirring for 1 hour. Filtration gave the desired product (24.3 g) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([I:10])=[CH:4][C:3]=1[O:11]C.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([I:10])=[CH:4][C:3]=1[OH:11]
Reactant: COc1cc(I)cc(OC)c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cc(I)cc(O)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.5 %

Procedure:
A solution of 2-chloro-5-iodo-1,3-dimethoxybenzene (3) (7.15 g, 23.9 mmol) in DCM (20 mL) was cooled to 0° C. Boron tribromide (11.3 mL, 120 mmol) was added dropwise over 30 min and the reaction mixture was allowed to slowly warm to RT and stirred for 20 h. The reaction mixture was cautiously added to iced water (30 mL) with stirring. The phases were separated and the organic solution was washed with brine (3×30 mL). The solvent was removed in vacuo to afford 2-chloro-5-iodobenzene-1,3-diol (4) (4.17 g, 64% yield) as a white solid: m/z 269 [M−H]− (ES−).
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:10]1[CH:14]=[C:13]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][N:18]=[C:17]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=3)[N:16]=2)[CH:12]=[N:11]1)[CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)#[N:2].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:5]1([CH:4]([N:10]2[CH:14]=[C:13]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][N:18]=[C:17]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:30])=[CH:26][CH:25]=4)[N:16]=3)[CH:12]=[N:11]2)[CH2:3][C:1]#[N:2])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COc1cnc(Nc2ccc(C(=O)O)cc2)nc1-c1cnn(C(CC#N)C2CCCC2)c1
Reactant: C1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(Nc2ccc(C(=O)N3CCOCC3)cc2)nc1-c1cnn(C(CC#N)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-5-methoxypyrimidin-2-ylamino)benzoic acid (25 mg, 0.058 mmol), morpholine (5.0 μL, 0.058 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (31 mg, 0.069 mmol) in N,N-dimethylformamide (0.4 mL) was added N,N-diisopropylethylamine (24 μL, 0.14 mmol). The reaction was stirred at room temperature for 1 h, quenched with water, purified on HPLC to give the desired product as a racemic mixture. LCMS (M+H) 502.5.
Reaction SMILES: CC1C(O)CC(=[O:5])C=1CC=C.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>C(Cl)Cl>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([OH:5])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: C=CCC1=C(C)C(O)CC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: -17 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
First, 8.6 g of (R) allethrolone and then 16 ml of triethylamine were added at -40° C. to 50 ml of methylene chloride and a solution of 21.4 g of p-toluene sulfonyl chloride in 150 ml of methylene chloride was added thereto over 15 minutes at -40° C. The mixture was stirred for 48 hours at -17° C. and was then poured into an aqueous iced 0.1 N hydrochloric acid solution. The mixture was stirred and the aqueous phase was extracted with ether. The ether extracts were washed with water and dried over magnesium sulfate to obtain 18.5 g of raw product. The latter was chromatographed over silica gel and was eluted with a 9-1 benzene-ethyl acetate mixture to obtain 3.7 g of p-toluene sulfonate of (R) allethrolone.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.ClCCl>O>[CH2:6]([O:10][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (15.45 g, 0.13 mol) was added to a mixture of n-butanol (10 g, 0.13 mol), triethylamine (26.3 g, 0.26 mol) and dichloromethane (150 g) at 10° C. After being stirred at room temperature overnight, water (100 g) was added to the reaction mixture and the layers were separated. The organic layer was concentrated in vacuo at room temperature. This gave 18 g (90%) of the title mesylate as an oil. 1H NMR analysis supports the stated structure. *Previously described in J. Am. Chem. Soc. 1933, 55, 345-349.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:13][CH2:12][CH2:11][CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: ClCCCBr
Reactant: Oc1ccccc1F
Product: Fc1ccccc1OCCCCl

Procedure:
Prepared by Procedure U and Scheme AK using 2-fluorophenol and 1-bromo-3-chloropropane.
Reaction SMILES: N1C2C(=CC=CC=2)N=CC=1.[N+:11]1([O-:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N+:14]([O-])=[CH:13][CH:12]=1.C(OO)(=O)C.C1(S([Cl:37])(=O)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C>[Cl:37][C:12]1[CH:13]=[N:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N+:11]=1[O-:22]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: [O-][n+]1cc[n+]([O-])c2ccccc21
Agent: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: [O-][n+]1c(Cl)cnc2ccccc21
Yield: 60 %

