Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.[H-].[Na+].[O:11]=[C:12]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]1[CH2:18][CH2:19]OS(C)(=O)=O>CN(C=O)C.CN(C)C1C=CN=CC=1>[Br:8][C:5]1[N:4]=[CH:3][C:2]([O:1][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[CH2:15][CH2:16][C:12]2=[O:11])=[CH:7][CH:6]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CS(=O)(=O)OCCN1C(=O)CCC1=O
Agent: CN(C)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1CCOc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
10 g (58 mmol) of 3-hydroxy-6-bromopyridine were dissolved in 40 ml of DMF and treated with 2.76 g (69 mmol) of sodium hydride (60% suspension in mineral oil). After stirring at room temperature for 1 h, 20 mg of 4-dimethylaminopyridine were added and the mixture was treated with 16.53 g (74.8 mmol) of methanesulfonic acid 2-(2,5-dioxopyrrolidin-1-yl)ethyl ester and heated to 100° C. for 3 h. Subsequently, the solvent was evaporated and the residue was taken up in water and extracted 4 times with ethyl acetate. The combined organic phases were dried and evaporated to dryness. The remaining material was purified by chromatography (silica gel, dichloromethane/methanol 98:2) followed by preparative HPLC (RP18, acetonitrile/water containing 0.1% TFA) to yield 10.8 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][O:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]([O:30]C)=[O:29])[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][O:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]([OH:30])=[O:29])[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C=Cc1cccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=Cc1cccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A mixture of methyl 3-[3-[(4,5-diphenyl-2-oxazolyl)methoxy]phenyl]-2-propenoate (3 g, 7.2 mmol), 5N sodium hydroxide solution (4.40 mL) and methanol (60 mL) was heated to reflux. After 30 minutes, the mixture was cooled, concentrated, diluted with water and acidified to pH=1 with 2N hydrochloric acid solution. A yellow solid was filtered off and recyrstallized from a mixture of hexanes and CH2Cl2 to give 3-[3-[(4,5-diphenyl-2-oxazolyl)methoxy]phenyl]-2-propenoic acid (2.25 g, 77%), mp 145°-147° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([NH2:20])=[N:9][CH:10]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=[S:22].[NH4+].[OH-].O>C1COCC1>[CH:1]1([O:6][C:7]2[C:8]([NH:20][C:21]([NH2:23])=[S:22])=[N:9][CH:10]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncc(Oc2ccccc2)cc1OC1CCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1ncc(Oc2ccccc2)cc1OC1CCCC1
Reaction time: 19 h
Yield: 87 %

