Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:21])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[CH3:32][O:31][C:29]1[CH:28]=[C:26]([N:27]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][C:11](=[O:21])[C:2]([CH3:1])=[C:3]2[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:25]=[C:24]([O:23][CH3:22])[CH:30]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CC(C(=O)CC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: COc1cc(OC)cc(-n2c(-c3ccccc3)cc(=O)c(C)c2-c2ccccc2)c1

Procedure:
to 170 ml of chlorobenzene were added 4.2 g (0.015 mole) of 2-methyl-1,5-diphenyl-1,3,5-pentanetrione, 11.5 g (0.075 mole) of 3,5-dimethoxyaniline, 5.2 g (0.027 mole) of para-toluenesulfonic acid and 35.0 g of Molecular Sieves 5A, followed by refluxing the resulting mixture for 2 hours. After cooling the reaction mixture, solid matter was removed from the reaction mixture, followed by addition of 200 ml of chloroform thereto. The organic layer was washed first with 200 ml of 10% hydrochloric acid and then with 200 ml of a 10% aqueous solution of sodium hydroxide. The organic layer was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate by filtration, the solvent was distilled off and the residue was subjected to chromatography on a silica gel column (eluent: ethyl acetate). Upon recrystallization of the resultant crystals from a 2:1 mixed solvent of acetone and hexane, 2.0 g of 1-(3,5-dimethoxyphenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone having a melting point of 232°-236° C. was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
In ethanol (50 ml) was dissolved 1-(4-nitrobenzyl)piperidine (6.41 g), and 10% dried palladium on carbon (0.33 g) was added to the mixture. Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 24 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was recrystallized from hexane to give 1-(4-aminobenzyl)piperidine (1.01 g) as pale yellow crystals.
Reaction SMILES: [Br-].[Li+].[CH2:3]([Mg]Cl)[CH3:4].S([O-])(=O)(=O)C.[Si:12]([C:19]#[C:20][CH2:21]O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>[Cu]Br>[C:15]([Si:12]([CH3:14])([CH3:13])[C:19]([CH2:3][CH3:4])=[C:20]=[CH2:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)C#CCO
Reactant: CC[Mg]Cl
Agent: [Cu]Br
Agent: CS(=O)(=O)[O-]
Agent: [Br-]
Product: C=C=C(CC)[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 2-L, three-necked, round-bottomed flask equipped with a nitrogen inlet adapter and two glass stoppers is charged with copper(I) bromide (40.0 g, 279 mmol) and lithium bromide (24.2 g, 279 mmol). The reaction vessel is evacuated, and the contents are heated briefly several times over the course of 30 minutes. The vacuum is then replaced by nitrogen and the apparatus is rapidly equipped with a mechanical stirrer and two rubber septa. Tetrahydrofuran (350 mL) is added, and the resulting green solution containing a small amount of undissolved solid is cooled with an ice bath while ethylmagnesium chloride (2M in tetrahydrofuran, 135 mL, 269 mmol) is added rapidly via a syringe over 3 minutes. After 20 minutes of stirring at 0° C., the viscous yellow-green suspension is cooled below -70° C. with a dry ice-acetone bath. The solution of the mesylate derivative of 3-(tert-butyldimethylsilyl)-2-propyn-1-ol prepared above is cooled below -70° C. and transferred dropwise via a cannula over 70 minutes to the rapidly stirred suspension of the cuprate reagent. The cold bath is then removed, and the green reaction mixture is allowed to warm to room temperature over 2.5 hours. The blue-gray mixture is then poured into a 2-L Erlenmeyer flask containing a magnetically stirred mixture of 400 mL of pentane, 200 mL of water, and 400 mL of saturated ammonium chloride solution. The organic phase is separated and washed successively with two 200 mL portions of saturated ammonium chloride solution, ten 500 mL portions of water, and 100 mL of saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered, and then concentrated by atmospheric distillation through a 4-cm Vigreaux column. The residual liquid is next carefully distilled through a 4-cm Vigreux column to provide the title compound.
Reaction SMILES: CCN(CC)CC.Br[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1.[C:30]([O:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][C:39]([C:42]#[CH:43])=[CH:38][CH:37]=1)([CH3:33])([CH3:32])[CH3:31]>C(#N)C.[Cu]I>[C:35]([C:36]1[CH:41]=[CH:40][C:39]([C:42]#[C:43][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[CH:38][CH:37]=1)([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:44]
Reactant: C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(C=Cc2ccc(Br)cc2)cc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(C#Cc2ccc(/C=C/c3ccc(C(=O)OC(C)(C)C)cc3)cc2)cc1
Reaction time: 0.33 h

