Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([OH:18])(=O)=[O:16].C[N:20](C)C=O>>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([NH2:20])(=[O:18])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a solution of thionyl chloride (11 mL) and 2-chloro-5-nitro-benzenesulfonic acid (4.78 g, 20.1 mmol) was added N,N-dimethylformamide (0.92 μL) and the reaction mixture was heated to reflux for 4 h. Upon cooling, the reaction mixture was azeotroped with toluene (2-3×). The sulfonyl chloride was dissolved in a minimal amount of toluene and then added to a mixture of concentrated aqueous ammonium hydroxide solution (25 mL) and tetrahydrofuran (25 mL) at −10° C. After stirring for 2 h the reaction was quenched by adding a 6.0 M aqueous hydrochloric acid solution until pH 4 was reached. The layers were separated and the organic layer was concentrated in vacuo to a slurry. Pentane was added and the product was isolated by vacuum filtration to afford the desired product, 2-chloro-5-nitrobenzenesulfonamide (2.0 g, 8.48 mmol, 42.4% yield) as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:30])[C:17]=2[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[N:10]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COCCc1nc2c(N)nc3c(c2n1CCCN)CCCC3
Product: COCCc1nc2c(N)nc3c(c2n1CCCNC(=O)N1CCOCC1)CCCC3
Yield: 44.4 %

Procedure:
Using the general method of Example 167, 1-(3-aminopropyl)-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 6.59 mmol) was reacted with 4-morpholinecarbonyl chloride (1.08 g, 7.25 mmol) to provide 1.22 g of N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide as a white powder, m.p. 171.8-173.2° C. Analysis: Calculated for C21H32N6O3: % C, 60.56; % H, 7.74; % N, 20.18. Found: % C, 60.30; % H, 7.72; % N, 20.11.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24](O)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH:10]([CH3:29])[CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[CH3:62][C:63]1([CH3:68])[CH2:67][CH2:66][NH2+:65][CH2:64]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:21][CH:22]([C:24]([N:65]4[CH2:66][CH2:67][C:63]([CH3:68])([CH3:62])[CH2:64]4)=[O:25])[CH2:23]3)[N:14]3[C:18]([N:19]=[C:11]2[CH:10]([CH3:29])[CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCc2c1nc1ccnn1c2N1CC(C(=O)O)C1
Reactant: CC1(C)CC[NH2+]C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)OC(C)(C)C)CCc2c1nc1ccnn1c2N1CC(C(=O)N2CCC(C)(C)C2)C1
Reaction time: 0.5 h

Procedure:
To 300 mg (0.57 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5-methyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) in 6.0 mL DMF was added 484 mg (1.51 mmol) TBTU and 243 μL (1.41 mmol) DIPEA and stirring was continued at room temperature for 30 min. Then 84.3 mg (0.62 mmol) of 3,3-Dimethyl-pyrrolidinium chloride was added and the reaction mixture was stirred additional 4 h. The reaction mixture was filtered and the purified by HPLC.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[C:12](=[O:16])[CH2:13][CH2:14][O:15][C:10]=2[C:9]=1[CH2:19][CH2:20][CH3:21].C([O:24][C:25](=[O:48])[CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([O:44]CC)=[O:43])[CH:37]=2)=[O:35])[CH:31]=[CH:30][C:29]=1[OH:47])C>CCCCCC.C(OCC)(=O)C>[C:42]([C:38]1[CH:37]=[C:36]([C:34]([C:32]2[CH:31]=[CH:30][C:29]([O:47][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:18]=[CH:17][C:11]4[C:12](=[O:16])[CH2:13][CH2:14][O:15][C:10]=4[C:9]=3[CH2:19][CH2:20][CH3:21])=[C:28]([CH2:27][CH2:26][C:25]([OH:48])=[O:24])[CH:33]=2)=[O:35])[CH:41]=[CH:40][CH:39]=1)([OH:44])=[O:43]
Reactant: CCCc1c(OCCCCCBr)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 36 %

