Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28](C)(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O
Reactant: N
Product: CC(C)(O)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 459, substituting 2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 479) in place of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone. mp 176–178° C., 1H NMR (300 MHz, CDCl3) δ 1.00 (s, 6H), 4.19 (s, 2H), 4.54 (s, 1H), 7.49 (s, 2H), 7.62 (t, 1H, J=9 Hz), 7.66 (ddd, 1H, J=2,5,9 Hz), 7.92 (s, 4.5H), 7.94 (d, 0.5H, J=2 Hz), 8.20 (s, 1H); MS (DCI/NH3) m/z 468 (M+H)+; 1 Cl, 490 (M+Na)+; 1 Cl; Anal. Calcd for C20H19ClFN2O5S: C 51.34, H 4.09, N 8.98. Found: C 51.33, H 4.23, N 8.76.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2O[C:13](=O)[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)(O)O.[NH2:26][NH:27][C:28]([NH2:30])=[NH:29]>N1C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][C:9]2[N:26]3[N:27]=[C:28]([NH2:30])[N:29]=[C:13]3[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1oc(Cc2ccc([N+](=O)[O-])cc2)nc2ccccc12
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Nc1nc2c3ccccc3nc(Cc3ccc([N+](=O)[O-])cc3)n2n1
Yield: 41.7 %

Procedure:
A solution of 2-(4-nitrobenzyl)-4H-3,1-benzoxazin-4-one (5.7 g, 20.2 mmol) and aminoguanidine hydrogencarbonate (2.7 g, 20.2 mmol) in pyridine (25 mL) was heated under microwave condition at 180° C. for 30 minutes. After cooling, the red solution was taken up in ethyl acetate, washed with brine and dried over Na2SO4. The solvent was removed in vacuum and the residue was chromatographed on silica gel eluting with DCM/CH3OH 95/5 to furnish the title compound (2.7 g, 42% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[C:26]=1[F:33].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:24][C:25]1[C:26]([F:33])=[C:27]([C:31]#[C:32][C:18]2[CH:19]=[CH:20][C:15]([N:11]3[C:12](=[O:14])[NH:13][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10]3)=[CH:16][C:17]=2[O:22][CH3:23])[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1I
Reactant: C#Cc1cccc(Cl)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C#Cc1cccc(Cl)c1F
Yield: 28.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-32, 0.050 g, 0.11 mmol), 1-chloro-3-ethynyl-2-fluorobenzene (Intermediate-24, 0.033 g, 0.22 mmol), TBAF (0.080 g, 0.30 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol) and DMSO (3.0 ml) at 80° C. to afford 0.015 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.89 (s, 3H), 7.28 (t, J=7.8 Hz, 1H), 7.48 (t, J=9.0 Hz, 1H), 7.56-7.70 (m, 7H), 12.79 (m, 1H); MS (m/z): 470.00 (M−H)−.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([NH:42][CH:43]([CH3:45])[CH3:44])=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[Cl-].[NH+]1C=CC=CC=1>CO>[OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([NH:42][CH:43]([CH3:45])[CH3:44])=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)NC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)NC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 60 °C
Yield: 84.5 %

Procedure:
A mixture of 6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-N-isopropyl-2-naphthamide (16.6 g) and pyridinium chloride (6.46 g) in methanol (84 mL) was heated at 60° C. for 3 h. The solvent was evaporated and the residue was dissolved in chloroform, which was washed with saturated sodium bicarbonate solution, dried and concentrated. The residue was purified by column chromatography (eluent; CHCl3: 8% methanolic ammonia=19:1→9:1) to give the titled compound (8.3 g) as a colorless powder.
Reaction SMILES: [C:1](=[O:7])=[N:2][S:3]([Cl:6])(=[O:5])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])=[CH:11][C:10]=1[N+:25]([O-:27])=[O:26]>C1(C)C=CC=CC=1>[Cl:6][S:3]([NH:2][C:1](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])=[CH:11][C:10]=1[N+:25]([O-:27])=[O:26])(=[O:5])=[O:4]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1[N+](=O)[O-])NS(=O)(=O)Cl