Procedure:
3-Cyclopentyloxy-5-phenoxy-pyridine-2-ylamine (0.33 mmol) is dissolved in THF (5 ml) and 1,1′-thiocarbonyldiimidazol (4 eq.) is added. The reaction solution is stirred 19 hours. 32% NH4OH (20 eq.) is added and stirred 3 hours at room temperature. Water (50 ml) is added and extracted with dichloromethane. The combined organic layers are washed with brine and dried over MgSO4. The solvent is removed in vacuo. (3-Cyclopentyloxy-5-phenoxy-pyridine-2-yl)-thiourea is obtained as brown oil in a yield of 87%; HPLC (method C): 2.13 min; LC-MS (method A): 2.18 min, 330.15 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[N+:19]([O-])=O>[Pd].CO>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]([F:18])([F:16])[F:17])[CH2:13][CH2:14]2)=[CH:5][C:4]=1[NH2:19]
Reactant: CNc1ccc(N2CCC(C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(N2CCC(C(F)(F)F)CC2)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-methyl-2-nitro-4-(4-trifluoromethyl-piperidin-1-yl)-aniline (220 mg, 0.7 mmol), MeOH (7 mL) and Pd/C (30 mg) was stirred for 18 h at rt under a hydrogen atmosphere (3.0 bar). The catalyst was removed by filtration, the filtrate was concentrated and directly used in the next step.
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:48])[CH2:26][C:27]([C:30]3[C:35](=[O:36])[C:34]([CH3:37])=[C:33]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])[C:32](=[O:46])[C:31]=3[CH3:47])([CH3:29])[CH3:28])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:48])[CH2:26][C:27]([C:30]1[C:35](=[O:36])[C:34]([CH3:37])=[C:33]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])[C:32](=[O:46])[C:31]=1[CH3:47])([CH3:29])[CH3:28]
Reactant: C=CCOC(=O)CCC1=C(C)C(=O)C(C(C)(C)CC(=O)OCCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)=C(C)C1=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: C=CCOC(=O)CCC1=C(C)C(=O)C(C(C)(C)CC(=O)OCCCCCN)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound J (250 mg, 0.38 mmol) dissolved in 10 mL of DMF was added piperidine (0.5 mL). The solution was stirred 10 min at room temperature. The solvent was evaporated and the residue was purified by flash chromatography using a gradient solvent system 10% MeOH/CH2Cl2 to 100% MeOH. After evaporation of the solvent 53 mg (33%) of the compound K was isolated as a yellow oil. 1H NMR 500 MHz (CD3OD) δ5.87 (m, 1H), 5.22 (m, 2H), 4.54 (dt, J=5.6 Hz, 1.2 Hz, 2H), 3.93 (t, J=7 Hz, 2H), 2.92 (s, 2H), 2.72 (t, J=8 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.45 (t, J=8 Hz, 2H), 210 (s, 3H), 1.96 (s, 3H), 1.58-1.42 (br, 4H), 1.38 (s, 6H), 1.30 (m, 2H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].Br[CH2:7][CH2:8][O:9][CH2:10][CH2:11]Br.CC([O-])(C)C.[K+]>CS(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C(Cl)Cl>[O:9]1[CH2:10][CH2:11][C:2]([C:1]#[N:5])([C:3]#[N:4])[CH2:7][CH2:8]1
Reactant: BrCCOCCBr
Reactant: N#CCC#N
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#CC1(C#N)CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24 %

Procedure:
Malononitrile (5.0 g) was dissolved in DMSO (5 mL). Subsequently, bis(2-bromoethyl)ether (9.49 mL) and TBAB (1.22 g) were added, followed by portionwise addition of KOtBu (8.49 g). The mixture was stirred for 4 h. at room temperature, taken up in DCM and extracted 3 times with 5% aqueous NaHCO3. The organic phase was dried over Na2SO4 and evaporated under reduced pressure. The crude material was purified by flash chromatography eluting with PA:Et2O 65:35 (Rf=0.24, visualized with KMnO4) to give 2.49 g (24%) of a solid. 1H NMR (400 MHz, CDCl3) δ 2.24 (t, 4H), 3.87 (t, 4H).
Reaction SMILES: [N:1]([C:8](OC(C)(C)C)=O)([CH3:7])[C@H:2]([C:4](O)=[O:5])[CH3:3].CCN=C=NCCCN(C)C.[CH2:26]([NH:34][C:35]([C@@H:37]1[CH2:41][CH2:40][C@H:39]([CH2:42][CH:43]=[CH2:44])[N:38]1[C:45](=[O:51])[C@@H:46]([NH2:50])[CH2:47][CH:48]=[CH2:49])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:26]([NH:34][C:35]([C@@H:37]1[CH2:41][CH2:40][C@H:39]([CH2:42][CH:43]=[CH2:44])[N:38]1[C:45](=[O:51])[C@@H:46]([NH:50][C:4](=[O:5])[C@@H:2]([N:1]([CH3:8])[CH3:7])[CH3:3])[CH2:47][CH:48]=[CH2:49])=[O:36])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C=CC[C@H]1CC[C@@H](C(=O)NCCc2ccccc2)N1C(=O)[C@@H](N)CC=C
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC[C@H]1CC[C@@H](C(=O)NCCc2ccccc2)N1C(=O)[C@H](CC=C)NC(=O)[C@H](C)N(C)C
Reaction time: 8 h

