Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([O:15]C)=[O:14].[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[C:20]=1[CH:21]=O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:21][C:20]1[C:19]([O:18][CH3:17])=[CH:26][C:25]([O:27][CH3:28])=[CH:24][C:23]=1[O:29][CH3:30])[C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)CC1=C(C)Cc2ccc(O)cc21
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Product: COc1cc(OC)c(C=C2C(C)=C(CC(=O)O)c3cc(O)ccc32)c(OC)c1

Procedure:
The reaction of Example 13(D) is repeated except that the starting materials are methyl 5-hydroxy-2-methyl-3-indenylacetate and 2,4,6-trimethoxybenzaldehyde. With the same reaction conditions and techniques, 5-hydroxy-2-methyl-1-(2,4,6-trimethoxybenzylidene)-3-indenyl-acetic acid is obtained. (R and R1 =H, R2 =OH, R3 and R4 =H, R5, R6 and R7 =OCH3, R8 =CH3, o=1, M=OH)
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=1[OH:21].[OH-].[Na+]>CC(C)=O>[OH:21][C:20]1[CH:19]=[C:18]([CH3:22])[CH:17]=[CH:16][C:15]=1[NH:14][C:11]([NH2:12])=[S:10]
Reactant: Cc1ccc(N)c(O)c1
Reactant: N#C[S-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: Cc1ccc(NC(N)=S)c(O)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
0.2 mole of benzoyl chloride is added dropwise to a solution of 0.22 mole of ammonium thiocyanate in 100 ml of anhydrous acetone. The mixture is boiled to reflux for 5 minutes after the addition is complete, and a solution of 0.2 mole of 6-amino-m-cresol in 50 ml of anhydrous acetone is then added dropwise so as to maintain gentle refluxing. Stirring and heating are continued for 5 minutes after the addition, the reaction mixture is poured into 1.5 l of ice-cold water, and the crystals obtained are drained and suspended in 300 ml of 10% strength sodium hydroxide solution. The mixture is is brought to boiling for 10 minutes, and the solution is filtered on glass wool and acidified strongly with concentrated hydrochloric acid. The solution is brought back to pH 8 with ammonia solution. The crystals which precipitate on cooling are drained, washed with water and recrystallized in ethanol. (M.p. 175°-7° C.) Yld: 65%.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:3]=1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][C:16]2([CH3:17])[O:21][CH2:20][CH2:19][O:18]2)[CH:3]=1
Reactant: OCCO
Reactant: COc1ccc2cc(CCC(C)=O)cc(F)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2cc(CCC3(C)OCCO3)cc(F)c2c1
Temperature: 25 °C
Yield: 53 %

Procedure:
4-(4-Fluoro-6-methoxy-2-naphthyl)butan-2-one (4.2 g), ethane-1,2-diol (30 ml) and toluene-4-sulphonic acid (0.2 g) were heated under reflux in benzene for 18 hours with continuous removal of water by means of a Dean-Stark trap. The solution was then cooled to room temperature and sodium hydrogen carbonate solution was added. The aqueous layer was washed with ether. The combined organic layers were washed with water and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure gave a crude product which was dissolved in 60-80 petroleum ether. The precipitated impurities were removed by filtration and the solvent was removed under reduced pressure to give a yellow oil which was triturated with cold 40-60 petroleum ether to give the title compound as pale yellow crystals (2.6 g., 53%; m.p. 51°-53°).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:5][CH:6]([CH:15]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:5]=[C:6]([CH:15]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]=1[C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C1C=C(c2ccccc2OCc2ccccc2)NC(N)=C1C(=O)OC(C)(C)C
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccccc2OCc2ccccc2)nc(N)c1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a solution of tert-butyl 2-amino-6-[2-(benzyloxy)phenyl]-4-{1-[(tert-butoxycarbonyl)amino]-2-phenylethyl}-1,4-dihydro-3-pyridinecarboxylate (1.200 g, 2.007 mmol) in methylene chloride (20.0 mL) at room temperature was added chloranil (0.543 g, 2.208 mmol), and the stirring was continued for 1 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and 10% aqueous NaHCO3 solution. The separated organic phase was washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was crystallized from ethanol to give tert-butyl 2-amino-6-[2-(benzyloxy)phenyl]-4-{1-[(tert-butoxycarbonyl)amino]-2-phenylethyl}nicotinate as a pale yellow solid (0.972 g, yield; 84%).
Reaction SMILES: Cl.[CH:2]12[NH:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][C:4](=[O:10])[CH2:3]2.Cl[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])(O)=O.[Na+]>C(O)(C)C>[N:13]1[CH:14]=[CH:15][CH:16]=[N:17][C:12]=1[N:9]1[CH:6]2[CH2:7][CH2:8][CH:2]1[CH2:3][C:4](=[O:10])[CH2:5]2
Reactant: Clc1ncccn1
Reactant: O=C1CC2CCC(C1)N2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: O=C1CC2CCC(C1)N2c1ncccn1
Yield: 63.7 %

