Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:12][CH:13]=[C:14]([C:16]([OH:18])=O)[N:15]=2)=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[N:39]1([CH2:44][CH2:45][CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)[CH:43]=[CH:42][N:41]=[N:40]1>ClCCl.C(OCC)(=O)C>[N:39]1([CH2:44][CH2:45][CH2:46][CH2:47][C:48]2[CH:49]=[CH:50][C:51]([NH:54][C:16]([C:14]3[N:15]=[C:11]([CH:10]=[CH:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:19])=[CH:8][CH:7]=4)[O:12][CH:13]=3)=[O:18])=[CH:52][CH:53]=2)[CH:43]=[CH:42][N:41]=[N:40]1
Reactant: O=C(O)c1coc(C=Cc2ccc(C(F)(F)F)cc2)n1
Reactant: Nc1ccc(CCCCn2ccnn2)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CCCCn2ccnn2)cc1)c1coc(C=Cc2ccc(C(F)(F)F)cc2)n1
Reaction time: 20 h

Procedure:
2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-oxazole-4-carboxylic acid (100 mg, 0.35 mmol), N-ethyl-N′-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (101 mg, 0.53 mmol), 1-Hydroxybenzotriazole hydrate (73 mg, 0.53 mmol) and triethylamine (71 mg, 0.71 mmol) are suspended in dichloromethane (5 ml). After stirring at room temperature for 15 min 4-(4-[1,2,3]Triazol-1-yl-butyl)-phenylamine (84 mg, 0.39 mmol) is added and stirring is continued for 20 h. Ethyl acetate (10 ml) is added and the mixture washed with aq. HCl (1N, 10 ml), sat. NaHCO3, (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/heptane 9:1) yielding 2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole-4-carboxylic acid [4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-amide 11 as a colorless solid. Yield 109 mg (64%); m.p. 183–185° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:18][CH2:17][C:12]3([O:13][CH2:14][CH2:15][O:16]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Fc1ccc(C=C2CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Fc1ccc(CC2CCC3(CC2)OCCO3)cc1
Reaction time: 2.5 h

Procedure:
To a stirring degassed solution of 8-[(4-fluorophenyl)methylene]-1,4-dioxaspiro[4.5]decane (18.9 g, 76 mmol) and 10% palladium on carbon (3.8 g, Aldrich) in 500 mL of ethyl acetate was added 40 psi of hydrogen gas. The reaction was stirred for 2.5 h and then filtered through a pad of silica gel. The silica gel was washed with ethyl acetate (300 mL). The organic layers were combined and conc in vacuo to a colorless oil yielding 18.0 g. MS (ESI) 253 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[Cl:28].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(Cl)cc(Cl)cc2Cl)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c2nc(Nc3c(Cl)cc(Cl)cc3Cl)n(CCCO)c12
Temperature: 50 °C
Reaction time: 14 h
Yield: 96.3 %

Procedure:
A mixture of methyl 4-chloro-2-[(3-hydroxypropyl)amino]-3-{[(2,4,6-trichlorophenyl)carbamothioyl]amino}benzoate (285 mg, 0.574 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.631 mmol) and triethylamine (0.0880 mL, 0.631 mmol) in tetrahydrofuran (6 mL) was stirred at 50° C. for 14 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (256 mg, 0.553 mmol, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[C:19](O)=[O:20].O.ON1C2C=CC=CC=2N=N1.CCN(CC)CC>C(Cl)Cl>[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[C:19]([N:13]1[CH2:12][CH2:11][NH:10][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14]1)=[O:20]
Reactant: Clc1ccc(C2CNCCN2)cc1Cl
Reactant: Cc1cc(C)cc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(C(=O)N2CCNC(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 57.8 %