Procedure:
30 ml of N-chlorosulfonyl isocyanate dissolved in 70 ml of toluene are rapidly added dropwise, at +10° C., to 88.2 g of 2-amino-5-phenoxysulfonylnitrobenzene in 750 ml of toluene. The mixture is stirred for a further hour while cooling, and the precipitate is filtered off with suction, washed with diisopropyl ether and dried in a desiccator over potassium hydroxide. 88 g of the 2-(3-chlorosulfonylureido)-5-phenoxysulfonylnitrobenzene produced are introduced, with stirring and cooling, into 800 ml of 1N HCl. After 30 minutes, the clear solution is briefly warmed to 80° C. (precipitation) and then left to stand. After cooling down, the solid is filtered off with suction and washed with water to neutrality, melting point 190° C.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:13]=[C:12]([NH:14][P:15]([NH2:18])([NH2:17])=[O:16])[S:11][N:10]=1)[C:6]([O-:8])=O)[CH3:2].[Na+].C(=O)(O)[O-].[Na+].CS(Cl)(=O)=O.O.O.Cl.Cl.[NH2:34][CH:35]1[C:52](=[O:53])[N:37]2[C:38]([C:49]([O-:51])=[O:50])=[C:39]([CH2:42][N+:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:40][S:41][C@H:36]12.C(OC(C)C)(C)C>CN(C)C(=O)C.C(Cl)Cl>[CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:13]=[C:12]([NH:14][P:15]([NH2:18])([NH2:17])=[O:16])[S:11][N:10]=1)[C:6]([NH:34][CH:35]1[C:52](=[O:53])[N:37]2[C:38]([C:49]([O-:51])=[O:50])=[C:39]([CH2:42][N+:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:40][S:41][C@H:36]12)=[O:8])[CH3:2]
Reactant: CCON=C(C(=O)[O-])c1nsc(NP(N)(N)=O)n1
Reactant: NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(NP(N)(N)=O)n1
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 32.8 %

Procedure:
To a mixture of sodium 2-ethoxyimino-2-(5-diaminophosphorylamino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (2.10 g) and sodium bicarbonate (1.12 g) in N,N-dimethylacetamide (21 ml) was added methanesulfonyl chloride (1.03 ml) under cooling in an ice-bath and stirring, which was continued for one hour and 45 minutes and cooled to -20° C. To the cold reaction mixture was added a solution of 7-amino-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate dihydrochloride dihydrate (2.39 g) and monotrimethylsilylacetamide (11.96 g) in methylene chloride (48 ml) at -18° C. under stirring, which was continued for 30 minutes at -18° to -12° C. and for 30 minutes at -10° to 0° C. The reaction mixture was poured into diisopropyl ether (700 ml) and the resulting precipitates were separated by decantation. The residue was dissolved in water (100 ml), adjusted to pH 3.8 with 1N hydrochloric acid and subjected to column chromatography on a non-ionic adsorption resin "Diaion HP-20" (105 ml). After the column was washed with water (500 ml), the elution was carried out with 20% aqueous methanol. The fractions containing the object compound were collected, evaporated to remove methanol and lyophilized to give 7-[2-ethoxyimino-2-(5-diaminophosphorylamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.11 g), mp 123° to 132° C. (dec.).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][CH2:12][NH:13][NH2:14])#[N:10]>>[C:9]([CH2:11][CH2:12][NH:13][N:14]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)#[N:10]
Reactant: N#CCCNN
Reactant: O=Cc1ccccc1
Product: N#CCCNN=Cc1ccccc1
Yield: 81 %

