Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16]CC)=[O:15])=[CH:7][C:6]=2[CH:19]=1.Cl>[OH-].[Na+].C1COCC1.C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([OH:16])=[O:15])=[CH:7][C:6]=2[CH:19]=1
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=CN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.6 %

Procedure:
In 1N sodium hydroxide (13.0 ml) and THF:ethanol (1:1, 50 ml) was dissolved ethyl 7-bromo-1-formyl-2,3-dihydro-1-benzazepine-4-carboxylate (2.77 g), and the mixture was stirred at room temperature for 15 hours. To the mixture was added 1N hydrochloric acid (12.5 ml), and the mixture was concentrated. To the residue was added water (200 ml), and the mixture was adjusted to pH 2 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate(300 ml×3), and the organic layer was dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 7-bromo-1-formyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (2.52 g, 100%).
Reaction SMILES: Cl.[O:2]1[C:31]2[C:5](=[CH:6][C:7]3[O:12][CH:11]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[O:25][CH:24]=[CH:23][C:22]5=O)[CH2:10][O:9][C:8]=3[CH:30]=2)[O:4][CH2:3]1.Cl.CC(O)C>CO.[Pd]>[O:25]1[C:26]2[C:21](=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH:11]3[CH2:10][O:9][C:8]4[CH:30]=[C:31]5[O:2][CH2:3][O:4][C:5]5=[CH:6][C:7]=4[O:12]3)=[CH:28][CH:27]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: O=c1ccoc2ccc(OCCCNCC3COc4cc5c(cc4O3)OCO5)cc12
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: c1cc2c(cc1OCCCNCC1COc3cc4c(cc3O1)OCO4)CCCO2
Reaction time: 24 h
Yield: 56.3 %

Procedure:
6-[3-[[(6,7-Dihydro-1,3-dioxolo[4,5-g][1,4]benzodioxin-6-yl)methyl]amino]propoxy]chromen-4-one hydrochloride (0.9 g, 2.0 mmole), prepared in Example 5 above, was dissolved in 50 ml of methanol and 4N HCl/IPA (12.5 ml, 50 mmole) and 10% Palladium on Carbon (0.2 g) were added. The mixture was hydrogenated on a Parr apparatus for 24 hours and 4 psi of hydrogen was absorbed. Water (10 ml) was added to dissolved the resulting mixture and the catalyst was removed by filteration. The filtrate was concentrated, and the residue was treated with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was chromatographed on a silica gel column using 5% methanol in dichloromethane as an eluent. The product-containing fractions (Rf=0.47 on silica gel with 5% chloroform/methanol) were combined, concentrated, dissolved in methanol and acidified with 4N HCl/IPA until the solution was 3 in pH. The resulting precipitate was collected on a Buchner funnel and recrystallized from methanol to give 0.45 g of title compound as a white solid hydrochloride, m.p. 217°-218° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[CH:11]=1>CC(C)=O>[N:1]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: BrCc1cccc(CBr)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: c1cc(Cn2ccnc2)cc(Cn2ccnc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a 500 mL round bottom flask equipped with a stirbar was added 11.6 g imidazole (170 mmol) and 9.55 g (170 mmol) finely pulverized potassium hydroxide. These were stirred in 200 mL acetone until the solution became yellow translucent. 15.0 g (56.8 mmol) α,α′-dibromo-m-xylene was then added, and the solution was stirred at room temperature overnight. The cloudy solution was filtered, and the white solids rinsed with acetone. The resulting filtrate was dried on silica and partitioned on a silica gel column using 30/70 acetonitrile/methanol as eluent. The product fractions were evaporated of solvent and the resulting oil recrystallized from ethyl acetate/hexanes to give 8.65 g 1-[3-(1H-imidazole-1yl-methyl)benzyl]-1H-imidazole as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:18])=[N-]>>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13])[CH:9]=[CH:10][C:2]=1[OH:1]
Reactant: CCC(C)(C)c1ccc(O)c(C(=O)O)c1
Reactant: C=[N+]=[N-]
Product: CCC(C)(C)c1ccc(O)c(C(=O)OC)c1

