Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][CH:12]([CH2:16][O:17][CH3:18])[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:34]([NH:41][C:13](=[O:15])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:16][O:17][CH3:18])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCC(NC(=O)OCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 11 (0.52 g, 2.04 mmol) in dry tetrahydrofuran (10 mL) was cooled to −78° C. in a dry ice-acetone bath under a N2 atmosphere. To this was added via a dry syringe 4-methylmorpholine (0.34 mL, 3.06 mmol). After stirring for 5 minutes, isobutyl chloroformate (0.4 mL, 3.06 mmol) was added via dry syringe and then the mixture stirred for 5 minutes. This was followed by the addition of benzylamine (0.32 mL, 3.06 mmol). After stirring at −78° C. for 5 minutes, the reaction was allowed to warm to room temperature, and stirring was continued at room temperature (30 min). The hydrochloride salt of 4-methyl morpholine was removed from the reaction by filtration. The clear filtrate was evaporated in vacuo and the residue was triturated with ethyl ether (5.0 mL). The white crystalline product obtained was isolated by filtration after washing with small amounts of ether and air-dried (0.55 g, 78%): mp 112°-114° C., Rf 0.6 (10% MeOH/CHCl3)
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]=[N:12][C:5]=3[CH:6]=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:17][CH:16]([CH3:18])[CH2:15][N:14]1[C:4]2[C:3]3[C:2]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:12]=[CH:13]1
Reactant: CC(C)Cn1cnc2cnc3cccc(Br)c3c21
Reactant: OB(O)c1ccccc1
Product: CC(C)Cn1cnc2cnc3cccc(-c4ccccc4)c3c21

Procedure:
9-Bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (0.34 mmol) and benzene boronic acid (62 mg, 0.51 mmol) were coupled according to Part J of Example 1. The work-up procedure described in Parts 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 85:15) to provide 1-(2-methylpropyl)-9-phenyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[O:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:19]=[CH:18]1>>[C:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:21]2[O:17][CH:18]=[N:19][CH:20]=2)=[CH:23][CH:24]=1)(=[O:29])=[O:30])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: O=C(c1ccccc1)c1cc(Br)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-amino-5-bromo-phenyl)-phenyl-methanone and 121 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.25-7.35 (m, 5H), 7.45-7.49 (m, 4H), 7.63-7.71 (m, 4H), 7.95 (s, 1H), 9.67 (s, 1H). MS: m/z 484.3 (M++1).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCS(=O)(=O)Cl
Reactant: CCCCc1cc(OC2CCN(CCCCN)CC2)c2ncccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1cc(OC2CCN(CCCCNS(=O)(=O)CC)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (for example, as prepared for Intermediate 37) (248 mg, 0.7 mmol) was dissolved in DCM (5 ml), and treated with triethylamine (156 μl, 1.12 mmol), and ethanesulfonyl chloride (commercially available, for example, from Aldrich) (80 μl, 0.84 mmol). The mixture was stirred at room temperature for 2 h, then left to stand at room temperature overnight. The mixture was washed with saturated aqueous sodium hydrogen carbonate, passed through a hydrophobic frit and the organic solution was concentrated in vacuo. The residue was applied to a silica cartridge (20 g), eluting with DCM-ethanol-aqueous 0.88 s.g. ammonia (100:8:1). The relevant fractions were concentrated in vacuo to give the title compound (as the free base) as a yellow gum (167 mg). LCMS RT=2.66 min, ES+ve m/z 448 (M+H)+; 1H NMR δ (CD3OD) 8.72 (1H, dd, J=4, 1.5 Hz), 8.21 (1H, dd, J=8, 1.5 Hz), 7.48 (1H, dd, J=8, 4 Hz), 7.26 (1H, s), 7.10 (1H, s), 4.74-4.64 (1H, m), 3.10-2.92 (6H, m), 2.78 (2H, t, J=7.5 Hz), 2.50-2.38 (4H, m), 2.20-2.10 (2H, m), 2.08-1.95 (2H, m), 1.76-1.53 (6H, m), 1.47-1.36 (2H, m), 1.30 (3H, t, J=7 Hz), 0.97 (3H, t, J=7 Hz).
