Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH:12]([CH2:16][CH2:17][CH2:18][Br:19])[C:13](Cl)=[O:14]>>[Br:19][CH2:18][CH2:17][CH2:16][CH:12]1[C:13](=[O:14])[NH:1][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=2[O:10]1
Reactant: COc1ccc(O)c(N)c1
Reactant: O=C(Cl)C(Br)CCCBr
Product: COc1ccc2c(c1)NC(=O)C(CCCBr)O2
Yield: 56.9 %

Procedure:
In a manner similar to that of Reference Example 16, 2-amino-4-methoxyphenol was allowed to react with 2,5-dibromovaleryl chloride, then cyclized to give 2-(3-bromopropyl)-6-methoxy-2H-1,4-benzoxazine-3(4H)-one as crystals. The yield was 56.9%. m.p. 102°-103° C. (recrystallization from ether).
Reaction SMILES: [OH:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH3:21])=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][C:4](=[O:22])[C:3]1=[O:23].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C.P([O-])(O)(O)=O.[K+]>[CH2:24]([O:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH3:21])=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=2)[NH:5][C:4](=[O:22])[C:3]1=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1nccn1-c1cc2[nH]c(=O)c(=O)n(O)c2cc1C(F)(F)F
Reactant: BrCc1ccccc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Product: Cc1nccn1-c1cc2[nH]c(=O)c(=O)n(OCc3ccccc3)c2cc1C(F)(F)F
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of 5.3 g (~16.3 mmol) of 1-hydroxy-6-(2-methyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxaline-2,3(1H,4H)-dione in a mixture of 80 ml ethanol and 80 ml 1M potassium dihydrogen phosphate buffer pH 7.4 was added 2.1 ml (17.7 mmol) benzylbromide. Stirring was continued at 25° C. for 1 h. The precipitate was filtered off and washed with water and a little ice-cooled ethanol to give the title compound (5.2 g; 78%). M.p. 156° C. (decomp.).
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[C:10]=2[CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[CH:35]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH:45]([CH3:48])[CH:46]=O)=[CH:40][CH:39]=1)([CH3:37])[CH3:36]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[C:10]=2[CH:15]=[CH:46][CH:45]([CH3:48])[CH2:44][C:41]2[CH:40]=[CH:39][C:38]([CH:35]([CH3:37])[CH3:36])=[CH:43][CH:42]=2)=[CH:7][CH:8]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C=O)Cc1ccc(C(C)C)cc1
Agent: [Br-]
Product: Cc1noc(-c2ccc(Br)cc2)c1C=CC(C)Cc1ccc(C(C)C)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-triphenyl-phosphonium bromide and 3-(4-isopropyl-phenyl)-2-methyl-propionaldehyde
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1>[Pd].CCO.C(OCC)C>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CN(C)CCOC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: CN(C)CCOC1CCNCC1
Yield: 43.5 %

Procedure:
Benzyl 4-(2-(dimethylamino)ethoxy)piperidine-1-carboxylate (84) (4.5 g, 14.69 mmol) and Palladium on carbon 5% (JM Type87L; 0.9 g, 0.21 mmol) in EtOH (50 mL) were stirred under an atmosphere of hydrogen at 5 bar and 50° C. for 3 hours. The reaction was filtered and the solvent evaporated to afford a yellow gum. This was dissolved in diethyl ether (50 mL) and filtered. The solvent was removed to afford an orange oil, this was purified by distillation at 1.0 mBar, collecting fractions that distilled at 70° C. to afford the desired material as a colourless liquid (1.100 g, 55.9%); 1H NMR (400.132 MHz, CDCl3) δ 1.47-1.38 (2H, m), 1.61 (1H, s), 1.93-1.89 (2H, m), 2.27 (6H, s), 2.50 (2H, t), 2.63-2.56 (2H, m), 3.11-3.05 (2H, m), 3.38-3.31 (1H, m), 3.56 (2H, t).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][CH:12]=3)[S:10][C:3]=12.[CH3:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([NH2:29])=[CH:24][CH:23]=2>>[CH3:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([NH:29][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[N:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][CH:12]=4)[S:10][C:3]=13)=[CH:24][CH:23]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: OCc1cccc(-c2cc3nccc(Cl)c3s2)n1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cccc(CO)n5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from [6-(7-chloro-thieno[3,2-b]pyridin-2-yl)-pyridin-2-yl]-methanol and 2-methyl-5-aminoindole by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.10 (d, 1H), 7.90 (s, 1H), 7.83 (m, 2H), 7.44 (m, 1H), 7.36 (s, 1H), 7.30 (d, 1H), 6.90 (d, 1H), 6.60 (d, 1H), 6.12 (s, 1H), 3.57 (s, 2H), 2.42 (s, 3H); RP18-HPLC RT: 4.59 minutes; API MS: 387 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:19]([C:20]([O:22]C)=O)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)[CH3:3].O.[NH4+:25]>>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:19]([C:20]([NH2:25])=[O:22])=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: COC(=O)c1cccc2nc(-c3ccc(CN(C)C)cc3)oc12
Reactant: [NH4+]
Solvent: O
Product: CN(C)Cc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1

