Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH2:14]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Reaction time: 0.33 h
Yield: 84.9 %

Procedure:
Prepared according to literature procedure (C. Martin and E. M. Carreira, J. Am. Chem. Soc., 2005, 127, 11505-11515). A stirred solution of isatin (10.0 g, 68 mmol) in dry DMF (125 mL) was cooled in an ice bath before addition of sodium hydride (60 wt % in mineral oil, 2.86 g, 71.5 mmol) in 10 portions, the orange solution turning quickly purple. When no further evolution of gas was observed, benzyl bromide (13.4 g, 78.0 mmol) was added by syringe. A colour change back to orange was observed within 20 min Water (300 mL) was added with stirring, and the resulting orange-red precipitate collected by filtration and washed with water and a little cold ethanol. The solid was then recrystallized from boiling ethanol (300 mL) to afford N-benzylisatin (13.7 g, 85%) as long, red needles.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([CH3:17])[C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1>CC(O)=O.[Pt]>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][NH:13][CH:12]([CH3:17])[C:11]=3[N:10]=[CH:9]2)=[N:4][CH:3]=1
Reactant: Cc1nccc2c1ncn2-c1ncc(F)cn1
Agent: [Pt]
Solvent: CC(=O)O
Product: CC1NCCc2c1ncn2-c1ncc(F)cn1
Yield: 51.5 %

Procedure:
A solution of 1-(5-fluoropyrimidin-2-yl)-4-methyl-1H-imidazo[4,5-c]pyridine (0.90 g, 3.91 mmol) in AcOH (50 ml) was passed through a 10% Pt/C catalyst cartridge on an H-Cube© hydrogenation apparatus at a pressure of 60 bar, a temperature of 60° C., and a flow rate of 1 ml/min. The reaction was concentrated, diluted with 1N NaOH, and extracted with DCM (100 mL×3). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (0.47 g, 51%). MS (ESI): mass calcd. for C10H1FN6, 234.10. m/z found, 235.0 [M+H]+.
Reaction SMILES: Cl[CH:2](Cl)[C:3]([OH:5])=[O:4].[H-].[Na+].[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([OH:25])=[C:14]([C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:17])[CH:15]=1>O1CCOCC1>[CH3:24][C:16]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:14]2[CH:15]=[C:10]([CH3:9])[CH:11]=[CH:12][C:13]=2[O:25][CH:2]([C:3]([OH:5])=[O:4])[O:17]1
Reactant: O=C(O)C(Cl)Cl
Reactant: Cc1ccc(O)c(C(C)(O)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)C(C)(c1ccccc1)OC(C(=O)O)O2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of 13 ml of dichloroacetic acid and 75 ml of dioxane was added over 40 minutes to a suspension of 1.6 g of dibenzo-18-courone-6, 20.2 g of sodium hydride as a 50% oil suspension and 250 ml of dioxane and then a solution of 30 g of the product of Step A in 150 ml of dioxane was added thereto at 60° C. over one hour. The mixture was heated at 90° C. for 2 hours, was cooled and poured into 500 ml of ice. The aqueous phase was washed 3 times with 300 ml of ether, was acidified with concentrated hydrochloric acid and was extracted 3 times with 300 ml of ether. The ether phase was extracted 4 times with 100 ml of aqueous sodium bicarbonate solution and the combined aqueous phase was acidified with hydrochloric acid and was extracted 3 times with 300 ml of ether. The ether phase was washed with water until the wash water was neutral, dried over magnesium sulfate and was evaporated to dryness under reduced pressure to obtain 28 g of raw 4,6-dimethyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of 2 diastereoisomeric racemates).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[Mg].C[O:13][B:14]([O:17]C)[O:15]C.S(=O)(=O)(O)O>O1CCCC1>[CH3:7][N:6]([CH3:8])[C:5]1[CH:9]=[CH:10][C:2]([O:13][B:14]([OH:17])[OH:15])=[CH:3][CH:4]=1
Reactant: CN(C)c1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(C)c1ccc(OB(O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution of the corresponding Grignard compound is prepared from 16.8 g 4-bromo-N,N-dimethyl-aniline and 2.04 g of magnesium in 150 ml of tetrahydrofuran. This is now slowly added dropwise while stirring at -60° to a solution of 9.4 ml of trimethylborate in 50 ml of tetrahydrofuran under argon. Subsequently, the mixture is stirred at room temperature overnight. The mixture is poured on to ice-water, adjusted to pH 3-4 with dilute sulphuric acid and extracted with diethyl ether. The extract is dried, evaporated and the residue is recrystallized from water. 5.6 g (40%) of 4-dimethylamino-phenylboric acid are obtained. Mass spectrum: peaks inter alia at m/e: 164 (M±H, 100%).
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([CH:7]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=[CH:25][C:10]=2[NH:9][C:8]1=[O:30])=[O:6]>CO.O1CCOCC1>[C:5]([CH:7]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[C:22]([C:26]([F:28])([F:29])[F:27])=[CH:23][CH:24]=[CH:25][C:10]=2[NH:9][C:8]1=[O:30])([OH:6])=[O:4]
Reactant: COC(=O)C1C(=O)Nc2cccc(C(F)(F)F)c2CC1c1ccccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccccc1C1Cc2c(cccc2C(F)(F)F)NC(=O)C1C(=O)O
Reaction time: 8 h

