Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=1>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:31]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)(=[O:33])=[O:32])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.291 mmol) and 3-pyridinesulfonyl chloride (94 mL, 0.430 mmol), the title compound was obtained as a tan solid (34 mg, 24% yield). MS (ESI): 485.0 [M+H]+.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:38]([F:41])([F:40])[F:39])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@@H:17]([C@:22]([NH:30]C(=O)OC(C)(C)C)([CH3:29])[CH2:23][O:24][P:25]([OH:28])([OH:27])=[O:26])[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(Cl)Cl>>[P:25]([OH:27])([OH:28])([O:24][CH2:23][C@:22]([NH2:30])([C@H:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:6][CH2:7]3)[C:13]=2[C:38]([F:39])([F:41])[F:40])[CH2:18]1)[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(O)O)[C@H]1CCc2c(ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)c2C(F)(F)F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2C(F)(F)F)CC[C@H]([C@@](C)(N)COP(=O)(O)O)C3)CC1
Reaction time: 1 h

Procedure:
tert-Butyl (R)-2-((S)-6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)-1-(phosphonooxy)propan-2-ylcarbamate (22.0 mg, 0.0000362 mol) was dissolved in trifluoroacetic Acid (1.0 mL, 0.013 mol) and methylene chloride (1.0 mL, 0.016 mol) was added and the mixture was stirred for 1 h. Concentration and lypholyzing gave pure (R)-2-amino-2-((S)-6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)propyl dihydrogen phosphate as a white solid (18.0 mg, 98%). LCMS: Rf=1.74min 508.41 [M+1]. 1H NMR (400 MHz, MeOD) δ=7.25 (d, J=9.0 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 4.23 (dd, J=4.9, 11.2 Hz, 1H), 4.18 (m, 1H), 4.03 (dd, J=4.1, 11.3 Hz, 1H), 3.22-2.82 (m, 3H), 2.77-2.64 (m, 1H), 2.15 (d, J=12.6 Hz, 2H), 2.02 (d, J=10.6 Hz, 1H), 1.87 (d, J=13.2 Hz, 2H), 1.56-1.35 (m, 2H), 1.33 (s, 3H), 1.24-1.01 (m, 2H), is 0.89 (s, 9H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl[O-].[Na+].N1C=CC=CC=1.Cl>ClCCl>[C:2]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)(=[O:1])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)c1cc(-c2ccccc2)no1
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)c1cc(-c2ccccc2)no1
Temperature: 20 °C

Procedure:
In 12.5 ml of dichloromethane, 4.4 g (20 mmol) of 5-(1-hydroxybutyl)-3-phenylisoxazole were dissolved. While the solution was being stirred, 35.2 g (60 mmol) of a 12.7% aqueous solution of sodium hypochlorite were added dropwise to the solution. Next, a liquid mixture which had been obtained by adding 0.48 g (6.1 mmol) of pyridine to 1.0 ml of 6 N hydrochloric acid) was added dropwise over 1 hour and the reaction temperature was maintained at 20° C. After completion of the reaction, the organic layer was collected and was washed successively with a 5% aqueous solution of sodium hydrogensulfite, water and 1 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was then recrystallized from ethanol, whereby the target compound, namely, 5-butyryl-3-phenylisoxazole was obtained as crystals.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:15]2[C@@H:6]([CH2:7][CH2:8][C:9]3[C@:14]2([CH3:16])[CH2:13][CH:12]([CH:17]=O)[C:11](=O)[CH:10]=3)[C@@H:5]2[CH2:20][CH2:21][C@:22]3([C:26]4([CH2:30][O:29][CH2:28][O:27]4)[O:25][CH2:24][O:23]3)[C@@:4]2([CH3:31])[CH2:3]1.[F:32][C:33]1[CH:34]=[C:35]([NH:40][NH2:41])[CH:36]=[CH:37][C:38]=1[F:39]>>[F:32][C:33]1[CH:34]=[C:35]([N:40]2[C:11]3[CH:10]=[C:9]4[CH2:8][CH2:7][C@H:6]5[C@H:15]([C@:14]4([CH3:16])[CH2:13][C:12]=3[CH:17]=[N:41]2)[C@H:2]([OH:1])[CH2:3][C@@:4]2([CH3:31])[C@@:22]3([CH2:21][CH2:20][C@H:5]52)[C:26]2([CH2:30][O:29][CH2:28][O:27]2)[O:25][CH2:24][O:23]3)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: NNc1ccc(F)c(F)c1
Reactant: C[C@]12CC(C=O)C(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@@]21OCOC12COCO2
Product: C[C@@]12Cc3cnn(-c4ccc(F)c(F)c4)c3C=C1CC[C@H]1[C@H]2[C@H](O)C[C@]2(C)[C@@H]1CC[C@]21OCOC12COCO2

