Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.[OH-].[Na+]>CS(C)=O>[Br:1][C:10]1[CH:9]=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: Br
Reactant: COc1cccc(N2CCNCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(N2CCNCC2)ccc1Br
Temperature: 65 °C

Procedure:
A solution of 1-(3-methoxyphenyl)piperazine dihydrobromide (3.5 g, 10 mmol) is dissolved in DMSO (30 mL) and heated at 65° C. for 4 h in a flask which is open to the atmosphere. After cooling, the mixture is poured into a separatory funnel containing 100 mL of 1 N sodium hydroxide solution and extracted with ethyl ether (3×100 mL). The organic extracts are dried (Na2SO4), filtered, and concentrated to provide 1-(4-bromo-3-methoxyphenyl)piperazine as a solid. 1H NMR (400 MHz, CDCl3) 7.34-7.36 (d, J=2.2 Hz, 1H,), 6.47 (s, 1H), 6.38-6.41 (d, J=2.8 Hz, 1H), 3.87 (s, 3H, OMe), 3.11-3.13 (m, 4H), 3.01-3.03 (m, 4H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43](O)(=[O:45])[CH3:44]>O1CCCC1>[C:43]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:45])[CH3:44]
Reactant: CC(=O)O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a stirred solution of 3β-hydroxy-5α-pregnan-20-one (4.5 g, 318.5 g/m, 14 mmol) in 150 mL of freshly distilled THF, triphenylphosphine (5.58 g, 262.3 g/m, 21 mmol), and acetic acid (1.22 mL) were added. To this stirred reaction mixture at room temperature was added a solution of diisopropylazidodicarboxylate (DIAD) (4.18 mL, 1.027 g/ml, 202.2 g/m, 21 mmol) in 75 mL of tetrahydrofuran dropwise over a period of 10 minutes. After 30 min., the reaction mixture was concentrated under reduced pressure and redissolved in 100 mL of chloroform and extracted twice with water. The chloroform extract was dried over magnesium sulfate and evaporated. The product residue was purified by flash chromatography on silica gel with a mixture of hexane/ethyl acetate (9:1). Fractions corresponding to the title compound were concentrated to give 4.95 g (97.5%) of 3α-acetoxy-5α-pregnan-20-one as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C@:10]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:14]([CH3:15])[C:13](=[O:16])[N:12]([C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C@:10]1([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH:14]([CH3:15])[C:13](=[O:16])[N:12]([C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:11]1
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CO)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
Tert-butyl(3S)-3-{[tert-butyl(dimethyl)silyloxy]methyl}-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (3.72 g, 8.31 mmol) was dissolved in tetrahydrofuran (70 mL), and tetrabutylammonium fluoride (12.5 mL, 1.0 mol/l solution in tetrahydrofuran, 12.5 mmol) was added dropwise in an ice bath. The mixture was stirred at the same temperature for 1 hour. After concentrating the mixture, saturated aqueous solution of ammonium chloride (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (elusion by hexane:ethyl acetate=3:1→1:2) to obtain 1.87 g (67%) of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[C:15]([NH2:23])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:23]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:22][CH:2]=2)=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=O)c1ccccc1
Product: CS(=O)(=O)c1ccc(-c2coc(-c3ccccc3)n2)cc1
Yield: 27.8 %

Procedure:
The mixture of the 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone (2 g, 7.2 mmol) and benzamide (0.87 g, 7.2 mmol) was heated to 140˜180° C. for 4 hours. When TLC showed that the reaction had completed, the mixture was cooled, and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice, and the combined organic layers were washed with water and brine, dried over MgSO4. After concentration, the residue was purified by column (eluted by PE:EA=10:1) to afford 0.6 g (yield 30%) of 4-[4-(methylsulfonyl)phenyl]-2-phenyl-1,3-oxazole.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20](=O)[CH2:21][CH2:22][C:23]([OH:25])=O)[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:28][NH2:29]>C(O)(=O)C>[C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20]4[CH2:21][CH2:22][C:23](=[O:25])[NH:28][N:29]=4)[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(c2ccc3c(c2)CC(NS(=O)(=O)c2ccccc2)C3)=NN1

Procedure:
3.0 g (8 mmol) of 4-(2-benzenesulphonamido-indan-5-yl)-4-oxobutyric acid and 0.53 g (10.4 mmol) of 99% hydrazine hydrate in 12 ml of glacial acetic acid are boiled for 3 hours. The mixture is evaporated in vacuo, water is added to the residue, which is neutralised with sodium carbonate solution, and the reaction product is filtered off with suction and recrystallised from n-propanol.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](Br)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:11]1([C:7]2[N:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(-c2ccccc2)nc1
Yield: 51 %

