Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[CH2:22]([N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:10])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1cccc(C(C)c2nccn2Cc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of the compound of Example 1 (100 mg, 0.50 mmol) and caesium carbonate (407 mg, 1.25 mmol) in acetone (4 ml) was added benzyl bromide (171 mg, 1.00 mmol). The reaction mixture was stirred at room temperature, under nitrogen, for 18 h and then concentrated in vacuo. The residue was partitioned between water (10 ml) and ethyl acetate (10 ml) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (10 ml) and the combined organic phases were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2C(C(=O)NC3C=CC=CC=3)=CN=C(S(C)(=O)=O)N=2)[CH:9]=1)(C)(C)C>CO.[Pd]>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(S(C)(=O)=O)ncc2C(=O)Nc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: COc1cccc(N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 295.3 %

Procedure:
To a solution of 7 (0.13 g, 0.275 mmol) in methanol (3 mL) was added Pd/C (26 mg, 20% w/w) under N2 atmosphere. Then the reaction mixture was stirred at room temperature under H2 pressure (bladder) for 16 h. It was filtered through celite bed and the filtrate was concentrated to give 8 (0.10 g, 82%) as green solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[CH2:2]2.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.[BH4-].[Na+]>CCO>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:18][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(N)c1
Reactant: O=C1CN2CCC1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(NC2CN3CCC2CC3)c1
Yield: 44.8 %

Procedure:
(Method 2A) A solution of 1-azabicyclo[2.2.2]octan-3-one (8.1 g, 50 mmol), m-anisidine (6.2 g, 50.0 mmol) and 4Å molecular sieves in 50 mL of EtOH was stirred at room temperature overnight. NaBH4 pellets were added until the reaction was judged complete by TLC, at which point most of the EtOH was evaporated in vacuo and the residue was partitioned between 3N NaOH and EtOAc. The aqueous layer was extracted with a second portion of EtOAc. The organic layers were combined and washed with water and then brine and then dried over NaSO4. The solution was filtered and the solvent was evaporated in vacuo. The residue was dissolved in 2-PrOH and treated with 1.5 g of fumaric acid. The product was collected and recrystallized from 2-PrOH to give N-(3-methoxyphenyl)-1-azabicyclo[2.2.2]octan-3-amine (5.2 g, 30%) as an intermediate, an off-white solid. MH+=233.
Reaction SMILES: [N:1]([C:4]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:12][C:11]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[N+:2]=[N-:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][O:36][CH2:37][CH2:38]Br>C(#N)C>[N:1]([C:4]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:38][CH2:37][O:36][CH3:35])=[CH:18][CH:19]=2)=[N:12][C:11]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[N+:2]=[N-:3]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(O)cc2)c1N=[N+]=[N-]
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCOc1ccc(-c2nc(-c3ccc(OC)cc3)cc(C(=O)OC)c2N=[N+]=[N-])cc1
Temperature: 75 °C
Yield: 43.7 %

Procedure:
A mixture of methyl 3-azido-2-(4-hydroxyphenyl)-6-(4-methoxyphenyl)isonicotinate (83 mg, 0.221 mmol), cesium carbonate (359 mg, 1.10 mmol), and 2-bromoethyl methyl ether (0.062 mL, 0.662 mmol) in acetonitrile (1 mL) was heated at 75° C. for 5 hr. The reaction was partitioned between EtOAc and water. The organic phase was separated and washed with brine, dried with sodium sulfate and the solvent removed. Radial silica gel chromatography (step gradient elution with hexane containing 0 to 30% EtOAc) afforded 42 mg of methyl 3-azido-2-(4-(2-methoxyethoxy)phenyl)-6-(4-methoxyphenyl)isonicotinate as an oil. MS (ESI) m/z 435.1 (M+H). 1H NMR (CDCl3) δ ppm 8.02 (2H, d, J=8.55 Hz), 7.93 (1H, s), 7.78-7.86 (2H, m), 7.05 (2H, d, J=8.85 Hz), 6.98 (2H, d, J=8.85 Hz), 4.16-4.24 (2H, m), 4.02 (3H, s), 3.85 (3H, s), 3.75-3.81 (2H, m), 3.47 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([CH:19]=1)[NH:7][CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>[Fe].O>[Br:1][C:2]1[CH:19]=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:17])([CH3:16])[CH3:18])([CH3:13])[CH3:14])[C:5]([NH2:20])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCNc1cc(Br)ccc1N
Temperature: 80 °C