Procedure:
Starting with 0.275 g (0.78 mmol) of 7-[(5-bromopentyl)oxy]-2,3-dihydro-8-propyl-4H-1-benzopyran-4-one, and 0.286 g (0.77 mmol) of 5-[[3-(ethoxycarbonyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, 5-[(3-carboxyphenyl)carbonyl]-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid (0.163 g; 52% overall yield) was obtained, as a white solid, mp 122°-128° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 19.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@H:7]1[C:12]([O:14]CC)=[O:13])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@H:7]1[C:12]([OH:14])=[O:13])=[O:5])[CH3:2]
Reactant: C=C1C[C@@H](C(=O)OCC)[C@H](C(=O)OCC)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=C1C[C@@H](C(=O)O)[C@H](C(=O)OCC)C1
Yield: 49.1 %

Procedure:
A suspension of 20.0 g of trans-(1SR,2SR)-4-methylene-cyclopentane-1,2-dicarboxylic acid diethyl ester and 36.6 g of potassium carbonate in 200 ml of MeOH was heated at reflux temperature for 2 h. The mixture was cooled to 22°, diluted with 200 ml of water, the pH was adjusted to 2 using 80 ml of 25% HCl and the mixture was evaporated to half of the volume. The aqueous layer was extracted with AcOEt, the organic layer was washed with water, dried and evaporated to give 16.7 g of a crude mixture of mono and diacid. Optionally this mixture can be purified on silica using CH2Cl2/MeOH (19:1) to give 8.60 g of the pure title compound 1a. MS: 183.3 (M−H)−.
Reaction SMILES: [C:1]([CH:5]1[CH2:15][CH2:14][C:8]2([O:12][CH2:11][C:10](=[O:13])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[H][H]>CO>[C:1]([CH:5]1[CH2:15][CH2:14][C:8]2([O:12][CH2:11][CH:10]([OH:13])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC2(CC1)CC(=O)CO2
Reactant: [H][H]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C1CCC2(CC1)CC(O)CO2
Temperature: 25 °C
Yield: 98679.1 %

Procedure:
To an ice cooled solution of 8-t-butyl-1-oxaspiro(4,5)decane-3-one (44.1 g, 0.21 mmol) in methanol (300 ml) was added sodium borohydride (10.8 g, 0.285 mol) in portions. After the evolution of hydrogen ceased the cooling bath was removed and the mixture was stirred at room temperature over night. The solvent was evaporated in vacuo and the residue was taken up in toluene/diluted hydrochloric acid. The organic layer was washed twice with water (200 ml), dried (MgSO4) and evaporated in vacuo to yield a colourless oil (44 g) which was recrystallised from light petroleum. 30 g of colourless crystals were obtained which melted at 82°-84° C. TLC and NMR-analysis indicated a single diastereoisomer only (cis).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:16][CH3:17])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([NH2:15])=O)[N:12]=2)[C:8]=1[CH3:9])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>O1CCCC1>[CH2:1]([C:3]1[C:4]([O:16][CH3:17])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13](=[S:27])[NH2:15])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(OC)nc2nc(C(N)=O)cn2c1C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCc1c(OC)nc2nc(C(N)=S)cn2c1C
Yield: 76595.1 %

