Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:32])[O:26][C@H:27]3[CH2:31][CH2:30][O:29][CH2:28]3)[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:33])=[CH:14][CH:15]=2)[N:10]=1.CCOCC.C(Cl)[Cl:40]>>[ClH:40].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:32])[O:26][C@H:27]3[CH2:31][CH2:30][O:29][CH2:28]3)[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:33])=[CH:14][CH:15]=2)[N:10]=1
Reactant: ClCCl
Agent: Cc1ccc2c(N3CC[C@@H](NC(=O)O[C@H]4CCOC4)C3)nc(-c3c(O)cccc3F)nc2c1
Solvent: CCOCC
Product: Cl
Reaction time: 0.5 h

Procedure:
To a solution of (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (160 mg, 0.35 mmol) in 2 mL CH2Cl2 was added 2 M HCL solution in ether (0.176 mL, 0.35 mmol) resulting in precipitation of a solid. After the addition of 10 mL ether, the reaction was stirred for 30 minutes, filtered and the resulting solid was dried to obtain (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate hydrochloride (130 mg, 76%).). LC/MS: m/z 453.5 (M+H)+ at 2.13 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSOd6) δ 8.29 (s, 1H), 7.57 (s, 2H), 7.43-7.49 (m, 1H), 6.83-6.89 (m, 2H), 5.08 (s, 1H), 4.23-4.42 (m, 4H), 3.62-3.73 (m, 5H), 2.24-2.34 (m, 1H), 2.04-2.11 (m, 2H), 1.86-1.92 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24]>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:28]1[CH:29]=[CH:30][C:25]([CH:23]=[O:24])=[CH:26][CH:27]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(C=O)cc4)c3)cnc2c1F
Yield: 83 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-formylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2′-fluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-4-carbaldehyde as an off-white solid (100 mg, 83%): m/z (ES+) 393 [MH+].
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:44]1[CH:51]=[CH:50][C:47]([CH:48]=[O:49])=[CH:46][CH:45]=1>>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:44]2[CH:51]=[CH:50][C:47]([CH:48]=[O:49])=[CH:46][CH:45]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:7])[CH3:6])[CH2:14][CH2:13]1)=[O:17]
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccc(Br)cc1
Product: COc1ccc(-c2ccc(C=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (600 mg, 0.96 mmol) is coupled to 4-bromobenzaldehyde (213 mg, 1.15 mmol) using Method A to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([Si:12]([CH3:15])([CH3:14])Cl)([CH3:11])([CH3:10])[CH3:9].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][OH:26])=[CH:19][C:18]=1[CH3:27]>ClCCl.CN(C1C=CC=CN=1)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][O:26][Si:12]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:15])[CH3:14])=[CH:19][C:18]=1[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(NCCO)ccc1Br
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NCCO[Si](C)(C)C(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
Triethylamine (0.39 ml, 2.80 mmol), dimethylaminopyridine (13 mg, 0.11 mmol) and tert-butyl-dimethyl-chloro-silane (319 mg, 2.11 mmol) were added to a solution of 2-(4-bromo-3-methyl-phenylamino)-ethanol (430 mg, 1.87 mmol) in dichloromethane (3.8 ml) at room temperature, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane, and the organic layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (4-bromo-3-methyl-phenyl)-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-amine (629 mg, 98%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[N:22][N:23]4[CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[N:22][N:23]4[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCCn1ncc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3cnn4CCCC(=O)O)no2)cc1Cl
Temperature: 80 °C
Yield: 72.2 %