Procedure:
Methyl 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate in ammonium water (10 mL) was stirred at 30° C. for 17 hr, then the solvents were evaporated and purified by pre-HPLC to obtain 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide as a white solid (10 mg). 1H-NMR (400 MHz, DMSO-d6) δ 2.18 (s, 6H), 3.5 (s, 2H), 7.47-7.49 (t, J=8 Hz, 1H), 7.54-7.56 (d, J=8.4 Hz, 2H), 7.79-7.81 (d, J=8 Hz, 1H), 7.86-7.90 (d, J=14.4 Hz, 2H), 7.94-7.96 (d, J=8 Hz, 1H), 8.24-8.26 (d, J=8 Hz, 2H); LC-MS (ESI) m/z 296 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:18])([F:20])[F:19])[N:16]=[C:10]2[CH:9]1[CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1COS(C)(=O)=O
Temperature: 0 °C

Procedure:
To a 0° C. solution of 100 mg (0.31 mmol) of 7-N-(tert-butoxycarbonyl)-8-(hydroxymethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine in 1.0 mL of dichloromethane was added sequentially 0.047 mL (0.341 mmol) of triethylamine and 0.029 mL (0.372 mmol) of methanesulfonyl chloride. The reaction mixture was stirred at 0° C. and allowed to warm to room temperature for 4 h. Aqueous sodium bicarbonate solution was added, and the resultant mixture was extracted with three portions of dichloromethane. The combined organics were washed with brine, dried over magnesium sulfate, and concentrated to give a yellow oil which was used without further purification. LC/MS 401 (M+1).
Reaction SMILES: [O:1]=[C:2]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:21][CH2:20]1)[CH2:3][CH:4]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:5](O)=[O:6].[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH:43]2[CH2:48][CH2:47][N:46]([C:5](=[O:6])[CH:4]([CH2:8][C:9]3[CH:18]=[CH:17][C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[CH:10]=3)[CH2:3][C:2]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[NH:27][C:26]4=[O:35])[CH2:21][CH2:20]3)=[O:1])[CH2:45][CH2:44]2)[CH2:39][CH2:38]1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1ccc2c(c1)CCCC2
Product: CN1CCN(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc4c(c3)CCCC4)CC2)CC1

