Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[N:7]([CH2:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=1.[C:24](O)(C(F)(F)F)=O.C=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl.O1CCOCC1>C(#N)C>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=3)[N:7]([CH2:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C:6]=2[CH2:24]1
Reactant: O=C(O)C(F)(F)F
Reactant: CNCCc1cn(CCc2ccc(C)nc2)c2ccc(C)cc12
Agent: C=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CN(C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The title compound was prepared by General Method 4. 150 mg of N-methyl-2-(5-methyl-1-(2-(6-methylpyridin-3-yl)ethyl)-1H-indol-3-yl)ethanamine was dissolved in acetonitrile (4 mL) containing 5% TFA and the reaction mixture was heated to reflux. 37% aqueous formaldehyde (0.04 mL) was added and the reflux was continued for additional 1.5 h. The reaction mixture was cooled to 25° C., concentrated under reduced pressure and partitioned between ethyl acetate and satd. Aqueous NaHCO3. The organic layer was dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by silica gel chromatography (eluent Methanol: aqueous NH3, 95:5) to obtain the product. The free base was converted into its dihydrochloride salt by treatment of dioxane-HCl. 1H NMR (DMSO) δ 11.7 (bs, 1H), 8.6 (s, 1H), 8.3 (d, 1H), 7.7 (d, 1H), 7.3 (d, 1H), 7.25 (s, 1H), 6.9 (d, 1H), 4.8 (m, 1H), 4.4 (m, 1H), 4.35 (t, 2H), 3.7 (bs, 1H), 3.55 (s, 3H), 3.5 (m, 1H), 3.4 (bs, 1H), 3.1 (t, 2H), 3.05 (bs, 1H), 2.65 (3, 3H), 2.35 (s, 3H). MS m/z observed 320. HPLC RT 3.63 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:38]([CH:39]=[CH2:40])=[N:37][N:36]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][Si](C(C)(C)C)(C)C)=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:48]1[CH:53]=[CH:52][C:51]([C:54]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[O:55])=[CH:50][CH:49]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:17]3[C:38](/[CH:39]=[CH:40]/[C:48]4[CH:49]=[CH:50][C:51]([C:54]([N:56]5[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]5)=[O:55])=[CH:52][CH:53]=4)=[N:37][N:36]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[CH:21]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Reactant: O=C(c1ccc(I)cc1)N1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2ccc(C(=O)N4CCCCC4)cc2)nn3C2CCCCO2)CC1
Temperature: 125 °C
Yield: 75.4 %

Procedure:
To a solution of 4-[6-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.3 g, 0.46 mmol) in DMF (2.1 mL) were added (4-iodo-phenyl)-piperidin-1-yl-methanone (0.175 g, 0.56 mmol), tri(o-tolyl)phosphine (28 mg, 0.09 mmol) and triethylamine (2.1 mL). The resulting solution was degassed using argon, palladium acetate (5 mg, 0.02 mmol) was then added and the reaction mixture was heated at 125° C. overnight. The reaction mixture was concentrated under vacuum and the residue taken up in water and then acidified to pH=1. The precipitate was filtered, washed with water and then dried under vacuum. The crude residue was purified on a silica gel column chromatography using a gradient of methanol (0-3%) in dichloromethane to yield the title compound as a light brown solid (0.25 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH3:19])([C:14]([O:16]CC)=[O:15])[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH3:19])([C:14]([OH:16])=[O:15])[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C1(C)CC(c2cc(Cl)cc(Cl)c2)=NO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C(=O)O)CC(c2cc(Cl)cc(Cl)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.00 g (16.55 mmol) of ethyl 3-(3,5-dichlorophenyl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylate were dissolved in 50 ml of ethanol, and 24.82 ml of 1N NaOH were then added. After 1 h of stirring at RT, the solvent was removed, 100 ml of water were added and the aqueous phase was adjusted to pH 2 by addition of 2N HCl. The product formed was obtained by extraction with 100 ml of ethyl acetate, drying the organic phase over Na2SO4, filtration and concentration.
Reaction SMILES: [CH2:1]([C:12]1[NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]=1)[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH2:2]([C:3]1[N:4]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH2:1][C:12]1[N:13]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc2[nH]c(CCc3nc4ccccc4[nH]3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2c(CCc3nc4ccccc4n3Cc3ccccc3)nc3ccccc32)cc1
Yield: 41.5 %

