Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([CH2:19][C:20](OCC)=[O:21])[CH:14]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH2:13][CH2:12]2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([CH2:19][CH:20]=[O:21])[CH:14]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH2:13][CH2:12]2
Reactant: CCOC(=O)CC1c2ccc(OC)cc2CCC1c1ccc(OC)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: [Al+3]
Agent: [H-]
Product: COc1ccc(C2CCc3cc(OC)ccc3C2CC=O)cc1

Procedure:
A stirred mixture of 3,4-dihydro-6-methoxy-2-methoxyphenylnaphthalen-1(2H)-one (10 g.), ethyl bromoacetate (17.8 g.), zinc (11.6 g.), benzene (200 ml.) and one crystal of iodine was heated under reflux under an atmosphere of argon for 10 minutes, allowed to continue to boil until the exothermic reaction subsided, heated again under reflux for a further 10 minutes and then cooled to laboratory temperature. Saturated aqueous ammonium chloride solution (100 ml.) was added, the mixture was filtered and the organic layer of the filtrate was separated, dried and evaporated to dryness. A 10% palladium-on-charcoal catalyst (2 g.) was added to a solution of the residue (13.1 g.) in ethyl acetate (300 ml.) and the mixture was stirred under an atmosphere of hydrogen for 3 hours, filtered, and rehydrogenated with fresh catalyst (2 g.) for 18 hours. The mixture was filtered, the filtrate was evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 25:1 v/v mixture of toluene and ethyl acetate. The ethyl [(1RS,2RS)-6-methoxy-2-p-methoxyphenyl-1,2,3,4-tetra-hydronaphth-1-yl]acetate thus obtained was reduced with lithium aluminium hydride (4.4 g.) by a similar process to that described in Example 7, and the ethanol thus obtained (m.p. 98°-99° C.) was oxidised with pyridinium chlorochromate (8.6 g.) by a similar process to that described in the 6th paragraph of Example 2. There was thus obtained the desired acetaldehyde, m.p. 101°-103 C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([CH:18]([CH2:20][N:21]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]#[CH:31])[OH:19])=[CH:13][C:12]=1[Cl:39]>C(NCC)C.C1COCC1.[Cu]I>[NH2:10][C:11]1[C:12]([Cl:39])=[CH:13][C:14]([CH:18]([CH2:20][N:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]#[C:31][C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[OH:19])=[CH:15][C:16]=1[Cl:17]
Reactant: COc1cccnc1Br
Reactant: C#CCOCCCCCCN(Cc1ccccc1)CC(O)c1cc(Cl)c(N)c(Cl)c1
Agent: [Cu]I
Solvent: CCNCC
Solvent: C1CCOC1
Product: COc1cccnc1C#CCOCCCCCCN(Cc1ccccc1)CC(O)c1cc(Cl)c(N)c(Cl)c1
Yield: 77.7 %

