Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6](O)[CH2:7][CH2:8][C:9]=2[CH:10]=1.[C:12]1(=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[CH2:8][CH2:7][CH:6]([N:13]3[C:14](=[O:21])[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:12]3=[O:22])[C:5]2=[N:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC1CCc2cc(Br)cnc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1CCc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(rac)-3-Bromo-6,7-dihydro-5H-[1]pyrindin-7-ol (4.84 g, 22.6 mmol) and isoindoline-1,3-dione (3.66 g, 24.9 mmol) were dissolved in THF (130 ml); then, triphenylphosphine (7.41 g, 28.3 mmol) was added, followed by a solution of di-tert-butyl azodicarboxylate (6.25 g, 27.1 mmol) in THF (3.0 ml) below 5° C.; stirring at RT was then continued for 20 hours. The reaction mixture was concentrated in vacuo to give a crude product (23.507 g), which was purified by flash chromatography (silica gel, 100 g, 10% to 50% EtOAc in heptane) to give 2-((rac)-3-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)isoindoline-1,3-dione (11.114 g, not pure). This intermediate was dissolved in ethanol (140 ml), then, while stirring, hydrazine hydrate (3.01 g, 2.95 ml, 75.1 mmol) was added and the reaction mixture was heated up to reflux. After 2 hours, it was poured into NaOH 1N (150 ml) and extracted with CH2Cl2 (2×100 ml). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (8.845 g) which was purified by flash chromatography (silica gel, 100 g, 0% to 20% MeOH in CH2Cl2) to yield the title compound (1.80 g, 37%) as purple oil. MS: 213.0 (MH+, 1Br).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=[O:6]>O.CO>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([C@@H:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:5]([OH:6])=[O:4])=[O:20])=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1C(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A solution of NaOH (128.2 g, 3.2 mol) in 700 mL water was added to a solution of cis-2-(4-bromo-benzoyl)-cyclopentanecarboxylic acid methyl ester (166.3 g, 534.3 mmol) in MeOH (700 mL). The reaction mixture was stirred at rt overnight. NMR analysis showed that little starting material remained. After ca. 1 L solvent was removed by rotary evaporation, the mixture was diluted with 1 L water. Conc. HCl was slowly added with stirring at <15° C., to adjust the acidity to pH <6. A precipitate formed, and stirring was continued for 1 h. The solid precipitate was filtered, and rinsed with water. The dried filter cake was dissolved in 1 L EtOAc, and dried over Na2SO4. Removal of solvent and drying in vacuo afforded the desired product (131 g, 83%). 1H NMR (CDCl3) δ 7.83 (d, 2H), 7.60 (d, 2H), 4.05 (m, 1H), 3.50 (m, 1H), 2.20 (m, 2H), 2.00 (m, 1H), 1.78 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH2:18][SH:19].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:13])[C:14](=[O:16])[S:19][CH2:18][CH3:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCS
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCSC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A 250 mL round bottom flask was charged with benzyloxy-carbonyl-L alanine (15.0 g, 67.2 mmol) and 67.2 mL of dichloromethane. To this mixture was added DMAP (0.82 g, 6.72 mmol) and chilled EtSH (0° C., 5.46 mL, 73.9 mmol) followed by the addition of DCC (15.2 g, 73.9 mmol) in one portion. The addition of the DCC is highly exothermic so the reaction will bubble upon addition, and the reaction should be kept well vented. The resulting mixture was stirred for 30 minutes at 22° C. The resulting white solid was then removed by vacuum filtration, and the filtrate was concentrated. Silica Gel chromatography using hexanes with polarization to 8:1 hexanes/ethyl acetate afforded 93% yield (18.0g, 62.5 mmol) of the desired product as a colorless oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([C:24]([C@H:26]2[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])[C:9]2[CH:13]=[C:12]([C:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH:15]=3)[S:11][C:10]=2[C:21]([OH:23])=[O:22])[CH2:4][CH2:3]1.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])(=O)C.[Na+]>O.C(O)C>[CH2:34]([O:41][N:42]=[C:17]1[CH2:18][CH2:19][C:14]([C:12]2[S:11][C:10]([C:21]([OH:23])=[O:22])=[C:9]([N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]3)[C:24]([C@H:26]3[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]3)=[O:25])[CH:13]=2)=[CH:15][CH2:16]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NOCc1ccccc1
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC(=O)CC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC(=NOCc4ccccc4)CC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4-oxo-cyclohex-1-enyl)-thiophene-2-carboxylic acid (30 mg, 0.065 mmol) in a 2:1 H2O-ethanol mixture (3 mL) were added O-benzylhydroxylamine hydrochloride (21 mg, 0.13 mmol) and sodium acetate (18 mg, 0.13 mmol), and the mixture was stirred at room temperature overnight. Then the mixture was extracted with CH2Cl2, organic phase was dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography on silica gel eluting with 2-15% MeOH in CH2Cl2 to give 20 mg (54%) of 5-{4-benzyloxyimino-cyclohex-1-enyl}-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20][CH3:21])[C:13]=1[N+:25]([O-])=O.Cl[Sn]Cl.O>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:9])[CH3:10])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20][CH3:21])[C:13]=1[NH2:25]
Reactant: CCC(COC)Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CCC(COC)Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1N
Yield: 107.6 %

Procedure:
[4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (30.0 mg, 0.076 mmol) and SnCl2.H2O (43.2 mg, 0.23 mmol) were treated substantially as described in Part D of Example 74a to yield 30 mg (100% crude) of 4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (EI) m/z 367.23 [(M+H)+, 100].
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[C:13](=O)[CH2:12][CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23].C(O)C.[ClH:28]>CCOCC>[ClH:28].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][N:23]1[C:6]([C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:9][S:10][CH2:11][CH2:12][C:13]1=2
Reactant: O=C(CC1CSCCC1=O)c1ccc(F)cc1
Reactant: CN(C)CCCN
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCCn1c(-c2ccc(F)cc2)cc2c1CCSC2

Procedure:
A solution of 4.0 g (0.016 mole) of 3-(4-fluorophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one [Example 5 (a)], 1.62 g of 3-dimethylaminopropylamine and 40 ml. of ethanol is heated under reflux for 2.5 hours, cooled, treated with 4 ml. of saturated ethereal hydrogen chloride, warmed to boiling, and diluted to the cloud point with ether. Upon cooling a solid separates. Recrystallization from ethanol gives off-white crystals of 1-(3-dimethylaminopropyl)-2-(4-fluorophenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole hydrochloride, m.p. 199° to 201°C. dec.