Procedure:
To a flask were added 0.5 g 2,2′-ethane-1,2-diylbis(1H-benzimidazole), 0.7 g potassium carbonate, 30 ml N,N-dimethylformamide and the mixture was stirred under nitrogen. 0.6 g Benzyl chloride were added and the mixture was heated to 60 C for 16 hours. Another 0.5 g benzyl chloride were added and the reaction was heated to 70 C for another 20 hours and then cooled to 22 C. The reaction was quenched with 30 ml water and the product was filtered and washed with water. The product was re-slurried in 80 ml hot acetonitrile, cooled, filtered and dried resulting in 0.35 g of a white solid.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][CH:7]([C:9]([O:11][CH3:12])=[O:10])C)[C:3](O)=[O:4].S(Cl)([Cl:15])=O>>[Cl:1][CH:2]([CH2:6][CH2:7][C:9]([O:11][CH3:12])=[O:10])[C:3]([Cl:15])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(C)CC(Cl)C(=O)O
Product: COC(=O)CCC(Cl)C(=O)Cl

Procedure:
A mixture of 6.2 g of 2-chloro-4-methoxycarbonyl valeric acid and 12.6 ml of thionyl chloride was refluxed for 30 minutes, then the solvent was distilled off under reduced pressure to leave 2-chloro-4-methoxycarbonyl butyryl chloride. A mixture of this product, 5.0 g of 2-benzylaminodiphenyl methanol, 100 ml of ethyl acetate and 100 ml of a saturated aqueous solution of sodium hydrogencarbonate was stirred for one hour at room temperature. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 5.3 g of 2-[N-benzyl-N-(2-chloro-4-methoxycarbonyl)butyryl]aminodiphenyl methanol as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(F)c1
Temperature: 60 °C

Procedure:
To methyl 3-fluoro-4-hydroxy-benzoate (2.00 g, 11.8 mmol) in DMF (12.5 mL) was added K2CO3 (6.50 g, 47.0 mmol) followed by 2-iodopropane (2.35 mL, 23.5 mmol). The mixture was heated at 60° C. for 1.5 h. The mixture was filtered using EtOAc and the filtrate was evaporated under reduced pressure. The residue was dissolved in EtOAc and was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl 3-fluoro-4-isopropoxybenzoate. ESI-MS m/z calc 212.1, found 213.3 (M+1)+. Retention time: 1.70 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[C:23](Cl)([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24]>O.O1CCOCC1>[CH:38]1[C:39]2[CH:27]([CH2:26][O:25][C:23]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]3[C:14]([OH:16])=[O:15])=[O:24])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]=2[CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a stirred mixture of (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.0 g, 4.34 mmol) and Na2CO3 (0.90 g, 10.80 mmol) in water (10 mL) was added solution of FMOC-Cl (1.23 g, 4.77 mmol) in 1,4-dioxane (10 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h then diluted with water (50 mL) and washed with MTBE (25 mL). The aqueous layer was acidified with 1N aqueous HCl (10 mL) to pH 2 and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound (0.87 g) as an off-white solid. The crude product was used in the next step without purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[N:5][CH:6]=[C:7](Br)[CH:8]=1.C([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[CH:21]=[C:20]1B(O)O)(OC(C)(C)C)=O>>[Cl:28][C:25]1[CH:26]=[C:27]2[C:22]([CH:21]=[C:20]([C:7]3[CH:6]=[N:5][CH:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:8]=3)[NH:19]2)=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Product: FC(F)(F)c1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1

