Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].S([O-])([O-])(=O)=O.[Mg+2].CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[N+:37]([CH3:40])([O-:39])=[O:38]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:40][N+:37]([O-:39])=[O:38])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: C[N+](=O)[O-]
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: O=[N+]([O-])CC(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-chloro-benzaldehyde (20 g, 0.142 mol) in nitromethane (100 mL) were added magnesium sulfate (37.6 g, 0.312 mol) and phosphazene base P1-t-bu-tris(tetramethylene) (4.43 g, 0.014 mol). The reaction mixture was stirred at room temperature for 2 h. After concentration in vacuo, the residue was purified by flash chromatography (25% EtOAc/hexane) to yield the title compound (26.4 g, 100%) as a green-yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.53 (1H, s), 7.35–7.42 (3H, m), 6.23 (1H, broad s), 5.32–5.33 (1H, m), 4.90 (1H, dd, J=3.2, 12.4 Hz), 4.60 (1H, dd, J=1.2, 12.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.O>C(OCC)C>[CH3:1][C:2]1[O:3][C:4]2[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: Cc1oc2cc(C(=O)O)ccc2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: Cc1oc2cc(CO)ccc2c1C
Yield: 100 %

Procedure:
2,3-Dimethylbenzofuran-6-carboxylic acid (20.0 g, 0.105 mol) was added portionwise to a stirred suspension of lithium aluminium hydride (4.0 g., 0.105 mol) in anhydrous diethyl ether (800 cm3) and the mixture was heated under reflux for 4 hr. Ethanol and water were added and the mixture was filtered. The filtrate was dried (NaSO4), filtered and the solvent was removed to give 2,3-dimethyl-6-hydroxymethylbenzofuran (18.5 g, 0.105 mol, 99.9%), m.p. 78°-79° C. (ex aqueous ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:21])[C@@H:12]([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].[CH2:22]([O:29][C:30]([NH:32][CH:33]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([CH3:45])[CH:38]=1)[C:34](O)=[O:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:21])[C@@H:12]([NH:20][C:34](=[O:35])[CH:33]([NH:32][C:30]([O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([CH3:45])[CH:38]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2ccccc2)n1
Reactant: COc1ccc(C(NC(=O)OCc2ccccc2)C(=O)O)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)C(NC(=O)OCc2ccccc2)c2ccc(OC)c(C)c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a solution of 2-((S)-2-amino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (0.93 g, 3.04 mmol), benzyloxycarbonylamino-(4-methoxy-3-methyl-phenyl)-acetic acid (1.0 g, 3.04 mmol), diisopropylethylamine (2.1 mL, 12 mmol) and 1-hydroxybenzotriazole (0.46 g, 3.04 mmol) in N,N-dimethylformamide (10 mL) at 0° C. was added O-benzotriazol-1-yl-N,N, N′,N′-tetramethyluronium hexaflurorophosphate (1.15 g, 3.04 mmol). The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography over silica gel eluted with 2:1 ethyl acetate/hexanes to give 2-{(S)-2-[2-benzyloxycarbonylamino-2-(4-methoxy-3-methyl-phenyl)-acetylamino]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid methyl ester as a white solid (1.3 g, 69%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=1)=[O:19])C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:30][C:26]3[C:25]([F:31])=[CH:24][C:23]([CH:21]4[CH2:22][CH:20]4[C:18]([OH:19])=[O:17])=[CH:28][C:27]=3[F:29])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Product: O=C(O)C1CC1c1cc(F)c(OCc2cccnc2SC2CCCC2)c(F)c1
Yield: 102.4 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.030 g, 0.13 mmol) obtained in Step C of Preparation Example 8 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.032 g, 0.13 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.054 g, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10])([O-:3])=[O:2].O.O.[OH-].[Li+].Cl>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:14][S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NS(=O)(=O)c1ccccc1
Temperature: 50 °C

