Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1.C(N(CC)CC)C.Cl[C:21]1[N:26]=[C:25]([NH2:27])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][CH:22]=1>CS(C)=O>[N+:28]([C:24]1[C:25]([NH2:27])=[N:26][C:21]([N:9]2[CH2:10][CH2:11][O:12][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8]2)=[CH:22][CH:23]=1)([O-:30])=[O:29]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: c1ccc(C2CNCCO2)nc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1nc(N2CCOC(c3ccccn3)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
To a solution of 2-(pyridin-2-yl)morpholine (0.1 g, 0.609 mmol) in dimethylsulfoxide (5 mL) was added triethylamine (0.17 mL, 1.2 mmol). The resulting solution was stirred for 10 min at room temperature, and then 6-chloro-3-nitropyridin-2-amine (105 mg, 0.609 mmol) was added. The reaction mixture was heated at 110° C. for 4 h, and then was cooled to room temperature. Ice water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (80% ethyl acetate in petroleum ether) to afford the title compound (0.1 g, 55%). MS (ES+) (M+H) 302.25.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:34][N:33]=[C:32]([CH3:35])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[CH:13][C:8]2[N:7]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[O:34][N:33]=[C:32]([CH3:35])[CH:31]=4)[CH:25]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(NC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(NC(C)C)c(Cl)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-chloro-5-isopropylamino-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M112) (0.16 g, 0.31 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale brown solid (120 mg, 93%).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F-].[K+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1B1OC(C)(C)C(C)(C)O1>O1CCCC1>[F:10][C:8]1[CH:9]=[C:2]([C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[F:13])[C:3]([C:4]#[N:5])=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1ccc(F)cc1Br
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(F)cc1-c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 2-bromo-4-fluorobenzonitrile (2.50 g, 12.5 mmol), potassium fluoride (2.40 g, 41.3 mmol) and 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4.67 g, 17.5 mmol) in tetrahydrofuran (50 ml) was degassed with nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium(0) and tri-tert-butylphosphine (0.2 M solution in 1,4-dioxane, 3.7 ml) were added and the mixture stirred at ambient temperature for 15 min then at 50° C. for 18 h. After cooling to ambient temperature, the resulting dark suspension was poured onto 0.5 M sodium hydroxide solution (500 ml) and stirred vigorously for 2 h. The dark solid was collected by filtration, washed with water (100 ml) and isohexane (50 ml) and left to air dry which gave the title compound as a brown/black solid: 1H NMR (360 MHz, CDCl3) 5 7.25-7.33 (2H, m), 7.40-7.44 (1H, m), 7.86 (1H, dd, J 9, 6 Hz), 8.35-8.42 (2H, m).
Reaction SMILES: [NH2:1][C:2]([NH:4][NH:5][C:6](=O)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[S:3].[O-]CC.[Na+]>C(O)C>[SH:3][C:2]1[NH:4][N:5]=[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:1]=1
Reactant: CCOC(=O)CCC(=O)NNC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1n[nH]c(S)n1
Temperature: 80 °C
Reaction time: 15 h
Yield: 90.7 %

Procedure:
A suspension of ethyl 4-[2-(aminocarbonothioyl)hydrazino]-4-oxobutanoate (16.8 g, 76.7 mmol) and sodium ethoxide (10.4 g, 153 mmol) in ethanol (200 mL) was stirred at 80° C. for 15 hr. The mixture was concentrated under reduced pressure, and the residue was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to give the title compound as a white powder (14.0 g, 91%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][CH2:25][C:24](=O)[C:23]=3[CH:28]=2)[CH:16]=[CH:17][CH:18]=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=1)[O:33][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].C([BH3-])#N.[Na+]>CO>[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][CH2:25][CH:24]([NH:29][C:30]4[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=4)[O:33][CH2:34][C:35]([O:37][CH:38]([CH3:39])[CH3:40])=[O:36])[C:23]=3[CH:28]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C1COc2ccc(-c3cccc(F)c3)cc21
Reactant: CC(C)OC(=O)COc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)OC(=O)COc1cccc(NC2COc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 5.6 %

