Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2](F)=[C:3]([F:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].C(OCC)(=O)C.Cl>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)C.O>[F:1][CH:2]=[C:3]([F:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1
Reactant: FC(F)=C(F)Cc1ccc(F)c(Oc2ccccc2)c1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: FC=C(F)Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.1 %

Procedure:
A solution of 1,1,2-trifluoro-3-(4-fluoro-3-phenoxyphenyl)-1-propene (17.7 g, 0.0627 mol) in tetrahydrofuran (90 ml) is added dropwise over a period of 15 minutes to an ice cooled mixture of tetrahydrofuran (90 ml) containing 18.8 ml (0.0627 mol) of a 65 wt. % solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene. After stirring at room temperature for 20 hours, the resultant mixture is cooled, treated sequentially with ethyl acetate, water and dilute hydrochloric acid, and diluted with diethyl ether. The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a yellow liquid (16.08 g, 97% yield). 1H NMR analysis shows this material to be a 95:5 mixture of E:Z isomers.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:17][CH3:18])[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][NH:8][CH2:9]2
Reactant: COc1cccc2c1CN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: COc1cccc2c1CNC2
Reaction time: 168 h
Yield: 64.9 %

Procedure:
1.5 g of 10% palladium on carbon was added to a solution of 8.5 g of 2-benzyl-4-methoxyisoindoline in 100 ml of methanol and hydrogenation was performed at 45° C. for 7 days. After removing the catalyst by filtration, the filtrate was concentrated and purified by vacuum distillation (bath temperature: 160°-180 ° C., pressure: 0.1 mmHg) to obtain 3.44 g of 4-methoxyisoindoline.
Reaction SMILES: O[C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])([CH:4]=[CH2:5])[CH3:3].C([O-])(=O)[CH2:18][C:19]([CH3:21])=[O:20]>>[CH3:3][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:4][CH2:5][CH2:18][C:19](=[O:20])[CH3:21]
Reactant: C=CC(C)(O)CCC=C(C)CCC=C(C)C
Reactant: CC(=O)CC(=O)[O-]
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C

Procedure:
Nerolidol [compound (5) (manufactured by Takasago International Corporation] to be used as a starting material was subjected to Carroll reaction using acetoacetate in accordance with the method of W. Kimel et al. [J. Org. Chem., 23(2), pp. 153-157 (1958)] to give 6,10,14-trimethyl-5,9,13-pentadecatrien-2-one [compound (6)].
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH:15]1[CH:20]=[C:19]2[C:21]([C:24]([C:26](Cl)=[O:27])=[O:25])=[CH:22][NH:23][C:18]2=[CH:17][CH:16]=1>>[NH:23]1[C:18]2[C:19](=[CH:20][CH:15]=[CH:16][CH:17]=2)[C:21]([C:24](=[O:25])[C:26]([N:10]2[CH2:9][CH2:8][CH:7]([O:6][C:5]3[CH:13]=[CH:14][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)=[O:27])=[CH:22]1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: Fc1ccc(OC2CCNCC2)cc1
Product: O=C(C(=O)N1CCC(Oc2ccc(F)cc2)CC1)c1c[nH]c2ccccc12

Procedure:
By following the manipulative procedure described in Example 4(b), 4-(p-fluorophenoxy)piperidine is reacted with indole-3-glyoxyloyl chloride to give 1-(indol-3-ylglyoxyloyl)-4-(p-fluorophenoxy)piperidine as an off-white solid. The solid is recrystallized twice from a methanol and water mixture to give white needles of the glyoxamide, m.p. 205°-207° C.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:27])[C:4]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)[CH2:6][CH2:5]1.CO.C(Cl)(Cl)[Cl:31]>CCl>[ClH:31].[ClH:1].[ClH:31].[CH3:27][N:3]([CH3:2])[C:4]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][NH:12][CH3:13])[CH2:6][CH2:5]1
Reactant: CN(CCN1CCC(c2ccccc2)(N(C)C)CC1)C(=O)OC(C)(C)C
Reactant: ClC(Cl)Cl
Agent: CCl
Agent: Cl
Solvent: CO
Product: CNCCN1CCC(c2ccccc2)(N(C)C)CC1
Yield: 96 %

