Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:32]([OH:35])([CH3:34])[CH3:33])=[N:4][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[CH:31]=[N:30][CH:29]=[CH:28][N:27]=4)([N:11]=[C:12]([NH:17]C(=O)C4C=CC=CC=4)[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.[OH-].[Li+]>CO>[NH2:17][C:12]1[S:13][CH2:14][C@@H:15]2[CH2:16][N:8]([C:5]3[N:4]=[C:3]([C:32]([OH:35])([CH3:33])[CH3:34])[C:2]([F:1])=[CH:7][N:6]=3)[CH2:9][C@:10]2([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)[N:11]=1
Reactant: CC(C)(O)c1nc(N2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cnccn3)C2)ncc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)c1nc(N2C[C@H]3CSC(N)=N[C@@]3(c3cnccn3)C2)ncc1F
Temperature: 60 °C
Yield: 56.1 %

Procedure:
N-[(4aR,7aR)-6-[5-fluoro-4-(1-hydroxy-1-methyl-ethyl)pyrimidin-2-yl]-7a-pyrazin-2-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (330 mg, 0.668 mmol) is dissolved in methanol (8 mL) with stirring. Lithium hydroxide (42.51 mg, 1 mmol) is added and the reaction is heated at 60° C. for 5 hours 30 minutes. The reaction is cooled to room temperature and loaded onto a silica gel column. The column is eluted with a 0-5% gradient of 0.14 M ammonia/methanol in dichloromethane. The product obtained is further purified by preparative HPLC using a 10% B to 100% B gradient over 9 minutes at 60 mL/minute (column=Phenomenex Gemini NX C18, 30×100 mm, 5 μm. Mobile phase A: water with 10 mM ammonium bicarbonate, pH adjusted to pH 10 with ammonia. Mobile phase B: acetonitrile) to give the title compound (146 mg, 56%). ES/MS (m/e): 390 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:34][CH2:35][OH:36]>C(O)C.C(Cl)Cl>[OH:36][CH2:35][CH2:34][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1
Reactant: OCCBr
Reactant: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCNCC4)cc23)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(CCO)CC4)cc23)cn1
Temperature: 80 °C
Reaction time: 13 h

Procedure:
4-(6-Methoxy-pyridin-3-yl)-1H-indole-2-carboxylic acid piperidin-4-ylamide (181), 150 mg, 0.43 mmol) is dissolved in 3 ml of ethanol under argon. After addition of sodium carbonate (182 mg, 1.7 mmol) and 2-bromo-ethanol (61 ul, 0.85 mmol), the reaction mixture is stirred at 80° C. for 13 h. The mixture is diluted with methylene chloride, filtrated and the filtrate is evaporated. Evaporation under reduced pressure gave 128 mg of crude product, which is further purified by Flash-chromatography (dichloro methane/methanol/25% ammonia (90:9:1). Yield: 90 mg (53%). MS (ESI): 395.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:23])([F:24])[F:25])[CH2:9][C:10]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C(F)(F)F
Product: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C(F)(F)F)ccn1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-(2-trifluoromethyl-phenyl)-propionamide and 4-bromo-2-methylpyridine was prepared the title compound as a white solid, MS (ESI+): m/z=448.0 ([M+H]+, 1Br).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13]([S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH2:14].C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:14]=[CH:13][S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(SCl)cc1
Reactant: C=CS(=O)(=O)C=C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)C=CSc1ccc(C(C)(C)C)cc1

Procedure:
In a manner analogous to Example 1, 4-t-butylphenylsulfenyl chloride was added in 1:1 proportion to divinyl sulfone, subjected to treatment with triethylamine in benzene, and purified by column chromatography. The product, vinyl 2-(4-t-butylphenylthio)vinyl sulfone, was obtained as a brown oil which crystallized on standing, m.p. 62-64° C; calculated for C14H18O2S2 :S, 22.7; found: S, 22.0; Cl, O.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[C:28](I)[C:27]([F:31])=[CH:26][N:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:28]2[C:27]([F:31])=[CH:26][N:25]=[C:24]([Cl:23])[CH:29]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: Fc1cnc(Cl)cc1I
Product: Cc1ccccc1C(CC(=O)c1cc(Cl)ncc1F)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) and 2-chloro-5-fluoro-4-iodopyridine (CAS RN: [659731-48-3]) was prepared the title compound as a white solid, MS (ESI−): m/z=430.0013 ([M−H]−, 1Br).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH2:18]([O:25][CH:26]1[CH2:29][C:28](=O)[CH2:27]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:18]([O:25][CH:26]1[CH2:29][C:28](=[CH:9][C:7]#[N:8])[CH2:27]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CC(OCc2ccccc2)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC(OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a mixture of 1.0000 M of potassium tert-butoxide in tetrahydrofuran (0.68 mL) and THF (5 mL) was added, at 0° C., diethyl cyanomethylphosphonate (0.11 mL, 0.00068 mol) dropwise. The reaction was warmed to rt and 30 min later cooled to 0° C. again. To the reaction mixture was added a solution of 3-(benzyloxy)cyclobutanone (0.1 g, 0.0006 mol) in THF (5 mL). The reaction was stirred over night, allowing warmed up to rt. The reaction was quenched with saturated aq. NH4Cl solution, extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated to dryness. The crude product was used directly in next step without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]1([C:10](=O)[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:4]1([C:10]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:3][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Temperature: 60 °C