Procedure:
Para-toluenesulfonic acid (76 mg, 0.43 mmol) was added to a solution of 5-(3-fluorophenyl)benzofuran-3(2H)-one (212 mg, 0.935 mmol) and isopropyl 2-(3-aminophenoxyl)acetate (202 mg, 0.964 mmol) in methanol (4 mL) at 25° C. The reaction was heated in an 80° C. oil bath and allowed to stir overnight for approximately 16 hours. The reaction was cooled to room temperature and concentrated in vacuo. The mixture was then dissolved in concentrated acetic acid (2 mL) and cooled to 0° C. Sodium cyanoborohydride (386 mg, 6.13 mmol) was added and the solution was stirred for 4 hours at room temperature. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (12 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 22 mg (6%) of isopropyl 2-(3-((5-(3-fluorophenyl)-2,3-dihydrobenzofuran-3-yl)amino)phenoxy)acetate.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.N1C=CC=CC=1.[ClH:33]>O>[ClH:33].[CH3:20][N:2]([CH3:1])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1
Reactant: C1CNCCN1
Reactant: CN(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CN(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21

Procedure:
A mixture of 2.86 g of 1-dimethylamino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 4.3 g of anhydrous piperazine and 30 ml of dry pyridine is heated at the boiling point under reflux for 6 hours. The pyridine is then stripped off in vacuo and 10 ml of water are added to the residue. The pH of the solution is brought to about 1 with concentrated hydrochloric acid and the precipitate is filtered off with suction in the cold and washed with a little ice-cold 10% strength hydrochloric acid and ethanol. After drying in vacuo at 100° C., 1.5 g of 1-dimethylamino-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride of decomposition point 284°-286° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Hydroxy-4-isopropylbenzaldehyde (6.69 g) and 11.26 g of potassium carbonate were suspended with 100 mL of N,N-dimethylformamide, and 5.33 mL of benzyl bromide was added to the stirred mixture at room temperature. After the mixture was stirred at room temperature for 16 hours, the insoluble material was removed by filtration. To the filtrate were added 10 mL of water and 10 mL of diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. After being washed with brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 10.44 g of 2-benzyloxy-4-isopropylbenzaldehyde.
Reaction SMILES: [O:1]([C@@H:19]1[CH2:27][C@@H:22]2[O:23][C:24](=[O:26])[CH2:25][C@@H:21]2[C@H:20]1[CH2:28][CH2:29][C:30]1([O:43][CH2:42][CH2:41][O:40]1)[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.C(OCC)(=O)C.C([O-])(=O)C(C(C([O-])=O)O)O.[K+].[Na+]>C1(C)C=CC=CC=1>[O:1]([C@@H:19]1[CH2:27][C@@H:22]2[O:23][CH:24]([OH:26])[CH2:25][C@@H:21]2[C@H:20]1[CH2:28][CH2:29][C:30]1([O:40][CH2:41][CH2:42][O:43]1)[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[Si:2]([C:15]([CH3:16])([CH3:18])[CH3:17])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)[Si](O[C@@H]1C[C@@H]2OC(=O)C[C@@H]2[C@H]1CCC1(COc2cccc(Cl)c2)OCCO1)(c1ccccc1)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](O[C@@H]1C[C@@H]2OC(O)C[C@@H]2[C@H]1CCC1(COc2cccc(Cl)c2)OCCO1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100.2 %

Procedure:
To a solution of 11 (945 mg, 1.55 mmol) in toluene (11 mL) at −78° C. (bath temperature) was added a 1.5 M solution of DIBAL-H in toluene (3.0 mL, 4.5 mmol). After 3.5 h, ethyl acetate (10 mL) was added, the mixture was warmed to room temperature, saturated sodium potassium tartarate (20 mL) was added, and the thick solution was stirred for 30 min to break the emulsion. The layers were separated, the aqueous phase was extracted with ethyl acetate (2×30 mL), the combined organic layers were dried (magnesium sulfate), filtered, concentrated, and chromatographed on a 13 cm tall×26 mm diameter silica gel column eluting with 40% ethyl acetate in hexane to afford 12 (968 mg, 100%).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].[CH2:16]([O:18][C:19](=[O:26])[C:20](=O)[CH2:21][C:22](=O)[CH3:23])[CH3:17]>CC(O)=O>[CH2:16]([O:18][C:19]([C:20]1[CH:21]=[C:22]([CH3:23])[N:2]([C:4]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[N:3]=1)=[O:26])[CH3:17]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NNc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)O)n1
Yield: 55.9 %