Procedure:
300 ml of NEt3 and 20.46 g of Pφ3 are added under nitrogen to 234 g of 4-bromo-4'-carbo-tert.-butoxystilbene in 1 l of absolute acetonitrile. Nitrogen is passed through the stirred suspension for 20 minutes and 9.12 g of (Pφ3)2PdCl2 and 2.5 g of copper(I)iodide are then added. 144 g of 4-Ethinyl benzoic acid tert.-butyl ester dissolved in 1 l of absolute acetonitrile are then added dropwise under reflux over a period of 6 hours and the reaction mixture is boiled under reflux overnight. The hot product obtained after suction filtration is dissolved in CH2Cl2, washed several times with H2O and dried and the solvent is removed.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)#[N:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=2)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]
Reactant: N#CCc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(CC#N)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.1 %

Procedure:
4-Cyanomethylaniline (0.212 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from a mixed solvent of ether and hexane (3:1) to obtain the titled compound (0.110 g, 0.225 mmol, 42%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9](Cl)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].C(NC1C(Cl)=CC(C(O)=O)=C(OC)C=1)(=O)C.[NH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[CH3:44][N:41]1[CH2:40][CH2:39][C:38]2[C:43](=[C:34]([NH:33][C:9](=[O:10])[C:8]3[CH:12]=[C:13]([Cl:14])[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=3[O:15][CH3:16])[CH:35]=[CH:36][CH:37]=2)[CH2:42]1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)Cl
Reactant: CN1CCc2cccc(N)c2C1
Agent: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)Nc1cccc2c1CN(C)CC2

Procedure:
To a cooled solution of 4-acetylamino-5-chloro-2-methoxybenzoyl chloride, (prepared from 4-acetylamino-5-chloro-2-methoxybenzoic acid, 3.19 g) in dichloromethane was added 8-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (2.1 g) and triethylamine (4 ml). After stirring at room temperature for 2.5h, the mixture was basified with 10% sodium hydroxide. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by chromatography on alumina eluting with chloroform, and then crystallised from ethyl acethate to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH2:30][NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: CN(C)CCN
Product: CN(C)CCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from N,N-dimethylethylenediamine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 170-183° C.; LC-MS: 443 (MH+); HPLC RT: 3.02 minutes.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:17][C:16]1[CH:18]=[CH:19][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 2,4-difluoronitrobenzene (5.5 ml),4-fluoro aniline (14.2 ml) and sodium carbonate (5.3 g) was heated at 180° for 3 h. The reaction mixture was cooled to room temperature, then diluted with DCM, washed with water (50 ml), brine (2×50 ml) dried and evaporated under vacuum to give the crude compound (22.6 g), which was purified by flash chromatography with CH-EA 4/1 to give the title compound as an orange solid (12.35 g).M.p. 115°-6° T.l.c. CH-EA (10:1), Rf 0.52.
Reaction SMILES: [CH3:1][CH:2]([C:6]1([CH2:13][OH:14])[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][CH2:7]1)[CH:3]([CH3:5])[CH3:4]>C1(C)C=CC=CC=1>[CH3:1][CH:2]([C:6]12[CH2:11][CH2:10][C:9]([CH3:12])([CH2:8][CH2:7]1)[O:14][CH2:13]2)[CH:3]([CH3:4])[CH3:5]
Reactant: CC1=CCC(CO)(C(C)C(C)C)CC1
Solvent: Cc1ccccc1
Product: CC(C)C(C)C12CCC(C)(CC1)OC2
Temperature: 60 °C
Reaction time: 12 h
Yield: 54.5 %

Procedure:
[1-(1,2-Dimethyl-propyl)-4-methyl-cyclohex-3-enyl]-methanol (268 g, obtained as detailed above), MSA (10 g), and toluene (300 mL) were charged to a 2 L reaction flask, heated to 60° C., and aged for 12 hours. The reaction mixture was cooled, washed with saturated sodium carbonate solution, and distilled to provide 4-(1,2-dimethyl-propyl)-1-methyl-2-oxa-bicyclo[2.2.2]octane (146 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19].N1C=CC=CC=1>C1C=CC=CC=1>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.7 %