Procedure:
2M Sodium hydroxide (1 ml, 2 mmol) was added to a solution of ethyl 4-[4-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]butanoate (D60) (N2666-13-A1) (0.062 g, 0.132 mmol) in ethanol (5 ml) and the reaction was heated to 80° C. to effect dissolution then left to cool for 2 hours. Evaporated, dissolved in ethyl acetate/water (25 ml of each) and acidified with acetic acid. Organic dried (magnesium sulphate), evaporated, azeotroped with 15 ml of toluene and triturated with ether. Filtered to give the title compound (42 mg) as a white solid. 5H (d6-DMSO, 400 MHz): 1.37 (6H, d), 2.09 (2H, m), 2.24 (2H, t), 4.54 (2H, t), 4.90 (1H, m), 7.47 (1H, d), 7.62 (1H, dd), 7.97 (1H, d), 8.01 (1H, d), 8.17 (1H, dd), 8.26 (1H, d), 8.56 (1H, s). MS (ES): C22H2135ClN4O4 requires 440; found (MH+) 441.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([CH3:32])([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=4)[N:19]=3)=[CH:16][N:17]=2)[CH2:9][CH2:8]1)[CH3:6])C.[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:32][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=4)[N:19]=3)=[CH:16][N:17]=2)[CH2:9][CH2:8]1)([CH3:6])[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)C(C)(C)C1CCN(c2ncc(-c3cccc(Nc4cc(C)ccn4)n3)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccnc(Nc2cccc(-c3cnc(N4CCC(C(C)(C)C(=O)O)CC4)s3)n2)c1
Reaction time: 15 h
Yield: 66.7 %

Procedure:
To a mixed solution of 2-methyl-2-(1-{5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}piperidin-4-yl)propionic acid ethyl ester (697 mg, 1.50 mmol) obtained in Step 3 in methanol (5 ml) and tetrahydrofuran (10 ml), 4N aqueous sodium hydroxide (3.7 ml, 15 mmol) was added and the mixture was stirred for 15 hours under refluxing. After concentrated, the reaction solution was neutralized with 1N hydrochloric acid (15 ml, 15 mmol), and the precipitated solid was collected by filtration, washed with water, ethyl acetate, tetrahydrofuran. After dried in vacuo, the title compound (438 mg, 67%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]#[C:26][Si](C)(C)C)[CH:22]=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[F-].[K+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[C:21]([C:31]([F:33])([F:34])[F:32])[CH:22]=[C:23]([C:25]#[CH:26])[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(C#C[Si](C)(C)C)cc(C(F)(F)F)c1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cc(C(F)(F)F)cc(S(=O)(=O)NC2CCCc3c2cnn3CC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of [4-(3-trifluoromethyl-5-trimethylsilanylethynyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (40.0 mg, 0.076 mmol) in N,N-dimethylformamide and water (3 mL, 150:1) was added potassium fluoride (23.0 mg, 0.30 mmol). The mixture was stirred at room temperature for 4 hours. The resulting mixture was poured into ice and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography (gradient elution, 0-5% methanol in dichloromethane) to afford [4-(3-ethynyl-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (34.0 mg, 98.2%) as a white solid. MS calcd. for C20H20F3N3O4S 455, obsd. (ESI+) [(M+H)+] 456.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2.[CH3:13][S:14]([CH:17]=[CH2:18])(=[O:16])=[O:15]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][CH2:17][S:14]([CH3:13])(=[O:16])=[O:15])[C:6]([CH2:11][OH:12])=[CH:5]2
Reactant: C=CS(C)(=O)=O
Reactant: OCc1cc2cc(Cl)ccc2[nH]1
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCn1c(CO)cc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of (5-chloro-1H-indol-2-yl)-methanol (3.6 g, 0.02 mol), Ce2CO3 (13 g, 0.04 mol) in 100 mL of DMF which was cooled to 0° C., was added methanesulfonyl-ethene (2.1 g, 0.02 mol) in portions. The reaction mixture was stirred at a temperature between 30° C. and 50° C. overnight. Ice-water was then added to the mixture, the precipitate was filtered and dried to give [5-chloro-1-(2-methanesulfonyl-ethyl)-1H-indol-2-yl]-methanol (2 g, yield: 34.7%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)C.[NH3:13]>CO>[NH2:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([NH2:13])=[O:3])[N:7]=1
Reactant: N
Reactant: CCOC(=O)Cc1csc(N)n1
Solvent: CO
Product: NC(=O)Cc1csc(N)n1
Yield: 95 %

