Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5](/[CH:6]=[CH:7]/[C:8]2[CH:16]=[CH:15][C:11]([N:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1C[O:22][CH2:21]C1.[Li]CCCC>CN(C=O)C>[CH3:13][N:12]([CH3:14])[C:11]1[CH:15]=[CH:16][C:8]([CH:7]=[CH:6][C:5]2[CH:17]=[CH:18][C:2]([CH:21]=[O:22])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: C1CCOC1
Reactant: CN(C)c1ccc(/C=C/c2ccc(Br)cc2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C=Cc2ccc(C=O)cc2)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a round bottom flask compound 17 (300 mg, 1 mmol) was transferred followed by THF (5 mL). The heterogeneous solution was cooled at −78° C. and n-BuLi (1.6M in hexane, 1 mmol) was added dropwise over 5 min, followed by DMF (1.5 mL). The reaction mixture was stirred at −78° C. for 3 hours then it was quenched by water (1 mL) and the mixture was extracted with ether (2×25 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure to give compound 18. 18: 60% yield; yellow powder; 1H NMR (400 MHz, CDCl3) δ9.96 (s, 1H), 7.83 (d, 2H, J=8.2 Hz), 7.60 (d, 2H, J=8.2 Hz), 7.44 (d, 2H, J=8.8 Hz), 7.22 (d, 1H, J=16.2 Hz), 6.94 (d, 1H, J=16.2 Hz), 6.72 (d, 2H, J=8.8 Hz), 3.01 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 191.8, 150.8, 144.7, 134.7, 134.6, 132.7, 130.4, 128.4, 126.4, 124.9, 122.8, 112.4, 40.5; HRMS calc for C17H17NO 252.1384 found 252.1383.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:27][Mg]Br.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:27]
Reactant: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C

Procedure:
In a solution of 1.4 g of 2-chloro-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]benzaldehyde in 50 mL of diethyl ether under nitrogen atmosphere, 6.6 mL of a solution (0.87 mol/L) of methyl magnesium bromide in tetrahydrofuran was added dropwise with stirring at room temperature. After the completion of the addition dropwise, the mixture was continued to stir under reflux with heating further for 30 minutes. After the completion of the reaction, 5 mL of ammonium chloride aqueous solution was added in the reaction mixture under cooling with ice and with stirring, the mixture was extracted with ethyl acetate (50 mL×1), the organic phase was washed with water (30 mL×2), and dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and then the solvent was distilled off under reduced pressure to obtain 1.5 g of the aimed product as pale yellow resinous substance.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.[Cl-].[NH4+]>C(Cl)Cl>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:10](=[O:11])[CH2:9][Cl:8])=[CH:26][CH:25]=1
Reactant: Nc1ccc(OCc2nc3ccccc3s2)cc1
Reactant: O=C(Cl)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 1 h
Yield: 65.5 %

Procedure:
0.24 ml of triethylamine and 0.17 ml of chloroacetyl chloride were added to a solution of 300 mg of 4-(benzothiazol-2-ylmethoxy)aniline [prepared as described in step (b) above] in 6 ml of methylene chloride cooled in an ice-water bath, and the resulting mixture was stirred for 1 hour. After this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The resulting extract was washed with water, dried over anhydrous sodium sulfate and the solvent was then removed by evaporation under reduced pressure. The resulting residue was recrystallized from a mixed solvent of methylene chloride and hexane to obtain 259.4 mg (yield 65.5%) of the title compound as a solid having a melting point of 196° to 197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(O)(=O)C>[C:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:6][CH:7]=1)(=[O:20])[CH3:19]
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Yield: 97.3 %