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].[Cl-].[NH4+].[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Cu]I>[CH3:1][C:2]([OH:5])([CH2:4][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:3]
Reactant: Cc1ccccc1
Reactant: CC1(C)CO1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(O)CCc1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
13.92 g of copper(I) iodide were added to the supernatant obtained according to example 1, and the flask was cooled to −10° C. Then, 52.70 g of isobutylene oxide were added gradually over a period of 1 hour using a dropping funnel, and the temperature was maintained between −10° C. and −6° C. A mild exotherm was observed during this latter process. After stirring the mixture for a further 2 hours at 0° C., a sample was taken for analysis by gas chromatography. This sample was worked up with ammonium chloride solution. The reaction mixture was worked up by addition of 400 ml of saturated ammonium chloride solution, and 200 ml of toluene were added. The organic phase was separated off and washed twice with 400 ml each time of saturated ammonium chloride solution. After drying over magnesium sulfate, the product was obtained by distillation in vacuo with a purity of >97%. A total of 88.9 g of 2-methyl-4-phenylbutan-2-ol were obtained, corresponding to a yield of 74%.
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[C:7]=1Cl)([O-:5])=[O:4]>>[CH3:1][NH:2][C:7]1[C:6]([N+:3]([O-:5])=[O:4])=[CH:11][C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17]
Reactant: CN
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Product: CNc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
Following the above procedure, two grams of 40% aqueous solution of methyl amine was reacted with 2.6 grams of 2,6-dinitro-4-t-butyl-chlorobenzene to give N-methyl-2,6-dinitro-4-t-butylaniline as orange needles melting at 129°-130° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27]([C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)(=[O:29])[CH3:28]>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([S:36]([C:32]5[CH:31]=[C:30]([C:27](=[O:29])[CH3:28])[CH:35]=[CH:34][CH:33]=5)(=[O:38])=[O:37])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(S(=O)(=O)N2CCN3C[C@H](Oc4cnc(C5CC5)cn4)C[C@H]3C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
To (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine (1 mmol, Example 27B) and triethylamine (1.5 mmol) in dichloromethane (6 mL) was added 3-acetylbenzene-1-sulfonyl chloride (1.1 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 18 hours. The mixture was concentrated, and the residue was purified by chromatography on silica gel (ethyl acetate) to give the title compound (370 mg) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.81 (m, 2H), 0.91 (m, 2H), 1.75 (m, 1H), 1.89 (m, 1H), 2.06 (m, 2H), 2.19 (m, 2H), 2.30 (m, 3H), 3.67 (s, 2H), 2.97 (m, 1H), 3.54 (m, 1H), 3.65 (m, 1H), 3.80 (m, 1H), 5.19 (m, 1H), 7.83 (m, 1H), 8.00 (m, 1H), 8.15 (m, 3H), 8.30 (m, 1H); MS (ESI) m/z 444 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([F:29])[CH:31]=2)[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Reactant: O=C(Cl)c1cccc(F)c1
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 3-fluorobenzoyl chloride gave the title compound. ES-MS m/e (%): 581.2(M+H+).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11](=[O:27])[CH:12]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:9])C.[OH-].[K+]>C(O)C.O>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:11]([NH:10][C:8](=[O:9])[NH:7][CH2:6][CH2:5][C:4]([OH:28])=[O:3])=[O:27])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