Procedure:
A solution of 2.5 g (15.0 mmol) (2-Amino-thiazol-4-yl)-acetic acid ethyl ester in 70 ml of 7N ammonia solution in methanol was stirred for 6 days at room temperature. After concentration in vacuo, one obtains 2.0 g (95%) of the title compound as a light brown solid, which was directly used in the next step without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([CH2:23][CH2:24][CH2:25][OH:26])[S:21][CH:22]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:27]([N:34]1C=CN=C1)(N1C=CN=C1)=[O:28].O1CCCC1.[NH2:44]N.O.NN>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([CH2:23][CH2:24][CH2:25][O:26][C:27]([NH:34][NH2:44])=[O:28])[S:21][CH:22]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: NN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)N1CCN(c2ccc(CCc3csc(CCCO)c3)nc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2ccc(CCc3csc(CCCOC(=O)NN)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a solution of 3-(4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}thiophen-2-yl)propan-1-ol (150.0 mg, 0.402 mmol) in anhydrous tetrahydrofuran (3 ml) was added 1,1′-carbonyldiimidazole (84.7 mg, 0.522 mmol), and the mixture was stirred at room temperature for 2 hrs. 1M Hydrazine tetrahydrofuran solution (1.21 ml, 1.21 mmol) was added, and the mixture was stirred at room temperature for 2 hrs. Since the reaction did not proceed, hydrazine monohydrate (26.1 mg, 0.522 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by aminopropylated silica gel column chromatography (5%-2-propanol-dichloromethane mixture) and aminopropylated silica gel column chromatography (2%-methanol-dichloromethane mixture) to give the title compound (148.8 mg, yield 85.9%) as a colorless syrup.
Reaction SMILES: [C:1]1([P:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([OH:21])C=CC=CC=1.N1C=CC=CC=1>CCOCC>[C:1]1([P:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[OH:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: Oc1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: OP(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
Diphenylphosphinous acid chloride [(C6H5)2PCl, 55 g.] was added to a solution of phenol (21.6g) and pyridine (18 g.) in 250 ml. of dry ether at 5°C. with stirring. After standing overnight, the precipitated pyridinium chloride was removed by filtration and the filtrate distilled. The phenyl ester of diphenylphosphinous acid [(C6H5)2POC6H5 ] obtained weighed 54 g. and boiled at 145°C. at 0.1 mm.
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[C:13]3[CH:20]([CH2:21][Cl:22])[CH2:19][N:18]([C:23]([O:25]C(C)(C)C)=O)[C:14]3=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=O)C1C=CC=CC=1.Cl.C(Cl)CCl.[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[NH:47][C:46](C(O)=O)=[CH:45]2>C(OCC)(=O)C>[Cl:22][CH2:21][CH:20]1[C:13]2=[C:12]3[C:17](=[CH:16][CH:15]=[C:14]2[N:18]([C:23]([C:46]2[NH:47][C:48]4[C:44]([CH:45]=2)=[CH:43][C:42]([O:41][CH3:40])=[CH:50][CH:49]=4)=[O:25])[CH2:19]1)[NH:9][C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:11]3
Reactant: CCOC(=O)c1cc2c3c(ccc2n1C(=O)c1ccccc1)N(C(=O)OC(C)(C)C)CC3CCl
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)c1cc2c3c(ccc2[nH]1)N(C(=O)c1cc2cc(OC)ccc2[nH]1)CC3CCl
Reaction time: 0.5 h
Yield: 105.4 %

