Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([Cl:18])=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:19])=[C:4]([F:22])[CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([Cl:18])=[CH:13][CH:14]=3)[N:9]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:8]2=[O:19])=[C:4]([F:22])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)n1Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Cl)cc21
Yield: 89.8 %

Procedure:
A solution of 3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (500 mg), ethyl bromoacetate (218 mg) and potassium carbonate (360 mg) in N,N-dimethylformamide (5 ml) was stirred at 30° C. for 30 minutes. The solution was evaporated and the residue was dissolved in ethyl acetate. The solution was washed in turn with 0.5N aqueous hydrochloric acid and water, and then dried over magnesium sulfate. The solvent was removed in vacuo to give a crystalline residue, which was crystallized from a mixture of ethyl acetate and n-hexane to give ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (550 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:9][N:8]([C@@H:23]3[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]([O:37]C)=[O:36])[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>CO.O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)=[CH:9][N:8]([C@@H:23]3[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C@H:25]([C:35]([OH:37])=[O:36])[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](n2cc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1cc(C#Cc2cn([C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
The (2S,4S)-1-tert-butyl 2-methyl 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1,2-dicarboxylate (393.8 mg) obtained in Example 66 (Step 6) was dissolved in methanol (6 ml). After cooling to 0° C., 4N aqueous sodium hydroxide (3 ml) was added thereto. The reaction suspension was stirred at room temperature for 3 hours. 5N hydrochloric acid was added to the reaction mixture to a pH of 5, and ethyl acetate and water were added to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a light-yellow solid (280 mg). Physical properties: m/z[M+H]+ 508.3
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:16][CH:17]1[C:50](=[O:51])[N:19]2[C:20]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:21]([CH2:24][S:25]/[CH:26]=[CH:27]\[C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:22][S:23][C@H:18]12.C[Si](NC(=O)N[Si](C)(C)C)(C)C.C(OCC)(=O)C>O1CCCC1.O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([NH:16][CH:17]2[C:50](=[O:51])[N:19]3[C:20]([C:34]([O:36][CH:37]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[O:35])=[C:21]([CH2:24][S:25]/[CH:26]=[CH:27]\[C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[CH2:22][S:23][C@H:18]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS/C=C\c3cccnc3)CS[C@H]12
Agent: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS/C=C\c3cccnc3)CS[C@H]12)c1csc(NC=O)n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) (1.06 g) was added to the mixture at 0° C. The mixture was stirred for 30 minutes at the same temperature to give an activated acid solution. On the other hand, to the suspension of benzhydryl 7-amino-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (2.38 g) in tetrahydrofuran (30 ml) was added bis(trimethylsilyl)urea (2.8 g) at ambient temperature. The mixture was stirred at 48° C. for 30 minutes to give a clear solution. The solution was cooled to -20° C. To this solution was added the activated acid solution obtained above at once at -20° C. The mixture was stirred at -20°~-12° C. for 40 minutes. To this mixture was added a mixture of ethyl acetate (150 ml) and water. The separated organic layer was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to give a solid. The solid was recrystallized from ethyl acetate to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (1.26 g).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22].CN(C1C=CC=CN=1)C.[C:34](O)([CH3:37])([CH3:36])[CH3:35].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.C(O)C>[C:1]([O:24][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22]
Reactant: C#CCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C#CCCCCCCCCCCCCCCCCCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