Reaction SMILES: Cl.[O:2]1CCO[CH:3]1[CH2:7][CH2:8][S:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1>O1CCCC1>[O:2]=[CH:3][CH2:7][CH2:8][S:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: c1ccc2sc(SCCC3OCCO3)nc2c1
Agent: Cl
Solvent: C1CCOC1
Product: O=CCCSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Aqueous 10% hydrochloric acid (50 cm3) was added to a solution of 2-(2-(1,3-dioxolan-2-yl)-ethyithio)benzthiazole (5.3 g) in tetrahydrofuran (50 cm3). After stirring at the ambient temperature for 6 hours the reaction mixture was left to stand for 48 hours during which time a white precipitate formed. The solid was collected by filtration, and a portion (2 g) dissolved in 2M sodium hydroxide solution and extracted with diethyl ether. The organic phase was dried with magnesium sulphate and evaporated under reduced pressure to give the crude 2-(3-oxopropylthio)-benzthiazole as a gummy yellow solid. This material was used without further purification in step 3. 1H NMR (CDCl3): δ9.85 (1H,s); 7.86 (2H,d); 7.78 (2H,d); 3.62 (2H,t); 3.12 (2H,t). Additional signals were observed at 611.73 and 67.50-7.00 but not assigned.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[C:15](Cl)(=[O:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCOCC1.O>[C:4]1([CH2:3][C@H:2]([NH:1][C:15](=[O:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([OH:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
L-phenylalanine (2 g) was dissolved in a mixed solvent of dioxane:water=1:1 (20 ml), and the reaction system was cooled to 0° C. The solution was added with 1 N aqueous sodium hydroxide (12.1 ml), and further added dropwise with 1 N aqueous sodium hydroxide (12.1 ml) and hydrocinnamoyl chloride (1.98 ml) simultaneously over 25 minutes, and then stirred at 0° C. for 2 hours. 1 N Hydrochloric acid was added to the mixture to adjust the pH to 3, and the precipitated crystals were washed with water and diethyl ether to obtain 3-phenyl-(2S)-(3-phenylpropanoylamino)propanoic acid (2.9 g, 79.9%).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[N:13]2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[CH3:18][C:14]1[CH:15]=[C:16]([CH3:17])[N:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[N:13]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](n2nc(C)cc2C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(C)n([C@H]2CC[C@H](C(=O)O)CC2)n1

Procedure:
A solution of trans-4-(3,5-dimethyl-pyrazol-1-yl)-cyclohexanecarboxylic acid ethyl ester (162 mg, 0.647 mmol) in 1,4-dioxane (6.5 ml) and 2 M aqueous sodium hydroxide solution (3.2 ml, 6.4 mmol) was stirred at room temperature for 15 h. The pH was adjusted to 3 by addition of 2 M aqueous hydrochloric acid. The mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (116 mg, 81%) as light brown solid. MS m/e: 221 ([M−H]−)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:16]2[CH2:18][CH2:17]2)(O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Cl-].[In+3].[Cl-].[Cl-].[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:16]2[CH2:18][CH2:17]2)([C:31]2[C:30]3[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=3)[NH:33][CH:32]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CCOC(=O)CC(O)(c1ccc(Cl)cc1)C1CC1
Agent: [Cl-]
Agent: [In+3]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CSC)cccc12)C1CC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
700 mg (2.61 mmol) of the compound from Example 90A and 576 mg (2.61 mmol) of indium(III) chloride were added to 462 mg (2.61 mmol) of the compound from Example 8A in 11 ml of toluene. The reaction mixture was stirred at 80° C. for 5 h. After cooling to RT, the solid was filtered off through silica gel, and the solvents were removed in a rotary evaporator. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 69 mg (6% of theory) of the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]([O:21][CH3:22])[CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:23][C:24]1[C:32]2[CH2:31][O:30][C:29](=[O:33])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH:34]1[CH2:36][O:35]1.CCO>C1COCC1>[OH:35][CH:34]([C:25]1[CH:26]=[CH:27][C:28]2[C:29](=[O:33])[O:30][CH2:31][C:32]=2[C:24]=1[CH3:23])[CH2:36][N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH:13]([C:4]2[CH:5]=[CH:6][C:7]3[C:8](=[O:12])[O:9][CH2:10][C:11]=3[C:3]=2[CH3:2])[O:21][CH3:22])[CH2:16][CH2:17]1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: COC(CN1CCNCC1)c1ccc2c(c1C)COC2=O