Procedure:
The compound was prepared from (8S,9S,10R,11S,13S,14S,17R)-11-hydroxy-10,13-dimethyl-3-oxo-1,2,3,6,7,8,9,10,11,12,13,14,15,16-tetradecahydrodispiro[cyclopenta[a]phenanthrene-17,4′-[1,3]dioxolane-5′,4″-[1,3]dioxolane]-2-carbaldehyde and (3,4-difluorophenyl)hydrazine according to the procedure for Intermediate 50. APCI-MS m/z: 541 [MH+].
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([O:11][CH3:12])=[C:8]([OH:10])[CH:9]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:15]([O:10][C:8]1[CH:9]=[C:4]([Br:3])[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:11][CH3:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(Br)cc(O)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)cc(OCc2ccccc2)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaH (60% in mineral oil, 300 mg) was added in 3 equal portions to a cooled 0° C. solution of 5-bromo-2,3-dimethoxyphenol (1.16 g) in DMF (10 mL) After 20 minutes, benzyl bromide (0.9 ml) was added, and the reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was then poured into 100 mL of water and extracted with ethyl acetate (4×50 mL). The combined organic layer was then washed with water (4×75 mL) followed by brine (75 mL) and then dried over sodium sulfate and concentrated under vacuum. Chromatography on silica with 5% ethyl acetate/hexane provided 3-benzyloxy-4,5-dimethoxybromobenzene as a colorless oil (1.4 g). 1H NMR (400 MHz) (CDCl3) δ 3.87 (s, 6H), 5.12 (s, 2H), 6.75 (s, 1H), 6.80 (s, 1H), 7.34-7.47 (m, 5H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32]([OH:34])=O)=[CH:23][CH:22]=1)([OH:19])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:17](=[O:19])[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:34])=[CH:23][CH:22]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(CC(=O)O)c2ccccc12
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)Cc1ccc(CC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)c2ccccc12
Yield: 74.1 %

Procedure:
Using General Procedure A with 200 mg (0.82 mmol) D-Proline benzyl ester hydrochloride and 100 mg (0.41 mmol) (4-carboxymethyl-naphthalen-1-yl)-acetic acid afforded, after flash chromatography (EtOAc), 188 mg (75%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH:11]3[CH2:13][CH:8]2[CH2:9][NH:10]3)=[CH:4][C:3]=1[O:16][CH3:17].[Cl:18][C:19]1[C:20]([C:29]([F:32])([F:31])[F:30])=[N:21][N:22]([CH2:25][C:26](O)=[O:27])[C:23]=1[CH3:24].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH:11]3[CH2:13][CH:8]2[CH2:9][N:10]3[C:26](=[O:27])[CH2:25][N:22]2[C:23]([CH3:24])=[C:19]([Cl:18])[C:20]([C:29]([F:32])([F:31])[F:30])=[N:21]2)=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COc1cc(CN2CC3CC2CN3)ccc1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CN2CC3CC2CN3C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(4-Chloro-3-methoxybenzyl)-2,5-diazabicyclo[2.2.1]heptane (96 mg), (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)acetic acid (96.8 mg), triethylamine (0.252 mL) in DMF (2 mL) was stirring at room temperature and a solution of T3P (50% in EtOAc, 0.55 mL) was slowly added. The reaction mixture was stirred at room temperature for 1 h and purified on preparative HPLC to afford 1-[5-(4-Chloro-3-methoxybenzyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(4-chloro-5-methyl-3-trifluoromethylpyrazol-1-yl)ethanone as white powder. LCMS (ES) M+H 477.0, Rf 3.975 min (acetonitrile/H2O 20-95% method).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]2[CH3:32])[CH2:20][CH2:19]1)=[O:17].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:3]([C:16]([N:18]3[CH2:19][CH2:20][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[C:24]4[CH3:32])[CH2:22][CH2:23]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)C(C)=Cc3ccccc34)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccccc3)c(C(=O)N3CCC4(CC3)C(C)=Cc3ccccc34)cnc12
Yield: 77.1 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.220 g, 0.488 mmol) obtained in step 2 and aniline (0.054 mL, 0.585 mmol), the title compound (0.191 g, 79%) was obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32](C)[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(OC(Cl)C)=O.[I-].[Na+]>ClCCCl>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Agent: CC(Cl)OC(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc(N2CCNCC2)c2oc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Yield: 63.6 %