Procedure:
To a solution of 2-hydrazinyl-5-nitrobenzoic acid hydrochloride (59.4 g, 255.1 mmol) in AcOH (500 mL) was added ethyl-2,4-dioxovalerate (31.0 g, 196.2 mmol). The reaction mixture was refluxed for 2 h. AcOH was evaporated invacuo and the residue was co-distilled with toluene (100 mL) twice. The residue was dissolved in EtOAc and washed with water until the aq. layer became neutral. The organic layer was dried over sodium sulphate and concentrated invacuo. The gummy material was triturated with diethyl ether to afford the title compound as a white solid 35 g (56%). Rf=0.30 (10% MeOH in DCM); 1H NMR (400 MHz, DMSO-d6): δ 13.90-13.60 (brs, 1H), 8.62 (d, J=2.5 Hz, 1H), 8.54 (dd, J=2.6 & 8.5 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 6.76 (s, 1H), 4.27 (q, J=7.0 Hz, 2H), 2.19 (s, 3H), 1.28 (t, J=7.1 Hz, 3H); LC-MS: m/z 320.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N:11]([C@@H:14]([CH:30]([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])[C:15](N1[C@H](CC2C=CC=CC=2)COC1=O)=[O:16])=[N+]=[N-].C(N(CC)CC)C.CCOC(C)=O.CCCCCC>C(Cl)Cl>[CH2:31]([CH:30]([CH2:35][CH2:36][CH2:37][CH3:38])[C@H:14]([NH:11][S:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])[CH2:15][OH:16])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCC(CCCC)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCC(CCCC)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 16.9 %

Procedure:
5-Chlorothiophene-2-sulfonyl chloride (2.42 g, 11.55 mmol) was added dropwise (5 min) as a solution in CH2Cl2 (20 mL) to a 0° C. solution of (4R)-3-[(2S)-2-azido-3-butylheptanoyl]-4-benzyl-1,3-oxazolidin-one (1.9 g, 10.14 mmol) and triethylamine (2.11 mL, 15.21 mmol). The solution was allowed to warm to 25° C. overnight (19 h). An aliquot was taken and TLC (1:1 EtOAc-hexane) indicated that reaction was complete. It was diluted with CH2Cl2 (100 mL) and the organic layer was washed with 1N HCl (2×50 mL) and saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain a crude oil (2.98 g). The crude product was purified by column chromatography, silica gel 230-400 mesh, eluent: starting with 1:3 EtOAc-hexane and ending with 1:2 EtOAc-hexane to furnish N-[(1S)-2-butyl-1-(hydroxymethyl)hexyl]-5-chloro-2-thiophenesulfonamide as an amorphous white solid (0.630 g, 16.9%). Mass Spectrum (−ESI): 366 (M−H)−. Anal. Calc'd for C15H25NClO3S2: C, 48.96; H, 7.12; N, 3.81. Found: C, 49.08, H, 6.83, N, 3.82.
Reaction SMILES: [Li+].[Cl-].[CH3:3][N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[CH:9]=[N:8][C:7]=2[N:6]([CH3:15])[C:5]1=[O:16].Br[CH2:18][C:19](=[CH2:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([Cu])#N>C1COCC1>[CH3:3][N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9]([CH2:25][C:19](=[CH2:18])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:8][C:7]=2[N:6]([CH3:15])[C:5]1=[O:16]
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: C=C(CBr)C(=O)OCC
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Cc1nc2c(c(=O)n(C)c(=O)n2C)n1C)C(=O)OCC
Temperature: -50 °C
Yield: 68.9 %