Procedure:
A solution of 8-aza-bicyclo[3.2.1]octan-3-one hydrochloric acid (5.0 g, 30.9 mmol), 2-chloro-pyrimidine (4.95 g, 43.2 mmol), NaHCO3(7.78 g, 92.7 mmol) and isopropanol (200 ml) was maintained at reflux over weekend. The resulting reaction mixture was concentrated and purified by ISCO to afford 8-pyrimidin-2-yl-8-aza-bicyclo[3.2.1]octan-3-one (4.0 g, 52.9%) as a white solid: MS (M+1)=204. 1H NMR (MeOH) 8.36 (d, J=12 Hz 2H), 6.75 (m, 1H), 4.97 (m, 2H), 2.75 (d, J=12 Hz, 1H), 2.71 (d, J=12 Hz, 1H), 2.32 (d, J=50 Hz, 2H), 2.22 (m, 2H), 1.87 (m, 2H).
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:22])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[CH2:25]([C:27]1[O:28][C:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:30]([C:32](Cl)=[O:33])[N:31]=1)[CH3:26]>C1COCC1.O>[C:3]([O:7][C:8](=[O:22])[N:9]([C:32]([C:30]1[N:31]=[C:27]([CH2:25][CH3:26])[O:28][C:29]=1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:33])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Reactant: CCc1nc(C(=O)Cl)c(-c2ccccc2)o1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(C(=O)N(C(=O)OC(C)(C)C)c2coc(CCCCC(C)=O)n2)c(-c2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.18 mL) in THF (1.0 mL) was added to a suspension of NaH (19 mg, 0.43 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 2-ethyl-5-phenyl-oxazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 16 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.25. LC-MS-conditions 02: tR=1.11 min, [M+H]+=482.83.
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:28][C:27]([C@@H:29]4[CH2:33][C@H:32]([CH2:34][O:35][CH3:36])[CH2:31][N:30]4[C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])=[N:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])=O)(C)(C)C.Cl.[CH3:48][O:49][C:50]([NH:52][C@@H:53]([CH:66]([CH3:68])[CH3:67])[C:54]([N:56]1[CH2:60][C@@H:59]([S:61][CH3:62])[CH2:58][C@H:57]1C(O)=O)=[O:55])=[O:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C.CO>[CH3:48][O:49][C:50]([NH:52][C@@H:53]([CH:66]([CH3:68])[CH3:67])[C:54]([N:56]1[CH2:60][C@@H:59]([S:61][CH3:62])[CH2:58][C@H:57]1[C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:28][C:27]([C@@H:29]4[CH2:33][C@H:32]([CH2:34][O:35][CH3:36])[CH2:31][N:30]4[C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:38])=[N:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:11])=[O:5])=[O:55])=[O:51]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](SC)C[C@H]1C(=O)O)C(C)C
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(C(=O)CNC(=O)OC(C)(C)C)cc4)cc3)[nH]2)N(C(=O)OCc2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(C(=O)CNC(=O)[C@@H]5C[C@H](SC)CN5C(=O)[C@@H](NC(=O)OC)C(C)C)cc4)cc3)[nH]2)N(C(=O)OCc2ccccc2)C1
Reaction time: 14 h
Yield: 57.9 %