Procedure:
5-Bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-nitroaniline from above was added to 2:1 2-propanaol:water (75 mL) (precipitate formed). Iron powder was added (1.147 g, 20.6 mmol) and the mixture was heated to 80° C. for 1 h. It turned black. After allowing to cool, the mixture was filtered through celite, rinsing with ethyl acetate. The filtrate was washed with water, washed with then brine, dried (MgSO4), filtered, and concentrated to give crude 5-bromo-N1-(3-((tert-butyldimethylsilyl)oxy)propyl)benzene-1,2-diamine.
Reaction SMILES: [C:1]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([OH:34])[C:28]([CH3:36])([CH3:35])[CH2:27]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([OH:21])[C:15]([CH3:23])([CH3:22])[CH2:14]1)=[O:11].[Cl-].[Ca+2].[Cl-].OO.C(=O)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50].[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[C:1]([O:25][CH:26]1[CH2:27][C:28]([CH3:36])([CH3:35])[N:29]([O:34][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH3:43])[C:30]([CH3:33])([CH3:32])[CH2:31]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:14][C:15]([CH3:22])([CH3:23])[N:16]([O:21][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:17]([CH3:19])([CH3:20])[CH2:18]1)=[O:11]
Reactant: CCCCCCCCC=O
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Agent: OO
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Temperature: 40 °C
Reaction time: 10 h

Procedure:
10.0 g Bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) sebacate (Prostab 5415, commercial product of Ciba Specialty Chemicals Inc.) are dissolved in 50 ml toluene/acetic acid (1:1) and 2.5 g calcium chloride are added. 10 ml 50% aqueous hydrogen peroxide are added, followed by 20 ml nonanal and 0.2 g CuCl2. The reaction mixture is stirred for 1 h at room temperature and afterwards for 10 h at 40° C. The mixture is pure into 100 ml 0.1 N NaOH and subsequently extracted with methylene chloride. The organic phase is washed twice with water and then with sat. sodium chloride solution and dried over sodium sulfate. The organic phase is removed in vacuo and the residue subjected to column chromatography on silica gel to afford 5.5 g of product.
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][N:33]1[C:37]([C:38]([C:40]2[N:44]([CH3:45])[C:43]([CH3:46])=[N:42][CH:41]=2)=[O:39])=[CH:36][N:35]=[C:34]1[CH3:47].C(=O)=O.CC(C)=O>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:38]([C:37]3[N:33]([CH3:32])[C:34]([CH3:47])=[N:35][CH:36]=3)([C:40]3[N:44]([CH3:45])[C:43]([CH3:46])=[N:42][CH:41]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: Cc1ncc(C(=O)c2cnc(C)n2C)n1C
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1nc2ccc(C(O)(c3cnc(C)n3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
n-BuLi (1.63 M in hexane, 0.124 mL, 0.203 mmol) was added dropwise under argon at ˜−70° C. to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (81.6 mg, 0.19 mmol, Intermediate 10) in THF (1.9 mL). After 2 additional minutes, an opaque milky suspension of bis(1,2-dimethyl-1H-imidazol-5-yl)methanone (42.4 mg, 0.194 mmol, Intermediate 11) in LaCl3-2LiCl (0.5 M in THF, 0.381 mL, 0.19 mmol) and THF (2.5 mL) was added rapidly dropwise over 1.5 minutes. The resulting yellow slurry was stirred in the dry ice/acetone bath for 10 minutes, and was then transferred to an ice bath and stirred overnight as the bath warmed to room temperature. The reaction was then quenched with 5 M aqueous NH4Cl (0.06 mL) and diluted with DCM (˜5 mL) and MeOH (˜2 mL), and the suspension was partitioned with 0.75 M aqueous tetrasodium EDTA (4 mL) and 9:1 DCM/MeOH (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by C18 HPLC (20% to 100% CH3CN gradient with 0.1% TFA throughout) and the lyophilisate neutralized with 9:1 DCM/MeOH) and 2 M aqueous K2CO3. The organic layer was dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound as a colorless film. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.86 (d, J=2.53 Hz, 1H), 7.63-7.70 (m, 2H), 7.58 (d, J=8.59 Hz, 2H), 7.38 (d, J=8.59 Hz, 2H), 7.37 (m, 1H), 6.42 (t, J=1.99 Hz, 1H), 6.14 (s, 2H), 5.82 (br. s., 1H), 4.29 (s, 2H), 4.08 (s, 3H), 3.38 (s, 6H), 2.26 (s, 6H); MS m/e 568.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1c(O)cccc1F
Agent: [Pd]
Solvent: CO
Product: Nc1c(O)cccc1F
Yield: 79.9 %