Procedure:
A mixture of 11.6 g (50 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid, 200 ml glacial acetic acid, and 10.5 ml (110 mmol) of acetic anhydride is heated at reflux for 4 hrs. The mixture is cooled, filtered, and the solid washed with ether and dried under vacuum at 50° to give 13.3 g of 2-[4-(acetylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid; mp>310°.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:3]=1[NH2:4].[CH3:20][O:21][C:22]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[C:27]([O:34][CH3:35])[C:23]=1[C:24](O)=[O:25].C(N(CC)CC)C.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>ClCCl>[CH3:19][C:5]1[CH:6]=[C:7]([C:9]([F:18])([C:10]([F:12])([F:13])[F:11])[C:14]([F:15])([F:16])[F:17])[CH:8]=[C:2]([CH3:1])[C:3]=1[NH:4][C:24](=[O:25])[C:23]1[C:27]([O:34][CH3:35])=[CH:28][CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:22]=1[O:21][CH3:20]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])c(OC)c1C(=O)Nc1c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-aniline (145 mg, 0.5 mmol) and 2,6-dimethoxy-3-nitrobenzoic acid (136 mg, 0.6 mmol) in dichloromethane (10 ml) was added triethylamine (210 μl, 1.5 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride “BOP-Cl” (153 mg, 0.6 mmol). The reaction mixture was heated to reflux for 48 hours. The reaction mixture was cooled to ambient temperature and quenched by the addition of a saturated sodium bicarbonate solution (10 ml). The phases were separated, the organic phase was dried over sodium sulfate and concentrated. Purification by chromatography over silica gel (eluent: hexane/ethyl acetate 2:1) gave N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2,6-dimethoxy-3-nitrobenzamide (222 mg, 89% yield).
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[CH3:52][N:53]([CH3:60])[CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.C(N(CC)CC)C>CN(C)C=O>[CH3:52][N:53]([CH3:60])[CH:54]1[CH2:59][CH2:58][N:57]([C:8]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)=[O:7])[CH2:56][CH2:55]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added 4-dimethylaminopiperidine dihydrochloride (80.5 mg) and triethylamine (0.112 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (52.1 mg, 90%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10].C(OC)(OC)OC.[C:21]([O:25][C:26](=[O:37])[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1)([CH3:24])([CH3:23])[CH3:22].[BH4-].[Na+]>CO>[C:21]([O:25][C:26](=[O:37])[NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])=[CH:33][CH:34]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCCN(CCC)CCOCCN
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCOCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
The compound (81.0 mg) obtained in Example 90-3 was dissolved in anhydrous methanol (2.0 ml) and added with trimethyl orthoformate (94.1 μl) and the compound (101 mg) obtained in Example 23-3 and the whole was stirred overnight at room temperature under a nitrogen atmosphere. Subsequently, sodium borohydride (32.6 mg) was added thereto in an ice bath and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with distilled water and the whole was stirred for a while. The resultant was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (158 mg) as a colorless oily substance.
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:32])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:32])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccc2c(c1)CCCN2

Procedure:
A nitrogen flushed mixture of 4-chloro-3-trifluoromethyl-phenyl-carbamic acid 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-yl ester (0.23 g. ½ mmol) and 5% Pd—C (0.02 g.) in absolute ethanol (20 ml) was shaken in a par apparatus at room temperature (38° C.) under 50 psi pressure of hydrogen for 5 hours. Pd—C was then discarded through filtration. The reaction mixture was concentrated under reduced pressure and the residue was washed dichloromethane (2×3 ml) to give 2e; yield: 0.16 g. (86.4%), m.p.: 150° C., C17H14ClF3N2O2; 1H NMR δ ppm (DMSO-d6): 1.89-1.95 (m, 2H.), 2.76 (t, 2H), 3.28 (t, 2H), 6.44-6.49 (m, 1H), 6.72-6.75 (m, 2H), 7.37-8.0 (m, 2H),10.14 (bs, 1H); IR vmax (KBr) (cm−1): 661, 698, 769, 796, 819, 892, 944, 1023, 1072, 1147, 1217, 1290, 1347, 1384, 1424, 1450, 1506, 1599, 1707, 1740, 2364, 2489, 2837, 2950, 3359, 3773, 3888.
Reaction SMILES: [Cl:1]Cl.[N+:3]([C:6]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:9]1[CH:10]=[C:11]([O:13][C:14]([F:15])([F:16])[F:17])[CH:12]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[NH2:8]
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reactant: ClCl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1c(Cl)cc(OC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Chlorine gas was passed through a solution of 2-nitro-4-trifluoromethoxy-aniline (14.5 g) in carbon tetrachloride (175 ml). As the mixture was stirred it became solid and more carbon tetrachloride (50 ml) was added. Chlorine gas was passed through the reaction mixture until thin layer chromatography (silica gel, using petroleum ether (boiling range 60°-80° C.) containing ethyl acetate (30% by volume) as eluent) demonstrated the absence of starting material. Evaporation of the solvent under reduced pressure gave a dark orange solid, which on trituration with petroleum ether (boiling range 60°-80° C.) gave a 2-chloro-4-trifluoromethoxy-6-nitro-aniline as an orange solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1.Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>CCCCCC.C1COCC1>[Br:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1
Reactant: O=C(CCl)N1CCCCC1
Reactant: CN1CCc2[nH]c3ccc(Br)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCc2c(c3cc(Br)ccc3n2CC(=O)N2CCCCC2)C1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
Sodium hydride (0.6 g, 15 mmol) washed with hexane for removal of oil and dried under vacuum. Then sodium hydride was taken in THF. To this solution 8-bromo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 7.5 mmol) in THF was added drop wise at 0° C. Then reaction mixture stirred for 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone (1.8 g, 11.3 mmol) in THF was added drop wise in reaction mixture. Then reaction mixture stirred at rt for 2 h. Reaction was monitored by TLC. After completion of the reaction, reaction mixture quench with ice-water. THF was evaporated and aqueous layer was extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to gives 1.5 g of desired compound then out of that 0.8 g compound was stirred in ethanolic HCl to give HCl salt of 2-(8-bromo-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][C:30](O)=[O:31])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:40]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][C:30]([NH2:40])=[O:31])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC(=O)O)(c2ccccc2)OC1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Yield: 46.8 %