A solution of 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-propionic acid ethyl ester (prepared in Example 12B-c, 94 mg, 0.22 mmol) in ethanol (5 mL) at 25° C. was treated with a solution of potassium hydroxide (43 mg, 0.77 mmol) in water (1 mL). This solution was stirred at 25° C. for 2 h. At this time, the reaction was diluted with water (5 mL) and the ethanol was removed in vacuo. The aqueous layer was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and extracted with methylene chloride (3×15 mL). The organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate plus 1% acetic acid) afforded 3-{3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-propionic acid (30 mg, 35%) as a white foam: FAB-HRMS m/e calcd for C18H22Cl2N2O4 (M+H)+401.1035, found 401.1022.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.[CH3:30][NH2:31]>O1CCCC1>[Cl:1][C:2]1[CH:28]=[C:6]([C:7]([NH:31][CH3:30])=[O:27])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:26])([F:24])[F:25])[CH:12]=2)=[O:8])=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.1 %

Procedure:
To a solution of the benzoxazinone product of Example 6, Step D (4.50 g, 10.18 mmol) in tetrahydrofuran (THF; 70 mL) was added methylamine (2.0 M solution in THF, 15 mL, 30.0 mmol) dropwise and the reaction mixture was stirred at room temperature for 5 minutes. The tetrahydrofuran solvent was evaporated under reduced pressure and the residual solid was purified by chromatography on silica gel to afford 4.09 g of the title compound, a compound of the present invention, as a white solid melting at 185-186° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1(=[O:16])[NH:14][C:13](=[O:15])[CH:12]=[CH:11]1.O>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:12]2[CH2:11][C:10](=[O:16])[NH:14][C:13]2=[O:15])=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1C=CC(=O)N1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC(c2c[nH]c3ccccc23)C(=O)N1
Reaction time: 24 h

Procedure:
Indole (4.38 g, 40 mmole) and maleimide (7.84 g, 80 mmole) were dissolved in concentrated acetic acid (35 ml) and stirred under reflux for 36 hours. After cooling the reaction mixture water (10 ml) was slowly added dropwise. The solution was then kept for 24 hours in a refrigerator. The solid thereby formed was filtered off. 3-(1H-indol-3-yl)-pyrrolidine-2,5-dione was thereby obtained as a brown solid in a yield of 3.24 g (38%).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16](=[O:36])[C:17](C(C)C)([NH2:32])C1C=CC(OCC3C=CC=CC=3)=CC=1)[CH:12]=[CH:11][C:10]=2[OH:37])=[O:6])[CH3:3].[CH3:38][OH:39]>[C].[Pd]>[ClH:1].[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([CH:16]([OH:36])[CH2:17][NH:32][CH:9]([CH3:10])[CH2:14][C:13]1[CH:16]=[CH:17][C:38]([OH:39])=[CH:11][CH:12]=1)[CH:12]=[CH:11][C:10]=2[OH:37])=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2c(C(=O)C(N)(c3ccc(OCc4ccccc4)cc3)C(C)C)ccc(O)c2[nH]1
Reactant: CO
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)c1cc2c(C(O)CNC(C)Cc3ccc(O)cc3)ccc(O)c2[nH]1

Procedure:
209 mg of 4-[2-(4-benzyloxyphenyl)-1-methylethyl-aminoacetyl]-7-hydroxyindole-2-carboxylic acid ethyl ester hydrochloride is hydrogenated in 20 ml of methanol for 2.5 hours at room temperature and under normal pressure in the presence of 42 mg of 10% palladium-carbon. The mixture is filtered, the filtrate is concentrated under vacuum, and the residue is recrystallized from acetone/diethyl ether, thus obtaining 115 mg of 4-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1-methylethylamino]ethyl}-7-hydroxy-indole-2-carboxylic acid ethyl ester hydrochloride, decomposition point 110° C.