Procedure:
To a solution of 2-nitro-3-fluorophenol(1 g, 6.4 mmol) in methanol(250 mL) was added 10% Pd/C (1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/CH2Cl2) gave the desired product(650 mg, 80.2%). 1H NMR (CD3OD): δ 6.41-6.17 (m, 3H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:43][CH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=1>>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([NH:50][CH2:49][C:48]3[CH:51]=[CH:52][C:45]([C:44]#[N:43])=[CH:46][CH:47]=3)=[O:31])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc3c(C(=O)NCc4ccc(C#N)cc4)noc3c2Cl)C[C@H](C)O1

Procedure:
Starting material: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and 4-(aminomethyl)benzonitrile.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=S)#[N:2].[C:13]1([NH:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]([NH:3][C:4]([NH:22][CH2:21][CH2:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)#[N:2]
Reactant: NCCNc1ccccc1
Reactant: N#CNC(=S)Nc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: N#CNC(=Nc1ccncc1)NCCNc1ccccc1
Reaction time: 72 h

Procedure:
N-Cyano-N'-4-pyridylthiourea (1.80 g) was suspended in dimethylformamide (5 ml). While stirring in an ice bath N-phenylethylenediamine (1.4 ml) and N,N'-dicyclohexylcarbodiimide (2.50 g) were added, resulting in a clear solution. The mixture was left at room temperature for 3 days, when the suspension formed was evaporated extensively under high vacuum. The residue was triturated repeatedly with ether (15 ml portions), and the residual solid was extracted with 1N hydrochloric acid (50 ml). After filtration, the crude product was precipitated from the filtrate by addition of 9N sodium hydroxide and taken up into ethyl acetate (3×75 ml).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:25]>CCOCC>[ClH:25].[ClH:25].[C:1]1([C:7]2[O:11][N:10]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc(-c3ccccc3)n2)CC1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(-c2nc(N3CCNCC3)no2)cc1
Yield: 93 %

