Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[CH2:12][CH:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([CH3:20])[C:9]2=[O:21])=[CH:6][CH:5]=[C:4]([CH3:22])[N:3]=1.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24].C(Cl)Cl>>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[CH3:1][C:2]1[C:7]([N:8]2[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[N:10]([CH3:20])[C:9]2=[O:21])=[CH:6][CH:5]=[C:4]([CH3:22])[N:3]=1
Reactant: Cc1ccc(N2CC(C(=O)OC(C)(C)C)N(C)C2=O)c(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N2CC(C(=O)O)N(C)C2=O)c(C)n1

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3.00 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 3-bromo-2,6-dimethylpyridine (557 mg, 3.00 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.49 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated at reflux under argon for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane. The residue was dissolved in methanol and applied to a SCX ion exchange cartridge and washed with methanol and then 2M ammonia in methanol. The basic fractions were combined and evaporated to give 1,1-dimethylethyl 1-(2,6-dimethyl-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (493 mg, 54%). LC/MS [M+H]+=306. (ii) A solution of 1,1-dimethylethyl 1-(2,6-dimethyl-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (0.489 g, 1.6 mmol) in TFA/DCM (1:2, 9 ml) was stirred at room temperature for 16 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give crude 1-(2,6-dimethyl-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid TFA salt, (assume ˜1.6 mmol) which was used in the next step. LC/MS [M+H]+=250.
Reaction SMILES: [CH2:1]([CH:9]([C:15](OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].IC[CH2:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26]>>[F:29][C:24]([F:30])([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][CH2:15][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C=CCCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: FC(F)(F)C(F)(F)CCCI
Product: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with the diethyl 2-(7-octenyl)malonate prepared in Example 5 and the 1-iodo-4,4,5,5,5-pentafluoropentane prepared in Example 1, the same procedure as shown in Example 5 was repeated to give ethyl 2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][Li]>C1COCC1>[CH3:12][C:8]1([OH:11])[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH2:9]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC1(O)CCC2(CC1)OCCO2
Temperature: -55 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a cooled solution of 1,4-dioxaspiro[4.5]decan-8-one (7.8 g, 50.0 mmol) in dry THF (75 mL) was added methyllithium solution (1.5 M in ether, 43.3 mL, 65.0 mmol) at −78° C. under argon while keeping inner temperature below −55° C. After addition, the mixture was stirred at −55° C. for additional 4 hours. The reaction was warmed to room temperature and then quenched by saturated NH4Cl solution. The separated organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (EA:PE=1:9 to 1:3) to afford the product as a white solid (6.8 g, yield: 80%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4]1)[CH3:2].Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=[C:14]([Br:16])[N:15]=1.C([O-])(=O)C>C(O)(C)C>[Br:16][C:14]1[N:15]=[C:10]([NH:8][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=2)[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CCn1cc(N)cn1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCn1cc(Nc2nc(Br)cn(C)c2=O)cn1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 123b (500 mg, 4.5 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (2.40 g, 9.0 mmol), DIPethyl acetate (3 mL), and isopropanol (50 mL). The mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford 123c (802 mg, 60%) as a white solid. MS-ESI: [M+H]+ 298.0
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[NH:12][CH3:13]>C(Cl)Cl>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[N:12]([CH3:13])[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CNc1ccccc1F
Reactant: COC(=O)CC(=O)Cl
Solvent: ClCCl
Product: COC(=O)CC(=O)N(C)c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-chloro-3-oxopropanoate (1.75 mL, 15.99 mmol) in dry DCM (32 ml) was added 2-fluoro-N-methylaniline (2 g, 15.99 mmol) and the reaction mixture was stirred at 0° C. for 1 h, evaporated then redissolved in EtOAc, washed with dilute NaHCO3, and brine. The organic phase was dried over sodium sulfate, and concentrated under reduced pressure to afford methyl 3-((2-fluorophenyl)(methyl)amino)-3-oxopropanoate as yellow oil which was used without further purification (3.3 g, 16 mmol, 97%, crude). To a solution of this material (3.3 g, 16 mmol) in THF (16 ml) and water (16 ml) was added LiOHH2O (1.35 g, 31.5 mmol) and the reaction mixture was stirred overnight, evaporated (to remove the THF) and then extracted with EtOAc. The aqueous phase was acidified to pH˜1 by addition of 1N HCl and extracted with EtOAc. The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound 245 as a brown solid, which was used without further purification (2.75 g, 13.03 mmol, 81% yield). MS (m/z): (M+1) 218.0 (88%), (2M+Li) 429.0 (100%).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C@@H:11]1[CH2:14][C@H:13]([OH:15])[CH2:12]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].C[OH:19]>[Pd]>[CH2:1]([N:8]([CH3:9])[C:10]([CH:11]1[CH2:12][C:13](=[O:15])[CH2:14]1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C[C@H]1C[C@@H](O)C1
Reactant: [H][H]
Reactant: CO
Agent: [Pd]
Product: CN(Cc1ccccc1)C(=O)C1CC(=O)C1
Yield: 100 %

