Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:21])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:24]=1[NH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:24]=1[N:25]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:11](=[O:21])[C:2]([CH3:1])=[C:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C(=O)CC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: Cc1c(-c2ccccc2)n(-c2cc([N+](=O)[O-])ccc2Cl)c(-c2ccccc2)cc1=O

Procedure:
To 170 ml of chlorobenzene were added 3.4 g (0.012 mole) of 2-methyl-1,5-diphenyl-1,3,5-pentanetrione, 10.4 g (0.060 mole) of 2-chloro-5-nitroaniline, 4.1 g (0.022 mole) of para-toluenesulfonic acid and 35.0 g of Molecular Sieves 5A, followed by refluxing for 2 hours. After cooling the reaction mixture, solid matter was removed from the reaction mixture, followed by addition of 200 ml of chloroform. The resultant mixture was washed first with 100 ml of 10% hydrochloric acid and then with 100 ml of a 10% aqueous solution of sodium hydroxide. The mixture was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: ethyl acetate). Upon recrystallization of the resultant crystals from a 2:1 mixed solvent of acetone and hexane, 1.9 g of 1-(2-chloro-5-nitrophenyl)-3-methyl- 2,6-diphenyl-4(1H)-pyridinone having a melting point of 277°-279° C. was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[CH3:31][C:32](=[CH2:36])[C:33](Cl)=[O:34].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:16]=[C:15]([C:33](=[O:34])[C:32]([CH3:36])=[CH2:31])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[CH3:13][N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:16]=[C:15]([C:33](=[O:34])[C:32]([CH3:36])=[CH2:31])[CH:14]=1)[C:3]([OH:2])=[O:30]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)c1cc(C(=O)O)cc(C(=O)N(C)CCC)c1
Product: C=C(C)C(=O)c1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Temperature: 60 °C

Procedure:
Dissolve N-methyl-N-propyl-5-tributylstannanyl-isophthalamic acid methyl ester (885 mg, 168 mmol), 2-methyl-acryloyl chloride (172 mg, 1.64 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol) and tricyclohexylphosphine (46 mg, 0.16 mmol)) in chloroform (15.5 mL) in a previously degassed vessel. Flush the mixture with nitrogen gas and heat the sealed mixture overnight at 60° C. Cool to room temperature and filter though a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([NH:9][CH3:10])[C:5]([NH2:8])=[CH:6][CH:7]=1.[NH:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:18]([C:20](O)=O)[CH3:19].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:26]([O:25][C:23](=[O:24])[NH:17][C@H:18]([C:20]1[N:9]([CH3:10])[C:4]2[C:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:19])([CH3:29])([CH3:28])[CH3:27]
Reactant: CNc1c(N)ccc(F)c1-c1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(-c3ccccn3)c2n1C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
A solution of 4-fluoro-N2-methyl-3-pyridin-2-yl-benzene-1,2-diamine (0.75 g, 3.44 mmol), Boc-Ala (0.72 g, 3.78 mmol), HOAt (0.52 g, 3.78 mmol) in DCM (10 mL) was cooled to 0° C. EDC (0.73 g, 3.78 mmol) was added portion wise and the resulting mixture was stirred for 1 h. The mixture was diluted with DCM (20 mL) and the organic layer was washed with citric acid, brine, dried (MgSO4) and evaporated. The resulting residue was purified by chromatography (Si—PPC, gradient 0-50% EtOAc/cyclohexane) to afford the title compound as a white solid (0.3 g, 24%). LCMS (Method J): RT 2.42 min [M+H]+ 371
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[OH:10].[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[Cl:25]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:26]([C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)(=[O:28])=[O:27])=[C:3]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[OH:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(O)c1ccccc1Cl
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Cl)cc1C(O)c1ccccc1Cl)c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To 0.9 g of (2-amino-5-chlorophenyl)(2-chlorophenyl)methanol dissolved in 4 ml of pyridine is added 0.822 g of 3,4-dichlorobenzenesulfonyl chloride, and the mixture is left for 30 minutes at room temperature. The reaction medium is taken up in ethyl acetate and washed with water, and then with 1M hydrochloric acid solution. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane, to give 0.601 g of the expected product.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C@@H:6]([O:8][C@H:9]2[CH2:25][C@:24]3([OH:26])[C@@:12]([CH:35]=[O:36])([CH:13]4[CH:21]([CH2:22][CH2:23]3)[C@:20]3([OH:27])[C@@:16]([CH3:34])([C@@H:17]([C:28]5[CH2:33][O:32][C:30](=[O:31])[CH:29]=5)[CH2:18][CH2:19]3)[CH2:15][CH2:14]4)[CH2:11][CH2:10]2)[CH2:5][CH:4]2[O:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([CH3:40])[O:39][C@H:3]12.[BH4-].[Na+].S(=O)(=O)(O)O>O1CCOCC1>[CH3:1][CH:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[CH2:25][C@:24]3([OH:26])[C@@:12]([CH2:35][OH:36])([CH:13]4[CH:21]([CH2:22][CH2:23]3)[C@:20]3([OH:27])[C@@:16]([CH3:34])([C@@H:17]([C:28]5[CH2:33][O:32][C:30](=[O:31])[CH:29]=5)[CH2:18][CH2:19]3)[CH2:15][CH2:14]4)[CH2:11][CH2:10]2)[CH2:5][CH:4]2[O:37][C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([CH3:40])[O:39][C@H:3]12
Reactant: CC1O[C@@H](O[C@@H]2CC[C@]3(C=O)C4CC[C@]5(C)[C@@H](C6=CC(=O)OC6)CC[C@]5(O)C4CC[C@]3(O)C2)CC2OC(C)(c3ccccc3)O[C@H]12
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1O[C@@H](O[C@H]2CC[C@]3(CO)C4CC[C@]5(C)[C@@H](C6=CC(=O)OC6)CC[C@]5(O)C4CC[C@]3(O)C2)CC2OC(C)(c3ccccc3)O[C@H]12
Reaction time: 1 h