Procedure:
HCl gas was passed for 30 minutes through a solution of 9 g (1 equiv.) of tert-butyl 2-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethyl(methyl)carbamate in 600 ml of CH3Cl. The progress of the reaction was monitored by means of thin-layer chromatography (20% MeOH/CHCl3). When the reaction was complete, HCl gas was passed through for a further 30 minutes and the complete reaction was again monitored by means of thin-layer chromatography (20% MeOH/CHCl3). When the reaction was complete, the solvent was removed under reduced pressure and 7.2 g (96%) of the desired product were obtained in the form of a white solid. The free base was obtained by dissolving the hydrochloride in aqueous sodium hydroxide solution and extracting with dichloromethane.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22]>>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:19]3[CH2:20][CH2:21][O:17][C:18]3=[O:22])=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Reactant: O=C1NCCO1
Product: O=C1OCCN1Cc1ccc(C#Cc2ccccc2)cn1

Procedure:
The title compound, white solid, MS: m/e=279.2 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and oxazolidin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][C@H:15]([CH3:18])[N:14]3[C:19](OC(C)(C)C)=[O:20])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:27][O:28][C:29]([NH:31][C@@H:32]([CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)C(O)=O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][C@H:15]([CH3:18])[N:14]3[C:19](=[O:20])[C@@H:32]([NH:31][C:29](=[O:30])[O:28][CH3:27])[CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: C[C@H]1CC[C@@H](c2ncc(-c3ccc(Br)cc3)[nH]2)N1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C1CCOCC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of (2S,5S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (0.50 g, 1.23 mmol) in a mixture of CH2CL2 (10 mL) and methanol (1.0 mL) was added HCl (4M in dioxane, 6.00 mL, 24 mmol). The solution was stirred at 40° C. for 1 h, cooled to room temperature and concentrated to dryness. The crude solid was suspended in CH2CL2 (10 mL), followed by the addition of (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (0.298 g, 1.37 mmol), HATU (0.562 g, 1.48 mmol) and DIPEA (0.60 mL, 3.44 mmol). The resulting solution was stirred at room temperature for 18 h. The solution was diluted with CH2CL2 and washed with a mixture of sodium bicarbonate (aqueous, sat) and brine. The aqueous layer was back-extracted with CH2CL2. The combined organic layers were dried over Na2SO4 and concentrated to provide a crude oil. Purification by column chromatography (SiO2, 10-100% EtOAc (10% MeOH)/Hexanes) provided methyl (S)-2-((2S,5S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate (0.614 g, 99%). MS (ESI) m/z 505.844 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:15]([O:17][CH3:18])=[O:16])[CH2:6][C:5]2=1.CC([O-])(C)C.[Na+].[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.[NH4+].[Cl-]>C1COCC1>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:11]2[C:10]3[CH2:9][CH2:8][CH:7]([C:15]([O:17][CH3:18])=[O:16])[CH2:6][C:5]=3[C:4]3[C:12]2=[CH:13][CH:14]=[C:2]([F:1])[CH:3]=3)=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)C1CCc2[nH]c3ccc(F)cc3c2C1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C1CCc2c(c3cc(F)ccc3n2C(=O)c2ccc(Cl)cc2)C1
Reaction time: 0.33 h
Yield: 14 %

Procedure:
To a cooled solution (ice bath, 0-5° C.) of methyl 6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylate (80 mg, 0.32 mmol) in THF (2.5 mL) was added tBuONa (2 M in THF, 194 μL, 0.39 mmol), and the mixture was stirred for 20 min at the low temperature. 4-Chlorobenzoyl chloride (67.9 mg, 0.39 mmol) was added and the reaction was aged overnight at room temperature. The reaction was poured into saturated aqueous NH4Cl (1 mL; provided in a 10 mL glass vial) and the organic compound extracted with ethyl acetate (3×3 mL), washed with brine and water, dried over Na2SO4 and concentrated in vacuo. The crude residue was subjected to flash chromatography (SiO2, ethyl acetate/hexane gradient) to afford the pure title compound as white crystalline solid in 14% yield (17 mg). C21H17ClFNO3, Mr=385.82; 1H NMR (400 MHz, DMSO-d6) d: 1.72-1.79 (m, 1H), 2.06-2.10 (m, 1H), 2.54-2.56 (m, 2H), 2.72-2.78 (m, 1H), 2.83-2.89 (m, 1H), 2.95 (dd, J=5.2/15.4 Hz, 1H), 3.65 (s, 3H), 6.99 (td, J=2.4/9.2 Hz, 1H), 7.23 (dd, J=4.6/9.0 Hz, 1H), 7.34 (dd, J=2.4/9.0 Hz, 1H), 7.62-7.69 (m, 4H); 19F NMR (282 MHz, DMSO-d6) d: −123.87 (q, 6′-F); LCMS (ESI) tR: 3.24 min (>99%, ELSD), m/z: 386.0 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:9])=O.S(=O)(=O)(O)O>C(O)C>[Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]1[S:9][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][N:6]=1
Reactant: O=C(NNC(=S)Nc1ccccc1)c1ccccc1Br
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Brc1ccccc1-c1nnc(Nc2ccccc2)s1
Temperature: 0 °C
Yield: 89 %