Procedure:
To a stirred warm solution of 58.0 g (0.88 mol) of potassium hydroxide (85%) in 500 ml of methanol was added portionwise 81.7 g (0.21 mol) of 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one - most of the solid dissolved. The mixture was diluted with 100 ml of dioxane and the resulting solution was refluxed for 6 hours. After standing overnight at room temperature, about 50% of the solvent was removed on a rotary evaporator and the residue was diluted with 4 liters of cold water. The insoluble material was filtered and dried (10 g) and the filtrate was cooled and treated portionwise with 270 ml of acetic acid to give a colorless granular solid. The latter was filtered, washed with cold water and dried in a desicator; yield 69.0 g, melting point 179°-181° C. (s. 128° C.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:20]=[C:14]([O:13][CH3:12])[CH:15]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Product: COc1cc(NC(=O)c2cc(Br)ccc2O)cc(C(F)(F)F)c1
Yield: 58.8 %

Procedure:
Using 5-bromosalicylic acid and 3-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[C:7](Cl)[C:6]=1[N+:19]([O-:21])=[O:20])[CH2:2][CH3:3].[NH3:25]>C(O)C>[CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[C:7]([NH2:25])[C:8]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:2][CH3:3]
Reactant: N
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Solvent: CCO
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(N)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A glass reaction tube was charged with 4.0 grams (0.0108 mole) of N,N-di-n-propyl-3-chloro-2,6-dinitro-4-trifluoromethylaniline, 5.82 grams (0.0237 mole) of 6.95% ethanolic ammonia and 35 ml. of ethanol. The tube was sealed and heated in an oven at 100° C. for 68 hours. The contents of the tube were cooled and the ethanol removed by evaporation. Water was added to the solid orange residue to dissolve the ammonium chloride and the insoluble produced was separated by filtration. The product was dissolved in refluxing 95% ethanol. Upon cooling, orange needles and a yellow powder crystallized. The yellow powder was identified as 2,4-dinitro-6-trifluoromethyl-1,3-phenylenediamine and was separated from the desired product by filtration after extracting with boiling hexane. The desired product dissolved in the hexane and was isolated from the filtrate by evaporation of the hexane. The residue was recrystallized from 95% ethanol to give orange needles, m.p. 124°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18].O>CN(C=O)C>[C:17]([C:10]1[C:11]2[NH:12][C:13]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:14]=3)[C:6]=2[CH:7]=[CH:8][N:9]=1)(=[O:19])[CH3:18]
Reactant: Clc1ccc2c(c1)[nH]c1cnccc12
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1nccc2c1[nH]c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product from example 12 (104 mg, 0.50 mmol) in DMF (2.0 ml) at 3° C. to 5° C. was added NaH (95%, 15 mg, 0.625 mmol). The resulting mixture was stirred for 15 min before adding acetic anhydride (0.083 ml, 0.875 mmol). The reaction was allowed to warm to RT and stirred for 3 h before pouring into with water (25 ml). The slurry was stirred for 12 h, and the product collected to give after chromatography (1:3 hexane-ethyl acetate) on silica gel 82 mg of 1-acetyl-7-chloro-β-carboline.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(=[O:31])C>OO>[OH:28][CH2:27][CH2:26][N:24]1[CH:25]=[C:21]([C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N+:1]([O-:31])=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[CH:20][CH:19]=2)[CH:22]=[N:23]1
Reactant: CC(=O)O
Reactant: OCCn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Agent: OO
Product: [O-][n+]1cccc2cc(Cn3nnc4ccc(-c5cnn(CCO)c5)nc43)ccc21
Reaction time: 12 h
Yield: 14 %