The acid (32) (6.4 g, 0.019 mol) was dissolved in dry, ethanol free, chloroform (120 ml) at room temperature under nitrogen and sequentially treated with dimethylaminopyridine (2.55 g, 0.0209 mol), tert butanol (14.09 g, 0.19 mol), dimethylaminopyridine-trifluoroacetic acid complex (4.94 g, 0.0209 mol) and dicyclohexylcarbodiimide (4.31 g, 0.0209 mol). The resulting solution was stirred at room temperature overnight then filtered, the organic layer washed with 5% acetic acid in water, then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel (50 g). Elution with 10% ether in petrol gave the title compound (33) as white crystals (6.45 g, 86%) mp 44°-45° C.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([F:23])[CH:11]=2)=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[OH:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CC(C)=O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([F:23])[CH:11]=2)=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: Oc1ccc(F)c(NCc2cc(F)cc(-c3cccc(F)c3)c2)c1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(F)cc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[3-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenol (350 mg, 1.0 mmol, 1.0 eq) in acetone (5 mL) was added Cs2CO3 (492.5 mg, 1.5 mmol, 1.5 eq). The resulting mixture was stirred for 30 min at room temperature then ethyl bromoacetate (202 mg, 1.21 mmol, 1.2 eq) was added. The resulting mixture was stirred 1 h then water added and the mixture extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as an oil (385 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[C:24]([OH:29])[CH:25]=[CH:26][C:27]=1[F:28].C(=O)([O-])O.[Na+]>C(Cl)(=O)C(Cl)=O.O1CCCC1.O>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[C:24]([OH:29])[CH:25]=[CH:26][C:27]=1[F:28])=[O:6]
Reactant: Nc1cc(O)ccc1F
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cc(O)ccc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (4.42 g, 20 mmol) produced in Example C62(ii) in oxalyl chloride (10 mL) was added N,N-dimethylformamide (100 μL), and the mixture was stirred at room temperature for 1 hr, and concentrated to dryness under reduced pressure. This was dissolved in tetrahydrofuran (10 mL), and the solution was added dropwise with vigorous stirring to a two-layer mixture of a solution of 3-amino-4-fluorophenol (2.54 g, 20 mmol) in tetrahydrofuran (10 mL) and a solution (10 mL) of sodium hydrogen carbonate (2.70 g, 30 mmol) in water under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50) to give the title compound (6.50 g, 98%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12](OC)[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[CH:4][CH:3]=1.[CH3:31][S-:32].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][S:32][CH3:31])[C:26]=2[Cl:27])=[O:21])=[CH:6][CH:7]=1
Reactant: C[S-]
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cc2)c1NC(=O)c1scc(CCl)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCc1csc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.52 g, 1.1 mmol) in DMF (12 mL) was added sodium thiomethoxide (0.39 g, 5.5 mmol) and the reaction mixture stirred at ambient temperature. After 16 hours, the mixture was poured into water (100 mL) and extracted with ethyl acetate (2×80 mL). The combined organics were washed with water (2×80 mL), 1M hydrochloric acid (2×80 mL) and brine (80 mL), dried over MgSO4 and concentrated of all volatiles in vacuo. Purification of the resulting solid by flash chromatography on silica gel afforded 0.36 g (68% yield) of N-(4-chlorophenyl)-2-[((3-chloro-4-((methylthio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a pale yellow solid; NMR (DMSO-d6) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 3.7 (s, 2), 2.0 (s, 3) ppm.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C)C=O.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1>O>[N+:22]([C:21]1[C:16]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)([O-:24])=[O:23]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.2 %

Procedure:
3.6 g (150 mmol) of sodium hydride were added, a little at a time, to a mixture of 12 g (128 mmol) of phenol and 100 ml of dimethylformamide. After the evolution of gas had ceased, the resulting mixture was treated with 18 g (114 mmol) of 2-chloro-3-nitropyridine. After the reaction mixture had been stirred at room temperature (approximately 25° C.) for 3 hours, it was treated with water. Following extraction with tert-butyl methyl ether, washing and drying the organic phase and removal of the solvent under reduced pressure, the product crystallized out. It was purified further by stirring with tert-butyl methyl ether/n-pentane. This gave 6.6 g (27%) of the title compound. A further 3.0 g (12%) of the title compound were obtained from the mother liquor.