Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].C(N(CC)CC)C.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C1COCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH:9]=1)[C:5]#[N:6]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc(F)cc(C#N)c1

Procedure:
To a solution of commercially available 3-bromo-5-fluorobenzonitrile (5 g, 25 mmol) and triethylamine (35 ml) in 35 ml of THF was bubbled nitrogen for 10 min. Then added trimethylsilylacetylene (5.0 g, 50 mmol), copper iodide (60 mg, 0.31 mmol), and PdCl2(PPh3)2 (80 mg, 0.11 mmol) and the reaction mixture was heated with a heating mantle. After an initial exotherm, the reaction was heated at reflux for 3 hrs. The reaction mixture was concentrated on a rotary evaporator and the dark residue diluted with hexane and washed with water three times. The hexane layer was filtered through Celite and the filtrate was concentrated to give a brown oil. The crude material was used without further purification. LCMS B: Ret time 3.96 min, (M+H)+=218.14. 1H NMR, 400 MHz, CDCl3: 7.57 (s, 1H), 7.43 (m, 1H), 7.35 (m, 1H), 0.26 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH:31]([CH3:33])[CH3:32])[CH3:14])=[CH:8][C:7]=1[CH3:34].[OH-].[Na+].Cl>CO.C1COCC1>[CH:31]([C:16]1[N:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:24][CH:25]=2)[O:19][C:15]=1[CH:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]([CH3:34])[CH:8]=1)[CH3:14])([CH3:32])[CH3:33]
Reactant: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(OC(F)(F)F)cc3)nc2C(C)C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OC(C)c2oc(-c3ccc(OC(F)(F)F)cc3)nc2C(C)C)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(4-{1-[4-Isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic acid methyl ester in MeOH (1.0 mL) and THF (0.5 mL) is treated with NaOH (1.5 mL, 2.0 M) and stirred at room temperature for 2 hours. The mixture is neutralized to pH=6 with HCl (5 N) and extracted with EtOAc (20 mL×2), and the combined organics are dried (Na2SO4), concentrated and purified on silica gel chromatography column with EtOAc/Hexanes (50/50) to yield the acid as white solid (14 mg). MS (ES): 478.2; the structure is also confirmed by proton NMR.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19](OCC)=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:27][C:26]=1[S:39]([NH2:42])(=[O:41])=[O:40].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[CH:27][C:26]=2[S:39](=[O:40])(=[O:41])[N:42]=1
Reactant: CCOC(=O)C1=C(O)c2ccccc2[C@@](C)(CCC(C)C)C1=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Temperature: 100 °C

Procedure:
To a solution of the product of Example 39-4 (320 g, 1.01 mol) in toluene (1100 mL) was added product of Example 17A-4 (291 g, 1.01 mol). The solution was heated to 100° C. for 4 h then cooled to RT. The solution was transferred to a pressure bottle and triethylamine (472, 4.66 mol) was added and the solution was heated to 100° C. for 26 h. The solution was concentrated to ⅓ of the original volume and ethyl acetate (2000 mL) was added. The organic layer was washed with 10% KH2PO4 and 10% NaCl then concentrated to a thick oil then chased with CH2Cl2. The crude product of Example 39-5 (assay for 406.5 g, 74.5%) was used directly.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[N:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:26][CH2:25][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:18])[N:24]=2)[N:3]=1
Reactant: Cc1cccc(CO)n1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccc(COc2nc(N)nc(-c3ccco3)c2C#N)n1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 6-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 330 (M+Na+, 10), 308 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[O:21]
Reactant: Nc1ccc(F)cn1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-5-fluoropyridine (300 mg, 2.60 mmol) in DCM (4.0 mL), DIPEA (1.36 mL, 7.79 mmol) was added, followed by chloracetylchloride (0.23 mL, 2.86 mmol). The resulting dark brown reaction mixture was stirred at rt for 2 h, then quenched with water and diluted with DCM. The org. layer was separated and the aq. layer extracted with DCM (1×). The combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent removed under reduced pressure to obtain 2-chloro-N-(5-fluoropyridin-2-yl)acetamide as a brown oil which was used in the next step without further purification. LC-MS conditions A: tR=0.60 min, [M+H]+=189.31.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][OH:31]>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([CH2:30][OH:31])[CH:32]=[CH:33][CH:34]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: OCc1cccc(Br)c1
Product: OCc1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and commercially available 3-bromobenzyl alcohol (243 mg, 1.3 mmol) according to general procedure II. Obtained as a brown solid (60 mg, 13%). MS (ISP) 462.2 [(M+H)+]; mp 177° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.O>[F:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1cnc(Cl)c2cc(F)ccc12
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cnc(F)c2cc(F)ccc12
Temperature: 145 °C
Yield: 49.8 %

