Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:6]([CH:11]=[O:12])=[C:7]([CH:9]=[CH2:10])[N:8]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O.O.[OH-].[Na+]>C1COCC1>[CH2:1]([C:4]1[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:6]([CH:11]=[O:12])=[C:7]([CH:9]=[CH2:10])[N:8]=1)[CH2:2][CH3:3]
Reactant: C=Cc1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C=Cc1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.6 %

Procedure:
2-n-propyl-1-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]-4-vinyl-imidazole-5-carboxaldehyde (330 mg), trifluoroacetic acid (1.65 mL), water (1.65 mL), and THF (1.65 mL) were mixed and stirred at room temperature. After 8 h, the mixture was neutralized to pH=7 with 10N NaOH and the solvents removed in vacuo. The residue was flash chromatographed in 1:1 hexane/ethyl acetate to 100% ethanol to yield 270 mg of a white glass. NMR (DMSO-d6) δ 9.92 (s,1H); 7.65-7.50 (m,1H); 7.50-7.12 (m,3H); 7.09 (d,2H,J=9Hz); 6.89 (d,2H,J=9Hz); 6.11 (d of d1H,J=17,3Hz); 5.55 (s,2H); 5.45 (d of d, 1H,J=12,3 Hz); 2.63 (t,2H,J=7Hz); 1.64 (t of q,2H,J=7,7Hz); 0.90 (t,3H,J= 7Hz). IR (Nujol) 1680 cm-1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][CH2:11][OH:12]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1
Reactant: OCCCBr
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Product: CN1CCN(CCCO)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
1-Methylpiperazine (6.99 mL, 63 mol) was dissolved in toluene (30 mL). 3-Bromopropanol (2.62 mL, 30 mmol) was added slowly and the mixture was stirred overnight. After heating to 80° C. for 2 h and cooling to r.t., the mixture was filtered and the filter cake was washed thoroughly with toluene. After removal of the toluene, the residue was subjected to Kugelrohr distillation (b.p., 180° C./2 mbar) to obtain a colourless oil (4.08 g, 25.8 mmol, 86%). 1H NMR (CDCl3): δ=1.70 (Ψ-quint, J≈5.8 Hz, 2 H), 2.26 (s, 3 H), 2.35-2.6 (m, 8 H), 2.60 (Ψ-t, J=5.8 Hz, 2 H), 3.77 (Ψ-t, J=5.3 Hz, 2 H), 4.09 (s, br., 1 H).
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH:8]([C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)[OH:9])(C)(C)C.[F-].C([NH3+])(C)(C)C.CCCCCC.C(OCC)(=O)C>C1COCC1>[N:20]1[CH:21]=[CH:22][C:17]([CH:7]([OH:6])[CH:8]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)[OH:9])=[CH:18][CH:19]=1
Reactant: Cc1cccc(C(O)C(O[Si](C)(C)C(C)(C)C)c2ccncc2)c1
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cccc(C(O)C(O)c2ccncc2)c1

