Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH3:8][N:9]([CH3:16])[CH2:10][CH2:11][CH2:12][C:13](O)=[O:14].[OH:17][C:18]([C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=1)([CH3:27])[CH2:19][NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH3:8][N:9]([CH3:16])[CH2:10][CH2:11][CH2:12][C:13]([NH:34][C:31]1[CH:30]=[CH:29][C:28]([C:18]([OH:17])([CH3:27])[CH2:19][NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:23])=[O:22])=[CH:33][CH:32]=1)=[O:14]
Reactant: CN(C)CCCC(=O)O
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(NC(=O)CCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
Into a 50 mL single-neck flask, 1 mL of oxalyl chloride was added syringe wise to 306 mg of 4-(dimethylamino)butyric acid hydrochloride in CH2Cl2 (20 mL) while stirring under a nitrogen atmosphere at room temperature. Then at this temperature. 1 drop of DMF was added by pipette and the mixture began to foam. The reaction was allowed to stir at this temperature for 1 h and was then concentrated under reduced vacuum to yield a yellow solid. This solid was added portion wise to a 100 mL single-neck flask containing 460 mg of [2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine (prepared in example 19) and 183 mg of triethylamine in THF (25 mL) while stirring at room temperature under a nitrogen atmosphere. After 2 h at this temperature, the mixture was concentrated under reduced vacuum and the resulting solid was taken into ethyl acetate. The organic layer was backwashed once with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 794 mg as an oil. This material was purified via silica gel chromatography employing the Chromatotron while using a 4000 micron rotor and eluting with an isocratic solvent of methanol/1% NH4OH to yield intermediate title compound (350 mg, 51%) as a viscous oil. Ion spray M.S. 385 (M*).
Reaction SMILES: C(O)=O.CCN(CC)CC.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25](=[O:29])[CH2:26][C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C@H:25]([OH:29])[CH2:26][C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CCC(=O)c1cccc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: N#CC[C@@H](O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
HCOOH (30.75 mL, 795 mmol) was added dropwise to a cooled (0° C.) solution of Et3N (41.0 mL, 318 mmol) in EtOAc (400 mL) while maintaining the temperature at 0° C. (R,R)—RuCl-TsDPEN (p-cymene) (100 mg, 0.2 mol %) was added to the reaction mixture followed by the addition of oxonitrile (3) (40.0 g, 159 mmol) and the reaction mixture was stirred at room temperature for 24 h. NaHCO3 (10%, 500 mL) was added and the mixture was extracted with EtOAc (500 mL). Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give (R)-3-(3-(benzyloxy)phenyl)-3-hydroxypropanenitrile (4) as a pale yellow solid. Yield (38.0 g, 95%); 1H NMR (400 MHz, DMSO-d6) δ 7.46-7.44 (m, 2H), 7.41-7.37 (m, 2H), 7.33 (t, J=7.2 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.99 (d, J=7.6 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.95 (d, J=4.4 Hz, 1H), 5.09 (s, 2H), 4.86 (d, J=5.2 Hz, 1H), 2.90 (dd, J=16.8, 4.8 Hz, 1H), 2.80 (dd, J=16.8, 6.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2].[CH2:11](O)[CH2:12][OH:13].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([C:6]1([CH3:7])[O:13][CH2:12][CH2:11][O:8]1)[CH3:9])[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)C(C)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)C1(C)OCCO1
Yield: 72.1 %

