Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][CH:7]([CH:14]1[CH2:17][CH2:16]C1)[C:6]([CH:18]=[O:19])=[CH:5]2.[BH3-]C#N.[Na+]>C1COCC1.CC(O)=O>[OH:19][CH2:18][C:6]1[C:7]2([CH2:16][CH2:17][CH2:14]2)[O:8][C:9]2[C:4](=[C:3]([CH3:20])[C:2]([OH:1])=[C:11]([CH3:12])[C:10]=2[CH3:13])[CH:5]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C=C(C=O)C(C1CCC1)O2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)C=C(CO)C1(CCC1)O2
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.5 %

Procedure:
To a stirred solution of 6-hydroxy-5,7,8-trimethyl-2-cyclobutyl-chromene-3-carbaldehyde (250 mg) in 10 mL of THF and 1 mL of AcOH was added NaCNBH3 (305 mg). The reaction mixture was allowed to stir at room temperature for 6 h. The mixture was concentrated and the residue was purified by flash chromatography eluted with 30% ethyl acetate in hexane to give 135 mg of 3-(hydroxymethyl)-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-6-ol as a light yellow solid. 1H-NMR (300 MHz, MeOD) δ=6.52 (s, 1H, C═CH), 4.35 (s, 1H), 2.36 (m, 4H), 2.20-1.75 (m, 11H) ppm. 13C-NMR (75 MHz, MeOD) δ=146.5, 144.5, 137.6, 124.9, 122.2, 119.3, 118.4, 117.0, 80.7, 62.0, 32.7, 14.3, 12.2, 11.2, 10.7 ppm. MS:(m/z)=243.2 (M−18+), 283.1 (M+Na+).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OCC)(=O)C.S(Cl)([Cl:23])=O.Cl>CN(C=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([Cl:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccc([N+](=O)[O-])cc1
Yield: 99.2 %

Procedure:
193.2 g (1 mole) of 4-nitrocinnamic acid and 650 g of ethyl acetate were placed in a reaction vessel. While 200 g of thionyl chloride with some drops of DMF was dropped into the reaction mixtures, the reaction mixtures were refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and was poured into hexane and then the precipitated solid was separated by filtration and dried. 210 g of 4-nitrocinnamoyl chloride was yielded. 64.5 g (0.3 mole) of 4-nitrocinnamoyl chloride and 300 g of acetone were placed in a reaction vessel. The reaction mixtures were heated at 50° C. with stirring under a nitrogen current. 41.73 g (0.3 mole) of 4-nitrophenol, 60 g of pyridine, and 300 g of acetone were added dropwise to the above reaction vessel using a dropping funnel. After the completion of the addition, the reaction mixtures were refluxed with stirring under a nitrogen current for 2 hours. After the reaction, a precipitate was separated by filtration, and the filtrated solid was washed by water and dried. 90 g of light yellow colored needle-like crystals ((4-nitrophenyl)-4-cinnamate)was yielded.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[NH:12][C:6]2=[N:7][CH:8]=[C:9]([NH2:11])[CH:10]=[C:5]2[CH:4]=1.[Cl:15][C:16]1[C:21]([C:22](O)=[O:23])=[C:20]([F:25])[C:19]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:15][C:16]1[C:21]([C:22]([NH:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[NH:12][C:6]3=[N:7][CH:8]=2)=[O:23])=[C:20]([F:25])[C:19]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])=[CH:18][CH:17]=1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cnc2[nH]c(C(F)(F)F)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]c(C(F)(F)F)cc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.5 %

Procedure:
2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (0.040 g, 0.199 mmol), 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (0.064 g, 0.219 mmol), EDCI (0.042 g, 0.219 mmol) and HOBt (0.027 g, 0.199 mmol) were dissolved in DMF (0.6 mL) and stirred at room temperature for 16 hours. The reaction mixture was directly purified by reverse phase HPLC to give 6-chloro-2-fluoro-3-(propylsulfonamido)-N-(2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.050 g, 52%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 12.91 (s, 1H), 10.99 (s, 1H), 9.96 (s, 1H), 8.60-8.56 (m, 1H), 8.56-8.52 (m, 1H), 7.54 (t, 1H), 7.44 (d, 1H), 7.10 (s, 1H), 3.21-3.12 (m, 2H), 1.76 (m, 2H), 0.99 (t, 3H); m/z (ES-MS) 479.1 (100.0%) [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)[CH:20]=[C:19]2[C:15]=1[C:16]([CH3:36])=[CH:17][N:18]2[CH:33]([CH3:35])[CH3:34])=[O:13].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)[CH:20]=[C:19]2[C:15]=1[C:16]([CH3:36])=[CH:17][N:18]2[CH:33]([CH3:34])[CH3:35])=[O:13]
Reactant: COC(=O)c1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(C)cn(C(C)C)c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C(=O)O)cc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 50 °C
Yield: 38.7 %