Procedure:
A solution of Example 95A (10.9 mg, 0.032 mmol) in methanol (0.9 mL) and distilled water (0.01 mL) was treated with lithium hydroxide monohydrate (4.0 mg, 0.096 mmol), heated to 50° C. for 4 hours, cooled to room temperature, treated with 2N HCl (1 mL), and concentrated. The resulting residue was purified by chromatography to provide the desired product as a white solid. MS (ESI(−)) m/e 321 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.62 (d, 1H), 8.06 (dd, 1H), 7.80 (m, 2H), 7.51 (m, 3H), 7.42 (d, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:13][CH:14]=O)[C:7]=2[CH:6]=[CH:5]1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18](=[O:39])[CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH3:16][O:17][C:18](=[O:39])[CH:19]=[CH:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH:6]=[CH:5][N:4]2[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)n1ccc2c(CC=O)cccc21
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C=CCc1cccc2c1ccn2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of 1-acetyl-indole-4-acetaldehyde (2.40 g, 11.93 mmol) prepared according to the method of H. Plieninger, et. al., Chem.Ber., 1956, 89:270 in THF (100 mL) was added methyl(triphenylphos-phoranylidene)acetate (4.78 g, 14.3 mmol). The solution was stirred at ambient temperature overnight. The solvent was removed in vacuo and the residue chromatographed (eluting with ethyl acetate/hexanes). Recrystallization from ethyl acetate/hexanes resulted in 2.12 g of the title compound as a white solid in two crops; MS(CI/NH3) m/e 258 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ2.60 (s, 3H), 3.70 (s, 3H), 3.75 (dd, 2H), 3.75 (m, 1H), 6.63 (dd, 1H), 7.05 (d, 1H), 7.12-7.22 (m, 2H), 7.29 (t, 1H), 7.43 (d, 1H), 8.35 (d, 1H).
Reaction SMILES: [Br-].C(CCCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.CC([O-])(C)C.[K+].CO.CC(O)=O.C(Cl)Cl.[CH:44]1([CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:55]([C:57]([NH:59][C:60]([C:62]2[CH:67]=[CH:66][C:65](/[C:68](/[C:77]3[CH:78]=[N:79][CH:80]=[CH:81][CH:82]=3)=[CH:69]\[CH2:70][CH2:71][CH2:72][CH2:73][C:74]([OH:76])=[O:75])=[CH:64][CH:63]=2)=[O:61])=[CH2:58])=[O:56])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C1COCC1>[CH:44]1([CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:55]([C@@H:57]2[CH2:58][O:61][C:60]([C:62]3[CH:63]=[CH:64][C:65](/[C:68](/[C:77]4[CH:78]=[N:79][CH:80]=[CH:81][CH:82]=4)=[CH:69]\[CH2:70][CH2:71][CH2:72][CH2:73][C:74]([OH:76])=[O:75])=[CH:66][CH:67]=3)=[N:59]2)=[O:56])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: C=C(NC(=O)c1ccc(/C(=C\CCCCC(=O)O)c2cccnc2)cc1)C(=O)NCCCCC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)CCCC/C=C(\c1ccc(C2=N[C@H](C(=O)NCCCCC3CCCCC3)CO2)cc1)c1cccnc1
Yield: 38 %

