Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH2:49]([NH:51][CH2:52][C:53]([OH:55])=[O:54])[CH3:50]>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[CH2:49]([N:51]([C:18](=[O:20])[C:15]1[CH:14]=[CH:13][C:12]([CH:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:17][CH:16]=1)[CH2:52][C:53]([OH:55])=[O:54])[CH3:50]
Reactant: CCNCC(=O)O
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC(=O)O)C(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 79.2 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (100 mg, 0.236 mmol) obtained in Example 50 were added triethylamine (80 μl, 0.566 mmol), 4-dimethylaminopyridine (14 mg, 0.118 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg, 0.283 mmol) and ethyl glycine hydrochloride (40 mg, 0.283 mmol). The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give the title compound (95 mg, 0.187 mmol, 79%) as a colorless amorphous substance.
Reaction SMILES: [CH:1](=[N:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:14]([CH2:17]O)[CH2:15][S:16][C@H:11]12)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].P(Cl)(Cl)(Cl)(Cl)[Cl:38].N1C=CC=CC=1>C(Cl)Cl>[CH:1](=[N:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:14]([CH2:17][Cl:38])[CH2:15][S:16][C@H:11]12)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CO)CS[C@@H]2C(N=Cc3ccccc3O)C(=O)N12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(N=Cc3ccccc3O)C(=O)N12
Temperature: -30 °C
Yield: 85.9 %

Procedure:
Benzhydryl 7-salicylideneamino-3-hydroxymethyl-3-cephem-4-carboxylate (1.01 g) was dissolved in methylene chloride (10 ml) and cooled to -30° C. To this solution was added phosphorus pentachloride (0.46 g), followed by addition of pyridine (0.18 ml). The reaction mixture was stirred for an hour at -30° to -20° C. and poured into ice-water. The separated organic layer was washed with water and an aqueous sodium chloride, followed by drying over magnesium sulfate. The solvent was evaporated in vacuo to give benzhydryl 7-salicylideneamino-3-chloromethyl-3-cephem-4-carboxylate (0.9 g).
Reaction SMILES: C(C1OC=CC=1)(=[O:3])C.N([O-])=O.[Na+].[C:13]([O-:24])(=[O:23])[C:14]1C(=[CH:19][CH:20]=[CH:21][CH:22]=1)C([O-])=O.[Na+].[Na+].N([O-])=O.[OH2:30]>Cl>[O:30]1[CH:19]=[CH:20][CH:21]=[C:22]1[C:14](=[O:3])[C:13]([OH:24])=[O:23]
Reactant: O
Reactant: CC(=O)c1ccco1
Reactant: O=C([O-])c1ccccc1C(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=C(O)C(=O)c1ccco1
Yield: 64.3 %

