Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O>O.C(O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[N:2][OH:3])[CH2:10][CH3:9])=[CH:14][CH:15]=1
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(=NO)c1ccc(OC)cc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of hydroxylamine hydrochloride (3.33 grams, 48 mmol) and sodium acetate (4.92 grams, 60 mmol) in 20 milliliters of water was added to a stirred solution of 4-methoxypropiophenone (5.26 grams, 30.0 mmol) in a mixture of water (30 milliliters) and ethanol (30 milliliters), a further 20 milliliters of ethanol was added to get a homogenous solution, which was stirred overnight. The resulting slurry was filtered, the filtrate was partially concentrated, to remove the ethanol and a white solid precipitated. The slurry was filtered and the solid was washed with water, and dried in vacuo (25° C., <1 mm) to afford 5.26 grams (98%) of product as a white solid: 1H NMR (CDCl3) δ7.64-7.42 (m , 2H), 7.04-6.81(m, 2H), 3.82(s, 3H), 2.81(q , J=7.6 Hz), 2H), 1.17(t , J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][C:20]([OH:22])=O)[CH:9]=[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:29]([OH:36])=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:27]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CC#N>[CH2:14]([O:13][C:10]1[CH:9]=[C:8]([CH:18]=[CH:19][C:20]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([C:32]([CH3:33])([CH3:35])[CH3:34])[C:29]([OH:36])=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:27]=2)=[O:22])[CH:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:11]=1[OH:12])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1cc(C=CC(=O)O)cc(OCCCC)c1O
Reactant: CC(C)(C)c1cc(CCN)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CCCCOc1cc(C=CC(=O)NCCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(OCCCC)c1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.5 %

Procedure:
To the solution of 3-(3,5-dibutoxy-4-hydroxyphenyl)acrylic acid (130 mg, 0.421 mmol), 4-(2-aminoethyl)-2,6-di-t-butylphenol (110 mg, 0.441 mmol) and HOBT (70 mg, 0.51 mmol) in MeCN 10 ml were DCC at 0° C. After 5 minutes, the solution was stirred for 2 hours at room temperature. And then the precipitate was removed by filtering it through a celite layer and the solution was poured into CH2Cl2. The solution was washed with 2N HCl and saturated NaHCO3 solution and the water was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by column chromatography (EtOAc:Hexane=1:3), yielding 208 mg (91%) of the title compound.
Reaction SMILES: C(OC(=O)N[C:8](=[O:40])[CH2:9][CH2:10][CH2:11][C@H:12]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)(C)C.[BH4-].[Na+]>CC(O)C.O>[C:36]([O:35][C:33](=[O:34])[NH:32][C@@H:12]([CH2:11][CH2:10][CH2:9][CH2:8][OH:40])[CH2:13][O:14][Si:15]([C:28]([CH3:29])([CH3:30])[CH3:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC(=O)CCC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a stirred solution of the material from Step 3 (128 g, 219 mmol) in 2-propanol (1800 mL) and water (180 mL) at room temperature was added sodium borohydride (8.28 g, 219 mmol). The reaction mixture was stirred at room temperature overnight. Additional 2 g of sodium borohydride was added and stirred at room temperature for an additional 4 hours. The reaction mixture was concentrated to ⅓ volume and diluted with EtOAc and 1 N NaOH (100 mL). The reaction mixture was partitioned, and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel using EtOAc-hexanes (0 to 50%) to afford 65 g of the title compound. 1H NMR (CHCl3-d): δ 7.67-7.62 (m, 4H), 7.45-7.35 (m, 6H), 4.72-4.65 (b, 1H), 3.72-3.62 (m, 2H), 3.60-3.52 (m, 3H), 1.62-1.42 (m, 4H), 1.42 (s, 9H), 1.42-1.23 (m, 2H), 1.05 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:20])=[O:19])[CH:14]=3)[CH:9]=2)[CH:2]=1.C(=O)(O)[O-].[Na+:25]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([O-:20])=[O:19])[CH:14]=3)[CH:9]=2)[CH:2]=1.[Na+:25]