Procedure:
Using the method described above at example 18-G, 1.472 g (3.4 mmol) of (4S)-4,5-dihydro-2-[4-(3-pyridylcarbonyl)phenyl]oxazole-4-[N-(4-cyclohexylbutyl)]-L-serinamide was treated with 3.08 g (6.8 mmol) of (5-carboxypentyl)triphenylphosphonium bromide and 13.6 mL (13.6 mmol) of 1.0 M t-BuOK in 10.0 mL of THF at 0° C. for 2.5 hr. Preparative HPLC with MeOH-AcOH-CH2Cl2 (3:0.5:96.5) yielded ~700 mg (38%) of the title product and ~670 mg (37%) of the β-elimination Wittig product (less polar material) (E)-7-[4-[[[1-[[(4-cyclohexylbutyl)amino]carbonyl]-eth-1-enyl]amino]carbonyl]phenyl]-7-(3-pyridyl)-hept-6-enoic acid (311030): mp 61-63° C.; 1H NMR (CDCl3) δ9.05 (s, 1H), 8.58 (s, 1H), 8.48 (d, J=3.3 Hz, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.43 (br d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.25 (buried, 1H), 6.63 (d, J=1.1 Hz, 1H), 6.55 (br s, 1H), 6.21 (t, J=7.4 Hz, 1H), 5.35 (s, 1H), 3.37 (dt, J=6.8, 6.3 Hz, 2H), 2.32 (dd, J=7.1, 6.9 Hz, 2H), 2.18 (ddd, J=7.3, 7.2, 7.1 Hz, 2H), 1.69-0.83 (m, 21H); FDMS 532 (M+1). Anal. (C32H41N3O4) C, H, N.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.[Cl:10][C:11]1[C:12](=[O:23])[C:13]2[C:18]([C:19](=[O:22])[C:20]=1Cl)=[CH:17][CH:16]=[CH:15][CH:14]=2.N>CN(C=O)C>[Cl:10][C:11]1[C:12](=[O:23])[C:13]2[C:18]([C:19](=[O:22])[C:20]=1[N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C:4]1=[O:3])=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C1CCCCN1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(Cl)=C(N2CCCCC2=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
NaH (440 mg) was added to a solution of 2-oxopiperidine (1.0 g) in DMF (20 ml) and the mixture was stirred at room temperature for 30 minutes. This solution was added in a single portion to a solution of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene (6.9 g) in DMF (150 ml) and the mixture was stirred at room temperature for 17 hours. The reaction solution was poured into saturated aqueous ammonia and the resulting precipitate was removed by filtration and then the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution with ethyl acetate-hexane 1:10 solution) to give 2-chloro-1,4-dihydro-1,4-dioxo-3-(2-oxopiperidino)naphthalene (0.49 g) as a light brown powder.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[C:14]([N:17]([CH3:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=O)(C)(C)C.Cl>>[CH3:25][C:10]1([CH3:26])[C:11]2[CH:12]=[N:13][C:14]([N:17]([CH3:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:16]=2[NH:8][CH2:9]1
Reactant: CN(c1ccccc1)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Agent: Cl
Product: CN(c1ccccc1)c1cc2c(cn1)C(C)(C)CN2
Reaction time: 4 h

Procedure:
3,3-Dimethyl-6-(methyl-phenyl-amino)-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (112 mg, 0.32 mmol) was treated with HCl (saturated solution in EtOAc) and stirred for 4 h. The mixture was then evaporated to dryness in vacuo to give a colourless gum which was used directly in the next step without further purification.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[C:10]([NH:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[N:18][CH:17]=1)([CH3:13])([CH3:12])[CH3:11].CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:10]([NH:14][C:15](=[O:23])[C:16]1[C:21]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])=[CH:20][C:19]([CH3:22])=[N:18][CH:17]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccc(C(=O)NC(C)(C)C)cn1
Reactant: Cc1ccccc1[Mg]Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2C)c(C(=O)NC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
38.9 ml (38.9 mMol) o-Tolylmagnesium chloride solution (1M in THF) were added over 15 minutes to a solution of 2.5 g (10.1 mMol) N-tert.-butyl-6-methyl-nicotinamide in 12.5 ml THF cooled to 0° C. The suspension obtained was stirred overnight at room temperature, then one more hour at 50° C. After cooling to 0° C., 2.1 ml (51.9 mMol) methanol were added over 30 minutes (exothermic!), followed after 10 minutes by 3.5 g (15.6 mMol) 2,3-dichloro-5,6-dicyano-benzoquinone. After one hour at room temperature, the reaction mixture was concentrated under reduced pressure to a still stirrable oil, heated to 50° C. and 100 ml tert.-butyl-methylether were added. The suspension was stirred 30 minutes at reflux, 1 hour at room temperature and filtered. The filtrate was evaporated and the residue was purified by flash chromatography (50 g SiO2, eluent:AcOEt/n-heptane 2:1) to yield 3.1 g (84.5%) N-tert.-butyl-6-methyl-4-o-tolyl-nicotinamide as a light brown resinous solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:37])([CH3:36])[CH2:4][NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7].FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[OH:1][CH2:2][C:3]([CH3:37])([CH3:36])[CH2:4][NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NCC(C)(C)CO)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NCC(C)(C)CO)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63.1 %