Procedure:
Following the procedure of Schmitt et al., Synthesis, 1984, 758-760; and treating the resulting 2-hydroxy-5-(1,1-dimethylpropyl)benzoic acid with diazomethane gave the title compound. 1H NMR (250 MHz, CDCl3) δ10.61 (s, 1H), 7.-75 (d, 1H), 7.44 (dd, 1H), 6.92 (d, 1H), 3.95 (s, 3H), 1.61 (q, 2H), 1.26 (s, 6H), 0.67 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][C:5]1[C:6](=O)[CH2:7][CH2:8][CH2:9][C:10]=1[O:11]CC(C)C.[CH2:18]([Li])[CH3:19]>CCOCC>[CH2:18]([C:6]1[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:5]=1[CH2:4][CH2:3][CH:2]([CH3:1])[CH3:17])[CH3:19]
Reactant: CC(C)CCC1=C(OCC(C)C)CCCC1=O
Reactant: [Li]CC
Solvent: CCOCC
Product: CCC1=C(CCC(C)C)C(=O)CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A solution of isobutyl ether 8 (88.0 g, 370 mmol) in anhydrous ether (250 mL) was cooled to 0° C. in an ice bath and treated dropwise with ethyl lithium (650 mL). The resulting mixture was stirred at 0° C. for 2 hours and then at room temperature for 48 hours. The reaction mixture was slowly quenched with water (200 mL) and extracted with ether (2×200 mL). The combined organic layer was dried (Na2SO4) and concentrated under vacuum to provide 75 g of crude oil, which was purified by chromatography (silica gel; hexane/ether 4:1) to give 58.0 g (80.1%) of 9 as an oil: MS m/z 195 (M+1); 1H NMR (300 MHz, CDCl3) δ 2.4-2.3 (m, 4H), 2.3-2.2 (m, 4H), 1.95-1.85 (m, 2H), 1.6-1.5 (m, 1H), 1.2-1.1 (m, 2H), 1.1 (t, 3H), 0.9 (d, 6H); 13C NMR (CDCl3) δ 199.2, 159.9, 135.4, 39.0, 38.1, 30.0, 28.5, 27.8, 22.9, 22.6, 22.5, 12.4.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([CH:22](C(OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O.[O-]CC.[Na+]>C(O)C.C(=O)(O)[O-]>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]=[C:14]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: 75 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Diethyl [6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]malonate (4.60 g, 9.95 mmol), was dissolved in ethanol (46 mL). Water (18 μL, 1.0 mmol) and 21% Sodium ethoxide in ethanol (0.37 mL, 1.0 mmol) were added. The reaction mixture was stirred at 75° C. for 1 hour. HPLC & LCMS analysis showed 60% decarboxylation. The heating was continued for another 2 hours (reaction complete). The reaction was diluted with aqueous bicarbonate, and extracted with EtOAc. The EtOAc extract was washed with brine, then dried (Na2SO4), and evaporated in vacuo to 3.4 g oil (88% yield). LCMS, HPLC, & NMR showed it to be clean enough to proceed. 1H NMR (400 MHz, DMSO-D6): δ7.20 (s, 1H); 5.20 (m, 1H, OCH); 4.10 (q, 2H, OCH2); 3.89 (s, 2H, CH2); 3.85 (s, 4H, OCH2); 1.5-2.0 (m, 8H); 1.15 (t, 3H, CH3). HPLC showed it to have UVmax 222 & 252 nm.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]CC)=O)=[CH:19][CH:18]=3)[CH:8]=2)[CH2:3]1.[NH3:29]>CO>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([NH2:29])=[O:26])=[CH:21][CH:22]=3)[CH:8]=2)[CH2:3]1
Reactant: N
Reactant: CCOC(=O)Cc1ccc(Nc2cc(C3CCC(O)C3)nc3c2CCC3)cc1
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(C3CCC(O)C3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 23 h
Yield: 25 %