Procedure:
5-acetyl-2-bromopyridine 38 (0.656 g, 3.28 mmol), phenylboronic acid (0.800 g, 6.56 mmol), Na2CO3 (0.243 g, 2.29 mmol), Pd(PPh3)2Cl2 (0.115 g, 0.16 mmol, 5% Pd), acetonitrile (26 mL) and H2O (26 mL) were added to 50 mL screw cap pressure vessel. The mixture was stirred, degassed by purging with argon for 15 min, sealed and placed in an 80° C. oil bath for 14 h (overnight). The dark colored mixture was cooled and extracted with ether. The organic layer was filtered through a pad of celite, rinsed with ether, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by flash column chromatography (SiO2, 20 g, 5% EtOAc/hexanes) to afford the coupled ketone 40 as a white solid (0.33 g, 52%): TLC Rf=0.4 (25% EtOAc/hexanes); mp 124.9126.2° C.; 1H NMR (500 MHz, CDCl3) δ 9.22 (d, J=2.0 Hz, 1H), 8.28 (dd, J=8.3, 2.2 Hz, 1H), 8.10-7.99 (m, 2H), 7.83 (d, J=8.3 Hz, 1H), 7.55-7.40 (m, 3H), 2.65 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 196.6, 161.1, 150.2, 138.2, 136.7, 130.9, 130.4, 129.2, 127.6, 120.4, 26.9; IR (neat cm−1) 3062, 2999, 2960, 2322, 1673, 1557, 1382, 1016, 736; HRMS (DART, M++H) m/z 198.0906 (calculated for C13H12NO, 198.0919).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]([CH2:24][CH2:25][CH3:26])[CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([NH2:23])=[CH:18][CH:19]=3)[CH2:14]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>ClCCl.CCN(C(C)C)C(C)C>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]([CH2:24][CH2:25][CH3:26])[CH:13]2[CH2:14][C:15]3[CH:16]=[C:17]([NH:23][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:18]=[CH:19][C:20]=3[CH2:21][CH2:22]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(C)C(=O)Cl
Reactant: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(N)cc2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(NC(=O)C(C)C)cc2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-(1-methanesulfonyl-piperidin-4-ylmethyl)-N-propyl-1,2,3,4-tetrahydro-naphthalene-2,7-diamine (200 μL of a 0.25 M solution in dichloromethane, 50 μmole) was added 220 μL of a 0.25 M solution of isobutyryl chloride in dichloromethane and 30 μL of DIEA. The solution was allowed to stir for 72 h at 25° C. under N2 and was then concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford N-{7-[(1-methanesulfonyl-piperidin-4-ylmethyl)-propyl-amino]-5,6,7,8-tetrahydro-naphthalen-2-yl}-isobutyramide (10.4 mg) 86, [M+H]+=450.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.[Cl:33][CH2:34][C:35](Cl)=[O:36]>C1COCC1>[Cl:33][CH2:34][C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1)=[O:36]
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@H](N)C3)s2)noc1C(F)(F)F
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](NC(=O)CCl)C3)s2)noc1C(F)(F)F
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of ((S)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 26, 79 mg, 0.20 mmol) and triethylamine (69 μL, 0.42 mmol) in THF (3 mL) was treated with chloroacetyl chloride (18 μL, 0.22 mmol), stirred for 1 hr and evaporated to a solid. The solid was triturated and filtered with the aid of water, then air dried to provide the 2-Chloro-N-{(S)-1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-acetamide intermediate as a colorless solid (75 mg, 86%). LC/MS 6.13 min, [M+1]+ 436. The chloroacetyl intermediate (35 mg, 0.08 mmol) was dissolved in acetonitrile (3 mL) containing anhydrous K2CO3, treated with morpholine (14 μL, 0.16 mmol), and stirred for 3 days. The reaction mixture was then evaporated and treated with water to provide an oil which was then triturated with water (3×2 mL), dissolved in EtOAc (4 mL), dried over MgSO4, filtered, and evaporated to afford product as an oil (34 mg, 87%). 1H NMR (CDCl3) 1.62-1.76 (m, 3 H), 1.88-1.98 (m, 1 H), 2.29 (d, J=1.3, 3 H), 2.45-2.48 (m, 4 H), 2.93 (s, 2 H), 3.52 (br s, 1 H), 3.63-3.67 (m, 4 H), 3.72-3.92 (m, 2 H), 3.98-4.08 (m, 1 H), 7.32 (br s, 1 H), 7.41 (s, 2 H). 19F NMR −63.1. LC/MS 4.68 min, [M+1]+ 487.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]1([C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)Cl)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>N1C=CC=CC=1>[C:5]1([C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:3][CH2:2][CH2:1][OH:4])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: OCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: OCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 2.4 %