Procedure:
3-Trifluoromethyl-5-bromopyridine and N-Boc-6-chloro-indole-2-boronic acid are processed according to the procedure described in Example 91 to give 6-chloro-2-(5-trifluoromethyl-pyridin-3-yl)-1H-indole. (ESI) m/z 297.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:11]([C:2]1[CH:6]([O:7][CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC1OC(=O)C=C1Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC1OC(=O)C=C1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
A mixture of 4-bromo-5-ethoxy-5H-furan-2-one (2.07 g, 10.0 mmol) and sodium azide (0.66 g, 10.2 mmol) in dimethylformamide (10 mL) was stirred at room temperature under nitrogen for 24 h. The reaction was diluted with ethyl acetate, was washed with 0° C. water and with brine, was dried over sodium sulfate, and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:9 ethyl acetate:hexanes afforded 4-azido-5-ethoxy-5H-furan-2-one (1.04 g, 62% yield) as a pale yellow oil. 1H-NMR (500 MHz, CDCl3) δ 5.83 (s, 1H), 5.63 (s, 1H), 3.99 (m, 1H), 3.88 (m, 1H), 1.35 (t, J=7.1 Hz, 3H) ppm.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[Br:15][CH2:16][C:17](Br)=[O:18]>C(Cl)Cl>[Br:15][CH2:16][C:17]([NH:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])=[O:18]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)/C=C(/C)NC(=O)CBr
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 15.1 %

Procedure:
A mixture of methyl 3-aminocrotonate (3.20 g, 27.79 mmol) and pyridine (2.64 g, 33.33 mmol) in CH2Cl2 (60 mL) was stirred at −20° C. for 20 min. To the mixture was added a solution of bromoacetyl bromide (5.61 g, 27.79 mmol) in CH2Cl2 (20 mL) dropwise. The mixture was stirred at rt for 2 h. The organic phase was washed with brine (100 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=5:1) to give the title compound as a reddish solid (0.99 g, 15%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(#N)C>[CH3:18][S:19]([O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CCCC[C@H]1CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)OC[C@@H]1CCCC[C@H]1COS(C)(=O)=O
Yield: 50.8 %

Procedure:
The thus obtained compound (2) (5.1 g; 35.4 mmol) is dissolved in triethylamine (10.37 g; 103 mmol) and acetonitrile (127 ml), and methanesulfonyl chloride (8.13 g; 71 mmol) is dropwise added thereto under ice-cooling. The resultant mixture is ice-cooled for 1 hour and allowed to react at room temperature for 3 hours. The reaction mixture is washed with water, dried and concentrated, followed by addition of diethyl ether. Precipitated crystals are collected by filtration to give trans-1,2-bis(methanesulfonyloxymethyl)cyclohexane (3) (5.4 g).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]1=2.[C:19]([Cu])#[N:20]>C1C=CC=CC=1.CCCCCC>[C:19]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]1=2)#[N:20]
Reactant: COc1ccc2c(c1)C(Cl)c1ccccc1CO2
Reactant: N#C[Cu]
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COc1ccc2c(c1)C(C#N)c1ccccc1CO2