Procedure:
Into a 50 mL round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 50 mg (0.115 mmol, 1.0 equiv.) of 6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (Example 31) and 10 mL of 1,2 dichloroethane. To this solution is then added via syringe 49 mg, 37 μL (0.348 mmol, 3.0 equiv.) of 1-chloroethyl chloroformate. A precipitate forms, indicating formation of an intermediate. The reaction is heated to reflux for 3 days, whereupon an analysis of an aliquot by LC/MS indicates only a trace of product has formed. At this time 52 mg (0.345 mmol, 3.0 equiv.) of sodium iodide are added to the refluxing reaction. LC/MS analyses then progressively show formation of demethylated product over 5 additional days. The reaction is then cooled, concentrated on a rotary evaporator, then dried over K2CO3 as a suspension in methylene chloride containing methanol, removal of solids by filtration, followed by flash chromatography of the solution, using a gradient of 5 to 20% methanol in methylene chloride, gives 34 mg (64%) of the pure product as a reddish solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]C2CCCCO2)=[C:7]([CH3:22])[C:6]=1[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:3])[CH3:2].Cl.O>O1CCCC1>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]([OH:15])=[C:7]([CH3:22])[C:6]=1[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(OC2CCCCO2)c(C)c1C(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
1-Acetoxy-2,6-di-tert-butyl-3-methyl-4-tetrahydropyranyloxybenzene (4.09 g) was dissolved in tetrahydrofuran (20 ml). After adding 10% HCl (3 ml), the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and subjected to extraction with diethyl ether. The extract was washed with 5% aqueous sodium hydrogen carbonate and saturated brine, then dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was recrystallized from n-hexane to afford 4-acetoxy-3,5-di-tert-butyl-2-methylphenol (3.1 g) as a colorless needle.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:11]=[CH:10]3)[N:5]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1.[OH-].[Na+].Cl[C:30]([O:32][C:33]([CH3:35])=[CH2:34])=[O:31]>CCOC(C)=O>[C:23]([C:4]1[CH:3]=[C:2]([NH:1][C:30]([O:32][C:33]([CH3:35])=[CH2:34])=[O:31])[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]=[CH:10]3)[N:5]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: C=C(C)OC(=O)Cl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(-n3nc(C(C)(C)C)cc3N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(C(C)(C)C)nn1-c1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A solution of tert-butyl 5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (see WO 2006/071940A2, 0.64 g, 1.80 mmol) in EtOAc (6 mL) was treated with 1M aq NaOH (2.7 mL). To the stirring biphasic reaction mixture at 0° C. was added isopropenyl chloroformate (0.26 mL) dropwise over 1 min. The reaction mixture was stirred for 4 h at RT. The reaction was diluted with EtOAc (20 ml). The organic layer was washed with H2O (2×10 ml), brine (10 ml) dried (MgSO4) and concentrated to afford tert-butyl 5-(3-tert-butyl-5-((prop-1-en-2-yloxy)carbonylamino)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (0.69 g, 87% yield) as a light yellow foam. 1H NMR (DMSO-d6) δ 9.77 (s, 1H), 8.52 (s, 1H), 8.17 (d, J=9 Hz, 1H), 7.97 (d, J=2 Hz, 1H), 7.74 (dd, J=9, 2 Hz 1H), 6.34 (s, 1H), 4.7 (m, 2H), 1.80 (s, 3H), 1.67 (s, 9H), 1.30 (s, 9H); MS (ESI) m/z: 440.2 (M+H+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][C:24]([F:27])([F:26])[F:25])[NH2:19]>CS(C)=O.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])[CH:20]=[CH:21][C:22]=1[O:23][C:24]([F:26])([F:27])[F:25]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(Nc2ccc(OC(F)(F)F)c(Cl)c2)c1
Yield: 37.6 %

Procedure:
A solution of methyl 3-fluoro-4-nitrobenzoate (1.99 g, 10 mmol) and 3-chloro-4-(trifluoromethoxy)aniline (4.23 g, 20 mmol) in dimethylsulfoxide (10 mL) was stirred at 160° C. for 2 days. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) and recrystallized from hexane/ethyl acetate to give the title compound (1.47 g, yield 38%) as orange crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1cccc(Cl)c1
Product: NS(=O)(=O)Oc1cccc(Cl)c1
Yield: 7.6 %