Procedure:
TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) was added to a solution of 1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione (12) (194 mg, 1.0 mmol) in THF (2 mL) at 25° C. and the reaction mixture was then stirred at this temperature for max. 5 min. After cooling down to −50 ° C., ethyl 2-(bromomethyl)acrylate (230 mg, 1.2 mmol) and CuCN.2LiCl (1.0 M solution in THF, 5 drops) were added and the resulting mixture was allowed to warm up slowly overnight. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/ether, 1:1) furnished compound 14b (211 mg, 69%) as a colourless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].Br[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12]>C(O)(C)C.ClCCl>[F:12][C:11]([F:14])([F:13])[C:10]1[N:7]=[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]2[CH:9]=1
Reactant: Nc1cnccn1
Reactant: O=C(CBr)C(F)(F)F
Solvent: CC(C)O
Solvent: ClCCl
Product: FC(F)(F)c1cn2ccncc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Pyrazinamine (11.89 g, 125 mmol, commercially available from e.g. Sigma-Aldrich, Fluka or Acros) was dissolved in isopropanol (IPA) (200 mL) and 3-bromo-1,1,1-trifluoro-2-propanone (12.98 mL, 125 mmol) was added. The solution was stirred at room temperature for 2 hours and the heated at reflux for 18 h. The solution was concentrated in vacuo and the residue partitioned between saturated sodium bicarbonate solution (200 ml) and 20% IPA/DCM (300 ml). The aqueous phase was extracted with 20% IPA/DCM (5×200 ml) and the combined extracts were concentrated in vacuo. The residue was dissolved in ethyl acetate (500 ml) and washed with brine (2×100 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude solid (17.69 g). The solid was dissolved in dichloromethane and initially purified by filtration through a plug of silica to afford product in 15.14 g. The solid was purified by flash chromatography (Biotage flash 65+, 0-100% [10% 2M NH3 in MeOH/DCM]/DCM) to afford the desired product in 5.61 g. LC/MS=408/410 (M+H)+, retention time=2.05 minutes (5 minute).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([N:10]1[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=[C:2]1[Br:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1
Reaction time: 12 h
Yield: 89 %

Procedure:
To a stirring suspension of 8-bromo-3-methylxanthine (prepared as for CT13430) (12.25 g, 50.0 mmol) and potassium carbonate (6.91 g, 50.0 mmol) in dimethylformamide (400 ml) was added benzyl bromide (9.24 g, 54.0 mmol). After stirring for 12 hours, the mixture was poured into cold water (680 ml). The precipitate was filtered, washed with water (3×50 ml), ether (3×50 ml) and dried under vacuum to provide 7-benzyl-8-bromo-3-methylxanthine (14.92 g, 89% yield) as a white powder.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[Cl:8][SiH:9]([Cl:11])[Cl:10]>C(P(CCCC)CCCC)CCC>[F:5][C:4]([F:7])([F:6])[CH2:3][CH2:2][Si:9]([Cl:11])([Cl:10])[Cl:8]
Reactant: Cl[SiH](Cl)Cl
Reactant: FC(F)(F)CCCl
Agent: CCCCP(CCCC)CCCC
Product: FC(F)(F)CC[Si](Cl)(Cl)Cl
Yield: 90.7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 1.33 g (10.0 mmol) of 1-chloro-3,3,3-trifluoropropane, and 6.77 g (50.0 mmol) of trichlorosilane were reacted at 150° C. for 15 hrs. The resulting mixture was distilled to give 2.1 g of (3,3,3-trifluoropropyl)trichlorosilane (bp; 114° C., yield; 90%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]([CH3:26])[C:14]([NH:16][C@@H:17]([CH3:25])[C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2].[ClH:27].C(OCC)C>>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]([CH3:26])[C:14]([NH:16][C@@H:17]([CH3:25])[C:18]([OH:20])=[O:19])=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2].[ClH:27]
Reactant: C[C@H](NC(=O)CNc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: C[C@H](NC(=O)[C@H](C)NC(=O)CNc1ncc(C=O)s1)C(=O)O