Procedure:
1.5 g. acetophenone-helveticoside are dissolved in 20 ml. of 80% aqueous dioxane and treated dropwise over a period of 1 hour with a solution of 0.35 g. sodium borohydride in 20 ml. of 75% dioxane. The reaction mixture is stirred for 1 hour, after which no more acetophenone-helveticoside can be detected. The solution is adjusted to pH 7 with dilute sulfuric acid, and the dioxane is removed under reduced pressure in a rotating evaporator. The aqueous phase is repeatedly extracted with chloroform. The combined chloroform extracts are dried over anhydrous sodium sulfate and evaporated. The residue is purified chromatographically over silica gel, using chloroform as solvent. Yield: 750 mg. acetophenone-helveticosol, melting point: 154°-164°C[αD20 ](C = 1, chloroform): ±0°.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.[CH3:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]>C1COCC1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:13]([OH:18])([CH2:14][CH2:15][CH2:16][CH3:17])[CH3:12]
Reactant: Brc1cccs1
Reactant: CCCCC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(C)(O)c1cccs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromothiophene (24.3 g, 0.15 mol) in dry THF (120 mL) was cooled to −78° C. under nitrogen. A solution of n-BuLi (2.5 M, 66.0 mL, 0.17 mol) was then added slowly, and the resulting mixture was stirred at −78° C. for 2 hours, before 2-hexanone (18.1 g, 0.18 mol) was added slowly. This mixture was stirred at −78° C. for an additional 1 hour, and then allowed to warm to room temperature, and stirred at room temperature overnight. Most of the solvent was removed in vacuo, and the residue was subjected to flash column chromatography on silica gel with a hexane:EtOAc (4:1, slowly up to 3:1, v/v) mixture, leading to a slightly yellow oil as the product (21.4 g, 77.7%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]1([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[C:4]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: c1ccc(C2CNc3ccccc32)cc1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)N1CC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
A solution of 2.0 g of diketene in 10 ml of dry benzene was added dropwise at 10°-15° C to a solution of 3.84 g of 3-phenylindolin in 35 ml of dry benzene. The solution was then stirred at room temperature for 90 minutes and the volatile components were removed in vacuo. The residue was recrystallized from ether to give 4.2 g of N-acetoacetyl-3-phenylindoline. A further recrystallization from ethanol gave a purer product having a melting point of 88°-9° C.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C12COCC1=CC=CC=2.[N+]([O-])(O)=O.O>C(O)(=O)C>[CH:9](=[O:10])[C:1]1[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:7]=[O:8]
Reactant: OCc1ccccc1CO
Agent: c1ccc2c(c1)COC2
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccccc1C=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
In a 1000-ml three-neck flask equipped with a thermometer, a reflux condenser and a stirrer were placed 13.3 g of o-xylylene glycol, 36.7 g of o-xylylene oxide, 85.1 g of 60% by weight nitric acid, 165.5 g of water, and 199.5 g of acetic acid. The mixture was raised in temperature to 70° C. on an oil bath and was stirred under these conditions for 1 hour. After cooling, the reaction mixture was analyzed by gas chromatography to find that the raw material o-xylylene glycol was completely absent and that phthalaldehyde was formed in a yield of 84%. The obtained reaction mixture was extracted with two portions of toluene, the organic layer was distilled and thereby yielded phthalaldehyde in a yield of 67% on the basis of o-xylylene glycol. Gas chromatographic analysis revealed that phthalaldehyde had a purity of 98.8%. In addition, phthalide was formed in a yield of 11%.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:14]([OH:17])[C:15]#[CH:16].C(NC(C)C)(C)C>C(#N)C.[Cu]I>[N:7]1([CH2:6][C:5]2[CH:12]=[CH:13][C:2]([C:16]#[C:15][CH2:14][OH:17])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Brc1ccc(CN2CCCC2)cc1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: OCC#Cc1ccc(CN2CCCC2)cc1
Temperature: 60 °C