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: COC(CN1CCN(CC(O)c2ccc3c(c2C)COC3=O)CC1)c1ccc2c(c1C)COC2=O
Temperature: 120 °C

Procedure:
4-Methyl-5-[1-(methyloxy)-2-piperazin-1-ylethyl]-2-benzofuran-1(3H)-one hydrochloride (40 mg, 0.14 mmol), 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (79 mg, 0.41 mmol), were added to a 5 mL microwave tube containing a stir bar; to the mixture was added EtOH (2 mL) and THF (0.5 Ml). The tube was capped, degassed and purged with N2. It was then placed in a microwave reactor and heated at 120° C. for 1 hour; LC indicated completion of the reaction. The solution was concentrated to dryness, dissolved in MeOH (3.5 Ml), filtered and was then purified by mass-directed HPLC to give 5-[2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-(methyloxy)ethyl]-4-methyl-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 481 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[O:21])[CH2:16]1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:36])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:34])([F:35])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(C2CCC(=O)CC2)n1
Reactant: O=C(CNC(=O)c1ccc(F)c(C(F)(F)F)c1)NC1CNC1
Product: Nc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4ccc(F)c(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(6-amino-pyridin-2-yl)-cyclohexanone (as prepared in the Example 22, Step C) and N-(azetidin-3-ylcarbamoylmethyl)-4-fluoro-3-trifluoromethyl-benzamide (analog synthesis by following the procedure described in Organic Synthesis XII, 40-2, 1932) using the procedure described in Step F of Example 1.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][S:18]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH:23]=[CH:24][N:25]=[CH:26]3)(=[O:20])=[O:19])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl>CO>[CH:26]1[C:27]2[C:22](=[C:21]([S:18]([NH:17][CH2:16][C:13]3[CH:14]=[CH:15][C:10]([CH2:9][NH2:8])=[CH:11][CH:12]=3)(=[O:19])=[O:20])[CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][N:25]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNS(=O)(=O)c2cccc3cnccc23)cc1
Agent: Cl
Solvent: CO
Product: NCc1ccc(CNS(=O)(=O)c2cccc3cnccc23)cc1
Yield: 80.5 %

Procedure:
According to Reference Example 5, Step C, a reaction was performed by using Intermediate 60 (6 g) and 10% hydrogen chloride in methanol (20 ml) to obtain the title compound (3.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Cl/[C:10](/[CH:16]=O)=[C:11](\[O:13][CH2:14][CH3:15])/[O-:12].[K+].S(=O)(=O)(O)O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:8]=[C:4]2[CH:3]=1
Reactant: CCO/C([O-])=C(\Cl)C=O
Reactant: Nc1cc(Br)ccn1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(Br)ccn12
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromopyridin-2-amine (10 g, 57.8 mmol) and potassium (Z)-2-chloro-1-ethoxy-3-oxoprop-1-en-1-olate (step 1) (23.4 g, 124 mmol) in ethanol (200 ml) was cooled to 5° C. Sulfuric acid (7.70 ml, 144 mmol) was added dropwise and the reaction heated to reflux at 90° C. for 3 hrs. The mixture was cooled to RT and TEA (20.03 ml, 144 mmol) was slowly added and heating continued at 90° C. for 18 hrs. After cooling to RT, the mixture was filtered and the solid was partitioned between EtOAc and aqueous 2M HCl. The aqueous layer was basified (NaOH, solid pellets) and extracted using EtOAc. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the title compound;
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:4]2[C:5]([O:7][C:8](=O)[CH:3]12)=[O:6].[CH3:11][NH:12][NH2:13]>C(O)C>[CH3:11][N:12]1[NH:13][C:5](=[O:6])[CH:4]2[CH:3]([C:2]2([CH3:10])[CH3:1])[C:8]1=[O:7]
Reactant: CNN
Reactant: CC1(C)C2C(=O)OC(=O)C21
Solvent: CCO
Product: CN1NC(=O)C2C(C1=O)C2(C)C
Yield: 27.4 %

Procedure:
In 5 ml of ethyl alcohol were added 949 mg (6.77 mmol) of 3,3-dimethyl-1,2-cyclopropanedicarboxylic acid anhydride and 0.36 ml (6.77 mmol) of methylhydrazine, and the mixture was heated under reflux for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography. Recrystallization from ethyl acetate/hexane afforded 312 mg (27.3%) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH:7]=O)[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:3]=1.[Cl-].[CH3:19][C:20]1[N:25]2[N:26]=[C:27]([CH2:29][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:28]=[C:24]2[C:23]([CH3:49])=[N:22][CH:21]=1>>[Br:1][C:2]1[N:6]=[C:5]([CH:7]=[CH:29][C:27]2[N:28]=[C:24]3[C:23]([CH3:49])=[N:22][CH:21]=[C:20]([CH3:19])[N:25]3[N:26]=2)[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:3]=1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: COc1ccc(Cn2nc(Br)nc2C=O)cc1
Agent: [Cl-]
Product: COc1ccc(Cn2nc(Br)nc2C=Cc2nc3c(C)ncc(C)n3n2)cc1
Yield: 67.2 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 1g) using 3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazole-5-carbaldehyde (50 mg, 169 μmol, Eq: 1.00) and ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (77.5 mg, 169 μmol, Eq: 1.00) as starting materials. Chromatography afforded 2-{2-[5-Bromo-2-(4-methoxy-benzyl)-2H-[1,2,4]triazol-3-yl]-vinyl}-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (50 mg, 35.4%) as a white solid. MS: m/z=442.3 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=3)[N:13]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=3)[CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C(=O)c2c[nH]c3ccc(F)cc3c2=O)cnc1C
Reactant: Cc1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3cnc(C)c(C)c3)c(=O)c3cc(F)ccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 71 mg (0.24 mmol) 3-(5,6-dimethyl-pyridine-3-carbonyl)-6-fluoro-1H-quinolin-4-one, 12 mg (0.29 mmol) of 60% sodium hydride, 53 mg (0.29 mmol) of 2-bromomethyl-6-methyl-pyridine and 1 mL of N,N-dimethylformamide. Yield: 67 mg of a white solid: LC-MSD, m/z for C24H20FN3O2 [M+H]+=402.1; HPLC retention time: 0.7 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][N:6]([CH2:17][CH:18]=C)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].O=[O+][O-].C(Cl)Cl.[CH3:35][OH:36]>CO>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][N:6]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:17][CH:18]([O:36][CH3:35])[N:20]1[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[O:28]
Reactant: CO
Reactant: C=CCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)C(=O)OCc1ccccc1
Agent: O=[O+][O-]
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC(OC)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
A solution containing 3-(allylbenzyloxycarbonylamino)-2-(S)-tert-butoxycarbonylamino propionic acid methyl ester (5.2 g, 12.8 mmol) in 550 mL of 10:1 CH2Cl2/MeOH is cooled to −78° C. Ozone gas is passed through the solution until a blue color persists. The solution is purged with N2 to remove excess ozone and is then treated with excess dimethylsulfide. The solution is allowed to warm to rt overnight and the next morning concentrated in vacuo. The crude residue obtained is re-dissolved in MeOH and treated with Dowex50x-200. After stirring for 4 h, the solution was filtered, concentrated and immediately purified by flash chromatography on silica gel (EtOAc/hexane) to afford 2.75 g (53% yield) of the desired product. 1H NMR (CDCl3) δ 7.40 (m, 5H), 5.60–3.40 (series of m, 6H), 5.19 (br s, 2H), 3.74 (s, 3H), 3.40 (series of s, 3H), 1.50 (series of s, 9H); MS 409 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16](/[CH:20]=[CH:21]/[S:22](Cl)(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=1>>[F:27][C:13]([F:12])([F:26])[C:14]1[CH:15]=[C:16](/[CH:20]=[CH:21]/[S:22]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:23])=[O:24])[CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)/C=C/c1cccc(C(F)(F)F)c1
Reactant: Nc1ccccc1S(N)(=O)=O
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1cccc(C(F)(F)F)c1
Yield: 37 %

Procedure:
The title compound was synthesized as described for Example 178 in 37% yield, starting from 2-aminobenzenesulfonamide and (E)-2-(3-(trifluoromethyl)phenyl)ethenesulfonyl chloride.