Procedure:
Benzoyl chloride (140.5 g., 1.0 mole) was added dropwise with stirring to a solution of p-chloro-m-(trifluoromethyl)aniline (181.5 g., 1.0 mole) and pyridine (79 g., 1.0 mole) in two liters of dry benzene. Although the reaction was heated initially, the addition of benzoyl chloride generated sufficient heat to maintain reflux conditions during the addition. The reaction mixture was stirred overnight at room temperature and then was heated under reflux for 2 hours. After being cooled to about 25° C., the reaction product was washed successively with 6 N hydrochloric acid and saturated aqueous sodium bicarbonate solution, was dried over magnesium sulfate and was filtered. The filtrate was evaporated by distillation in vacuo, and the residue was crystallized from a benzene-hexane solvent to give two grams of 4'-chloro-3'-(trifluoromethyl)benzanilide, having a melting point of 130°-131° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.C(Cl)Cl.[Pd]>[O:14]1[C:13]2([CH2:18][CH2:19][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[O:17][CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc(N2CCC3(CC2)OCCO3)cc1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A mixture of 8-(4-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane (Synthesis, 606, 1981) (3.5 g, 13.3 mmol) and 10% Pd/C (0.5 g) in 100 mL of ethanol/methylene chloride (2:1) was pressurized with 30 psi hydrogen and shaken over 1 hours. The catalyst was then removed by filtering through a short pad of silica gel to give the title compound (2.8 g, 90%) as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.85–2.00 (m, 4 H), 3.00–3.10 (m, 4 H), 3.93 (s, 4 H), 6.60 (d, J=6.0 Hz, 2 H), 6.80 (d, J=6.0 Hz, 2 H); MS (ES) m/z: 235.2 (MH+); HRMS Calcd. for C13H18N2O2: 234.1380. Found: 234.1371.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=O)=[CH:5][C:4]=1[CH3:16].[C:17]([Mg]Cl)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:10]1[C:11]2[C:6](=[CH:5][C:4]([CH3:16])=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH3:15])([CH3:14])[CH2:8][CH:9]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Mg]Cl
Reactant: COc1cc2c(cc1C)C(C)(C)CCC2=O
Product: COc1cc2c(cc1C)C(C)(C)CC=C2C(C)(C)C
Yield: 35.3 %

