Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(OC(=O)C)(=[O:15])C>>[CH3:1][C:2]1[NH:3][C:4](=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2ccccc2c[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: Cc1cc2ccccc2c(=O)[nH]1
Yield: 27 %

Procedure:
3-Methyisoquinoline oxide (3.60 g, 22.6 mmol) and acetic anhydride (38 mL) are heated at reflux for 6 hr. After cooling the volatiles are removed and the residue is distilled at 220° C. under 0.5 mbar using a Kugelrohr distillation apparatus to afford 3-methyl-2H-isoquinolin-1-one (900 mg, 27% yield). LC/MS: MS m/e=160 (M+H); RT 2.45 min.
Reaction SMILES: CO[C:3](OC)(OC)[CH2:4][CH2:5][CH2:6][CH3:7].Cl.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:29]=1[NH:30][CH2:31][C:32]1([OH:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:27][CH:26]=[CH:25][CH:24]=2>C1(C)C=CC=CC=1>[CH2:4]([C:3]1[N:30]([CH2:31][C:32]2([OH:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:19]=1)[CH2:5][CH2:6][CH3:7]
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCOCC1
Reactant: CCCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CC1(O)CCOCC1
Temperature: 25 °C

Procedure:
Trimethylorthovalerate (1.8 mL, 10.4 mmol) and pyridine hydrochloride (92 mg, 0.8 mmol) were added to a suspension of 4-[(3-aminoquinolin-4-ylamino)methyl]tetrahydropyran-4-ol (8.0 mmol) in toluene (40 mL). The reaction mixture was heated at reflux for 2.5 hours and then cooled to ambient temperature. A precipitate was isolated by filtration and dried to provide 4-[(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a white solid, mp 180-181° C. MS (ESI) m/z 340 (M+H)+; Anal. calcd for C20H25N3O2: C, 70.77; H, 7.42; N, 12.38. Found: C, 70.58; H, 7.53; N, 12.40.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:8]=1>C(Cl)(Cl)Cl>[Br:1][C:6]1[S:5][C:4]([CH3:3])=[N:8][C:7]=1[C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccc([N+](=O)[O-])cc2)c(Br)s1
Yield: 60 %

Procedure:
Bromine (6 mmol) was added dropwise to a solution of 2-methyl-4-(4-nitrophenyl)-1,3-thiazole (5 mmol) in chloroform (20 mL) and the solution refluxed for 4 h. The solvent was evaporated and the product purified by crystallization from ether to afford the title compound (60%). ESMS [M+H]+: 300.2
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:21]([CH:22]=O)=[CH:20][C:11]3[C:12]([C:15]4[S:16][CH:17]=[CH:18][N:19]=4)=[N:13][O:14][C:10]=3[C:9]=2[F:24])[CH2:5][C@@H:4]([CH3:25])[O:3]1.[NH:26]1[C:31](=[O:32])[CH2:30][C:29](=[O:33])[NH:28][C:27]1=[O:34]>C(O)C>[F:24][C:9]1[C:10]2[O:14][N:13]=[C:12]([C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[C:11]=2[CH:20]=[C:21]2[C:8]=1[N:6]1[CH2:7][C@@H:2]([CH3:1])[O:3][C@@H:4]([CH3:25])[C@@H:5]1[C:30]1([C:29](=[O:33])[NH:28][C:27](=[O:34])[NH:26][C:31]1=[O:32])[CH2:22]2
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(-c4nccs4)noc3c2F)C[C@@H](C)O1
Solvent: CCO
Product: C[C@@H]1CN2c3c(cc4c(-c5nccs5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 90 °C
Yield: 71.6 %

Procedure:
A mixture of 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-(thiazol-2-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 430, 1.414 g, 3.91 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (0.501 g, 3.91 mmol) in ethanol (200 ml) was heated at 90° C. for 5 days. Solvent removed. LCMS of crude reaction indicates 9:1 mixture of two diastereomeric products. The major product was purified by reverse phase preparative HPLC to give the title compound (1.320 g, 71.6%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH2:13](O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: OCCc1ccccc1
Reactant: COC(=O)c1ccc(F)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1OCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (1.00 g) and phenethyl alcohol (0.64 mL) were added to triphenylphosphine (1.54 g) and diisopropylazodicarboxylate (1.04 mL) in tetrahydrofuran (20 mL) at 0° C., and the reaction was stirred at room temperature for 24 hours. The mixture was chromatographed on silica gel with 5% ethyl acetate/hexanes.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][CH:12]3[N:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]4=[N:14][C:13]3=[S:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][S:21][C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]2[C:12]=1[CH2:11][C:9]1[C:10]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[S:7][CH:8]=1
Reactant: Cc1cccc2scc(CC3C(=S)N=C4C=CC=CN43)c12
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCSc1nc2ccccn2c1Cc1csc2cccc(C)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 472 mg (1.5 mmol) of 3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-imidazo[1,2-a]pyridine-2-thione and 407 mg (2.3 mmol) of methyl 4-bromobutyrate and 415 mg (3.0 mmol) of potassium carbonate in 5 mL of DMF is stirred at room temperature for 18 h. The mixture is diluted with water and the product is extracted with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel eluted with 1˜5% methanol in dichloromethane to give the desired compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([N:11]1[C:15]2[C:16](Cl)=[N:17][N:18]([CH3:21])[C:19](=[O:20])[C:14]=2[N:13]=[CH:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH2:4]([N:11]1[C:15]2[C:16]([N:2]([CH3:3])[CH3:1])=[N:17][N:18]([CH3:21])[C:19](=[O:20])[C:14]=2[N:13]=[CH:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNC
Reactant: Cn1nc(Cl)c2c(ncn2Cc2ccccc2)c1=O
Solvent: CCO
Product: CN(C)c1nn(C)c(=O)c2ncn(Cc3ccccc3)c12
Temperature: 130 °C