Procedure:
11-Chloro-2-methoxy-6,11-dihydrodibenz[b,e]oxepin (10.1 g; 0.038 mole) of Example 24A is dissolved in dry benzene (170 ml) and placed under a dry nitrogen atmosphere. To this solution is added in one portion, CuCN (8.5 g; 0.095 mole). The reaction is brought to reflux (twenty minutes), filtered while hot and the salts are washed with benzene. Removal of the solvent in vacuo yields an oil. The oil is dissolved in a minimal amount of benzene and hexane is added with cooling. The resulting solid is filtered and recrystallized from ethanol to give a solid of 11-cyano-2-methoxy-6,11-dihydrodibenz[b,e]oxepin, m.p. 120°-122° C.
Reaction SMILES: [CH2:1]([C:5]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]2[CH2:10][N:11]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24]C(=O)OC(C)(C)C)=[O:15])[CH2:12][CH2:13][C:8]=2[C:7](=[O:32])[O:6]1)[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:14]([N:11]1[CH2:12][CH2:13][C:8]2[C:7](=[O:32])[O:6][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:9]=2[CH2:10]1)=[O:15]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1NC(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1N)CC2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To an ice-cold solution of tert-butyl 2-((3-isobutyl-1-oxo-3-phenyl-1,3,4,5,6,7-hexahydrofuro[3,4-c]pyridine-5-carboxamido)methyl)phenylcarbamate (62 mg, 0.119 mmol) in dichloromethane (5 mL) was added TFA (1 mL). The reaction mixture stirred at 0° C. for 5 hours and concentrated to dryness to provide crude N-(2-aminobenzyl)-3-isobutyl-1-oxo-3-phenyl-3,4,6,7-tetrahydrofuro[3,4-c]pyridine-5(1H)-carboxamide. The residue was added to a solution of 2-phenylacetic acid (32 mg, 0.238 mmol), BOP (79 mg, 0.179 mmol), and N,N′-diisopropylethylamine (62 mg, 0.477 mmol) in dichloromethane (5 mL), and stirred at room temperature for 16 hours. The crude reaction mixture was concentrated to dryness and purified by column chromatography (12 g, SiO2, 0 to 100% ethyl acetate in hexanes) to provide 3-isobutyl-1-oxo-3-phenyl-N-(2-(2-phenylacetamido)benzyl)-3,4,6,7-tetrahydrofuro[3,4-c]pyridine-5(1H)-carboxamide (66 mg, 93%) as a colorless oil: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.81-0.98 (m, 6H), 1.65 (dd, J=11.87, 6.59 Hz, 1H), 1.73-1.84 (m, 1H), 2.24-2.47 (m, 4H), 3.30 (dt, J=13.19, 6.22 Hz, 1H), 3.52 (dt, J=13.56, 5.09 Hz, 1H), 3.75 (s, 2H), 3.91 (d, J=18.84 Hz, 1H), 4.21-4.48 (m, 2H), 5.22 (br. s., 1H), 6.97-7.09 (m, 1H), 6.99-7.10 (m, 1H), 7.18 (d, J=6.78 Hz, 1H), 7.23-7.47 (m, 9H), 7.75 (br. s., 1H), 7.96 (d, J=7.91 Hz, 1H), 9.65 (br. s., 1H); MS m/z 538 (M+H)+, 560 (M+23)+, 536 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:18][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=1)=[O:17]
Reactant: CCCCCCCOc1ccc(C(C)=O)cc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 137.7 %