Procedure:
To a solution of 1-chloro-7-fluoro-4-methoxyisoquinoline (3.7 g, 17.48 mmol) in DMSO was added cesium fluoride (10.26 g, 69.9 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (1.7 g, 49%) as white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.20-8.18 (m, 1H), 7.69-7.66 (m, 1H), 7.54-7.47 (m, 1H), 7.46 (s, 1H), 4.04 (s, 3H); 19F NMR: δ ppm 109.65 (1 F), −78.53 (1 F); MS: MS m/z 196.1 (M++1).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]([C:12]2[CH:13]=[N:14][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[CH:16][CH:17]=2)O)=[CH:2]1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.O>[F:28][C:26]([F:27])([F:29])[C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][O:18][C:15]1[N:14]=[CH:13][C:12]([CH2:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[CH:17][CH:16]=1
Reactant: OC(c1ccc(OCc2cccc(C(F)(F)F)c2)nc1)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: FC(F)(F)c1cccc(COc2ccc(Cc3c[nH]c4ncccc34)cn2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(1H-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanol 74 was dissolved in 9:1 trifluoroacetic acid:triethylsilane. The reaction was stirred at room temperature for 15 hours. The reaction was diluted with water and extracted with ethyl acetate and concentrated. The crude material was purified by reverse phase HPLC to provide 3-[6-(3-Trifluoromethyl-benzyloxy)-pyridin-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine P-0057. MS (ESI) [M+H+]+=384.3.
Reaction SMILES: O[C@H:2]([CH3:36])[C@H:3]([NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=3)[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=2)=[CH:11][CH:12]=1)=[O:7])[CH3:4].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:4][C@@H:3]1[C@H:2]([CH3:36])[O:7][C:6]([C:8]2[NH:9][C:10]([C:13]3[CH:18]=[C:17]([CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=3)[O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[N:22][CH:21]=3)=[CH:11][CH:12]=2)=[N:5]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](C)[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
N-[(1R,2R)-2-Hydroxy-1-methylpropyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (1.33 g, 2.57 mmol) synthesized in Example (88b) was dissolved in tetrahydrofuran (25 mL), and anhydrous methanesulfonic acid (0.92 g, 5.14 mmol) and triethylamine (1.43 mL, 10.28 mmol) were added, followed by stirring at 50° C. for 5 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (40 mL) was added, and the solution was separated with ethyl acetate (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=40%-70%) to afford the desired compound (0.95 g, yield 74%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:29]=[O:30])[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.[BH4-].[Na+]>CCO.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:29][OH:30])[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(C=O)cc(C)c32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(CO)cc(C)c32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of (±)-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole-5-carbaldehyde (221 mg, 0.52 mmol) and NaBH4 (98 mg, 2.6 mmol) in EtOH (5 mL) was stirred at 0° C. for 0.5 h. The reaction mixture was diluted with CH2Cl2. The mixture was washed with H2O, half satd. KHSO4 aqueous solution, H2O, and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave the title compound, which was used in the next reaction without any further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=3.79 Hz, 1H), 7.60 (d, J=8.34 Hz, 2H), 7.38 (d, J=8.34 Hz, 2H), 7.14 (s, 1H), 6.98 (d, J=3.79 Hz, 1H), 5.01 (t, J=5.56 Hz, 1H), 4.87 (d, J=11.37 Hz, 1H), 4.67 (d, J=11.37 Hz, 1H), 4.55-4.63 (m, 3H), 3.73-3.85 (m, 1H), 3.37-3.51 (m, 1H), 2.34 (s, 3H), 2.08 (s, 3H), 1.51-1.71 (m, 2H), 1.30-1.51 (m, 4H).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=[O:15].[C:17]([O-])(O)=O.[Na+]>CO>[CH3:17][O:15][C:14](=[O:16])[CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[Br:6]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccccc1Br
Temperature: 25 °C

Procedure:
2 mL H2SO4 is added to (2-bromo-phenyl)-acetic acid (15 g, 70 mmol) in 150 mL methanol. The reaction mixture is refluxed 16 hours and cooled to room temperature. 100 mL saturated NaHCO3 (aq) is added. Methanol is removed in vacuo. The resulting mixture is extracted with Ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O>CN(C)C=O>[C:27]([O:26][C:24]([CH2:23][N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc2cc(C(=O)OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 108.2 %