Procedure:
A 10-mL vial was charged with ethyl 2-(4-((2-(3-hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (diastereomer A, 0.022 g, 0.058 mmol), methanol (2 mL) and ammonia (1.7 mL, 7N in methanol, 11.5 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 23 h. After this time, LCMS analysis of the cooled reaction showed ˜88% conversion. Additional ammonia (1.0 mL, 7N in methanol, 7.0 mmol) was added and the mixture was heated at 100° C. for 2 h. Then, the cooled reaction mixture was concentrated under reduced pressure. The residue was absorbed on silica (2 g) and purified by chromatography on silica using dichloromethane/(80:20:1 dichloromethane/methanol/conc. NH4OH) (10:0 to 0:10) as eluent to afford the title compound (0.005 g, 25%) as a light brown solid. MW=351.44 1H NMR (DMSO-d6, 500 MHz) δ 7.86 (s, 1H), 7.41 (s, 1H), 7.23-7.19 (m, 2H), 7.12-7.08 (m, 2H), 6.84 (br s, 1H), 6.60 (s, 1H), 4.39 (d, J=4.0 Hz, 1H), 4.25-4.20 (m, 1H), 3.33 (s, 2H), 3.18 (quin, J=6.5 Hz, 1H), 2.78 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.05-1.88 (m, 4H), 1.83-1.72 (m, 2H), 1.67-1.56 (m, 1H), 1.53-1.45 (m, 1H); APCI m/z 352 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH2:12])[N:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[F:21][C:22]1[CH:23]=[C:24]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1>C(#N)C>[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH:12][C:34]([NH:33][C:24]2[CH:25]=[CH:26][C:27]([N:28]3[CH2:29][CH:30]([OH:32])[CH2:31]3)=[C:22]([F:21])[CH:23]=2)=[O:35])[N:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Nc1ccc(N2CC(O)C2)c(F)c1)Oc1ccccc1
Reactant: CC(C)(C)c1cc(CN)n(-c2ccc(F)c(F)c2)n1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(N3CC(O)C3)c(F)c2)n(-c2ccc(F)c(F)c2)n1
Yield: 46.4 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3,4-difluorophenyl)-1H-pyrazol-5-yl)methanamine hydrochloride (85 mg, 0.282 mmol, 1.0 eq) in acetonitrile (6.7 mL) was added TEA (0.16 mL, 1.1 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1-yl)phenylcarbamate (86 mg, 0.287 mmol, 1.02 eq) and stirred at reflux for 16 h. The solvent of the reaction mixture was evaporated and the residue was purified by column chromatography (EtOAc/cyclohexane (1:2) as eluent) to get 1-((3-tert-butyl-1-(3,4-difluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)urea (62 mg, 46%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N+:9]([O-])([OH:11])=[O:10]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:8]
Reactant: Cc1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1cccc([N+](=O)[O-])c1O
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 2-methylphenol (10.8 g, 0.1-mmol) in acetic acid, fuming nitric acid (6.3 g) was slowly added with stirring to start reaction. The reaction mixture was stirred at a temperature of 20° C. or below for 1 h and thereafter poured into ice water. The reaction product was extracted with ethyl acetate and the extracted layer was washed with water, saturated sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride in the order written. Thereafter, the washed layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography with a benzene-ethyl acetate mixture used as eluant, thereby giving the desired compound, 2-methyl-6-nitrophenol, in an amount of 1.3 g.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[CH2:7][CH3:8].[B:16](OC)([O:19]C)[O:17]C.Cl>O1CCCC1.O>[CH2:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:16]([OH:19])[OH:17])[CH2:7][CH3:8]
Reactant: COB(OC)OC
Reactant: CCCc1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccccc1B(O)O
Temperature: -70 °C
Reaction time: 1 h

