Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(N(C(C)C)CC)(C)C.[O:43]1[CH2:47]CCC1>>[F:1][C:2]([F:7])([F:6])[CH:3]([O:5][C:47]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:43])[C:2]([F:7])([F:6])[F:1]
Reactant: C1CCOC1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC2)cc1
Reaction time: 0.17 h
Yield: 28 %

Procedure:
Triphosgene (1.6 g, 5.5 mmol) was added in portions to a solution of 1,1,1,3,3,3-hexafluoro-2-propanol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 790 mg, 5 mmol) in a mixture of pyridine (0.48 mL, 6 mmol) and carbon tetrachloride (25 mL) under nitrogen. The solution was stirred at 60° C. for 5.5 h and then cooled using an ice bath. 1 M aqueous hydrochloric acid (4 mL) was added and then the mixture was diluted with water and the layers were separated. The organic layer was dried (sodium sulfate), and filtered to give approximately 20 mL of solution, of which 6 mL were used directly in the next reaction without further purification. The solution (7 mL) as added to a mixture of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27; 240 mg, 0.5 mmol) in tetrahydrofuran (1 mL). Diisopropylethylamine (0.5 mL, 2.8 mL) was added slowly and the mixture was stirred for 10 min and then evaporated to dryness and chromatographed using a 30 mm×3″ column of silica gel, eluting with 75% ethyl acetate/hexanes, to give 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 2,2,2-trifluoro-1-trifluoromethyl-ethyl ester (70 mg, 28%) as an off-white powder.
Reaction SMILES: [H-].[Na+].ClCCl.CN(C)C=O.[F:11][C:12]([F:32])([F:31])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[CH2:21][C@@H:22](OS(C)(=O)=O)[CH2:23][CH3:24])=[CH:15][CH:14]=1>O>[CH2:23]([C@H:22]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:32])([F:31])[F:11])=[CH:14][CH:15]=2)[C:20](=[O:30])[CH2:21]1)[CH3:24]
Reactant: CC[C@@H](CC(=O)Nc1ccc(C(F)(F)F)cc1)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
158.7 mg of sodium hydride (60 wt %; 3.97 mmol) was suspended in a mixed solution of dichloromethane (2.7 mL) and dimethylformamide (10.8 mL) and to the solution, a mixed solution of 1,346.2 mg (3.97 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-methanesulfonyloxypentanoic acid amide produced in Example 3, dichloromethane (2.7 mL) and dimethylformamide (10.8 mL) was added dropwise at room temperature for 15 minutes. After stirring at room temperature for further 1 hour, water (25 mL) was added and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine and the product was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone as a brown solid (996.3 mg, crude yield: 87%). The optical purity of the product was determined by HPLC analysis (column; Daicel Chiral Pack AD-H 4.6×250 mm: eluent; hexane/isopropanol=95/5: flow rate; 1.0 mL/min: column temperature; 30° C.: detector; UV 210 nm: retention time; (S) antipode=7.6 minutes, (R) antipode=8.8 minutes) to be 83.0% ee. 1H-NMR (CDCl3, 400 MHz/ppm): δ 0.99 (3H, t), 1.63-1.73 (1H, m), 2.11-2.21 (1H, m), 2.79 (1H, dd), 3.23 (1H, dd), 4.07-4.13 (1H, m), 7.47 (2H, d), 7.58 (2H, d)
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH:45]#[C:46][CH2:47][CH2:48][CH2:49][CH3:50]>CN(C=O)C.[Cu](I)I>[C:1]([C:5]1[N:10]=[C:9]([C:45]#[C:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2Cl)CN(C(=O)OC(C)(C)C)C1
Reactant: C#CCCCC
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCC#Cc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate (300 mg), dichloro[bis(triphenylphosphine)]palladium (412 mg), copper iodide (112 mg) and N,N-diisopropylethylamine (0.51 μL) were dissolved in DMF (8 ml), and the mixture was stirred at room temperature for 15 min. 1-Hexyne (0.08 ml) was added and the mixture was stirred at room temperature 2 hr, and further at 70° C. for 8 hr. The mixture was cooled to room temperature, adsorbed to silica gel (10 g), and a fraction eluted with ethyl acetate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with hexane-ethyl acetate (95:5-30:70) was concentrated under reduced pressure to give the object product (218 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([OH:17])[C:11]3[S:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:25][C:26]([F:32])([F:31])[S:27](O)(=[O:29])=[O:28]>C(Cl)Cl>[F:25][C:26]([F:32])([F:31])[S:27]([O:17][C:10]1[C:11]2[S:16][CH2:15][CH2:14][C:12]=2[N:13]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Oc1nc(-c2cccc(Cl)c2)nc2c1SCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1nc(-c2cccc(Cl)c2)nc2c1SCC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
To a suspension of 2-(3-chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (1.9 g, 7.2 mmol) in methylene chloride (50 mL) at 0° C. was added N,N-dimethylaminopyridine (0.020 g, cat.), triethylamine (2.0 mL, 14.4 mmol) and trifluoromethanesulfonic acid (1.3 mL, 7.9 mmol). The suspension was warmed to rt and stirred for 3 h. The mixture was cooled to 0° C. and the reaction was quenched with a saturated solution of NaHCO3. The organic layer was washed a saturated solution of NaHCO3 and brine. The organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (1.23 g, 44%) as a light yellow solid. MW=396.79. 1H NMR (CDCl3, 500 MHz) δ 8.35-8.32 (m, 1H), 8.24-8.20 (m, 1H), 7.48-7.38 (m, 2H), 3.59-3.49 (m, 4H); APCI MS m/z 397 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([C:32](=[O:33])[CH2:31][N:7]2[C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])[N:3]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)[C:2]2=[O:1])=[CH:35][CH:36]=1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(OCC(F)(F)F)cc(=O)[nH]c2=O)cc1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cn2c(=O)cc(OCC(F)(F)F)n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethoxy)-3,4-dihydropyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.65 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.33 g) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.071 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.59 g, 91%).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24](Br)=[O:25].[CH3:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][N:9]1[CH2:23][C:24]([NH:31][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[CH3:27])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1CN
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccccc1)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccccc1)N(CC(=O)NCc1ccccc1C)CC2