Procedure:
Hydrazine monohydrate (2.16 mL) is added to a solution of 1,3-diphenylpropane-1,3-dione (10.0 g) in ethanol (100 mL) and the mixture is heated to 60° C. for 2.5 h forming a white precipitate over this time. Ethanol is removed in vacuo and the residue is taken up in ethyl acetate. The resulting suspension is filtered to give 3,5-diphenyl-1H-pyrazole, 22 (3.44 g) as a white powder. The filtrate is washed with water (2×100 mL), dried over magnesium sulfate and concentrated to give further 3,5-diphenyl-1H-pyrazole, 22 (5.90 g) as a solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:18](=[N:19][OH:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:27]([O:29][C:30](=[O:37])[CH2:31][NH:32][C:33](=[O:36])[CH2:34]Br)[CH3:28].O>CN(C=O)C>[CH2:27]([O:29][C:30](=[O:37])[CH2:31][NH:32][C:33](=[O:36])[CH2:34][O:20][N:19]=[C:18]1[C:5]2[C:6](=[N:7][C:8]([C:9](=[O:10])[NH2:11])=[C:3]([C:1]#[N:2])[N:4]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]1=2)[CH3:28]
Reactant: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NO
Reactant: CCOC(=O)CNC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNC(=O)CON=C1c2ccccc2-c2nc(C(N)=O)c(C#N)nc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.2 %

Procedure:
To a suspension of 33 (212 mg, 0.80), Cs2CO3 (260 mg, 0.80) in DMF (15 ml), 39 (200 mg, 0.89 mmol) was added portionwise and the mixture was stirred at room temperature for 2 days. H2O (30 ml) was added and the suspension was extracted with CH2Cl2 (70 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (CH2Cl2/MeOH 9:1) affording 40 (56 mg, 17%) as yellow-brown solid. 1H NMR (300 MHz, DMSO d6): δ 8.78 (m, 2H), 8.12 (bs, 1H), 8.05-7.78 (m, 3H), 7.67 (m, 1H), 4.72 and 4.69 (s, 2H), 4.10 (q, 2H), 3.92 and 3.90 (s, 2H), 1.19 (t, 3H). ESI+MS: calcd for C19H16N6O5: 408.38; found: 409.1 (MH+).
Reaction SMILES: [CH2:1]=[C:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][C:6](=[O:14])[CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19]COCC>>[OH:14][C:6]1([CH3:19])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:2](=[CH2:1])[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[CH2:5]1
Reactant: CCOCC
Reactant: C=C1c2ccccc2CC(=O)Cc2ccccc21
Product: C=C1c2ccccc2CC(C)(O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Upon completion of the addition, the mixture was heated at reflux for one hour, then cooled to room temperature. A solution of 15.1 g. (0.065 mole) of 12-methylene-6-oxo-5,6,7,12-tetrahydrodibenzo[a,d]cyclooctene in 100 ml. of ether was added over 5 minutes to the stirred Grignard solution, and the resulting mixture was stirred for one hour at room temperature and quenched in 1 liter of ice water containing 5 g. of ammonium chloride. The resulting suspension was extracted three times with ether (200 ml.), and the combined ether layers were washed once with dilute aqueous sodium bisulfite, once with dilute sodium bicarbonate, and twice with water. The washed ether solution was dried over potassium carbonate, filtered, and evaporated in vacuo to give 6-hydroxy-6-methyl-12-methylene-5,6,7,12-tetrahydrodibenzo[a,d]cyclooctene as a colorless oil, 17.7 g.
Reaction SMILES: [OH:1][C:2]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11](O)=[O:12])[C:7]1([CH3:15])[CH3:14])([C:4]#[CH:5])[CH3:3].[Cl-].[NH4+].F[B-](F)(F)F.[N:23]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][C:2]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11]([NH2:23])=[O:12])[C:7]1([CH3:15])[CH3:14])([C:4]#[CH:5])[CH3:3]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C#CC(C)(O)C1CC(CC(=O)O)C1(C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CC(C)(O)C1CC(CC(N)=O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a mixture of Example 29A (84 mg, 0.4 mmol), ammonium chloride (32 mg, 0.6 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (154 mg, 0.48 mmol) in N,N-dimethylformamide was added N,N-diisopropylethylamine (348 μL, 2.0 mmol). The reaction mixture was stirred at room temperature overnight. It was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine twice, dried (MgSO4), filtered and concentrated in vacuo to provide the title intermediate as a white solid (50 mg, 60% yield).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4].[CH3:39][CH:40]1[CH2:45][CH:44](O)[CH2:43][CH2:42][O:41]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:44]3[CH2:43][CH2:42][O:41][CH:40]([CH3:39])[CH2:45]3)=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reactant: CC1CC(O)CCO1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(C)n(-c2ccc(OC3CCOC(C)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a solution of 6-butyl-3-(4-hydroxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (0.5 g), 2-methyltetrahydro-2H-pyran-4-ol (0.26 g) and triphenylphosphine (0.58 g) in tetrahydrofuran (5 mL) was added dropwise diisopropyl azodicarboxylate (1.9 M toluene solution, 1.2 mL). After stirring for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and a mixture of the residue, hydroxylammonium chloride (0.77 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.36 g, 53%) as an amorphous solid.
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[CH2:37]([NH2:39])[CH3:38]>>[N:39]1([CH2:14][CH2:15][NH:16][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:24]=[CH:25][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:27][CH:28]=2)=[O:10])[CH2:11][CH2:9][O:10][CH2:38][CH2:37]1
Reactant: CCN
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)NCCN4CCOCC4)cc32)cc1