Reaction SMILES: Cl.[CH:2]12[CH:7]([CH2:8][OH:9])[CH:6]1[CH2:5][NH:4][CH2:3]2.CCN(CC)CC.[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>C(Cl)Cl>[C:21]([O:20][C:18]([N:4]1[CH2:5][CH:6]2[CH:2]([CH:7]2[CH2:8][OH:9])[CH2:3]1)=[O:17])([CH3:24])([CH3:23])[CH3:22]
Reactant: OCC1C2CNCC12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2C(CO)C2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a solution of (3-Aza-bicyclo[3.1.0]hex-6-yl)-methanol-HCl (11.8 gm, 78.7 mmol) in 350 mL of anhydrous CH2Cl2 at room temperature was added Et3N (32.9 mL, 236 mmol), followed by (BOC)2O (18.9 gm, 86.6 mmol) in portions. The reaction was stirred at room temperature for 18 hours. The mixture was washed with saturated NaHCO3, water, brine and dried over anhydrous MgSO4. The mixture was filtered and concentrated under reduced pressure to yield the crude material, which was purified via flash chromatography with 10% MeOH/EtOAc. The product containing fractions were collected and concentrated to yield the desired product (15.6 gm). 400 MHz 1H NMR (CDCl3) δ 3.42-3.56 (m, 4H), 3.24-3.37 (m, 2H), 1.72 (brs, 1H), 1.37-1.41 (m, 10H), 0.87-0.93 (m, 1H); MS (M+1) 213.2.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH:23]=C)[CH:18]=2)[C:13]=1[O:25][S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C[O:36]CC1>O>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH:23]=[O:36])[CH:18]=2)[C:13]=1[O:25][S:26]([C:29]([F:32])([F:30])[F:31])(=[O:27])=[O:28])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1ccc2c(OS(=O)(=O)C(F)(F)F)c([C@H](OC(C)(C)C)C(=O)OCC)c(C)cc2c1
Reactant: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(C=O)ccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 0.33 h

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate (0.60 g, 1.3 mmol) in THF (7 mL) at room temperaturewas treated with a previously prepared mixture of K2OsO4.2H2O (0.023 g, 0.063 mmol) and NaIO4 (0.81 g, 3.8 mmol) in water (5 mL). The resulting suspension becomes thick and opaque. After vigorous stirring for 20 min, the suspension is filtered through a pad of Celite, and the filtrate is washed with batches of EtOAc until white in color. The collected mother liquor is further diluted with water and EtOAc. Following separation, the aqueous layer is extracted with EtOAc until colorless. The combined organics are washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue is purified by Yamazen column chromatography (15-35% EtOAc/hex) to afford the desired material. 1H-NMR: 400 MHz, (CDCl3) δ: 10.19 (s, 1H); 8.31 (br s, 1H); 8.16 (d, J=8.8 Hz, 1H); 8.05 (dd, J=8.8, 1.6 Hz, 1H); 7.85 (s, 1H); 5.76 (s, 1H); 4.28-4.10 (m, 2H); 2.61 (s, 3H); 1.22 (s, 9H); 1.18 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[Cl:11][C:12]1[CH:24]=[C:23]([Cl:25])[C:22]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[O:15].C1CCN2C(=NCCC2)CC1>O1CCCC1>[Cl:11][C:12]1[CH:24]=[C:23]([Cl:25])[C:22]([S:26](=[O:28])(=[O:29])[NH:27][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[O:15]
Reactant: COCCNC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1Cl
Reactant: O=C(O)c1ccccc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COCCNC(=O)c1cc(S(=O)(=O)NC(=O)c2ccccc2Cl)c(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
At room temperature, 1.0 g (6.1 mmol) of 2-chlorobenzoic acid are dissolved in 120 ml of tetrahydrofuran and mixed with 1.0 g (6.1 mmol) of N,N′-carbonyldiimidazole. After 30 minutes at room temperature and a further 30 minutes at reflux temperature, 2.0 g (6.1 mmol) of 2,4-dichloro-N-(2-methoxyethyl)-5-sulfamoylbenzamide are added at reflux temperature. After 10 minutes, 0.9 g (6.1 mmol) of 1,5-diazabicyclo[5.4.0]-5-undecene are added and the mixture is kept at reflux temperature for a further 3 hours. The mixture is subsequently evaporated to dryness, the residue is taken up in 60 ml of acetonitrile and the solution is poured into 60 ml of water. The solution is acidified to pH 1 using 2N HCI and the precipitate is separated off, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([OH:27])=O)=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:30][O:31][CH:32]1[CH2:35][NH:34][CH2:33]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:34]4[CH2:35][CH:32]([O:31][CH3:30])[CH2:33]4)=[O:27])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Reactant: COC1CNC1
Agent: Cl
Product: COC1CN(C(=O)c2cnn(C)c2C(=O)Nc2ccn3nc(-c4cccc(F)c4)nc3c2)C1
Yield: 14.1 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (60 mg, 158 μmol) and 3-methoxyazetidine hydrochloride (58.5 mg, 473 μmol) as starting materials. The reaction affords 4-(3-methoxy-azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(3-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (10 mg, 14.1%) as white solid. mp.: 255-257° C., MS: m/z=450.0 (M+H+).
