Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14].[CH2:25]([O:27][C:28](=[O:41])[CH2:29][CH:30]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[C:31]#[C:32][CH3:33])[CH3:26].Cl>CN(C=O)C.O>[CH2:25]([O:27][C:28](=[O:41])[CH2:29][CH:30]([C:34]1[CH:35]=[CH:36][C:37]([O:40][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:38][CH:39]=1)[C:31]#[C:32][CH3:33])[CH3:26]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Reactant: CC#CC(CC(=O)OCC)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(CC(=O)OCC)c1ccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
Cesium carbonate (0.51 g, 1.57 mmol) was added to a solution of 18.2 (216 mg, 0.79 mmol) and phenol 16 (220 mg, 0.79 mmol) in DMF (8 mL). The reaction was stirred at room temperature overnight and then taken up in water (500 mL). The solution was adjusted to pH=4.0 with 1N HCl(aq) and extracted with ethyl acetate (2×25 mL). The combined organics were washed with water, followed by brine. The solvent was removed under reduced pressure and the resulting residue was purified via radial chromatography (20% diethyl ether in hexanes) to yield 304 mg (82%) of 3-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl ester. LC/MSD m/e: 472.0 (M+H); 1H NMR (400 MHz) (CDCl3) δ 8.16 (2H, d, J=8.0 Hz), 7.73 (2H, d, J=8.0 Hz), 7.33 (2H, m), 6.99 (2H, m), 5.01 (2H, s), 4.14 (3H, m), 2.72 (2H, m), 2.48 (3H, s), 1.85 (3H, s), 1.26 (3H, t, J=8.0 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[F:54][C:55]1[CH:62]=[CH:61][C:58]([CH2:59][NH2:60])=[CH:57][CH:56]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([NH:60][CH2:59][C:58]3[CH:61]=[CH:62][C:55]([F:54])=[CH:56][CH:57]=3)=[O:21])=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a solution of 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.32 g, 1.00 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.20 g, 1.30 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.80 mmol) in N,N-dimethylformamide (20 mL) was added 1-hydroxybenzotriazole (0.16 g, 1.20 mmol). The resulting mixture was stirred at ambient temperature for 15 minutes and 4-fluorobenzylamine (0.17 mL, 1.45 mmol) was added. The reaction mixture was kept stirring for 27 hours at ambient temperature, then was diluted with ethyl acetate (300 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography to afford the title compound as a white powder in 58% yield (0.25 g): mp 147-148° C.: 1H NMR (300 MHz. DMSO-6) δ 7.35-7.20 (m, 7H), 7.02-6.96 (m, 2H), 6.00 (s, 1H), 4.55-4.44 (m, 4H), 4.04 (t, J=7.5 Hz, 2H), 3.42 (t, J=7.5 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.8, 162.4, 160.5, 157.3, 155.3, 153.2, 135.5, 133.8, 129.4, 128.9, 128.2, 117.0, 115.7, 47.9, 43.2, 42.0, 41.6, 17.1; MS (ES+) m/z 425.2 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1.[CH:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:19]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[N:18]=2)=[O:21])=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)O)n1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3ccc(C(C)C)cc3)n1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-[2-(Methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]pyridine-2-carboxylic acid (600 mg, 1.98 mmol), 4-isopropylaniline (0.28 ml, 1.98 mmol) and DIEA (1.64 ml, 9.90 mmol) in DMF (10 ml) was treated with HATU (828 mg, 2.18 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (MgSO4), filtered and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 1:1 hexanes:EtOAc) gave the title compound as an oil which crystallized on standing (804 mg, 97%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17].O>C(O)C>[CH2:1]([NH:3][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: CCN
Reactant: O=c1[nH]cnc2cc(Cl)c([N+](=O)[O-])cc12
Solvent: O
Solvent: CCO
Product: CCNc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A 70% aqueous ethylamine solution (40 ml) was added to a solution (70 ml) of 7-chloro-6-nitro-4(3H)-quinazolone (6.31 g, 28.4 mmol) in ethanol and the mixture was heated with stirring at 110° C. for 4 hours in a sealed tube. After cooling to room temperature, the reaction mixture was poured into water and the precipitated crystals were filtered off. The crystals were washed with ethanol and dried to give the title compound (2.6 g, 39%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21]#[N:22])[N:3]=1.[NH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>C(O)(C)C>[CH2:24]([NH:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21]#[N:22])[N:3]=1)[CH2:25][CH:26]=[CH2:27]