Procedure:
A solution of 2-bromo-3-methoxypyridine (2 g), 4-amino-3,5-dichloro-α-[[(phenylmethyl)[6-[(2-propynyl)oxy]hexyl]amino]methyl]benzenemethanol (5.74 g), BTPC (150 mg), copper (I) iodide (15 mg) in diethylamine (20 ml) and THF (10 ml) was stirred under nitrogen overnight. The solution was concentrated in vacuo to give a brown oil which was purified by FCC eluting with System C (95:5:1) to give the title compound as a brown oil (4.6 g), t.l.c. (System A 80:20:1) Rf 0.6.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Cl-].[Cl-].[Cl-].[Al+3].ClC(N(C)C)=C(C)C.[CH2:24]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([C:35]2[CH:36]=[C:37]([CH2:42][C:43](O)=[O:44])[CH:38]=[CH:39][C:40]=2[F:41])=[O:34])[CH2:29][CH2:28]1)[CH3:25].Cl>C(Cl)Cl>[CH2:24]([O:26][CH:27]1[CH2:28][CH2:29][N:30]([C:33]([C:35]2[CH:36]=[C:37]([CH2:42][C:43]([C:5]3[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([CH3:1])[NH:3][C:4]=3[CH3:11])=[O:44])[CH:38]=[CH:39][C:40]=2[F:41])=[O:34])[CH2:31][CH2:32]1)[CH3:25]
Reactant: COC(=O)c1cc(C)[nH]c1C
Reactant: CCOC1CCN(C(=O)c2cc(CC(=O)O)ccc2F)CC1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Product: CCOC1CCN(C(=O)c2cc(CC(=O)c3c(C)[nH]c(C)c3C(=O)OC)ccc2F)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
A solution of methyl 2,5-dimethyl-1H-pyrrole-3-carboxylate (0.545 g, 3.56 mmol) in anhydrous DCM (10 mL) was added dropwise to a stirred suspension of aluminum trichloride (1.078 g, 8.08 mmol) in anhydrous DCM (20 mL) at 0° C., under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of the requisite acid chloride [prepared earlier; by stirring 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.428 mL, 3.23 mmol) was added to a solution of 2-(3-(4-ethoxypiperidine-1-carbonyl)-4-fluorophenyl)acetic acid (1.000 g, 3.23 mmol) in anhydrous DCM (10 mL) at 0° C. and stirred for 2 hours] was added dropwise to the stirred suspension at 0° C. The resulting suspension was allowed to warm to room temperature and then stirred at room temperature for a further 18 hours. The reaction was incomplete and further aluminum trichloride (1.078 g, 8.08 mmol) was added and the solution was stirred at room temperature for a further 1 hour. The reaction mixture was poured onto ice (100 mL) and concentrated HCl (5 mL). The layers were separated and the aqueous layer extracted with DCM (2×100 mL). The combined organics were washed sequentially with 2M HCl (2×150 mL), water (100 mL), and saturated NaHCO3 (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a beige solid (1.241 g, 86% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.14 (3H, t), 1.42-1.66 (2H, m), 1.71 (1H, m), 1.85 (1H, m), 2.00 (3H, s), 2.32 (3H, s), 3.06 (1H, m), 3.39-3.52 (5H, m), 3.75 (3H, s), 3.93-4.02 (3H, m), 6.92 (1H, t), 7.07 (1H, m), 7.17 (1H, m), 8.43 (1H, s); m/z (LC-MS, ESI+), RT=2.02 min (M+H=445.24).
Reaction SMILES: Br[O-:2].[Na+].BrBr.[OH-].[Na+].[CH3:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](C)=[O:18])=[CH:13][CH:12]=1>O.O1CCOCC1>[CH2:10]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([OH:18])=[O:2])=[CH:15][CH:16]=1)[CH2:9][CH3:8]
Reactant: CCCc1ccc(C(C)=O)cc1
Reactant: [O-]Br
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1ccc(C(=O)O)cc1

Procedure:
A solution of sodium hypobromite prepared by dissolving bromine (1.0 mole) in a solution of sodium hydroxide (3.5 mole) in water (700 ml) at 0° C. was added to a well stirred solution of 4-n-propylacetophenone (0.2 mole), prepared in step A1, in dioxan (500 ml). Throughout the addition and for 0.25 hours afterwards the temperature was maintained at 35°-45° C. The excess of sodium hypobromite wad destroyed by adding a solution of sodium metabisulphite. Water (3.5 L) was added and bromoform distilled from the reation mixture. On cooling, the solution was acidified with concentrated hydrochloric acid and the precipitated product filtered off and washed with water. The product was crystallised from ethanol/water to yield white crystals mpt 141.2° C.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].OCCCNC1C=CC=C[N+]=1[O-].O[C:32]1[CH:49]=[CH:48][C:35]2[CH2:36][CH:37]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:38](=[O:42])[N:39]([CH3:41])[CH2:40][C:34]=2[CH:33]=1.OC1C=CC2CC(CC(OC)=O)C(=O)NCC=2C=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:32]2[CH:49]=[CH:48][C:35]3[CH2:36][CH:37]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:38](=[O:42])[N:39]([CH3:41])[CH2:40][C:34]=3[CH:33]=2)=[O:11])=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: COC(=O)CC1Cc2ccc(O)cc2CN(C)C1=O
Reactant: O=C(NCCCO)OCc1ccc([N+](=O)[O-])cc1
Agent: COC(=O)CC1Cc2ccc(O)cc2CNC1=O
Agent: [O-][n+]1ccccc1NCCCO
Product: COC(=O)CC1Cc2ccc(OCCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)cc2CN(C)C1=O

