Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:34])[C:18](=[O:33])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:34])[C:18](=[O:33])[NH:19][N:20]=2)[CH2:11]1
Reactant: C[C@H]1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4CNC4)cc3N21
Yield: 100 %

Procedure:
A solution of 3-(4(S)-methyl-3-oxo-7-phenyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (enantiomer 2, SFC (Table 1, Method 1), Rt=4.333 min., 0.252 g, 0.54 mmol) in TFA (4 mL) and DCM (24 mL) was stirred at ambient temperature for 3 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-4(S)-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #1-2, Enantiomer 2, SFC (Table 1, Method 1), Rt=5.572 min, 0.261 g, 100%) as yellow solid. LC/MS (Table 1, Method 5) Rt=2.117 min.; MS m/z: 364 [M+H]+
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][CH:41]=[C:42]([CH:45]=2)[C:43]#[N:44])O1>>[C:43]([C:42]1[CH:45]=[C:38]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[C:12]([F:21])[CH:11]=3)=[O:8])[CH:22]=2)[CH:39]=[N:40][CH:41]=1)#[N:44]
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)c(F)c3)cnc2N2CC[C@H](CO)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (S)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 201.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a white powder. UPLC-MS (Condition 3) tR=1.06 min, m/z=502.4 [M+H]+, m/z=500.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.66 (m, 1H) 1.79-1.92 (m, 1H) 2.16-2.30 (m, 1H) 2.96 (dd, J=11.00, 6.85 Hz, 1H) 3.10-3.28 (m, 4H) 3.32-3.41 (m, 1H) 4.60 (t, J=5.26 Hz, 1H) 7.50-7.65 (m, 2H) 7.98 (dd, J=13.08, 2.32 Hz, 1H) 8.07 (d, J=2.45 Hz, 1H) 8.40 (t, J=2.20 Hz, 1H) 8.79 (d, J=2.45 Hz, 1H) 8.90 (d, J=1.96 Hz, 1H) 9.02 (d, J=1.96 Hz, 1H) 10.30 (s, 1H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][C:20]#[N:21]>>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1c[nH]c2ccc(O)cc12
Reactant: BrCc1ccccc1
Product: N#CCc1c[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
The title compound was prepared by a method analogous to that described in Example 1 from benzyl bromide and 5-hydroxyindole-3-acetonitrile. MS ES (MH−)=263.
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[S:1]1[C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2c(s1)CCCC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2c(s1)CCCC2
Temperature: 0 °C

Procedure:
4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid (1.0 g, 5.50 mmol) is dissolved in dichloromethane [DCM] (25 mL) that contains 5 drops of N,N-dimethylformamide [DMF] under nitrogen and cooled to 0° C. Oxalyl chloride (13.7 mL of a 2.0M solution in DCM) is added via syringe and allowed to warm to RT over 1 hour. All solvent is then removed under reduced pressure, and the resultant oil is reduced from toluene (3×20 mL) to remove residual oxalyl chloride. The residue is then dissolved in ethyl acetate and washed with saturated sodium bicarbonate (1×100 mL), then washed with saturated sodium chloride (1×100 mL) and dried over sodium sulfate. The solution is then filtered and concentrated under reduced pressure to give 4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl chloride (8) as an off-white solid (1.03 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][C:14]#[N:15])([O-:3])=[O:2].O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10]([NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH2:15])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: N#CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Solvent: O
Solvent: C1CCOC1
Product: NCCc1c[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 8 h