Procedure:
To a solution of 1-(2-bromobenzoyl)-4-phenylthiosemicarbazide (250 mg, 0.71 mmol; Reference Compound 5-(6)) in ethanol (2.5 mL) was added concentrated sulfuric acid (0.5 mL) at room temperature, and then the mixture was refluxed for 30 minutes. The reaction solution was poured into ice water and the precipitated solid was filtered off. The solid was dried under a reduced pressure at 60° C. to give 210 mg (87%) of the titled compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=O)=[CH:4][N:3]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH:38]([NH:42]C(=O)OC(C)(C)C)[CH2:37]1.Cl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][N:36]2[CH2:41][CH2:40][CH2:39][CH:38]([NH2:42])[CH2:37]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(-c2csc3c(/C=C/CN4CCCC(N)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Yield: 19.6 %

Procedure:
N-(4-{4-Amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (100 mg, 0.207 mmol) and tert-butyl piperidin-3-ylcarbamate (124 mg, 0.621 mmol), were reacted according to General Procedure B. The crude product (137 mg, 0.206 mmol) was dissolved in methanol (1 mL) and treated with 6.0 M hydrochloric acid in 1,4 dioxane (0.514 mL, 2.06 mmol) and heated to 55 degrees Celsius for 20 hours. The mixture was cooled to room temperature then 1M sodium carbonate solution (5 mL) was added and product was extracted with ethyl acetate (3×10 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified via HPLC preparation to furnish the title compound as an ivory powder (23.0 mg, 0.0406 mmol): LCMS (Conditions a): MH−=565 RT=3.35 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.45 (1 H), 7.91 (2 H), 7.65 (1 H), 7.28 (3 H), 7.10 (3 H), 7.01 (1 H), 6.64 (1 H), 6.15 (1 H), 5.59 (1 H), 3.71 (3 H), 3.85 (3 H), 3.52 (1 H), 3.14 (2 H), 2.89 (1 H), 2.78 (1 H), 2.62 (1 H), 2.16 (1 H), 2.03 (1 H), 1.66 (1 H), 1.42 (1 H), 1.15 (1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])/[C:7](=[C:13](\[C:19]#[N:20])/C(OCC)=O)/[CH2:6][CH2:5]2.[C-:21]#[N:22].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7]([CH2:13][C:19]#[N:20])([C:21]#[N:22])[CH2:6][CH2:5]2
Reactant: [C-]#N
Reactant: CCOC(=O)/C(C#N)=C1\CCc2cc(Cl)c(OC)cc21
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1Cl)CCC2(C#N)CC#N
Temperature: 67.5 °C
Reaction time: 24 h
Yield: 13.3 %

Procedure:
To a solution of (E)-ethyl 2-(5-chloro-6-methoxy-2,3-dihydro-1H-inden-1-ylidene)-2-cyanoacetate (Prep16, 6.02 g, 24.4 mmol) in ethanol (25 ml) was added a solution of KCN (3.61 g, 60 mmol) in water. The mixture was stirred for one day at 65-70° C. Water was added and extracted with ethyl acetate twice. The organic phases were combined and dried over anhydrous Na2SO4, concentrated and purified by FC to afford the title compound (800 mg, y=16%).
Reaction SMILES: [K].CCO.[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6](OCC)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH3:32])[C:20]([N+:29]([O-])=O)=[C:21]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:22]=1>CCOCC>[CH3:28][N:26]([CH3:27])[CH2:25][CH2:24][O:23][C:21]1[CH:22]=[C:17]([O:16][CH3:15])[CH:18]=[C:19]2[C:20]=1[NH:29][C:6]([C:5]([O:12][CH2:13][CH3:14])=[O:11])=[CH:32]2
Reactant: COc1cc(C)c([N+](=O)[O-])c(OCCN(C)C)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [K]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc2cc(OC)cc(OCCN(C)C)c2[nH]1
Temperature: 100 °C
Reaction time: 115 h
Yield: 18.2 %