Procedure:
prepared by reaction of 1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methylbenzylamine
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[CH2:21]([NH:28][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)cc1NCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2,4-Difluoronitrobenzene E-1.1′″ (3.448 ml; 31.429 mmol) is dissolved in dioxane (35.000 ml). DIPEA (6.601 ml; 40.857 mmol) and benzylamine (3.429 ml; 31.429 mmol) are added. The reaction mixture is stirred at 50° C. overnight. The reaction mixture is concentrated under reduced pressure. The residue crystallises after some minutes. It is triturated with diethyl ether to give the pure crystalline compound.
Reaction SMILES: [P:1]([O-:28])([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].COC(C)(C)C.N12CCCNC1C=CCCC2.[C:46]([S:50][CH2:51][C:52](=[O:54])[CH3:53])([CH3:49])([CH3:48])[CH3:47]>C1(C)C=CC=CC=1.CS(C)=O>[C:46]([S:50][CH2:51][C:52]([OH:54])([CH3:53])[P:1]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:28])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:49])([CH3:48])[CH3:47]
Reactant: CCCCCCCCCCCCOP([O-])OCCCCCCCCCCCC
Reactant: CC(=O)CSC(C)(C)C
Agent: C1=CC2NCCCN2CCC1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CCCCCCCCCCCCOP(=O)(OCCCCCCCCCCCC)C(C)(O)CSC(C)(C)C
Temperature: 60 °C