Procedure:
Sodium hydride (115 mg) was added to a solution of benzyl 1H-indole-5-carboxylate (600 mg) in N,N-dimethylformamide (2 ml) with ice cooling, and the mixture was stirred for 30 minutes. t-Butyl bromoacetate (562 mg) was added thereto and stirred for 2 hours. Water was added thereto, and the aqueous phase was neutralized and then extracted with dichloromethane. The organic phase was dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give benzyl 1-t-butoxycarbonylmethyl-1H-indole-5-carboxylate (944 mg, Y.: quant.).
Reaction SMILES: [Na].[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([OH:9])[CH2:4]1.CCCCCCC.[CH:17]1([C:22]([C:29]#[C:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([OH:28])[C:23](OCC)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1>CCOCC>[CH:17]1([C:22]([C:29]#[C:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([OH:28])[C:23]([O:9][CH:5]2[CH2:6][CH2:7][CH2:8][N:3]([CH3:2])[CH2:4]2)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)C1CCCC1
Reactant: CN1CCCC(O)C1
Agent: [Na]
Solvent: CCOCC
Solvent: CCCCCCC
Product: CN1CCCC(OC(=O)C(O)(C#Cc2ccccc2)C2CCCC2)C1
Reaction time: 8 h

Procedure:
Sodium (~0.05 g.) and 1-methyl-3-piperidinol (4.0 g., 0.035 mole) were refluxed in 250 ml. of dry n-heptane in a reaction flask equipped with a Dean-Stark trap until all of the sodium reacted. Then 6.5 g. (0.024 mole) of ethyl α-cyclopentyl-α-phenylethynylglycolate, undiluted, was added dropwise over a 0.25 hour period. The reaction mixture was subsequently refluxed for 20 hours, and about 30 ml. of solvent was collected toward the end of that period. The reaction mixture was kept overnight. No crystallization occurred during that time, but some tarry material was present and was filtered. Ether (acidic) and chloroform (basic) extracts were made of the filtrate as described previously. The chloroform extract yielded, after the solvent was stripped, 6.2 g. of a red-brown oil. The oil was dissolved in ether and petroleum ether (20°-40°) was added until turbidity was produced. The material was then placed in a freezer for four days and the product precipitated. It weighed 3.2 g., (39%) and melted at about 85° after being filtered and dried. The solid was recrystallized from 20°-40° petroleum ether. The first batch yielded off white crystals melting at 112°-113°.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:6]=1.O.O.Cl[Sn]Cl.CCO.[OH-].[K+]>O>[CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])cc2)co1
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(N)cc2)co1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-methyl-4-(4-nitrophenyl)oxazole (J. Heteocyclic Chemistry, 1981, 885)(1.12 g, 5.48 mmol) was added to a refluxing solution of SnCl2.2H2O (6.33 g, 28.1 mmol), conc HCL (10 mL) and EtOH (20 mL). The reaction is stirred for 30 min then cooled to room temperature and poured into a solution of 24 g of KOH in 100 mL of water. The resulting mixture was cooled in an ice bath and stirred for an additional 30 min. The product was collected by filtration as a yellow solid (1.35 g, 83%). LC-MS (M+H): 191
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=NOC)[CH:6]([C:11](=O)[CH3:12])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].Cl.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[NH:27][NH2:28]>C(O)(=O)C.COCCO>[CH2:1]([O:3][C:4]([C:5]1[N:27]([C:21]2[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:26])[N:28]=[C:11]([CH3:12])[C:6]=1[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=NOC)C(CC(C)C)C(C)=O
Reactant: NNc1c(Cl)cccc1Cl
Agent: Cl
Solvent: COCCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CC(C)C)c(C)nn1-c1c(Cl)cccc1Cl
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 3-acetyl-2-methoxyimino-5-methyl-hexanoic acid ethyl ester (1 g, 4.1 mmol), 2,6-dichlorophenylhydrazine hydrochloride (1.76 g, 8.2 mmol) in glacial acetic acid (10 mL) and 2-methoxy-ethanol (5 mL) is stirred at 105° C. for 3 hours. The reaction is concentrated and the residue is partitioned between EtOAc and 1N HCl. The organic layer is concentrated and purified by column chromatography (0-20% EtOAc in hexanes) to give the title product as an oil, 1.1 g (76%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12](N)=[O:13]>>[Br:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:12]([OH:13])[N:11]=[CH:4]2
Reactant: Nc1ccc(Br)cc1C=O
Reactant: NC(N)=O
Product: Oc1ncc2cc(Br)ccc2n1
Temperature: 180 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
A mixture of 2-amino-5-bromobenzaldehyde (29) (6 g, 30.0 mmol) and urea (30) (27 g, 450.0 mmol) was heated to 180° C. and stirred for 5 hours. LCMS showed the reaction was completed. The reaction mixture was cooled to room temperature, and the resulting precipitate was washed with H2O (3×500 mL) and co-evaporated with toluene three times to completely remove the moisture trapped. 6-bromoquinazolin-2-ol (31)(6 g, 89%) was obtained as a yellow solid. MS (ES+) C8H5BrN2O requires: 224. found: 225, 227 [M+H]+.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:24]([O:20][C@@H:5]1[C@@H:4]([O:21][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:3]([O:22][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:2]([CH2:1][O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:7][C@H:6]1[O:8][C@@H:9]1[C@@H:10]([CH2:18][O:19][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:11][CH:12]([O:17][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:13]([O:16][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:14]1[O:15][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)C(OC(=O)c3ccccc3)O[C@@H]2COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
Cellobiose (1.0 g, 2.92 mmol) was dissolved in dry pyridine (20 mL) at 0° C. DMAP (cat.) was added. Benzoyl chloride (2.5 equiv., 58 mmol, 6.8 mL) was added dropwise and the solution stirred at room temperature overnight. The solution was poured onto a mixture of ice-water and DCM. The organic layer was washed with NaHCO3(sat.) (×7), brine, H2SO4 (5%) (×2), followed by brine. The solution was dried (Na2SO4) and the solvent evaporated. The product was passed through a short silica plug to remove the remaining benzoyl chloride and the solvent was evaporated to yield 740 mg (22%) of the white solid product which was reacted on without further purification or characterisation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([NH2:14])[CH3:13]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:14][CH2:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCN
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Product: CCNc1cc(Cl)ncc1[N+](=O)[O-]