Procedure:
According to the procedure of Example 1(a), except substituting 3-(4-nitrobenzyloxycarbonylamino)-1-propanol for the 2-[(3-hydroxy-1-propyl)amino]pyridine-N-oxide, and substituting methyl (±)-8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate for the methyl (±)-8-hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the tile compound was prepared as a colorless oil: MS (ES) m/e 500.3 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[N:31]#[C:32]Br>C(Cl)(Cl)Cl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:18][CH2:19][N:20]([C:32]#[N:31])[CH2:21][CH2:22]4)[S:15][CH:16]=3)=[CH:23][CH:24]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: N#CBr
Reactant: c1cc(-n2cnnn2)ccc1OCc1csc(C2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine (1.00 g, 2.92 mmol) and potassium carbonate (1.5 g, 10.9 mmol) in chloroform (25 mL) was added cyanogen bromide (0.371 g, 3.5 mmol). The slurry was refluxed for 48 hours then stirred at room temperature for an additional 48 hours. The reaction was filtered through a pad of celite, concentrated and chromatographed on silica gel (1:1 Hexanes/EtOAc) to afford the desired compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1.CO.[Cl-].[Zn+2].[Cl-].O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([F:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: Nc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: Fc1ccc(NC2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 20 h
Yield: 93.2 %

Procedure:
Benzylpiperidone (2 g), dissolved in toluene (10 cc), is stirred under argon for 48 hours at room temperature in the presence of 4-fluoroaniline (1.4 g) and 5 Å molecular sieve (4 g). After filtration and concentration to dryness under reduced pressure (5.2 kPa), yellow crystals are obtained, which are then dissolved in methanol (30 cc). This solution is then added to a solution, cooled to 0°-5° C., of sodium cyanoborohydride (1.34 g) and zinc chloride (1.4 g) in methanol (20 cc). After 20 hours at room temperature, the product is taken up with 10N sodium hydroxide solution (5 cc) and with water (20 cc) and the mixture is heated to reflux for 1 hour. The mixture is filtered through a sinter and the filtrate is extracted twice with dichloromethane (100 cc). The organic phase is then dried over magnesium sulphate and thereafter concentrated to dryness under reduced pressure (5.2 kPa). N-Benzyl-4-(4-fluoroanilino)piperidine (2.8 g) is thereby obtained in the form of a whitish powder, m.p. 84° C.
Reaction SMILES: S([O:11][C@H:12]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[CH2:39](O)[CH2:40][OH:41].O>O1CCOCC1>[CH3:28][CH:26]([CH2:25][CH2:24][CH2:23][C@H:22]([C@@H:21]1[C@:30]2([CH3:38])[C@H:18]([C@H:17]3[C@H:33]([CH2:32][CH2:31]2)[C@:34]2([CH3:37])[C:14]([CH2:13][C@@H:12]([O:11][CH2:39][CH2:40][OH:41])[CH2:36][CH2:35]2)=[CH:15][CH2:16]3)[CH2:19][CH2:20]1)[CH3:29])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)cc1
Reactant: OCCO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCO)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 70.3 %

Procedure:
A solution of 10 g of cholesterol tosylate and 25.3 g of ethylene glycol in 180 ml of dioxan is heated to 120° C. while stirring. The mixture is then treated with 200 ml of water and extracted with ether. The ethereal phase is washed firstly with 10% sodium carbonate solution and then with water. The organic phase is dried and evaporated. The residue is chromatographed on silica gel while eluting with ether/hexane. There are obtained 5.6 g of 2-(cholest-5-en-3β-yloxy)-1-ethanol, m.p. 92°-95° C., the starting material in Example 2q.
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:20](Cl)(=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:21][C:20]([NH:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)[C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc(CC(N)C(=O)OC(C)(C)C)ccc1O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: COc1cc(CC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ccc1O
Reaction time: 0.17 h
Yield: 59 %

Procedure:
Prepared using General Procedure 2: To a stirred solution of tert-butyl 2-amino-3-(4-hydroxy-3-methoxyphenyl)propanoate INT-1 (5.29 g, 19.8 mmol) and TEA (4.29 mL, 29.7 mmol) in DCM (50 mL) at 0° C. was treated with benzyl carbonochloridate (3.00 mL, 21.1 mmol) dropwise over 5 min. After stirring for 10 min, the mixture was washed with 1M HCl (150 mL), dried over MgSO4, and concentrated. The residue was taken up in MeOH (20 mL) and treated with 2 N NaOH (5 mL). After 10 min, the mixture was acidified and the product was purified by chromatography (EA/hexanes) to afford 4.7 g (59%) of tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxy-3-methoxyphenyl)propanoate INT-2. LCMS-ESI (m/z) calculated for C22H27NO6: 401; found 424 [M+Na]+, tR=2.47 min (Method 6).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:24]([CH3:26])[CH3:25])[C:5]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].[CH:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([N:4]([CH:24]([CH3:26])[CH3:25])[CH2:3][CH2:2][NH:1][C:31]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[O:32])([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[C:6](=[O:15])[NH:7]2)=[CH:12][CH:11]=1
Reactant: O=C(O)C1CCC1
Reactant: CC(C)N(CCN)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CCNC(=O)C1CCC1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reaction time: 2 h
Yield: 84.3 %