Procedure:
(2S,4S)-benzyl 2-(5-(4′-(2-(tert-butoxycarbonylamino)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (640 mg, 1.02 mmol) was dissolved in DCM (8 mL), MeOH (2 mL) and HCl (4 M in dioxane, 2 mL) was added. The reaction mixture was stirred for 14 h and then concentrated under reduced pressure. The crude residue was treated with (2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylic acid (324 mg, 1.02 mmol), HATU (388 mg, 1.02 mmol) and DMF (10 mL), then DIPEA (0.9 mL, 5.12 mmol) was added dropwise. After 1 h, the mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford (2S,4S)-benzyl 2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxamido)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (487 mg, 58%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[CH:11]=1)([O-])=O.[H][H]>[Pd].C(O)C>[CH3:18][C:12]1([CH3:19])[CH2:13][C:14]([CH3:16])([CH3:17])[CH2:15][CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])[CH2:11]1
Reactant: CC1(C)C=C(c2ccccc2[N+](=O)[O-])CC(C)(C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccccc2N)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 78 h

Procedure:
A mixture of 1-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (130.0 g, 501.3 mmol), 10% palladium on carbon (13.0 g, wet) and ethyl alcohol (1820 mL) was placed in a flask, then the inside of the flask was replaced with hydrogen, and the mixture was stirred for 78 hours at room temperature under a hydrogen atmosphere at atmospheric pressure. Reaction was repeated two more times on the same scale as above, by the same procedure under the same reaction conditions. The three reaction mixtures were combined and subjected to the following treatment.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=S)[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36](OCC)(=[O:39])[NH:37][NH2:38]>C1COCC1.C([O-])(=O)C.[Hg+]>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:38][NH:37][C:36](=[O:39])[N:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=S)NCC4)cc2)CCC1
Reactant: CCOC(=O)NN
Agent: CC(=O)[O-]
Agent: [Hg+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]c(=O)n3CC4)cc2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of tert-butyl(1-(4-(3-phenyl-5-thioxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (55 mg, 0.113 mmol) in THF (7 mL) was added ethyl carbazate (23.6 mg, 0.226 mmol) and mercury acetate (54.1 mg, 0.17 mmol) under nitrogen. The resulting mixture was stirred at r.t. for 2 h. The mixture was concentrated to dryness under reduced pressure and partitioned between DCM (15 ml) and water (15 ml). The organic phase was separated and concentrated to dryness under reduced pressure. The resulting residue was suspended in toluene (7 ml). The resulting mixture was heated under reflux for 3 h. After cooled down to room temperature, the mixture was concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 4% MeOH in dichloromethane) to give tert-butyl(1-(4-(3-oxo-9-phenyl-2,3,5,6-tetrahydro-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-8-yl)phenyl)cyclobutyl)carbamate (32 mg, 56%). LCMS (Method A): RT=6.29 min, M+1=510. 1H NMR (500 MHz, CDCl3): 9.83 (1H,S), 8.10 (1H, s), 7.29 (2H, d), 7.22 (2H, d), 7.19-7.18 (3H, m), 7.13-7.11 (2H, m), 5.1 (1H, br), 4.01 (2H, t), 3.36 (2H, t), 2.43-2.28 (4H, m), 2.02-1.97 (1H, m), 1.76-1.70 (1H, m), 1.30-1.14 (9H, br).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](C2C=NC=CC=2)[CH:26]=1)(C)(C)C.[C:40](O)([C:42](F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:8]4[CH:9]=[N:21][CH:22]=[CH:40][CH:42]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from {2′-fluoro-3-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example M26) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (127 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].C(=O)(O)[O-].[Na+]>ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])[CH:7]=[CH:6][CH:5]=3)[C:16]=12
Reactant: CC(C)n1nc(-c2cccc(N)c2)c2c(N)ncnc21
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)Nc1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Reaction time: 1 h
Yield: 23 %