Procedure:
A mixture of 4.8 g (20.0 mmol) 1-(4-bromo-benzyl)-pyrrolidine, 1.75 mL (30.0 mmol) propargylalcohol, 2.31 g (2.0 mmol) tetrakis-triphenylphosphane-palladium, 381 mg (2.0 mmol) CuI and 7.07 mL diisopropylamine in 100 mL acetonitrile is heated for 14 h at 60° C. under an argon atmosphere. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5](=[CH:26][CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[N:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].[Cl:36][C:37]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:38]=1[CH:39]=O.N1C=CC=CC=1.N1C=CC=CC1>C(#N)C>[Cl:36][C:37]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:38]=1[C:39]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1
Reactant: COC(=O)C(=CC=Cc1ccc(Cl)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: C1=CCNC=C1
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
The residue of 3-methoxycarbonyl-6-(4-chlorophenyl)-1,1,1-triphenyl-2-aza-1λ5-phosphahexa-1,3,5-triene (10.2 mmol) from Step D was dissolved in acetonitrile (40 mL) and 2,4-dichlorobenzaldehyde (1.78 g, 10.2 mmol) was added. The reaction was heated to 60° C. under a condenser (left open to the air) for 20 h. HPLC/MS indicated a mixture of the desired title pyridine and dihydropyridine intermediate 394 (M+1), 396 (M+3), Rt=4.75 min). The reaction was heated a further 4 h and was then concentrated. The residue was purified by flash column chromatography on silica gel eluted with 0 to 20% ethyl acetate in hexanes to afford methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-2-carboxylate. HPLC/MS: 392 (M+1), 394 (M+3); Rt=4.16 min. 1HNMR (CDCl3): δ 4.039 (s, 3H), 7.09 (br d, J=8.5 Hz, 2H), 7.26 (br d, J=8.4 Hz, 2H), 7.28 (d, J=2 Hz, 1H), 7.30 (dd, J=2.0 and 8.3 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 8.26 (d, J=8.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:24][C:25](=[O:40])[CH2:26][N:27]2[C:35]3[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=3[C:29]([C:36]([F:39])([F:38])[F:37])=[N:28]2)C2N(C3C=CC(OC)=CC=3)C=CN=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51](C(N)CC3C=C(F)C=C(F)C=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1.FC(F)(F)C1C2CCCCC=2N(CC(O)=O)N=1>>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]2[O:50][C:51]([CH:10]([NH:24][C:25](=[O:40])[CH2:26][N:27]3[C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=4[C:29]([C:36]([F:38])([F:39])[F:37])=[N:28]3)[CH2:9][C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)=[CH:52][N:53]=2)=[CH:47][CH:48]=1
Reactant: NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1
Reactant: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Agent: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 19E and 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.35 (s, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.69-6.52 (m, 3H), 5.24 (q, J=7.6 Hz, 1H), 4.69 (s, 2H), 3.09 (ddd, J=33.5, 13.7, 7.3 Hz, 2H), 2.54 (m, 2H), 2.42-2.37 (m, 2H), 1.81-1.70 (m, 4H). MS (m/z) 565.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[F:26])[C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1)=[O:5].[CH2:32](O)[CH:33]=C>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:1][C:2]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH:12]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[F:26])[C:13]([O:15][CH2:16][CH:32]=[CH2:33])=[O:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: COC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1ccc(C(=O)c2ccc(C)cc2C)n1C
Reactant: C=CCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: C=CCOC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1ccc(C(=O)c2ccc(C)cc2C)n1C
Temperature: 25 °C
Reaction time: 36 h
Yield: 97 %