Procedure:
To a solution of methyl 4-[4-({[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-3-methyl-1-(1-methylethyl)-1H-indol-6-yl]benzoate (30 mg, 0.062 mmol) in MeOH (2 mL) and THF (1 mL) was 3 N NaOH (0.031 mL, 0.185 mmol). The reaction was heated at 50° C. for 12 h, at which time it was allowed to cool to ambient temperature and treated with acidic ice water to bring pH to 6. The solid was filtered and washed several times with water and an 8:2 mixture of acidic (pH2) ice water:MeOH. Purification by reverse phase Gilson HPLC (10-80%, acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column 7 minutes) provided the title compound (12 mg, 0.024 mmol, 39.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.91 (br. s., 1 H) 11.48 (br. s., 1 H) 8.23 (t, J=5.05 Hz, 1 H) 8.02 (d, J=8.34 Hz, 3 H) 7.87-7.94 (m, 4 H) 7.38 (s, 1 H) 7.32 (d, J=1.52 Hz, 1 H) 5.87 (s, 1 H) 4.91 (quin, J=6.63 Hz, 1 H) 4.36 (d, J=4.80 Hz, 2 H) 2.24 (s, 3 H) 2.18 (s, 3 H) 2.11 (s, 3 H) 1.44 (d, J=6.57 Hz, 6 H). MS (ES) [M+H]+ 486.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[C:21]1([CH3:30])[C:22]([C:27](Cl)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:30])=[O:28])[CH2:2][CH2:3]2)[N:14]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Product: Cc1ccccc1C(=O)N1CCC(COc2cccc3nc(N)nc(N)c23)CC1
Yield: 70 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using o-toluoyl chloride (57 mg; 0.37 mmol) via Method AA to yield 101 mg. (70% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.35 (t, J=8.4 Hz, 1H), 7.25 (m, 6H), 6.76 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.59 (br d, J=13.2 Hz, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.3 (m, 1H), 3.04 (t, J=11.6 Hz, 1H), 2.88 (t, J=12.0 Hz, 1H), 2.23 (m, 4H), 1.89 (br d, J=13.2 Hz, 1H), 1.69 (m, 1H), 1.24 (m, 2H). MS m/z (ESI) 392 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.Cl[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11].O>CC(N(C)C)=O>[CH3:1][N:2]1[C:6]([NH:7][C:10](=[O:11])[O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1cc(N)n(C)n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)n(C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 1,3-dimethyl-1H-pyrazol-5-amine (500 mg, 4.50 mmol) in dimethylacetamide (15 ml) was added 2,2,2-trichloroethyl chloroformate (0.747 ml, 5.40 mmol) with ice-cooling, and the mixture was stirred at 0° C. for 1 hour. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 526 mg (40.8%) of the desired product as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:18]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)c2ccccc2)c(O)c1
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
To a suspension of 4-amino-3-hydroxybenzoic acid (7.66 g, 50.0 mmol) in THF (100 mL) was added pyridine (4.3 mL, 53.2 mmol, 1.06 eq) followed by benzoyl chloride (6.1 mL, 52.6 mmol, 1.05 eq) at 0° C. After 5 min, the reaction was quenched with H2O then extracted with CH2Cl2 (4×80 mL). Crude product precipitated out of organic layer then was collected by filtration to afford 4-benzamido-3-hydroxybenzoic acid (10.1 g, 39.3 mmol, 79%). The product was carried over to next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[O:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>CCO.O>[CH:12]([NH:11][C:8]1[O:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1)([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1coc(NC(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Nc1nc(C(=O)O)co1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To 2-isopropylamino-oxazole-4-carboxylic acid ethyl ester (2.5 g, 10.9 mmol) in EtOH (42 mL) and water (28 mL) was added NaOH (3.1 g, 77.4 mmol). The mixture was stirred at rt for 16 h, then cooled in an ice-bath and acidified to pH 3 with conc. HCl. The mixture was concentrated in vacuo to remove ethanol. The remaining aqueous phase was extracted with CH2Cl2 (3×200 mL). The organic phases were combined, dried over MgSO4 and concentrated to give 2-isopropylaminooxazole-4-carboxylic acid (1.86 g, 87% yield). LCMS found 171 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:3])[CH3:2].C(SCC(OC)CNS(CCC[I:60])(=O)=O)CCCCCCCCCCCCCCC>>[C:1]([NH:4][CH:5]([CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][I:60])(=[O:28])=[O:27])[CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)NC(C)=O
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)NC(C)=O