Procedure:
A mixture of 2-methyl-3-oxo-butyric acid ethyl ester (50 g, 0.347 mol), ethylene glycol (65 g, 1.05 mol) and p-toluenesulfonic acid monohydrate (0.2 g) in anhydrous toluene (200 mL) was refluxed using a Dean-Stark trap until the theoretical amount of water (6.3 mL) was collected. After cooling, the mixture was extracted with saturated bicarbonate solution (100 mL), water (100 mL×5), and brine (100 mL×2). After drying with sodium sulfate, filtration, and concentration on a rotary evaporator, the product was purified by distillation (fraction with b.p. 74-76° C./2 mm Hg) to yield 47.12 g (72%) of 2-(2-methyl-[1,3]dioxolan-2-yl)-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH:13]=O)[C:7](=[O:15])[CH:6]=[CH:5]2.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:13][CH2:12][N:8]4[C:9]5[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=5)[CH:5]=[CH:6][C:7]4=[O:15])[CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: Cc1ccc2c(ccc(=O)n2CC=O)c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(ccc(=O)n2CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To 10 mL of a chloroform solution containing 229 mg of (6-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde and 340 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 55 μL of acetic acid was added and stirred at room temperature for 1 hour. To the reaction mixture, 314 mg of sodium triacetoxyborohydride was added and stirred for 2 hours. Aqueous saturated sodium hydrogen carbonate solution was added and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=50:1], to give 228 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH:8]=O)=[CH:4][CH:3]=1.C([O-])=O.[Na+].Cl.[NH2:17]O.O>C(O)=O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][C:8]#[N:17])=[CH:4][CH:3]=1
Reactant: O=CC=Cc1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#CC=Cc1ccc(F)cc1
Yield: 70.4 %

Procedure:
p-Fluorocinnamaldehyde (9.0 g.) was refluxed for 1 hr. in 98% formic acid containing sodium formate (10 g.) and hydroxylamine hydrochloride (7 g.). The solution was cooled and poured into water (275 ml.), giving a solid. This was washed well with water, leaving p-fluorocinnamonitrile (6.21 g., 70%), m.p. 64°-65°, λmax. (EtOH) 271 nm ε 22500.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O:45][C:46](=[O:68])[C@H:47]([CH2:66][OH:67])[CH2:48][C@H:49]([NH2:65])[C:50]([C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:55][CH:54]=1)([CH3:52])[CH3:51])C.[Li+].[OH-]>CN(C=O)C.CCO>[C:56]1([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:55]=[CH:54][C:53]([C:50]([CH3:52])([CH3:51])[C@@H:49]([NH:65][C:7]([C:5]2[O:4][N:3]=[C:2]([OH:1])[CH:6]=2)=[O:9])[CH2:48][C@@H:47]([CH2:66][OH:67])[C:46]([OH:68])=[O:45])=[CH:58][CH:57]=1
Reactant: O=C(O)c1cc(O)no1
Reactant: CCOC(=O)[C@H](CO)C[C@H](N)C(C)(C)c1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(-c2ccccc2)cc1)[C@H](C[C@@H](CO)C(=O)O)NC(=O)c1cc(O)no1
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
3-Hydroxyisoxazole-5-carboxylic acid (15.8 mg, 122 μmol) was combined with HATU (46.6 mg, 122 μmol) in DMF (1.0 mL) and stirred for 5 minutes. DIPEA (53.3 μL, 0.306 mmol) was added, followed by (2S,4S)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-5-methylhexanoic acid ethyl ester (HCl salt; 40 mg, 0.1 mmol). The mixture was stirred at room temperature for 20 minutes. The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated and 1 M aqueous LiOH (1.0 mL, 1.0 mmol) and EtOH (2.0 mL) were added. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with AcOH and purified by preparative HPLC. The clean fractions were combined and lyophilized to yield the title compound (40 mg, 95% purity). MS m/z [M+H]+ calc'd for C24H26N2O6, 439.18. found 439.4.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([S@:7]([N:9]=[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[CH2:12][CH2:11]1)=[O:8])([CH3:6])[CH3:5].C1COCC1.CO>C(=O)=O>[CH3:6][C:4]([S@:7]([NH:9][C@H:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=2)[CH2:12][CH2:11]1)=[O:8])([CH3:3])[CH3:5]
Reactant: CC(C)(C)[S@@](=O)N=C1CCc2ccc(C(F)(F)F)cc21
Agent: O=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@H]1CCc2ccc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 26.7 %

Procedure:
Sodium borohydride (756 mg, 20.0 mmol) was stirred in a round-bottomed flask under argon at −40 to −50° C. The reaction mixture of Intermediate 4A was added dropwise to the flask, and THF was added to the reaction mixture (ca. 0.6 M). The resulting mixture was allowed to warm up to 0° C. during 1.5 h period. The reaction mixture was cooled in dry ice and MeOH was added dropwise until gas evolution stopped. The mixture was stirred at rt for 20 min, filtered through Celite and rinsed with EtOAc then CH2Cl2. The filtrate was washed with brine (2×) and dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc) to give Intermediate 4B (370 mg, 1.21 mmol, 26.7% yield) as colorless crystals. LC-MS (ESI) 306.0 (M+H), RT=2.10 min (Method B).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[CH:26][CH:25]=1>CN1CCCC1=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[N:15]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH:34]=[N:33][CH:32]=[N:31]3)=[CH:28][CH:29]=2)[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: BrCc1ccc(-n2cncn2)cc1
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1cccc([C@H](C)c2nccn2Cc2ccc(-n3cncn3)cc2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.4 %