Reactant: C=CCCN
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3cccc(F)c3)c2c1
Solvent: CC(C)O
Product: C=CCCNc1nc(C#N)c(-c2cccc(F)c2)c2cc(OC)ccc12
Temperature: 25 °C

Procedure:
To a suspension of 1-chloro-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile (150 mg) in 15 mL isopropanol was added to 6 mL of a 0.81 M solution of 4-amino-1-butene. The mixture was heated to reflux for 4 days, then cooled to room temp and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic solutions were washed with brine (1×), dried over MgSO4, and concentrated. Flash chromatography (3% to 50% EtOAc in hexanes) provided 146 mg of 1-(but-3-enylamino)-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile as a tan solid.
Reaction SMILES: [Si:1]([C:8]1[S:9][C:10]([C:13]2([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O=[C:21]1[CH2:24][CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[Si:1]([C:8]1[S:9][C:10]([C:13]2([OH:19])[CH2:18][CH2:17][N:16]([CH:21]3[CH2:24][CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:22]3)[CH2:15][CH2:14]2)=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Reactant: CC(C)(C)[Si](C)(C)c1ncc(C2(O)CCNCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(N2CCC(O)(c3cnc([Si](C)(C)C(C)(C)C)s3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 8 mL vial, was placed a solution of 4-(2-(tert-butyldimethylsilyl)thiazol-5-yl)piperidin-4-ol (as prepared in the previous step) (80 mg, 0.27 mmol, 1.00 equiv) in dichloromethane (1 mL), tert-butyl 3-oxocyclobutylcarbamate (as prepared in Step B, 128.8 mg, 0.70 mmol, 1.00 equiv) and NaBH(OAc)3 (273 mg, 1.29 mmol, 3.00 equiv). The reaction mixture was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 4 ml, of H2O. The resulting solution was extracted with 3×5 mL of DCM. The combined organic layers washed with 2×5 mL of brine, dried (Na2SO4), and concentrated under vacuum. The title compound was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH:19]=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8]/[C:9](=[CH:19]\[C:18]3[CH:21]=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:16]([O:15][CH3:14])[CH:17]=3)/[C:10](=[O:11])/[C:12](=[CH:19]/[C:18]3[CH:17]=[C:16]([O:15][CH3:14])[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=3)/[O:13][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: COc1cc(/C=C2\Oc3ccc(C)cc3O/C(=C\c3cc(OC)c(OC)c(OC)c3)C2=O)cc(OC)c1OC

Procedure:
Calone is reacted with 3,4,5-trimethoxybenzaldehyde analogously to the reaction conditions of Example 1, giving 7-methyl-2,4-bis[1-(3,4,5-tri-methoxyphenyl)meth-(Z)-ylidene]benzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[CH:39]=[CH:38][C:15]([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]2[C@H:29]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:28][O:27][C:26]2=[O:37])=[O:24])=[CH:14][C:13]=1[CH3:40].CC(C1C=C(C(C)C)C(S([N:56]=[N+:57]=[N-:58])(=O)=O)=C(C(C)C)C=1)C.CC(O)=O>C1COCC1.[Cl-].[Na+].O>[F:11][C:12]1[CH:39]=[CH:38][C:15]([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([N:56]=[N+:57]=[N-:58])[C:23]([N:25]2[C@H:29]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:28][O:27][C:26]2=[O:37])=[O:24])=[CH:14][C:13]=1[CH3:40]
Reactant: Cc1cc(COCCCCCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(COCCCC[C@@H](N=[N+]=[N-])C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
To a cooled (−78° C.) solution of KHMDS (3.49 mL, 1.745 mol, 0.5 M in toluene) in 5 mL of THF was added a cooled (−78° C.) solution of (R)-3-(6-(4-fluoro-3-methylbenzyloxy)hexanoyl)-4-benzyloxazolidin-2-one (0.481 g, 1.163 mmol) in 4 mL of THF. The reaction was stirred at −78° C. under N2 for 1 h. Then a cooled (−78° C.) solution of trisyl azide (0.448 g, 1.454 mmol) in 4 mL of THF was added. After 1-2 min, a solution of HOAc (0.321 g, 5.350 mmol) in 4 mL of THF was added. After warmed slowly to room temperature and stirred for overnight, the reaction mixture was diluted with brine (50 mL) and extracted with dichloromethane (40 mL×3). The combined organic extracts dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.252 g, 48% yield). FT-IR (neat): 2104, 1778, 1704 cm−1.