Procedure:
Following the general procedure as described in Example 68, except using material from Example 101 (780 mg, 2.03 mmol) and HCl, 1.0M in diethyl ether (125 mL, 125 mmol), the title compound is isolated in quantitative yield as a bis HCl salt by weight. LC/MS (Condition A): ret. T=1.3 min, (M+H)+ 329.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.[CH2:10]=[O:11]>CC(C)=O>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][N:6]([CH2:10][OH:11])[CH:7]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: C=O
Solvent: CC(C)=O
Product: OCn1cc(C(F)(F)F)cn1
Temperature: 130 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
The mixture of 0.59 g of 4-(trifluoromethyl)-1H-pyrazole and 0.26 g of paraformaldehyde was stirred at 130° C. for 4 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The residue was concentration under reduced pressure to obtain 0.60 g of 4-(trifluoromethyl)-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [OH-:1].[Na+:2].[C:3]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5]1)=[O:4]>>[OH:1][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[C:3]([O-:5])=[O:4].[Na+:2]
Reactant: [OH-]
Reactant: O=C1OCc2ccccc21
Agent: [Na+]
Product: O=C([O-])c1ccccc1CO
Reaction time: 1 h

Procedure:
An aqueous solution (200 ml) of phthalide (134 g) and sodium hydroxide (40 g) was heated. After stirring for 1 hour, the mixture was concentrated under reduced pressure for removal of water to obtain sodium 2-hydroxymethylbenzoate as colorless crystals. p-Cymene (480 ml) and 2,5-xylenol (122 g) were added to the crystals. Azeotropic dehydration was carried out with heating under reflux for 7 hours by using an azeotropic dehydration apparatus. After cooling, ice water was added. Concentrated hydrochloric acid was added dropwise to make the mixture acidic. The precipitates were separated by filtration and recrystallized from ethyl acetate to obtain the title compound (155 g, Yield: 60.5%), mp: 162°-163° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][O:5][C:4]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:3]1=2.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:4]3[O:5][CH2:6][C:2]([CH3:19])([CH3:1])[C:3]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:24]
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)C(C)(C)CO2
Reactant: O=C(Cl)c1ccccc1F
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)C(C)(C)CO2
Yield: 48.7 %

Procedure:
Similarly, (2-fluorophenyl)-N-[5-(3,3,6-trimethyl(2,3-dihydrobenzo[b]furan-5-yl))-pyrazin-2-yl]carboxamide (179) (13.8 mg, yield: 48.7%, purity>95%) was prepared from 5-(3,3,6-trimethyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (177) (19 mg, 0.075 mmol) and 2-fluorobenzoyl chloride (18 μl).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C@@H:12]([OH:15])[CH2:13][OH:14])=[CH:8][CH:7]=1.CO[C:20](OC)([CH3:22])[CH3:21].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1COCC1>[CH3:21][C:20]1([CH3:22])[O:15][C@H:12]([CH2:11][O:10][C:9]2[CH:16]=[CH:17][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:7][CH:8]=2)[CH2:13][O:14]1
Reactant: OCCCCc1ccc(OC[C@@H](O)CO)cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](COc2ccc(CCCCO)cc2)O1

Procedure:
To (S)-3-[4-(4-Hydroxy-butyl)-phenoxy]-propane-1,2-diol (43 g, 179 mmol) in THF (700 ml) is added 2,2-dimethoxypropane (94 ml, 760 mmol) followed by PPTS (4.5 g, 17.9 mmol). The resultant mixture is stirred at room temperature overnight. The solution is concentrated in vacuo and the residue taken up in DCM (500 ml). This is washed with water, dried (MgSO4) and concentrated in vacuo. The residue is purified through a silica plug (300 g) eluting with 10% followed by 25% EtOAc/iso-hexanes. The desired fractions are concentrated to give 4-[4-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-butan-1-ol as a clear oil; 1H NMR (CDCl3): 1.42, (3H, s), 1.48 (3H, s), 1.53-1.73 (4H, m), 2.20 (1H, t, J=2.5 Hz), 2.60 (2H, t, J=7.2 Hz), 3.68 (2H, t, J=6.4 Hz), 3.92 (2H, dt, J=5.8 and 8.5 Hz), 4.07 (1H, dd, J=5.4 and 9.5 Hz), 4.19 (1H, dd, J=6.4 and 8.5 Hz), 4.49 (1H, p, J=5.7 Hz), 6.85 (2H, d, J=8.7 Hz), 7.11 (2H, d, J=8.7 Hz).