Procedure:
To a cooled solution of CH2Cl2 (600 mL) containing 2-(3,4-dichlorophenyl)piperazine (6.934 g, 30 mmol), 3,5-dimethylbenzoic acid (4.55 g, 30 mmol), and N-hydroxybenzotriazole monohydrate (4.05 g, 30 mmol) at -20° C. were added Et3N (4.2 mL, 30 mmol) and N,N-dimethylaminopropylethylcarbodimide (DEC) (5.86 g, 30 mmol) under nitrogen. The reaction was kept at -20° C. for an hour and gradually warmed to RT overnight. After stirring 22 hours, the reaction was complete and CH2Cl2 (200 mL) was added. The organic solution was washed with brine (150 mL, 3×), dried over MgSO4, filtered and concentrated under vacuum to give 8.2 g of crude product. The product was crystallized from CH2Cl2 /Hexane to give a light yellow solid (6.3 g, 17.34 mmol, 57.8%). M.p. 139°-141° C.; FAB MS [M+1]+ 35 Cl 363.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)(=O)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][S:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[O:31])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CSc2ccccc2F)CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(CS(=O)c2ccccc2F)CC1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
After dissolving 79 mg of 1-(tert-butoxycarbonyl)-4-[(2-fluorophenylthio)methyl]piperidine in 3 ml of chloroform, 42 mg of 3-chloroperbenzoic acid was added while cooling on ice, and the mixture was stirred for 30 minutes. Aqueous sodium thiosulfate solution was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (68 mg, 82% yield).
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:23])[N:12]([CH2:14][CH2:15][O:16]C3CCCCO3)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[C:24]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:23])[N:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: CO
Solvent: O
Product: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCO
Reaction time: 48 h
Yield: 55.5 %

Procedure:
To a stirring solution of 5-(diphenylmethyl)-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-2(1H)-pyridinone (46 mg) in MeOH (1.38 mL) was added pyridium p-toluenesulfonate (9 mg) at ambient temperature. After 48 hours, water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:EtOAc=1:2) to give 5-(diphenylmethyl)-1-(2-hydroxyethyl)-2(1H)-pyridinone (20 mg).
Reaction SMILES: Cl.[Sn](Cl)Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:8]([N+:18]([O-])=O)[CH:7]=1.C(=O)(O)[O-].[Na+]>CO>[F:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:8]([CH:7]=1)[NH2:18]
Reactant: O=[N+]([O-])c1cc(F)ccc1N1CCCCC1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1cc(F)ccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 100.5 %

Procedure:
Concentrated hydrochloric acid (1.20 ml, 14.4 mmol) and anhydrous tin dichloride (1.22 g, 6.43 mmol) were sequentially added at 0° C. to a methanol (5 ml) solution of 1-(4-fluoro-2-nitrophenyl)piperidine (289 mg, 1.28 mmol), obtained as described in Referential Example 17-1. The resulting mixture was warmed to room temperature and stirred for 21 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture. The mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25 g, hexane/ethyl acetate=12/1). Thus, 5-fluoro-2-(1-piperidinyl)aniline (250 mg, quant.) was yielded as a colorless oily material.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH:19]C=O)=[N:13][C:14]=2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:25](O)(=[O:27])C>CO>[NH2:19][C:12]1[N:11]=[C:10]2[C:15]([N:16]=[CH:17][N:9]2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([O:27][CH3:25])[N:13]=1
Reactant: O=CNc1nc(Cl)c2ncn(OCc3ccccc3)c2n1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc2c1ncn2OCc1ccccc1
Yield: 76 %