Procedure:
To a solution of example 146 (0.100 g, 0.269 mmol) in acetic acid (1 ml), hydrogen peroxide solution (50%, 1 ml) and heated to 100° C. After 12 h, the mixture was concentrated, extracted with chloroform, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using dichloromethane: methanol to afford the title compound as an off-white solid (0.015 g, 14%). M.P.: 222-224° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.58-8.48 (m, 4H), 8.19 (s, 1H), 8.08 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.85 (dd, J=9.0, 1.8 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 6.0 Hz, 1H), 6.12 (s, 2H), 4.95 (t, J=5.2 Hz, 1H), 4.22 (t, J=5.5 Hz, 2H), 3.77 (q, J=5.5 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[O-]S([O-])(=O)=O.[Mg+2]>C1CCCCC1>[CH:6]1([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C1CCNC1
Reactant: O=C1CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCCCC1
Product: C1CCC(N2CCCC2)CC1
Yield: 91 %

Procedure:
Cyclohexylpyrrolidine was prepared as described in the procedure below illustrated in Scheme 1. In a 3-neck reaction flask equipped with a mechanical stirrer and heating mantle, a 2 molar equivalent of pyrrolidine were mixed with 1 molar equivalent of cyclohexanone in dry cyclohexane to make a 1M solution with respect to the cyclohexanone. To the mixture, 2 molar equivalents of anhydrous MgSO4 (as dehydrating agent) were added. The resulting mixture was refluxed for 94 hours. The progress of the reaction was monitored by NMR analysis.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.N1C=CC=CC=1>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:1])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc[nH]c1=O
Reactant: OB(O)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a mixture of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (6.0 g, 39 mmol), 4-fluorophenylboronic acid (16.3 g, 116 mmol), cupric acetate (14 g, 78 mmol) and pyridine (12 g, 0.156 mol) in DCM (300 mL) is added 4 Å molecular sieves (5 g). The reaction mixture is stirred at RT overnight open to air. After the solids are filtered and washed with water, the filtrate is extracted with DCM (100 mL). The organic layer is dried over MgSO4 and concentrated. The residue is purified by silica gel column chromatography eluting with PE:DCM (2:1 to 0:1) to give the product (9.6 g, 100% yield). MS (m/z): 248.0 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]1[CH3:18])([CH3:6])[CH3:5].[Mn]([O-])(=O)(=O)=[O:20].[K+]>CC(C)=O.O>[CH3:1][O:2][CH2:3][C:4]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:20])=[O:17])=[C:8]1[CH3:18])([CH3:6])[CH3:5]
Reactant: COCC(C)(C)n1c(C)c(C=O)c2ccccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COCC(C)(C)n1c(C)c(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a solution of 1-(1-methoxy-2-methylpropan-2-yl)-2-methyl-1H-indole-3-carbaldehyde (50 mg, 0.2 mmol) in acetone (2 mL) and water (2 mL) was added potassium permanganate (95 mg, 0.6 mmol). The resulting reaction mixture was allowed to stir for 3 hours at room temperature. The reaction mixture was lyophilized directly to give 1-(1-methoxy-2-methylpropan-2-yl)-2-methyl-1H-indole-3-carboxylic acid (50 mg, 94%) as a brown solid. LCMS (M+H+) m/z: calcd. 261.14. found 261.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[C:9]1[C:15]1[CH:27]=[CH:26][C:18]2[NH:19][C:20](=O)[O:21][C:22]([CH3:24])([CH3:23])[C:17]=2[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[C:13]([C:12]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([C:15]2[CH:27]=[CH:26][C:18]3[NH:19][C:20](=[S:37])[O:21][C:22]([CH3:24])([CH3:23])[C:17]=3[CH:16]=2)=[CH:10][CH:11]=1)#[N:14]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=S)N2
Temperature: 80 °C
Yield: 34.1 %