Procedure:
A suspension of potassium (0.308 g, 7.87 mmol) in xylenes (6 mL) was heated to 100° C. and stirred rapidly as it was allowed to cool. The xylenes were removed and the potassium was washed with Et2O (×3) and covered with Et2O (10 mL). The mixture was treated with absolute EtOH (1.30 mL, 22.2 mmol) and stirred at reflux until the potassium had dissolved (3 h). The cooled mixture was treated with diethyl oxalate (1.07 mL, 7.87 mmol) then with a solution of the above nitrotoluene (2.00 g, 7.87 mmol) in dry Et2O (5 mL). After 115 h, the dark red precipitate was removed by filtration and washed with Et2O. The red solid (1.189 g) was dissolved in absolute EtOH (45 mL), acidified with AcOH (0.78 mL), and hydrogenated over Pd/C (10%, 0.44 g) at 1 atm H2 for 8 h. The mixture was filtered through Celite, concentrated, diluted with 0.2 M aqueous Na2CO3 (100 mL), and extracted with EtOAc (×4). The combined extracts were washed with water (×2), dried (Na2SO4), evaporated and purified by flash chromatography (2% Et3N/EtOAc) to give ethyl 7-[2-(dimethylamino)-ethoxy]-5-methoxyindole-2-carboxylate as a clear oil (0.44 g, 18%). 1H NMR (CDCl3) δ 10.93 (br s, 1 H, NH), 7.09 (d, J=2.1 Hz, 1 H, H-3), 6.67 (d, J=2.0 Hz, 1 H, H-4), 6.43 (d, J=2.0 Hz, 1 H, H-6), 4.38 (q, J=7.0 Hz, 2 H, OCH2CH3), 4.16 (t, J=6.5 Hz, 2 H, OCH2CH2N), 3.88 (s, 3 H, OCH3), 2.79 (t, J=7.0 Hz, 2 H, NCH2), 2.37 (s, 6 H, N(CH3)2), 1.40 (t, J=6.5 Hz, 3 H, OCH2CH3); 13C NMR δ 161.9 (CO2), 155.0, 146.0, 128.1, 127.7, 124.9 (C-2, 3a, 5, 7, 7a), 108.1 (C-3), 99.1 (C-4), 94.6 (C-6), 65.9 (OCH2CH2N), 60.6 (OCH2CH3), 58.3 (NCH2), 55.6 (OCH3), 45.1 (N(CH3)2), 14.4 (OCH2CH3). Calc for C16H22N2O4, M+306.1580. Found, 306.1577. Starting material (0.77 g, 39%) was recovered from the ethereal washes by extraction into acid, basification, and extraction with Et2O.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3([N:14]4[CH:18]=[N:17][C:16]([Cl:19])=[N:15]4)[CH2:13][CH2:12]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2([N:14]3[CH:18]=[N:17][C:16]([Cl:19])=[N:15]3)[CH2:13][CH2:12]2)([OH:9])[CH2:10][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: Clc1ccc(C2(C3(n4cnc(Cl)n4)CC3)CO2)cc1
Solvent: CN(C)C=O
Product: OC(Cn1cncn1)(c1ccc(Cl)cc1)C1(n2cnc(Cl)n2)CC1
Temperature: 100 °C
Yield: 44.3 %

Procedure:
A solution of 21 g (0.071 mol) of 2-(4-chlorophenyl)-2-[1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropyl]-oxirane in 30 ml of absolute dimethylformamide is added dropwise at 80° C. to a stirred mixture of 15.6 g (0.276 mol) of 1,2,4-triazole and 1.7 g (0.015 mol) of potassium tert.-butylate in 40 ml of absolute dimethylformamide. The reaction mixture is stirred for 6 more hours at 100° C. and then concentrated by stripping off the solvent under reduced pressure. The residue which remains is taken up in a mixture of ethyl acetate/toluene, and the mixture is washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica gel using a mixture of dichloromethane/ethanol=98:2 as the eluent. Concentration of the eluate by evaporation gives 11.5 g of 1-(4-chlorophenyl)-1-[1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropyl]-2-(1,2,4-triazol-1-yl)-ethan-1-ol in the form of a solid of melting point 156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2([C:25]([O:27]CC)=[O:26])[CH2:24][CH2:23][CH2:22]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2([C:25]([OH:27])=[O:26])[CH2:22][CH2:23][CH2:24]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C)cc3)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C3(C(=O)O)CCC3)cc(Cl)c2OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
A mixture of ethyl 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (300 mg, 0.70 mmol) and lithium hydroxide monohydrate (280 mg, 11.6 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (185 mg, 66%) as white solid. 1HNMR (CDCl3): 7.42 (m, 2H); 7.32 (s, 1H), 7.23 (d, 2H), 7.18 (s, 1H), 3.87 (q, 2H); 2.85 (m, 2H), 2.54 (m, 2H), 2.39 (s, 3H), 2.12 (m, 1H); 1.83 (m, 1H).
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9]/[C:10]/2=[CH:13]\[C:14](Cl)=[O:15])=[CH:6][CH:5]=1>ClCCl>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9]/[C:10]/2=[CH:13]\[C:14]([NH2:2])=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(Cl)/C=C1\CCc2ccc(F)cc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)/C=C1\CCc2ccc(F)cc21
Yield: 90.6 %