Procedure:
To a solution of methyl 2-[5-(2,4-dimethylbenzoyl)-1-methylpyrrol-2-yl)-2-(2-fluoro-4-nitrophenyl)acetate (3.51 g, 8.27 mmol) [prepared as described in Example 6, Step(c)] in 75 ml allyl alcohol was added titanium tetraisopropoxide (0.244 ml, 0.827 mmol), and the reaction mixture was heated to reflux. After 36 h, the reaction mixture was cooled to room temperature, and partitioned between ether and water. The organic layer was separated, dried over magnesium sulfate, and concentrated to dryness to give allyl 2-[5-(2,4-dimethylbenzoyl)-1-methylpyrrol-2-yl)-2-(2-fluoro-4-nitrophenyl)-acetate (3.60 g, 97%) as a pale yellow oil. ##STR36##
Reaction SMILES: [Na].CO.C[O-].[Na+:6].[OH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:8][O-:7].[Na+:6].[CH3:12][CH:11]([CH2:16][CH3:17])[CH2:10][CH2:9][CH2:8][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCC(C)CCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
Sodium methylate was prepared by reacting sodium (2.3 g, 0.1 mol) with 100 ml anhydrous methanol. To the sodium methylate was added methyl 4-hydroxybenzoate (15.2 g, 0.1 mol). Excess methanol was removed under reduced pressure and toluene was added and removed under reduced pressure to remove any residual methanol. The solid residue was dissolved in 2:1 toluene-dimethylformamide and S-4-methylhexyl bromide (17.9 g, 0.1 mol) was added as a single portion and the mixture was refluxed for 1 day. The reaction product was cooled and washed 3 times with 100 ml water. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. This crude methyl S-4-(4-methylhexyloxy)benzoate was refluxed in 100 ml of 10% aqueous sodium hydroxide for 1 day. The reaction product was cooled to room temperature (25° C.) and acidified with concentrated aqueous HCl. The precipated solid was collected by filtration and washed several times with cool water. This material was purified by recrystallization from ethanol-water. S- 4-(4-Methylhexyloxy)benzoic acid (20 g, 85% yield) was obtained. NMR and MS were consistent for the product.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][CH:4]=[C:3]([CH:9]=[O:10])[CH:2]=1.C(OC(=O)C)(=O)C.[N:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.Cl>C(O)(=O)C>[CH:9]([C:3]1[CH:2]=[CH:1][C:6]([CH:7]=[CH:24][C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)=[CH:5][CH:4]=1)=[O:10]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: Cc1ccncc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=Cc1ccc(C=Cc2ccncc2)cc1