Reaction SMILES: [CH3:1]C1CCCC2(C(=O)CCC2)C1.[CH3:13][CH:14]1[CH2:24][CH2:23][C:17]2([C:21](=[O:22])[CH2:20][CH2:19][CH2:18]2)[CH2:16][CH2:15]1.C[Li]>>[CH3:1][C:21]1([OH:22])[C:17]2([CH2:23][CH2:24][CH:14]([CH3:13])[CH2:15][CH2:16]2)[CH2:18][CH2:19][CH2:20]1
Reactant: CC1CCCC2(CCCC2=O)C1
Reactant: CC1CCC2(CCCC2=O)CC1
Agent: [Li]C
Product: CC1CCC2(CCCC2(C)O)CC1
Yield: 43 %

Procedure:
A mixture of 7-methylspiro[4,5]decan-1-one and 8-methylspiro[4,5]decan-1-one and methyl lithium were reacted together according to the general procedure (example 2, procedure 5) to give the title compound in 43% yield. The crude product was purified by column chromatography on silicagel (eluent: cyclohexane/ethyl acetate 29:1) and bulb-to-bulb distillation (B.p.=68° C./0.04 mbar).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18])(=[O:12])[CH3:11]>>[C:10]([NH:13][C:14]1[C:23]([CH3:24])=[CH:22][C:21]([N+:1]([O-:4])=[O:2])=[C:16]([CH:15]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:12])[CH3:11]
Reactant: COC(=O)c1ccc(C)c(NC(C)=O)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(NC(C)=O)c(C)cc1[N+](=O)[O-]
Yield: 84.3 %

Procedure:
a mixture of fuming nitric acid (8.4 g) and conc. sulfuric acid (260 g) was cooled to 0°-10° C. and the known methyl 3-acetylamino-4-methylbenzoate (26.3 g, 127 mmol) was added portionwise with stirring. After stirring for several hours, the mixture was poured onto ice which subsequently melted. The product was collected by suction filtration, washed with water and dried. The solid was recrystallized from isopropanol to give 27 g of yellow powder.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>>[CH:19]1([CH2:18][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH2:21][CH2:20]1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: BrCC1CC1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC1CC1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and (bromomethyl)cyclopropane: 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 2H), 6.57 (s, 1H), 4.04 (d, J=6.6 Hz, 2H), 2.50 (s, 3H), 1.16 (m, 1H), 0.60 (m, 2H), 0.34 (m, 2H); MS (ES) m/z 279 (M+1).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52](=[O:64])[C@H:53]([OH:63])[C@H:54]([NH2:62])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH3:50]>C(Cl)Cl>[CH2:55]([C@@H:54]([NH:62][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3])[C@H:53]([C:52]([O:51][CH2:49][CH3:50])=[O:64])[OH:63])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=C(O)CCCc1ccccc1C(=O)O
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)CCCc1ccccc1C(=O)O
Reaction time: 1 h
Yield: 8.6 %

Procedure:
2-(3-Carboxy-propyl)benzoic acid (69.9 mg, 336 μmol, 1.0 eq.) was combined with DIPEA (187 μL, 3.2 eq.) and HATU (128 mg, 336 μmol, 1.0 eq.) in DCM (7 mL). (2R,3R)-3-Amino-2-hydroxy-4-phenyl-butyric acid ethyl ester (75 mg, 340 μmol, 1.0 eq.) was added and the resulting mixture was stirred for 1 hour. The reaction was quenched by adding saturated NH4Cl and the product was extracted with DCM, dried, and evaporated. One third of the crude product (was dissolved in AcOH (1 mL) and purified by preparative HPLC to yield the title compound (12 mg, 95% purity). MS m/z [M+H]+ calc'd for C23H27NO6, 414.18. found 414.2.