Procedure:
A 29.6% aqueous ammonium hydroxide solution (17.6 mL, 134 mmol) was added dropwise to a stirred, chilled (ice bath) solution of (E)-2-(6-fluoro-1-indanylidene)acetyl chloride (14.1 g, 67 mmol) in dichloromethane (165 mL). After an hour, the resulting white precipitate was collected by filtration, dissolved in ethyl acetate (600 mL) and washed with water (3×300 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated in vacuo. The resulting off-white solid was washed with hexane, giving 11.6 g (91%) of (E)-2-(6-fluoro-1-indanylidene)acetamide, m.p., 180°-183° C.; NMR (DMSO-d6): d6.91-7.41 (m, 5H, Ar+NH2), 6.37 (t,1H, =CH), 2.92-2.96, 3.16-3.22 (2m's, 4H, 2XCH2); steady-state nOe:irradiation at 6.37 d, observed 23% nOe at 7.28 d.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[NH:10][C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([OH:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[NH2:41][C@@H:42]([CH3:61])[C:43]([N:45]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:46][CH:47]([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])=[O:44]>ClCCl>[CH2:54]([N:45]([CH2:46][CH:47]([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])[C:43](=[O:44])[C@@H:42]([NH:41][C:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[NH:10][C:9]([NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:19])=[O:18])[CH3:61])[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)N)OCC
Reactant: O=C(NCc1ccccc1)Nc1ccsc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)NC(=O)c1sccc1NC(=O)NCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a solution of 3-(3-benzylureido)thiophene-2-carboxylic acid (Compound V-1) 49.7 mg (0.18 mmol) and N-hydroxybenzotriazol 6.1 mg (0.045 mmol) in dichloromethane 1 ml, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 43.1 mg (0.225 mmol) was added and the mixture was stirred at room temperature for 0.5 hr. A solution of (S)-2-amino-N-benzyl-N-(2,2-diethoxyethyl)propanamide (Compound VI-1) 44.2 mg (0.15 mmol) in dichloromethane 1 ml was added to the reaction mixture and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was washed with sat. NaHCO3 aq. 1 ml, water 1 ml and brine 1 ml. The organic phase was filtered on celite 1 g and magnesium sulfate 150 mg. The mother solution was concentrated in vacuo and the residue was purified with PTLC (development solvent: chloroform:methanol=98:2) to obtain the titled compound 44.7 mg (54%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:25]=[CH:24][C:23]([N:26]2[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28][CH2:27]2)=[CH:22][C:10]=1[C:11]([NH:13][CH2:14][C:15]([O:17][C:18](C)(C)C)=[O:16])=[O:12]>ClCCl.CO>[NH2:8][C:9]1[CH:25]=[CH:24][C:23]([N:26]2[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28][CH2:27]2)=[CH:22][C:10]=1[C:11]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1cc(N2CCN3CCC2CC3)ccc1N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1cc(N2CCN3CCC2CC3)ccc1N
Reaction time: 7 h

Procedure:
2,2,2-Trifluoroacetic acid (3.26 g, 28.0 mmol) was added to a solution of tert-butyl 2-(2-amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetate (Intermediate 7B) (1.0 g, 2.67 mmol) in dichloromethane (20 mL) and methanol (2 mL). The resulting solution was stirred for 7 hours before leaving to stand over the weekend. The resultant crude material purified using a 5 g SCX cartridge to afford methyl 2-(2-amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetate. This was dissolved in tetrahydrofuran (20 mL) and 1M lithium hydroxide solution (5.34 mL, 5.34 mmol) and water (2 mL) was added and the solution stirred overnight. The reaction mixture was then acidified and purified using a 5 g SCX cartridge to afford 2-(2-amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetic acid (849 mg, 2.67 mmol).