Procedure:
2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-2,2-dimethyl-propyl)-amide (82 mg, 0.156 mmol) was suspended in dichloromethane (1.1 ml) and cooled in ice bath. Trifluoroacetic acid (0.5 ml) was added slowly and the reaction was stirred at room temperature for 3.5 h. The reaction was evaporated and the residue was dissolved in dichloromethane (1.6 ml). Ethylenediamine (0.63 ml, 9.3 mmol) was added and the mixture was stirred at room temperature for 18 h. Water and then ethyl acetate were added to the mixture, the layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (methanol/dichloromethane) to give 39 mg (63%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-2,2-dimethyl-propyl)-amide as an off-white solid. (M+Na)+=419; mp=291-293° C. 1H NMR (300 MHz, DMSO-d6) δ: 9.10 (s, 1H), 8.45 (s, 1H), 8.41-8.49 (m, 1H), 8.19-8.27 (m, 1H), 7.67 (dd, J=9.8, 2.3 Hz, 1H), 7.14-7.23 (m, 1H), 4.63-4.72 (m, 1H), 4.14 (s, 3H), 3.37-3.43 (m, 2H), 3.16-3.24 (m, 2H), 0.90 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([NH2:14])=[CH:4][CH:3]=1.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:20]([OH:21])=[N:14][C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)Nc1nc(Cl)ccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCC(CC)n1c(O)nc2ccc(Cl)nc21
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a solution of 6-chloro-N2-(pentan-3-yl)pyridine-2,3-diamine (936 mg, 4.37 mmol) in THF (10 mL) and CDI (1.1 g, 12.9 mmol) was added as a solid. After heating for 3 h, the reaction was cooled to room temperature. The excess CDI was quenched by the careful addition of water. The mixture was diluted with EtOAc and washed three times with water and once with brine. The solution was then dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (5%-40% EtOAc/hexanes) provided the title compound as a light purple solid (682 mg, 65%). m/z=240.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH:31]1([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:37]5[CH2:38][CH2:39][N:34]([CH:31]6[CH2:33][CH2:32]6)[CH2:35][CH2:36]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:29])([F:30])[F:28])[CH:3]=1
Reactant: C1CN(C2CC2)CCN1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCN(C3CC3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-cyclopropyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-cyclopropyl-piperazine following General Procedure B.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][NH2:15])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1c[nH]c(-c2ccccc2)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCc1c[nH]c(-c2ccccc2)n1
Temperature: 2.5 °C
Yield: 77.2 %

Procedure:
To a solution of 2-[3-(2-phenyl-1H-imidazol-4-yl)-propyl]-isoindole-1,3-dione (4.16 g) in ethanol (50 ml) was added hydrazine hydrate (3.18 g). The reaction mixture was stirred under reflux for 4 h, cooled down to 0-5° C., and the precipitate was filtered off. The filtrate was concentrated, and the oily residue was quenched with cooled 1N NaOH solution (20 ml) and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and concentrated to dryness to obtain 3-(2-phenyl-1H-imidazol-4-yl)-propylamine (1.95 g) as a yellow foam, which was sufficiently pure to be used directly in the next step.
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)[C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C1(C)C=CC([Bi](Cl)(Cl)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.N12CCCN=C1CCCCC2.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:22][C:19]1([CH3:23])[O:18][CH2:17][C:16]([NH:24][C:25](=[O:27])[CH3:26])([CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:6]3[S:7][C:3]([C:2](=[O:1])[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)=[CH:4][CH:5]=3)=[CH:13][CH:12]=2)[CH2:21][O:20]1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(C(O)c4ccc(C)cc4)s3)cc2)COC(C)(C)OC1
Agent: Cc1ccc([Bi](Cl)(Cl)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NC1(CCc2ccc(-c3ccc(C(=O)c4ccc(C)cc4)s3)cc2)COC(C)(C)OC1
Reaction time: 2 h
Yield: 63.1 %