Procedure:
The invented compounds may be made from known starting materials by readily practiced processes. Starting wth quinoxaline, this is oxidized to quinoxaline-1,4-dioxide with 1.2 molar peracetic acid in acetic anhydride (melting point of the product equals 241.5°-242°C.). The yield obtained is 50 to 60% of theoretical. See Journal of the Chemical Society, page 2816 (1953, J. K. Landquist). The quinoxaline-1,4-dioxide is reacted with a 6 molar excess of benzenesulfonyl chloride and the greygreen solid obtained is then reacted with 10% aqueous sodium bicarbonate, to yield 2-chloroquinoxaline-1-oxide in 60% yield (m. p. equals 115°-116°C.). See Journal of General Chemistry, U.S.S.R., volume 34, page 2836 (1964, A. S. Elina). The reaction of 2 -chloroquinoxaline-1-oxide with three molar equivalents of one molar aqueous sodium hydrosulfide results in a yellow aqueous solution of the sodium salt of 2-mercaptoquinoxaline-1-oxide. The yield is essentilly quantitative. The salt is convertible to the water-insoluble 2-mercaptoquinoxaline- 1-oxide by precipitation thereof with an acid, such as concentrated aqueous hydrochloric acid. 2-(1-Oxoquinoxalinyl) disulfide is obtainable from 2-mercaptoquinoxaline-1-oxide by oxidation of the 2-mercaptoquinoxaline-1-oxide. Such oxidation may be effected with air (with the 2-mercaptoquinoxaline-1-oxide being oxidized by the air in a solvent such as acetone, methanol, ethanol or other suitable solvent, preferably at an elevated temperature such as that at which the solvent boils) or with other oxidizing agents, such as aqueous potassium triiodide, aqueous 3% hydrogen peroxide, or a dilute aqueous solution of a percarboxylic acid. Various other metal, ammonium or quaternary ammonium salts of 2-mercaptoquinoxaline-1-oxide may be obtained by treatment of a solution of a soluble salt thereof with an acid such as dilute hydrochloric acid or other suitable inorganic or organic acid, followed by addition of a dilute aqueous solution of the water soluble salt of the cation, e.g., a solution of the metal- or ammonium halide or sulfate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:44][Si](C(C)(C)C)(C)C)[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F.F.F.C(N(CC)CC)C>O1CCCC1.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:44])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[C:34]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(Oc2cccc(-c3ccccc3)c2)cc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1ccc2c([C@@H](O)CNCCc3ccc(Oc4cccc(-c5ccccc5)c4)cc3)ccc(OCc3ccccc3)c2[nH]1
Yield: 45.7 %

Procedure:
The product of step (d) (275 mg) and triethylamine trihydrofluoride (1.0 mL) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 h. The solution was diluted with sodium hydroxide (0.5M, 10 mL), extracted with dichloromethane (2×10 mL) and the combined organics dried over sodium sulfate and evaporated to afford the title intermediate (105 mg), which was used directly in the next step without further purification.
Reaction SMILES: O(C)[Na].[Br-].[O:5]1CCCO[CH:6]1[CH2:11][P+](CCCC)(CCCC)CCCC.[CH3:25][O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][C:30]([CH:31]=O)=[C:29]([N+:37]([O-:39])=[O:38])[CH:28]=1.O>CN(C=O)C>[CH3:25][O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][C:30](/[CH:31]=[CH:11]/[CH:6]=[O:5])=[C:29]([N+:37]([O-:39])=[O:38])[CH:28]=1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: CCCC[P+](CCCC)(CCCC)CC1OCCCO1
Agent: CO[Na]
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(/C=C/C=O)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
At room temperature, NaOCH3 (335 mg, 6.19 mmol) was added to a solution of 1,3-dioxan-2-ylmethyltributylphosphoniumbromide (C. Spangler; R. McCoy, Synthetic communications, 18, 51, (1988)) (5.17 ml, 1 M in DMF, 5.71 mmol) and 4,5-dimethoxy-2-nitro-benzaldehyde (1.25 g, 4.76 mmol) in DMF (20 ml). After heating the mixture at 50° for overnight, the mixture was poured over water, and extracted with ether, washed with brine and dried over MgSO4. The solvent was evaporated and the residue was dissolved in THF (100 ml) and treated with 2 N HCl (50 ml). After stirring the mixture at room temperature for 2 h, the THF was evaporated, and the yellow solid was filtered, and suspended in ether/ethylacetate 4:1. The suspension stirred at room temperature for 1 h, filtered and washed with ether to afford (E)-3-(4,5-dimethoxy-2-nitro-phenyl)-propenal (624 mg, 55%) as a yellow solid, m.p. 103-105°. IR (KBr): 1689, 1605 cm-1. MS (EI): 237 (M).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:25])=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:12]=[CH:13]2)=[C:8]([CH:26]2[CH2:28][CH2:27]2)[CH:7]=1)=[O:5])C.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.O>[CH:26]1([C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15](=[O:16])[N:14]3[C:9]=2[C:10]([CH3:25])=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:12]=[CH:13]3)[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(OC)cc3)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccn3c(=O)c(C(=O)O)cc(C4CC4)c3c2C)cc1
Temperature: 60 °C