Procedure:
Benzaldehyde (2-cyanoethyl)hydrazone is prepared by condensation of benzaldehyde with (2-cyanoethyl)hydrazine according to the following procedure:
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([N:25]=[N+:26]=[N-:27])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]([O:30][C:31](=[O:38])[CH:32]=[C:33](NC)NC)[CH3:29]>O1CCOCC1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([N:25]5[CH:33]=[C:32]([C:31]([O:30][CH2:28][CH3:29])=[O:38])[N:27]=[N:26]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=C(NC)NC
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(N=[N+]=[N-])cc32)n1)c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2ccc3ncn(-c4ccnc(N[C@@H](C)c5ccccc5)n4)c3c2)nn1

Procedure:
The title compound was prepared from 266 mg of 2-[(S)-1-phenylethylamino]-4-[6-azidobenzimidazol-1-yl]pyrimidine, about 100 μL ethyl-3,3-dimethylaminoacrylate and 5 mL 1,4-dioxane using the procedure described in EXAMPLE 276 to give 283 mg of the title compound. RF: 0.4 (5% MeOH in CH2Cl2). 1H NMR (500 MHZ, DMSO): δ 1.33 (t, J=7.0 Hz, 3H), 1.50 (d, J=6.9 Hz, 3H), 4.38 (q, J=7.1 Hz, 2H), 5.24 (m, 1H), 7.05-7.45 (m, 5H), 7.87 (d, J=8.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 8.2 (m, 1H), 8.44 (m, 1H), 8.91 (m, 1H), 9.14 (br s, 1H), 9.50 (s, 1H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 455.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[C:16]1([S:22]([N:11]2[C:12]3[C:8](=[C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)[CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1cc(-c2cnccn2)c2cc[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c(-c3cnccn3)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Pyrazin-2-yl-1H-indole (0.060 g, 0.307 mmol, Intermediate 65), benzensulfonyl chloride (0.071 g, 0.40 mmol) and tetrabutylammonium hydrogen sulfate (0.010 g, 0.031 mmol) were dissolved in dichloromethane (3 mL) and NaOH (0.061 g, 1.5 mmol) in water (1 mL) was added. The mixture was stirred at rt overnight and the mixture was diluted with dichloromethane and water and extracted with dichloromethane (2×). The organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography using CH2Cl2 to 1% MeOH in CH2Cl2 as the eluent. Yield: 81 mg (79%). White solid. MS (electronspray; [M+H]+) m/z 336.4.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:3]=1[CH:4]=[CH:5][C:6]#[N:7].[H-].C([Al+]CC(C)C)C(C)C.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C@H:32](N)[CH3:33])[CH:29]=[CH:30][CH:31]=1.[BH4-].[Na+]>>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:3]=1[CH:4]=[CH:5][CH2:6][NH:7][C@@H:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH3:24])[CH:27]=1)[CH3:33]
Reactant: Cc1cc(C)c(C=CC#N)c(C)c1
Reactant: COc1cccc([C@@H](C)N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Product: COc1cccc([C@@H](C)NCC=Cc2c(C)cc(C)cc2C)c1