Procedure:
Following General Procedure A, 7-methoxy-4,4,6-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 6, 1.5 g, 6.9 mmol) was reacted with a solution of 2 M tert-butylmagnesium chloride (12 mL, 23 mmol), and the crude product was purified by flash column (hexane:ethyl acetate=4:1) to give 0.63 g (36%) of the title product as a clear oil.
Reaction SMILES: Cl.Cl.Cl.[NH:4]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:14][CH2:15][CH2:16][NH:17][C:18](=[NH:22])[C:19](=[NH:21])[NH2:20])[N:12]=1)[C:5]([NH2:7])=[NH:6].C(Cl)Cl.[S:26](N1C(=O)C2=CC=CC=C2C1=O)N1C(=O)C2=CC=CC=C2C1=O.[OH-].[Na+]>C(N(CC)CC)C>[NH2:21][C:19]1[C:18]([NH:17][CH2:16][CH2:15][S:14][CH2:13][C:11]2[N:12]=[C:8]([NH:4][C:5]([NH2:7])=[NH:6])[S:9][CH:10]=2)=[N:22][S:26][N:20]=1
Reactant: O=C1c2ccccc2C(=O)N1SN1C(=O)c2ccccc2C1=O
Reactant: N=C(N)Nc1nc(CSCCNC(=N)C(=N)N)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N=C(N)Nc1nc(CSCCNc2nsnc2N)cs1
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A mixture of crude N-{2-[(2-guanidinothiazol-4-yl)methylthio]ethyl}ethanediimidamide trihydrochloride (5.65 g, 13.7 mmoles) [prepared in Step A], 50 ml of CH2Cl2 and 5.7 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (5.44 g; 13.7 mmoles) and stirred for one hour to give a thick suspension. The mixture was treated with 40 ml of 2N NaOH and the solvents were decanted from the gum-like material which had separated. The gum was washed with 40 ml of 2N NaOH, water, and then dissolved in methanol and concentrated to give 3.0 g of crude product. The product was purified by flash chromatography on 90 g of silica gel (230-400 mesh) using ethyl acetate-methanol (97:3) as the eluent to give 2.44 g (54%) of the title compound. Treatment of the product in 35 ml of acetone with one equivalent of cyclohexylsulfamic acid gave the salt which was then recrystallized from 95 % aqueous ethanol to give the title compound as its cyclohexylsulfamate salt, mp. 171°-173.5° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH:6]([NH:8]C(=O)OC(C)(C)C)[CH2:5][C@H:4]([CH3:16])[O:3]1.[ClH:17]>O1CCOCC1>[CH3:1][C@@H:2]1[CH2:7][CH:6]([NH2:8])[CH2:5][C@H:4]([CH3:16])[O:3]1.[ClH:17]
Reactant: C[C@@H]1CC(NC(=O)OC(C)(C)C)C[C@H](C)O1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CC(N)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl (2R,65)-2,6-dimethyltetrahydro-2H-pyran-4-ylcarbamate (crude, 0.6 g) was added 4M HCl in 1,4-dioxane (15 ml) at r.t. It was stirred further at room temperature for 2 h, at which time LC/MS analysis confirmed full consumption of starting material. Solvent was removed in vacuo to get the desired (2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-amine as an HCl salt.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C@@H:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C@@H:8]([CH3:17])[C:9]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32](=[O:36])[N:33]([CH3:35])[CH3:34]>>[Cl:25][C:26]1[CH:27]=[C:28]([C:2]2[S:6][C:5]([C@@H:7]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C@@H:8]([CH3:17])[C:9](=[O:10])[NH:11][C:12]3[S:13][CH:14]=[N:15][N:16]=3)=[CH:4][CH:3]=2)[CH:29]=[CH:30][C:31]=1[C:32]([N:33]([CH3:35])[CH3:34])=[O:36]
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1Cl
Reactant: C[C@@H](C(=O)Nc1nncs1)[C@H](c1cccc(F)c1)c1ccc(Br)s1
Product: C[C@@H](C(=O)Nc1nncs1)[C@H](c1cccc(F)c1)c1ccc(-c2ccc(C(=O)N(C)C)c(Cl)c2)s1