Procedure:
A 2 ml aqueous solution of 50% dimethylamine was added to a 2 ml ethanol solution of 0.138 g of 1-benzyl-7-chloro-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one, and the mixture was heated at 130° C. for 72 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.139 g of the title compound was obtained from the fraction eluted with methanol-ethyl acetate (1:19).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[CH:6][C:5]([O:17][CH3:18])=[C:4]([C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][N:24]3[C:32]([C:35]([OH:37])=O)=[CH:33][CH:34]=[C:23]3[CH2:22]2)=[O:20])[CH:3]=1.[NH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[CH:6][C:5]([O:17][CH3:18])=[C:4]([C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][N:24]3[C:32]([C:35]([NH:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=4)=[O:37])=[CH:33][CH:34]=[C:23]3[CH2:22]2)=[O:20])[CH:3]=1
Reactant: CCOc1ccccc1-c1cc(OC)c(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)cc1Cl
Reactant: NCc1ccccn1
Product: CCOc1ccccc1-c1cc(OC)c(C(=O)N2Cc3ccc(C(=O)NCc4ccccn4)n3Cc3ccccc32)cc1Cl

Procedure:
Prepared by coupling the 10-{[6-chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step C with 2-(aminomethyl)pyridine (1.25 equiv.) in the manner of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[C:9]([Cl:16])=[CH:8][C:4]=1[C:5]([OH:7])=O.ClC(OCC)=O.[CH2:23]([N:25]1[CH2:32][CH:31]2[CH:27]([CH2:28][CH2:29][CH2:30]2)[CH:26]1[CH2:33][NH2:34])[CH3:24]>O1CCCC1.C(N(CC)CC)C>[CH2:23]([N:25]1[CH2:32][CH:31]2[CH:27]([CH2:28][CH2:29][CH2:30]2)[CH:26]1[CH2:33][NH:34][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:16])[C:10]([NH:12][C:13](=[O:15])[CH3:14])=[CH:11][C:3]=1[O:2][CH3:1])[CH3:24]
Reactant: CCN1CC2CCCC2C1CN
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN1CC2CCCC2C1CNC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 6 parts of 2-methoxy-4-acetylamino-5-chloro benzoic acid in 50 parts of anhydrous tetrahydrofuran, were added 2.5 parts of triethylamine. The solution thus obtained was poured portionwise in a mixture of 2.7 parts of ethyl chloroformate in 80 parts of tetrahydrofuran maintained at 0° C. After stirring for 10 minutes, 4.1. parts of N-ethyl-2-aminomethyl-3-azabicyclo (3,3,0) octane were added. After being maintained at room temperature for 10 minutes, the temperature was progressively increased and, finally, the reaction mixture was refluxed for 60 minutes. After cooling, the mixture was filtered and the filtrate was evaporated in vacuo. After recrystallization in 50 parts of ethyl acetate, there were obtained 5.5 parts of N-ethyl-2-(2-methoxy-4-acetylamino-5-chloro benzamido methyl)-3-azabicyclo (3,3,0) octane, M.P. 156°-157° C (ethyl acetate).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>CO.Cl.O>[Cl:6][CH2:7][CH2:8][CH2:9][C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNC(N)=S
Reactant: O=C(CCCCl)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=S)NN=C(CCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
Thiosemicarbazide (9.11 g, 0.1 mol) was added under nitrogen to a solution of 4-chlorobutyrophenone (16 mL, 0.1 mol) in 350 mL of methanol plus 27 mL of 1 N HCl plus 25 mL of water. After approximately 30 minutes of stirring at room temperature, all of the solid had dissolved. The reaction was then stirred at room temperature for 24 hours (overnight). The solid that had formed was collected by filtration and dried under high vacuum to give 17.41 g (68%) of the title compound as a white solid, mp 128-130° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[Cl:32]CCl.ClN1C(=O)CCC1=O.[OH-].[K+]>O>[C:1]([C:5]1[C:9]([Cl:32])=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C)c1-n1nc(C(C)(C)C)cc1Nc1cccnc1C(=O)O
Reactant: ClCCl
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(C)c1-n1nc(C(C)(C)C)c(Cl)c1Nc1cccnc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a solution of 3-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}pyridine-2-carboxylic acid (Example 10, 50 mg, 0.14 mmol) in an acetic acid/dichloromethane mixture (1 mL of each) was added N-chlorosuccinimide (18 mg, 0.14 mmol). The solution was stirred at rt for 12 h, and then water (10 mL) was added. The reaction mixture was basified to pH 9 using KOH (1.0 M ice cold solution). The water layer was extracted with dichloromethane (50 mL), and the organic phase was subsequently washed with saturated sodium sulfite, brine, and concentrated to dryness. The crude material was subjected to HPLC purification to give the desired product (42 mg, 76%). 1H NMR (300 MHz, CD2Cl2) δ 10.45 (s, 1H), 9.30 (s, 1H), 8.04 (d, 1H), 7.50 (m, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 2.02 (s, 6H), 1.43 (s, 9H). ES-MS m/z 399.0 (MH+); HPLC RT (min) 3.33.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)=[C:11]3[N:10]=[C:9](SC)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:31]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([NH:36][C:9]2[N:8]=[C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:6][CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH:17]=4)=[C:11]3[N:10]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CSc1nc(NC2CCCC2)n2nc(-c3ccccc3)c(-c3ccnc(F)c3)c2n1
Reactant: NC1CCCC1
Product: c1ccc(-c2nn3c(NC4CCCC4)nc(NC4CCCC4)nc3c2-c2ccnc(NC3CCCC3)c2)cc1
Temperature: 160 °C
Yield: 34 %