Procedure:
In a similar fashion, 2,4,6-trimethylcinnamonitrile was treated with diisobutyl aluminum hydride and the intermediate aluminum-imine complex treated with (R)-1-(3-methoxyphenyl)ethylamine. The intermediate imine was treated with ethanolic sodium borohydride. Work-up and chromatography yielded (R)-N-[3-(2,4,6-trimethylphenyl)prop-2-enyl]-1-(3-methoxyphenyl)ethylamine, 12D, as a clear, colorless oil; m/z (rel. int.) 309 (M+, 8), 294 (25), 174 (82), 159 (100), 135 (52), 129 (29), 105 (21), 91 (17), 77 (14).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=3)[N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:9]([N:14]1[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=2)=[C:12]2[C:7](=[CH:8][CH:9]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:10](=[O:29])[NH:11]2)[C:6]([OH:36])=[C:5]1[C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)C1=C(O)C2=CC(c3ccccc3)C(=O)NC2=C(c2cncc(F)c2)N1Cc1ccccc1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
A mixture of 1-benzyl-8-(5-fluoro-pyridin-3-yl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (32 mg, 0.067 mmol), β-alanine (593 mg, 6.7 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (5-80% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 14 mg of the title compound as a light yellow solid. MS: (+) m/z 539.29 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15]([O-])([O-])=O.[Na+].[Na+].IC>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.5 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitrobenzoic acid (5.5 g, 21 mmol) in DMF (42 ml) under nitrogen, was added Na2CO3 (3.4 g, 32 mmol) followed by iodomethane (2.0 ml, 32 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with deionized water (150 ml) and extracted with EtOAc (4×50 ml). The combined organic phases were washed with saturated NaHCO3 (aq) (2×50 ml), dried over MgSO4, filtered and concentrated in-vacuum to give the title compound (6.3 g, 61%) as a yellow oil. LC-MS 57%, 2.20 min (3.5 minute LC-MS method), no ionization; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.38 (d, J=2.05 Hz, 1H) 7.23 (d, J=2.05 Hz, 1H) 3.20 (s, 3H) 1.82 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:15]Br.O>C(O)(=O)C>[C:9]1([C:6]2[S:5][C:4]([C:1]([CH2:2][Br:15])=[O:3])=[CH:8][CH:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(-c2ccccc2)s1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C(CBr)c1ccc(-c2ccccc2)s1
Reaction time: 0.5 h

Procedure:
A solution of 2-acetyl-5-phenylthiophene (11.7 g, 0.058 mole), described in Examples 1 and 2, in 100 ml of glacial acetic acid is treated dropwise with bromine (9.3 g, 0.058 mole). The mixture is stirred for 1/2 hr, poured into cold water and extracted with chloroform. The extract is washed with water, 5% NaHCO3 and brine, dried (K2CO3) and concentrated to give a yellow solid. The solid is subjected to chromatography on silica gel to give bromomethyl 5-phenyl-2-thienyl ketone (ArCOCHR2Y; Ar is 5-phenyl-2-thienyl, R2 = H and Y = Br); mp 114° C.
Reaction SMILES: Br[C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]([CH3:22])=[N:17]2.[CH3:28][Zn]C>O1CCOCC1.C(Cl)Cl>[C:24]([NH:23][C:15]1[C:16]([CH3:22])=[N:17][C:18]2[C:13]([N:14]=1)=[C:12]([C:3]1[NH:4][C:5]3[CH2:10][CH2:9][NH:8][C:7](=[O:11])[C:6]=3[C:2]=1[CH3:28])[CH:21]=[CH:20][CH:19]=2)([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1nc2cccc(-c3[nH]c4c(c3Br)C(=O)NCC4)c2nc1NC(C)(C)C
Reactant: C[Zn]C
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3[nH]c4c(c3C)C(=O)NCC4)c2nc1NC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (349) (61 mg, 0.14 mmol), dimethylzinc in hexanes (0.39 mL of 10% wt. in hexanes, 0.570 mmol, Strem Chemicals, Inc.,), and (A-Phos)2PdCl2 (10 mg, 0.014 mmol) in dioxane (1.42 mL) was stirred at 80° C. for 2 h when product was observed via lcms. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-4% of 2 M NH3 in MeOH/DCM to give impure 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one contaminated with starting material. The impure product was purified via SFC [IC (3×15 cm, 5 μm), 60% 0.2% DEA in MeOH: EtOH: isopropanol (1:1:1) (NH4OH)/CO2, 100 bar; 65 mL/min, 220 nm; inj vol.: 1.5 mL, 3.5 mg/mL in MeOH] to give 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (350, 10 mg, 0.028 mmol, 19% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.60 (s, 9H) 2.55 (s, 3H) 2.69 (s, 3H) 2.95 (t, J=6.85 Hz, 2H) 3.61 (td, J=6.85, 2.54 Hz, 2H) 4.79 (s, 1H) 5.18 (br. s., 1H) 7.42 (t, J=7.92 Hz, 1H) 7.68 (dd, J=8.12, 1.27 Hz, 1H) 7.85 (dd, J=7.53, 1.08 Hz, 1H) 11.62 (br. s., 1H). MS (ESI, pos. ion) m/z: 364.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2[Cl:17].C([O:20][CH:21]=[C:22]([C:28]([CH3:30])=[O:29])[C:23](OCC)=O)C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:28]([CH:22]1[C:21](=[O:20])[C:3]2[C:2](=[C:11]3[C:6](=[CH:5][CH:4]=2)[C:7]([Cl:17])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[N:10]3)[N:1]=[CH:23]1)(=[O:29])[CH3:30]
Reactant: CCOC(=O)c1cnc2c(N)cccc2c1Cl
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c3c(ccc2c1Cl)C(=O)C(C(C)=O)C=N3
Temperature: 90 °C
Yield: 29 %