Procedure:
Prepared analogously to Example 76e) from 4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butanoic acid and 1-methyl-4-piperidin-4-yl-piperazine.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[SH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23].C([O-])(O)=O.[Na+]>ClCCl>[S:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][S:15][CH:6]1[C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([OH:2])[CH:4]=1
Reactant: COc1cc(C=O)cc(O)c1OC
Reactant: SCc1ccccc1S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C2SCc3ccccc3S2)cc(O)c1OC
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
Hydrogen chloride gas was bubbled for three minutes at 22° C. through a solution of 3-hydroxy-4,5-dimethoxybenzaldehyde (0.55 g, 3.0 mmol) and 2-(mercaptomethyl)benzenethiol (0.52 g, 3.3 mmol) in dichloromethane (15 ml). After an additional 15 min., the reaction mixture was poured into saturated NaHCO3 (50 ml) and extracted with dichloromethane (2×75 ml). The combined organic layer was washed with brine (30 ml), dried (Na2SO4), filtered and concentrated providing a crude solid. This solid was triturated with hexane and then purified by flash chromatography using a gradient of hexanes (100%) up to hexanes (70%:30%). Concentration of the product containing fractions provided the above subtitle compound (0.76 g, 78%) as a white solid. 1H NMR (300 MHz, CDCl3, ppm) δ 3.84 (s, 3H), 3.90 (s, 3H), 3.94 (d, J=15 Hz, 1H), 4.00 (d, J=15 Hz, 1H), 5.42 (s, 1H), 5.89 (br s, 1H), 6.63 (d, J=2 Hz, 1H), 6.78 (d, J=2 Hz, 1H), 7.15-7.36 (m, 4H); 13C NMR (75 MHz, CDCl3, ppm) δ 34.3, 51.5, 56.0, 61.0, 104.1, 108.2, 126.4, 127.7, 128.5, 129.6, 135.2, 135.3, 135.5, 135.7, 149.4, 152.5; MS calculated for C16H16O3S2-H 319 observed 319.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Br:20][CH2:21][CH:22]=[CH:23][CH2:24]Br>CN1C(=O)CCC1>[Br:20][CH2:21][CH:22]=[CH:23][CH2:24][O:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: BrCC=CCBr
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(OCC=CCBr)c([N+](=O)[O-])c1
Temperature: 45 °C
Yield: 46.7 %

Procedure:
A mixture of 2,4-dinitrophenol (4.6 g, 80 wt %), potassium carbonate (4.2 g), NMP (40 mL) and 1,4-dibromo-2-butene (12.8 g) was heated to 45° C. for 2 hr. Extraction in the normal fashion and Kugelrohr distillation of the excess dibromide (0.1 mm Hg, 80° C.) gave 1-bromo-4-(2,4-dinitrophenyloxy)but-2-ene (3.7 g, mp 55-57° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]1(O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccccc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenol: ESMS m/e: 535.0 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[S:8][C:9]=1[NH:10]C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C:3]([C:5]1[N:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[S:8][C:9]=1[NH2:10])=[O:4]
Reactant: CNC(=O)c1nc(-c2ccccn2)sc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1nc(-c2ccccn2)sc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
A solution of 5-tert-butoxycarbonylamino-2-pyridin-2-yl-thiazole-4-carboxylic acid methylamide (34 mg, 0.10 mmol) in dichloromethane (0.5 ml) was treated with trifluoroacetic acid (0.5 ml) and stirred at ambient temperature for 3 h. After solvent evaporation, the residue was dissolved in ethyl acetate and washed with NaOH (1N aqueous solution), water and brine. The organic layer was dried and the solvent was evaporated. The remaining residue was suspended in diethylether, sucked off, and the remaining material was dried to yield the product as yellow solid (10 mg, 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[Se:4][C:3]=1[C:11]([NH2:13])=[O:12].[N:14]([O-])=O.[Na+]>S(=O)(=O)(O)O>[C:7]([C:5]1[Se:4][C:3]2[C:11](=[O:12])[NH:13][N:14]=[N:1][C:2]=2[CH:6]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)(C)c1cc2nn[nH]c(=O)c2[se]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To an ice cold solution (0° C.) of 3-amino-5-(tert-butyl)selenophene-2-carboxamide (3.0 g, 12.2 mmol) in concentrated sulfuric acid (50 mL) was added a cold (0° C.) solution of sodium nitrite (0.92 g, 13.4 mmol) in concentrated sulfuric acid (10 mL) for 10 min (while adding, the temperature should keep between −5-0° C.). After addition, the mixture was stirred at 0° C. for 1 h and at rt for 1 h. The reaction mixture was cooled and poured into crushed ice slowly with stirring for 15 min and stirred at the same temperature for 15 min. The solid was filtered, washed with ice cold water and dried to give the product as a off-white color solid (2.4 g, 77%), mp 158-160° C. 1H NMR (400 MHz, CDCl3): δ 7.67 (1H, s, H-7), 1.50 (9H, s, tert-butyl); LC-MS (negative ion mode): m/z 254, 256 (M−H)—.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.[CH3:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1)=[O:27].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:17]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:13]3[CH:12]=[CH:11][C:10]([C:8]4[O:9][C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][C:6]=5[N:7]=4)=[CH:16][C:14]=3[N:15]=2)=[CH:31][CH:30]=1)(=[O:27])[CH3:25]
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NC1CCOCC1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2nc3cc(-c4nc5cc(Cl)ccc5o4)ccc3n2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a solution of 5-chloro-2-(2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 100-2) (250 mg, 0.727 mmol) in dimethylformamide (3 mL) was added 4-formylacetanilide (142 mg, 0.872 mmol) and oxone (313 mg, 0.509 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (261 mg, 74% yield) as white crystals.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[N:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:3]=[C:4]3[CH:5]=[CH:6][NH:7][C:8]3=[N:9][CH:10]=2)=[CH:13][CH:12]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: c1cc(-c2cnc3[nH]ccc3n2)ccn1
Yield: 60 %

