Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[CH:22]=[N:23]O)=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]#[N:23])=[C:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Sc2cccc(C=NO)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(Sc2cccc(C#N)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 135 °C

Procedure:
3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzaldehyde oxime from the previous step was dissolved in acetic anhydride (0.500 mL) and the reaction was heated to 135° C. overnight. The reaction mixture was diluted with EtOAc then concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([Cl:16])=[O:6])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: Cc1cccc(C(=O)Cl)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 101.7 %

Procedure:
In this example 2.14 moles of 3-methyl-2-nitrobenzoic acid were refluxed with 6.43 moles (468 ml) of thionyl chloride for three hours and then allowed to stand overnight. The mixture was then again refluxed until the mixture turned a dark brown color. Excess thionyl chloride was removed by evaporation affording 434.4 g of the title product.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1.C1OCCOCCOCCOCCOCCOC1.Cl[C:35]1[N:36]=[N:37][CH:38]=[C:39]2[C:43]([CH3:44])=[C:42]([CH3:45])[N:41]([CH2:46][CH:47]=[CH2:48])[C:40]=12>O1CCCC1>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][O:13][C:35]2[N:36]=[N:37][CH:38]=[C:39]3[C:43]([CH3:44])=[C:42]([CH3:45])[N:41]([CH:46]=[CH:47][CH3:48])[C:40]=23)=[CH:10][CH:9]=1
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccc(F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=Cn1c(C)c(C)c2cnnc(OCc3ccc(F)cc3)c21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 39.3 %

Procedure:
1.62 g (0.014 mole) of potassium tert-butoxide was added to a solution of 1.02 g (0.0081 mole) of 4-fluorobenzyl alcohol and 0.12 g (0.00045 mole) of 18-crown-6 in 10 ml of tetrahydrofuran and the resulting mixture was stirred at room temperature for 25 minutes. A solution of 0.60 g (0.0027 mole) of 7-chloro-1-(2-propenyl)-2,3-dimethylpyrrolo[2,3-d]pyridazine in 5 ml of tetrahydrofuran was added dropwise to the mixture and stirred at room temperature for 10 hours. After completion of the reaction, the reaction mixture was poured into ice-water and the aqueous mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 2:3 mixture of ethyl acetate and hexane as an eluent to give 0.33 g of 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-(1-propenyl)pyrrolo[2,3-d]pyridazine (trans) as a pale yellow powder.
Reaction SMILES: [OH:1][CH:2]([C:8]1[N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:23](Br)([CH3:26])([CH3:25])[CH3:24]>C1CCCCC1.ClCCl.[Ag-]=O>[C:23]([O:1][CH:2]([C:8]1[N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)C(O)c1cc2ccccc2n1-c1ccccc1
Reactant: CC(C)(C)Br
Agent: O=[Ag-]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CCOC(=O)C(OC(C)(C)C)c1cc2ccccc2n1-c1ccccc1
Reaction time: 24 h
Yield: 33.5 %

Procedure:
A mixture of ethyl 2-hydroxy-2-(1-phenyl-1H-indol-2-yl)acetate (5b) (50 mg, 0.17 mmol), silver (I) oxide (130 mg, 0.56 mmol) and tertbutylbromide (114 μL, 1.02 mmol) in cyclohexane (4 mL) and dichloromethane (2 mL) was vigorously stirred for 24 hours. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to afford the desired ether oxide (5c) as a white solid (20 mg, 0.057 mmol, 33%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1.[OH:19]CC1C=CC2C=CC3C=CC=CC=3SC=2C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:19])[C:10]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: OCc1ccc2c(c1)Sc1ccc(F)cc1CC2
Reactant: OCc1ccc2c(c1)Sc1ccccc1C=C2
Product: O=S1c2ccc(F)cc2CCc2ccc(CO)cc21

Procedure:
Repeat the process of Example 2, substituting an equivalent quantity of 8-fluoro-3-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin for the 3-hydroxymethyldibenzo[b,f]thiepin, to obtain the title product (m.p. 181°-183° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13].Cl.[C:15](=N)(OCC)[CH3:16]>C(O)C>[CH3:15][C:16]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]=1
Reactant: Nc1ccccc1NCCCCO
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: Cc1nc2ccccc2n1CCCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
2-(4-Hydroxybutylamino)phenylamine (3.6 g) and ethyl acetimidate hydrochloride (3.7 g) was dissolved in ethanol (20 ml) and stirred at room temperature for 11/2 hours. The mixture was evaporated under vacuum and the residue partitioned between ethyl acetate (30 ml) and water (20 ml). The organic phase was separated, dried over Na2SO4, filtered and evaporated to give the title compound as a brown oil (2.8 g).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[C:11]1([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:11]1([N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:24]=2)[C:2]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CNc2ccccc2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1ccc(CN(C(=O)c2cccnc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.8 %