Procedure:
Dissolve (5-nitro-1H-indol-3-yl)-acetonitrile (9 g, 44.7 mmol) in 250 mL dry THF and treat with 90 mL 1 M BH3 in THF at ambient temperature. Stir overnight and quench the reaction cautiously by the dropwise addition of 10 mL water. Concentrate to dryness under vacuum and partition the residuc between 5 N HCl and EtOAc. Extract the aqueous layer with EtOAc and combine with the original EtOAc layer. Treat the aqueous layer with 5 N NaOH and extract 3 times with 10% MeOH in EtOAc. Purify by flushing the extracts through a pad of 100 g SCX ion exchange resin, rinsing with 2 liters of MeOH which was discarded, and then eluting with the 2 M NH3 in MeOH and concentrating to give the title compound as a dark solid: ISMS 206 (M+1); Analysis for C20H18F6N2O2 0.3H2O 0.1C7H8: calcd: C, 57.34; H, 5.74; N, 19.29. found: C, 57.30; H, 5.38; N, 19.08. 1H NMR (DMSO-d6) 11.9-11.2 (bs, 1H), 8.50-8.49 (d, 1H), 7.95-7.92 (m, 1H), 7.47-7.45 (m, 1H), 7.38 (s, 1H), 2.79 (s, 4H), 2.2-1.3 (bs, 2H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[N:5]([CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][CH2:38][CH2:39][Cl:40]>C(#N)C>[Cl:40][CH2:39][CH2:38][CH2:37][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3]([C:1]#[N:2])=[C:4]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=3)[N:5]2[CH:13]2[CH2:14][CH2:15][CH2:16]2)=[CH:10][CH:9]=1
Reactant: CC(C)NC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCCl)cc3n2C2CCC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of 1-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-3-isopropyl-urea (750 mg, 1.93 mmol) in 10 mL of acetonitrile is added anhydrous K2CO3 (800 mg, 5.79 mmol) and 1-bromo-3-chloropropane (382 μL, 3.86 mmol). After stirring overnight at 80° C., the reaction mixture is cooled and solvent is removed. The reaction is re-suspended in 100 mL of ethyl acetate. The organic phase is washed with 200 mL of H2O, and the aqueous phase is re-extracted 2× with 100 mL of ethyl acetate. The organic phases are combined, dried over MgSO4 and the solvent is removed to afford 769 mg (86%) of 1-{4-[6-(3-chloropropoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-3-isopropyl-urea as a tan powder.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[CH2:5][N:6]1[CH:14]([CH:15]([N+:17]([O-])=O)[CH3:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:20])[CH3:2]>[Pd].C(O)(=O)C.O>[CH2:22]([O:21][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[CH:14]([CH:15]([NH2:17])[CH3:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:20])[CH3:23]
Reactant: CCOC(CN1C(=O)c2ccccc2C1C(C)[N+](=O)[O-])OCC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(CN1C(=O)c2ccccc2C1C(C)N)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.8 %