Procedure:
Ethylene glycol (3.10 g, 49.9 mmol) (Wako Pure Chemical Industries, Ltd.) and triphenylchloromethane (1.39 g, 49.9 mmol) (Wako Pure Chemical Industries, Ltd.) were dissolved in pyridine (6 mL) (Wako Pure Chemical Industries, Ltd.), and the solution was heated to 45° C. and stirred for 2 hours. Water (50 mL) was poured into the reaction solution, and mixture was extracted with toluene (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with an hydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled of funder reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):methanol (Wako Pure Chemical Industries, Ltd.)=9:1), to thereby obtain the title compound (0.37 g, 24% yield).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][C:10]=2[F:24])[C:6]2[S:25][C:26]([CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]=2[C:4](=[O:33])[NH:3]1.Br[CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45])=[O:37].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:24][C:10]1[CH:11]=[C:12]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[C:14]([F:15])[C:9]=1[CH2:8][N:7]1[C:6]2[S:25][C:26]([CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]=2[C:4](=[O:33])[N:3]([CH2:35][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:44][CH3:45])=[O:37])[C:2]1=[O:1]
Reactant: COc1ccccc1C(=O)CBr
Reactant: N#Cc1ccccc1-c1cc(F)c(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)Cn1c(=O)c2cc(CC(F)(F)F)sc2n(Cc2c(F)cc(-c3ccccc3C#N)cc2F)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′,5′-difluorobiphenyl-2-carbonitrile (0.65 g), 2-bromo-1-(2-methoxyphenyl)ethanone (0.34 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.082 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.48 g, 59%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][NH2:11].O1CCOCC1>C(OCC)(=O)C>[NH:10]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[C:8]([NH2:9])=[N:11]1
Reactant: N#Cc1cccnc1Cl
Reactant: NN
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1n[nH]c2ncccc12
Temperature: 150 °C

Procedure:
2-Chloro-3-cyanopyridine (2.77 g), hydrazine (5 mL), and dioxane (100 mL) were combined in a sealed tube and heated at 150° C. for 16 hr. The reaction mixture was cooled to room temperature and concentrated in vacuo to provide a crude residue. The resultant residue was dissolved in ethyl acetate (100 mL) and washed with saturated NaCl solution (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1H-pyrazolo[3,4-b]pyridin-3-ylamine as a yellow solid which was used without further purification.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4](OC)=[O:5].O.[NH2:15][NH2:16]>CCO>[CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH:15][NH2:16])=[O:5]
Reactant: COC(=O)C(SC)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CSC(C(=O)NN)c1ccccc1
Reaction time: 18 h

Procedure:
To a stirred solution of methyl 2-(methylthio)-2-phenylacetate (0.300 g, 1 equiv) in anhydrous EtOH (5 mL) was added hydrazine hydrate (0.15 mL, 2 equiv) and heated to reflux. Stirring was then continued for 18 hours. The reaction mixture was then cooled and the solvents removed under reduced pressure. The crude oil was diluted with EtOAc and washed with H2O and the organic phase dried over Na2SO4, filtered, and the solvents removed under reduced pressure to yield a yellow oil which was purified by flash chromatography on silica gel using ethyl acetate and hexanes. The purified product was a white solid (193 mg, 66%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[ClH:13].Cl.[CH3:15][O:16][C:17]1[CH:31]=[CH:30][C:20]([C:21](=[O:29])[CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:1].[ClH:13].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21](=[O:29])[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:2][C:3]([NH:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:4])[CH2:25][CH2:24]2)=[CH:30][CH:31]=1
Reactant: O=C(CCl)NCc1ccccc1
Reactant: COc1ccc(C(=O)CN2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CN2CCN(CC(=O)NCc3ccccc3)CC2)cc1

Procedure:
A mixture of chloroacetylbenzylamine (3.06 mmol), N-(4-methoxyphenacyl) piperazine dihydrochloride (3 mmol, prepared by using the general preparation 1) and K2CO3 (10.5 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-28), 0.86 g (74%), M+ 381.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([CH2:27][C:28](O)=[O:29])=[O:26])=[CH:21][CH:22]=2)[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([CH3:31])[CH2:16][C:15]1([CH3:39])[CH3:38])(=[O:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([CH2:27][C:28]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:29])=[O:26])=[CH:21][CH:22]=2)[C:17]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH3:31])[CH2:16][C:15]1([CH3:39])[CH3:38])(=[O:13])[CH3:12]
Reactant: COc1ccc(CN)cc1
Reactant: CC(=O)N1c2ccc(NC(=O)CC(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
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: C1CCOC1
Product: COc1ccc(CNC(=O)CC(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc1