Procedure:
To a room temperature slurry of 1.03 g of nicotinoyl chloride hydrochloride in 20 ml of methylene chloride is added, via cannula, 2.0 g of product from Example 145 in 30 ml of methylene chloride. After 5 minutes, 2.05 g of triethylamine is added and the reaction stirred at room temperature for 72 hours. The solution is poured into saturated sodium bicarbonate and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 40% ethyl acetate/hexane) to give 2.35 g of the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][C:7]1[C:8](S(C)(=O)=O)=[N:9][CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Cl:6][C:7]1[C:8]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1cc[nH]c1
Reactant: CS(=O)(=O)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccnc1-n1cccc1
Temperature: 60 °C
Reaction time: 27 h
Yield: 63.9 %

Procedure:
A mixture of 1.0 g of pyrrole, 3.0 g of 3-chloro-2-methanesulfonylpyridine, 6.6 g of cesium carbonate and 10 ml of N,N-dimethylformamide was stirred at 60° C. for 27 hours. After the reaction mixture was allowed to cool to room temperature, water was poured and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 1.7 g of 3-chloro-2-(1H-pyrrol-1-yl)pyridine of the formula:
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].[ClH:10].[CH2:11](OC(OCC)C)[CH3:12]>C(O)C(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[ClH:10].[NH2:8][C:7]1[NH:6][C:4]([N:2]([CH3:3])[CH3:1])=[N:5][CH:11]([CH3:12])[N:9]=1
Reactant: CCOC(C)OCC
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)CO
Solvent: O
Product: CC1N=C(N)NC(N(C)C)=N1
Temperature: 10 °C
Yield: 77.6 %

Procedure:
Comparative experiment: A mixture of 250.2 g of metformin hydrochloride, 213.6 g of acetaldehyde diethyl acetal and 12.5 g of toluene-4-sulfonic acid monohydrate in 500 ml of isobutanol was heated under reflux for 40 hours. Some of the solvent was removed by distillation. The mixture was cooled to 10° C., and the white precipitate was separated off, giving 224.7 g (77.4%) of 4-amino-3,6-dihydro-2-dimethylamino-6-methyl-1,3,5-triazine hydrochloride.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][C:24]1[S:28][C:27]([C:29](=O)[CH2:30][NH:31][C:32](=O)[C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:23][C:24]1[S:28][C:27]([C:29]2[S:10][C:32]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)=[N:31][CH:30]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(C(=O)CNC(=O)c2ccc(C(F)(F)F)cc2)s1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(-c2cnc(-c3ccc(C(F)(F)F)cc3)s2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.9 %

Procedure:
To a stirred suspension of Lawesson's Reagent (2.3 g, 0.0057 mole) in approximately 40 ml of toluene was added a mixture of N-[2-(5-methylthienyl)-2-oxoethyl]-4-trifluoromethylbenzamide (3.0 g, 0.011 mole) in toluene (35 ml). After complete addition the reaction mixture was heated at reflux for approximately four hours, then was allowed to cool to room temperature and stirred for two days. The solvent was removed from the reaction mixture by evaporation under reduced pressure, leaving an oil. The oil was dissolved in a small amount of methylene chloride and purified by column chromatography on silica gel, eluting with methylene chloride, yielding 1.0 g of 5-(5-methylthien-2-yl)-2-(4-trifluoromethylphenyl)thiazole as a solid, m.p. 150°-152° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)=[N:8]2)[CH2:5][CH2:4][NH:3]1.[H-].[Na+].[C:31]([O:35][C:36]([CH:38]=C1CCCCCC1N1C(=O)C=CC(C2C(C3C=CC=CC=3)=NN3C=CC=CC=23)=N1)=[O:37])(C)(C)[CH3:32].BrCC(OCC)=O>CN(C)C=O.O>[CH2:31]([O:35][C:36]([CH2:38][N:3]1[CH2:4][CH2:5][CH:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)=[N:8]2)[C:2]1=[O:1])=[O:37])[CH3:32]
Reactant: O=C1NCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: CC(C)(C)OC(=O)C=C1CCCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCC(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1=O
Reaction time: 0.5 h
Yield: 633.2 %

