Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH:14]([CH:15]([CH3:18])[CH2:16][OH:17])[O:13][C:12](=[O:19])[NH:11]1)C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][C@@H:10]1[CH:14]([CH:15]([CH3:18])[CH2:16][OH:17])[O:13][C:12](=[O:19])[NH:11]1
Reactant: CC(CO)C1OC(=O)N[C@@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(CO)C1OC(=O)N[C@@H]1CO
Reaction time: 15 h
Yield: 99 %

Procedure:
To a solution of (4R)-4-(benzyloxymethyl)-5-(1-hydroxypropan-2-yl)oxazolidin-2-one (1.0 equiv.) in methanol, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 15 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding (4R)-4-(hydroxymethyl)-5-(1-hydroxypropan-2-yl)oxazolidin-2-one (99%). LCMS (m/z): 176.1 (MH+).
Reaction SMILES: [F:1][C:2]([F:24])([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[F:23])[C:3]([NH:5][CH2:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.[BH4-].[Na+].ClC1C2C(=CC=CC=2)C=CC=1OCC(C)(NCC1SC=CC=1)C>C1COCC1>[F:24][C:2]([F:1])([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[F:23])[CH2:3][NH:5][CH2:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(NCc1ccco1)C(F)(F)Oc1ccc2ccccc2c1F
Agent: CC(C)(COc1ccc2ccccc2c1Cl)NCc1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1c(OC(F)(F)CNCc2ccco2)ccc2ccccc12
Yield: 91.6 %

Procedure:
A microwave vial was charged with 2,2-difluoro-2-[(1-fluoronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)acetamide (60 mg, 0.18 mmol), sodium borohydride (16 mg, 0.41 mmol) and 2 mL of dry THF. To this mixture, a solution of 12 (51 mg, 0.20 mmol) in 1 mL of dry THF was added. The vial was sealed and placed in the microwave reactor and irradiated for 30 min at 110° C. until the starting materials had been completely consumed as judged by TLC (petroleum ether/ethyl acetate 80:20). The mixture was evaporated under reduced pressure and the crude was purified by preparative HPLC to afford 2,2-difluoro-2-[(1-fluoronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamine as orange oil (53 mg, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1/[CH:17]=[CH:18]/[C@@H:19]1[O:24][C:23](=[O:25])[CH2:22][C@@H:21]([OH:26])[CH2:20]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:3]=1[CH2:17][CH2:18][C@@H:19]1[O:24][C:23](=[O:25])[CH2:22][C@@H:21]([OH:26])[CH2:20]1
Reactant: O=C1C[C@@H](O)C[C@H](/C=C/c2c(Cl)cc(Cl)cc2OCc2ccccc2)O1
Solvent: C1CCOC1
Product: O=C1C[C@@H](O)C[C@H](CCc2c(Cl)cc(Cl)cc2OCc2ccccc2)O1

Procedure:
A solution of trans-(E)-6-[2-(2,4-dichloro-6-phenylmethoxyphenyl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (1.1 g, 28 mmole) in tetrahydrofuran (50 ml) was magnetically stirred and hydrogenated at room temperature and atmospheric pressure in the presence of 110 mg of 5% rhodium on carbon catalyst until 1.5 molar equivalents of hydrogen had been consumed. After removing the catalyst by filtration, the filtrate was evaporated in vacuo leaving the title compound as a pale yellow oil. The oil was chromatographed on a silica gel column (200 g). Elution with acetone-methylene chloride (1:9, v:v; 560 ml) provided a forerun which was discarded. Continued elution with the same eluant (240 ml) gave the title compound as a colorless oil which solidified when it was triturated with ether. The title compound was purified by recrystallization from ether-hexane (1:1, v:v; 20 ml) to give colorless needles (0.67 g, 61%) melting at 99°-101° C.; pmr (CDCl3) δ1.83 (4 H, m), 2.60 (2H, m), 2.90 (2H, m), 4.30 (H, m), 4.62 (H, m), 5.05 (2H, s), 7.42 (5H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9]CC)=O)[C:2]=1[C:12]([O:14]CC)=O.[C:17]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].CC[O-].[Na+].CCO.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CC(O)=O>[OH:9][C:7]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([C:17]([O:26][CH2:27][CH3:28])=[O:25])[C:12]([OH:14])=[C:2]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:1]2
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: CCOC(=O)c1cccnc1C(=O)OCC
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C(=O)OCC)c(O)c2ncccc2c1O
Temperature: 0 °C
Yield: 76.7 %