Procedure:
A mixture of 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanoic acid (500 mg, 1.12 mmol), HOBT (302 mg, 2.24 mmol), EDCl (440 mg, 2.24 mmol) and DIEA (1 mL) in anhydrous CH2Cl2 (10 mL) were stirred at 0□ under NH3. Then the solution was stirred at rt overnight. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to afford 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide (234 mg, yield 48%). 1H NMR (CDCl3): 1.49 (m, 3H), 1.91-2.02 (m, 1H), 1.87-1.98 (m, 1), 2.10-2.31 (m, 5H), 2.39-2.5 (m, 1H), 2.87 (m, 1H), 5.27 (s, 1H), 5.51 (s, 1H), 5.64 (m, 1H), 6.94 (m, 2H), 7.04 (m, 2H), 7.21-7.35 (m, 6H), 7.39 (m, 2H). LC-MS Method 3 tR=1.3, min, m/z=447, 469; 1H NMR (CDCl3) 1.49 (m, 3H), 1.91-2.02 (m, 1H), 1.87-1.98 (m, 1), 2.10-2.31 (m, 5H), 2.39-2.5 (m, 1H), 2.87 (m, 1H), 5.27 (s, 1H), 5.51 (s, 1H), 5.64 (m, 1H), 6.94 (m, 2H), 7.04 (m, 2H), 7.21-7.35 (m, 6H), 7.39 (m, 2H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[N:31]=[CH:30][C:14]2[NH:15][C@@H:16]([CH3:29])[CH2:17][N:18]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[CH:12]=1.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[Br:10][C:11]1[N:31]=[CH:30][C:14]2[N:15]([C:32](=[O:34])[CH3:33])[C@@H:16]([CH3:29])[CH2:17][N:18]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=3)(=[O:21])=[O:20])[C:13]=2[CH:12]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H](C)Nc3cnc(Br)cc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2cnc(Br)cc2N(S(=O)(=O)c2ccc(C)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
N,N-Diisopropylethylamine (0.018 mL, 0.102 mmol) was added to a solution of (S)-7-bromo-3-methyl-1-tosyl-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine (0.013 g, 0.034 mmol) and acetyl chloride (3.6 μL, 0.051 mmol) in dichloromethane (2.0 mL), and the mixture stirred at room temperature for 2 h. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(7-bromo-3-methyl-1-tosyl-2,3-dihydropyrido[3,4-b]pyrazin-4(1H)-yl)ethanone (0.010 g, 69%) as an off-white solid. MS (ESI, pos. ion) m/z 424, 426.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[CH:10]=2)[C:4](=O)[O:3]1.[CH3:22][NH:23][NH2:24]>C(O)C>[OH:20][C:17]1[CH:18]=[CH:19][C:14](/[CH:13]=[CH:12]/[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[C:4](=[O:3])[N:23]([CH3:22])[N:24]=[CH:2]3)=[CH:15][CH:16]=1
Reactant: CNN
Reactant: COc1ccc(/C=C/c2ccc3c(c2)C(O)OC3=O)cc1
Solvent: CCO
Product: Cn1ncc2cc(/C=C/c3ccc(O)cc3)ccc2c1=O