Procedure:
Compound 3.7(100 mg, 0.21 mmol) was treated with a solution of hydrochloric acid in ethyl acetate (4M, 500 μL). After 30 min, the solvent was concentrated and DMF (1 mL) was added. The solution was treated with EDC (120 mg, 0.63 mmol) and 5-methoxyindole-2-carboxylic acid (120 mg, 0.63 mmol). After 16 h, the solvent was removed under reduced pressure and the residue (the 6N-benzoyl protected precursor of compound 3.8) was dissolved in CH3OH (1 mL). A solution of NaOCH3 in CH3OH (2M, 100 μL) was then added and the solution stirred for 10 minutes. The solvent was removed and chromatography (SiO2, 10% ethyl acetate/hexanes) gave the product (3.8) (100 mg, 86%). FABMS (NBA/NaI) m/z 557 (M+H+ expected 557).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[P:17]([O-:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([O:18][P:17]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)(=[O:24])[O:21][CH2:22][CH3:23])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOP(=O)(OCC)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 1-bromo-4-nitrobenzene (400 mg, 2.00 mmol), tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.20 mmol) and cesium carbonate (734 mg, 2.2 mmol) in a 30 mL microwave vial was purged and backfilled with nitrogen. Tetrahydrofuran (20 mL) was added followed by diethyl phosphite (0.360 mL, 2.8 mmol). The mixture was vortexed, then microwaved for 45 minutes at 120° C. Reaction was repeated three times to achieve total scale then the combined reaction mixtures were purified via chromatography (120 g silica gel 5%->75% ethyl acetate in hexane). (4-Nitro-phenyl)-phosphonic acid diethyl ester isolated as a light yellow oil (969 mg, 47%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.35 (d, J=8.0 Hz, 2H), 7.16 (s, 1H), 5.93 (s, 2H), 3.40 (s, 4H), 2.36 (s, 4H), 2.20 (s, 3H), 8.05-7.95 (m, 2H), 4.09 (m, 4H), 1.25 (t, J=13.8, 7.4 Hz, 6H).
Reaction SMILES: [OH-].[K+].[C:3]([OH:11])(=[S:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12]OS(O)(=O)=O.C(OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O>[C:3]([S:10][NH2:12])(=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NOS(=O)(=O)O
Reactant: OC(=S)c1ccccc1
Agent: O=C(OC(=O)c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To a stirred solution of KOH (560 mg, 10 mmol) in water (15 mL) was added thiobenzoic acid (690 mg, 5 mmol) and hydroxylamine-O-sulfonic acid (565 mg, 5 mmol). The solution was stirred for 20 min at rt. The white solid (S-benzoylthiohydroxylamine) was collected by filtration and then dissolved in CH2Cl2 (10 mL). To this mixture was added benzoic anhydride (2.26 g, 10 mmol). The resulting solution was allowed to stir overnight at rt. The crude product was purified by recrystallization (CH2Cl2/hexane) to give 2 as white solid. m.p. 138-140° C.; 1H NMR (300 MHz, CDCl3) δ 7.92 (m, 4H), 7.60 (m, 1H), 7.53 (m, 1H), 7.39 (m, 4H), 7.17 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 190.0, 159.1, 134.6, 134.4, 133.3, 132.8, 129.3, 129.0, 128.0, 127.3; IR (thin film) cm−1 3265, 3062, 1696, 1659, 1451, 1419, 1257, 1207; HRMS m/z 258.0598 [M+H]+; calcd for C14H12NO2S 258.0589; overall yield: 64% (2 steps).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:18]([OH:19])=[N:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[OH:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29].O>ClCCl>[Cl:1][C:2]1[C:3]([C:9]2[C:18](=[O:19])[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[O:20][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1nc2nccnc2c(O)c1-c1ncc(Cl)cc1Cl
Reactant: CC(C)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)Oc1c(-c2ncc(Cl)cc2Cl)c(=O)[nH]c2nccnc12
Reaction time: 0.17 h