Procedure:
Boc-N-MeAlaOH (5.36 g, 26.4 mmol) is suspended in dichloromethane (200 mL) and EDCI (5.4 g, 28 mmol) and DMAP (3.4 g, 28 mmol) are added to obtain a clear solution. 11G in dichloromethane (50 mL) is added and stirred overnight followed by quenching with saturated bicarb and extracting with dichloromethane then washing with brine, drying over anhydrous magnesium sulfate, filtering and concentrating. LCMS characterization ES+541.2 (m+1).
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([OH:10])[CH2:8][OH:9].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:33]3[C:28](=[CH:29][C:30](F)=[CH:31][CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CS(C)=O>C([O-])(O)=O.[Na+]>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:9][CH2:8][CH2:7][OH:10])=[CH:31][CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCO)ccc23)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 80.8 %

Procedure:
KOtBu (1.17 g, 10.4 mmol) was added to ethylene glycol (10 mL, 179 mmol) to provide a homogeneous solution. 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.61 g, 7.89 mmol), as prepared in Example 65b, was added, and the opaque white slurry was stirred at rt for 3.5 hr. DMSO (5 mL) was then added, and the mixture stirred at 110° C. for 20 min at which point it became a homogeneous solution. The reaction was then stirred at rt overnight, at which point it became a translucent white slurry. The mixture was then diluted with 0.1M NaHCO3 and extracted with EtOAc (2×50 mL). The combined organic layers were washed with 0.1M NaHCO3 (1×100 mL), dried (Na2SO4), concentrated, and dissolved in ˜15 mL toluene. The title compound crystallized upon standing at rt, was filtered, and the crystalline filter cake washed with toluene (1×10 mL). The filter cake was dried under high vacuum at 100° C. to afford the title compound as a white powder (2.38 g, 81%). LC/MS (ESI): calc mass 373.2, found 374.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32][CH3:33])[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH3:35]C1N=C(NCCC)N=C(C(O)=O)C=1.OCC(NCC(O)COC1C(C)=CC(C(=N)NO)=CC=1C)=O>>[CH3:34][C:15]1[CH:16]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32][CH2:33][CH3:35])[N:25]=3)[O:21][N:20]=2)[CH:18]=[C:3]([CH3:1])[C:4]=1[O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Reactant: CCCNc1nc(C)cc(C(=O)O)n1
Agent: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Product: CCCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)n1

Procedure:
rac-N-(3-{2,6-Dimethyl-4-[5-(6-methyl-2-propylamino-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 6-methyl-2-propylamino-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.92 min, [M+H]+=471.25.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[NH2:4].[CH:11]12[CH2:16][CH:15]1[C:14](=O)[O:13][C:12]2=[O:18]>CN(C)C=O>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:4]=[C:14]([C@H:15]2[CH2:16][C@H:11]2[C:12]([OH:18])=[O:13])[O:1][N:2]=1
Reactant: O=C1OC(=O)C2CC12
Reactant: NC(=NO)c1ccccn1
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1C[C@@H]1c1nc(-c2ccccn2)no1
Yield: 86.6 %

Procedure:
N′-hydroxy-2-pyridinecarboximidamide (0.137 g) with 3-oxabicyclo[3.1.0]hexane-2,4-dione (0.112 g) in dimethylformamide (2 drops) was heated for 4 times 30 seconds in a CEM MARS 5 microwave at 100% of 300 W to leave a fused mass. The reaction was allowed to cool and triturated with diethyl ether and filtered to leave cis-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxylic acid (0.200 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:18][C:17]([O:21][CH3:22])=[O:20])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cc(F)cc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 96 h