Procedure:
2-Acetylfuran (22 g) in 6N hydrochloric acid (200 ml) at 65° was treated with a solution of sodium nitrite (35 g) in water (100 ml) over 95 minutes. A 1.3M solution of disodium phthalate (230 ml) was added over 5 minutes whilst a solution of sodium nitrite (28 g) in water (70 ml) was being added over 85 minutes. One hour after the end of the addition of the nitrite the solution was cooled and acidified to pH 1.4 with hydrochloric acid and the precipitated phthalic acid filtered off. The solution was next adjusted to pH 3.5 and extracted with methylene chloride (2 × 100 ml) to remove unreacted 2-acetylfuran (1.8 g; 8%), then adjusted to pH 2.8 and extracted with ethyl acetate (4 × 100 ml) to remove furoic acid and phthalic acid (8.6 g) and finally adjusted to pH 0.2 and extracted with ethyl acetate (5 × 100 ml). Evaporation of the ethyl acetate gave 18 g (64.3%) of fur-2-ylglyoxylic acid m.p. 81°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:21](OC(C)(C)C)(=[O:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C(OCC)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH2:9][C:21](=[O:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Reactant: CC(=O)c1cccc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Under an atmosphere of nitrogen, a solution of 3′-chloroacetophenone (1.015 mL, 7.82 mmol) in anhydrous diethyl ether (50 mL) was allowed to cool to −78° C. for 15 minutes prior to the slow addition of a 1.0 M solution of LHMDS (8.60 mL, 8.60 mmol) in THF. The enolate formation was allowed to stir for 45 minutes at −78° C., after which di-tert-butyl oxalate (1.898 g, 9.38 mmol) was added as a single portion. The pale yellow reaction mixture was allowed to warm to RT and stir for 18 hours. The dark-green solution was then quenched with 50 mL of a 1.0 M aq. solution of HCl. The two layers were separated and the aq. layer was extracted twice more with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and the filtrate concentrated under reduced pressure to afford an orange oil. The crude reaction mixture was purified by silica gel chromatography (40 g REDISEP® column, eluting with a gradient from 100% hexanes to 80:20 hexanes:EtOAc solution). Fractions containing the product were combined and evaporated to afford Intermediate A129A (2.17 g, 98%) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.94-7.99 (1H, m), 7.86 (1H, dt, J=7.78, 1.38 Hz), 7.58 (1H, ddd, J=7.97, 2.20, 1.13 Hz), 7.43-7.49 (1H, m), 6.94-6.99 (1H, m), 1.58-1.63 (9H, m).
Reaction SMILES: [CH2:1]([C@H:3]1[NH:8][CH2:7][C@@H:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[O:5][CH2:4]1)[CH3:2].Cl[C:19]1[N:24]=[CH:23][CH:22]=[C:21]([Cl:25])[N:20]=1.CC[N:28](C(C)C)C(C)C>CC#N.O>[NH2:28][C:19]1[N:24]=[C:23]([N:8]2[C@H:3]([CH2:1][CH3:2])[CH2:4][O:5][C@H:6]([C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:10])[CH2:7]2)[CH:22]=[C:21]([Cl:25])[N:20]=1
Reactant: CC[C@@H]1CO[C@H](C(=O)Nc2ccccc2)CN1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ccnc(Cl)n1
Solvent: O
Solvent: CC#N
Product: CC[C@@H]1CO[C@H](C(=O)Nc2ccccc2)CN1c1cc(Cl)nc(N)n1
Yield: 87 %

Procedure:
(2S,5R)-5-Ethyl-N-phenyl-2-morpholinecarboxamide (0.3118 g, 1.331 mmol) and 2,6-dichloropyrimidine (0.218 g, 1.331 mmol) were added to a 20 mL microwave vessel and dissolved in CH3CN (5 mL). Hunig's base (1.162 mL, 6.65 mmol) was added, and the reaction was capped and irradiated at 150° C. for 2 hours. The reaction mixture was then diluted with H2O and extracted with EtOAc. The organic layers were combined and dried to afford the title compound (0.419 g). LC-MS (ES) m/z=362 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][NH2:21]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][NH:21][C:11]([C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=1)=[O:13]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1

Procedure:
Using preparation method 1, 4-phenylbenzoic acid (125 mg, 0.63 mmol) was reacted with 3,4-dichlorobenzylamine (123 mg, 0.7 mmol). The product was purified by flash chromatography on SiO2 using CH2Cl2/hexanes 50:50 then CH2Cl2 100%. White crystals were obtained (210 mg, 94%). NMR 1H (ppm, CDCl3): 7.87-7.82 (m, 2H), 7.67-7.56 (m, 4H), 7.48-7.36 (m, 5H), 7.19 (tt, J3=7.8 Hz, J4=2.1 Hz, 1H), 6.51 (br. s, 1H), 4.61 (m, 2).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[C:12]([NH:20][C:21]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOCC
Product: CNC(=O)c1ccccc1NC(=S)NC(=O)c1ccccc1
Yield: 87.9 %

Procedure:
To a stirred mixture of 12 g of 2-amino-N-methylbenzamide and 200 ml of ether was added dropwise, a solution of 13.1 g of benzoyl isothiocyanate in 100 ml of ether over 30 minutes. The solid was collected, giving 22 g of the desired product as cream-colored crystals, mp 203°-205° C. (dec.).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][CH2:13][CH2:14][OH:15].[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:9][C:4]1[C:3]([NH:12][CH2:13][CH2:14][OH:15])=[C:2]([F:1])[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1NCCO
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(F)c(F)c1NCCO