Procedure:
To a mixture of the compound of Example 58 (90 mg, 0.45 mmol) and caesium carbonate (244 mg, 0.75 mmol) in 1-methyl-2-pyrrolidinone (1 ml) was added 1-[4-(bromomethyl)phenyl]-1H-1,2,4-triazole (83 μl, 0.5 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was dissolved in 1-methyl-2-pyrrolidinone (0.8 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm×22.4 mm LUNA C18(2) 5 μm column, 20 ml/min) using an acetonitrile:water gradient [15:85 (3 min) to 98:2 (11 min)]. The appropriate fractions were combined and concentrated to give the title compound (57 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH3:17])[CH2:13][CH:14]=1.Cl>[Pd].CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1
Reactant: CCCN1CC=C(c2cccc(F)c2F)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCN1CCC(c2cccc(F)c2F)CC1

Procedure:
Preparation according to Example 2: 4-(2,3-difluorophenyl)-1-propyl-1,2,3,6-tetrahydropyridine (3.35 g, 14.1 mmol), methanol (30 ml), palladium on carbon (0.8 g) and hydrochloric acid (1.5 ml, conc). Yield: 1.29 g (38%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 237-238° C. MS m/z (relative intensity, 70 eV) 239 (M+, 4), 211 (13), 210 (bp), 127 (20) 70 (38).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.FC(F)(F)C(O)=O.[CH2:48]1[NH:54][CH2:53][CH2:52][CH2:51][N:50]2[CH:55]=[C:56]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH:57]=[C:49]12>CN(C=O)C.C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:54]1[CH2:53][CH2:52][CH2:51][N:50]2[CH:55]=[C:56]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH:57]=[C:49]2[CH2:48]1)=[O:9]
Reactant: Cn1cccc1C(=O)O
Reactant: CCOC(=O)c1cc2n(c1)CCCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2n(c1)CCCN(C(=O)c1cccn1C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a vial containing N-methylpyrrole-2-carboxylic acid (0.025 g, 0.2 mmol) was added HATU (0.076 g, 0.2 mmol), DCM (2 mL), and triethylamine (0.112 mL, 0.8 mmol). The solution was stirred at rt for 30 min then ethyl 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylate 2,2,2-trifluoroacetate (0.0644 g, 0.2 mmol) in DMF (0.5 mL) was added. The mixture was stirred at rt for 2 h. The reaction was quenched by addition of DCM (1 mL), sat. NaHCO3 solution (0.5 mL), and water (1 mL). After separation, the aqueous layer was extracted with DCE (2×3 mL). The combined organic layers were concentrated to give crude ethyl 2-(1-methyl-1H-pyrrole-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 84.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 3-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.060 g (83%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.Cl.[NH2:16][OH:17]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CCN(Cc2ccncc2)CC1
Agent: Cl
Product: ON=C1CCN(Cc2ccncc2)CC1

Procedure:
1-(4-Pyridinylmethyl)-4-piperidone oxime is prepared from 1-(4-pyridinylmethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)(CO)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C=O)c1ccc(F)cc1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of oxalyl chloride (2.81 ml) in dichoromethane (30 ml) at −60° C. was added dropwise a solution of dry dimethyl sulphoxide (4.84 ml) in dichloromethane (20 ml). The mixture was stirred for 15 min at −60° C. and then a solution of 2-(4-fluoro-phenyl)-2-methyl-propan-1-ol (4.59 g; CAS 703-10-6) in dichloromethane (20 ml) was added dropwise. The mixture was stirred at −60° C. for 2 hours and then triethylamine (18.9 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and diluted with water and with dichloromethane. The phases were separated and the organic phase was washed with water and then dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc gradient) to yield a colourless oil, (3.47 g, 77%).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32]>>[CH3:26][C:23]1[C:22]([CH2:27][CH2:28][O:29][CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]4)=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Reactant: CC(Br)c1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCOC(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 14, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and (1-bromoethyl)benzene.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:18].[K+].[K+].OO>CS(C)=O>[CH:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: N#Cc1ccc(Oc2ccc(C=O)s2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)s2)cc1
Temperature: 0 °C
Yield: 152.5 %