Procedure:
A mixture of 400 parts of terephthaldehyde, 120 parts of acetic acid and 300 parts of acetic anhydride was refluxed for two hours. 188 parts of 4-picoline were then added over a period of 45 minutes, and the dark brown mixture was refluxed for a further 2 hours. 3300 parts of 1M aqueous hydrochloric acid were then added. The desired product was extracted with toluene and treated with 5M sodium hydroxide to a pH between 5 and 6. The crude solid product was dissolved in hot ethyl acetate and the solution was filtered. Cooling of the filtrate gave the desired product, 4-(2-(4-formylphenyl)-ethenyl)-pyridine.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:18]=[C:17]([NH:19][N:20]=[C:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:21]1(=[N:20][NH:19][C:17]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([S:6](=[O:7])(=[O:8])[NH2:5])[CH:18]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc(NN=C2CCCC2)cc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NN=C2CCCC2)cc1S(N)(=O)=O
Yield: 90.9 %

Procedure:
3.9 g (10.6 mmol) of methyl 2-(N-tert-butylsulfamoyl)-4-cyclopentylidenehydrazinobenzoate are stirred in 40 ml of trifluoroacetic acid at 25° C. for 2 hours. The mixture is evaporated and the residue is triturated with diethyl ether. After filtering off with suction and drying, 3.0 g (91% of theory) of methyl 4-cyclopentylidenehydrazino-2-sulfamoylbenzoate of melting point: 227-229° C. (decomposition) are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[Cl:8][C:9]1[CH:10]=[C:11]([S:16](Cl)(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[Cl:15].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([S:16]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)(=[O:17])=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CCN1
Yield: 90.3 %

Procedure:
Sulfonylation of piperazine-2-one (326.2 mg, 3.3 mmol) with 3,4-dichlorobenzene-sulfonyl chloride (800 mg, 3.3 mmol) was carried out according to a similar procedure described for example 15A using anhydrous dichloromethane (8 mL) as solvent and diisopropylethylamine (1.42 mL, 8.2 mmol) as base. 4-(3,4-dichloro-benzenesulfonyl)-piperazin-2-one was obtained in 90.3% yield (912 mg) as white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.17-3.24 (m, 2H) 3.25-3.30 (m, 2H) 3.59 (s, 2H) 7.79 (dd, J=8.46, 2.15 Hz, 1H) 7.94 (d, J=8.34 Hz, 1H) 8.06 (d, J=2.02 Hz, 1H) 8.08 (s, 1H).
Reaction SMILES: ClCCl.[O:4]1[C@@:21]2([CH3:22])[C@@H:5]1[CH2:6][C@@H:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][C@@H:9]([O:16][C:17](=[O:20])[NH:18][CH3:19])[C@H:8]12.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[Cl-].ClC1N(C)CC[NH+:33]1C>ClCCl.CO.C(N(CC)CC)C>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([NH:33][C:13]([C:12]2[C@H:7]3[CH2:6][C@@H:5]4[O:4][C@:21]4([CH3:22])[C@@H:8]3[C@H:9]([O:16][C:17](=[O:20])[NH:18][CH3:19])[O:10][CH:11]=2)=[O:15])[CH2:26][CH2:25]1
Reactant: CN1CC[NH+](C)C1Cl
Reactant: CN1CCNCC1
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)O)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(=O)O[C@@H]1OC=C(C(=O)NN2CCN(C)CC2)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Temperature: 25 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
A dichloromethane solution containing 400 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid described in Example 1 was cooled with ice followed by addition of 0.20 ml of 1-methylpiperazine, 2 ml of triethylamine and 301 mg of 2-chloro-1,3-dimethylimidazolinium chloride and stirring for 15 hours at room temperature. The reaction mixture was then extracted with dichloromethane. After washing the organic phase with saturated aqueous sodium bicarbonate and brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the dichloromethane-methanol eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid 4-methylpiperazylamide (264 mg, yield: 50%). The physicochemical properties of this compound are described in Table 5, Compound No. 20.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](=O)[CH3:7].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14].C(O)(C)C>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:4]([C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[CH3:1])[CH:5]=[C:6]([CH3:7])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CC(=O)C=Cc1ccccc1C
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)NC(C)=CC1c1ccccc1C
Yield: 61 %

Procedure:
Upon heating a solution of 16.0 g of 2-methylbenzylideneacetone and 13.0 of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2-amino-6-methyl-4-(2-methylphenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 159°C (isopropanol) is obtained. Yield: 61 percent of theory.