Procedure:
A mixture of 9-benzyloxy-6-chloro-2-formamidopurine (440 mg, 1.60 mmol), 1.2M sodium methoxide in methanol (5.3 ml) and methanol (10 ml) was heated at reflux temperature for 1 hour and then cooled. Acetic acid (4 ml) was added and the solution evaporated to dryness. The residue was suspended in water and extracted with chloroform (2×25 ml). The combined chloroform extracts were washed with brine, dried (magnesium sulphate) and evaporated under reduced pressure. Column chromatography on silica gel (eluted with chloroform-methanol, 100:1) afforded the title compound (331 mg, 76%). IR: νmax (KBr) 3480, 3310, 1625, 1585, 1505, 1485, 1460, 1400 cm-1 ; 1H NMR: δH [(CD3)2SO] 3.96 (3H, s, CH3), 5.31 (2H, s, CH2Ph), 6.64 (2H, br.s, D2O exchangeable, NH2), 7.42 (5H, s, Ph), 7.75 (1H, s, H-8). Found: C, 57.18, H, 4.84; N, 25.85%). m/z 271.1075. C13H13N5O2 requires: C, 57.56, H, 4.83, N, 25.82%; m/z 271.1069.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]([CH3:20])[CH3:19])[N:13]=[CH:12]2)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>CO>[CH:18]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[N:13]1)([CH3:20])[CH3:19]
Reactant: CC(C)n1ncc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: F
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)n1ncc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
5-{[tert-Butyl(dimethyl)silyl]oxy}-1-isopropyl-1H-indazole (Preparation 40, 238 mg, 0.819 mmol), triethylamine trishydrofluoride (132 mg, 0.819 mmol) and methanol were combined and stirred at room temperature for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated in vacuo and the residue redissolved with methanolic ammonia and again concentrated in vacuo. The procedure was repeated once more and the residue purified by silica gel chromatography eluting with 0 to 30% EtOAc in heptane to yield the title compound (123 mg, 86%):
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11](C)[CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27]>O>[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[O:10])=[CH:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CN(Cc1ccncc1)C(=O)Nc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(NC(=O)NCc2ccncc2)cc1
Reaction time: 0.5 h

Procedure:
To a chilled (circa 0° C.) solution of 5.12 gms. (0.02 mole) of 1-(p-aminophenyl)-3-methyl-3-(4-pyridylmethyl)urea (Example 6., supra.) in 75 ml. of pyridine there is added dropwise 1.48 gms. (0.02 mole) of acetyl chloride with stirring, while maintaining the temperature of the reaction mixture at circa 0° C. Stirring is continued for 30 minutes and then the reaction mixture is allowed to stand at room temperature overnight. Solvent is stripped and the residue suspended in water. Upon removal of the water there is obtained 1-(p-acetamidophenyl)-3-(4-pyridylmethyl)urea.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11]C1CCCC1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:17][C:18]([CH3:22])([CH3:21])[CH:19]=O.[Si](OCCN)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:19][C:18]([CH3:22])([CH3:21])[CH3:17])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CCCC1
Reactant: CC(C)(C)C=O
Agent: CC(C)(C)[Si](C)(C)OCCN
Product: CC(C)(C)CNCCO[Si](C)(C)C(C)(C)C

Procedure:
This compound was prepared following the same method as described for [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopentyl-amine (8e) from 2,2-dimethyl-propionaldehyde (1 g, 11.61 mmol) and 2-(tert-butyl-dimethylsilanyloxy)-ethylamine (8c) (2.0 g, 11.6 mmol) as colorless oil (1.1 g, 38.6%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C@@H:9]([NH:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:29][CH3:30])[N:20]2C2CCCCO2)=[C:16]([NH2:31])[N:15]=1)[CH2:10][CH2:11][CH3:12]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C@@H:9]([NH:13][C:14]1[NH:22][C:21]2[C:17]([N:18]=[C:19]([O:29][CH3:30])[N:20]=2)=[C:16]([NH2:31])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Nc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Nc1nc(N)c2nc(OC)nc-2[nH]1
Yield: 103.3 %

Procedure:
Trifluoroacetic acid (1 ml, 1.48 g, 7.08 mmol) was added to a stirred solution of N2-[(1R)-1-methylbutyl]-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (0.613 g, 1.833 mmol) in methanol (10 ml). The resultant mixture was stirred for 66 hours under an atmosphere of nitrogen and then evaporated to give the title compound as an off-white solid (0.690 g).
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:18]3[C:9](=[CH:10][C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=4)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:27]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:27][C:17]1[C:18]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:13]=[CH:12]3)=[CH:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:20][CH:19]=2
Reactant: c1ccc(-c2ccc3cc4cc(-c5ccccc5)ccc4cc3c2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1c2ccc(-c3ccccc3)cc2cc2ccc(-c3ccccc3)cc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 81.9 %