Procedure:
A mixture of the two isomers of 2,3-dihydro-2-(2,2-diethoxyethyl)-3-(1-nitroethyl)-isoindol-1-one (2.5 g, described in Example 30) and 10% palladium on carbon (0.25 g) in acetic acid-water (4:1, 50 ml) is stirred under an atmosphere of hydrogen at 50 psi and 25° C. for 18 hr and filtered. The filtrate is evaporated and dissolved in 2% hydrochloric acid. The solution is washed with diethyl ether, basified to pH 9 with ammonium hydroxide and extracted with ethyl acetate. The organic extract is dried, evaporated and chromatographed on silica gel using acetone-benzene (2:3). Evaporation of the eluates gives isomer A (1.14 g) of the title compound, ir (CHCl3) 1675, 1120 and 1050 cm-1 and isomer B (0.88 g) of the title compound, ir (CHCl3) 1675, 1120 and 1050 cm-1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:13]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:12]=1.C(OCC)(=O)C>[C].[Pd].CO>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:12]=1
Reactant: Cc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)c1C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc(CCc2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the obtained tert-butyl 4-((E)-2-(2,3-dimethylphenyl)vinyl)-2-(4-fluoroanilino)benzoate were added ethyl acetate 1.5 mL, methanol 1.5 mL and 10% palladium-carbon 27 mg sequentially, and it was stirred under hydrogen atmosphere at room temperature for 3 hours and 20 minutes. The solvent was removed under reduced pressure after insoluble matter was filtrated. Dichloromethane 1.0 mL and trifluoroacetic acid 7.5 mL were added to the obtained residue, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 4-(2-(2,3-dimethylphenyl)ethyl)-2-(4-fluoroanilino)benzoic acid 17 mg of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][C:15](=[O:17])[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[NH:18][C:19]([C:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1)=[O:20].[F:30][C:31]([Si](C)(C)C)([F:33])[F:32].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:17][C:15]1([C:31]([F:33])([F:32])[F:30])[CH2:16][CH:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:4]=3)[N:12]=2)[CH2:14]1
Reactant: Cc1ccc(-c2noc(C3CC(=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2noc(C3CC(O)(C(F)(F)F)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of N-(2-methyl-5-(5-(3-oxocyclobutyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (10) (150 mg, 0.387 mmol) in ahydrous THF (2.5 mL) at 0° C. was added trifluoromethyltrimethylsilane (121 μL, 0.774 mmol) and TBAF (100 μL in THF and 5% water). The reaction was stirred to room temperature for 3 hours. Then TBAF (0.5 mL in THF and 5% water) was added and the reaction was stirred for 1 hour. The solvent was concentrated and the crude product was dissolved in ethyl acetate. The organic phase was washed with a water, brine and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography to yield N-(5-(5-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F25). 1H NMR (400 MHz, d6-DMSO) δ 10.04 (s, 1H), 9.47-9.45 (m, 1H), 8.60 (s, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.83 (dd, J=2.0, 8.0 Hz, 1H), 7.80-7.78 (m, 1H), 7.55-7.50 (m, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.20-7.16 (m, 1H), 6.92 (s, 1H), 3.32-3.28 (m, 1H), 2.99-2.93 (m, 2H), 2.68-2.60 (m, 2H), 2.37 (s, 3H). MS m/z 458.41 (M+1)+.
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=[CH2:2]>C(O)C.[C].[Pd]>[CH2:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:13][CH2:14]2)=[O:8])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Yield: 82.9 %

Procedure:
1-[1-(4-Vinylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.6 g) is dissolved in ethanol (10 ml) and thereto is added 10% palladium-carbon (0.1 g) and the mixture is stirred under hydrogen atmosphere. After the reaction, the catalyst is removed by filtration and the filtrate is concentrated. The resultant is purified by silica gel column chromatography-(solvent: n-hexane:ethyl acetate=1:1) and recrystallized from n-hexane/ethanol to give 1-[1-(4-ethylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.5 g) as white powder, m.p.: 133°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:13]([CH2:14][CH2:15][CH:16]=2)=[N:12][N:11]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:10]=3)=[CH:4][CH:3]=1.C(O)C.[H][H]>[Pt](=O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[C:9]2=[CH:10][N:11]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[N:12]=3)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCC=C3c2ccc(Cl)cc2)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCCC3c2ccc(Cl)cc2)cc1
Yield: 68.8 %

Procedure:
4-(4-Chlorophenyl)-2-(p-tolylsulfonyl)-6,7-dihydroindazole (0.62 g, 1.89 mmol) is added to ethanol (20.0 mL) and ethyl acetate (10 mL). Platinum (IV) oxide (0.22 g) is added and the reaction is stirred under 40 psi of hydrogen at room temperature for 6.0 h. The mixture is filtered through a plug of diatomaceous earth and evaporated under reduced pressure to give the title compound (0.503 g, 80%). LC/MS m/z 389 (M+H), Tr=2.704 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23]CCO)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[F:32][C:33]([F:38])([F:37])[CH2:34]C=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:23])[CH2:34][C:33]([F:38])([F:37])[F:32])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=CCC(F)(F)F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Agent: [Li]C(C)(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(O)CC(F)(F)F)nc3N21