Procedure:
A mixture of 20.0 g (0.0854 mmol) of 6-ethyl-7-methoxy-5-methylimidazo-[1,2-a]pyrimidine-2-carboxamide and 25.4 g (0.0629 mmol) of Lawesson's Reagent in 470 ml of tetrahydrofuran (THF) was refluxed for 4 hours. The mixture was then cooled, and the product was filtered and washed with THF, then ether to obtain 12.06 g (56%) of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-thiocarboxamide as a yellow solid melting at 248°-259° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:13]=1[NH:20][CH2:21][CH3:22])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:24][C:25](OCC)=[O:26].C1CCN2C(=NCCC2)CC1>C(O)C>[CH2:1]([N:8]1[C:25](=[O:26])[CH2:24][S:10][C:9]1=[N:11][C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][C:13]=1[NH:20][CH2:21][CH3:22])[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCl
Reactant: CCNc1ccc(C#N)cc1NC(=S)NCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1ccccc1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
To a 100 mL flask was added 1-benzyl-3-(5-cyano-2-ethylaminophenyl)thiourea (1.0 g, 3.2 mmol), anhydrous ethanol (40 mL), ethyl chloroacetate (0.39 g, 3.2 mmol) and then DBU (0.58 g, 3.8 mmol). The reaction was heated at 80° C. for 30 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and chromatographed (silica gel, 1:1 EtOAc/Hex) to afford the title product (0.98 g, 87%). 1H-NMR (CDCl3): δ 7.38 (6H, m), 7.11 (1H, d), 6.50 (1H, d), 5.05 (2H, s), 3.96 (2H, s), 3.01 (2H, m), 1.03 (3H, t).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1)=O.C1(P(=[CH:31][C:32]([O:34][CH3:35])=[O:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:35][O:34][C:32](=[O:33])/[CH:31]=[CH:1]/[C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7](/[CH:8]=[CH:31]/[C:32]([O:34][CH3:35])=[O:33])[CH:10]=1
Reactant: O=Cc1ccc(O)c(C=O)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(O)c(/C=C/C(=O)OC)c1
Reaction time: 8 h
Yield: 92.4 %

Procedure:
A mixture of 5.0 g (33.3 mmol) of 5-formylsalicylaldehyde and 24.5 g (73.3 mmol) of methyl (triphenyl phosphoranylidene)acetate, in 150 mL of toluene was stirred and refluxed for 2.5 hr and then kept at room temperature overnight. The solvent was removed in vacuo and the solid residue was flash-chromatographed on silica gel. There was obtained 8.07 g (92.5%) of the title compound as a colorless solid.
Reaction SMILES: [OH-].[Li+].[OH:3][C:4]1[C:5]([C:23]([O:25]C)=[O:24])=[N:6][C:7]([CH2:11][C:12]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:8][C:9]=1[OH:10]>O.O1CCCC1>[OH:3][C:4]1[C:9](=[O:10])[NH:8][C:7]([CH2:11][C:12]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:14][CH2:15][CH2:16]2)=[N:6][C:5]=1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)[nH]c(=O)c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.7 %

Procedure:
A solution of lithium hydroxide (7.66 mg, 320 μmol) in water (1.00 ml) was added to a stirred mixture of methyl 5,6-dihydroxy-2-((1-phenylcyclopentyl)methyl)pyrimidine-4-carboxylate (0.035 g, 107 μmol) in tetrahydrofuran (THF) (4 ml). The mixture was stirred at RT for 72 h and then quenched with amberlyst (H+) IE resin, filtered and evaporated to dryness. The residue was triturated with EtOAc and dried under vacuum to give the title product as a white solid (0.012 g; 32%). LCMS: m/z=315 (MH+).
Reaction SMILES: [N:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([O:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>ClCCl>[C:9]([O:13][C:14]([NH:16][CH:17]1[CH2:18][CH2:19][N:20]([C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[CH2:21][CH2:22]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C(Cl)N1CCCC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCCC2)CC1
Reaction time: 72 h

Procedure:
1-Pyrrolidine carbonylchloride (1.10 g, 9.99 mmol) was dissolved in 400 ml if dichloromethane under N2. (Tert-butoxy)-N-(4-piperidyl)carboxamide (2.0 g, 9.99 mmol) and triethyl amine (1.40 mL, 9.99 mmol) were added and the reaction mixture was stirred for three days. The reaction was quenched with sat. NaHCO3 solution and extracted with dichlorormethane. The combined organic phases were dried over MgSO4 and the solvent evaporated to give the product as a white solid. (2.63 g, 8.84 mmol, 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][CH:21]([N:24]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25]2)[CH2:20][CH2:19]1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([Cl:47])[C:33]=1[OH:48]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][CH:18]2[CH2:23][CH2:22][CH:21]([N:24]4[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25]4)[CH2:20][CH2:19]2)=[CH:3][C:2]([C:36]2[CH:37]=[C:32]([Cl:31])[C:33]([OH:48])=[C:34]([Cl:47])[CH:35]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: COC1CCN(C2CCC(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Product: COC1CCN(C2CCC(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)CC2)C1
Yield: 63.8 %