Procedure:
To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-2-pyridine-4-yl-1-m-tolyl-ethanol (5 g, 14.5 mmole) in THF (50 mL) was added t-butylamonium fluoride (1M, 16 mL, 16 mmole) at 25° C. The solution was stirred at that temperature for 1 hr before evaporation of solvent and purification (silica gel, hexane/ethyl acetate) to give the title compound. MS (m/z): Calcd. C14H15NO2(M+): 229, found (M+H)+: 230.1, (M−H)−: 228.1
Reaction SMILES: CO/C(/C)=C\C(Cl)=O.S1C2C=CC=CC=2N=C1S[S:19][CH:20]1[N:23](/[C:24](=[C:28](\[O:30][CH3:31])/[CH3:29])/[C:25](Cl)=[O:26])[C:22](=[O:32])[CH:21]1[NH:33][C:34](=[O:43])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.[C:51]([OH:55])([CH3:54])([CH3:53])[CH3:52]>C(Cl)Cl>[C:51]([O:55][C:25]([CH:24]1[N:23]2[C:22](=[O:32])[C@@H:21]([NH:33][C:34](=[O:43])[CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:20]2[S:19][CH:29]=[C:28]1[O:30][CH3:31])=[O:26])([CH3:54])([CH3:53])[CH3:52]
Reactant: CO/C(C)=C(/C(=O)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Reactant: CC(C)(C)O
Agent: CO/C(C)=C\C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 266 mg (0.5 mM) of a crude mixture consisting of 2-[4-benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid chloride and 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid chloride in 5 ml of dry methylene chloride is added dropwise over the course of 15 minutes at 0° C., whilst stirring, to a solution of 0.10 ml of triethylamine in 0.5 ml of dry tert.-butanol and 3 ml of methylene chloride. After a further 15 minutes stirring, the reaction mixture is diluted with methylene chloride, washed with water, with dilute hydrochloric acid and again with water, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 10 g of acid-washed silica gel, using toluene/ethyl acetate (4:1) as the running agent. 7β-Phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid tert.butyl ester is obtained. IR spectrum (in CH2Cl2): characteristic bands at 5.60, 5.77, 5.90 and 8.29μ.
Reaction SMILES: [Na+].[I-:2].CNCCNC.Br[C:10]1[CH:22]=[CH:21][C:13]2[S:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:12]=2[CH:11]=1>O1CCOCC1.[Cu]I>[I:2][C:10]1[CH:22]=[CH:21][C:13]2[S:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:12]=2[CH:11]=1
Reactant: [I-]
Reactant: COC(=O)c1cc2cc(Br)ccc2s1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc2cc(I)ccc2s1

Procedure:
Under an argon atmosphere 0.35 g (1.84 mmol) of CuI, 5.53 g (36.88 mmol) of NaI, and 0.39 mL (3.67 mmol) of N,N′-dimethylethylenediamine were added to a solution of 5.0 g (18.4 mmol) of methyl 5-bromobenzo[b]thiophen-2-carboxylate in 18 mL of 1,4-dioxane and after rinsing again with argon the reaction mixture was heated overnight to 110° C. After cooling, the reaction mixture was combined with 30% aqueous ammonia and water, exhaustively extracted with EtOAc, and the combined organic phases were twice washed with water and dried over magnesium sulfate. After the desiccant and solvent had been eliminated, the residue was triturated with DIPE and MTBE, suction filtered, and dried in the air. Yield: 3.4 g (58% of theoretical); C10H7IO2S (M=318.132); calc.: molpeak (M)+: 318; found: molpeak (M)+: 318; HPLC-MS: 6.4 minutes (method B).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[C:32]([C:35]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH2+:38][CH2:37][CH2:36]1)(=[O:34])[NH2:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:38]3[CH2:37][CH2:36][C:35]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([C:32]([NH2:33])=[O:34])[CH2:40][CH2:39]3)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: NC(=O)C1(c2ccccc2)CC[NH2+]CC1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(C(N)=O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Yield: 52.3 %