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][CH2:25][C:26](Cl)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][CH2:25][C:26]1[S:38][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(CCC(=O)Cl)c(OC)c1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Product: COc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)c(OC)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg; 1 mmol), TEA (0.153 ml; 1.1 mmol), 2,4-dimethoxyphenylpropionylchloride (228 mg, 1.1 mmol) and Lawesson's reagent (606 mg; 1.5 mmol) as described in method 1; yield: 0.022 g (6.0%); MS m/z: 367.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 2.94 (t, 2H, 3J=7.9 Hz); 3.30 (t, 2H, 3J=7.9 Hz); 3.70 (s, 3H); 3.74 (s, 3H); 6.41 (dd, 1H, 4J=2.5 Hz, 3J=8.3 Hz); 6.51 (d, 1H, 4J=2.5 Hz); 7.05 (d, 1H, 3J=8.3 Hz); 7.68 (d, 1H, 3J=8.7 Hz); 7.74 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.09 (br s, 1H); 8.34 (s, 1H); HPLC (METHOD [A]): rt 12.63 min (97.6%)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][CH3:15].[N+:20]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])([O-:22])=[O:21]>O1CCCC1.O>[OH:26][CH:25]([C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[N+:20]([O-:22])=[O:21])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (6.6 ml, 47.1 mmole) in tetrahydrofuran (80 ml) at -78° C. under an argon atmosphere was added 2.5N butyllithium (17.4 ml, 43.5 mmole), and the mixture was stirred for 30 minutes. To this reaction mixture were next added a solution of ethyl propionate (4.0 ml, 39.5 mmole) in tetrahydrofuran (20 ml) and a solution of 2-nitrobenzaldehyde (4.0 g, 26.5 mmole) in tetrahydrofuran (20 ml) in this sequence, and the resulting mixture was further stirred at -78° C. for 30 minutes. To the reaction mixture were added tetrahydrofuran (10 ml) followed by water, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(2-nitrophenyl)-2-butynoate as an oily product. After the ethyl 4-hydroxy-4-(2-nitrophenyl)-2-butynoate thus obtained was dissolved in toluene (80 ml), 4-methoxybenzylazide (13.0 g, 79.7 mmole) was added to the solution and stirred under heating at 100° C. for 3 hours. The reaction mixture was then cooled to room temperature. Precipitates were collected by filtration, washed with toluene and desiccated to give ethyl 5-[hydroxy-(2-nitrophenyl)methyl]-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (a-2: highly polar product (MP)) (2.55 g, 15.7%). Furthermore, the filtrate was concentrated and purified by silica gel column chromatography (toluene:ethyl acetate=1:1) to give a 3:1 mixture (6.09 g, 37.4%) of ethyl 4-(hydroxy-(2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (a-1: low polar product (LP)) and a compound a-2.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[F:15][C:16]([F:29])([F:28])[C:17](=[O:27])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C(O)(=O)C.N1CCCCC1>ClCCl>[F:15][C:16]([F:28])([F:29])[C:17](=[O:27])[C:18](=[CH:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:1])=[CH:11][C:10]2=[O:12])[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1cc(=O)c2cccc(C=C(C(=O)c3ccccc3)C(=O)C(F)(F)F)c2o1

Procedure:
A solution of 200 mg (1.06 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 20 ml of dichloromethane is mixed with 229.73 mg (1.06 mmol) of 4,4,4-trifluoro-1-phenyl-1,3-butanedione, 0.08 ml (1.33 mmol) of acetic acid and 0.01 ml (0.11 mmol) of piperidine and stirred under reflux with a water trap overnight. After cooling, the mixture is diluted with dichloromethane and washed with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated. 474 mg (>100% of theory) of the desired product are obtained as a yellow oil which is reacted further without purification.
Reaction SMILES: [F:1][C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:34])[N:13]([CH3:33])[C:14]([CH:23]([O:26]C4CCCCO4)[C:24]#N)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:10]=3[C:9]3[CH2:35][O:36][CH2:37][CH2:38][C:8]2=3)=[CH:4][CH:3]=1.[OH-:41].[Na+].Cl.[Si](C=[N+]=[N-])(C)(C)C.[CH3:51][OH:52]>CCOCC.C(O)C>[F:1][C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:34])[N:13]([CH3:33])[C:14]([CH:23]([OH:26])[C:24]([O:52][CH3:51])=[O:41])=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=4)[C:10]=3[C:9]3[CH2:35][O:36][CH2:37][CH2:38][C:8]2=3)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CO
Reactant: Cc1ccc(-c2c(C(C#N)OC3CCCCO3)n(C)c(=O)c3c2c2c(n3Cc3ccc(F)cc3)CCOC2)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2c3c(n(Cc4ccc(F)cc4)c2c(=O)n1C)CCOC3
Temperature: 140 °C
Reaction time: 18 h
Yield: 16.89 %