Procedure:
Following general procedure D, (6-bromo-4-(4-(3-methoxypyrrolidin-1-yl)cyclohexylamino)quinolin-3-yl)(cyclopropyl)methanone (60 mg, 0.13 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (55 mg, 0.19 mmol) to afford the desired product (46 mg, 64%) as a brown solid: 1H NMR 1H NMR (500 MHz, MeOD+TFA-d) δ 9.42 (s, 1H), 8.46 (s, 1H), 8.31-8.23 (m, 1H), 8.04-7.97 (m, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 4.99 (br s, 1H), 4.23-4.14 (m, 1H), 3.82-3.61 (m, 2H), 3.43-3.30 (m, 6H), 3.27-3.19 (m, 1H), 2.93-2.82 (m, 1H), 2.60-2.03 (m, 7H), 2.02-1.61 (m, 3H), 1.37-1.18 (m, 4H).; ESI MS m/z 554 [C30H33Cl2N3O3+H]+; HPLC>99.0% (AUC), tR=10.97 min.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=2[C:26]#[N:27])=[CH:20][CH:19]=1>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=3[C:26]#[N:27])=[CH:20][CH:19]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2[nH]1
Reactant: N#Cc1ccc(Cl)cc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2cc(Cl)ccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
522 g of 2-n-butylbenzimidazole was dissolved in 10 ml of dimethylformamide and dropwise added to 130 g of sodium hydride. The mixture was stirred at room temperature for 30 min, and 920 mg of 2-(4-bromomethylphenyl)-4-chlorobenzonitrile dissolved in 10 ml of dimethylformamide was dropwise added thereto. The mixture was stirred at room temperature for 10 min, and the reaction mixture was filtered. The filtrate was concentrated and water and ethyl acetate were added to the residue. The organic phase was separated, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by column chromatography (chloroform:ethanol=98:2) (yield: 1.12 g).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]2[CH2:14][O:13][CH2:12][CH:11]([CH3:15])[NH:10][CH2:9]2)=[CH:4][C:3]=1[CH3:18].[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25](O)=[O:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]2[CH2:14][O:13][CH2:12][CH:11]([CH3:15])[N:10]([C:25](=[O:26])[C:24]3[CH:28]=[C:20]([CH3:19])[CH:21]=[CH:22][C:23]=3[N:29]3[N:33]=[CH:32][CH:31]=[N:30]3)[CH2:9]2)=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: Cc1cc(OCC2CNC(C)COC2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC(COc3ccc(F)c(C)c3)COCC2C)c1

Procedure:
A solution of 6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-1,4-oxazepane (4-7, 13 mg, 0.051 mmol, 1 equiv), 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (16 mg, 0.077 mmol, 1.5 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 15 mg, 0.077 mmol, 1.5 equiv), 1-hydroxybenzotriazole (12 g, 0.077 mmol, 1.50 equiv) and triethylamine (21 uL, 0.15 mmol, 3.0 equiv) in DMF (5 mL) was stirred at 23° C. for 20 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (100% hexanes initially, grading to 40% hexanes in EtOAc) to provide 6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-oxazepane (4-8) as a mixture of diastereomers. LRMS m/z (M+H) 439.0 found, 439.2 required.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]3=[O:17])=[CH:6][N:5]2[C:18]=1[CH3:19].[Cl:20][C:21]1[S:25][C:24]([CH2:26]O)=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:20][C:21]1[S:25][C:24]([CH2:26][O:16][C:13]2[CH:14]=[CH:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]4[N:5]([C:18]([CH3:19])=[C:2]([CH3:1])[N:3]=4)[CH:6]=3)[C:11](=[O:17])[CH:12]=2)=[CH:23][CH:22]=1
Reactant: OCc1ccc(Cl)s1
Reactant: Cc1nc2ccc(-n3ccc(O)cc3=O)cn2c1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nc2ccc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)cn2c1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 24.7 %