Procedure:
A solution of 1-cyclopropyl-8-(4-methoxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (68 mg, 0.180 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (33 mg, 0.78 mmol). The reaction was heated to 60° C. overnight and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 47 as yellow solid (22 mg, 35%). ESI-MS m/z: 350 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.30 (d, J=7.5 Hz, 1H), 8.23 (s, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.12 (d, J=7.5 Hz, 2H), 3.84 (s, 3H), 2.86 (s, 3H), 2.53-2.51 (m, 1H), 1.06-1.04 (m, 2H), 0.78-0.75 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(OC1C=CC(N)=CC=1)C.Br[CH:21]([CH:39]([CH3:41])[CH3:40])[C:22]([O:24]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:23]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C@H:21]([C:22]([OH:24])=[O:23])[CH:39]([CH3:41])[CH3:40]
Reactant: COc1ccccc1N
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Agent: CCOc1ccc(N)cc1
Product: COc1ccccc1N[C@H](C(=O)O)C(C)C

Procedure:
Using the procedure of Example 1, each of 2-methoxyaniline and 4-ethoxyaniline is reacted with m-phenoxybenzyl α-bromoisovalerate to yield the m-phenoxybenzyl ester of N-(2-methoxyphenyl)valine, MS m/e 405.2 (M+), and the m-phenoxybenzyl ester of N-(4-ethoxyphenyl)valine, MS m/e 419.1 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][N:9]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:10][CH:11]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26](=[O:39])[C@@H:27]([NH2:38])[CH2:28][CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.C(N(CC)CC)C.B.N1C=CC=CC=1>ClCCCl.C(O)C.C(O)(=O)C>[CH3:24][O:25][C:26](=[O:39])[C@@H:27]([NH:38][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])[CH2:28][CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)CCN(CC=O)C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CCOCc1ccccc1
Agent: B
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClCCCl
Product: COC(=O)[C@H](CCOCc1ccccc1)NCCN(CCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
3.71 g (11.55 mmol) of 3-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid tert-butyl ester and 3.00 g (11.55 mmol) of (S)-2-amino-4-benzyloxy-butyric acid methyl ester; hydrochloride (intermediate 7) were dissolved in 1,2-dichloroethane/ethanol 1:1 80 ml) and treated with 1.93 ml (13.86 mmol) of triethylamine, 3.03 ml of acetic acid and 3.03 ml (24.25 mmol, 8 M in pyridine) of pyridine-borane complex (cooling with a water bath to room temperature). The reaction was stirred at room temperature over 1¼ h, then partitioned between aq. sodium hydrogencarbonate solution and diethyl ether (3×). The organic phases were washed with sat. aq. sodium hydrogencarbonate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated and purified by flash silica gel column (dichloromethane/n-heptane 1:1 to dichloromethane, then dichloromethane/ethyl acetate 4:1 to ethyl acetate) to yield 4.81 g (79%) of the title compound as colorless oil. MS: 529.2 (MH+).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: C1CCNCC1
Product: N#Cc1ccc(N2CCCCC2)cc1
Temperature: 100 °C
Yield: 89 %

Procedure:
To commercially available 4-chlorobenzonitrile 17 (1 g, 7.26 mmol) 3 ml of piperidine were added and the reaction was heated at 100° C. for 72 hours in closed vessel. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The purification of the crude residue by chromatographic column using AcOEt 1/Petroleum ether 9 as eluant gave 1.2 g of a pale yellow oil. Yield=89% 1HNMR (DMSO, 200 MHz) δ 1.57 (6H, m), 3.34 (4H, m), 6.98 (2H, d, J=9 Hz), 7.53 (2H, d, J=9 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:21])[C@@H:12]([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].[C:22]([O:26][C:27]([NH:29][C@H:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:21])[C@@H:12]([NH:20][C:31](=[O:32])[C@H:30]([NH:29][C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:28])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccccc2)n1
Reaction time: 0.08 h