Procedure:
15.5 mL of butyl lithium (1.6 mol/L solution in hexane) was placed in a reaction vessel, which was chilled in a dry ice-acetone bath. To this was added a solution of 4.412 g of 2-propylbromobenzene in 45 mL of tetrahydrofuran at −70° C. dropwise over 85 minutes under a nitrogen atmosphere. The mixture was stirred at −70° C. for 30 minutes, to which 3.75 mL of trimethyl borate was then added at −70° C. dropwise over 15 minutes. The mixture was stirred at −70° C. for one hour and then at room temperature for 18 hours. To the reaction mixture was added 33 mL of 2N hydrochloric acid dropwise over 10 minutes and then the mixture was stirred at room temperature for 4 hours. To the mixture was added 20 mL of water, which was extracted with 70 mL of ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to a silica gel column chromatography (as eluent, ethyl acetate:hexane=1:2, and then 2:1) to yield 1.641 g of the title compound as colorless crystals.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[N:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])=[N:22][CH:21]=1>>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:23]2[CH:24]=[CH:25][N:20]=[CH:21][N:22]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1ccncn1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1ccncn1
Yield: 33 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(pyrimidin-4-yl)but-3-yn-2-ol to give the titled compound as a brown solid (60 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C1COCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([F:12])[CH:14]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(F)c1
Reaction time: 18 h

Procedure:
5-Amino-2-chloro-benzoic acid (0.96 g, 5.58 mmol) was diluted with THF (60 mL), treated with 3-fluoro-benzoyl chloride (0.738 mL, 6.14 mmol) and stirred for 18 h. Solvents were then removed and resulting solids were triturated with DCM. After filtration, the title compound was obtained as a white solid (1.7 g, 99%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]([CH2:13][C:14](Cl)=[CH2:15])[C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.C(C(C)=O)C(C)C.Cl.C(=O)([O-])O.[Na+]>O>[NH:12]=[C:10]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)[CH:13]=[C:14]([CH3:15])[S:11]1
Reactant: C=C(Cl)CN(C(N)=S)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Temperature: 90 °C
Reaction time: 7 h
Yield: 83.8 %

Procedure:
N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea (1.47 g) and stannic chloride n-hydrate (n=4 to 5) (0.09 g) were added to methyl isobutyl ketone (7.50 g) at room temperature, and the mixture was heated to 90° C. and stirred at the same temperature for 7 hours. After cooling, 35% hydrochloric acid (0.52 g) was added to the reaction mixture with stirring, and the mixture was heated to 90° C. and stirred at the same temperature for 2.5 hours. After cooling, water was added to the reaction mixture, which was then neutralized by addition of sodium hydrogen carbonate and extracted with methyl isobutyl ketone. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 1.08 g of 2-imino-3-(3-(trifluoromethyl)phenyl)-5-methyl-4-thiazoline (75% yield as a corrected value from the below-mentioned purity). From the results of analysis by liquid chromatography, the purity was determined to be 89%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]2[CH:11]([O:21]2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCC2OC2C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 166.1 %

Procedure:
To a solution of cyclohex-3-enylmethyl-carbamic acid tert-butyl ester (1.5 g, 7.10 mmol) in 20 ml of anhydrous dichloromethane was added 3-chloroperoxybenzoic acid (2.45 g, 14.2 mmol) under cooling. The resulting mixture was stirred for 19 hours at room temperature and washed with saturated sodium bicarbonate and 0.5M aqueous solution of sodium thiosulphate. The aqueous phase was extracted three times with dichloromethane and the combined organic phases were washed with brine. The resulting organic phase was dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield 1.48 g of crude product. Column chromatography of 3.17 g of crude product (silica, petrol ether/ethyl acetate=3/1) resulted in (7-oxa-bicyclo[4.1.0]hept-3-ylmethyl)-carbamic acid tert-butyl ester (Rf=0.19, 2.68 g, 81% yield) as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[CH:21][C:19]=2[N:20]=1.[NH4+].[Cl-].C[N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([NH2:31])=[O:27])[CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(N)=O)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
To a mixture of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (containing 1 equivalent of DMA, 145 mg, 0.33 mmol), NH4Cl (160 mg, 3.0 mmol) and HATU (141 mg, 0.37 mmol) in DMF (2 mL) was added DIEA (0.52 mL, 388 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 3 h and heated at 60° C. for 15 h, and then evaporated under reduced pressure. The residue was purified by chromatography (333:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (29 mg, 24%). 1H NMR (DMSO-d6) δ 3.94 (s, 3H), 7.11-7.17 (2H), 7.36 (br s, 1H), 7.64 (d, J=9 Hz, 1H), 7.67 (d, J=9 Hz, 1H), 7.83-7.88 (2H), 8.05 (br s, 1H), 8.19-8.21 (2H), 8.30 (s, 1H). ESI-MS m/z 361.3 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([CH3:12])[CH:11]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[CH3:16][N:17]([CH3:21])[C:18](=[O:19])[O:13][C:8]1[CH:9]=[C:10]([CH3:12])[CH:11]=[C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:14][CH3:15])[CH:7]=1
Reactant: COC(COc1cc(C)cc(O)c1)OC
Reactant: CN(C)C(=O)Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: COC(COc1cc(C)cc(OC(=O)N(C)C)c1)OC
Temperature: 80 °C