Procedure:
A solution of tert-butyl 4-(5-phenyl-1,2,4-oxadiazol-3-yl)piperazine-1-carboxylate (5 g) in a 2M solution of HCl in ether (100 mL) was stirred at RT for 6 hours. The solvent was removed under vacuum to afford 4.3 g (93%) of the title compound as a solid. TLC—Chloroform/methanol (8/2): Rf=0.2. HPLC purity: 97%.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH2:25]C)=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].O.[NH2:28][NH2:29]>O1CCCC1>[C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1[NH:28][NH2:29])(=[O:3])[NH2:2]
Reactant: CCOc1cc(C(=O)OC)ccc1Nc1nc(SC)nc(Cl)c1C(N)=O
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc(SC)nc(NN)c2C(N)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the product of Example 11A (1.2 g, 3.1 mmol) in tetrahydrofuran (400 mL) was added hydrazine hydrate (550 mg, 9.4 mmol) and the mixture was stirred at ambient temperature for 12 hours. After concentration, the residue was washed with methanol and dried under vacuum to give the title compound, which was used in the next step without further purification. MS: 379 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C.[OH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C1(C)C=CC(S(O[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)(=O)=O)=CC=1>O>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[CH:37][CH:38]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1ccc(OCCc2ccc(Cl)cc2)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
Potassium carbonate (54.9 g, 397 mmol) was added to a N,N-dimethylacetamide (330 mL) solution of methyl 4-hydroxybenzoate (25.2 g, 165 mmol) and 2-(4-chlorophenyl)ethyl p-toluenesulfonate (compound described in J. Am. Chem. Soc., (1978), 100, 228-246, 61.7 g, 199 mmol) at room temperature. The mixture was stirred at 120° C. for 1.5 hours. The reaction solution was cooled to room temperature, and water (1 L) was added thereto. The resulting mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with water (three times) and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate, 10:1, V/V) to give 43.2 g of methyl 4-[2-(4-chlorophenyl)ethoxy]benzoate (white solid). All this solid was dissolved in ethanol (430 mL), and a 2 M lithium hydroxide aqueous solution (148 mL, 297 mmol) was added thereto. The mixture was stirred at 60° C. for 2 hours, and the solvents (mainly ethanol) were evaporated. The residue was suspended in water (300 mL), and 2 N hydrochloric acid (160 mL) was added thereto under ice-cooling with stirring. The precipitated white solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure to give 41.0 g of the title compound (white solid, yield: 90%).
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Li+].Cl.[NH2:13]O.Cl>C(O)C.O>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:13]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
In a 1 l. 3-neck round bottom flask there was placed 30 g. of pivalyl acetonitrile, 13.5 g. of lithium hydroxide, 394 ml. of water and 281 ml. of ethanol. This mixture was heated to reflux and there was added thereto over a period of 10 minutes 94 ml. of an aqueous solution of 22.2 g. of hydroxylamine hydrochloride. The pH of the reaction mixture after the addition was complete was about 7.3. This pH was adjusted to about pH 6.7 using concentrated aqueous hydrochloric acid. After 30 minutes the pH was about 6.1. After 1 hour the pH was about 6.3. The pH was checked again at 2 hours and at 3 hours after the addition was complete and the pH at those times was about 6.6. A recheck of the pH at 4 hours, 5 hours, and 6 hours revealed the pH to be at about 6.7. The reaction mixture was then refluxed overnight. The following morning the pH was about 6.8. The reaction mixture was cooled and the ethanol removed from the mixture on the rotovapor at room temperature. A solid which separated was filtered off and dried. It weighed 18.65 g. and it was determined by vpc that the product contained 97% of the desired 3-amino-5-(t-butyl)isoxazole, and 1.6% of 5-amino-3-(t-butyl)isoxazole. Yield: 52% of desired isomer.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[S:19]1[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20]1>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:24]([C:21]3[CH:22]=[CH:23][S:19][CH:20]=3)=[O:25])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: O=C(Cl)c1ccsc1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: Cc1noc(-c2sc(NC(=O)c3ccsc3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and thiophene-3-carbonyl chloride.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:15]1[S:16][C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=1.O>CN(C=O)C>[C:24]1([C:17]2[S:16][C:15]([S:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:19][C:18]=2[C:20]([O:22][CH3:23])=[O:21])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)c1nc(Cl)sc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(Sc2ccccc2)sc1-c1ccccc1