Procedure:
To a solution of 1-(2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chlorothiophen-2-yl)methanol (174 mg) and tributylphosphine (358 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (447 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine successively, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (56 mg) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[CH2:11]([C:13]1[NH:17][N:16]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])[CH:14]=1)[CH3:12].Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:17]1[C:13]([CH2:11][CH3:12])=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])=[N:16]1)=[O:10]
Reactant: CN=C=O
Reactant: CCc1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])nn1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Potassium carbonate (0.72 g, 5.2 mmol) and methyl isocyanate (0.29 g, 5.0 mmol) were added to a solution of 5-ethyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole (1.58 g, 5.2 mmol) in ethyl acetate (20 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a yellow solid of N-methyl-5-ethyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.68 g, yield: 38.0%). mp: 89-91° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.29 (t, J=7.4 Hz, 3H), 2.91 (d, J=5.0 Hz, 3H), 3.09 (q, J=7.4 Hz, 2H), 5.92 (s, 1H), 6.55-6.85 (m, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.85 (dd, J=2.1 and 8.7 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH:20]=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([NH2:36])[C:32]([NH2:35])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:34]=[CH:33][C:32]3[N:35]=[C:20]([C:14]4[C:13]5[C:17](=[CH:18][CH:19]=[C:11]([O:10][C:7]6[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=6)[CH:12]=5)[NH:16][N:15]=4)[NH:36][C:31]=3[CH:30]=2)[CH2:27][CH2:28]1
Reactant: O=Cc1n[nH]c2ccc(Oc3ccc([N+](=O)[O-])cn3)cc12
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5ccc(Oc6ccc([N+](=O)[O-])cn6)cc45)[nH]c3c2)CC1

Procedure:
The tide compound was synthesized from 5-(5-nitro-pyridin-2-yloxy)-1H-indazole-3-carbaldehyde and 4-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine using the method described above in Example 4. LC/MS (m/z) 471.3 (MH+), Rt 2.94 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:18]4[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=4)[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: ClCc1cn2cc(Cl)cc(Cl)c2n1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Fc1ccc(N2CCN(Cc3cn4cc(Cl)cc(Cl)c4n3)CC2)cc1
Temperature: 82.5 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A mixture of 6,8-dichloro-2-(chloromethyl)imidazo[1,2-α]pyridine (0.3064 g), 1-(4-fluorophenyl)piperazine (Aldrich; 0.266 g), triethylamine (Aldrich; 0.21 mL), and ethylene glycol (2 mL) is stirred for 1 h at 80-85° C. After cooling, the mixture is partitioned between water and dichloromethane and the organic layers are washed with brine and dried over MgSO4. After concentration under reduced pressure, the residue is chromatographed on silica gel using methanol/dichloromethane (4/96) and the appropriate fractions are combined and concentrated and the residue is crystallized from ethyl acetate/hexane to give 0.3098 g of the title compound; mp 126.5-127.5° C.; MS m/z 378, 380; IR (mineral oil) 1510, 1215, 1335, 826, 1224 cm-1 ; 1H NMR (CDCl3) δ2.75, 3.15, 3.83, 6.87, 6.96, 7.26, 7.62, 8.09.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.[CH3:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH:22]=[O:23]>C1COCC1>[CH3:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH:22]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)[OH:23]
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Reactant: Cn1ccnc1C=O
Solvent: C1CCOC1
Product: Cn1ccnc1C(O)c1ccc(OC2CCCCO2)cc1
Reaction time: 3 h
Yield: 100.2 %

Procedure:
4-(2-Tetrahydro-2H-pyranoxy)phenylmagnesium bromide (0.5M in THF, 160 mL, 80 mmol) was added slowly to a solution of 1-methyl-2-imidazolecarboxaldehyde (8 g, 72.7 mmol) in THF (100 mL) via syringe at −78° C. The reaction mixture was stirred at this temperature for 3 hours and quenched with saturated NH4Cl (aq). The mixture was extracted with EtOAc (2×100 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 9.1 as a colorless oil (21 g), which was used directly in the next step.