Procedure:
First, 33.0 g of 2,6-diphenylanthracene were dissolved in 200 mL of N,N-dimethylformamide under heat, and then a solution of 18.0 g of N-bromosuccinimide in 20 mL of N,N-dimethylformamide was added to the solution. The mixture was stirred at 60° C. for 6 hours under heat. After having been cooled to room temperature, the reaction solution was poured into 1 L of water. The resultant solid was sequentially washed with methanol, water, and methanol. After that, the solid was repeatedly recrystallized with toluene and hexane and washed. Thus, 33.5 g of 9-bromo-2,6-diphenylanthracene were obtained (in 82% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=O)[C:24](F)(F)F)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[C:30]1[C:31](C2C=CN=CC=2)=C(C2C=CC(F)=CC=2)N([Si](C(C)C)(C(C)C)C(C)C)[CH:34]=1.C1C2N(CCC(=O)C2)CC1.C(N1CCC(=O)CC1)C1C=CC=CC=1>>[CH2:34]1[CH:30]2[N:22]([CH2:21][CH:20]=[C:19]([C:11]3[C:12]([C:13]4[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=4)=[C:8]([C:5]4[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=4)[NH:9][CH:10]=3)[CH2:31]2)[CH2:23][CH2:24]1
Reactant: O=C(NCCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)C(F)(F)F
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c(-c2ccncc2)c1-c1ccc(F)cc1
Agent: O=C1CCN(Cc2ccccc2)CC1
Agent: O=C1CCN2CCCC2C1
Product: C1=C(c2c[nH]c(-c3ccccc3)c2-c2ccncc2)CC2CCCN2C1

Procedure:
In a similar manner to the procedures described in Examples 9(i) and 9(iii) above, coupling, dehydration and desilylation reactions were carried out using 4-bromo-2-phenyl-3-(pyridin-4-yl)-1-triisopropylsilyl-1H-pyrrole (prepared as described in Preparative Example 2 below), instead of 4-bromo-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1-triisopropylsilyl-1H-pyrrole, and (±)-1,2,3,5,6,7,8,8a-octahydroindolizine-7-one, instead of 1-benzylpiperidine-4-one, as starting materials to afford a mixture of the title compound and the (1,2,3,5,6,8a-hexahydroindolizin-7-yl) isomer thereof (which is the compound of Example 100 below). The mixture was separated by chromatography on a silica gel column using a 30:1 by volume mixture of ethyl acetate and isopropylamine as the eluant to give the title compound (yield 14%, Rf value=0.24) as a pale brown powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1I>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:18]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[F:22])(=[O:20])=[O:19])[CH:14]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccccc1I
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ccccc1F
Yield: 29.9 %

Procedure:
The title compound was prepared from sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (2.2 g, 7.13 mmol) and 1-fluoro-2-iodobenzene (820 μL, 7.03 mmol) according to the method of Example 6 Step 4. Purification by flash column chromatography eluting with 60% dichloromethane/isohexane gave 2-(4-fluorophenyl)-6-[(2-fluorophenyl)sulfonyl]naphthalene (0.80 g, 30%). 1H NMR (500 MHz, CDCl3) δ 8.66 (1H, s), 8.20-8.18 (1H, m), 8.07 (1H, d, J=8.5 Hz), 8.03 (1H, s), 7.98 (1H, d, J=8.7 Hz), 7.94 (1H, d, J=8.7 Hz), 7.83 (1H, dd, J=1.7, 8.5 Hz), 7.71-7.62 (2H, m), 7.60-7.56 (1H, m), 7.38-7.30 (1H, m), 7.21-7.17 (2H, m), 7.14-7.05 (1H, m).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[NH:29][CH2:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:29]([C:23]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=2[CH3:21])[CH2:30][C:31]2[NH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: Cc1ccc(NCc2ncc[nH]2)c(C)c1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2ccc(C)cc2C)[C@@H]1O
Yield: 33.7 %

