Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[Br:9]Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:9][C:3]1[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: Cc1ccc(C=O)s1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1sc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methylthiophene-2-carbaldehyde (2.00 g) in acetic acid (20 mL) was added dropwise bromine (0.90 mL). The reaction mixture was stirred at room temperature for 8 hr, saturated aqueous sodium hydrogen carbonate was added by small portions, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate, saturated sodium thiosulfate aqueous solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (2.11 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16](=O)[NH2:17])=[CH:11][C:10]=1[CH2:19][CH3:20])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][C:10]=1[CH2:19][CH3:20])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCc1cc(C(N)=O)cc(C)c1CCC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C#N)cc(C)c1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of 3-(4-carbamoyl-2-ethyl-6-methyl-phenyl)-propionic acid tert-butyl ester (30.0 g, 103 mmol) and NEt3 (31.3 g, 309 mmol) in DCM (300 mL), trifluoroacetic anhydride (23.8 g, 113 mmol) is added slowly. The exothermic reaction is kept below 5° C. with cooling. After complete addition, the mixture is stirred at rt for 1 h. The mixture is washed twice with water (2×300 mL) and the org. extract is evaporated to dryness to give 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid tert-butyl ester (28.4 g) as a pale yellow oil; 1H NMR δ 1.25 (t, J=7.5 Hz, 3 H), 1.48 (s, 9 H), 2.32-2.37 (m, 2 H), 2.38 (s, 3 H), 2.70 (q, J=7.5 Hz, 2 H), 2.95-3.02 (m, 2 H), 7.30 (s, 1 H), 7.34 (s, 1 H).
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[NH:18][C:17](=[O:26])[C:16]=1[C:27]#[N:28]>C1(C)C=CC=CC=1>[CH3:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:26])[C:16]([C:27]#[N:28])=[C:15]2[N:4]1[CH2:5][CH2:6][N:1]([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: Cc1ccc2[nH]c(=O)c(C#N)c(Cl)c2c1
Solvent: Cc1ccccc1
Product: Cc1ccc2[nH]c(=O)c(C#N)c(N3CCN(C(=O)c4cccs4)CC3)c2c1
Temperature: 110 °C
Yield: 92.1 %

Procedure:
Piperazine-1-yl-thiophen-2-yl-methanone (8.73 g, 41.16 mmol) was added to a solution of Compound 106 (4.5 g, 20.08 mmol) in toluene (50 mL) and heated overnight at 110° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered. The crude product was purified by flash chromatography eluting with 0-2% methanol in dichloromethane gradient to yield 7.0 g (92%) of white solids. M.P. 269° C. 1H NMR (DMSO-d6): δ 2.34 (s, 3H), 3.65 (m, 4H), 3.92 (m, 4H), 7.14 (m, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.49 (d, J=3.5 Hz, 1H), 7.51 (s, 1H), 7.81 (d, J=4.8 Hz, 1H). EIMS m/z 379 (M+1).
Reaction SMILES: [Na:1].[CH2:2]1[O:4][CH2:3]1.[C:5]([OH:10])(=[O:9])[C:6]([CH3:8])=[CH2:7].[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:22])[CH:20]=[CH2:21].C(OCCCC)(=O)CS.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O>[CH:11]([CH2:7][C:6](=[CH2:8])[C:5]([OH:10])=[O:9])=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:22])[CH:20]=[CH2:21].[Na:1].[CH2:3]1[O:4][CH2:2]1.[C:5]([OH:10])(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)O
Agent: C=CC(=O)OCCCC
Agent: CCCCOC(=O)CS
Solvent: O
Solvent: C1CO1
Product: C=C(CC=Cc1ccccc1)C(=O)O
Temperature: 75 °C
Reaction time: 5 h