Procedure:
3-(2,2-Dimethoxyethoxy)-5-methylphenol (0.05 mole), N,N-dimethylcarbamoyl chloride (0.08 mole), triethylamine (0.05 mole) and xylene (50 ml) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture is stirred and heated at 80° C. for a period of about 12 hours. After this time the reaction mixture is cooled to room temperature and is filtered. The filtrate is then washed with water and dried over anhydrous magnesium sulfate. The dried solution is then filtered and stripped of solvent and unreacted starting materials to yield the desired product O-[3-(2,2-dimethoxyethoxy)-5-methylphenyl] N,N-dimethylcarbamate as the residue.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]3[CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[O:23][C:13]=3[C:12]2=[O:24])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([CH3:57])([OH:56])[CH3:55])[N:49]=1>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]3[CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[O:23][C:13]=3[C:12]2=[O:24])[C:8]([NH:47][C:48]2[CH:52]=[CH:51][N:50]([CH2:53][C:54]([OH:56])([CH3:55])[CH3:57])[N:49]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)N1CC2=C(Oc3ccccc3C2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2CC3=C(Oc4ccccc4C3)C2=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A solution of (S)-3-Cyclopentyl-2-(3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionic acid (200 mg, 0.61 mmol) in methylene chloride (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI-HCl) (130 mg, 0.67 mmol), 1-hydroxybenzotriazole (HOBT) (90 mg, 0.67 mmol) and commercially available 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (114 mg, 0.73 mmol). The reaction mixture was stirred for 18 hours at 25° C., under N2. The reaction mixture was diluted with methylene chloride, washed with 2N HCl, saturated sodium bicarbonate solution, and a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after concentration was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; (0% to 100% ethyl acetate/hexane) to afford (S)-3-Cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamide as a white powder, 205 mg (72% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (br. s., 3 H), 1.06 (br. s., 3 H), 1.09-1.83 (m, 10 H), 1.83-1.97 (m, 1 H), 3.75 (s, 2 H), 3.89 (s, 2 H), 4.03 (d, J=19.2 Hz, 1 H), 4.40 (d, J=19.2 Hz, 1 H), 4.67 (s, 1 H), 4.87 (dd, J=10.3, 4.8 Hz, 1 H), 6.44 (d, J=1.8 Hz, 1 H), 7.03-7.15 (m, 2 H), 7.20-7.28 (m, 2 H), 7.53 (d, J=1.8 Hz, 1 H), 10.86 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[NH:7][C:6](C(O)=O)=[CH:5]2.[H-].[Na+].[CH3:20][C@@H:21]1[CH2:23][O:22]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])[N:7]([CH2:20][C@H:21]([OH:22])[CH3:23])[CH:6]=[CH:5]2
Reactant: O=C(O)c1cc2cc(F)c(C(F)(F)F)cc2[nH]1
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1ccc2cc(F)c(C(F)(F)F)cc21
Reaction time: 4 h
Yield: 18.9 %

Procedure:
A suspension of 0.75 g of 5-fluoro-6-trifluoromethylindole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 4 hours and, after cooling to 0°, diluted with 16 ml of tetrahydrofuran. 113 mg of sodium hydride dispersion were added and the mixture was stirred for 1 hour. Subsequently, 0.43 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 60 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium sulfate. The solvent was removed and the residue was chromatographed over 40 g of silica gel with hexane-toluene (1:1) and subsequently with toluene-ethyl acetate (15:1). There was obtained 0.15 g (18.9%) of (R)-1-(5-fluoro-6-trifluoromethyl-indol-1-yl)-propan-2-ol as light brown crystals.