Procedure:
The mixture of rac-3-[(2-Amino-ethyl)-isopropyl-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (60 mg, 0.15 mmol), cyclobutanecarboxylic acid (18.4 mg, 0.18 mmol), EDCl (37 mg, 0.19 mmol), HOBt (30 mg, 0.19 mmol) and DIPEA (40 uL, 0.225) in DCM (2 mL) was stirred at root temperature for 2 hr. The mixture was purified by flash column chromatography to give 60 mg rac-Cyclobutanecarboxylic acid (2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-amide. MS: [M+H]+=474
Reaction SMILES: [C:1]([C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:11])=[CH:8][CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].[F:21][C:22]([F:37])([F:36])[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[F:37][C:22]([F:21])([F:36])[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:34]=[CH:33][C:32]([NH:35][CH:1]([C:6]3[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:11])=[CH:8][CH:7]=3)[CH2:2][CH2:3][CH3:4])=[CH:31][CH:30]=2)=[CH:27][CH:28]=1
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CCCC(=O)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCCC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(4-butyrylbenzamido)propanoate (128 mg, 0.46 mmol) and 6-(4-(trifluoromethyl)phenyl)pyridin-3-amine (100 mg, 0.42 mmol, prepared as in Example 2.7, Step B) in dry methanol (4.8 mL) was added decaborane (31 mg, 0.25 mmol). The resulting mixture was stirred at 30° C. overnight. The solvent was removed under reduced pressure and the residue was purified by preparative TLC to provide impure methyl 3-(4-(1-(6-(4-(trifluoromethyl)phenyl)pyridin-3-ylamino)butyl)benzamido)propanoate. This material was dissolved in THF (3 mL) and water (3 mL). Aqueous lithium hydroxide (1.00 mmol) was added. The resulting mixture was stirred at 20° C. for 1 h. The solvent was removed underreduced pressure. The residue dissolved in water and the solution brought to pH 3-4 by addition of 1N aqueous HCl. The mixture was extracted with dichloromethane (10 mL*2). The combined organic layers were concentrated. Purified by preparative HPLC (column: Phenomenex Gemini C18 250×21.2 mm×10 μm; modifier: 0.225% formic acid; gradient: 10 to 30% acetonitrile in water) to give 3-(4-(1-(6-(4-(trifluoromethyl)phenyl)pyridin-3-ylamino)butyl)benzamido)propanoic acid (20 mg) as a colorless solid. 1H NMR (400 MHz, CD3OD) δ 7.90-7.95 (m, 3H), 7.86-7.79 (m, 5H), 7.52 (d, J=8.0 Hz, 2H), 7.43-7.47 (m, 1H), 4.57-4.60 (m, 1H), 3.60-3.64 (m, 2H), 2.62-2.65 (m, 2H), 1.94-1.96 (m, 1H), 1.82-1.86 (m, 1H), 1.57-1.43 (m, 2H), 1.01 (t, J=7.2 Hz, 3H). MS (M+1)=486.3.
Reaction SMILES: [OH:1][C:2]1C=CC(C=O)=C(OC)C=1.C([C:14]1[CH:15]=[C:16]([CH:21]=[C:22](C)[C:23]=1[OH:24])[C:17]([NH:19][OH:20])=[NH:18])C>>[OH:24][C:23]1[CH:22]=[CH:21][C:16]([C:17]([NH:19][OH:20])=[NH:18])=[C:15]([O:1][CH3:2])[CH:14]=1
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: COc1cc(O)ccc1C=O
Product: COc1cc(O)ccc1C(=N)NO