Procedure:
5% Pd/C (1 g) was added to a solution of intermediate 3, cis-3-{[Benzyl(methyl)amino]methyl}cyclobutanol (8.6 g, 0.042 mol) in MeOH (100 mL). The mixture was stirred in a flow of hydrogen for 48 h and filtered through Celite. The solid was washed on the filter with MeOH (2×50 mL). The filtrate was evaporated. Obtained crude intermediate 4 (5.3 g, ˜100%) was used in the next stage without additional purification. 1H NMR-data (DMSO-d6): 4.87-5.49 (br.s, 2H, NH, OH); 3.86-3.96 (m, 1H); 2.73 (d, 2H, CH2, J=7.1); 2.39 (s, 3H, NCH3); 2.24-2.34 (m, 2H); 1.85-1.97 (m, 1H); 1.46-1.57 (m, 2H).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5].[P:16](Cl)(Cl)(=[O:28])[O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:1][C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]=1[O:17][P:16](=[N:2][C@@H:3]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5])=[O:28]
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: CCCOC(=O)[C@@H](N)c1ccccc1
Reactant: Cl
Solvent: ClCCl
Product: CCCOC(=O)[C@@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)c1ccccc1
Yield: 83 %

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates, the HCl salt of (S)-propyl 2-amino-2-phenylacetate (1 g), naphthalen-1-yl phosphorodichloridate (1.14 g), TEA (1.21 mL) and DCM (30 mL) were combined to give (2S)-propyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate in an 83% yield (1.51 g) as a pale yellow thick oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]2[S:16][N:15]3[C:17]([C:23]4[CH:32]=[CH:31][C:30]5[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=5[CH:24]=4)=[C:18]([CH2:20][CH2:21][OH:22])[S:19][C:14]3=[N:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>O>[C:33]([O:22][CH2:21][CH2:20][C:18]1[S:19][C:14]2[N:15]([S:16][C:12](=[N:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])[N:13]=2)[C:17]=1[C:23]1[CH:32]=[CH:31][C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=1)(=[O:35])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)N=c2nc3sc(CCO)c(-c4ccc5c(c4)CCCC5)n3s2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCc1sc2nc(=NS(=O)(=O)c3ccc(C)cc3)sn2c1-c1ccc2c(c1)CCCC2
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of 2-[2-(4-methylphenyl)sulfonylimino-6-(5,6,7,8-tetrahydro-2-naphthyl)-2H-thiazolo[3,2- b][1,2,4]thiadiazol-5-yl]ethanol (500 mg), acetic anhydride (1 ml) and pyridine (5 ml) was stirred at room temperature for i hour. The reaction mixture was added to water, and the resulting crystal was collected by filtration and washed with water. The obtained crystal was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (1:1, v/v). The separating crystal was recrystallized from dichloromethane-methanol to yield 2-[2-(4-methylphenyl)sulfonylimino-6-(5,6,7,8-tetrahydro-2-naphthyl)-2H-thiazolo[3,2- b][1,2,4]thiadiazol-5-yl]ethyl acetate (355 mg, yield 65%) as a colorless needle.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:20]=[CH:21][C:22]3[C:28](=[O:29])[NH:27][C:26]4[CH:30]=[C:31]([CH2:34][C:35]([N:37]5[CH2:41][CH2:40][CH:39]([NH:42]C(=O)OC(C)(C)C)[CH2:38]5)=[O:36])[CH:32]=[CH:33][C:25]=4[NH:24][C:23]=3[CH:50]=2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]>C(Cl)Cl>[NH2:42][CH:39]1[CH2:40][CH2:41][N:37]([C:35](=[O:36])[CH2:34][C:31]2[CH:32]=[CH:33][C:25]3[NH:24][C:23]4[CH:50]=[C:19]([C:12]5[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([O:9][CH3:8])[CH:11]=5)[CH:20]=[CH:21][C:22]=4[C:28](=[O:29])[NH:27][C:26]=3[CH:30]=2)[CH2:38]1