Procedure:
To a mechanically stirred solution of diethyl pyridine-2,3-dicarboxylate 1 (86%, 85.6 g, 330 mmol) and diethyl succinate (70 ml, 414 mmol) in toluene (100 ml) at 95 C was added slowly a solution of NaOEt in EtOH (21%, 311 ml, 825 mmol) and this mixture was stirred at reflux o.n. It was then poured into an ice cold solution of sat NH4Cl (1.5 L) containing 60 ml AcOH. The products were extracted into EtOAc, dried over Na2SO4 and this solution was filtered through a pad of silica (400 ml) and concentrated to dryness. The residue was triturated into ether:hexane 1:2, the solid filtered, washed with hexane and air dried to yield 77.3 g (77% yield) of 2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.C1([C:25](=[O:34])[CH2:26][C:27]2[CH:28]=[C:29](C)[CH:30]=[CH:31][CH:32]=2)C=CC=CC=1>C1COCC1>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([C:25](=[O:34])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: Cc1cccc(CC(=O)c2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
To a solution of 4-bromobiphenyl (683 mg, 2.9 mmol) in anhydrous THF (5 mL) was added n-BuLi (1.2 mL, 2.9 mmol) dropwise at −78° C. After being stirred at the temperature for 0.5 h, a solution of N-methoxy-N-methyl-2-phenyl-acetamide (prepared following step 1 of Intermediate 4) (500 mg, 2.8 mmol) in anhydrous THF (5 mL) was added via a syringe, and the mixture was stirred at −78° C. for 2 h. The reaction was quenched with saturated NH4Cl aqueous solution, and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE:EtOAc=20:1) to give 1-(biphenyl-4-yl)-2-phenylethanone (180 mg, yield 24%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15](C(O)=O)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]CCC.C[Li].[Cl-].[NH4+]>CCOCC>[CH3:3][CH2:4][CH2:5][CH:1]([O:11][C:12]1([C:1]([CH3:2])=[O:11])[CH:13]=[CH:14][CH:15]=[CH:19][CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCC(CCC)OC1(C(C)=O)C=CC=CC1
Temperature: 25 °C

Procedure:
To a mixture of 27.8 g (0.1 mole) of 4-decyloxybenzoic acid and 300 ml of anhydrous ether stirred at room temperature is slowly added with stirring 100 ml of 2 M methyllithium in ether. The reaction mixture is stirred at room temperature for 2 hours then poured into 1 liter of a saturated ammonium chloride solution. The organic layer is separated, washed with 5% sodium bicarbonate and brine and evaporated to dryness to give a low melting solid which is recrystallized from hexane to give methyl 1-(4-decyloxy)phenyl ketone, M.P. 38°-39° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:19][CH:20]([O:26][CH:27]([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:5]=[C:6]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]=1[O:8][CH3:9].[C-:30]#[N:31].[Na+].C(OCC)(=O)C>C(#N)CC.[Cu](I)I>[C:30]([C:2]1[CH:3]=[C:4]([CH2:19][CH:20]([O:26][CH:27]([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:5]=[C:6]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]=1[O:8][CH3:9])#[N:31]
Reactant: CCOC(=O)C(Cc1cc(Br)c(OC)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Reactant: [C-]#N
Agent: I[Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC#N
Product: CCOC(=O)C(Cc1cc(C#N)c(OC)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Temperature: 25 °C
Yield: 75.5 %

Procedure:
876 mg of ethyl 3-(3-bromo-5-[(tertiary butoxycarbonyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropionate was dissolved in 5 ml propionitrile, and 182 mg of sodium cyanide, 214 mg of tetrakistriphenylphosphine palladium and 70 mg of copper iodide were added, followed by heating under reflux overnight in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, ethyl acetate was added thereto and filtered through Celite. The filtrate was evapoarated and the residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (4:1), 586 mg of ethyl 3-(3-cyano-5-[(tertiary butoxycarbonyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropionate was obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[O:8]1[C:12]2([CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([CH2:24][CH2:25][CH2:26][NH:27]4)=[CH:22][C:21]=3[O:30][CH3:31])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1>N1C=CC=CC=1>[C:1]([N:27]1[C:28]2[C:23](=[CH:22][C:21]([O:30][CH3:31])=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][C:12]4([O:11][CH2:10][CH2:9][O:8]4)[CH2:17][CH2:16]3)[CH:29]=2)[CH2:24][CH2:25][CH2:26]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1CCN1CCC3(CC1)OCCO3)NCCC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc2c(cc1CCN1CCC3(CC1)OCCO3)N(C(C)=O)CCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3 ml of acetic anhydride and 3 ml of pyridine were added to 251 mg of 7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline, and the obtained mixture was then stirred at room temperature for 90 minutes. The reaction solution was concentrated under a reduced pressure. The residue was diluted with ethyl acetate and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate) and then by silica gel column chromatography (ethyl acetate-methanol), so as to obtain 162 mg of the subject compound.
Reaction SMILES: C(O)C.[OH-].[K+].[CH:6]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[S:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH2:30][N:29](C(=O)C(F)(F)F)[CH2:28][CH2:27]4)(=[O:23])=[O:22])=[C:16]([F:49])[CH:15]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1>O1CCCC1.O>[CH:6]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[S:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH2:30][NH:29][CH2:28][CH2:27]4)(=[O:22])=[O:23])=[C:16]([F:49])[CH:15]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COc1ccc(CN(c2ccc(CCCC3CCCC3)cc2F)S(=O)(=O)c2ccc3c(c2)CCN(C(=O)C(F)(F)F)C3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccc(CCCC3CCCC3)cc2F)S(=O)(=O)c2ccc3c(c2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
An aqueous solution (10 mL) of ethanol (20 mL) and potassium hydroxide (730 mg, 12.86 mmol) was added to a solution of N-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-N-(4-methoxybenzyl)-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (4.07 g, 6.43 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 15 hr. The mixture was diluted with water and extracted with chloroform. The organic layer was concentrated under reduced pressure, a mixed solvent of hexane and ethyl acetate (6:1) was added to the residue, and a precipitated solid was collected by filtration to afford the title compound as a colorless powder (3.11 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N:11][C:12]([Cl:16])=[C:13](Br)[CH:14]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:12]1[N:11]=[CH:10][C:9]([O:8][CH2:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[CH:14][C:13]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1cnc(Cl)c(-c2cccnc2)c1
Temperature: 25 °C
Yield: 220.1 %