Procedure:
A 10 mL microwave vial was charged with 5-bromo-4,7-diazaindole (0.471 g, CASRN 875781-43-4), 4-pyridylboronic acid (0.58 g), 1M Na2CO3 (3 mL), 1,1′-(dppf)Pd(II)Cl2 (0.097 g) and MeCN (3 mL), capped and irradiated in a microwave reactor at 150° C. for 30 min. The reaction was cooled and partitioned between H2O and EtOAc. The aqueous layer was twice washed with EtOAc. The combined organic layers were washed once with brine, dried (MgSO4), filtered and concentrated to afford a solid residue. The crude purified by SiO2 chromatography eluting with an EtOH/EtOAc gradient (1 to 20% EtOH over 12 min) to afford 0.28 g of pure 2-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin (22).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C=O.S[C:12]1[N:17]([CH3:18])[C:16](=[O:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:13]=1>C(OCC)(=O)C>[Cl:3][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:13]=1
Reactant: Cn1c(S)nc(-c2ccncc2)cc1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.2 %

Procedure:
Phosphorous oxychloride (26.11 g, 170 mmol) was added to dimethyl-formamide (180 ml) and stirred 20 min. 2-Mercapto-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (24.15 g, 110 mmol) was added to the solution and stirred 5 min and then stirred at 70° C. for 2 hours. Ethyl acetate (630 ml) was added to the ice-cooled solution and precipitate was collected by filtration after stirring for 20 minutes. After drying, the precipitate was dissolved in water (400 ml) and pH was adjusted to 10 by using aqueous sodium hydroxide. The precipitate was washed with water, filtered and dried to give the title compound (18.82 g, 77%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]2[N:7]([C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]6[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=56)[C:23]([Cl:35])=[CH:22][N:21]=4)=[C:12]([O:36][CH3:37])[CH:11]=3)[CH2:8][CH2:9][C@@H:4]2[CH2:3]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:1][N:2]1[CH2:6][C@@H:5]2[N:7]([C:10]3[CH:11]=[C:12]([O:36][CH3:37])[C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]6[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=56)[C:23]([Cl:35])=[CH:22][N:21]=4)=[CH:14][C:15]=3[NH2:16])[CH2:8][CH2:9][C@@H:4]2[CH2:3]1
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 71.3 %

Procedure:
A mixture of N-[4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrol-1-yl]-2-methoxy-5-nitrophenyl]-5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 36, 155 mg, 0.30 mmol), iron (100 mg, 1.79 mmol) and NH4Cl (11.2 mg, 0.21 mmol) in ethanol (12 mL) and water (4 mL) was heated at reflux for 2 h. The mixture was then cooled and filtered though decalite (a type of diatomaceous earth) and the filtrate was concentrated in vacuo to provide a brown gum. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (105 mg, 72%) as a gum; 1H NMR: (CDCl3) 1.76-1.80 (1H, m), 2.03-2.20 (2H, m), 2.28 (3H, s), 2.48 (1H, dd), 2.59-2.63 (2H, m), 2.76-2.98 (2H, m), 3.46 (1H, dt), 3.78 (2H, s), 3.84 (3H, s), 4.07-4.10 (1H, m), 6.73 (1H, s), 6.94 (1H, td), 7.36 (1H, ddd), 7.51 (1H, s), 7.86 (1H, s), 8.35 (1H, s), 8.54 (1H, d), 8.65 (1H, d), 8.93 (1H, s); m/z: ES+ MH+ 491.29.
Reaction SMILES: [N:1]1(C(N2C=CN=C2)N)C=CN=[CH:2]1.[NH2:13][C:14]1[C:23]([OH:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>C1COCC1>[NH2:1][C:2]1[O:24][C:23]2[C:14](=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:20]=[C:21]([CH3:25])[CH:22]=2)[N:13]=1
Reactant: COC(=O)c1cc(C)cc(O)c1N
Reactant: NC(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)cc2oc(N)nc12
Temperature: 25 °C
Yield: 45 %