Reaction SMILES: [F:1][C:2]1[C:18]([F:19])=[CH:17][C:5]2[N:6]([OH:16])[C:7]([C:9]3[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=3)=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:22]I>C1COCC1>[F:1][C:2]1[C:18]([F:19])=[CH:17][C:5]2[N:6]([O:16][CH3:22])[C:7]([C:9]3[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: On1c(-c2cncc(F)c2)nc2cc(F)c(F)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COn1c(-c2cncc(F)c2)nc2cc(F)c(F)cc21
Reaction time: 1 h

Procedure:
To a solution of 5,6-difluoro-2-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-1-ol 0.15 g, 0.0003 mol) in THF (3.5 ml) was added NaH (0.045 g, 0.0011 mol) at room temperature. After stirring for 5 min at room temperature MeI (0.04 mL, 0.00059 mol) was added in one shot and further stirred for another 1 hr. After the consumption of the starting material (by TLC) the reaction mixture was washed with H2O and extracted with EtOAc (2×30 mL). The organic phase was dried and concentrated under vacuum. The crude was washed with Hexanes and further purified by chromatography (5-40% EtOAc/Hexanes) to give the desired compound 372 as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 9.28 (s, 1H), 8.62 (s, 1H), 8.24 (s, 1H), 7.58 (s, 1H), 7.32 (s, 1H), 4.06 (s, 3H). MS (M+1): 280, Purity 99.67%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[C:19](O[IH]C1C=CC=CC=1[IH]OC(=O)C)(=[O:21])C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1([O:21][CH3:19])[C:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][C:6](=[O:9])[CH:7]=[CH:8]1
Reactant: CC(=O)O[IH]c1ccccc1[IH]OC(C)=O
Reactant: COc1ccc(OC)c(NC(=O)OC(C)(C)C)c1
Solvent: CCOC(C)=O
Product: COC1(OC)C=CC(=O)C=C1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
A methanolic (700 mL) solution of compound 2 (29 g, 115 mmol) was cooled in an ice bath before the addition of bis(acetoxyiodo) benzene (62 g, 194 mmol) in six portions over a period of 30 minutes. The solution was stirred in the ice bath for 2 hours then brought to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (1.5 L) and rinsed with water, dilute hydrochloric acid, and brine. The aqueous was back-extracted once with ethyl acetate and the organics combined before drying over anhydrous magnesium sulfate, followed by filtration, and solvent evaporation. The resulting liquid was purified over silica gel using a gradient of ethyl acetate (0 to 2%) in heptane, giving 6.9 g (21%) (3) as a yellow-orange solid. Material was sufficiently pure (approx. 95%) by 1H NMR, which was consistent with that reported in the literature (Synthesis 1998, 775).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6](=[O:37])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:22]([C:34](=[O:36])[CH3:35])[CH:21]=1)[NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH3:4]>CO>[CH2:3]([O:5][C:6](=[O:37])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[C:22]([CH:34]([OH:36])[CH3:35])[CH:21]=1)[NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)=O)c1)NC(=O)c1c(Cl)cccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)O)c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
NaBH4 (12 mg) was added to a solution of 3-acety-1N-(2,6-dichlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester (0.1 g) in MeOH (3 mL) and the mixture was stirred at room temperature for 2 h. The mixture was quenched with 1 N HCl and extracted with CH2Cl2. The extract was washed successively with 1 N HCl and brine, dried and evaporated. The residue was purified by a flash column chromatography (silica gel; eluent: hexanes/EtOAc 3:1) to yield 45 mg of N-(2,6-dichlorobenzoyl)-3-(1-hydroxyethyl)-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester. ESMS: m/z 516 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:6]=[C:5]2[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1.Cl>C(O)(=O)C.[Fe]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[N:8]=[C:7]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:6]=2)=[CH:22][CH:21]=1