Procedure:
23.0 g (55 mmol) of didodecyl phosphite are initially introduced into a mixture of 20 ml of tert-butyl methyl ether and 5 ml of dimethyl sulfoxide. 1.0 g of 1,8-diazabicyclo[5.4.0]undec-5-ene (DBU) are added, and 8.04 g (55 mmol) of (t-butylthio)acetone are then added dropwise at 30° C. The reaction mixture is heated for 5 hours at 60° C., cooled, diluted with 150 ml of toluene and washed with 100 ml of water. The organic phase is dried over sodium sulfate, and the solvent and remainders of the educts are distilled off in vacuo (finally at 0.5 mbar and 55° C. bath temperature).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4][C@H:3]1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([C:35]#[N:36])=[N:15][C:16]=2[NH:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N.[H][H]>C(O)C.[Pd]>[NH2:36][CH2:35][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[C@H:3]2[C@H:2]([OH:1])[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4]2)=[C:16]([NH:20][CH2:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:15]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#N)nc32)[C@H](O)[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CCO
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carbonitrile (preparation 12) (2.15 g, 4.42 mmol) in ethanol (120 ml) saturated with ammonia gas was treated with 5% palladium on charcoal (1 g), pressurised to 1034 kPa (150 psi) with hydrogen in a sealed vessel and stirred at room temperature for 24 hr. The mixture was then filtered through Arbocel (trade mark) and the residue washed with ethanol. The solvent was removed under reduced pressure from the filtrate, the residue dissolved in ethanol and the solvent again removed under reduced pressure. A solid precipitated on re-evaporation which was then dissolved in hot ethanol (100 ml) and the solution cooled and filtered. The residue was washed with ethanol then diethyl ether and dried to give the title compound as an off white solid (1.05 g, 48%). The filtrate and washings were combined and the solvent removed under reduced pressure to give a residue which was then triturated with dichloromethane and a few drops of ethanol and filtered to afford a further portion of product (0.45 g). MS: 491 (MH+).
Reaction SMILES: C([C:5]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:11]=[C:10]2[C:6]=1[C:7]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[C:8]([Br:24])[C:9]2=[O:23])(C)(C)C.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Br:24][C:8]1[C:9](=[O:23])[C:10]2[C:6]([C:7]=1[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[CH:5][CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:19][CH2:18]1)[CH:11]=2
Reactant: CC(C)(C)c1cc(OCCC2CCNCC2)cc2c1C(c1cc(F)cc(F)c1)=C(Br)C2=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of t-butyl 6-(2-(piperidin-4-yl)ethoxy)-2-bromo-3-(3,5-difluorophenyl)-1H-inden-1-one (211 mg, 1.2 eq, 1.03 mmol) obtaind in Step 2 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (58%).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH2:13][O:14][C:15]([NH:17][C:18]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]2)=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)C>[Pd].C(O)C>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15]([NH:17][C:18]2([C:21]([OH:23])=[O:22])[CH2:19][CH2:20]2)=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(/C=C/c1ccccc1)OCCOC(=O)NC1(C(=O)O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(CCc1ccccc1)OCCOC(=O)NC1(C(=O)O)CC1
Yield: 80.4 %

Procedure:
A dry 100 mL round-bottomed flask equipped with a magnetic stir bar and a rubber septum was charged with 1-{[((2E)-3-phenylprop-2-enoyloxy)ethoxy]carbonylamino}cyclopropanecarboxylic acid (16) (0.8 g, 2.5 mmols) and 10% palladium on carbon in 1:1 mixture of ethylacetate and ethanol. The reaction was done at 1 atm pressure under a hydrogen balloon at room temperature. After the reaction was complete, the solution was filtered through Celite and the solvents removed in vacuo using a rotary evaporator. The dry, crude residue was dissolved in a small amount of a mixture of 60% (v/v) acetonitrile/water (ca. 10 mL), and the solution filtered through a 0.2 μm nylon syringe filter. Final purification was achieved by mass-guided preparative HPLC. After lyophilization of the solvents, 0.646 g (80% yield) of the title compound (17) was obtained as a white solid. M.p: 132.9-134.4° C. 1H NMR (CDCl3, 400 MHz): δ=7.31 (t, 2H), 7.19 (t, 3H), 6.82 (q, 1H), 6.38 (s, 0.3H), 5.50 (s, 0.7H), 2.99 (t, 2H), 2.72 (m, 2H), 1.71 (m, 2H), 1.42 (d, 3H), 1.30 (m, 2H). MS (ESI) m/z 343.93 (M+Na)+, 319.96 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:10][CH2:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[CH2:3]1.[I:12]I.[OH-].[K+]>CN(C=O)C>[I:12][C:5]1[C:4]2[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:10][CH2:9][C:8]=2[NH:7][N:6]=1
Reactant: II
Reactant: CC1(C)CCc2[nH]ncc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1(C)CCc2[nH]nc(I)c2C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 70.1 %