Procedure:
To a solution of 3-[2-(2-oxopyrrolidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (740 mg) in N,N-dimethylformamide (5 ml) was added 60% sodium hydride in mineral oil (120 mg) at O° C. After the mixture was stirred for 30 minutes, to this was added ethyl 2-bromoacetate (0.22 ml). After the reaction mixture was stirred at 0° C. for 1 hour, it was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (CHCl3 -CHCl3 :MeOH (30:1)) to give 3-[2-(1-ethoxycarbonylmethyl-2-oxopyrrolidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.7 g) (yellow oil).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:27]1[C:31]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH2:50])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:34][CH:33]=2)=[CH:30][N:29]=[CH:28]1>CN(C=O)C>[S:27]1[C:31]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH:50][C:10](=[O:12])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:34][CH:33]=2)=[CH:30][N:29]=[CH:28]1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, 2.66 g (15.2 mmol) of N-methoxycarbonyl-(L)-valine, 5.46 g (28.5 mmol) of EDC and 2.57 g (19 mmol) of HOBT are dissolved in 42 ml of DMF. 7.9 ml (57 mmol) of TEA are added and after 20 min a solution of 4.46 g (9.5 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 2b) in 85 ml of DMF is added dropwise. After 1.5 hours, the reaction mixture is worked up analogously to Example 2c. Crystallisation from THF/ether yields the title compound: m.p: 114°-115° C.; HPLC20-100 : tRet =15.1; FAB MS (M+H)+ =626.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[CH3:19][N:20](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:21].F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.CNC>C1COCC1>[CH3:19][N:20]([CH3:21])[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:8][C:9]=2[CH:15]=1)=[O:18]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOC(=O)Cc1nc2ccc(C(=O)O)cc2[nH]1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nc2ccc(C(=O)N(C)C)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[(Ethoxycarbonyl)methyl]benzimidazole-5-carboxylic acid (1.0 equivalent) was dissolved in THF. HBTU (1.1 equivalents) and diisopropylethylamine (2.0 equivalents) were added, followed by dimethylamine (2.0 M in THF, 1.1 equivalents). The reaction was stirred at room temperature overnight then concentrated and the resulting residue was purified by silica gel chromatography (5:95 MeOH:CH2Cl2) to afford the desired compound. LC/MS m/z 276.2 (MH+), Rt 1.18 minutes.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5](N2C3C(=CC(F)=C(C4CCC(N)C4)N=3)C(=O)C(C(O)=O)=C2)=[CH:4][CH:3]=1.[CH:29]1([N:32]2[C:41]3[C:36](=[CH:37][C:38]([F:48])=[C:39]([CH:42]4[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43]4)[N:40]=3)[C:35](=[O:49])[C:34]([C:50]([OH:52])=[O:51])=[CH:33]2)[CH2:31][CH2:30]1.C(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:29]1([N:32]2[C:41]3[C:36](=[CH:37][C:38]([F:48])=[C:39]([CH:42]4[CH2:46][CH2:45][C:44](=[N:47][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:43]4)[N:40]=3)[C:35](=[O:49])[C:34]([C:50]([OH:52])=[O:51])=[CH:33]2)[CH2:30][CH2:31]1
Reactant: NC1CCC(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Reactant: NC1CCC(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Solvent: Cc1ccccc1
Solvent: O=Cc1ccccc1
Product: O=C(O)c1cn(C2CC2)c2nc(C3CCC(=Nc4ccccc4)C3)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
In a round-bottomed flask equipped with a magnetic stirring bar are placed 2 grams of (I) the product of Example 2 (Z= ##STR31## A=N, R=cyclopropyl, R3 =H, R1 =OH), 20 ml of toluene, and 1.5 ml of benzaldehyde. The system is equipped with a Dean-Stark trap containing four angstrom molecular sieves. The reaction mixture is heated at reflux for one day and cooled to room temperature. The solid imine (I) Z= ##STR32## A=N, R=cyclopropyl, R3 =H, R1 =OH) is collected by suction filtration.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[N+:18]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].CCN(CC)CC.C(OC(C)(C)C)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:8][C@H:7]([O:9][S:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)(=[O:28])=[O:29])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:17]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2cccc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 18 h