Procedure:
This compound was prepared in analogy to Example 38 intermediate, from (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b), tert-butyllithium and 3,3,3-trifluoropropanal.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]=[C:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:24].O>N1C=CC=CC=1>[C:1]([O:10][CH:11]=[C:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CCC(=CO)C2=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc2c(c1)CCC(=COC(=O)c1ccccc1)C2=O
Reaction time: 2 h
Yield: 80 %

Procedure:
Benzoyl chloride (11.4 ml, 0.1 mole) was added to a stirred solution of 2-hydroxymethylene-6-methoxy-1-tetralone 2 (10 g, 0.05 mole) in about 60 mL of pyridine at about 0°. After the addition was complete, the mixture was stirred at about 23° for about 2 hours then poured into water. The solid was filtered and washed with water. The pure product was obtained by recrystallization from methanol to yield 2-benzoyloxymethylene-6-methoxy-1-Tetralone (12.1 g, 0.04 mole, 80% yield), mp 128.5°-129.5°, [Lit. Kieboom et al., Synthesis, 476-478, (1970), mp 130°-130.5°].
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[OH:20]O.O>C(O)(=O)C>[NH2:1][C:2]1[N+:10]([O-:20])=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: Nc1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: Nc1c2ncn(Cc3c(Cl)cccc3Cl)c2nc[n+]1[O-]
Reaction time: 120 h
Yield: 40 %

Procedure:
The crude 6-amino-9-(2,6-dichlorobenzyl)purine obtained from the initial reaction was dissolved in one liter of acetic acid. A 30% aqueous solution of hydrogen peroxide was then added in the amount of 350 milliliters. The solution was allowed to stand for 5 days at room temperature, after which about 400 milliliters of water was added and the solution was cooled. The resulting precipitate was recovered by filtration, reslurried in 500 milliliters of a 30% aqueous solution of acetic acid, and then in one liter of water. The solids recovered from the aqueous slurry were vacuum dried to yield 75 grams of a crude 6-amino-9-(2,6-dichlorobenzyl)purine-N1 -oxide having a melting point of 296°-301° C, representing a 40 percent yield. An analytical sample of the same having a melting point of 298°-302° C. was prepared by recrystallization from acetic acid.
Reaction SMILES: [Si]([C@@:8]1([OH:42])[C@@H:12]([CH2:13][O:14][Si](C(C)(C)C)(C)C)[O:11][C@@H:10]([N:22]2[CH:29]=[C:28]([CH2:30][O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH:39]([CH3:41])[CH3:40])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[CH2:9]1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][O:31][CH2:30][C:28]1[C:26](=[O:27])[NH:25][C:23](=[O:24])[N:22]([CH:29]=1)[C@@H:10]1[O:11][C@H:12]([CH2:13][OH:14])[C@@H:8]([OH:42])[CH2:9]1)([CH3:41])[CH3:40]
Reactant: CC(C)c1ccccc1COCc1cn([C@H]2C[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccccc1COCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compounds 3′,5′-O-bis-(tert-butyldimethylsilyl)-5-(2-isopropylbenzyl-oxy)methyl-2′-deoxyuridine (134 mg, 0.22 mmol) and (3′ or 5′)-O-(tert-butyldimethylsilyl)-5-(2-isopropylbenzyloxy)methyl-2′-deoxyuridine (98 mg, 0.19 mmol) were dissolved in THF (5 mL), and a solution of tetra-n-butylammonium fluoride trihydrate (323 mg, 1.05 mmol) in THF (2 mL) was added. The mixture was stirred at room temperature for one hour, then concentrated in vacuo and purified by silica gel column chromatography to give 5-(2-isopropylbenzyloxy)methyl-2′-deoxyuridine dU.n6 (108 mg, 67%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:31]([O:34][CH2:35]OC)(=O)C>CCCCCC>[C:1]([O:7][CH2:8][CH:9]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[O:10][CH2:31][O:34][CH3:35])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COCOC(C)=O
Reactant: CC(C)(C)C(=O)OCC(O)COC(=O)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: O
Product: COCOC(COC(=O)C(C)(C)C)COC(=O)C(C)(C)C
Reaction time: 1 h