Procedure:
In a round-bottomed flask, 5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole (0.50 g, 3.33 mmol) was dissolved in DMF (7 mL). Iodine (1.69 g, 6.66 mmol) was added followed by potassium hydroxide (723 mg, 12.9 mmol). The dark reaction mixture was stirred at room temperature for 1.25 h. Additional iodine (1.69 g, 6.66 mmol) and potassium hydroxide (723 mg, 12.9 mmol) were added and the dark brown reaction mixture was stirred at room temperature for 1.5 h. The reaction was quenched with 10% aqueous NaHSO3 solution and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/Hexanes (gradient 0-20% EtOAc) to give 645 mg (70%) of 3-iodo-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 2.66 (t, J=6.6 Hz, 2H), 2.14 (s, 2H), 1.59 (t, J=6.4 Hz, 2H), 1.01 (s, 6H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:15]([O:17][CH3:18])=[O:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>C1COCC1>[CH2:31]([C:7]1([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:9][C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:15]([O:17][CH3:18])=[O:16])[CH:1]=2)[CH2:6]1)[CH:30]=[CH2:29]
Reactant: COC(=O)c1ccc2c(c1)CCC(C(=O)OC)C2
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)CCc2cc(C(=O)OC)ccc2C1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (±)-dimethyl 1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate from Step A (10.0 g, 40.4 mmol) in THF (200 mL) at −70° C. was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 45 mL, 45 mmol) dropwise, over 10 min, such that the reaction temperature was maintained below −65° C. during the addition. The mixture was stirred at −70° C. for a further 40 min, then allyl bromide (5.87 g, 48.5 mmol) was added dropwise over 3 min. Stirring was continued at −70° C. for 2 h, then the mixture was partitioned between H2O (300 mL) and EtOAc (300 mL). The aqueous phase was extracted further with EtOAc (2×300 mL), and the combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=289 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[F:32])=[O:20])=[CH:14][CH:13]=3)=[CH:10][C:4]=2[N:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O.CO>N1C=CC=CC=1>[F:32][C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:29])[F:30])=[CH:27][C:22]=1[NH:21][C:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])=[N:3][C:4]=3[CH:10]=2)=[CH:17][CH:16]=1)=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc2cc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)ccc2[nH]1
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)(=O)Nc1nc2cc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)ccc2[nH]1
Reaction time: 168 h
Yield: 40 %

Procedure:
2-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole (the product of Example 22–600 mg) and methanesulfonyl chloride (5 equiv.) in pyridine was stirred at room temperature for 2 days. The resulting mixture was treated with K2C03 (10 equiv.) and H2O (10 mL) and MeOH (10 mL), and heated at 60 C. for 7 days. The crude solid was collected by filtration. Recrystallization from hot MeOH afforded the title compound (280 mg, 40%);
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=CC=1)([O-])=O.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH2:42][CH2:43][CH2:44][NH2:45])[CH:36]=1>O1CCCC1>[N+:22]([C:18]1[CH:17]=[C:16]([C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:45][CH2:44][CH2:43][CH2:42][CH2:41][C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: NCCCCc1cccnc1
Reactant: O=C(/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1)NCCCCc1cccnc1
Yield: 84.3 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3-nitrophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (0.950 g) and 3-pyridinebutanamine (0.34 g) in tetrahydrofuran (10 mL) was stirred at room temperature for 1 hour. The crude amide that had been isolated in the usual way, was crystallized from ethyl acetate-hexane to yield 0.82 g of (E)-5,5-bis(3- nitrophenyl)-N-[4-(3-pyridinyl)butyl)-2,4-pentadienamide mp 158°-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.IC.I[CH2:30][CH2:31][CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:10]([CH2:30][CH2:31][CH2:32][CH3:33])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCI
Reactant: O=c1c(-c2ccc(Cl)cc2)c[nH]c2ccnc(NCc3ccccc3)c12
Solvent: CI
Product: CCCCn1cc(-c2ccc(Cl)cc2)c(=O)c2c(NCc3ccccc3)nccc21

Procedure:
The title compound was prepared as described in Example 2 above except that 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-(2-phenethylamino)-1,6-naphthyridine was replaced with 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-benzylamino-1,6-naphthyridine and iodomethane was replaced with iodobutane. MS 428 (M+1)+.