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CC(=O)N4CCC(NC(=O)OC(C)(C)C)C4)cc2NC3=O)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CC(=O)N4CCC(N)C4)cc2NC3=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.5 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of Example 365 (35 mg, 0.06 mmol) in CH2Cl2 (3 mL) and stirred at room temperature for 5 hours. Concentrated under vacuum. Residue was purified by preparative HPLC to provide 25 mg (70%) of the desired product as the trifluoroacetate salt. MS (DCI) m/e 488 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 9.87 (s, 1H), 7.99-8.08 (m, 4H), 7.95 (s, 1H), 7.80 (d, J=8.42 Hz, 1H), 7.52 (s, 1H), 7.36 (s, 1H), 7.34 (dd, J=8.42, 1.56 Hz, 1H), 7.30 (dd, J=8.11, 1.25 Hz, 1H), 6.82-6.97 (m, 2H), 4.03 (s, 3H), 3.83 (m, 1H), 3.64-3.74 (m, 2H), 3.38-3.57 (m, 4H), 2.19 (m, 1H), 1.95 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](=O)[CH3:5].[C:9](O)(=O)C.[CH:13]([NH2:15])=[NH:14]>C(O)CCC>[CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]1[CH:5]=[CH:9][N:15]=[CH:13][N:14]=1
Reactant: CC(=O)CC(C)(C)C
Reactant: N=CN
Reactant: CC(=O)O
Solvent: CCCCO
Product: CC(C)(C)Cc1ccncn1
Temperature: 130 °C
Reaction time: 24 h
Yield: 33.3 %

Procedure:
A 100 mL reaction flask is charged with 4,4-dimethyl-pentan-2-one (10 g, 0.1 mol), formamidine acetate (57 g, 0.5 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 4-(2,2-dimethyl-propyl)-pyrimidine (˜5 g) is obtained.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][CH2:14][CH:15]([OH:32])[CH2:16][N:17]1[C:29]2[CH:28]=[CH:27][C:26]([Br:30])=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:31])[CH:22]=2.CCN(CC)CC.C(Cl)Cl.CCOC(C)=O>C(Cl)Cl>[Br:31][C:21]1[CH:20]=[CH:19][C:18]2[N:17]([CH2:16][CH:15]3[O:32][C:2](=[O:4])[NH:13][CH2:14]3)[C:29]3[C:24]([C:23]=2[CH:22]=1)=[CH:25][C:26]([Br:30])=[CH:27][CH:28]=3
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCC(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NCC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)O1
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
A solution of triphosgene (0.0890 g, 0.300 mmol, 0.35 equiv) in 2 mL anhydrous CH2Cl2 was added dropwise to a solution of 1-amino-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol (0.3413 g, 0.857 mmol) and Et3N (0.1909 g, 1.886 mmol) in 1 mL CH2Cl2 under N2 atmosphere at 4° C. The reaction mixture was stirred for 15 min at 4° C. and then warmed to room temperature and stirred for 1 hour. CH2Cl2 was removed under vacuum. Saturated NH4Cl (5 mL) and 10 mL EtOAc was added to the residue and stirred for 20 min. Then the aqueous layer was separated and the organic layer was washed with water 2×10 mL. The combined aqueous layers were extracted with EtOAc, dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using CH2Cl2/EtOAc to afford 0.1173 g white solid, yield 20.0% over 2 steps.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH2:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21]([C@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:22])[N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:35][OH:36].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[OH:36][N:35]=[N:2][CH2:1][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH2:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21]([C@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:22])[N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1
Reactant: NO
Reactant: CCOC(=O)CN1CCC[C@@H]1C(=O)N1CCC[C@H]1CCc1cc2ccc(C#N)cc2n1CC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CN1CCC[C@@H]1C(=O)N1CCC[C@H]1CCc1cc2ccc(CN=NO)cc2n1CC
Yield: 5.2 %