Procedure:
50.45 g of 1,3-dipivaloyl glycerol was dissolved in 200 ml of methoxymethyl acetate. After the addition of 2.5 g of p-toluenesulfonic acid monohydrate, the mixture was stirred for 1 hr then diluted with 200 ml of hexane and washed twice with 200 ml saturated aqueous sodium carbonate, once with aqueous NaCl solutions, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 1,3-dipivaloyl-2-methoxymethyl glycerol as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14](=[O:23])(=[O:22])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1.[OH-].[Na+]>CO>[C:16]1([NH:15][S:14]([C:10]2[CH:9]=[C:8]([C:7]#[C:6]/[CH:5]=[CH:4]/[C:3]([OH:24])=[O:2])[CH:13]=[CH:12][CH:11]=2)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a solution of E-5-(3-phenylsulfamoylphenyl)pent-2-en-4-ynoic acid methyl ester (55a) (0.34 g, 1 mmol) in methanol (3 ml) 1N solution of sodium hydroxide (3 ml) was added and the mixture was stirred at ambient temperature for 3 hours. Methanol was removed under reduced pressure, to the residue water (5 ml) was added and the mixture was acidified with 3% HCl. The precipitate was filtered, washed with water, and dried to give the title compound (0.31 g, 95%) as white crystals. M.p. 188–190° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.36 (1H, d, J=15.8 Hz, CH); 6.92 (1H, d, J=15.8 Hz, CH); 7.01–7.36 (5H, m, C6H5); 7.38–7.89 (4H, m, C6H4); 10.32 (1H, s, NH).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C@H:10]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:11][C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1COCO[CH2:36]1>ClCCl.S(=O)(=O)(O)O>[CH2:15]([N:14]1[C:12](=[O:13])[CH2:11][C@H:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:34])[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:36]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(S(=O)(=O)N[C@H](CC(=O)NCc2ccccc2)C(=O)OCc2ccccc2)cc1
Reactant: C1OCOCO1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To the solution of N-benzyl-2(R)-[(4-methoxyphenyl)sulfonylamino]-succinamic acid benzyl ester as an oil (2.10 g, 4.4 mmol) in 200 mL of dichloromethane is added, with stirring, 1.3,5-trioxane (1.57 g, 17.4 mmol) followed by two drops of sulfuric acid. The reaction is heated at reflux for 3 hours at which time mass spectrometry (ES) indicates the reaction to be complete. The reaction is allowed to cool to room temperature, diluted with dichloromethane (250 mL), and washed with water (2×). The product is purified by flash silica gel chromatography (1:1 hexanes-ethyl acetate), to give benzyl 1-benzyl-3-[(4-methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine-4(R)-carboxylate.
Reaction SMILES: C[Mg]Br.[CH:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4:21]>CCOCC>[C:13]1([Zr:21][C:13]2[C:14]3[NH:15][C:16]4[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=4)[C:9]=3[CH:10]=[CH:11][CH:12]=2)[C:14]2[NH:15][C:16]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: [Zr+4]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: C[Mg]Br
Agent: [Cl-]
Solvent: CCOCC
Product: c1ccc2c(c1)[nH]c1c([Zr]c3cccc4c3[nH]c3ccccc34)cccc12
Temperature: 25 °C

Procedure:
The procedure of Example 16 of U.S. Pat. No. 5,539,124 is followed to prepare a bis(carbazolyl) zirconium complex. This procedure uses methylmagnesium bromide to deprotonate carbazole, and combines the resulting anion with 0.5 eq. of zirconium tetrachloride in ether at −78° C. After warming to room temperature, the mixture is stripped to remove ether. Toluene is added, and the mixture is filtered to remove insoluble material. The filtrate is then stripped to yield the bis(carbazolyl) complex.