Procedure:
To a solution of 2-[(2,3-difluoro-6-nitrophenyl)amino]ethanol (3.8 g, 17.4 mmol) in 70 ml of ethyl acetate and 30 ml of ethanol is added 10% Pd/C (380 mg). The reaction is shaken under 50 PSI of hydrogen for 3 hours. The pressure is periodically adjusted to 50 PSI. The reaction is filtered through celite, rinsed with ethanol and concentrated. The resulting material is used without further purification in the next step. 1H NMR (400 MHz, CDCl3) δ ppm 3.17-3.27 (m, 2H) 3.68-3.78 (m, 2H) 6.38 (ddd, J=8.89, 4.69, 2.05 Hz, 1H) 6.61-6.70 (m, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[CH2:12]Cl)[CH3:2].[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[CH2:16]([O:15][P:14]([CH2:12][C:5]1[CH:6]=[C:7]([CH:8]=[O:9])[CH:10]=[CH:11][C:4]=1[O:3][CH2:1][CH3:2])(=[O:21])[O:18][CH2:19][CH3:20])[CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: CCOc1ccc(C=O)cc1CCl
Product: CCOc1ccc(C=O)cc1CP(=O)(OCC)OCC

Procedure:
4-Ethoxy-3-chloromethylbenzaldehyde and triethyl phosphite were added together in a 1:1 ratio and heated until no more gas evolved. The reaction solution was then vacuum distilled to give the desired product. bp 170°-171° C. at 0.75mm Hg.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])[C:3](=[O:5])[CH3:4].[I-].[CH3:17][S+](C)(C)=O.[H-].[Na+]>>[CH3:1][C:2]1([C:3](=[O:5])[CH3:4])[CH2:17][CH:6]1[CH2:7][CH:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14]
Reactant: CC(=O)C(C)=CCC1CC=C(C)C1(C)C
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: CC(=O)C1(C)CC1CC1CC=C(C)C1(C)C
Yield: 44.6 %

Procedure:
11.3 g (55 mmol) of 3-methyl-5-(2,2,3-trimethylcyclopent-3-enyl)-pent-3-en-2-one was cyclopropanated with 14.1 g (63 mmol) of trimethylsulfoxonium iodide and 3.08 g (64 mmol) of 50% oil suspension of sodium hydride according to Example 11a giving 5.4 g (45% yield) of 1-[1-methyl-2-(2,2,3-trimethylcyclopent-3-enylmethyl)cyclopropyl]ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:29])[CH:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=3)=[CH:17][CH:16]=2)[CH2:12][CH:13]=C)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CC(C)=[O:32].O>O=[Os](=O)(=O)=O>[C:27]([C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH:11]([CH2:12][CH:13]=[O:32])[C:10]([NH:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[O:29])=[CH:16][CH:17]=2)[CH:26]=[CH:25][CH:24]=1)#[N:28]
Reactant: CC(C)=O
Reactant: C=CCC(C(=O)Nc1cc(Cl)cc(Cl)c1)c1ccc(-c2cccc(C#N)c2)cc1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: N#Cc1cccc(-c2ccc(C(CC=O)C(=O)Nc3cc(Cl)cc(Cl)c3)cc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 44 %

Procedure:
To a solution of 2-(3′-cyano-biphenyl-4-yl)-pent-4-enoic acid (3,5-dichloro-phenyl)-amide (680 mg, 1.6 mmol) in 9 mL of acetone/H2O (2:1 v/v) was added OsO4 (4% in H2O, 100 L, 1 mmol %) and NaIO4 (860 mg, 4.0 mmol, 2.5 eq). The reaction mixture was stirred at r.t. for 6 h. The mixture was then partitioned between CH2Cl2 (20 mL) and 10% NaHCO3 (20 mL) and the organic layer separated. The aqueous layer was extracted with CH2Cl2 (10 mL×3) and the combined organic layer was washed with saturated brine (10 mL), dried (Na2SO4), and concentrated. Chromatography on silica gel (20% EtOAc/hexanes) gave 2-(3′-cyano-biphenyl-4-yl)-N-(3,5-dichloro-phenyl)-4-oxobutyramide as a light yellow oil (300 mg, 44%). MS(ESI): 423.0 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C1COCC1.[BH4-].[Na+].Cl>CCOC(C)=O.CO>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: O=Cc1cccc(-c2ccc(N3CCOCC3)cc2)c1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccc(N3CCOCC3)cc2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
2-Fluoro-4′-(morpholin-4-yl)biphenyl-3-carboaldehyde (288 mg) was mixed with THF (3 ml), and NaBH4 (40 mg) was added thereto. MeOH (3 ml) was added to the reaction mixture dropwise, followed by stirring at room temperature for 30 minutes. EtOAc and 1 M hydrochloric acid were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [2-fluoro-4′-(morpholin-4-yl)biphenyl-3-yl]methanol (259 mg).
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:31])[C:10]([C:26]([O:28]CC)=[O:27])=[CH:11][N:12]3[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])=[C:7]([CH3:32])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O1CCOCC1>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:31])[C:10]([C:26]([OH:28])=[O:27])=[CH:11][N:12]3[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])=[C:7]([CH3:32])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC3)cc(C)c2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3c(C)cc(N4CCC4)nc32)c(OC)c1
Temperature: 60 °C