Procedure:
480 mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-cyano-1-ethylindol-2-yl)ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]acetate obtained in Example 60-a) was dissolved in methanol. 304 mg of hydroxylamine hydrochloride and 695 mg of sodium carbonate were added and the reaction solution was refluxed overnight with stirring. After water was added, the reaction solution was extracted two times with dichloromethane. The extract was dried over MgSO4 and distilled under reduced pressure. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(20:1)] to obtain 27 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH3:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[C:9]=2[O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.Cl.C[CH2:39][O:40]C(C)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH3:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[C:9]=2[O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]([O:40][CH3:39])=[O:26])=[C:23]([C:29]([F:30])([F:31])[F:32])[CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2cc(O)ccc2c(Oc2ccc(C=O)c(C(F)(F)F)c2)c1-c1cccc(F)c1
Reactant: CCOC(C)=O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2c(-c3cccc(F)c3)c(C)cc3cc(O)ccc23)cc1C(F)(F)F
Temperature: -20 °C
Reaction time: 3 h

Procedure:
A stirring solution of 286 (0.30 g, 0.62 mmol) in CH2Cl2 (10 mL) was chilled to −20° C. under N2 and BBr3, 1 M in CH2Cl2 (2.86, 2.86 mmol, 1 M), was added drop wise. The resulting orange-brown reaction was stirred at −20° C. for 3 h and the reaction then poured onto ice followed by 1 N HCl (20 mL) and EtOAc (100 mL).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:21][C:20]4[C:22]([N+:28]([O-])=O)=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=4[O:18][CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C=O.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:21][C:20]4[C:22]([NH2:28])=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=4[O:18][CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc([N+](=O)[O-])c2c1OCC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N)c2c1OCC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Temperature: 55 °C
Reaction time: 3 h
Yield: 24.6 %