Procedure:
N-Cyclopentyl-8-(2-fluoro-4-pyridiny)-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin -4amine 60 mg, 0.14 mmol) was dissolved in cyclopentylamine and heated at 160° C. in a glass pressure vessel for 24 hours. The resulting solution was concentrated in vacuo to give a residue that was purified by silica gel chromatography (ethyl acetate:hexane 1:1 to ethyl acetate) to yield 25 mg (34%) of N2,N4-dicyclopentyl-8-[2-(cyclopentylamino)-4-pyridinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine as a foam. 1H-NMR (CDCl3): δ 7.94 (d, 1H), 7.60 (m, 2H), 7.45 (m, 3H), 6.81 (d, 1H), 6.36 (m, 1H), 5.13 (d, 1H), 4.60 (m, 1H), 4.44 (m, 2H), 3.74 (m, 1H), 2.1–1.4 (m, 24H); MS m/z 523 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[CH:10][C:9]([CH:12]([OH:14])[CH3:13])=[CH:8][CH:7]=2)=[CH:2]1.[CH:15]1[N:19]=[CH:18][N:17]([C:20](N2C=NC=C2)=[O:21])[CH:16]=1>C(#N)C>[N:17]1([C:20]([O:14][CH:12]([C:9]2[CH:10]=[N:11][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[CH:7][CH:8]=2)[CH3:13])=[O:21])[CH:16]=[CH:15][N:19]=[CH:18]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(O)c1ccc(-c2ccoc2)nc1
Solvent: CC#N
Product: CC(OC(=O)n1ccnc1)c1ccc(-c2ccoc2)nc1

Procedure:
Synthesized using compound 47a (110 mg, 0.58 mmol), CDI (471 mg, 2.91 mmol) and acetonitrile (7 mL) according to Method E. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:2) as eluent. White solid. Yield: 40 mg, 24%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=1.78 (d, J=6.6 Hz, 3H), 6.11 (q, J=6.7 Hz, 1H), 6.89 (dd, J=1.9, 0.9 Hz, 1H), 7.07 (dd, J=1.6, 0.6 Hz, 1H), 7.40-7.44 (m, 1H), 7.46-7.52 (m, 2H), 7.74 (dd, J=8.4, 2.7 Hz, 1H), 8.04 (dd, J=1.4, 0.8 Hz, 1H), 8.12-8.18 (m, 1H), 8.67 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=21.4, 74.9, 108.5, 117.0, 119.9, 126.5, 130.8, 132.8, 134.6, 137.0, 141.6, 144.0, 147.9, 148.0, 152.4; MS (ESI): m/z=284.25 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[S:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1>C(OCC)C>[CH3:1][N:2]([CH3:3])[C:5]1[S:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Reactant: CNC
Solvent: CCOCC
Product: CCOC(=O)c1sc(N(C)C)nc1C(F)(F)F
Yield: 64.8 %