Procedure:
To a solution of 3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine (500 mg, 1.28 mmol) in toluene (10 mL) was added 3-pyridinyltributyltin (564 mg, 1.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.04 mmol). After being heated under reflux for 16 h, the resulting mixture was cooled to room temperature. Solvent was removed, and the residue was chromatographed (silica gel; EtOAc/hexane, 2:19 to 1:1) to afford an oil (428 mg, 86%): 1H NMR (CDCl3, 300 MHz) δ 1.45 (s, 9H), 1.94 (m, 1H), 1.98-2.10 (m, 2H), 3.31-3.45 (m, 2H), 3.88-4.30 (m, 4H), 7.22 (m, 1H), 7.40 (m, 1H), 7.83 (td, 1H, J=1.5, 9.0 Hz), 8.16 (d, 1H, J=3.0 Hz), 8.64-8.73 (m, 2H); MS (CI/NH3) m/z 390 (M+H)+.
Reaction SMILES: [CH2:1]([N:3](C(C)C)[CH:4](C)C)C.[C:10]([C:13]1[CH:14]=[C:15]([C:30]([OH:32])=O)[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:19][C:18]2=[O:29])(=[O:12])[CH3:11].Cl.CNC>C(Cl)Cl>[C:10]([C:13]1[CH:14]=[C:15]([C:30]([N:3]([CH3:4])[CH3:1])=[O:32])[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:19][C:18]2=[O:29])(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 44.4 %

Procedure:
N-ethyl-N-isopropylpropan-2-amine (9.4 mL, 53.9 mmol) was added to 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (5.7 g, 18 mmol) in DCM (100 mL). Five minutes later dimethylamine hydrochloride (2.9 g, 35.9 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (6.92 g, 21.6 mmol) were added. The mixture was diluted with DCM, washed with NaHCO3, dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH/DCM. The solvent was evaporated to dryness to afford 8-acetyl-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (2.75 g, 46%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][N:33]([C@H:34]1[CH2:35][CH2:36][C@H:37]([CH3:40])[CH2:38][CH2:39]1)[C:6](=[O:8])[CH:5]=[CH:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[F:1]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)C=Cc1ccccc1F)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1.0 g of 2-fluorocinnamic acid, 1.4 ml of diethyl chlorophosphate, 1.4 ml of triethylamine, 60 ml of methylene chloride, 1.4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.25 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 1.69 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-2-fluorocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH2:1]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:1]([C:13]1[CH:14]=[C:15]2[C:16]([N:17]=[C:26]3[C:25](=[C:23]2[OH:22])[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)C1CCCCC1
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCc1ccc2nc3c(c(O)c2c1)CCCC3
Reaction time: 72 h

Procedure:
4-Dodecylaniline (15.7 g) was dissolved in 100 mL of benzene and then 2-ethoxycarbonylcyclohexane (10.2 g) was added, followed by 0.20 g of p-toluenesulfonic acid. The reaction mixture was stirred for three days and then refluxed for 2 hours with the separation of H2O. The benzene was evaporated from this mixture, which was then dissolved in 100 mL of phenyl ether and refluxed for 45 minutes. At the end of this time the reaction mixture was allowed to cool and the precipitated product was filtered off. This crude product was purified by flash chromatography (20% ethyl acetate/CH2Cl2) and then recrystallized from 1,2-dichloroethane/methanol to give 1.31 g, mp 225°-226°.
Reaction SMILES: C([S:9][CH:10]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:11]([NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH:22]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=2[CH2:15]1)=[O:12])(=O)C1C=CC=CC=1.Cl>CO>[SH:9][CH:10]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:11]([NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH:22]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:18][C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=2[CH2:15]1)=[O:12]
Reactant: CC(C)CC(C(=O)OC(C)(C)C)N1Cc2ccccc2CC(NC(=O)C(Cc2ccccc2)SC(=O)c2ccccc2)C1=O
Agent: Cl
Solvent: CO
Product: CC(C)CC(C(=O)OC(C)(C)C)N1Cc2ccccc2CC(NC(=O)C(S)Cc2ccccc2)C1=O