Procedure:
In a reactor equipped with a stirring rod and a thermometer were placed 683 parts of water, 11 parts of a sodium salt of sulfuric acid ester of ethylene oxide adduct of methacrylic acid ELEMINOL RS-30 (trade name, available from Sanyo Chemical Industries, Ltd., Japan), 103 parts of styrene, 83 parts of methacrylic acid, 90 parts of butyl acrylate, 12 parts of butyl thioglycolate and 1 part of ammonium persulfate, and the mixture was stirred at 400 rpm for 15 minutes to yield a white emulsion. The emulsion was heated to an inner temperature of 75° C., followed by reaction for 5 hours. The reaction mixture was further treated with 30 parts of a 1% aqueous solution of ammonium sulfate, was aged at 75° C. for 5 hours and thereby yielded an aqueous dispersion [Fine Particle Dispersion 3] of a vinyl resin (a copolymer of styrene-methacrylic acid-butyl acrylate-sodium salt of sulfuric acid ester of ethylene oxide adduct of methacrylic acid). Fine Particle Dispersion 3 had a volume-average particle diameter of 110 nm when measured with a laser diffraction-scattering size distribution analyzer LA-920. Part of Fine Particle Dispersion 3 was dried to isolate the resin component. The resin component had a Tg of 78° C. and a weight-average molecular weight of 2.5×104.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.COC(=O)[C:17]([CH2:19][Cl:20])=O.[OH-].[NH4+]>CO.[Cl-].[Na+].O>[Cl:20][CH2:19][CH:17]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)CCl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: ClCC1NCCc2c1[nH]c1ccccc21
Yield: 77.4 %

Procedure:
A susension of 108.4 g (0.55 mol) of tryptaminehydrochloride in 1 liter of dry methanol and 93.2 g (0.68 mol) of methyl-3-chloropyruvate* was refluxed under N2 for 24 h. The cooled mixture was poured into brine, made basic with ammonium hydroxide and extracted with dichloromethane. Concentration and trituration with ethyl acetate gave 94.0 g (61.3%) of the chloromethyl tetrahydro-β-carboline, melting point ("mp") 123°-125° C. The product was recrystallized from dichloromethane/pentane.
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]([NH:12][CH2:13][CH2:14][CH3:15])(Cl)[CH:6]=[N:7][C:8]=1[C:9]#[N:10])#[N:2].[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22][SH:23])=[CH:18][CH:17]=1.N1C=CC=CC=1.O>CC(C)=O>[C:9]([C:8]1[C:3]([C:1]#[N:2])=[N:4][C:5]([NH:12][CH2:13][CH2:14][CH3:15])=[C:6]([S:23][CH2:22][C:19]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[N:7]=1)#[N:10]
Reactant: CCCNC1(Cl)C=NC(C#N)=C(C#N)N1
Reactant: SCc1ccccc1
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCCNc1nc(C#N)c(C#N)nc1SCc1ccccc1
Yield: 30.4 %

Procedure:
2,3-Dicyano-6-n-propylamino-6-chloropyrazine (1.11 g; 0.005 mole) and 0.87 g (0.007 mole) of benzylthiol were dissolved in 50 ml of acetone. The solution was cooled to 0° to 5° C. With stirring, a solution prepared from 0.40 g (0.005 mole) of pyridine and 20 ml of water was added dropwise over the period of 30 minutes. The mixture was further stirred at 20° to 30° C. for 1 hour, and concentrated under reduced pressure to remove acetone. The residue was extracted with 100 ml of chloform. The extract was washed twice with 50 ml of water, dried over anhydrous calcium chloride, and concentrated under reduced pressure to afford a yellowish solid. Recrystallization of the solid from ethanol afforded 0.47 g (yield 30%) of 2,3-dicyano-5-n-propylamino-6-(benzylthio)pyrazine.
Reaction SMILES: Cl.N[C@@H]1C[C@H](NC2C(C)=NC3C(N=2)=C([C:18]2[NH:26][C:25]4[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=4[CH:19]=2)C=CC=3)C1.ClCCOCCCl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:26]1[C:25]2[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=2[CH:19]=[CH:18]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1C[C@@H](N)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCOCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCc2[nH]ccc21
Temperature: 150 °C
Reaction time: 1.17 h
Yield: 20 %