Procedure:
A solution of dichloromethane (2 mL), compound 22 (20 mg, 0.075 mmol) and triethylamine (11 μL, 0.079 mmol) was cooled to 0° C. 2-chloro-1-ethane sulfonyl chloride (7 μL, 0.067 mmol) was added and the reaction was allowed to proceed for 1 hour prior to addition of saturated sodium bicarbonate (10 mL) and extraction with dichloromethane (3×10 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The product was purified by preparative RP-HPLC and lyophilized (5.6 mg, 23% yield): 1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 8.31 (s, 1H), 7.49 (t, J=7.9, 1H), 7.45 (s, 1H), 7.38 (d, J=7.8, 1H), 7.27 (d, J=7.3, 1H), 6.86 (dd, J=16.4, 10.0, 1H), 6.17 (d, J=16.4, 1H), 6.08 (d, J=9.9, 1H), 5.08 (hept, J=6.7, 1H), 1.50 (d, J=6.7, 6H). 13C NMR (100 MHz, DMSO) δ 155.01, 151.96, 151.19, 144.29, 138.50, 136.32, 133.09, 130.22, 127.79, 123.73, 120.09, 119.20, 96.94, 48.85, 21.73; [M+H]+ calculated for C16H18N6O2S 359.1, found 359.4.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[CH:5]=2)[CH2:3][CH2:2]1.[H][H]>[Pt]=O.C(O)C>[NH2:7][C:6]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[CH:5][C:4]([CH:1]1[CH2:2][CH2:3]1)=[O:8]
Reactant: [H][H]
Reactant: c1cc(-c2cc(C3CC3)on2)ccn1
Agent: O=[Pt]
Solvent: CCO
Product: NC(=CC(=O)C1CC1)c1ccncc1

Procedure:
A solution of 3 g. of 4-(5-cyclopropyl-3-isoxazolyl)pyridine in 50 ml. of ethanol is treated with 0.5 g. of platinum oxide and the mixture is treated with hydrogen on a Parr apparatus at 44 psi for 5 hours at 25° C. The mixture is filtered and the filtrate is evaporated to dryness under reduced pressure to give a semi-solid residue which is recrystallized from ethyl acetate to give light tan crystals, melting point 159°-166° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:8])[O:4][CH2:5][CH2:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[F:16].C(=O)([O-])[O-].[K+].[K+].[F-].[K+]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[F:9][C:10]1[CH:11]=[C:12]([C:2]2[C:3](=[O:8])[O:4][CH2:5][CH2:6][CH:7]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C1OCCC=C1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1OCCC=C1c1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 33.6 %