Procedure:
N-Boc-cis-4-hydroxy proline methyl ester (1.0 eq, 6.0 g) were dissolved in MeCl2 (60.0 ml) and 3-nitrobenzenesulfonyl chloride (1.06 eq; 5.747 g) was added. This clear colorless solution was cooled to 0-5° C. and the Et3N (3.0 eq., 10.19 ml) was carefully added. After 0.5 h a yellowish thin suspension was formed, which was stirred for 18 h at ambient temperature. The mixture turned then into a light brown suspension. LC-MS-analysis revealed that the reaction was complete. The reaction mixture was diluted with additional MeCl2 (100 ml) and extracted in succession with aq. 0.5 N HCl, 10% Na2CO3. The combined org. layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to yield a light brown viscous oil (10.8 g; 102%). MS (ESI): m/z=331.2 [M+H-Boc]+
Reaction SMILES: C([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=O)C.Cl[C:32]([O:34][CH2:35][CH2:36][F:37])=[O:33]>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:32]([O:34][CH2:35][CH2:36][F:37])=[O:33])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: O=C(Cl)OCCF
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(C(=O)OCCF)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 2-fluoroethyl chloroformate and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.34-7.26, 5.21, 4.70-4.58, 4.56, 4.42, 4.34, 4.10, 3.99, 3.75-3.30, 2.71, 2.47, 1.32-1.26, 1.15; IR (liq.) 2973 (s), 2347 (b), 2181 (w), 1709 (s), 1567 (s), 1553 (s), 1500 (s), 1470 (s), 1445 (s), 1426 (s), 1396 (s), 1347 (s), 1140 (s), 1103 (s), 1060 (s), cm−1HRMS (FAB) calcd for C23H29Cl2FN4O3+H 499.1679, found 499.1673. Anal. Calcd for C23H29Cl2FN4O3: C, 55.32; H, 5.85; N, 11.22. Found: C, 55.20; H, 5.91; N, 10.95.
Reaction SMILES: CC(C)=O.[CH:5]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[C:10](=[C:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][O:29][C:30]([C:32]4[CH:37]([C:38]5[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=5)[C:36]([C:45]([OH:47])=[O:46])=[C:35]([CH3:48])[NH:34][C:33]=4[CH3:49])=[O:31])[CH2:22][CH2:21]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.[N+]([O-])([O-])=O.[NH4+].[Ce]>O>[Cl:44][C:40]1[CH:39]=[C:38]([C:37]2[C:36]([C:45]([OH:47])=[O:46])=[C:35]([CH3:48])[N:34]=[C:33]([CH3:49])[C:32]=2[C:30]([O:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][C:20](=[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:15]=4[CH:14]=[CH:13][C:12]4[CH:16]=[CH:17][CH:18]=[CH:19][C:11]3=4)[CH2:25][CH2:24]2)=[O:31])[CH:43]=[CH:42][CH:41]=1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)OCCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)=C(C)N1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc(C)c(C(=O)OCCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)c(-c2cccc(Cl)c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 ml of acetone was added to 132 mg (0.21 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid mono (3-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene) piperidine-1-yl) propan-1-yl) ester. 233 mg (0.43 mmol) of cerium ammonium nitrate suspended in 5 ml of water was added and stirred at room temperature for 2 hours. After acetone was evaporated under reduced pressure, ethyl acetate was added and precipitates were taken by the filtration and dried under reduced pressure to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: Nc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
The procedure of Zahler et al. was followed with minor modification (Zahler, R.; Koster, W. H.; Slusarchyk, W. A. EP 0138407). To a solution of benzyl bromoacetate (18.0 g, 12.5 mL, 79.6 mmol) and o-fluoroaniline (8.8 g, 7.7 mL, 100 mol %), in anhydrous DMF (60 mL) was added anhydrous K2CO3 (11 g, 100 mol %), and the mixture was stirred at rt overnight. The reaction mixture was diluted with water (120 mL) and extracted with EtOAc (3×200 mL). The combined organic layer was washed with water, dried, and then concentrated. Purification by LPLC (5% EtOAc- hexane) provided 18.0 g (88%) of the title compound as a colorless oil: 1H NMR (CDCl3) δ7.39-7.35 (m, 5H), 7.03-6.97 (m, 2H), 6.72-6.67 (m, 1H), 6.59 (dt, J=8.4, J=1.2, 1H), 5.23 (s, 2H), 4.01 (s, 2H); 13C (CDCl3) δ170.59, 151.66 (d, J=240), 135.24, 128.64 (2 carbons), 128.52, 128.39 (2 carbons), 124.55 (d, J=3.5), 117.79 (d, J=7.1), 114.71 (d, J=17.7), 112.28 (d, J=3.5), 67.11, 45.54; MS (EI, m/z)259 (M+).