Procedure:
A solution of EXAMPLE 18A (0.320 g) in 1,4-dioxane (7.3 mL) was treated with lithium hydroxide monohydrate (0.0919° g), heated at 60° C. for 18 hours then cooled, poured into 1M HCl, and filtered to provide the desired product.
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].[F:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:26]2[CH:25]=[CH:24][N:23]=[C:22]([F:21])[CH:27]=2)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1ccnc(F)c1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccnc(F)c3)ccn2c1=O
Yield: 89.3 %

Procedure:
Methyl 1-cyclopropyl-8-(2-fluoro-pyridin-4-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 2-fluoro-pyridin-4-yl-boronic acid (72 mg, 0.51 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (107 mg, 89%). ESI-MS m/z: 353 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3F)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:20][CH2:21][O:22][C:5]2=[CH:4][CH:3]=1.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)C.CN(C=O)C>[ClH:1].[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:20][CH2:21][O:22][C:5]2=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: Fc1cccc2ncnc(Nc3c(Cl)ccc4c3OCO4)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Clc1ccc2c(c1Nc1ncnc3cccc(Oc4ccccc4)c13)OCO2
Temperature: 90 °C
Yield: 34.8 %

Procedure:
A mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-5-fluoroquinazoline (0.213 g), phenol (0.45 g), potassium carbonate (0.828 g) and DMF (3 ml) was stirred and heated to 90° C. for 30 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a 2N aqueous sodium hydroxide solution. The organic layer was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 99:1 mixture of methylene chloride and methanol as eluent. The material so obtained was dissolved in diethyl ether and a 6M solution of hydrogen chloride in diethyl ether (1 equivalent) was added. The resultant solid was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.05 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 6.18 (s, 2H), 6.95 (d, 1H), 7.05 (d, 1H), 7.1 (d, 1H), 7.35 (d, 1H), 7.42 (m, 1H), 7.52–7.62 (m, 3H), 8.0 (m, 1H), 9.0 (s, 1H); Mass Spectrum: M+H+ 392 and 394.
Reaction SMILES: [CH2:1]([C:3]1([CH3:19])[NH:14][C:13]([CH2:16][CH3:17])([CH3:15])[CH2:12][C:5]2([NH:9][C:8](=[O:10])[NH:7][C:6]2=[O:11])[CH:4]1[CH3:18])[CH3:2].[O:20]1[CH2:44][CH:21]1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](C2C=CC(OCC3OC3)=CC=2)([CH3:32])[CH3:31])=[CH:26][CH:25]=1.[OH-:45].[K+]>CN(C)C=O.CO>[OH:45][CH:21]([CH2:44][N:7]1[C:6](=[O:11])[C:5]2([CH2:12][C:13]([CH2:16][CH3:17])([CH3:15])[NH:14][C:3]([CH2:1][CH3:2])([CH3:19])[CH:4]2[CH3:18])[NH:9][C:8]1=[O:10])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH:21]([OH:20])[CH2:44][N:7]3[C:6](=[O:11])[C:5]4([CH2:12][C:13]([CH3:15])([CH2:16][CH3:17])[NH:14][C:3]([CH3:19])([CH2:1][CH3:2])[CH:4]4[CH3:18])[NH:9][C:8]3=[O:10])=[CH:25][CH:26]=2)([CH3:31])[CH3:32])=[CH:26][CH:25]=1
Reactant: CCC1(C)CC2(NC(=O)NC2=O)C(C)C(C)(CC)N1
Reactant: [OH-]
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCC1(C)CC2(NC(=O)N(CC(O)COc3ccc(C(C)(C)c4ccc(OCC(O)CN5C(=O)NC6(CC(C)(CC)NC(C)(CC)C6C)C5=O)cc4)cc3)C2=O)C(C)C(C)(CC)N1