Procedure:
A suspension of 2-(3-((cis-3-aminocyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one hydrochloride (Example 435; 26.0 mg, 0.065 mmol), bis(2-chloroethyl) ether (Aldrich; 0.015 mL, 0.130 mmol), and DIPEA (0.068 mL, 0.391 mmol) in DMF (1.0 mL) was stirred in a sealed flask at 150° C. for 70 min. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 0-10% (2M NH3 in MeOH)/DCM). Product-containing fractions were combined and diluted with DCM (20 mL), and the resulting mixture was sequentially washed with half-saturated brine (30 mL) and water (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-(2-methyl-3-((1s,3s)-3-morpholinocyclobutyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (5.8 mg, 0.013 mmol, 21% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 12.63 (1H, br. s.), 7.95 (1H, dd, J=7.5, 1.3 Hz), 7.68 (1H, dd, J=8.1, 1.3 Hz), 7.41 (1H, t, J=7.8 Hz), 7.14 (1H, d, J=2.0 Hz), 5.25-5.33 (1H, m), 5.09 (1H, d, J=4.1 Hz), 4.22-4.32 (1H, m), 3.75 (4H, t, J=4.5 Hz), 3.70 (2H, m, J=6.8, 6.8, 2.5 Hz), 3.61-3.67 (1H, m), 3.00 (2H, t, J=6.8 Hz), 2.82-2.92 (2H, m), 2.57 (3H, s), 2.42 (4H, br. s.), 1.90-2.01 (2H, m). m/z (ESI, +ve) 433.1 (M+H)+.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([NH:22][CH3:23])[CH:14]=1)=[O:12].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:14][C:15]=1[NH:22][CH3:23]
Reactant: CNc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CNc1cc(C(=O)OC)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
Add an aqueous solution of sodium hydrosulfite (17.4 g, 100 mmol in 80 mL of water) to methyl-3-(methylamino)-4-nitrobenzene carboxylate (855 mg, 4.75 mmol) in tetrahydrofuran (70 mL) and ethanol (30 mL) at 0° C. The orange solution turned to an orange suspension upon addition. Stir the mixture at room temperature for 2 hours. The orange suspension turned to a yellow suspension over this time. Add saturated sodium bicarbonate (100 mL) then the yellow suspension turned colorless. Extract the mixture with ethyl acetate (2×100 mL). Wash the combined organics with brine (30 mL). Dry over magnesium sulfate, filter, concentrate, and dry under high vacuum to yield methyl 4-amino-3-(methylamino)benzoate (586 mg, 68%) as a yellow oil. The resulting oil began to crystallize upon standing after 10 minutes. 1H NMR (400 MHz, CDCl3) δ ppm 2.89 (s, 3 H), 3.37-3.81 (m, 2 H), 3.85 (s, 3 H), 6.67 (d, J=8.01 Hz, 1 H), 7.33 (d, J=1.37 Hz, 1 H), 7.44 (dd, J=8.11, 1.66 Hz, 1 H).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[CH:14]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[CH:14]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:8]([C:7]2[CH:6]=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:20][CH:19]=1)([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(NC(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
3-(Chlorosulfonyl)benzoyl chloride (5.00 g) was added to a toluene (50 mL) solution of 4-isopropoxyaniline (3.17 g), and stirred overnight at room temperature. The solid in the reaction system was removed through filtration, and the filtrate was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 100%, gradient), then the resulting compound was suspended in diisopropyl ether added thereto, and the solid was collected through filtration to give the entitled compound (2.27 g, 35%) as a pale blue solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:21]3[N:22]([CH:25]([C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[CH3:26])[CH:23]=[N:24][C:20]=3[CH:19]=[C:18]([C:34]#[N:35])[N:17]=2)[CH:13]=[N:14][CH:15]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:23]1[N:22]([CH:25]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH3:26])[C:21]2[C:16]([C:12]3[CH:13]=[N:14][CH:15]=[C:10]([Cl:9])[CH:11]=3)=[N:17][C:18]([C:34]#[N:35])=[CH:19][C:20]=2[N:24]=1
Reactant: CC([C@H]1CC[C@H](C)CC1)n1cnc2cc(C#N)nc(-c3cncc(Cl)c3)c21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC([C@H]1CC[C@H](C)CC1)n1c(Br)nc2cc(C#N)nc(-c3cncc(Cl)c3)c21
Temperature: 25 °C

Procedure:
N-bromosuccinimide (4.07 g, 22.9 mmol) was added to a room temperature solution of racemic 4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (4.14 g, 7.63 mmol) stirring in degassed chloroform (38 mL). The reaction was heated to reflux for 1.5 hours. The mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated aqueous sodium thiosulfate (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-80% ethyl acetate/hexanes, linear gradient) to afford racemic 2-bromo-4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. The racemic material was then purified by chiral supercritical fluid chromatography (Chiralpak IB, 21×250 mm, 25% methanol in CO2) to afford 2-bromo-4-(5-chloropyridin-3-yl)-3-[(1S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile and 2-bromo-4-(5-chloropyridin-3-yl)-3-[(1R)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. Faster eluting enantiomer 1: MS ESI calc'd. for C21H21BrClN5 [M+H]+ 458. found 458. Slower eluting enantiomer 2: MS ESI calc'd. for C21H21BrClN5 [M+H]+ 458. found 458.
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[CH:5][C:4]([Br:24])=[N:3]1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)=[CH:5][C:4]([Br:24])=[N:3]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cn1nc(Br)cc1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cn1nc(Br)cc1-c1ccc(C(F)(F)F)cc1
Yield: 56.2 %