Procedure:
To a solution of N-{5-[2-(4-{5-[hydroxy(4-methylphenyl)methyl]-2-thienyl}phenyl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (0.35 g) in methylene chloride (5 mL) were added tri(p-tolyl)bismuth dichloride (393 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (108 mg) at room temperature, and the mixture was stirred at the same temperature for 2 hr. Chloroform was added to the reaction mixture, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.22 g) as brown crystals.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[C:13]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])([F:15])[F:14]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]([P:16](=[O:23])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])([F:15])[F:14])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(I)c([N+](=O)[O-])c1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C)cc1[N+](=O)[O-]

Procedure:
Commercially available 4-iodo-3-nitrotoluene was reacted with diethyl bromodifluoromethylphosphonate under Cd coupling conditions using Example 25 to yield diethyl (4-methyl-2-nitrophenyl)difluoromethylphosphonate. The diethyl (4-methyl-2-nitrophenyl)difluoromethylphosphonate (500 mg, 1.55 mmol) was dissolved in EtOAc (10 mL) and EtOH (10 mL). Five percent Pd—C (approximately 20 mg) was added and the mixture placed under H2 (1 atm.) and stirred at room temperature overnight. The mixture was then filtered and concentrated in vacuo to give diethyl (4-methyl-2-aminophenyl)difluoromethylphosphonate. The diethyl (4-methyl-2-amino-phenyl)difluoromethylphosphonate was converted to diethyl (2-iodo-4-methylphenyl)-difluoromethylphosphonate using Example 86. Compound 95 was synthesized from this corresponding diethyl phosphonate using procedures similar to those of Example 40. MS (ES−): m/z 347.1 (M−H). 1H NMR: (CD3OD, 400 MHz) δ 7.90 (s, 1H), 7.49 (dd, J=0.8, 8.2, 1H), 7.27 (d, J=8.2, 1H), 2.31 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][OH:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:13](OC=C)(=[O:15])[CH3:14]>>[C:13]([O:10][CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:11][OH:12])(=[O:15])[CH3:14]
Reactant: C=COC(C)=O
Reactant: OCC(CO)c1ccc(Br)cc1
Product: CC(=O)OCC(CO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 65 %

Procedure:
To a solution of 2-(4-bromophenyl)propane-1,3-diol (9.01 g, 39.0 mmol) in vinyl acetate (100 ml) was added Lipase AK Amano (purchased from WAKO, 12.0 g) at room temperature. The mixture was stirred at room temperature for 11 hours and filtered through a pad of Celite to remove solid materials. After concentration, to the residue dissolved into ethanol (35 ml) and diisopropyl ether (200 ml) was added Lipase from porcine pancreas (type II, purchased from SIGMA, 22.2 g). The mixture was stirred at room temperature for 107 hours and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=2/1) to afford (−)-2-(4-bromophenyl)-3-hydroxypropyl acetate as colorless oil (6.88 g, 65%). [α]D=−11.2 (C=0.5, CHCl3).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[N:14]3)=[CH:5][CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:14]1[C:15]2[C:10](=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2cccc3ncccc23)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(-c2cccc3ncccc23)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 5-(4-methoxyphenyl)quinoline (compound 28) (1.08 g) in methylene chloride (10 ml), a solution of boron tribromide in methylene chloride (1.0 M) (5.5 ml) was added at -40° C. under the inert atmosphere. The reaction mixture was stirred at room temperature for 15 hrs, then it was poured into a cooled solution of sodium hydrocarbonate (NaHCO3). The solution was extracted with ethyl acetate and then the organic layer was washed with satd. NH4Cl aq, water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The concentrate was crystallized with ethyl ether-methanol (10:1). The resulting precipitate was collected by filtration. 4-(quinoline-5-yl)phenol (29) was obtained as a yellow crystal (0.82 g).