Procedure:
To a solution of N-(4-morpholinophenyl)-8-methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxamide (1.2 g, 2.9 mmol) in N,N-dimethylformamide (10 mL) was added a solution of sodium dithionite (2.1 g, 12 mmol) in water (5 mL). The mixture was stirred at 55° C. for 3 h and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate as the eluent affording 273 mg of the title compound (55% yield): EIMS (70eV) m/z (relative intensity) 383 (100, M+).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH3:16])[CH:11]=[N:10][C:9]=2[N:8]([CH3:17])[C:6]1=[O:7])CC=C.C[N+]1([O-])CC[O:22]CC1.S([O-])([O-])=O.[Na+].[Na+].[CH3:32][C:33]([CH3:35])=[O:34]>O>[OH:34][CH:33]([CH2:35][OH:22])[CH2:32][CH2:1][N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH3:16])[CH:11]=[N:10][C:9]=2[N:8]([CH3:17])[C:6]1=[O:7]
Reactant: C=CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cn1cnc2c1c(=O)n(CCC(O)CO)c(=O)n2C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
A solution of 1-(3-Butenyl)-3,7-dimethylxanthine (5.8 g, 24.8 mmol), 4-methylmorpholine-N-oxide (3.63 g, 31 mmol) and potassium osmate dihydrate (18.3 mg; 0.05 mmol) in acetone (40 mL) and water (10 mL) was stirred for 6 hours. A solution of 20% aqueous sodium sulphite (20 ml) was added and stirred for 30 minutes. The reaction mixture was extracted with 25% ethanol/dichloromethane (4×250 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using an acetone eluant to yield 4.5 g (67.7% yield) 1-(3,4,-dihydroxybutyl)-3,7-dimethylxanthine (inventive compound no. 2509).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:16][S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])=[O:6].[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:6]1[CH2:2][CH2:3][N:4]=[C:5]1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:16][S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18]
Reactant: O=C(NCCBr)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cccc2cc(C3=NCCO3)[nH]c12)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of N-(2-bromoethyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.35 g) in tetrahydrofuran (6 mL) was slowly added sodium hydride (60% in oil, 0.04 g) at 0° C., and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.20 g, yield 71%) was obtained as colorless crystals from a fraction eluted with ethyl acetate. The crystals were recrystallized from ethyl acetate-hexane. melting point>260° C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:7]=1)[CH3:2].[CH3:24][C@@H:25]1[C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[C@H:25]([CH3:24])[C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:7]=1)[CH3:2]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(Br)cc2CBr)c1
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: C([O:8][CH2:9][C:10]1([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:15][CH2:14][C:13]([C:16]2[CH:21]=[C:20]([N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]3[N:39]=[CH:40][CH:41]=[C:18]3[N:17]=2)=[CH:12][CH2:11]1)C1C=CC=CC=1>C1COCC1.[Pd]>[CH3:29][Si:27]([CH3:28])([CH3:30])[CH2:26][CH2:25][O:24][CH2:23][N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:20]1[N:19]2[N:39]=[CH:40][CH:41]=[C:18]2[N:17]=[C:16]([CH:13]2[CH2:12][CH2:11][C:10]([CH2:9][OH:8])([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:15][CH2:14]2)[CH:21]=1
Reactant: CCOC(=O)C1(COCc2ccccc2)CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CO)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Temperature: 50 °C
Yield: 27.6 %

Procedure:
A mixture of ethyl 1-(benzyloxymethyl)-4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohex-3-enecarboxylate (3.06 g, 4.59 mmol) and Pd/C (cat.) in THF (25 mL) was heated at 50° C. under 1.0 atm of H2 for 16 h. LCMS indicated complete reduction of double bond. The reaction mixture was filtered and evaporated. The residue was dissolved in MeOH and HCO2NH4 and Pd/C (cat.) was added. The resulting mixture was heated under reflux for 24 h. After cooling to rt, the reaction mixture was filtered. The filtrate was concentrated and purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.5 in 50% EtOAc) to afford ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate as colorless oil (733 mg). HPLC-MS TR=2.78 min (UV 254 nm, 5 min method); mass calculated for formula C28H50N4O5Si2 578.3, observed LCMS m/z 579.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[N:23]([CH2:24][C:25](O)=[O:26])[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:30][CH:31]1[O:36][CH:35]([CH3:37])[CH2:34][NH:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:19][O:20][C:21]([CH3:29])([CH3:28])[CH2:22][N:23]3[CH2:24][C:25]([N:33]3[CH2:32][CH:31]([CH3:30])[O:36][CH:35]([CH3:37])[CH2:34]3)=[O:26])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN(CC(=O)O)C(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: CC1CNCC(C)O1
Product: CC1CN(C(=O)CN2CC(C)(C)OCC2C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CC(C)O1

Procedure:
The desired compound was prepared using [5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and 2,6-dimethyl morpholine following Method F. Chromatographic purification gave the desired product in 70-80% yield. 1H-NMR (300 MHz, CDCl3): δ 9.31 (s, 1H), 8.75 (d, 1H), 8.55 (d, 1H), 8.37 (d, 1H), 8.14 (m, 1H), 4.73 (m, 2H), 4.96 (m, 1H), 4.37 (m, 2H), 3.69 (m, 2H), 3.57 (m, 4H), 2.82 (t, 1H), 2.47 (t, 1H), 1.50 (d, 3H), 1.42 (d, 3H), 1.18 (m, 6H). Retention Time (LC, method: formic acid standard): 1.14 min (Diode Array).