Procedure:
The title compound is prepared from commercially available 4-hydroxy-2-methoxybenzaldehyde in analogy to literature procedures (see 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine); LC-MS: tR=0.41 min; [M+1]+=183.06; 1H NMR (D6-DMSO): δ3.74 (s, 3H), 5.47 (s, 2H), 6.35 (dd, J=8.3, 1.5 Hz, 1H), 6.45 (s, 1H), 7.21 (d, J=8.5 Hz, 1H), 9.42 (s, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:26])[C@@H:6]([NH2:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH3:3].[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]1([C:39](O)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1)=[N+:28]=[N-:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([O:4][C:5](=[O:26])[C@@H:6]([NH:25][C:39]([C:34]1([CH2:33][CH2:32][CH2:31][CH2:30][N:27]=[N+:28]=[N-:29])[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:40])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCOC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: [N-]=[N+]=NCCCCC1(C(=O)O)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)C1(CCCCN=[N+]=[N-])CCCC1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 8, starting from (S)-2-amino-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester (10.78 g, 30 mmol), 1-[4-azidobutyl]cyclopentanecarboxylic acid (8.24 g, 39 mmol), HBTU (14.79 g, 39 mmol), and DIPEA (11.63 g, 15.68 mL, 90 mmol), and after ISCO column chromatography purification, resulted in an amorphous off-white solid (14.1 g, 85%). ES(+)-HRMS m/e calcd. for C29H40N6O5 (M+H)+ 553.3133, obsd. 553.3133.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:10]([OH:23])[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:24][CH2:25][C:26](O)=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:10]([O:23][C:26](=[O:27])[CH2:25][Cl:24])[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CC[C@@H](CCCc2ccccc2)[C@H](O)C1
Reactant: O=C(O)CCl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCOC(=O)N1CC[C@H](CCCc2ccccc2)[C@H](OC(=O)CCl)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.242 g (0.75 mmol) of 1-butyloxycarbonyl (trans)-3-hydroxy4-(3-phenylpropyl)piperidine, 0.189 g (1.5 mmol) of chloroacetic acid, and 0.524 g (1.5 mmol) of triphenylphosphine in 5 mL of THF at 0° C. was slowly added 0.348 g (1.5 mmol) of diethylazodicarboxylate (DEAD). The reaction mixture was allowed to warm to rt and was stirred for 16 h. To the reaction mixture was added 20 mL of ether and it was filtered through a thin pad of celite. The filtrate was washed with sat'd NaHCO3 solution and sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 1:1) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Na+].[F:18][C:19]([F:49])([F:48])[C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28][N:27]2[C:36](OC2C=CC([N+]([O-])=O)=CC=2)=[O:37])=[CH:22][CH:21]=1.O>C1COCC1.CO>[C:7]([C:6]1[CH:9]=[C:2]([NH:1][C:36]([N:27]2[CH2:28][CH2:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:26]2[C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:48])([F:18])[F:49])=[CH:21][CH:22]=2)=[O:37])[CH:3]=[N:4][C:5]=1[O:10][CH2:11][C:12]([F:15])([F:13])[F:14])#[N:8]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cc(N)cnc1OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-amino-2-(2,2,2-trifluoroethoxy)nicotinonitrile (49 mg, 226 μmol) in THF (1.0 mL) was added sodium hydride, 60% dispersion in mineral oil (26 mg, 678 μmol). The resulting mixture was then stirred at RT for 15 min. Then, (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 226 μmol, example 88) was added and the mixture was stirred at RT for overnight. Then, a solution of H2O and MeOH (1:1, 0.2 mL) was added and the solvents were removed. The residue was then dissolved in a solution of DMSO and MeOH (1:1, 1 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP resin (polymerlabs, 200 mg/6 mL tube) and the resin was washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 521 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.Cl.[CH3:14][O:15][C@@H:16]1[C@@H:20]([O:21][CH3:22])[CH2:19][NH:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:18]1[CH2:19][C@H:20]([O:21][CH3:22])[C@@H:16]([O:15][CH3:14])[CH2:17]1
Reactant: CO[C@H]1CNC[C@@H]1OC
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: Cl
Product: CO[C@H]1CN(c2ccnc3ccc(Br)cc23)C[C@@H]1OC
Yield: 35.7 %

Procedure:
697 mg 6-bromo-4-chloroquinoline and 482 mg (3S,4S)-3,4-dimethoxytetrahydro-1H pyrrole monohydrochloride were reacted by the same method as in Production Example 82, to give 346 mg of the title compound as pale brown crystals.