Procedure:
By the procedure of Example 34,96 g (0.75 mole) of 3-chlorophenol and 67.5 ml (0.75 mole) of chlorosulfonyl isocyanate gave 122.9 g of solid product. A 25 g portion was recrystallized from 100 ml of toluene to give 11.8 g of white solid, mp 82°-83° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][C:18]([OH:29])=[O:17])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Reactant: ClCc1cccc(SC2CCCC2)n1
Product: O=C(O)CCc1ccc(OCc2cccc(SC3CCCC3)n2)c(Cl)c1
Yield: 57.4 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (46 mg, 0.20 mmol) obtained in Step C of Preparation Example 27 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (51 mg, 0.22 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (45 mg, 71%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[N:24][CH:25]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[N:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)Cc1ccc(N)cn1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: COC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cn1
Yield: 71 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.110 g, 0.36 mmol) was reacted with methyl 2-(5-aminopyridin-2-yl)acetate (0.067 g, 0.40 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.110 g, 74%) as a white solid. MW=466.79. 1H NMR (DMSO-d6, 500 MHz) δ 14.31 (s, 1H), 10.00 (s, 1H), 8.63 (d, J=2.5 Hz, 1H), 7.97-7.93 (m, 2H), 7.78-7.75 (m, 1H), 7.69-7.66 (m, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.12 (s, 1H), 3.95 (s, 2H), 3.65 (s, 3H), 3.19 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.26 (quin, J=7.5 Hz, 2H); APCI MS m/z 394 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]1[OH:15])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1O.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:15][C@@H:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH2:14][C@H:5]1[CH2:4][N:2]([CH3:1])[CH3:3]
Reactant: COc1ccccc1O
Reactant: CN(C)C[C@@H]1CCc2ccccc2[C@H]1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COc1ccccc1O[C@@H]1c2ccccc2CC[C@H]1CN(C)C
Reaction time: 2 h

Procedure:
A mixture of 8.21 g (0.04 M) of TRANS-1,2,3,4-tetrahydro-2-(N,N-dimethylaminomethyl)naphthalen-1-ol, 11.54 triphenyl phosphine, 5.46 g (0.044 M) of triphenyl phosphine, 5.46 g (0.044 M) of 2-methoxyphenol and 100 ml of benzene was stirred and a solution of 7.83 g (0.004 M) of 95% diethyl azodicarbox-ylate in 25 ml of benzene was added dropwise over 45 minutes. After 2 hours, the mixture was filtered and extracted with cold 3% hydrochloric acid. The acid extracts were made basic with dilute sodium hydroxide and the oil which separated was extracted into ether. The solvent was removed and the residual oil chromatographed on silica gel.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)=[CH:17][C:16]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][O:27][C:2]3[CH:12]=[C:6]4[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]4[C:4](=[O:13])[N:3]=3)=[CH:24][CH:25]=2)=[CH:17][C:16]=1[C:30]([F:31])([F:32])[F:33]
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)methanol.
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH:3]=[CH2:4].[Sn](Cl)(Cl)(Cl)[Cl:16]>>[CH2:2]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:16])[C:7]=1[NH2:12])[CH:3]=[CH2:4]
Reactant: C=CCNc1ccncc1[N+](=O)[O-]
Reactant: Cl[Sn](Cl)(Cl)Cl
Agent: Cl
Product: C=CCNc1ccnc(Cl)c1N
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
55 ml of 35% hydrochloric acid was added to 3.02 g of allyl-(3-nitropyridin-4-yl)amine, and the mixture was heated to 90° C. 19.1 g of tin chloride was added to the solution, and the mixture was kept at 90° C. for 30 minutes. The reaction solution was cooled in an ice-water bath, and then 250 ml ice/water was added thereto. The reaction solution was concentrated under reduced pressure, and then 250 ml of ammonia-saturated methanol was added thereto. The mixture was stirred for 20 hours. 750 ml of ethyl acetate was added to the solution, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.88 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:29]2[O:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1ccc(O)cc1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.1 %

Procedure:
To a 25 mL vial which contained a suspension of -(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (293 mg, 1 mmol) and dry Cs2CO3 (400 mg, 1.2 mmol) in anhydrous acetone (15 mL) was added 2-chloro-benzooxazole (154 mg, 1 mmol) at rt. The reaction mixture which resulted was allowed to stir at rt for 72 h. The mixture was poured onto 100 mL ice-water solution and this solution was allowed to stir at 0° C. for 1 h. The solid formed was filtered out, dried through air to provide the title product (300 mg, 75%); LCMS; 88% APCI+, Calcd: 410.50. Found m/z: 411.28 (M+1). 1H NMR (400 MHz, CDCl3); δ 1.48 (s, 9H), 1.78-2.01 (m, 4H), 3.28-3.46 (m, 2H), 3.73-3.97 (m, 1H), 4.08-4.21 (m 2H), 6.93-7.02 (m, 2H), 7.18-7.33 (m, 4H), 7.41 (d, J=7.2 Hz, 1H), 7.50 (d, J=7.2 Hz, 1H)