Reactant: O=C(O)c1ccc2cc(Cc3cccnc3)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C([O-])c1ccc2cc(Cc3cccnc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-pyridylmethyl)naphthalene-6-carboxylic acid is dissolved in methanol and to this solution a stoichiometric amount of sodium bicarbonate dissolved in water is added. The mixture is stirred at room temperature for one hour, azeotroped with benzene twice and dried under high vacuum for 3 hours. The solid material is recrystallized from methanol and diethyl ether mixture and dried in vacuum at room temperature overnight to give sodium 2-(3-pyridylmethyl)naphthalene-6-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH:25]3[CH2:27]O3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:10][C:9]=1[O:28][CH2:29][O:30][CH3:31])([CH3:4])([CH3:3])[CH3:2].NC(N)=[S:35]>C(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH2:24][CH:25]3[CH2:27][S:35]3)(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:10][C:9]=1[O:28][CH2:29][O:30][CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(N)=S
Reactant: COCOc1cc(Oc2ccc(S(=O)(=O)CC3CO3)cc2)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: COCOc1cc(Oc2ccc(S(=O)(=O)CC3CS3)cc2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
To a solution of 20 (0.40 g, 0.86 mmol) in CH2Cl2 (5 mL) was added a mixture of thiourea (0.10 g, 1.3 mmol, 99%) in methanol (5 mL). The resulting mixture was stirred for 24 h at room temperature, after which the solvent was removed under reduced pressure. The residue was partitioned between CH2Cl2 and water. The organic layer was dried over anhydrous Na2SO4 and was filtered. Evaporation of solvent and purification by silica gel chromatography (hexanes/EtOAc=4/1) gave 0.34 g of 21 (83%). 1H NMR (500 MHz, CDCl3) δ 1.53 (s, 9H), 2.14 (dd, J=1.8, 5.0 Hz, 1H), 2.52 (dd, J=1.5, 5.9 Hz, 1H), 3.04 (dq, J=5.6, 7.8 Hz, 1H), 3.15 (dd, J=8.0, 14.2 Hz, 1H), 3.47 (s, 3H), 3.51 (dd, J=5.6, 14.4 Hz, 1H), 5.19 (s, 2H), 6.72 (dd, J=2.6, 8.8 Hz, 1H), 6.91 (d, J=2.6 Hz, 1H), 7.08-7.01 (m, 3H), 7.85-7.80 (m, 2H), 8.16-8.08 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 24.4, 26.2, 28.5, 56.6, 62.7, 80.8, 95.3, 107.3, 114.1, 117.3, 119.4, 126.2, 130.8, 131.6, 146.6, 149.3, 152.8, 163.5. HRMS (FAB) calcd for C22H28NO7S2 (M+H+) 482.1302. found 482.1301.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH:16]3[CH:14]([C:15]3([C:19]3[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)[CH3:18])[CH2:13]2)=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:12]2[CH2:13][CH:14]3[CH:16]([C:15]3([C:19]3[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH3:18])[CH2:17]2)=[CH:4][CH:3]=1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3ccc(F)cc3)CC21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCc3ccc(F)cc3)CC21
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
To a solution of N-(3-{3-[3-(4-fluorophenyl)propanoyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide (Preparation 118, 86 mg, 0.21 mmol) in anhydrous tetrahydrofuran (2 ml) under a nitrogen atmosphere at 0° C. was added dropwise lithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.42 ml, 0.42 mmol) and the mixture was stirred at room temperature for 3 h. The rapidly stirred reaction mixture was treated sequentially with water (0.42 ml), sodium hydrogen carbonate (400 mg) and ethyl acetate (10 ml). After 30 min the reaction mixture was filtered and concentrated in vacuo to afford a colourless oil. The oil was purified by preparative HPLC (condition 8) to give a pale yellow oil which was partitioned between dichloromethane (10 ml) and aqueous potassium carbonate solution (4% w:v, 5 ml). The layers were separated and the organic layer was washed with water (3 ml), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a colourless oil (52 mg, 62%). The free base (45 mg, 0.112 mmol) was dissolved in anhydrous diethyl ether (5 ml) and dichloromethane (1 ml) and the solution was treated with hydrogen chloride (1.0M solution in diethyl ether, 0.123 ml). The heterogeneous suspension was concentrated in vacuo to afford the hydrochloride salt of the title compound as a white solid (46 mg, 94%).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][C@@H:31]([C:39]([OH:41])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C[O-].[Na+]>COCCO.C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][C@H:31]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]([OH:41])=[O:40])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.16 mmol), D-phenylalanine (514 mg, 3.1 mmol), and NaOMe (126 mg, 2.3 mmol) in 2-methoxyethanol (10 mL) was refluxed for 2 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 36 mg of the title compound as a dull yellow solid. MS: (+) m/z 520.27 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=O)[CH:33]=2)=[CH:4][N:3]=1.[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:42]([CH2:43][CH3:44])[CH2:40][CH3:41])[CH:33]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(-c4cccc(C=O)c4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CCNCC