Reactant: CCN(CC)c1cc(-c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2n1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: CCN(CC)c1cc(-c2ccc(N)cc2)c2cc(Cl)ccc2n1

Procedure:
179 mg of iron powder were added to a solution of 380 mg of 6-chloro-2-diethylamino-4-(4-nitrophenyl)quinoline in 12.7 ml of glacial acetic acid and then 3.0 ml of concentrated hydrochloric acid were added dropwise, and the mixture was boiled at 70° C. for 2 hours. The solvent was removed by distillation, and the residue was mixed with water and made alkaline with 2N NaOH. This aqueous phase was extracted with ethyl acetate. The product is a dark brown viscous oil.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].Cl[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1.Cl>C(COC)OC>[Cl:19][C:18]1[C:13]([CH2:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:14][CH:15]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:17]=1
Reactant: CC(=O)c1ccccc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Cc1ncc(C(F)(F)F)cc1Cl)c1ccccc1
Reaction time: 0.75 h

Procedure:
To a suspension of 2.6 g (0.065 mol) of sodium hydride 60% in dimethoxyethane at room temperature is added 3.4 mL (0.029 mol) of acetophenone. After 45 min., 5.55 mL (0.038 mol) of 2,3-dichloro-5-(trifluoromethyl)pyridine is added. After 25 min., the reaction mixture is poured over 100 mL of hydrochloric acid 1N, extracted twice with 100 mL of ethyl acetate.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[N:8]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[O:5][C:4]([C:22]([O:24]CC)=[O:23])=[CH:3]1.[OH-].[Na+].O>C(O)C>[O:1]=[C:2]1[C:7]2[N:8]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[O:5][C:4]([C:22]([OH:24])=[O:23])=[CH:3]1
Reactant: CCOC(=O)c1cc(=O)c2c(o1)c1ccccc1n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(=O)c2c(o1)c1ccccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6.0 g (0.017 mole) of ethyl 4,5-dihydro-4-oxo-5-(phenylmethyl)pyrano [3,2-b]indole-2-carboxylate, 80 ml 1% aqueous sodium hydroxide, and 450 ml water was stirred at room temperature for 3 hr. Ethanol (~150 ml) was then added until virtually all of the insoluble material present had dissolved. After washing twice with 250 ml of chloroform, the aqueous layer was filtered by gravity, cooled in ice, and acidified with 4 N hydrochloric acid. The tan precipitate was filtered, digested for 15 min on the steam bath with 100 ml of water and re-filtered while still warm. Recrystallization of the final product from DMF-water yielded a white powder of mpt. 290°-dec.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11].[OH-].[Na+].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].Cl>O1CCCC1.O>[CH2:34]([O:33][C:31]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:18][CH:19]=1)[C:10]([OH:12])=[O:11])=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 27.6 %

Procedure:
A solution of (2S)-2-amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid trifluoroacetate (45 mg, 109 μmol), sodium hydroxide (26.2 mg, 655 μmol), water (100 μL) and tetrahydrofuran (2 mL) was cooled to 0° C. and then benzyl chloroformate (18.7 μL, 131 μmol) was added. The reaction was warmed to 25° C. and stirred for 20 h. The solution was acidified with 1 N aq. HCl solution (1.00 mL) and the crude residue was purified by preparative LCMS to yield the desired product (13 mg, 28%). MF=C20H20N2O7S; LCMS found for C20H21N2O7S (M+H)+: m/z=433.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.Cl.[NH2:10][OH:11].[OH-].[Na+]>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:10][OH:11])[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1cccnc1