Procedure:
To a solution of di (1H-imidazole-1-yl)methanamine (1.56 g, 9.67 mmol) in THF (30 mL) was added methyl 2-amino-3-hydroxy-5-methylbenzoate (1.40 g, 7.73 mmol) at room temperature and the resulting reaction mixture was heated at reflux for 6 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL), treated with saturated aqueous ammonium chloride (25 mL), and then extracted with CH2Cl2 (2×100 mL). The combined organic phase was washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford a yellow solid. The solid was triturated from CH3OH to afford methyl 2-amino-6-methylbenzoxazole-4-carboxylate (0.717 g, 45%). 1H NMR and MS consistent.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([N:6]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[Si](C(C)C)(C(C)C)C(C)C)=[O:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH:11]1[C:12]2[C:8](=[C:7]([N:6]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:4](=[O:5])[CH2:3][NH:2][CH3:1])[CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: CNCC(=O)N(c1ccccc1)c1cccc2c1ccn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CNCC(=O)N(c1ccccc1)c1cccc2[nH]ccc12
Reaction time: 18 h

Procedure:
To a room temperature solution of 2-methylamino-N-phenyl-N-(1-triisopropylsilanyl-1H-indol-4-yl)-acetamide XXIII in THF (5 ml) was added tetrabutylammonium fluoride (TBAF) (149 mg, 0.566 mmol). The mixture was stirred for 18 hours and then partitioned between EtOAc and a saturated solution of NaHCO3. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude N-(1H-indol-4-yl)-2-methylamino-N-phenyl-acetamide XXIV (122 mg, pale yellow solid) was used without further purification for the next reaction.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[F:14][C:15]1[CH:16]=[C:17](Br)[CH:18]=[C:19]([F:22])[C:20]=1[F:21].C(N(CC)CC)C>C(OC)(C)(C)C.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.[Cu]I>[F:14][C:15]1[CH:16]=[C:17]([C:13]#[C:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=2)[CH:18]=[C:19]([F:22])[C:20]=1[F:21]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: C#Cc1ccc(OCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C#Cc2cc(F)c(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.4 mmol of bis(triphenylphosphine)palladium(II) chloride and 0.2 mmol of CuI are added at room temperature to a mixture of 0.02 m of 4-butoxyphenylacetylene, 0.02 m of 3,4,5-trifluorobromobenzene and 50 ml of triethylamine. The reaction mixture is stirred at room temperature for 2 hours, diluted with methyl tert.-butyl ether and filtered with suction, and the solution is evaporated. Purification by chromatography and/or crystallization gives 3,4,5-trifluoro-4'-butoxytolan.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[CH:13](=O)[C:14]([CH3:16])=[O:15]>O>[C:1]1([NH:7][N:8]=[CH:13][C:14](=[O:15])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C=O
Reactant: NNc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C=NNc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a solution of phenylhydrazine (10.0 g, 92.5 mmol) in water (30 mL) was added acetic acid (8.8 mL) followed by the dropwise addition of pyruvaldehyde (16.7 g, 92.5 mmol) in water (400 mL) over a 15 minute period. The solution was stirred at room temperature overnight. The reaction was filtered and the resultant solid was washed with water (2×30 mL) to provide 2-oxopropanal phenylhydrazone as a yellow solid (15.2 g, 101%).