Procedure:
To a solution of 1-(benzyloxy)-3-bromo-5-fluorobenzene (6.60 g) in acetonitrile (130 mL) were added methyl acrylate (13.7 g), triphenylphosphine (3.36 g) and triethylamine (14.5 g), and toluene (2.0 mL) and palladium acetate (480 mg) were further added. The reaction mixture was stirred at 100° C. for 96 hr, and the solvent was evaporated under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11]([O:19][C@@H:20]([C@@H:22]3[CH2:26][C:25](=[O:27])[NH:24][CH2:23]3)[CH3:21])[C:12]3[N:13]([N:15]=[CH:16][C:17]=3[CH3:18])[CH:14]=2)[CH:6]=[CH:5][C:4]=1[N:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11]([O:19][C@@H:20]([C@H:22]3[CH2:23][NH:24][C:25](=[O:27])[CH2:26]3)[CH3:21])[C:12]3[N:13]([N:15]=[CH:16][C:17]=3[CH3:18])[CH:14]=2)[CH:6]=[CH:5][C:4]=1[N:28]1[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]1.[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42]
Reactant: COc1cc(-c2cn3ncc(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cn3ncc(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl 4-(2-methoxy-4-(3-methyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazin-6-yl)phenyl)piperazine-1-carboxylate 5.59 (35 mg, 0.06 mmol) was dissolved in TFA (2.5 mL, 32.7 mmol) and mixture was stirred at room temperature. After 2 hours, reaction mixture was concentrated and azeotroped with toluene to yield (R)-4-((R)-1-((6-(3-methoxy-4-(piperazin-1-yl)phenyl)-3-methylpyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.60 as a trifluoroacetic acid salt (36 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22]CC3C=CC=CC=3)[C:17]2=[O:30])=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]2=[O:30])=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2cccc(OCc3ccccc3)c2=O)sc1C(=O)NCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(-n2cccc(O)c2=O)sc1C(=O)NCc1ccccc1
Reaction time: 2 h
Yield: 24.7 %

Procedure:
A mixture of N-benzyl-2-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide (0.14 g, 0.32 mmol) and 20 wt. % palladium on activated carbon (0.10 g) in methanol (50 mL) was stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography followed by recrystallization from methanol (10 mL) to afford the title compound (0.027 g, 8%): mp 225-228° C.; 1H NMR (300 MHz, CD3OD) δ 8.63 (d, J=7.6 Hz, 1H), 7.42-7.26 (m, 5H), 6.20-6.10 (m, 1H), 5.87-5.83 (m, 1H), 4.36 (d, J=6.0 Hz, 2H), 2.58 (s, 3H); MS (ES+) m/z 342.2 (M+1).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>C(C(CC)C(N)=O)C.O>[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: Nc1ccc(S(=O)(=O)c2ncccn2)cc1
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Agent: CCC(CC)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=C(Nc1ccc(S(=O)(=O)c2ncccn2)cc1)C(O)(C(F)F)C(F)F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmoles) in di ethyl acetamide (10 ml) at -10° C. was added thionyl chloride (0.34 g, 2.84 mmoles) dropwise. The resulting solution was stirred at -10° C. for approximately 30 mins. 4-(2-pyrimidylsulfonyl)aniline (0.59 g, 2.5 mmoles) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and sodium bicarbonate solution was added to give a pH of 7-7.5. A dark colored precipitate was formed that was filtered, washed with water and dried. The crude material was preabsorbed onto silica gel and chromatographed on silica gel eluting with 70-80% ethyl/acetate/hexane. Evaporation of product-containing fractions and crystallization from methylene chloride/methanol/hexane gave the title compound (0.33 g, 34%) as a white solid; mp 209°-210° C. 1H-NMR (300 MHz, d6 -DMSO):6.46(t, J=54.06 Hz, 2H, HCF2), 7.78 (t, J=4.8 Hz, 1H, ArH), 7.95-7.98(m, 3H, ArH, OH), 8.02-8.06(m, 2H, ArH), 9.01 (d, J=5.01 Hz, 2H, ArH), 10.58 (s, 1H, NH). MS(CI):394(M+1, 100%).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[C:25]([CH3:27])([CH3:26])[O:24][C:23]([NH:28][C@H:29]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[F:46])[CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)=[N:22][S:21]3(=[O:48])=[O:47])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[H][H].Cl>CO.[Pd]>[CH3:26][C:25]1([CH3:27])[O:24][C:23]([NH:28][C@H:29]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[CH2:30][CH2:31][OH:32])=[N:22][S:21](=[O:48])(=[O:47])[CH:20]1[C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C3C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c4ccccc4F)=NS3(=O)=O)cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2F)=NS(=O)(=O)C1c1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of 1-Boc-4-(4-{2-[(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamino]-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl}phenyl)-3,6-dihydro-2H-pyridine (575 mg) in methanol (25 ml) was admixed with palladium on charcoal (10%, 260 mg) and stirred in a hydrogen atmosphere for 1.5 h. The mixture was filtered and concentrated. The residue was dissolved in 5 ml of dichloromethane, and 1 ml of trifluoroacetic acid was added. After stirring at room temperature for 1 h, the solvent was removed under reduced pressure and TFA ester formed was cleaved by treatment with 1 N HCl. Extraction with ethyl acetate gave the crude product (91%), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH2:13])=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:14]([O-])=O.CN>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH2:13])=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[NH2:14]
Reactant: COc1cc2ncnc(N)c2cc1[N+](=O)[O-]
Agent: CN
Product: COc1cc2ncnc(N)c2cc1N
Yield: 92 %