Procedure:
Trans-3-Hydroxy-5-[2-(4-methoxyphenyl)ethenyl]phthalide (15 g) was dissolved in refluxing ethanol (85 ml) and methylhydrazine (10 ml) was added slowly. The resulting suspension was refluxed for 3 hours, then cooled and filtered to give the 2-methyl-1(2H)-phthalazinone, mp 223°-225° C. The methoxy phthalazinone (10 g) was mixed with pyridine hydrochloride (35 g) and heated to 180° C. for 10 hours. The mixture was diluted with water, filtered and washed with isopropanol to give the desired phenol (4.3 g), mp 282°-284° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][CH:12]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([NH:21][CH2:20][CH2:19][NH2:22])=[N:13][CH:12]=1
Reactant: NCCN
Reactant: Nc1cc(F)ccc1NC(=O)c1ccc(Cl)nc1
Product: NCCNc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Yield: 61 %

Procedure:
N-(2-Amino-4-fluorophenyl)-6-chloronicotinamide (266 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 80° C. for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (176 mg, 61% yield) as a brown solid. LC-MS (m/z) 290 (M+1).
Reaction SMILES: [I-].[CH:2]([O:15][C:16]([C:18]1[N:23]2[C:24](=[O:33])[C:25](=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:22]2[S:21][CH:20]([NH2:34])[C:19]=1[CH2:35][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[C:57](=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[CH:26](=[C:25]1[C:24](=[O:33])[N:23]2[C:18]([C:16]([O:15][CH:2]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:17])=[C:19]([CH:35]=[CH2:57])[CH:20]([NH2:34])[S:21][C@H:22]12)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC1S[C@@H]2C(=Cc3ccccc3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(=Cc3ccccc3)[C@H]2SC1N
Temperature: 25 °C

Procedure:
To a solution of [4-benzhydryloxycarbonyl-7-benzylidene-amino-3-cephem-3-yl]methyl-triphenylphosphonium iodide (16.9 g) in methylene chloride (200 ml) and water (100 ml) was added 36% aqueous formaldehyde (48 ml), followed by adjusting to pH 9.0 with sodium carbonate. After the mixture was stirred at ambient temperature for an hour, the separated organic solution was washed with an aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave benzhydryl 7-benzylidene-amino-3-vinyl-3-cephem-4-carboxylate (8.6 g), mp 124°-132° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a solution of 1H-indole-2-carboxylic acid ethyl ester (1.89 g, 10.0 mmol) and benzylbromide (1.71 g, 10.0 mmol) in acetone (50 mL) was added cesium carbonate (3.26 g, 10.0 mmol). The mixture was heated to reflux overnight and then allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and brine and the layers were then separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 6/94) to give 1-benzyl-1H-indole-2-carboxylic acid ethyl ester (2.38 g, 85%) as a white solid. 1H NMR (400 MHz, CDCl3); δ 7.68 (d, 1H), 7.37-7.11 (m, 7H), 7.02 (d, 2H), 5.82 (s, 2H), 4.30 (q, 2H), 1.33 (t, 3H).
Reaction SMILES: Br[C:2]([CH2:4][CH:5]([OH:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH2:3].C[O-].[Na+].Cl>CN1CCCC1=O>[C:7]1([CH2:6][CH:5]([OH:13])[CH2:4][C:2]#[CH:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=C(Br)CC(O)Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C#CCC(O)Cc1ccccc1

Procedure:
20.00 Grams of the 2-bromo-5-phenyl-1-penten-4-ol obtained above were dissolved in 160 g of N-methyl-2-pyrrolidone, and 11.20 g of sodium methylate were added. The mixture was allowed to react at 30° C. for 14 hours and then was neutralized with concentrated hydrochloric acid. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The resultant oily substance was purified by silica gel column chromatography to give 9.96 g of 5-phenyl-1-pentyn-4-ol, nD25 =1.519, FI-MS m/e 160(M+), propargyl compound/allene compound 97.9/2.1.