Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:13]2[C:14]3[C:10]([CH:11]=[CH:12]2)=[CH:9][C:8]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)=[CH:7][C:6]=3[CH2:5][NH:4][CH2:3]1.[CH3:23][NH2:24]>>[CH3:23][NH:24][CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:8]2[CH:9]=[C:10]3[C:14]4=[C:6]([CH2:5][NH:4][CH2:3][C:2](=[O:1])[N:13]4[CH:12]=[CH:11]3)[CH:7]=2)=[CH:22][CH:21]=1
Reactant: CN
Reactant: O=Cc1ccc(-c2cc3c4c(ccn4C(=O)CNC3)c2)cc1
Product: CNCc1ccc(-c2cc3c4c(ccn4C(=O)CNC3)c2)cc1
Yield: 71 %

Procedure:
Using the reductive amination procedure described in Example 82, the title compound was synthesized from 4-(1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-6-yl)-benzaldehyde and methylamine in 71% yield as a pale-yellow solid: mp 178-180° C.; 1H NMR (DMSO-d6) δ 2.29 (s, 3H), 3.48 (br s, 2H), 3.70 (s, 2H), 4.30-4.33 (m, 2H), 6.68 (s, 1H), 7.16 (t, 1H, J=9.0 Hz), 7.45 (d, 2H, J=6.0 Hz), 7.55 (d, 2H, J=6.0 Hz), 7.77 (d, 1H, J=9.0 Hz), 7.80 (d, 1H, J=9.0 Hz), 8.36 (t, 1H, J=6.0 Hz). HRMS calcd. for C19H19N3O 305.3828 (M+), found 305.1536. Anal. (C19H19N3O.0.1H2O) C, H, N.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].CN(C)S(=O)=O.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:29])[CH:25]=2)[N:20]=1>O>[Br:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([N:2]([CH3:1])[CH:3]([CH3:5])[CH3:4])[CH:28]=[CH:27]2
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: CNC(C)C
Agent: CN(C)[SH](=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)N(C)c1ccc2cc(Br)ccc2n1
Temperature: 110 °C
Reaction time: 4 h
Yield: 2.6 %

Procedure:
Under nitrogen atmosphere, 180 mg of N-methylisopropylamine, and 200 g of potassium carbonate were added at room temperature sequentially to 5 ml solution of dimethylsulfonamide with 63 g of 2-chloro-6-bromoquinoline, and the mixture was stirred at 110° C. for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by silicagel chromatography (hexane/ethyl acetate=3/1) to obtain 18 mg of the above compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3([C:18]#N)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:8][CH2:7]2)[CH:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][NH:3]1.[C:26]1([Mg]Br)[CH:31]=[CH:30]C=[CH:28][CH:27]=1>C1COCC1>[C:20]1([CH:5]2[C:6]3([CH2:7][CH2:8][N:9]([C:12]4([C:18]5[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=5)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[CH2:10][CH2:11]3)[C:2](=[O:1])[NH:3][CH2:4]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#CC1(N2CCC3(CC2)C(=O)NCC3c2ccccc2)CCCCC1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C1NCC(c2ccccc2)C12CCN(C1(c3ccccc3)CCCCC1)CC2
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a solution of rac-1-(1-oxo-4-phenyl-2,8-diaza-spiro[4.5]dec-8-yl)-cyclohexanecarbonitrile (400 mg, 1.2 mmol) in dry THF (12 mL) under argon at 0° C. was added phenylmagnesium bromide (1 M in THF, 3.5 mL, 3.6 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The reaction was quenched by the addition of ammonium chloride solution (sat., 20 mL) and the product extracted with ethyl acetate (2×50 mL). The combined organic extracts were then washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with DCM:MeOH:NH4OH (95:4.5:0.5) to afford the title compound (430 mg, 94%) as a white solid. MS: m/e=389.3 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:9]>>[C:8](=[O:9])([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)[O:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCOC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 1 starting from 3-hydroxytetrahydrofuran (Aldrich, Cat. #H59109) and p-nitrophenyl chloroformate.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.