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 2-N-morpholino)ethylamine according to Procedure K: mp210-212° C.; Anal. Calcd for C21H24N6O5S.1/4H2O: C, 52.88; H, 5.18; N, 17.62. Found: C, 52.91; H, 5.24; N, 17.35.
Reaction SMILES: [CH3:1][C@@H:2]1[N:5]([P:6](=[O:10])([O-:9])[O:7][CH3:8])[C:4](=[O:11])[C@H:3]1[NH:12]C(OC(C)(C)C)=O.[K].[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C1(OC)C=CC=CC=1>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:12][C@H:3]1[C@H:2]([CH3:1])[N:5]([P:6](=[O:9])([OH:10])[O:7][CH3:8])[C:4]1=[O:11]
Reactant: COP(=O)([O-])N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Agent: [K]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COP(=O)(O)N1C(=O)[C@@H](N)[C@@H]1C
Reaction time: 1.25 h

Procedure:
(3S-trans)-[4-Methyl-2-oxo-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-azetidinyl]phosphonic aicd, methyl ester, potassium salt (300 mg) suspended in dry anisole (0.3 ml), under a nitrogen atmosphere, was cooled to 0°-5° C. and trifluoracetic acid (3 ml) was added while stirring. After 1.25 hours, trifluoroacetic acid was removed in vacuo without heating and residual acid was chased under reduced pressure with toluene. The residual oil was solidified and triturated with ether yielding a powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11](=O)[CH3:12].Br[CH2:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH:18]1([C:16]([C:15]2[O:1][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=3[C:11]=2[CH3:12])=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: O=C(CBr)C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a mixture of 2′-hydroxy-5′-nitroacetophenone (5.00 g), 2-bromo-1-cyclohexylethanone (6.79 g) synthesized in Example A51(1) and N,N-dimethylformamide (50 mL) was added potassium carbonate (7.63 g), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (4.18 g, 53%) as a yellow solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCCCCCOCc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOCc2ccccc2)CC1
Yield: 42.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.8 g) and 5-benzyloxypentyl bromide (2.08 g) were reacted and treated in the same manner as in Example 168 to give 0.82 g of 4-amino-N-((1-(5-benzyloxypentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34](I)=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34]([C:3]3[S:4][C:5]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[C:2]=3[CH3:1])=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1csc2cccnc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc4cccnc4c3C)c(C)nc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 34.8 %