Procedure:
A solution of 1-methyl-3-bromo-5-(nonafluorobutanesulfonyloxy)pyrazole from Example 69 Step 2 (0.16 g, 0.35 mmol), 4-trifluoromethylbenzeneboronic acid (0.07 g, 0.36 mmol), tetrakis(triphenylphosphine) palladium (0) (0.04 g, 10 mol %), sodium carbonate (0.04 g, 0.38 mmol) in dry N,N-dimethylformamide (2 mL) was stirred under nitrogen at 40° C. for 18 hours. The cooled reaction mixture was poured into 1M hydrochloric acid (10 ml) and extracted with diethyl ether (2×10 mL). The combined organic layers were dried (Na2SO4) and concentrated to give an oil which was purified by flash column chromatography on silica eluting with 5% ethyl acetate—isohexane to give 1-methyl-3-bromo-5-(4-trifluoromethylphenyl)pyrazole as a white solid (0.06 g, 56%). δ (1H, 400 MHz, CDCl3) 3.86 (3H, s), 6.37 (1H, s), 7.53 (2H, d, J=8 Hz), 7.74 (2H, d, J=8 Hz). Step 2: [6S,9R,11R] 2′,3′,4′,5,5′,6,7,8,9,10-decahydro-2-(5-(4-trifluoromethylphenyl)-1-methyl-pyrazol-3-yl)-5′-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3′-[1,2,5]thiadiazole] 1′,1′-dioxide
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13]2.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:22]([O:21][C:19]([C:14]1[NH:15][C:16]2[C:12]([C:13]=1[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][C:10]([F:9])=[CH:18][CH:17]=2)=[O:20])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C(=O)OCC)[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
A solution of 40 ml (313 mmol) of ethyl chloroglyoxylate and of 36 ml (313 mmol) of titanium tetrachloride in 1 l of dichloromethane is stirred for 15 min at room temperature. A solution of 50 g (241 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate in dichloromethane is added and the mixture is stirred for 2 h at room temperature. The mixture is poured into water and the organic phase is separated by settling, washed with dilute sodium hydroxide solution and dried over sodium sulphate. 31.5 g (102 mmol) of product are obtained, which product is used as is in the following stage.
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][C:22]([C@H:24]2[CH2:29][CH:28]3[CH:26]([CH2:27]3)[N:25]2C(OC(C)(C)C)=O)=[O:23])[CH3:20])=[CH:15][CH:14]=1)=[O:12]>>[CH:26]12[CH2:27][CH:28]1[CH2:29][C@H:24]([C:22]([NH:21][C@H:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:18][CH:17]=1)[CH3:20])=[O:23])[NH:25]2
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC3CC3N2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC3CC3N2)cc1
Yield: 98.8 %

Procedure:
The title compounds (D106) (11 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (3R)-tert-butyl 3-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (diastereoisomers mixture) (D74a) (15 mg)
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][C:8]([C:14](=[O:16])[CH3:15])=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:17](=[O:19])[CH3:18])[CH:2]=1.[H-].[Na+].Cl.Cl[CH2:24][CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH3:31].C(Cl)(Cl)Cl.CO>CN(C=O)C.O>[CH3:31][N:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH2:25][CH2:24][N:12]1[C:13]2[CH:1]=[CH:2][C:3]([C:17](=[O:19])[CH3:18])=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[C:8]([C:14](=[O:16])[CH3:15])[CH:7]=2
Reactant: CC(=O)c1ccc2[nH]c3ccc(C(C)=O)cc3c2c1
Reactant: CN1CCCC1CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)c1cc(C(C)=O)ccc1n2CCC1CCCN1C
Temperature: 25 °C
Reaction time: 0.07 h
Yield: 64.3 %