Procedure:
2-Acetamido-3-(3-chloropropylsulfonylamino)-1-hexadecylthiopropane IIIg2 is allowed to react and worked up by the same procedure as described in (5). m.p. 75°-76° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:20]1[CH2:28][CH2:27][CH2:26][C@H:21]1[C:22]([O:24][CH3:25])=[O:23]>>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([N:20]1[CH2:28][CH2:27][CH2:26][C@H:21]1[C:22]([O:24][CH3:25])=[O:23])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
Cbz-L-LeuOH (0.01 mol) was coupled to L-ProOMe (0.01 mol) to form Cbz-L-Leu-L-ProOMe which was then deesterified to yield Cbz-L-Leu-L-ProOH, using the procedure outlined in Example 8 for the preparation of Cbz-L-Asn-L-(O-t-butyl)-ThrOH.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:28](=[O:27])[C:23]5=[CH:22][C:21]([F:20])=[CH:31][CH:30]=[C:24]5[C:25]4=[O:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: ClCCl
Product: O=C1c2ccc(F)cc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.63 g, 0.01 mole) and 4-fluorophthalic anhydride (1.83 g, 0.011 mole) in dichloromethane (100 ml) is stirred at room temperature for 4 hours. The solvent is then removed under reduced pressure and the residual solids are purified by flash chromatography. The product is further purified by recrystallization to afford N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-fluorophthalimide.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C:13]1[O:14][C:15]([CH2:18][CH3:19])=[CH:16][N:17]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:18]([C:15]1[O:14][C:13]([CH2:12][CH2:11][NH2:10])=[N:17][CH:16]=1)[CH3:19]
Reactant: CCc1cnc(CCNC(=O)OCc2ccccc2)o1
Agent: [Pd]
Solvent: CO
Product: CCc1cnc(CCN)o1
Reaction time: 5 h

Procedure:
2.86 g (10.43 mmol) benzyl[2-(5-ethyl-oxazol-2-yl)-ethyl]-carbamate are placed in 130 ml of methanol, 0.910 mg palladium/charcoal 10% are added, then the mixture is hydrogenated for 5 hours at ambient temperature under a pressure of 14 psi. Then the catalyst is removed by suction filtering, and the solution is evaporated down.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([CH2:42][N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(CN3CCCC3)ccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(CN4CCCC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and Compound 109A. MS (ES+): m/z 663.51 (100) [MH+]; HPLC: tR=0.74 min (UPLC, purity).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][NH:25]C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>FC(F)(F)C(O)=O.ClCCl>[NH2:25][CH2:24][C@H:16]([NH:15][C:13]([O:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[O:14])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Yield: 93.7 %

Procedure:
A solution of 8.7 g (19.22 mmol) of tert-butyl (S)-2-(1-adamantylmethyloxycarbonylamino)-3-tert-butoxycarbonylamino-propionate in 180 ml of trifluoroacetic acid/dichloromethane (1:1) was added after 1 min to 1.5 l of ice-cold NaHCO3 solution, the mixture was extracted three times with dichloromethane and the dichloromethane phases were then dried over sodium sulfate. After filtration and removal of the solvent in vacuo, 6.35 g (94%) of tert-butyl (S)-3-amino-2-(1-adamantylmethyloxycarbonylamino)-propionate were obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Yield: 27.7 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)pentanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (665 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.9 ml) and 1-methyl-2-chloropyridinium iodide (1.05 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)pentanamide (387 mg).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([CH2:9][O:10][CH:11]([CH3:13])[CH3:12])[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.[CH3:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>C(#N)C>[CH:11]([O:10][CH2:9][C:4]1[CH:5]=[C:6]([N:56]2[CH2:57][CH2:58][N:53]([CH3:52])[CH2:54][CH2:55]2)[N:7]=[C:2]([NH2:1])[N:3]=1)([CH3:13])[CH3:12]
Reactant: CN1CCNCC1
Reactant: CC(C)OCc1cc(=O)[nH]c(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)OCc1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14 %

Procedure:
To a solution of 2-amino-6-isopropoxymethyl-3H-pyrimidin-4-one (0.050 g, 0.27 mmol) in acetonitrile (2.37 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.157 g, 0.355 mmol), DBU (0.82 mL, 0.55 mmol), and 1-methyl-piperazine (0.091 ml, 0.82 mmol). The reaction mixture was stirred at rt for 12 h, then at 60° C. for 3 h. The mixture was concentrated and the resultant residue was purified (2 M NH3 in MeOH/CH2Cl2) to yield a white solid (10 mg, 14%). MS (ESI): mass calcd. for C13H23N5O, 265.4; m/z found, 266.3 [M+H]+. 1H NMR (MeOD): 6.55 (s, 1H), 4.49 (s, 2H), 3.78 (quintet, J=6.1, 1H), 3.70-3.00 (m, 8H), 2.95 (s, 3H), 1.25 (d, J=6.1, 6H).
Reaction SMILES: [H-].[Na+].[C:3]1([C:18]([O:20]CC)=O)[C:4](C(OCC)=O)=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[CH:10]C=C2.C(OCC)(=[O:25])C>>[C:18]1(=[O:20])[C:3]2[C:12](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:11](=[O:25])[CH2:10]1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1ccc2ccccc2c1C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: O=C1CC(=O)c2ccccc21
Reaction time: 0.12 h