Procedure:
In a similar manner to Example 43, the Suzuki coupling reaction of the title compound of Example 97, (2R,3R)-3-(5-bromothiophen-2-yl)-3-(3-fluorophenyl)-2-methyl-N-(1,3,4-thiadiazol-2-yl)propanamide (240 mg, 0.563 mmol), and 3-chloro-4-(dimethyl-carbamoyl)phenylboronic acid (256 mg, 1.126 mmol) afforded the title compound of Example 110 (147 mg, 0.278 mmol, 49.4% yield). 1H NMR (400 MHz, MeOD) δ ppm 8.96 (1H, s) 7.71 (1H, d, J=1.51 Hz) 7.61 (1H, dd, J=7.93, 1.64 Hz) 7.39 (1H, d, J=3.78 Hz) 7.33 (1H, d, J=8.06 Hz) 7.19-7.28 (2H, m) 7.15 (1H, dd, J=10.07, 2.01 Hz) 7.11 (1H, d, J=3.78 Hz) 6.83-6.89 (1H, m) 4.51 (1H, d, J=1.33 Hz) 3.48-3.57 (1H, m) 3.11 (3H, s) 2.91 (3H, s) 1.32 (3H, d, J=6.55 Hz). LC/MS (m/z) 529.11 (M+H)+]; HPLC Rt: 3.448 min.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C-:11]#[N:12].[Na+]>CC#N.CCOC(C)=O.[Cu]I>[C:11]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)#[N:12]
Reactant: [C-]#N
Reactant: Ic1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 5-iodoindole (0.36 g; 1.48 mmol), NaCN (0.15 g; 3 mmol), Pd(Ph3)4 (0.23 g; 0.22 mmol) and CuI (0.06 g; 0.3 mmol) in anhydrous CH3CN (3 ml) was refluxed for 2.5 h under N2. After cooling to room temperature, the mixture was diluted to 20 ml with EtOAc and filtered through a pad of Celite. The filtrate was washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure, dissolved in a small volume of CH2Cl2 and filtered through a small pad of SiO2, which was washed with fresh CH2Cl2. The combined filtrates were evaporated to dryness under reduced pressure to give the title compound (0.2 g; 95%) as colourless solid. 1H-NMR (CDCl3) 6.62 (tr, 1H, J=2.5 Hz); 7.33 (tr, 1H, J=2.5 Hz); 7.39-7.47 (m, 2H); 7.98 (s, 1H); 8.51 (broad s, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:15]=[C:14]2[O:16][CH2:17][O:18][C:13]2=[CH:12][C:10]=1[NH2:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[O:20]([C:22]#[N:23])[Na]>CC(O)=O>[CH2:17]1[O:18][C:13]2[CH:12]=[C:10]3[C:9]([C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:23][C:22](=[O:20])[NH:11]3)=[CH:15][C:14]=2[O:16]1
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1)OCO2
Reactant: N#CO[Na]
Solvent: O
Solvent: CC(=O)O
Product: O=c1nc(-c2ccccc2)c2cc3c(cc2[nH]1)OCO3
Temperature: 10 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a solution of 2-benzoyl-4,5-(methylenedioxy)aniline (200 mg) in AcOH (10 mL) was added water (1 mL) and NaOCN (64 mg) at 10° C. The mixture was stirred at 10° C. for 1 h, then at rt for 2 h. Water (70 mL) was added to the mixture. The resulting yellow solid was collected by filtration, washed with water and 3:2 hexane/EtOAc, recrystallized from DMSO/water to yield the title compound as a yellow solid (104 mg, 47%), mp: 351-354° C. 1H NMR (DMSO-d6): 11.86 (s, 1H), 7.63-7.58 (m, 5H), 6.94 (s, 1H), 6.85 (s, 1H), 6.16 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]1[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]1)[CH:6]=[CH:5]2.[F:21][C:22]([F:31])([F:30])[CH:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[F:21][C:22]([F:31])([F:30])[CH:23]1[CH2:28][CH2:27][CH:26]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([CH2:12][N:13]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]2)[CH:6]=[CH:5]3)[CH2:25][CH2:24]1
Reactant: OC1CCC(C(F)(F)F)CC1
Reactant: COC(=O)C1CN(Cc2ccc3cc(O)ccc3c2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(Cc2ccc3cc(OC4CCC(C(F)(F)F)CC4)ccc3c2)C1
Yield: 27 %

Procedure:
To a vial was added methyl 1-((6-hydroxynaphthalen-2-yl)methyl)azetidine-3-carboxylate (271 mg, 1.0 mmol), 4-(trifluoromethyl)cyclohexanol (252 mg, 1.5 mmol, 1.5 equiv), PPh3 (524 mg, 2.0 mmol, 2.0 equiv) and toluene (0.8 mL) under N2 atmosphere. While stirring, DIAD (404 mg, 2.0 mmol, 2.0 equiv) was added to the reaction mixture quickly at r.t and stirred for 10 min. The reaction mixture was then purified by silica gel chromatography (PE:EA=5:1) to give the title compound (114 mg, 28%) as a slight yellow oil. ESI-MS (M+1)+: 408.2. 1H NMR (400 MHz, CD3OD) δ: 7.76 (d, 1H), 7.70 (d, 1H), 7.66 (s, 1H), 7.36 (dd, 1H), 7.24 (d, 1H), 7.17 (dd, 1H), 4.86-4.76 (m, 1H), 3.74 (s, 2H), 3.70 (s, 3H), 3.56-3.51 (m, 2H), 3.32-3.34 (m, 3H), 2.33-2.22 (m, 1H), 2.20 (d, 2H), 1.82-1.67 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([C:6]([CH3:9])([CH3:8])[CH3:7])[NH2:5].[C:11](O)(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:11]([NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17]
Reactant: C=CCCCCC(=O)O
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C=CCCCCC(=O)N[C@H](C(=O)OC)C(C)(C)C
Yield: 80.7 %

Procedure:
A solution of L-t-leucine methyl ester (1.00 g, 6.89 mmol), 6-heptenoic acid (1.06 g, 8.26 mmol), EDC (1.58 g, 8.26 mmol) and HOAt (1.23 g, 8.26 mmol) in DMF (10 mL) was stirred at RT for 2 hours. The reaction mixture was diluted with aqueous saturated NaHCO3 (30 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×30 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica (5-50% EtOAc/hexane), to give the title compound (1.42 g). LRMS (ESI) m/z 256.3 [(M+H)+; calcd for C14H26NO3: 256.2].