Procedure:
A mixture of 8-amino-4-chloro-3-ethoxycarbonylquinoline (0.3 g) and ethyl 2-ethoxymethyleneacetoacetate (Annalen, 1897, 297, 16, 0.25 g) was heated at 90° C. for 2.5 hours. The mixture was cooled to ambient temperature and the resulting solid added to diphenyl ether at reflux. The mixture was refluxed for 45 minutes, and cooled to 60° C. The mixture was diluted with carbon tetrachloride (50 ml) and cooled to ambient temperature with stirring. The mixture was filtered and the solid so obtained purified by flash chromatography on silica using increasingly polar mixtures of methanol and chloroform. The product so obtained was recrystallised from methanol to give 3-acetyl-7-chloro-8-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline in 29% yield, mp 288-290° C.
Reaction SMILES: O[C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:11][CH:12]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C=C(C)c1ccc(-c2ccc(Cl)cc2)cc1
Yield: 91 %

Procedure:
To a solution of crude ethyl 3-hydroxy-3-(4′-chloro-[1,1′-biphenyl]-4-yl)-butanoate (2g) in benzene (200 ml) was added p-toluenesulfonic acid (3 gm) and was refluxed for 3 h 30 minutes. The reaction mixture was cooled, neutralized with NaHCO3 solution, diluted with water and organic layer was extracted. Organic layer was washed with water, dried (NaHCO3) and concentrated. Crude product was purified by column chromatography on silica gel to furnish 5.27 g (47.=91% yield) of ethyl 3-(4′-chloro-[1,1′-biphenyl]-4-yl)-but-2-enoate (3g, formula 3, R=p-Cl—C6H4) m.p. 91-94° C.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([CH3:24])[CH:18]=1>>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[CH:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:19]([CH3:24])[CH:18]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(Cl)cc1C
Yield: 47.7 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (5.00 g, 24.1 mmol) and 4-chloro-2-methylaniline (5.13 g, 36.2 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (3.80 g, 48%) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:15][N:2]([CH3:1])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19][CH2:18]2)=[O:9])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CN(C)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)NC2CCN(C(c3ccccc3)c3ccccc3)CC2)c([N+](=O)[O-])c1

Procedure:
Step 3): The mixture of 4-dimethylamino-2-nitrobenzoic acid (4.20 g, 20 mmol), 4-amino-1-diphenylmethylpiperidine (5.33 g, 20 mmol). EDCl (4.00 g, 21 mmol) and DMAP (2.45 g, 20 mmol) in CH2Cl2 (60 ml) was stirred at room temperature for 17.5 hours. The reaction mixture was diluted with CH2Cl2, washed with H2O and brine. The organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified with chromatography on SiO2 (50% AcOEt in hexane) and recrystallized from AcOEt to obtain 4-dimethylamino-2-nitro-N-(1-diphenylmethylpiperidin-4-yl)benzamide. 5.44 g (59%): mp 183° C.