Procedure:
The title compound (231 mg, 33%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (400 mg, 1.42 mmol) and 2,4-dimethylphenyl-1H-imidazol-2-ylmethylamine (287 mg, 1.42 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9]([CH3:11])[C:8]([O:12]C(=O)C)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].Cl>>[CH3:1][S:2]([C:5]1[N:10]=[C:9]([CH3:11])[C:8]([OH:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(=O)Oc1ccc(S(C)(=O)=O)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(S(C)(=O)=O)ccc1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
Acetic acid 6-methanesulfonyl-2-methyl-pyridin-3-yl ester (331 mg, 1.44 mmol) was added to 4 M aqueous sodium hydroxide solution (2 mL) at 0° C. to give a suspension, and the mixture was stirred at 0° C. for 15 min and then at room temperature for 1 h. 2 M Aqueous hydrochloric acid was added to bring the pH to 6, and the mixture was extracted four times with ethyl acetate. The organic layers were combined and the solvent was evaporated under vacuum to give 6-methanesulfonyl-2-methyl-pyridin-3-ol (261 mg, 97%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 2.38 (s, 3H), 3.13 (s, 3H), 7.29 (d, 1H, J=8.4 Hz), 7.72 (d, 1H, J=8.2 Hz), 11.01 (br s, 1H).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Zn+])=[CH:5][CH:4]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[NH:14][N:13]=1>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]nc(Cc2ccc(Cl)cc2)c2ccccc12

Procedure:
A solution of (4-chlorobenzyl)zinc(II) chloride in THF was added to a suspension of 4-chlorophthalazin-1(2H)-one and Pd(PPh3)4 in THF, and subjected to microwave conditions at 180° C. for 20 minutes. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated to give crude 4-(4-chlorobenzyl)phthalazin-1(2H)-one. This material was treated with O-(diphenylphosphoryl)hydroxylamine similar to that described in Example 1B to give the title compound. LC/MS (APCI) M/Z 286 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:24]=4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.NC1C=C(C2N=C3N(C=2C2C=CN=C(NC4C=CC=C(OCCCN5CCOCC5)C=4)N=2)C=CS3)C=CC=1.[F:75][C:76]1[CH:84]=[CH:83][CH:82]=[CH:81][C:77]=1[C:78](Cl)=[O:79].FC1C=CC=C(F)C=1C(Cl)=O>>[F:75][C:76]1[CH:84]=[CH:83][CH:82]=[CH:81][C:77]=1[C:78]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:24]=4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:3]=1)=[O:79]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1
Agent: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Agent: O=C(Cl)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1)c1ccccc1F

Procedure:
The title compound was prepared as described in EXAMPLE 297, with the following substitutions: 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(2-morpholinoethyl)phenyl)pyrimidin-2-amine for 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(3-morpholinopropoxy)phenyl)pyrimidin-2-amine and 2-fluorobenzoyl chloride for 2,6-difluorobenzoyl chloride. (ESI(+)) m/e 620 (M+H)+; (ESI(−)) m/e 618 (M−H)−; 1H-NMR (300 MHz, DMSO-d6) □ 10.54 (s, 1H), 9.62 (s, 1H), 8.81 (d, 1H), 8.29 (d, 1H), 8.03 (s, 1H), 7.84 (d, 1H), 7.67 (td, 1H), 7.53-7.62 (m, 3H), 7.50 (d, 1H), 7.42-7.48 (m, 1H), 7.30-7.40 (m, 3H), 7.22 (t, 1H), 6.87 (d, 1H), 6.63 (d, 1H), 3.52-3.59 (m, 4H), 3.17 (d, 1H), 3.66-3.77 (m, 2H), 2.51-2.55 (m, 1H), 2.37-2.43 (m, 4H).