[C:10]1([S:16]([C:19]2[CH:20]=[C:21]([CH:39]=[CH2:40])[C:22]3[O:31][C:30]4[CH2:29][CH2:28][N:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26][C:25]=4[C:23]=3[CH:24]=2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl.O>[C:10]1([S:16]([C:19]2[CH:20]=[C:21]([CH2:39][CH2:40][B:4]3[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:9])([CH3:1])[O:3]3)[C:22]3[O:31][C:30]4[CH2:29][CH2:28][N:27]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:26][C:25]=4[C:23]=3[CH:24]=2)(=[O:18])=[O:17])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=Cc1cc(S(=O)(=O)c2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Reactant: CC1(C)OBOC1(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2oc3c(CCB4OC(C)(C)C(C)(C)O4)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a suspension of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.05 mL, 0.33 mmol) and Rh(CO)(PPh3)2Cl (2 mg, 2.7 mmol) in dichloromethane (4 mL) at ambient temperature was added tert-butyl 8-(phenylsulfonyl)-6-vinyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (120 mg, 0.27 mmol). The reaction mixture was stirred for 4 h then diluted with water and extracted with dichloromethane. The organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 7:3 hexanes/ethyl acetate) to give tert-butyl 8-(phenylsulfonyl)-6-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (85 mg, 55%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.01-7.92 (m, 3H), 7.72 (br s, 1H), 7.58-7.46 (m, 3H), 4.56 (s, 2H), 3.97 (q, J=6.4 Hz, 2H), 3.83 (br s, 2H), 3.16 (t, J=6.4 Hz, 2H), 2.86 (br s, 2H), 1.51 (s, 9H), 1.39-1.19 (m, 12H).
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](=[O:6])[CH2:4][OH:5].CC(C)([O-])C.[K+].[F:19][C:20]([F:34])([F:33])[C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24](Cl)[O:23][N:22]=1.C(Cl)Cl>C1COCC1>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](=[O:6])[CH2:4][O:5][C:24]1[O:23][N:22]=[C:21]([C:20]([F:34])([F:33])[F:19])[C:25]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1noc(Cl)c1-c1ccccc1
Reactant: CN(C(=O)CO)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C(=O)COc1onc(C(F)(F)F)c1-c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
0.99 g (6.0 mmole) of N-methyl-N-phenyl-2-hydroxyacetamide was dissolved in THF (6 ml) and the solution was mixed with 0.75 g (6.0 mmole) of 90% potassium t-butoxide with ice cooling. The mixture was stirred for 30 minutes and then 1.24 g (5.0 mmole) of 3-trifluoromethyl-4-phenyl-5-chloroisoxazole was added dropwise to the mixture. After being stirred for 30 minutes, the mixture was refluxed for 24 hours. After cooling the reaction mixture, 60 ml of methylene chloride was added and the mixture was washed with a 5% solution of HCl and water. The methylene chloride phase was evaporated under reduced pressure and the residue was purified by chromatography on silica gel to give 1.15 g of colorless crystals. These were recrystallized from n-hexane to give 950 mg of the titled compound, yield 50.5%, m.p. 93.0°-94.0° C.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:23]1([CH3:30])[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][CH:24]=1.OS(O)(=O)=O.[OH-].[Na+]>C(O)(=O)C.O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:2]2([C:25]3[CH:26]=[CH:27][C:28]([OH:29])=[C:23]([CH3:30])[CH:24]=3)[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=3[C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:20][CH:19]=1
Reactant: COc1ccc(C2(O)c3ccccc3-c3ccccc32)cc1
Reactant: Cc1ccccc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C2(c3ccc(O)c(C)c3)c3ccccc3-c3ccccc32)cc1
Reaction time: 0.01 h
Yield: 95.2 %

Procedure:
4-Bromoanisole (46.7 g) was added dropwise to a stirred mixture of magnesium (6.0 g) in dry THF (250 mL). When all the magnesium had dissolved, 9-fluorene (40.0 g) in THF (400 mL) was added dropwise. The mixture was then stirred at room temperature for 3 hours and quenched with saturated ammonium chloride solution. The excess solvent was evaporated in vacuo and the residue extracted with ethyl acetate. The organic layers were dried (MgSO4), filtered, evaporated and recrystallized from hexane/ether to give 9-hydroxy-9-(4-methoxyphenyl)fluorene as a solid (48.2 g) M.P. 91°-93° C. This trityl alcohol (3.2 g) and o-cresol (1.8 g) were dissolved in acetic acid (25 mL) and concentrated H2SO4) (0.5 mL) was added dropwise. A deep red color developed rapidly and the reaction mixture decolorized after 30 seconds. After five minutes, the mixture was poured into water, neutralized with NaOH solution, and extracted with ethyl acetate. The organic layers were dried (MgSO4), filtered, evaporated in vacuo to give 9-(4-methoxyphenyl)-9-(3-methyl-4-hydroxyphenyl)fluorene (4.0 g) as an oil, which was used in the next step without further purification. Ethanethiol (3.7 g) was added dropwise to a stirred suspension of sodium hydride (2.3 g, 60% in mineral oil) in dry DMF (20mL). After the hydrogen bubbling had ceased, the above-mentioned oil was added and the mixture refluxed for 2 hours under nitrogen. The excess solvent was evaporated in vacuo and the residue extracted with ethyl acetate. The organic layers were dried (MgSO4), filtered, evaporated in vacuo and the residue recrystallized from chloroform-hexane to give the title compound (2.5 g) as a solid. M.P. 186°-188° C.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]CC.[Mg+2].[O-]CC.[N+:20]([C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26])([O-:22])=[O:21].Cl>C(OCC)C>[C:10]([CH:9]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[C:25]([C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[N+:20]([O-:22])=[O:21])=[O:26])(=[O:12])[CH3:11]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)C(C(=O)c1ccccc1)C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 73.2 %

Procedure:
A mixture of benzoylacetone (8.1 g, 0.05 mole), magnesium ethoxide (5.7 g, 0.05 mole) and ethyl ether (100 ml) was heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, and 2-nitrobenzoyl chloride (11.1 g, 0.06 mole) was added dropwise over a period of 15 minutes. The reaction mixture was then heated at reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured into 50 ml of 2N hydrochloric acid, and the phases separated. The ether layer was extracted with 5% potassium carbonate. The basic extract was acidified with hydrochloric acid and extracted with ether. The ether extract was washed with saturated sodium chloride, dried over magnesium sulfate and concentrated under vacuum yielding 11.4 g of the desired product as a white solid with a melting point of 99°-103° C. It was identified as such by nuclear magneticresonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:13][OH:14]>>[CH:6](=[N:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:5]1[C:13](=[CH:10][CH:2]=[CH:3][CH:4]=1)[OH:14]
Reactant: CO
Reactant: NC(Cc1ccccc1)C(=O)O