Procedure:
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq, 130 mg, 0.306 mmol), 4-carbamoyl-4-phenylpiperidin-1-ium trifluoroacetate (1.1 eq, 69 mg, 0.337 mmol), benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1.1 eq., 149 mg, 0.337 mmol), and triethylamine (3 eq, 0.13 mL, 0.92 mmol) was stirred in tetrahydrofuran (5 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 1-{[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide (98 mg, 52%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.10 (dd, J=9.75, 3.63 Hz, 1H) 2.18 (s, 3H) 2.20-2.28 (m, 1H) 2.46 (d, J=14.03 Hz, 2H) 3.65 (t, J=10.31 Hz, 1H) 3.75-3.88 (m, 1H) 3.95-4.07 (m, 1H) 4.15-4.28 (m, 1H) 5.17-5.50 (m, 2H) 7.00 (d, J=8.38 Hz, 2H) 7.12-7.50 (m, 10H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[F:18])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].O.[CH3:34][S:35]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)(=[O:37])=[O:36]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd]Cl>[C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([S:35]([CH3:34])(=[O:37])=[O:36])[CH:43]=2)=[CH:13][C:12]=1[F:18])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(Br)cc1F)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1F)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 0.450 g (0.943 mmol) rac-[2-(4-bromo-2-fluoro-phenyl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester in 10.5 ml toluene/ethanol 19:1 were added 69 mg (0.094 mmol) PdCl2 (dppf), 0.238 g (2.83 mmol) sodium bicarbonate, 5 ml water and 212 mg (1.04 mmol) 3-methylsulfonylphenylboronic acid and the mixture heated to reflux for 18 h. The reaction mixture was cooled to ambient temperature, filtered through a Dicalite pad and the filtrated extracted with tertiary butyl methyl ether. The combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash-chromatography over silica gel with a heptane/AcOEt gradient with 10-50% AcOEt: rac-[1-(3,4-dichloro-phenyl)-2-(3-fluoro-3′-methanesulfonyl-biphenyl-4-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester was obtained as colorless solid: MS (ISN): 550.2 and 552.2 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cc(Br)c2cccnc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cc(Br)c2cccnc2c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
To a solution of 5-bromo-8-hydroxyquinoline-7-carboxylic acid (0.402 g) of Preparation 2 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxy-benzotriazole monohydrate (0.217 g). The mixture is stirred overnight. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried to yield 0.157 g of the title product as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([S:11][CH:12]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13]([OH:15])=[O:14])[N:4]=1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>CO>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([S:11][CH:12]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:13]([O-:15])=[O:14])[N:6]=1.[CH:21]([NH3+:24])([CH3:23])[CH3:22]
Reactant: COc1cc(OC)nc(SC(C(=O)O)C2CCCC2)n1
Reactant: CC(C)N
Solvent: CO
Product: CC(C)[NH3+]
Product: COc1cc(OC)nc(SC(C(=O)[O-])C2CCCC2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.8 %

Procedure:
A mixture of 5.0 g of 2-(4,6-dimethoxypyrimidin-2-yl)thio-2-cyclopentyl acetic acid, 1.0 g of isopropylamine and 80 ml of methanol was stirred at room temperature for 1.5 hours. Methanol was removed by distillation under reduced pressure. Isopropyl ether was added to the residue, and the mixture was stirred at room temperature for 0.5 hour. Formed crystals were collected by filtration, washed with n-hexane and then dried to obtain 4.3 g of the desired product.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18]>O1CCOCC1>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:3]3[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CSc1ncc2ncnc(Cl)c2n1
Solvent: C1COCCO1
Product: CSc1ncc2ncnc(Nc3ccc(F)c(Cl)c3)c2n1

Procedure:
3.0 g of 4-chloro-6-methylthiopyrimido[5,4-d]pyrimidine, 3.8 g of 3-chloro-4-fluoroaniline and 10 ml of dioxane are heated at 80° C. for 2 hours. After cooling, the reaction mixture is concentrated and triturated first with water and then with diethyl ether, filtered off with suction and dried.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C@H:26]([O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=1)[C:33]([OH:35])=O)[CH2:27][CH3:28].[NH2:47][C:48]1[CH:52]=[CH:51][N:50]([CH3:53])[N:49]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:25][C@H:26]([O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=1)[C:33]([NH:47][C:48]1[CH:52]=[CH:51][N:50]([CH3:53])[N:49]=1)=[O:35])[CH2:27][CH3:28]
Reactant: CC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 16 h