Procedure:
3-Pyridinecarboxaldehyde oxime was prepared by treating 3-pyridinecarboxaldehyde (10 mL, 106 mmol) with hydroxylamine hydrochloride (8.10 g, 117 mmol) and 50% aqueous sodium hydroxide (2 mL) in ethanol (100 mL) and water (200 mL) for 17 hours. The solution was adjusted to pH 14 with the addition of 50% (w/w) aqueous sodium hydroxide. The solution was extracted with several portions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 8.3 g of a white solid. The aqueous layers were combined and back-extracted with chloroform (5×1 L) to yield additional product. The total amount of 3-pyridinecarboxaldehyde oxime obtained was 12.24 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[C:4]([N+:17]([O-])=O)[C:3]=1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24].[Cl-].[NH4+]>CO.O.[Zn]>[NH2:17][C:4]1[CH:5]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[C:2]([F:1])[C:3]=1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24]
Reactant: CCOC(=O)Nc1c(F)cc(NCc2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CCOC(=O)Nc1c(N)cc(NCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
To a stirred solution of compound 3 (0.075 g, 0.24 mmol, 1.0 equiv) in methanol (3 mL) was added zinc powder (0.0800 g, 1.22 mmol, 5.00 equiv) followed by ammonium chloride solution (0.065 g, 1.2 mmol, 5.0 equiv) in water (1 mL). The reaction mixture was stirred at RT for 4 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with DCM (10 mL), water (10 mL) and filtered through a pad of celite. The organic layer was separated from filtrate and the aqueous layer was extracted with DCM (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, concentrated under vacuum to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane, 1:4) to afford compound 2A (0.050 g, 71%) as an off-white solid. TLC: 40% EtOAc/Hexane (Rf: 0.20); 1H NMR (400 MHz, CDCl3): δ 7.32-7.29 (m, 2H), 7.04 (t, J=8.8 Hz, 2H), 5.84 (d, J=9.6 Hz, 1H), 5.78 (s, 1H), 4.25-4.18 (m, 4H), 4.04-3.96 (m, 3H), 1.30 (t, J=6.8 Hz, 3H); LC-MS: m/z=322 (M++1) at RT 3.38 (99.0% purity); UPLC purity: 99.5%.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[Na].[C:7]1([C:13](=O)[C:14](OCC)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[OH:15][C:14]1[C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:1](=[O:3])(=[O:2])[N:4]=1
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: NS(N)(=O)=O
Agent: [Na]
Solvent: CCO
Product: O=S1(=O)N=C(O)C(c2ccccc2)=N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
Sulfamide (4.8 g, 50 mmoles) in ethanol (90 ml) was added slowly with stirring under nitrogen to a solution of sodium (1.15 g, 50 mmoles) dissolved in ethanol (35 ml). The suspension was stirred for 15 minutes at room temperature and then ethyl phenylglyoxylate (8.9 g, 50 mmoles) in ethanol (15 ml) was added. After stirring 15 minutes, the mixture was refluxed overnight and concentrated under vacuum. The residue was suspended in diethyl ether, filtered and the collected solid dissolved in water (25 ml). Acidification with hydrochloric acid precipitated the product which was collected by filtration, washed with water and recrystallized from a mixture of acetonitrile (12 ml) and toluene (8 ml) to obtain 4.2 g (40%) of the title compound, mp 202°-4°. Nmr (DMSO-d6): δ 7.29-7.89 (m, 3H), 8.19-8.49 (m, 2H).