Procedure:
To a 50% dispersion of sodium hydride in mineral oil (4.55 g) was added to a solution of diethyl naphthalene 1,2-dicarboxylate (18.5 g) in ethyl acetate (22 ml.) and the mixture refluxed for 3.5 hrs. on a steam bath. After cooling the precipitated orange solid was filtered and decarboxylated with hydrochloric acid (35 ml.) in water (350 ml) at 70° C over 7 mins. to yield benze(e) indane-1,3-dione, m.p. (benzene) 178° C (decomp.) (Found: C, 79.21; H, 4.22; C13H8O2 requires: C, 79.58; H, 4.11%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](=[O:20])[N:16]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])[CH:15]=1)=[O:13].CN(C(ON1N=NC2[CH:40]=[CH:41][CH:42]=[N:43]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:43][CH:42]2[CH2:40][CH2:41]2)=[O:8])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](=[O:20])[N:16]([C:21]2[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=2[Cl:27])[CH:15]=1)=[O:13]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(Cl)c(NC(=O)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(C(=O)NC2CC2)ccc1Cl)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a solution of 4-chloro-3-({[1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinyl]carbonyl}amino)benzoic acid (1.74 g) in DMF (17 mL) were added HATU (3.03 g), cyclopropanamine (680 mg) and iPr2NEt (3.08 g) successively at 0° C., and the mixture was stirred at room temperature for 16 hr under a nitrogen atmosphere. The mixture was partitioned between EtOAc (50 mL) and 1 M HCl (50 mL), and the precipitates produced were removed by filtration. The organic layer of the filtrate was separated and washed with 1 M HCl (50 mL), saturated aqueous NaHCO3 (50 mL×2) and brine successively, dried over MgSO4 and filtered. The filtrate was evaporated in vacuo, and the residue was triturated with a mixture of IPE and MeOH. The precipitates were collected by filtration, triturated with EtOH and collected by filtration to give N-{2-chloro-5-[(cyclopropylamino)carbonyl]phenyl}-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide (890 mg).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Al+3].[Cl-:10].[Cl-].[Cl-].ClCl.Cl>C(Cl)(Cl)Cl>[Cl:10][C:7]1[CH:8]=[C:4]([C:1](=[O:3])[CH3:2])[S:5][CH:6]=1
Reactant: [Cl-]
Reactant: CC(=O)c1cccs1
Agent: Cl
Agent: ClCl
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(Cl)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
2-Acetylthiophene (21.6 ml, 0.20 mol) was dissolved in chloroform (200 ml) at −10° C. AlCl3 (54 g, 0.40 mole) was added in small portions at such a rate as to keep temperature below 5° C. A saturated solution of chlorine, Cl2, in chloroform (100 ml) was then added dropwise at −10° C. over a period of 30 minutes. After the addition was completed, the reaction mixture was immediately poured into a mixture of 1 L ice water and 500 ml of 1 N HCl and stirred for 30 minutes. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to a yellow liquid. NMR analysis showed this to be a 3:1 mixture of 4-chloro-2-acetylthiophene and 4,5-dichloro-2-acetylthiophene. Partial purification was achieved by a Kugelrohr distillation, yielding 4-chloro-2-acetylthiophene (31 g, 83% pure, 80% yield). This material was used without further purification in the next step. 1H NMR (300 MHz, CDCl3) δ7.53 (1H, d, J=1.2 Hz), 7.41 (1H, d, J=1.2 Hz), 2.54 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][CH:37]([NH:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]4[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=4)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4ccc(O)cc4)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-phenol and Reference Example 73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 101-106° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.15-1.30 (m, 2H), 1.70-1.90 (m, 2H), 2.50-2.90 (m, 5H), 3.61 (s, 3H), 3.63 (s, 3H), 3.60-3.90 (m, 5H), 6.45 (dd, 1H), 6.60-6.80 (m, 8H), 6.90 (d, 1H), 7.45 (d, 1H); MS (ES) m/z: 557.9 (MH+); HRMS Calcd. for C28H36N3O7S (MH+): 558.2274. Found: 558.2293.