Procedure:
The procedure of Example 23 was repeated except for using 7-methoxy-6-nitroquinazolin-4-ylamine instead of 7-methoxy-6-nitroquinazolin-4-yl)methylamine in <Step 7> to obtain the title compound (158 mg, 92%).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:25][C@@H:26]([CH2:28][OH:29])[CH3:27]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][C@H:26]([CH3:27])[CH2:28][OH:29])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: C[C@@H](N)CO
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Product: C[C@H](CO)NC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 41 %

Procedure:
As described for example 325, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (60 mg, 0.18 mmol) was converted, using D-alaninol instead of rac-2-amino-1-propanol, to the title compound (28 mg, 41%) which was obtained as a white solid MS: m/e=372.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C@H:6]([OH:8])[CH3:7])[C:3]([OH:5])=[O:4].O=[CH:10][C:11]([Cl:14])([Cl:13])[Cl:12].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:12][C:11]([Cl:14])([Cl:13])[C@H:10]1[O:4][C:3](=[O:5])[CH:2]([CH3:1])[C@@H:6]([CH3:7])[O:8]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CC(C(=O)O)[C@@H](C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1C(=O)O[C@H](C(Cl)(Cl)Cl)O[C@@H]1C
Yield: 83.5 %

Procedure:
A mixture of (3R)-2-methyl-3-hydroxybutanoic acid 3.6 g, chloral 8.3 g, pyridinium p-toluenesulfonate (PPTS) 0.7 g and dichloromethane 20 ml was refluxed for 25 hours under a dehydration condition. 40 ml of a saturated aqueous sodium hydrogen carbonate was added thereto and the resulting separated organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain 6.3 g of (2R, 6R)-2-trichloromethyl-5,6-dimethyl-1,3-dioxan-4-one.
Reaction SMILES: [CH:1]([P:3](=[O:6])([CH3:5])[CH3:4])=[CH2:2].C[O-].[Na+].[P:10]([O-:15])([O:13][CH3:14])[O:11][CH3:12]>O1CCOCC1>[CH3:12][O:11][P:10]([CH2:2][CH2:1][P:3]([CH3:5])([CH3:4])=[O:6])(=[O:15])[O:13][CH3:14]
Reactant: C=CP(C)(C)=O
Reactant: COP([O-])OC
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COP(=O)(CCP(C)(C)=O)OC
Yield: 53.2 %

Procedure:
95 g of vinyldimethylphosphine oxide are dissolved in dioxane and rendered alkaline with sodium methoxide solution. 100 g of dimethyl phosphite are added dropwise, in an exothermic reaction. The mixture is then subjected to fractional distillation, which gives 104 g of product, boiling point at 0.4 mm Hg: 182° C. (yield: 53% of theoretical). The first runnings of the distillation contain unreacted dimethyl phosphite and vinyldimethylphosphine oxide, which can be used again in a further batch.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:6]=[C:7]([NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:4]([C:5]1[CH:6]=[C:7]([NH:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)#[CH:3]
Reactant: C[Si](C)(C)C#Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Yield: 25 %

Procedure:
Under the conditions of example 21 C, 2 g of N-[3-(2-trimethylsilylethinyl)-phenyl]-1,1,1-trifluoromethanesulfonamide is reacted with 6.9 ml of a 1-molar solution of tetrabutylammonium fluoride in tetrahydrofuran and worked up. 387 mg of N-(3-ethinylphenyl)-1,1,1-trifluoromethanesulfonamide is obtained as oily crude product.