Procedure:
4.1 g of 7,9-diethyl-6,7,9-trimethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione, 2.5 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane and 0.05 g of potassium hydroxide were reacted in a mixture of 150 ml of N,N-dimethylformamide and 20 ml of methanol, following substantially the same procedure as described in Example 1. The desired Compound No. 104 was obtained in the form of a white powder, showing an Rf value of 0.66 on thin-layer chromatography on silica gel using a 8:1:1:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine as developing solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:37][CH2:36]1>C1COCC1>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:16](=[O:18])[C:15]#[C:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:13][CH:12]=3)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CN1CCN(Cc2ccc(NC(=O)C#Cc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
A solution of 0.26 g (1 mmol) of (4′-chlorobiphenyl-4-yl)propynoic acid and 0.12 mL (1.1 mmol) of N-methylmorpholine in 20 mL of absolute THF is combined at −15° C. with 0.14 mL (1.1 mmol) of isobutyl chloroformate and stirred for ten minutes. Then 0.226 g (1.1 mmol) of 4-(4-methylpiperazin-1-ylmethyl)phenylamine dissolved in 7 mL of THF is added and the reaction mixture is stirred for 2 hours until ambient temperature is reached. The reaction mixture is evaporated down and the residue is dissolved in dichloromethane. The organic phase is washed twice with water and then dried over sodium sulfate. The desiccant is filtered off and the solvent is distilled off. The residue is triturated with ether and suction filtered. The purification is carried out by column chromatography on silica gel (dichloromethane/methanol/ammonia (90/10/0.1)). Yield: 60 mg (14% of theory); melting point: 182° C.-185° C.; C27H26ClN3O (M=443.97); calc.: molecular ion peak (M+H)+: 444/446 (Cl); found: molecular ion peak (M+H)+: 444/446 (Cl); Rf value: 0.4 (silica gel, dichloromethane/methanolic ammonia (90:10:0.1)).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:19])[C:5]1([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[C:20](Cl)(Cl)=[O:21].C(N(CC)CC)C.Cl.[C:32]([C:34]1[CH:46]=[CH:45][C:37]([CH2:38][N:39]2[C:43]([NH2:44])=[CH:42][N:41]=[CH:40]2)=[CH:36][CH:35]=1)#[N:33]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:2][O:3][C:4](=[O:19])[C:5]1([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:6][CH2:7][N:8]([C:20]([NH:44][C:43]2[N:39]([CH2:38][C:37]3[CH:45]=[CH:46][C:34]([C:32]#[N:33])=[CH:35][CH:36]=3)[CH:40]=[N:41][CH:42]=2)=[O:21])[CH2:9][CH2:10]1
Reactant: COC(=O)C1(Cc2ccccc2C)CCNCC1
Reactant: N#Cc1ccc(Cn2cncc2N)cc1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1(Cc2ccccc2C)CCN(C(=O)Nc2cncn2Cc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4-(2-methylbenzyl)-isonipecotic acid methyl ester hydrochloride (50 mg, 0.176 mmol) in toluene (2 ml) was added phosgene (0.912 ml of a 1.93M solution in toluene, 1.76 mmol) and triethylamine (0.074 ml, 0.528 mmol) and the mixture stirred for 48 hrs at room temperature. The excess phosgene was removed by purging the solution with argon gas for 10 min. The suspension was added to 1-(4-cyanobenzyl)-5-amino-1H-imidazole hydrochloride (100 mg, 0.528 mmol) in CH2Cl2 (10 ml) and the mixture stirred at 50° C. for 72 hrs. The solvent was evaporated in vacuo and the residue purified by preparative HPLC (C18, 95:5 to 5:95 water: acetonitrile containing 0.1% TFA). The residue after lyophilisation was partitioned between CH2Cl2 and saturated NaHCO3 solution. The organic extract was dried (MgSO4), and evaporated to dryness