Procedure:
The title compound was prepared by the method of Example 1, Step 4 starting from the product of Example 1, Step 3 and ethylamine. MS (ES+) m/e 202 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[CH3:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[N:21][OH:22])[CH3:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4.0 g of 4-acetyl-piperidine-1-carboxylic acid benzyl ester, 25 mL of pyridine, and 6 g of hydroxylamine hydrochloride were heated to 100° C. for 12 h. The mixture was concentrated under reduced pressure and partitioned between 200 mL of ethyl acetate and 50 mL of 1N HCl. The organic extract was dried over magnesium sulfate and concentrated to dryness under reduced pressure. Drying under vacuum gave 4-(1-hydroxyimino-ethyl)-piperidine-1-carboxylic acid benzyl ester as a solid:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.[OH-].[K+].FC(F)(F)C(O)=O>CO>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([N:9]2[CH:8]=[N:7][C:6]3[C:10]2=[N:11][C:12]([C:14]([F:17])([F:15])[F:16])=[N:13][C:5]=3[NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:23][CH:22]=1)([OH:26])=[O:25]
Reactant: COC(=O)c1ccc(-n2cnc3c(NC4CC4)nc(C(F)(F)F)nc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-n2cnc3c(NC4CC4)nc(C(F)(F)F)nc32)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.7 %

Procedure:
6-Cyclopropylamino-9-(4-methoxycarbonylphenyl)-2-trifluoromethylpurine (20 mg, 0.053 mmol) was treated with 0.53 mmol of 1-2 M KOH in methanol (containing 5% water) and stirred for 14 hours at room temperature. The reaction mixture was acidified with trifluoroacetic acid (30% in dichloromethane) to pH=2 and concentrated under vacuum. The residue was extracted with 20% methanol in dichloromethane. The extraction was loaded on a silica gel column and eluted with 20% methanol in dichloromethane to give 9-(4-carboxyphenyl)-6-cyclopropylamino-2-trifluoromethylpurine (14 mg, 70% yield). 1H NMR (300 MHz, DMSO) δ 8.85 (s, 1H), 8.70 (s, 1H), 8.15 (d, J=8.4 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H), 3.07 (b, 1H), 0.78 (b, 2H), 0.68 (b, 2H). [ESMS m/z (363.9 (M+1)+)]