Product: CCN(CC)Cc1cccc(-c2cnc(N)c3c(-c4ccc(NC(=O)c5cc6ccccc6n5C)c(OC)c4)csc23)c1

Procedure:
The title compound was prepared using N-{4-[4-amino-7-(3-formylphenyl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide, N,N-diethylamine, and General Procedure B. 1H NMR (DMSO-d6, 400 MHz) δ 9.53 (s, 1H), 8.02 (d, 1H), 7.92 (s, 1H), 7.71 (d, 1H), 7.67 (s, 1H), 7.64 (m, 2H), 7.60 (s, 1H), 7.52 (m, 1H), 7.47 (t, 1H), 7.35 (m, 1H), 7.32 (m, 1H), 7.24 (m, 1H), 7.15 (m, 1H), 7.12 (m, 1H), 5.62 (br, 2H), 4.05 (s, 3H), 3.92 (s, 3H), 3.62 (s, 2H), 2.53 (qt, 4H), 1.02 (t, 6H); MS: (MH)+ 590.
Reaction SMILES: Br[C:2]1[C:3]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[O:21][CH3:22])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].O.[CH3:24][O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:3]2[C:2]([C:31]3[C:26]([O:25][CH3:24])=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=2)=[C:15]([O:21][CH3:22])[CH:16]=1
Reactant: COC(=O)c1cc(Br)c(Oc2ccc(Cl)cc2OC)cc1F
Reactant: COc1ncccc1B(O)O
Solvent: O
Product: COC(=O)c1cc(-c2cccnc2OC)c(Oc2ccc(Cl)cc2OC)cc1F
Temperature: 50 °C
Yield: 27 %

Procedure:
Prepared according to Preparation 2 using methyl 5-bromo-4-(4-chloro-2-methoxyphenoxy)-2-fluorobenzoate (Preparation 17, 0.165 g, 0.423 mmol) and (2-methoxypyridin-3-yl)boronic acid mono hydrate (0.109 g, 0.637 mmol) with an extra addition of water (0.5 mL) and heating for 18 hours at 50° C. The crude product was purified by silica gel chromatography eluting with 0 to 10% EtOAc in DCM to afford the title compound as a clear gum (47.7 mg).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:10]=2[C:9](=[O:19])[C:8]2[C:3]1=[CH:4][C:5]([OH:20])=[CH:6][CH:7]=2.S(=O)(=O)(O)O.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:20][C:5]1[CH:4]=[C:3]2[C:8]([C:9](=[O:19])[C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][C:15]=3[C:2]2=[O:1])=[CH:7][CH:6]=1)(=[O:28])[CH3:27]
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1cc(O)ccc1C2=O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc2c(c1)C(=O)c1cc(C(=O)O)ccc1C2=O
Reaction time: 6 h

Procedure:
9,10-Dihydro-9,10-dioxo-7-hydroxyanthracene-2-carboxylic acid (36.39 g) was suspended in glacial acetic anhydride (364 ml). Concentrated sulphuric acid (5 ml) was added and the mixture was stirred magnetically at 110°±5° C. for 6 hours in a heating mantle.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCC)=[O:23])[C:4]1=[O:27])[CH3:2].[NH2:28][C@H:29]([CH3:32])[CH2:30][OH:31]>>[CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:28][C@H:29]([CH3:32])[CH2:30][OH:31])=[O:23])[C:4]1=[O:27])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Reactant: C[C@@H](N)CO
Product: CCn1c(=O)c(C(=O)N[C@H](C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 85 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.162 mmol) and (2R)-2-amino-1-propanol (0.05 mL) was prepared 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-methylethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (50 mg, 85% yield) as a white solid after purification by reverse phase HPLC. Analytical data was identical to that described in example 576.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:35][CH:36]1[CH2:40][CH2:39][CH:38]([CH3:41])[NH:37]1.O>C(#N)C>[CH3:35][CH:36]1[CH2:40][CH2:39][CH:38]([CH3:41])[N:37]1[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CC1CCC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1CCC(C)N1CC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-Chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and 2,5-dimethylpyrrolidine (81 μl). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. The product was purified by column chromatography using gradient elution with methanol-dichloromethane (2%->5%). 1H-NMR (300 MHz; d6-DMSO) δ: 9.66 (s, 1H), 8.35 (d, 1H, J 2.7 Hz), 8.06 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.32 (m, 5H), 6.93 (d, 1H, J 8.8 Hz), 6.88-6.84 (m, 3H), 5.12 (dd, 1H, J 2.1, 9.9 Hz), 3.22 (s, 2H), 3.05-2.88 (m, 1H), 2.78-2.66 (m, 3H), 2.22-2.12 (m, 1H), 2.08-1.92 (m, 1H), 1.90-1.79 (m, 2H), 1.43-1.34 (m, 2H), 1.06 (d, 6H, J 6.1 Hz).