Procedure:
190 mg of 3-Methyl-thieno[3,2-b]pyridine (1.28 mmol) is dissolved in 3.0 ml of dry THF and cooled to −78° C. 0.62 ml of n-BuLi 2.5M in hexane (1.54 mmol) is added at −78° C. and stirred at −78° C. for 10 min and room temperature for 10 min. The reaction vessel is cooled to −78° C. again and 3.3 ml of 0.5 M ZnCl2 in THF (1.66 mmol) is added at −78C and stirred at room temperature for 15 min. 343 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.0 mmol) and 41 mg of PdCl2(pddf) (0.05 mmol) are added and the tube is capped. The tube is heated at 80° C. for overnight. The reaction is quenched by NH4Claq. and extracted by CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=10:3:1) to give 127 mg of the title compound. Yield 35%. mass spectrum (m/e): 365 (M+1); 1H-NMR (CDCl3): 8.79 (dd, 1H, J=4.8 Hz, 1.4 Hz), 8.21 (dd, 1H, J=7.9 Hz, 1.4 Hz), 7.33 (dd, 1H, J=7.9 Hz, 4.8 Hz), 6.76 (s, 1H), 3.38 (m, 1H), 2.55 (s, 6H), 2.47 (s, 3H), 1.89 (m, 4H), 0.92 (t, 6H, J=7.5 Hz) ppm.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:11][C:12]([NH:14]C(=O)C1C=CC=CC=1)=[O:13])#[N:2].[OH-].[Na+]>CCO>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:9][CH3:10])[NH:11][C:12](=[O:13])[N:14]=1
Reactant: CNc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1cccc2[nH]c(=O)nc(N)c12
Temperature: 25 °C
Yield: 56.3 %

Procedure:
A solution of N-(2-cyano-3-(methylamino)phenylcarbamoyl)benzamide (Example 157a) (0.05 g, 0.17 mmol) and NaOH (2N, 0.17 mL) in EtOH (6 mL) was stirred at 90° C. under nitrogen for half an hour. The reaction mixture was cooled down to room temperature, and concentrated under vacuum. H2O (1 mL) was added and the reaction mixture was neutralized to pH˜4 with 10% AcOH. The resultant precipitation was filtered and dried under vacuum. The crude product was purified by preparative thin layer chromatography using a DCM/MeOH (9:1) solution as eluant, to give 4-amino-5-(methylamino)quinazolin-2(1H)-one (18.2 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 2.76 (s, 3H), 6.10 (d, J=7.6 Hz, 1H), 6.12 (d, J=8 Hz, 1H), 7.13 (t, J=8 Hz, 1H), 7.25 (bs, NH), 9.66 (bs, NH,) 10.13 (bs, 2H). MS 191 (MH+).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1([NH:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23](=[O:36])[C:24](C=O)=[CH:25][N:26]3[CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:21][C:20]=2[F:37])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>ClCCl>[CH:12]1([NH:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23](=[O:36])[C:24]([OH:9])=[CH:25][N:26]3[CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:21][C:20]=2[F:37])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(O)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Reaction time: 2 h
Yield: 99.6 %

Procedure:
6.1 g of metachloroperbenzoic acid was gradually added to a 100 ml of dichloromethane solution of 8.0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde at room temperature, followed by stirring for 2 hours. Aqueous saturated sodium hydrogen carbonate and aqueous sodium hydrogenthiosulfate were added to the reaction mixture, followed by stirring for 30 minutes and then extraction with chloroform. After drying over anhydrous sodium sulfate and subsequent evaporation under a reduced pressure, the residue was purified by silica gel column chromatography to obtain 7.7 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-hydroxyquinolin-4(1H)-one.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N+:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57]O)([O-:52])=[O:51]>C(Cl)Cl>[N+:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][O:12][C:11](=[O:13])[C@H:10]([OH:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)([O-:52])=[O:51]
Reactant: O=[N+]([O-])OCCCCO
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](O)C(=O)OCCCCO[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
(2R,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxypentanoic acid (30 mg, 78 μmol), HOBt (63 mg, 470 μmol), and EDCI (83 μL, 470 μmol) were dissolved into DCM. After stirring for 10 minutes, 4-nitrooxybutan-1-ol (84.1 mg, 623 μmol) was added. The resulting mixture was stirred at room temperature and the reaction monitored for completion (˜30 minutes). The mixture was stirred for an additional 2 hours and then left open to dry. The product was then purified (Interchim reverse phase chromatography column; 35-95% MeCN in water with 0.05% TFA) to yield the title compound (18 mg).