Procedure:
7-(3,5-Dichloro-pyrid-2-yl)-pyrido[2,3-b]pyrazine-6,8-diol (Example 1.2) (1.6 g) was dissolved in dichloromethane (50 ml) containing pyridine (0.445 g) and the reaction mixture stirred for 10 minutes. Isobutyryl chloride (0.556 g) was added dropwise over 5 minutes and the reaction mixture stirred for two hours. Water was added and the mixture extracted with ethyl acetate. The phases were separated and the organic fraction was washed with aqueous sodium carbonate (1M). The organic fraction was dried over sodium sulfate and concentrated to give a pale yellow solid which was recrystallized from ethyl acetate/hexane to give Compound No. A5 of Table A (1.02 g).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:1]([C:4]1[CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Yield: 73 %

Procedure:
A suspension of 2-nitro-4-bromoaniline (5 g, 23 mmol) in toluene was admixed with 2.8 g (23 mmol) of phenylboronic acid, 9.5 g (0.069 mol) of potassium carbonate and 1.3 g of tetrakis(triphenylphosphine)palladium. The mixture was heated to reflux for 4 hours and the reaction was stopped by adding 100 ml of water. The mixture was extracted with ethyl acetate and dried over sodium sulphate, and the solvent was removed under reduced pressure. Purification by column chromatography gave 3.6 g (73% yield).
Reaction SMILES: N1C=CC=C[C:2]=1[C:7]([OH:9])=[O:8].C(N(CC)CC)C.[C:17]([Cl:23])(=[O:22])C(C)(C)C>ClCCl>[Cl:23][C:7]([O-:9])=[O:8].[CH2:7]([O:8][C:17]([Cl:23])=[O:22])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(O)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cl
Product: O=C([O-])Cl

Procedure:
Picolinic acid compound 4 is reacted with an organic base, e.g., triethylamine, followed by an acid chloride, e.g., pivaloyl chloride or a chloroformate, e.g., C2H5OCOCl in a suitable solvent such as dichloromethane at a temperature of about −30° C. to 0° C. to give a mixed anhydride. To the mixture is added NH2R5 at a temperature of −30° C. to 0° C. either neat or as a solution in a suitable solvent to form amide compound 2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[C:7]=1[CH:8]=[CH:9][C:10](O)=[O:11])#[N:2].S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[C:7]=1[CH:8]=[CH:9][C:10]([Cl:26])=[O:11])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)O
Solvent: Cc1ccccc1
Product: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl
Temperature: 98 °C

Procedure:
A stirred slurry of 1.1 grams (0.003 mole) of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid and 1.0 mL of thionyl chloride in 20 mL of toluene was heated at about 72° C. for 25 minutes. The slurry was warmed to 98° C. over a 45 minute period, during which time the reaction mixture became homogeneous. The reaction mixture was heated at 98° C. for 35 minutes. After this time, the reaction mixture was cooled and concentrated under reduced pressure, yielding 1.1 grams of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid chloride. The acid chloride was used without purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1>>[CH3:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[CH:24][N:23]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccnc(C)c3)ccn2c1=O

Procedure:
Methyl 8-(2-methylpyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (2-methylpyridin-4-yl)boronic acid (56.3 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded quantitatively the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=[O:7].CCN(CC)CC.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]=[C:27]=[O:28]>C(COC)OC>[O:7]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:8]([C:27](=[O:28])[NH:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[Cl:18])[C:9]#[N:10]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: N#CCC(=O)c1ccc[nH]1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: N#CC(C(=O)Nc1ccc(Cl)cc1Cl)C(=O)c1ccc[nH]1
Reaction time: 8 h

Procedure:
A solution of 2.1 g of 2-pyrroloylacetonitrile in 15 ml of glyme and 1.8 g of Et3N is treated with a solution of 3 g of 2,4-dichlorophenyl isocyanate in 15 ml of glyme similarly to the preceding examples. Mildly exothermic reaction results in formation of a thick suspension of crystals. After standing overnight, dilution with dry ether and filtration gives the triethylamine salt of β-oxo-α-(2,4-dichlorophenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile, m.p. 180°-2° dec., in form of the enol structure as represented by formula Ia, wherein Py is 2-pyrrolyl, R is hydrogen and Ph is 2,4-dichlorophenyl.