Procedure:
A 6 mL microwave vial was charged with 2-(5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridin-8-yl)-2-((tetrahydro-2H-pyran-2-yl)oxy)acetonitrile (170 mg, 0.314 mmol), Ethanol (5 ml) and 20% NaOH (2.54 ml, 14.60 mmol). The reaction vessel was sealed and heated in a 140° C. oil bath. After 18 h, the reaction mixture was cooled in an ice bath and conc HCl was added until pH <2. The residue was suspended in a mixture of MeOH (2 mL) and Et2O (2 mL), cooled to 0° C. and treated dropwise with TMS diazomethane (0.628 ml, 1.256 mmol). The reaction mixture was concentrated in vacuo and purified by ISCO (0-50% EtOAc-hexanes) to afford methyl 2-(5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridin-8-yl)-2-hydroxyacetate (26 mg, 0.053 mmol, 16.89% yield) as a white solid. LCMS (m/z) ES+=491 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][NH:11][C:10]2=[S:20])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:23](I)[CH3:24]>>[CH2:23]([S:20][C:10]1[N:9]([CH2:8][C:7]2[CH:21]=[CH:22][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:11]=1)[CH3:24]
Reactant: O=[N+]([O-])c1ccc(Cn2c(-c3ccccc3)n[nH]c2=S)cc1
Reactant: CCI
Product: CCSc1nnc(-c2ccccc2)n1Cc1ccc([N+](=O)[O-])cc1
Yield: 91 %

Procedure:
Reaction of 2,4-dihydro-4-(4-nitrobenzyl)-5-phenyl-3H-1,2,4-triazole-3-thione with ethyl iodide according to the procedure of Example 6, Part B, gave a 91% yield of the desired product as a solid, mp 107.5°-108.5° C., homogeneous by TLC in 97:3 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 341 (M+1)+.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[CH3:14][Mg]Cl.O>[Ni+2].ClC(Cl)(CP(C1C=CC=CC=1)C1C=CC=CC=1)CP(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O1CCCC1>[CH3:13][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[C:11]([F:12])[C:2]=2[CH3:14])[N:7]=1
Reactant: Cc1ccc2c(Br)c(F)ccc2n1
Reactant: C[Mg]Cl
Agent: [Ni+2]
Agent: ClC(Cl)(CP(c1ccccc1)c1ccccc1)CP(c1ccccc1)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc2c(C)c(F)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Under a nitrogen atmosphere, 28.0 g (0.05 mole) of dichloro[1,3-bis(diphenylphosphino)propane] nickel (II) catalyst (prepared by the method of G. R. Van Hecke and W. DeW. Horrocks, Inorganic Chemistry, 5, 1968 (1966), incorporated herein by reference) was added to a solution of 240 g (1.0 mole) of 5-bromo-6-fluoro-2-methylquinoline in 3.8 liters of toluene. 440 ml (1.4 mole) of 3.17 molar methylmagnesium chloride in tetrahydrofuran was added rapidly to the above mixture, the resulting exotherm being controlled with an ice bath. The reaction was allowed to stir at room temperature overnight. The reaction was treated with 1 liter of water to destroy the excess Grignard reagent, and the organic layer and aqueous layers were then separated. The organic layer was extracted twice with 1 liter portions of 3N hydrochloric acid. The acid extracts were combined, extracted twice with 1 liter portions of methylene chloride, and made basic (pH>9) with ammonium hydroxide and ice. The product was collected as a tan solid (156.4 g, 0.894 mole). This material was recrystallized from 1 liter of hexane to give 77.1 g (0.44 mole) of 2,5-dimethyl-6-fluoroquinoline which was 98.7% pure as determined by gas chromatography analysis.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([N-]C(C)C)([CH3:25])[CH3:24].[Li+].C(Br)C=C>C1COCC1>[CH2:25]([C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])[CH:23]=[CH2:24]
Reactant: COC(=O)C(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(C(=O)OC)(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of dimethyl 2-(4-phenoxyphenyl)malonate (2.56 g, 8.54 mmol) in dry THF (50 mL) was cooled to −78° C. and then lithium diisopropylamide (4.7 mL of a 2M solution in ThF, 9.8 mmol) was added. The reaction was stirred at −78° C. for 1 hour and then allyl bromide (11.4 mg, 9.4 mmol) was added. The reaction was stirred at −78° C. for 3 hours and then allowed to warm to room temperature and heated in a 75° C. oil bath until the reaction was shown to be complete by TLC. The reaction was cooled to room temperature and quenched with 1N HCl. Extraction with ether and drying of the ether extracts (MgSO4) gave crude product. Purification by filtration through silica gel 60 (70-230 mesh) using EtOAc, followed by HPLC (porasil) using 11% EtOAc/hexanes gave 1.8 g of dimethyl 2-(2-propenyl)-2-(4-phenoxyphenyl)malonate as a viscous oil: 1H NMR (200 mHz, CDCl3) δ 7.4-6.85 (9H, m), 5.75 (1H, m), 5.05 (2H, m), 3.75 (6H, s), 3.1 (2H, d).