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[CH2:3][N:4]([C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([NH:12][CH3:13])=[O:11])[C:5](=[O:8])[CH2:6]Cl.C(=O)([O-])O.[Na+].O>CO>[CH3:13][NH:12][C:10](=[O:11])[C@H:9]([N:4]1[CH2:3][C@@H:2]([CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[NH:1][CH2:6][C:5]1=[O:8])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C[C@H](N)Cc1ccc2ccccc2c1)C(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=O)[C@@H](Cc1ccccc1)N1C[C@@H](Cc2ccc3ccccc3c2)NCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
##STR101## (2R)-2-(N-((2R)-2-Amino-3-(2-naphthyl)propyl)-N-chloroacetyl-amino)-N-methyl-3-phenylpropionamide (0.69 g, 1.58 mmol) was dissolved in methanol (14 ml) and sodium hydrogen carbonate (0.40 g, 4.73 mmol) and water (7 ml) were added. The mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was dissolved in a mixture of ethyl acetate (30 ml) and saturated aqueous sodium hydrogen carbonate (20 ml). The mixture was extracted with ethyl acetate (4×20 ml). The combined organic phases were dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was chromatographed on silica (2×20 cm) using methylene chloride/methanol/25% aqueous ammonia (100:10:1) to afford 0.19 g of (2R)-N-methyl-2-((5R)-5-((2-naphthyl)methyl)-2-oxopiperazin-1-yl)-3-phenylpropionamide
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:7]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Nc1ccc(S(=O)(=O)c2cc(-c3cccc(Cl)c3)nc(N3CCCC3)c2)cc1
Yield: 22.7 %

Procedure:
A mixture of 191 mg (0.5 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 84 mg (0.55 mmole) 3-chlorophenylboronic acid, 18 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 2 hours in 7 ml toluene and 2 ml 2N aqueous potassium carbonate. The solvents are removed in vacuo. Flash chromatography (silicagel, ethyl acetate/hexane 1/1) of the residue yields 47 mg (22%) pure 4-[2-(3-chloro-phenyl)-6-pyrrolidine-1-yl-pyridine-4-sulfonyl]-phenylamine as a pale yellow solid mp.: 260-261° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[C:35]([F:38])([F:37])[F:36])[CH2:24][CH:23]2[OH:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[C:35]([F:37])([F:38])[F:36])[CH2:24][C:23]2=[O:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3C(F)(F)F)CC2O)CCCCC1)c1cc2ccccc2o1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3C(F)(F)F)CC2=O)CCCCC1)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-trifluoromethylphenyl)piperidin-3-ol (0.15 g) obtained in Step 1 in 3 ml of dimethyl sulfoxide (DMSO), was added 0.16 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.15 g) was added slowly to the reaction mixture, which was then stirred for about 4 hours at room temperature, diluted with 20 ml of ethyl acetate, washed with brine, and dried and concentrated. The resulting residue was purified with column chromatography to give 84 mg of the titled compound as white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:18][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])[CH:17]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 474 [M+1]+.