Procedure:
HATU (1.19 g, 3.13 mmol) was added to 3-{[(1S)-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoic acid (750 mg, 2.5 mmol) and 3-amino-1 methylpyrazole (291 mg, 3 mmol) in DMF (5 mL) followed by addition of DIPEA (0.807 mL, 6.25 mmol) and the reaction was stirred for 16 hours. The reaction mixture was added to ethyl acetate (30 mL), washed with water (10 mL), 2N citric acid (10 mL), saturated aqueous sodium hydrogencarbonate (10 mL) and brine (10 mL), then dried (MgSO4), filtered and evaporated to a gummy residue. The residue was taken up in 50% ether in ethylacetate (50 mL), washed with 2N hydrochloric acid (10 mL), water (10 mL), saturated aqueous sodium hydrogencarbonate (10 mL) and brine (10 mL) then dried (MgSO4), filtered and evaporated to a foam (900 mg) which was used without further purification in the next step. 1H NMR δ (CDCl3): 0.96 (t, 3H), 1.28 (d, 3H), 1.51-1.80 (m, 2H), 3.78 (s, 1H), 4.31 (q, 1H), 5.06 (s, 2H), 6.68 (t, 1H), 6.82 (d, 1H), 7.00 (s, 1H), 7.06 (s, 1H), 7.29 (s, 3H), 7.31-7.47 (m, 5H), 8.63 (s, 1H); m/z 380 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=1.C[O-].[Na+].[CH:19]([C:21]([CH3:23])=[O:22])=[CH2:20]>C1C=CC=CC=1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:9]([CH2:20][CH2:19][C:21](=[O:22])[CH3:23])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:15])=[CH:4][N:3]=1
Reactant: C=CC(C)=O
Reactant: CCOC(=O)CC(=O)c1ccc(C)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CCOC(=O)C(CCC(C)=O)C(=O)c1ccc(C)nc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a stirred solution containing 48 g. of ethyl 3-(2-methyl-5-pyridinyl)-3-oxopropanoate in a mixture of 300 ml. of dry benzene and 100 ml. of dry methanol, said solution kept under nitrogen, was added 0.1 g. of sodium methoxide followed by the dropwise addition over a period of about one hour of the solution containing 16 g. of freshly distilled methyl vinyl ketone in a mixture of 60 ml. of benzene and 10 ml. of methanol. After the reaction had proceeded slowly at room temperature overnight, an additional 0.1 g. of sodium methoxide plus 4 ml. of additional methyl vinyl ketone were added and the reaction mixture was heated with stirring at 40° C. for eight hours. The solvent was distilled-off in vacuo; 300 ml. of benzene was added; the benzene solution was washed once with brine, dried over anhydrous sodium sulfate and heated in vacuo to remove the benzene thereby yielding a quantative yield (63.5 g.) of ethyl 2-(2-methyl-5-pyridinylcarbonyl)-5-oxohexanoate which was added to a mixture containing 95 ml. of concentrated sulfuric acid and 185 ml. of water. The acidic reaction mixture was slowly heated. After about thirty minutes, the temperature reached 55° C. and the evolution of carbon dioxide became noticeable. The temperature of the reaction mixture was maintained at 65° C. for about one hour and then heated to 80° C. and held there for several minutes. By this time the evolution of carbon dioxide appeared to be over. The reaction mixture was cooled and poured into a solution of 305 g. of potassium carbonate in 1 liter of ice water. Chloroform was added; the mixture was shaken well and filtered to remove the precipitated potassium sulfate; and, the layers were separated. The aqueous layer was extracted further with chloroform; the combined chloroform extracts were dried over anhydrous sodium sulfate and filtered; the dried filtrate was heated in vacuo to remove the chloroform to yield, after air-drying, 27.4 g. (80%) of 1-(2-methyl-5-pyridinyl)hexan-1,5-dione, a tan solid melting at 85°-87° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12][C@H:11]1[CH:25]=O)=[O:9])([CH3:6])([CH3:5])[CH3:4].CO.C([O-])(O)=[O:30].[Na+].[CH2:34]1[CH2:38][O:37][CH2:36][CH2:35]1>>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12][C@H:11]1[CH:25]=[CH:35][C:36]([O:37][CH2:38][CH3:34])=[O:30])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: C1CCOC1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C=O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C=C[C@@H]1C[C@@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 0.91 g (4.08 mmol) triethyl phosphonoacetate in 10 ml THF was first treated with 0.18 g (4.08 mmol) 55% NaH and after cooling (−78° C.) with 1.2 g (3.4 mmol) (2S,4R)-2-formyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. The reaction was warmed up to room temperature and stirred over night. The solution was cooled (0° C.) and treated with 1 ml MeOH followed by 10 ml saturated aqueous Na/K-tartrate and after 10 min with aqueous 10% NaHCO3 solution. The aqueous phase was filtered, extracted (EtOAc 2×) and the organic phase was dried (Na2SO4), evaporated and purified on silica gel column (Hexane/EtOAc 9:1 to 7:3) to give 0.57 g (40%) of (2S,4R)-2-(2-ethoxycarbonyl-vinyl)-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 422 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=1[S:44](Cl)(=[O:46])=[O:45].O>ClCCl>[CH3:25][C:21]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([S:44]([C:36]3[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:35]=3[CH3:34])(=[O:45])=[O:46])[C:13]2=[O:26])=[CH:20][CH:19]=1)([CH3:24])[C:22]#[N:23]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: Cc1ccc2ncc3[nH]c(=O)n(-c4ccc(C(C)(C)C#N)cc4)c3c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc2ncc3c(c2c1)n(-c1ccc(C(C)(C)C#N)cc1)c(=O)n3S(=O)(=O)c1cc([N+](=O)[O-])ccc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 3, 100 mg, 0.29 mmol) and triethylamine (60 mg, 0.58 mmol) in dichloromethane (6 ml) was added 2-methyl-5-nitrobenzene-1-sulfonyl chloride (103.35 mg, 0.44 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 20 mg (12%); 1H NMR (CDCl3, 300 MHz): δ 9.560 (s, 1H), 9.155-9.163 (d, 1H, J=2.4 Hz), 8.384-8.420 (dd, 1H, J=8.4, 2.4 Hz), 8.050-8.079 (d, 1H, J=8.7 Hz), 7.696-7.724 (d, 2H, J=8.4 Hz), 7.538-7.564 (d, 1H, J=7.8 Hz), 7.458-7.486 (d, 3H, J=8.4 Hz), 6.708 (s, 1H), 2.760 (s, 3H), 2.236 (s, 3H), 1.742 (s, 6H); MS: m/z 542 (M+).
Reaction SMILES: ClCC([O:5][CH2:6][CH3:7])=O.[N:8]1C=CC=CC=1.Cl.CN(C)[CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.C([O-])(=O)C.[NH4+]>C(O)C>[C:21]1([C:19]2[NH:8][C:6](=[O:5])[CH:7]=[CH:17][CH:18]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)CCC(=O)c1ccccc1
Reactant: c1ccncc1
Reactant: CCOC(=O)CCl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Product: O=c1cccc(-c2ccccc2)[nH]1