Procedure:
A solution of 2-((S)-2-amino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (prepared as described in example 3, step c) (0.61 g, 2.0 mmol), (R)-tert-butoxycarbonylamino-phenylacetic acid (0.55 g, 2.2 mmol), diisopropylethylamine (1.40 mL, 7.88 mmol) and 1-hydroxybenzotriazole (0.324 g, 2.40 mmol) in N,N-dimethylformamide (5 mL) was stirred in an ice bath for 5 minutes To the cooled yellow-orange solution was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexaflurorophosphate (0.91 g, 2.40 mmol). The reaction mixture was stirred for 5 minutes and the ice bath was removed and stirring continued for 1 hour. The reaction mixture was then diluted with ethyl acetate, washed brine and the aqueous layer extracted with ethyl acetate. The combined organic extracts were passed through a pad of sodium sulfate layered on the top of a pad of silica gel contained in a 60 mL vacuum filtration funnel. Residual material was eluted from the pad of sodium sulfate and silica gel with ethyl acetate and the filtrate was concentrated in vacuo to give —[(S)-2-((R)-2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-3-phenyl-propionylamino]-thiazole-4-carboxylic acid methyl ester which was taken into dry dichloromethane (10 mL) under argon and cooled in an ice bath. To this was added trifluoroacetic acid (5 mL, 64.9 mmol) and the mixture stirred at 0° C. for 2 hours. The reaction mixture was then concentrated to dryness. The residue was taken into dichloromethane and precipited with ether and the suspension was stirred for 15 minutes. The solid was isolated by filtration and washed with ether and dried to give a tan solid. The solid was taken into dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, concentrated and dried to give 2-[(S)-2-((R)-2-amino-2-phenyl-acetylamino)-3-phenyl-propionylamino]-thiazole-4-carboxylic acid methyl ester as an off white foam (0.80 g, 91%).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]CC)=[O:11])[CH:6]=1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)O)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: CC(C)(O)c1cc(C(=O)O)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
Ethyl 5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylate (0.436 g, 2.189 mmol) was dissolved in methanol (20 ml). A solution of cesium carbonate (1.426 g, 4.38 mmol) in 20 ml of water was added and the reaction mixture was stirred at RT for 18 h. Solvents were evaporated and the residue was taken into a mixture of ethyl acetate and water, pH was adjusted to 2.5 with 10% citric acid solution and the layers were separated. Water layer was extracted three times with ethyl acetate and the combined organic layers were dried with Na2SO4, filtered and evaporated affording 0.246 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.49 (s, 6H), 5.75 (m, 1H), 6.60 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17]C)[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-methoxy-1H-indole-3-carboxamide (Compound 7, 452 mg, 1.0 mmol) in CH2Cl2 (20 ml) at 0° C. was added BBr3 (1.0 M in CH2Cl2, 3.0 ml, 3.0 mmol) dropwise. The reaction was stirred for 1 h at 0° C. and 1 h at room temperature, quenched with ice, extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH:23]3[C:29]4=[CH:30][CH:31]=[CH:32][N:28]4[CH2:27][C:26]4[CH:33]=[CH:34][CH:35]=[CH:36][C:25]=4[O:24]3)[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)(C)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([CH:23]3[C:29]4=[CH:30][CH:31]=[CH:32][N:28]4[CH2:27][C:26]4[CH:33]=[CH:34][CH:35]=[CH:36][C:25]=4[O:24]3)[CH2:21][CH2:22]2)=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: c1ccc(COc2ccc(CCN3CCC(C4Oc5ccccc5Cn5cccc54)CC3)cc2)cc1
Agent: [Pd]
Solvent: CC(C)O
Product: Oc1ccc(CCN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)cc1

Procedure:
To 200 ml isopropanol was added 11-{1-[2-(4-benzyloxyphenyl)-ethyl]piperidin-4-yl}-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (2.8 g, 0.006 mole) and 10% Pd/C (3.0 g). After shaking on a Parr apparatus under 50 psi of hydrogen for twenty-four hours, the solution was filtered and evaporated to a solid (2.2 g, m.p. 77° C.).
Reaction SMILES: [N+]([N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10]2)=[N:5]1)([O-])=O.[CH3:16][O-:17].[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:16][O:17][C:12]1[C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc2cn([N+](=O)[O-])nc2c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1n[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2,6-dinitro-2H-indazole(1 mmol) (prepared by nitration of 6-nitroindazole; Wrzeciono, et al., E. Pharmazie, 1980, 35, 593-596) in dry THF (4 mL) at 0° C., solid sodium methoxide (4 mmol) was added in portions. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The contents were diluted with ethyl acetate (20 mL), washed with water (2×10 mL) and brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to yield 3-methoxy-6-nitro-1H-indazole as a brown solid, which was reduced to 3-methoxy-1H-indazol-6-ylamine by hydrogenation following general procedure F.