Procedure:
To a stirring solution of 1-(4-(heptyloxy)phenyl)ethanone (500 mg, 2.13 mmol) in THF (8.5 mL) under nitrogen was added phenyltrimethylammonium tribromide (842 mg, 2.24 mmol). The reaction mixture was stirred at RT for 2 h, filtered under vacuum and the captured solid washed with THF. The combined liquors were concentrated to afford 919 mg (100%) of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4 as a yellow oil. LCMS-ESI (m/z) calculated for C15H21BrO2: 313.2. found 313.0 [M+H]+, tR=2.12 min. (Method 4).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C(OC(Cl)(Cl)Cl)([O:15][C:16](Cl)(Cl)[Cl:17])=O>O1CCCC1>[C:16]([Cl:17])(=[O:15])[O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N:4]([CH3:12])[CH3:3])[CH:6]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1cccc(OC(=O)Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (130 mg, 3.25 mmol, 1.11 equiv, 60%) was added in several batches to a solution of 3-(dimethylamino)phenol (400 mg, 2.92 mmol, 1.00 equiv) in tetrahydrofuran (15 mL). The mixture was stirred at 0° C. for 30 min then ditrichloromethyl carbonate (296.74 mg, 1.00 mmol, 0.34 equiv) was added in several batches to the mixture at 0° C. The resulting solution was stirred for 4 h at 50° C. and used in the next step without any purification
Reaction SMILES: C(OC([N:8]1[CH2:27][CH2:26][CH2:25][C:10]2([N:13]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH:11]2[CH3:24])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([N:13]1[C:10]2([CH2:25][CH2:26][CH2:27][NH:8][CH2:9]2)[CH:11]([CH3:24])[CH2:12]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC1CN(C(=O)OCc2ccccc2)C12CCCN(C(=O)OC(C)(C)C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(C(=O)OCc2ccccc2)C12CCCNC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of an optically-active compound of 3-methyl-1,6-diazaspiro[3,5]nonane-1,6-dicarboxylic acid 1-benzyl ester 6-tert-butyl ester (5.54 g) in chloroform (83 ml) cooled to 4° C. was added a solution of trifluoroacetic acid/chloroform (28 ml/55 ml), and the mixture was warmed to room temperature and stirred for additional 2 hours. The reaction mixture was cooled to 4° C., and thereto was added 4M aqueous sodium hydroxide solution (90 ml). The mixture was basified to be pH 9 to 10, and extracted with chloroform/methanol (4/1, 60 ml×2) twice. The combined organic layer was sequentially washed with 5% aqueous sodium bicarbonate solution, 10% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol/28% ammonia water=90/10/1) to give the titled compound (2.20 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[O:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([C:13]2([OH:16])[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: O=C1CCOCC1
Solvent: C1CCOC1
Product: OC1(c2cc(F)cc(F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (1.6 equiv.) in THF (0.26 M) under Ar was added Mg turnings (1.6 equiv.). A reflux condenser was attached and the solution was submerged in a 90° C. oil bath and refluxed for two hours. The dihydro-2H-pyran-4(3H)-one (1.0 equiv.) was added in THF via syringe. The solution was left stirring at rt under Ar for 5 hrs. The reaction solution was quenched by addition of NH4Cl(sat) and the solution was extracted with EtOAc, washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography (0-100% EtOAc/n-heptanes gradient) to yield 4-(3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol in 71% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.59-1.68 (m, 3H), 2.07-2.19 (m, 2H), 3.87-3.93 (m, 4H), 6.72 (tt, J=8.75, 2.20 Hz, 1H), 6.97-7.06 (m, 2H).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:7]1[C:11]([CH:12]=O)=[CH:10][N:9]([CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH:29][CH3:30])=[O:28])=[O:16])[N:8]=1)([CH3:6])([CH3:5])[CH3:4].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[C:3]([C:7]1[C:11]([CH2:12][NH:2][CH3:1])=[CH:10][N:9]([CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH:29][CH3:30])=[O:28])=[O:16])[N:8]=1)([CH3:4])([CH3:5])[CH3:6]
Reactant: CNC(=O)c1c(NC(=O)Cn2cc(C=O)c(C(C)(C)C)n2)sc2c1CCCC2
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CNCc1cn(CC(=O)Nc2sc3c(c2C(=O)NC)CCCC3)nc1C(C)(C)C
Reaction time: 17 h
Yield: 31.9 %

Procedure:
Methylamine (45.0 mg, 50 μl, 1.449 mmol) was added to a solution of 2-(2-(3-tert-butyl-4-formyl-1H-pyrazol-1-yl)acetamido)-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (100 mg, 0.248 mmol) and acetic acid (100 μl, 1.74 mmol) in DMF (1 mL). Sodium triacetoxyborohydride (527 mg, 2.484 mmol) was added and the reaction stirred for 17 h. The reaction was quenched with water (500 μl) and purified by preparative reverse phase HPLC. The clean fractions were passed down an SCX cartridge and eluted with 2M NH3 in MeOH. Volatiles were blown down under a nitrogen atmosphere to yield the title product (33 mg, 0.079 mmol, 32%).