Procedure:
Condensation of 4-methoxybenzylamine (5.2 mg) with 1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), under the agency of HATU (19 mg) and N,N-diisopropylethylamine (16 l) in tetrahydrofuran (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2N(O)N=[N:7][C:5]=2[CH:6]=1.O.[CH3:12][N:13]([CH3:16])C=O>O1CCCC1>[CH2:1]1[CH2:2][CH2:3][CH:12]([N:13]=[C:16]=[N:7][CH:5]2[CH2:4][CH2:3][CH2:2][CH2:1][CH2:6]2)[CH2:5][CH2:6]1
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
The subtitled compound was prepared substantially in accordance with the procedure detailed in Example 33, using 0.41 g (0.12 mmol) of S-2-N(t-butoxycarbonyl)amino-3-naphth-2-ylthio propanoic acid, 0.47 g (0.12 mmol) of the subtitled intermediate of Preparation 3B and 0.16 g (0.12 mmol) of HOBT.H2O, and 0.24 g (0.12 mmol) of DCC in 8 mL of tetrahydrofuran and 0.5 mL of dimethylformamide to provide 0.86 g of crude material. This material was purified using flash chromatography (eluent of 10% methanol in methylene chloride) followed by flash chromatography (eluent of 3.5% methanol in methylene chloride) to provide 0.45 g of a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]2[N:8]=[C:7]([NH:18][NH:19][C:20](=O)[CH2:21][CH3:22])[CH:6]=[CH:5][C:4]=2[NH:3]1>CC(O)=O>[CH2:21]([C:20]1[N:8]2[C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:2](=[O:1])[NH:3][C:4]=3[CH:5]=[CH:6][C:7]2=[N:18][N:19]=1)[CH3:22]
Reactant: CCC(=O)NNc1ccc2[nH]c(=O)c(-c3ccccc3)cc2n1
Solvent: CC(=O)O
Product: CCc1nnc2ccc3[nH]c(=O)c(-c4ccccc4)cc3n12
Temperature: 180 °C

Procedure:
A mixture of N′-(6-oxo-7-phenyl-5,6-dihydro-1,5-naphthyridin-2-yl)propanohydrazide (7-3) (70 mg, 0.227 mmol) in AcOH (5 mL) was heated under microwave irradiation at 180° C. for 15 minutes. The solvent was removed under reduced pressure to give 1-ethyl-8-phenyl[1,2,4]triazolo[4,3-a]-1,5-naphthyridin-7(6H)-one (7-4) as pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=3)[CH:32]=2)[O:27]1)[CH2:9][C@@H:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2C(C)=CC=C2C)=[CH:16][CH:17]=1)[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NO.[OH-].[K+]>C(O)C>[NH2:18][C:15]1[N:14]=[CH:13][C:12]([C@@H:10]([OH:11])[CH2:9][N:8]([CH2:25][C@H:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:36]4[CH:37]=[CH:38][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:44][CH:45]=4)[CH:32]=3)[O:27]2)[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CN(C[C@H](O)c2ccc(-n4c(C)ccc4C)nc2)C(=O)OC(C)(C)C)O3)cc1
Agent: NO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CN(C[C@H](O)c2ccc(N)nc2)C(=O)OC(C)(C)C)O3)cc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 57.7 %

Procedure:
To a solution of methyl 4-{(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}benzoate (Example 375, 162 mg, 0.26 mmol) in ethanol (4 mL) was added hydroxylamine monohydrate (182 mg, 2.65 mmol) and 2 N aq. potassium hydroxide (0.66 mL, 1.32 mmol). The mixture was stirred at room temperature for 70 hours and then concentrated in vacuo. Flash chromatography of the residue using 10% methanol/ethyl acetate afforded 80 mg (43%) of the desired product containing trace impurities. This material was taken on without further purification. Mass spectroscopy gave m/z=534.3 [M+H]+ (calc'd exact mass for C30H35N3O6=533.3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=4[Cl:28])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.CN.[CH3:34][N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23](=[O:24])[NH:35][CH3:34])=[CH:21][C:20]=4[Cl:28])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: Cn1c(Nc2ccc(C(=O)O)cc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Nc2nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3n2C)c(Cl)c1

Procedure:
Prepared analogously to example 3c from 4-(5-(4-bromophenylcarbamoyl)-1-methyl-1H-benzimidazol-2-ylamino)-3-chlorobenzoic acid, methylamine (solution in THF), TBTU and TEA in THF.