Procedure:
A solution of 3-bromo-5,6-dihydropyran-2-one (87.4 g, 0.49mol), 3,4-difluorophenylboronic acid (91.4 g, 0.58 mol), potassium carbonate (99.9 g, 0.72 mol), potassium fluoride (85.4 g, 1.47 mol) and tetrakis(triphenylphosphine)palladium (0) (12 g, 0.01 mol) in tetrahydrofuran (600 ml) was thoroughly degassed and then heated at reflux for 48 hours under an atmosphere of nitrogen. The solution was cooled to room temperature and water (1000 ml) and ethyl acetate (1000 ml) were added. The organic phase was washed with saturated brine and dried (MgSO4) and the solvent removed in vacuo. The residue was dissolved in dichloromethane and the solution filtered through a pad of silica gel. The filtrate was evaporated to dryness and the residue recrystallized from diethyl ether to give the title compound 34.6 g. mp 82-85° C. 1H NMR (360 MHz. CDCl3) δ 2.63 (2H, td J 6.2 Hz and 4.5 Hz), 4.49 (2H, t J 6.3 Hz), 7.01 (1H, t J 4.5 Hz), 7.11-7.23 (2H, m), 7.32-7.38 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[C:11]([CH2:18][N:19]2[C:23](=[O:24])[N:22]([CH2:25][C@H:26]([OH:31])[C:27]([F:30])([F:29])[F:28])[C:21]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)=[N:20]2)[CH:10]=1.C1C=CC2N(O)N=[N:45]C=2C=1.C(Cl)CCl.N>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([NH2:45])=[O:16])=[C:11]([CH2:18][N:19]2[C:23](=[O:24])[N:22]([CH2:25][C@H:26]([OH:31])[C:27]([F:30])([F:29])[F:28])[C:21]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)=[N:20]2)[CH:10]=1
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: NC(=O)c1ccc(-c2cccc(Cl)c2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
45 mg (0.07 mmol) of the compound from Example 134 were initially charged in 1 ml of DMF, and 13 mg (0.09 mmol) of HOBt and 18 mg (0.09 mmol) of EDC were added. After 10 min of stirring at RT, 80 μl (1.44 mmol) of ammonia solution (35% strength in water) were added, and the mixture was stirred at RT for 16 h. Under reduced pressure, the reaction solution was then freed of excess ammonia, about 3 ml of water were added and the mixture was extracted three times with in each case 5 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 20 mg (46% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8]([OH:10])=O)[S:6][CH:7]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[CH:28]=[CH:27][C:26]=1[C:34](=[O:36])[CH3:35]>C(Cl)Cl.O1CCOCC1>[C:34]([C:26]1[C:25]([NH:24][C:8]([C:5]2[S:6][CH2:7][CH:3]([C:2]([F:1])([F:12])[F:11])[N:4]=2)=[O:10])=[C:30]([CH3:31])[C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:36])[CH3:35]
Reactant: COc1ccc(C(C)=O)c(N)c1C
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(NC(=O)C2=NC(C(F)(F)F)CS2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a stirred solution of 4-(trifluoromethyl)-1,3-thiazole-2-carboxylic acid (3.5 g, 1 eq.) in DCM (35 mL) at 0° C. under nitrogen was added anhydrous DMF (few drops) and oxalyl chloride (3.14 mL, 2 eq.). At the end of the gas evolution, the reaction mixture was allowed to warm up to room temperature. The mixture was stirred at room temperature for 2 hrs and was evaporated. Dioxane (70 mL) was added under nitrogen followed by a solution of 1-(2-amino-4-methoxy-3-methyl-phenyl)-ethanone 9 (3.18 g, 1 eq.) in dioxane (15 mL). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was washed with saturated NaHCO3. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was triturated in Et2O to yield compound 202b as a white solid in 86% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.15 (s, 3H), 2.58 (s, 3H), 3.94 (s, 3H), 6.82 (d, J=8.55 Hz, 1H), 7.78 (d, J=8.55 Hz, 1H), 8.01 (s, 1H), 11.25 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C@H:7]2[CH2:12][C@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2C(OCC2C=CC=CC=2)=O)=[N:3]1.Br>>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C@H:7]2[CH2:12][C@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][NH:8]2)=[N:3]1
Reactant: Cn1nnc([C@H]2C[C@H](c3cc(=O)[nH]o3)CCN2C(=O)OCc2ccccc2)n1
Agent: Br
Product: Cn1nnc([C@H]2C[C@H](c3cc(=O)[nH]o3)CCN2)n1

Procedure:
Trans-benzyl 2-(2-methyl-2H-tetrazol-5-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (99 mg, 0.26 mmol) (from example 81, step 3) was dissolved in hydrogen bromide (33% in HOAc, 1.35 mL, 7.73 mmol) and reacted for 1 h. The mixture was evaporated and the residue was partitioned between water and EtOAc. The aqueous phase was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 0-15% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. 5-(Trans-2-(2-methyl-2H-tetrazol-5-yl)piperidin-4-yl)isoxazol-3(2H)-one (45 mg, 70%). 1H NMR (400 MHz, cd3od) δ 1.83-2.05 (m, 2H), 2.21-2.31 (m, 1H), 2.36-2.44 (m, 1H), 2.93-3.06 (m, 2H), 3.17-3.25 (m, 1H), 4.37 (s, 3H), 4.49 (t, 1H), 5.77 (s, 1H). HRMS Calcd for [C10H14N6O2+H]+: 251.1256. Found: 251.1262.