Procedure:
Ethyl 2-chloroacetate (10.6 ml, 0.1 mol) is slowly added to hot (105° C.) pyridine (8.9 ml, 0.11 mmol whereby the temperature is maintained in the range of 100° C. to 110° C. The resulting brown oil is dissolve in ethanol (60 ml), β-dimethylamino propiophenone hydrochloride (17.7 g, 0.1 mol; prepared to according to Example 1) and ammonium acetate (60 g) are added and the mixture is boiled under reflux for 4 h. After cooling, the mixture is filtered and the solvent is evaporated in vacuo. The residue is crystallized from water, collected by filtration and purified by re-crystallization from toluene. The title compound is obtained as colorless crystals (4.7 g, 28% of th.) with mp 200° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(C(C)C)CC)(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:28]([NH:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Sc3ccccc3)c(N)c2)CC1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Sc1ccccc1
Temperature: 25 °C
Yield: 102.3 %

Procedure:
A solution of tert-butyl 4-[3-amino-4-(phenylsulfanyl)phenyl]-1-piperazinecarboxylate (0.69 g, 1.6 mmol) in 7 mL of dry CH2Cl2 is cooled to 0° C. Acetyl chloride (0.13 mL, 1.8 mmol), diisopropylethylamine (0.32 mL, 1.8 mmol), and DMAP (0.020 g, 0.16 mmol) are added and the solution allowed to warm to rt overnight with stirring. Water and CH2Cl2 (10 mL each) are added and the layers separated. The aqueous layer is extracted with CH2Cl2 (3×10 mL) and the combined organic layers are washed with 1 N HCl, H2O, and brine. After drying over MgSO4, the mixture is filtered and concentrated to give the crude product. Purification by column chromatography (25% EtOAc/hexane) gives 0.70 g (99%) of the titel compound as a oil.