Procedure:
To 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-cyano-pyrrole-1-carboxylic acid tert-butyl ester (1.3 g, 35 mmol, 1 eq) in toluene (130 mL) was added Lawesson's reagent (1.58 g, 3.9 mmol, 1.1 eq) and the reaction mixture was heated to 80° C. for 2 h. The solvent was removed in vacuo and the residue was dissolved in acetone/dichloromethane and adsorbed onto silica gel. Purification by flash column chromatography (10% ethyl acetate/hexane) gave the product (0.51 g, 38%) as yellow crystals. 1H NMR (DMSO-d6) δ1.35 (s, 9H), 1.64 (s, 6H), 6.47 (d, 1H, J=3.6 Hz), 7.07 (d, 1H, J=8.1 Hz), 7.32 (d, 1H, J=3.6 Hz), 7.37 (dd, 1H, J=1.8, 8.1 Hz), 7.43 (d, 1H, J=1.8 Hz), 12.28 (s, 1H); MS (ESI) [M−H]−=382; Anal. Calcd. For C20H21N3O3S: C, 62.64; H, 5.52; N, 10.96. Found: C, 62.53; H, 5.6; N, 10.87.
Reaction SMILES: S[C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=[C:5]2[N:6]=1.C(=O)([O-])O.[Na+]>[N+]([O-])(O)=O>[N:3]1[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][C:5]2=[N:6][CH:2]=1
Reactant: Sc1nc2cccccc-2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: c1ccc2ncnc-2cc1

Procedure:
In accordance with the method described in Journal of the Americal Chemical Society, Vol. 76, pages 3352 and 3353 (1954), 23 g of 2-mercaptocycloheptimidazole, as obtained in Example 1-(b), was added to 210 ml of 10% nitric acid and everything was stirred under heating at an internal temperature of from 80° to 90° C. for 1 hour. Sodium hydrogencarbonate was added to the reaction solution so as to neutralize the solution, and this was extracted with chloroform (250 ml×2). The chloroform layer was dried with anhydrous sodium sulfate, and then the solvent was evaporated off until the amount of the chloroform solution became 50 ml. Next, 200 ml of hexane was added thereto. The crystals precipitated were separated by filtration and dried.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:18][C:19](=[O:35])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[CH2:28]([O:27][C:21]1[CH:22]=[CH:23][C:24]([Br:26])=[CH:25][C:20]=1[C:19]([NH:18][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[C:3]([OH:36])=[O:2])=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1cc(Br)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
2-(S)-(2-Benzyloxy-5-bromo-benzoylamino)-3-biphenyl-4-yl-propionic acid methyl ester (50 mg, 0.092 mmol) was dissolved in 5 mL of THF-MeOH (4-1), cooled to 0° C. and 1.1 equiv of 2 N LiOH added. After 30 minutes, 3.3 additional equiv of 2N LiOH was added and the reaction stirred for 60 minutes. The reaction was worked up according to general procedure C to give 2-(S)-(2-benzyloxy-5-bromo-benzoylamino)-3-biphenyl-4-yl-propionic acid (34 mg)
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH3:7][NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1.C(N(CC)CC)C>C(#N)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][N:8]([CH3:7])[CH2:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: NC(=O)CCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(CCN(C)CCC(N)=O)cc1OC
Yield: 64.1 %