Procedure:
The diacetyl derivative 31 (0.97 g, 3.86 mmol) was dissolved in DMF (7 mL). NaH (0.54 g, 13.5 mmol) was added, and the mixture was stirred for 3-5 min at room temperature. 2-(2-Chloroethyl)-1-methylpyrrolidine hydrochloride (1.07 g, 5.8 mmol) was added. The reaction mixture was stirred for 24 h at 60° C. (TLC monitoring, CHCl3/MeOH, 9:1), diluted with water, and extracted with ethyl acetate. The extract was dried with Na2SO4 and evaporated. The residue was purified by column chromatography (silica gel, CHCl3/MeOH 99:1→90:10) to give 0.90 g (64%) of the product. 1H NMR (DMSO-d6): δ 1.41-1.49 (1H, m); 1.54-1.73 (3H, m); 1.76-1.85 (1H, m); 1.97-2.13 (3H, m); 2.14 (3H, s); 2.70 (6H, s); 2.86-2.93 (1H, m); 4.46-4.50 (2H, m); 7.72 (2H, d, J=8.8 Hz); 8.12 (2H, dd, J=8.8 Hz, J=1.6 Hz); 9.04 (2H, d, J=1.6 Hz). ELSD: 100%, ESI-MS: m/z 363 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][CH:18]=[C:17]2[O:26][Si](C)(C)C)=[CH:12][CH:11]=1>C1COCC1.O.CCOC(C)=O>[Br:1][CH:18]1[C:17](=[O:26])[CH:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)[CH2:25][C:20]2([O:24][CH2:23][CH2:22][O:21]2)[CH2:19]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)OC1=CCC2(CC1c1ccc(F)cc1)OCCO2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1C(Br)CC2(CC1c1ccc(F)cc1)OCCO2
Reaction time: 2 h
Yield: 240.9 %

Procedure:
Step AAC (2): Followed a method described by A. de Meijer et. al Chem. Eur. J. 2007, 13, 3739. N-bromosuccinimide (52 mg, 0.29 mmol) was added to a solution of (9-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-en-8-yloxy)trimethylsilane (89 mg, 276 mmol) in THF/water (1:1, 1.4 mL). The resulting mixture was allowed to stir for 2 hr. The crude reaction was diluted with EtOAc and washed with water. The organic layer was concentrated in vacuo to afford 7-bromo-9-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-on (230 mg, 253%) yield). The crude product was used for subsequent chemistry without purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[CH:16](I)([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(OCC)C>[Cl:1][C:2]1[N:6]([CH:16]([CH3:18])[CH3:17])[C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(-c2nc(C)[nH]c2Cl)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: COc1ccc(-c2nc(C)n(C(C)C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 8.9 grams (0.04 mole) of 5-chloro-4-(4-methoxyphenyl)-2-methyl-imidazole, 34.0 grams (0.20 mole) of isopropyl iodide, and 27.8 grams (0.02 mole) of potassium carbonate in 200 mL of acetone is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is shaken with 100 mL of water and 100 mL of diethyl ether. The organic layer is separated, washed with water, and dried with magnesium sulfate. The mixture is filtered and the filtrate is concentrated under reduced pressure to a residue. The residue is purified with column chromatography, yielding 5-chloro-1-(1-methylethyl)-4-(4-methoxyphenyl)-2-methylimidazole.
Reaction SMILES: C(NC(C)C)(C)C.O1CCCC1.C([Li])CCC.[NH2:18][C:19]1[C:20]([Cl:28])=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23].[N:29]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:30]=[O:31]>CCCCCC>[CH2:32]([NH:29][C:30](=[O:31])[NH:18][C:19]1[C:20]([Cl:28])=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23])[CH2:33][CH2:34][CH3:35]
Reactant: Nc1cccc(C(=O)O)c1Cl
Reactant: CCCCN=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCNC(=O)Nc1cccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
To N,N-diisopropylamine (1.72 mL, 0.0122 mol) in tetrahydrofuran (12 mL, 0.14 mol), was added 1.6 M n-butyllithium in hexane (7.6 mL) at −78° C. under an atmosphere of nitrogen. After 30 minutes, 3-amino-2-chlorobenzoic acid (586, 1.00 g, 0.00583 mol) was added. After another 30 minutes, 1-isocyanatobutane (2.60 mL, 0.0233 mol) was added at −78° C. under an atmosphere of nitrogen and allowed to stir for two hours. The reaction mixture was warmed up to room temperature and stirred at room temperature for 30 minutes. The reaction was quenched with 1M HCl (aqueous) solution and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane:methanol:acetic acid 40:2:1 to give the compound as an off-white solid (587, 147 mg, 9%).