Procedure:
A stirred suspension of K2CO3 (4.15 g, 30 mol) in 100 ml of DMF was treated in one portion with thiophenol (1.65 g, 15 mol). The compound of Example 2 (3.8 g, 15 mol) was then added and the mixture heated at 110° C.±5° C. for 2 days. Water was added and the mixture extracted twice with ether. The ether extracts were washed with H2O, dried over MgSO4 and concentrated in vacuo to yield a yellow oil. Bulb to bulb distillation yielded methyl 5-phenyl-2-phenylthio-4-thiazolecarboxylate, as a yellow oil at 130°-170° C./1 mm. This oil was crystallized from etherpetroleum ether mixtures to yield 1.6 g of white crystals, methyl 5-phenyl-2-phenylthio-4-thiazolecarboxylate, m.p. 67°-70° C., yield 33%.
Reaction SMILES: [CH:1]1([N:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][C:8]([C:19]([O:21]C)=[O:20])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].CO.OS(O)(=O)=O>O>[CH:1]1([N:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][C:8]([C:19]([OH:21])=[O:20])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(-c2ccccn2)c(=O)n(C2CCCC2)c1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2ccccn2)c(=O)n(C2CCCC2)c1
Yield: 88.9 %

Procedure:
The pyridone (Step 3, 57 mg, 0.19 mmol) and lithium hydroxide (16 mg, 0.38 mmol) were stirred at room temperature in a solution of 2 mL of MeOH and 0.3 mL of H2O, for 2 h. The reaction mixture was diluted with water and the pH was adjusted to pH ˜2 with concentrated H2SO4. The mixture was extracted 3×20% IPA:CHCl3 and the combined organic fractions were dried over MgSO4 and concentrated. The crude residue was purified to obtain the title compound as a white powder (48 mg, 89%). MS m/z: 285 (M+1).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[O:8][C:7]([CH:9]2[C:14]3=[C:15]4[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[C:16]4=[C:17]([C:18]4[S:19][CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=4)[N:13]3[CH2:12][CH2:11][S:10]2)=[CH:6][CH:5]=1.[Cl-].[Li+]>C(O)C.C1COCC1>[Cl:3][C:4]1[O:8][C:7]([CH:9]2[C:14]3=[C:15]4[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[C:16]4=[C:17]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][OH:24])[N:22]=4)[N:13]3[CH2:12][CH2:11][S:10]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCSC3c2ccc(Cl)o2)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3nc(CO)cs3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)SCC3
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Sodium borohydride (45.1 mg, 1.191 mmol) was added to a solution of ethyl 2-(10-(5-chlorofuran-2-yl)-1,3-dimethyl-2,4-dioxo-2,3,4,7,8,10-hexahydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazin-5-yl)thiazole-4-carboxylate (302 mg, 0.596 mmol) and lithium chloride (50.5 mg, 1.191 mmol) in ethanol (7.50 ml) and THF (15 ml) at 0° C. The mixture was warmed to room temperature and stirred for 7 hours. Further portions of lithium chloride (50.5 mg, 1.191 mmol) and sodium borohydride (45.1 mg, 1.191 mmol) were added to allow the reaction to run to completion. The reaction was quenched with saturated NaHCO3(aq) solution (50 ml), diluted with water (20 ml) and extracted with DCM (3×75 ml). The combined organic extracts were washed with water (20 ml), passed though a hydrophobic frit and evaporated under vacuum to afford the title compound.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:8]1([C:14]2[N:15]=[C:16]([C:26](O)=[O:27])[N:17]([CH3:25])[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[N:2]1([NH:1][C:26]([C:16]2[N:17]([CH3:25])[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:15]=2)=[O:27])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: NN1CCOCC1
Reactant: Cn1c(C(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Product: Cn1c(C(=O)NN2CCOCC2)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
Using essentially the same procedure as Example 4, Step B, but using 4-aminomorpholine (0.025 mL), 4,5-diphenyl-1-methylimidazole-2-carboxylic acid (30 mg, 0.10 mmol) from Example 4, Step A was converted to the title compound.