Procedure:
Combine 4-(5-formyl-thiophen-2-yloxy)-benzonitrile (772 mg, 3.36 mmol), K2CO3 (powder, 232 mg, 50 mol %) and DMSO (33 mL). Cool down to 0° C. Add hydrogen peroxide (1.01 mL) dropwise. Stir the resulting reaction mixture for 3 hours. Pour the reaction mixture onto H2O (5 mL). Stir for 5 min till a white precipitate appears, then filter and dry under vacuum to provide 633 mg (76%) of the title compound. Part C would be the reaction of this intermediate with an amine to make the final compound. Example 1 was prepared using Method A; Example 2 used Medthod B.
Reaction SMILES: [Br: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].N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20].Cl>C(Cl)Cl.O>[C:19]([O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Br:1])(=[O:21])[CH3:20]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(OC(C)=O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a stirred suspension of methyl 3-bromo-4-hydroxybenzoate (270 g, 1168 mmol) in DCM (1.5 L) was added pyridine (150 mL). Acetyl chloride (87 mL, 1227 mmol) was then added dropwise at room temperature and under nitrogen. The mixture was left to stir for 2 hrs at room temperature. Water (1 L) was then added followed by HCl 2N until pH 1. The organic layer was then washed with water, brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford methyl 4-acetoxy-3-bromobenzoate (300 g, 94%) as a white powder. NMR Spectrum: (DMSOd6) 2.34 (s, 3H), 3.87 (s, 3H), 7.47 (d, 1H), 8.01 (dd, 1H), 8.20 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]([O:38]CC3C=CC(OC)=CC=3)[CH:17]([CH2:25][CH2:26][N:27]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:37])[C:18]([O:20]C(C)(C)C)=[O:19])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH:16]([OH:38])[CH:17]([CH2:25][CH2:26][N:27]3[C:28](=[O:37])[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:35]3=[O:36])[C:18]([OH:20])=[O:19])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(CCc2ccc(-c3ccc(Cl)cc3)cc2)C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(O)CCc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of the compound (120 mg) obtained from step 8 above in dichloromethane (5 ml) was added trifluoroacetic acid (2 ml) and stirred the reaction mixture for 2 hours at room temperature. The solvent was evaporated under reduced pressure and the residue thus obtained was purified by preparative thin layer chromatography (eluant: 60% ethyl acetate in hexane) to furnish the title compound (68 mg).
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])CC1C=CC=CC=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15].N[C@H](C(O)=O)CC1C=CC(O)=CC=1.N[C@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][CH2:2][C:10](=[O:11])[OH:12]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C[C@H](N)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
1.02 His: 0.95 Phe: 0.95 Ala: 2.00 Tyr: 0.91 Leu: 1.00 Arg: 0.90 Pro: 0.96
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[CH3:15][C@H:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[C:17]1([C@@H:16]([N:23]2[C:10](=[O:11])[C:5]3[C:6](=[CH:12][CH:13]=[CH:14][C:4]=3[N+:1]([O-:3])=[O:2])[C:7]2=[O:9])[CH3:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: C[C@H](N)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@@H](c1ccccc1)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 180 °C
Yield: 74.9 %

Procedure:
386 mg of 3-nitrophthalic anhydride and 242 mg of (S)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 1.5 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 443 mg of the desired product as a light yellow powder. Yield: 75%. m.p. 115-117° C.; MS(EI+) 296(M)+
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[Br:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:17]=[CH:18][C:19](O)=O>>[Br:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)cc1Br
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)cc1Br
Yield: 43.3 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.00 g (11.8 mmol) of 5,6-diamino-1,3-dimethyluracil and 3.32 g (12.9 mmol) of 3-bromo-4-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide to give 2.00 g (yield 43%) of Compound 120 as a pale yellow powder.