Procedure:
Combine 2-[4-(2-Benzoylsulfanyl-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-4-methyl-valeric acid, tert-butyl ester (0.229 mmol) in degassed methanol (3 mL) and cool in an ice bath. Treat with degassed 1N aqueous lithium hydroxide (1.0 mL) and stir, allowing the ice bath to warm gradually over 3 hours. With the reaction at 0° C., acidify with 5% hydrochloric acid. Partition between methylene chloride and water, dry (Na2SO4) and purify by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:15]([OH:17])=O)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:18][C@@H:19]([CH2:36][CH3:37])[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[N:31]1[CH:35]=[N:34][N:33]=[N:32]1)=[O:21].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CO>[C:4]([O:3][C:1]([NH:8][C@@H:9]([C:15]([NH:18][C@H:19]([C:20]([NH:22][CH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[N:31]1[CH:35]=[N:34][N:33]=[N:32]1)=[O:21])[CH2:36][CH3:37])=[O:17])[CH2:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC[C@H](N)C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Boc-D-tert-butyl-alanine (74 mg, 0.30 mmol), (2S)-2-amino-N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]butanamide (99 mg, 0.30 mmol), HOAt (41 mg, 0.30 mmol), EDC (86 mg, 0.45 mmol), and Et3N (42 μL, 0.30 mmol) in DMF (1.0 mL) was stirred at rt overnight. A small amount of MeOH was added to aid in dissolution. Solvent was removed in vacuo to give the title compound, which was carried on directly to deprotection. LCMS (M+H): 522.0.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=2)([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCN(Cc3ccccc3)CC2)c1

Procedure:
This compound is prepared by the procedure described in step A of preparation 1.7, from 1.55 g of magnesium in 25 ml of THF, a solution of 12 g of 3-bromoanisole and 15 ml of THF and a solution of 10 g of 1-benzyl-4-piperidone in 30 ml of THF. The product obtained is chromatographed on silica gel, eluting with a DCM/MeOH (97/3 to 95/5; v/v) mixture. This gives 13.7 g of the expected product.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][CH:7]=[C:8]([C:14](=[O:26])[C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([O:23][CH3:24])[C:16]=2F)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl>O1CCCC1>[CH:3]1([N:6]2[C:16]3[C:15](=[CH:20][C:19]([F:21])=[C:18]([F:22])[C:17]=3[O:23][CH3:24])[C:14](=[O:26])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7]2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(OC)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
150 mg (0.0035 mole) of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 1.20 g (0.0035 mole) of ethyl 3-cyclopropylamino-2-(3-methoxy-2,4,5-trifluorobenzoyl)acrylate (XXXI) [prepared as described in Step (E11) above] in 30 ml of anhydrous tetrahydrofuran, and the mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was acidified by adding 1N aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was removed by evaporation under reduced pressure to afford 0.83 g of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XXXII) as colorless needles, melting at 180°-182° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[C:11]([Cl:33])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:15][C:13]1[CH:14]=[C:9]([OH:8])[CH:10]=[C:11]([Cl:33])[C:12]=1[O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1
Reactant: [H][H]
Reactant: O=C(NCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(NCCCOc1c(Cl)cc(O)cc1Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Benzyloxy-3,5-dichloro-4-(3-(4-trifluoromethylbenzamido)propyloxy)benzene was dissolved in ethyl acetate, which was put into a reaction vessel, and the air in the vessel was replaced with nitrogen gas. A catalytic amount of 10% palladium on carbon was added, and the nitrogen gas in the vessel was replaced with hydrogen gas, followed by vigorous stirring at room temperature for 24 hours. The hydrogen gas in the vessel was replaced with nitrogen gas, after which the reaction mixture was filtered through cerite and the filtrate was concentrated to give 3,5-dichloro-4-(3-(4-trifluoromethylbenzamido)propyloxy)phenol.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]>C(OCC)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=1
Reactant: CN(C)CCCN
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: CCOC(C)=O
Product: CN(C)CCCNc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 14 h

Procedure:
N,N-Dimethyl-1,3-propanediamine (2.92 ml) was added to 2,5-dichloronitrobenzene (2.23 g) and stirred for 14 hours at 125° C. The reaction mixture, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution, water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (2.99 g) as brown oil.