Procedure:
6.42 g (60 mmol) 3-Chloropropanamide, 5.85 g (30mmol) N-methyl-3,4-dimethoxybenzeneethanamine and 7.7 g (75 mmol) triethylamine in 100 ml acetonitrile were stirred under reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by chromatography on silicagel using methylene chloride/methanol: 92/8 to yield 5.12 g (64.1%) of the desired compound as an orange oil.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6][CH2:5]1.[O:19]1[CH2:21][CH:20]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C.O>[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:21][CH:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[OH:19])[C:7]=2[CH2:6][CH2:5]1
Reactant: c1cncc(C2CO2)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2cccnc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.6 %

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (94 mg, 3.92 mmol) in 5 mL of DMF, 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.3 g, 1.40 mmol) was added and stirred at RT for 5 min. 3-(Oxiran-2-yl)pyridine (254 mg, 1.54 mmol) in DMF (5 mL) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 200 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-3-yl)ethanol as the TFA salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([NH2:9])[C:6](=[NH:8])[NH2:7])[CH3:2].[F:11][C:12]([F:22])([F:21])[C:13](=O)[C:14](=O)[C:15]([F:18])([F:17])[F:16]>CN(C=O)C>[NH2:8][C:6]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:10])=[N:9][C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([C:12]([F:22])([F:21])[F:11])[N:7]=1
Reactant: O=C(C(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C(N)C(=N)N
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N
Temperature: 25 °C
Reaction time: 600 h

Procedure:
To a solution of amino-carbamimidoyl-acetic acid ethyl ester (Int E2)(1.25 g, 8.61 mmol) in DMF (5 ml) was added 1,1,1,4,4,4-hexafluorobutane-2,3-dione (5 g, 25.8 mmol) and the mixture was stirred at RT for 25 days. The yellow suspension was partitioned between EtOAc (50 ml) and water (50 ml) and the organic portion was washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by mass directed LC-MS eluting with MeCN/Water/0.1% TFA. The clean fractions were poured into EtOAc (50 ml) and washed with saturated NaHCO3 (50 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound; 19F NMR (400 MHz, DMSO-d6): Peak 1 at −62 ppm, peak 2 at −64.6 ppm
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH:21]=[CH:20][CH2:19][CH2:18][C:8]=2[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[Li+].[F-].[CH2:26]([N:33]([CH2:39]OC)[CH2:34][Si](C)(C)C)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH:21]3[CH2:34][N:33]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:39][CH:20]3[CH2:19][CH2:18][C:8]=2[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C=CCC2
Agent: [F-]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C1CN(Cc3ccccc3)CC1CC2
Reaction time: 6 h

Procedure:
4-Oxo-7,8-dihydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.92 g, 9.15 mmol), LiF (296 mg, 11.4 mmol) and benzyl-methoxymethyl-trimethylsilanylmethyl-amine are mixed together in CH3CN (10 ml). The reaction mixture is sonicated under N2. The water bath is kept under 35° C. with ice. After 6 h, solvents are removed in vacuo. The residue is put on a column (1:1 EtOAc hexanes) to afford the title compound as clear oil, which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 1.23 (3H, t), 1.56 (9H, s), 1.88-2.00 (2H, m), 2.65 (1H, m), 2.92-3.02 (4H, m), 3.24 (1H, m), 3.50-3.59 (3H, m), 4.06 (1H, q), 4.19 (2H, q), 7.18-7.27 (5H, m), 7.62 (1H, s). MS (ES+) 453 (M+1) Step 2: 6-Benzyl4-oxo-4,4a,5,6,7,7a,8,9-octahydro-1H-1,6-diaza-cyclopenta[f]azulene-3-carboxylic acid pyridin-2-ylamide