Procedure:
To a vessel containing 591 g of ethyl ether cooled in a dry ice-acetone bath was added 12.5 g of dimethylamine with stirring. Then, to a reaction vessel cooled in a dry-ice acetone bath there was placed 11.5 g of the previously-prepared dimethylamine-in-ether solution followed by addition of 5.79 g (23 mmol) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate in 20 ml of ethyl ether. A white precipitate formed immediately. The reaction mixture was stirred for 10 minutes and filtered. The ether filtrate was washed with 5% sodium hydroxide, dried over anhydrous calcium sulfate and concentrated under reduced pressure. The residual solid was treated with petroleum ether and filtered to provide 4.0 g of white solid product (m.p. 78°-79° C.) identified in Table I. ##STR18##
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([CH3:14])[CH:6]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([CH3:14])[CH:6]=2)[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: Cc1cc(OCCCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
A solution of 4-(2-chloroethoxy)-2-methyl-1-nitrobenzene (2.1 g, 9.7 mmol), N-methylpiperazine (1.5 g, 15 mmol) and potassium carbonate (3.4 g, 0.025 mol) in N,N-dimethylformamide (15 mL) was stirred with heating at 70° C. for 18 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(dichloromethane/methanol) to afford 1-methyl-4-[2-(3-methyl-4-nitrophenoxy)ethyl]piperazine as solid (1.8 g, y. 64%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc2cc(OC)ccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1csc2cc(O)ccc12
Temperature: -5 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4.72 g (20 mMol) 6-methoxy-benzo[b]thiophene-3-carboxylic acid ethyl ester in 200 ml CH2Cl2 at −10° C., 40 ml of a 1 M solution of BBr3 in CH2Cl2 are added via syringe during 12 min. The solution is stirred for 3.5 h at −10 to 0° C., then diluted with 600 ml EtOAc and poured into 450 ml of a mixture of sat. NaHCO3 and ice. After 5 min, the aq. layer is separated off and extracted 3× with 120 ml EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and after addition of SiO2 concentrated. The resulting powder is put on top of a SiO2-column and the title compound eluted with hexan/EtOAc 4:1: m.p.: 128-129° C.; TLC(hexane/EtOAc 4:1): Rf=0.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[CH:6][C:7]=1[F:8].P(Br)(Br)[Br:12]>C(Cl)Cl>[Br:12][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: OCc1ccc(F)c(Cl)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Fc1ccc(CBr)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of (3-chloro-4-fluoro-phenyl)-methanol (4.3 g, 26.8 mmol) in DCM (20 mL) was added PBr3 (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 hour before it was quenched with satd. aq. NaHCO3 solution. The organic solution was washed with water, brine, dried over anhy. Na2SO4 and concentrated in vacuo to give the desired product (3.7 g, 61.9%). It was used directly in the next step, without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:20]([O:22][CH3:23])=[O:21]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](CC1CCCCC1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-cyclohexylpropionate (Novabiochem), the title compound was prepared as a solid (mp=116-119° C.). The reaction was monitored by tlc (Rf=0.4 in 4% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/hexanes.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]1([CH2:7][C:8]([N:13]=[C:12]=[S:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#C[S-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)N=C=S
Reaction time: 2 h

Procedure:
2-Phenylacetyl chloride (0.180 ml) was dissolved in acetonitrile (20 ml) under a nitrogen atmosphere, and then potassium thiocyanate (197 mg) was added thereto at 50° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was concentrated under a reduced pressure to give a residue, to which ethyl acetate (20 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml) were then added, followed by stirring for 30 min. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to provide 2-phenylacetyl isothiocyanate, which was used to prepare a solution in toluene (5 ml)-ethanol (5 ml). To the solution was added 4-(4-amino-2-fluorophenoxy)-2-[(4-hydroxypiperidin-1-yl)carbonylamino]pyridine (168 mg), followed by stirring overnight. The reaction mixture was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (20 ml) was added to suspend. The resultant solid was filtered off and dried under aeration to provide the titled compound (106 mg, 42%) as white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:37](O)[CH3:38]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:37][CH3:38])=[C:12]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Product: CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting ethanol in place of 2-ethyl-1-hexanol (yield: 25 mg, 12%). mp 121-123° C. 1H NMR (300 MHz, DMSO-d6) δ 1.23 (t, J=7 Hz, 3H), 3.30 (s, 3H), 4.51 (q, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 407 (M+H)+; (APCI−) m/z 441 (M+Cl)−. Anal. calc. for C19H16F2N2O4S.0.25H2O: C, 55.53; H, 4.04; N, 6.81. Found: C, 55.58; H, 4.21; N, 6.61.