Product: O=C(O)[C@@H](Cc1ccccc1)N=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 12.4 g (0.075 mol) of DL-phenyl alanine, 15.5 g (0.086 mol) of l-N-methyl ephedrine, 10.5 g (0.086 mol) of salicyl aldehyde and 135 ml of methanol was stirred at room temperature for about 2 hours until dissolution was complete. The solvent was removed under reduced pressure and the oily residue taken up in 170 ml of ethyl acetate. The clear solution was seeded with a crystal of the salt of l-N-methyl ephedrine and N-salicyliden-D-phenyl alanine, whereupon a yellow crystal magma formed after a short stirring at room temperature. The crystals were filtered off immediately and washed with a small amount of ethyl acetate. After drying at 50° C., 6.7 g (40% of the theory) of the salt of l-N-methyl ephedrine and N-salicyliden-D-phenyl alanine having a specific rotation of [α]D20 of +107.4° were obtained.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18](O)[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.O.[CH:23]([OH:25])=[O:24]>>[CH:23]([O:25][CH2:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH:13]=[C:14]4[C@:15]3([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19]4)[C@@H:7]1[CH2:8][CH2:9][C:10]2=[O:11])=[O:24]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=CO
Solvent: O
Product: C[C@]12CCCCC1=CC[C@H]1[C@@H]3CCC(=O)[C@@]3(COC=O)CC[C@@H]12
Temperature: 60 °C

Procedure:
Following the procedure described by Ringold (H. J. Ringold, et al., J. Am. Chem. Soc. 78, 816, 1956), dehydroepiandrosterone (2.88 g, 10 mmol) dissolved in 85% formic acid (100 mL) is heated at 60° C for 1 h. After cooling, the mixture is poured into iced water and after 16 h, crystals are filtered and dried in vacuo.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][N:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1noc2ccccc12
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCN(c2noc3ccccc23)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a stirred solution of 100 mg (0.65 mmol) of 3-chloro-1,2-benzisoxazole in pyridine (1 mL) was added 145 mg of piperazine-1-carboxylic acid tert-butyl ester (0.78 mmol) and 0.18 mL of DBU (0.78 mmol). The mixture was stirred at 100° C. overnight and then partitioned between EtOAC (50 mL) and water (20 mL) and separated. The aqueous layer was extracted with EtOAC (2×30 mL). The combined organic layers were then washed with water (25 mL), brine, dried over Na2SO4, and the solvent was removed under reduced pressure to give crude product. Purification by column chromatography (silica, 60-100% CH2Cl2/hexanes) gave 82 mg (42%) of the desired product as a light yellow solid. MS (electrospray): exact mass calculated for C16H21N3O3, 303.16; m/z found, 326.1 [M+Na]+. 1H NMR (CDCl3, 400 MHz): 7.68 (dt, J=8.02, 0.98 Hz, 1H), 7.52-7.44 (m, 2H), 7.24 (ddd, J=8.42, 6.46, 1.57 Hz, 1H), 3.66-3.61 (m, 4H), 3.56-3.49 (m, 4H), 1.49 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])C.[CH:17]1([C:23]2[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[Cl:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:20]3[CH:19]=[CH:18][C:17]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:22][CH:21]=3)[CH:12]=2)[NH:7][C:6]=1[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1Cl
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Product: O=C(O)c1[nH]c2ccc(-c3ccc(C4CCCCC4)cc3)cc2c1Cl

Procedure:
The sub-title compound was prepared in accordance with Example 1(a) from 5-bromo-3-chloroindole-2-carboxylic acid ethyl ester (see Example 35, Method 1, step (a)) and 4-cyclohexylphenylboronic acid.
Reaction SMILES: [CH:1]1([CH2:6][O:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:28])=[C:23]([CH:27]=2)[C:24]([OH:26])=O)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH:1]1([CH2:6][O:7][NH:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:28])=[C:23]([C:24]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:26])[CH:27]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccc1F
Product: CN1CCN(C(=O)c2cc(CNc3ccccc3C(=O)NOCC3CCCC3)ccc2F)CC1

Procedure:
Prepared by a similar procedure as described for the preparation of Example 499, starting from 5-[(2-cyclopentylmethoxycarbamoyl-phenylamino)-methyl]-2-fluoro-benzoic acid (Example 496) and 1-methyl-piperazine.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:18]=2/[CH:19]=[C:20]2/[C:21](=[O:26])[NH:22][C:23](=[O:25])[S:24]/2)[CH2:13]1)(C(C)(C)C)(C)C>Cl.CO>[OH:8][CH2:9][CH2:10][NH:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:18]=2/[CH:19]=[C:20]2/[C:21](=[O:26])[NH:22][C:23](=[O:25])[S:24]/2)[CH2:13]1
Reactant: COc1cc(/C=C2\SC(=O)NC2=O)c(N2CCC(NCCO[Si](C)(C)C(C)(C)C)C2)cc1OC
Agent: Cl
Solvent: CO
Product: COc1cc(/C=C2\SC(=O)NC2=O)c(N2CCC(NCCO)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
A mixture of (Z)-5-(2-(3-(2-(tert-butyldimethylsilyloxy)ethylamino)pyrrolidin-1-yl)-4,5-dimethoxybenzylidene)thiazolidine-2,4-dione (Method 77) (120 mg, 0.24 mmol) in 5 mL of 1.25 M HCl in methanol was stirred at room temperature for 30 min. The mixture was then conc. in vacuo to afford the product which was purified via reverse phase HPLC (acetonitrile:water: 0.1% NH4OAc=5% to 55%) to yield the title compound as a yellow solid (45.0 mg, 48.4%). 1H NMR (300 MHz, DMSO-D6) δ ppm 7.40 (s, 1 H) 7.07 (s, 1 H) 6.57 (s, 1 H) 3.78 (s, 3 H) 3.70 (s, 3 H) 3.45 (m, 2 H) 3.27-3.15 (m, 4 H) 2.92 (m, 1 H) 2.59 (m, 2 H) 2.08 (m, 1 H) 1.66 (m, 1 H); m/z 394.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][C:31]([OH:33])=O)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[N:17](CC[Si](C)(C)C)[S:16]1(=[O:28])=[O:27])C1C=CC=CC=1.[CH2:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36][NH:35]1>>[CH2:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36][N:35]1[C:31](=[O:33])[CH2:30][CH2:29][C:11]1[CH:12]=[CH:13][C:14]([N:15]2[S:16](=[O:27])(=[O:28])[NH:17][C:18](=[O:20])[CH2:19]2)=[C:9]([OH:8])[CH:10]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCC(=O)O)cc2OCc2ccccc2)S1(=O)=O
Reactant: c1ccc2c(c1)CCNC2
Product: O=C1CN(c2ccc(CCC(=O)N3CCc4ccccc4C3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid and tetrahydroisoquinoline analogous to Example 97, steps D, E and F: (M−1)−=414.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[F:26][C:27]([F:46])([F:45])[C:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[CH:5]=[CH:4][C:3]([CH3:25])=[C:2]([C:33]5[CH:34]=[CH:35][C:30]([C:28](=[O:29])[C:27]([F:45])([F:46])[F:26])=[CH:31][CH:32]=5)[N:7]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: CC1(C)OB(c2ccc(C(=O)C(F)(F)F)cc2)OC1(C)C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C(=O)C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (163 mg, 0.444 mmol) was dissolved in 1,2-dimethoxyethane (4.5 mL) in a reaction tube. 2,2,2-Trifluoro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone (200 mg, 0.666 mmol), aqueous 2 M sodium carbonate (0.444 mL), and (Ph3P)4Pd (26 mg, 0.022 mmol) were added and the reaction mixture was heated at 120° C. under N2 atmosphere for 30 minutes in the microwave. The mixture was cooled to room temperature, filtered, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(4-(2,2,2-trifluoroacetyl)phenyl)-pyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 522.1, found 523.5 (M+1)+. Retention time 1.87 minutes.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Yield: 90 %

Procedure:
A solution (0.5 M) of 3-cyclohexenyl-1H-indole-6-carboxylic acid (from Step 1) in THF/MeOH (0.5 M, 1:1, v/v) was hydrogenated for 14 h over Pd(OH)2/C (0.1 eq., 20%) at 60 psi. The catalyst was removed by filtration on a pad of Celite™ and the filtrate evaporated to dryness to afford 3-cyclohexyl-1H-indole-6-carboxylic acid (90%) as a white solid. 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.20-1.53 (m, 5H), 1.70-1.87 (m, 3H), 1.90-2.02 (m, 2H), 2.69-2.86 (m, 1H), 7.40 (s, 1H), 7.55-7.65 (m, 2H), 8.0 (s, 1H), 11.40 (s, 1H); MS (ES+) m/z 244 (M+H)+.