Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=4)[CH:23]=[C:22]([C:34]([F:37])([F:36])[F:35])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:28]1[CH:27]=[C:26]([C:24]2[CH:23]=[C:22]([C:34]([F:35])([F:36])[F:37])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=3)[N:25]=2)[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.9 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.41 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield the title compound as an off-white solid (0.2 g, 38%). MS (ISN) 528.9 [(M−H)−]; mp 266° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH:20]=O.[CH3:22][C:23]1([CH3:31])[O:30][C:28](=[O:29])[CH2:27][C:25](=[O:26])[O:24]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH:20]=[C:27]1[C:28](=[O:29])[O:30][C:23]([CH3:31])([CH3:22])[O:24][C:25]1=[O:26]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COCOc1cc(OC)c(OCOC)c(CC=O)c1OC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COCOc1cc(OC)c(OCOC)c(CC=C2C(=O)OC(C)(C)OC2=O)c1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.7 Grams (9.0 mM) of 2-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]acetoaldehyde was dissolved in 80 ml of benzene, then to this solution was added 1.56 g (10.8 mM) of Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) and 2.18 g (21.6 mM) of triethylamine were added and the reaction mixture was stirred at room temperature for 12 hours. 100 Milliliters of benzene was added to the reaction mixture and washed twice with 200 ml of water and further washed twice with a saturated sodium chloride aqueous solution, then the benzene solution was dried over anhydrous magnesium sulfate. The benzene solution was concentrated under reduced pressure and the residue obtained was purified by a silica gel column chromatography (diameter 5 cm×length 15 cm, eluent: 30% ethyl acetatehexane, "Wakogel C-200") to yield 2.9 g of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethane. Light yellow indefinite form powdery substance.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([OH:20])[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([Cl:18])[C:9]=2[Cl:19])=[CH:5][CH:4]=[N:3]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:6]([C:7]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([Cl:18])[C:9]=2[Cl:19])=[O:20])=[CH:5][CH:4]=[N:3]1
Reactant: COc1cc(C(O)c2ccnn2C)c(Cl)c(Cl)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.3 %

Procedure:
20 g of manganese dioxide are added to a solution of 7.08 g of α-(1-methylpyrazol-5-yl)-2,3-dichloro-4,5dimethoxybenzylalcohol in methylene chloride and the mixture is stirred at room temperature for 3 days. The reaction mixture is filtered and washed with chloroform. The filtrate and the washings are combined and evaporated to remove solvent. The residue is crystallized from n-hexane to give 6.35 g of (1-methylpyrazol-5-yl)-(2,3-dichloro-4,5-dimethoxyphenyl)-methanone.
Reaction SMILES: N1[CH:6]=[CH:5]C=CC=1.[CH:7]1([CH:13]=[C:14]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:15]([OH:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(=O)(O)[O-:27].[Na+]>C(OC(=O)C)(=O)C>[C:5]([O:20][CH:15]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]([N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)=[CH:13][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)(=[O:27])[CH3:6]
Reactant: CC(C)(C)C(O)C(=CC1CCCCC1)n1cncn1
Reactant: c1ccncc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(C(=CC1CCCCC1)n1cncn1)C(C)(C)C
Temperature: 70 °C
Reaction time: 4 h
Yield: 70.8 %

Procedure:
A solution of 13.15 g (0.05 mol) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-ol (prepared as described in Example II-2) in 50 ml of dioxane was added dropwise to a suspension of 1.5 g of 80% strength sodium hydride in 50 ml of dioxane. After the evolution of hydrogen had ceased, 3.9 g (0.05 mol) of acetyl chloride were added dropwise to the mixture. The mixture was heated under reflux for 4 hours. After the mixture had cooled, the solvent was distilled off in vacuo, and the residue was taken up in methylene chloride and the solution was extracted with water. The organic phase was dried over sodium sulphate and filtered, and the solution was concentrated. The residue was purified over a column (silica gel; methanol: chloroform=1:3). 5.6 g (35.4% of theory) of 3-acetoxy-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-ene were obtained as a slightly yellow oil. 2 ml of pyridine were added to a solution of 13.15 g (0.05 mol) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-ol (prepared as described in Example II-2) in 100 ml of acetic anhydride. The mixture was stirred for four hours at 70° C. The reaction mixture was thereafter poured onto water and was neutralized with sodium bicarbonate. The aqueous phase was extracted several times with ether. The combined ether phases were dried over sodium sulphate and concentrated. 11.2 g (70.8% of theory) of 3-acetoxy-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-ene were obtained as a slightly yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[N:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:20]1[CH2:21][CH2:22][C@H:18]([NH:17][C:15]2[N:16]=[C:7]([C:4]3[NH:3][C:2](=[O:1])[NH:6][N:5]=3)[CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccnc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]nc(-c2cc3cccnc3c(N[C@H]3CCNC3)n2)[nH]1

Procedure:
A mixture of (S)-tert-butyl 3-((6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,7-naphthyridin-8-yl)amino)pyrrolidine-1-carboxylate (80 mg, 0.201 mmol) in DCM (3 mL) was treated with TFA (1.5 mL) for 2 hours. The solvent was removed in vacuo to give the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:30])[CH:28]=[CH2:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[C:27](=[O:30])[CH2:28][CH2:29][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: Ic1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 39, Step 1, using 1-{4′-[4-(1-hydroxy-allyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and iodobenzene. The crude material was purified on silica gel (0-60% EtOAc in hexanes) to give a separable mixture of two compounds, one of which was the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[K+].CN(C=O)C>[Cu]I.C(OCC)(=O)C>[C:11]1([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccccc1
Reactant: c1ccc2ocnc2c1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(-c2nc3ccccc3o2)cc1
Yield: 16.9 %

Procedure:
Copper(I) iodide (19.1 mg, 0.1 mmol), benzoxazole (119 mg, 10.0 mmol), bromobenzene (471 mg, 3.0 mmol), t-BuOK (224 mg, 2.0 mmol), and DMF (1.0 mL). After column chromatography (hexanes, then 10% ethyl acetate in hexanes) and preparative HPLC (5% ethyl acetate in hexanes) 99 mg (51%) of 2-phenylbenzoxazole is obtained. Table I, entry 2.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=O)[CH:10]([CH3:12])[CH3:11].[Cl:14][CH2:15][C:16]#[N:17]>O1CCOCC1>[Cl:14][CH2:15][C:16]1[N:17]=[C:9]([CH:10]([CH3:12])[CH3:11])[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:2]=1
Reactant: N#CCCl
Reactant: CC(C)C(=O)c1ccccc1N
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1nc(CCl)nc2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dry hydrogen chloride gas is piped through a solution of 2.86 g of 1-(2-amino-phenyl)-2-methyl-propan-1-one and 1.33 ml of chloroacetonitrile in 14 ml dioxane with stirring at ambient temperature for approx. five hours. Then the dioxane is largely distilled off in a water jet vacuum. The honey-like residue is combined with ice water and the resulting suspension is made alkaline with saturated potassium carbonate solution while cooling with an ice bath. The precipitate is suction filtered, washed with water and dried. The crude product is purified by chromatography over a silica gel column with petroleum ether/methylene chloride (8:2 to 0:1) as eluant.
Reaction SMILES: [C:1]([O:4][C:5]1([CH3:29])[CH2:7][N:6]1[C:8]1[CH2:9][C@@H:10]2[CH2:27][C:26](=[O:28])[N:11]2[C:12]=1[C:13]([O:15]CC1C=CC([N+]([O-])=O)=CC=1)=[O:14])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+:34]>O1CCOCC1.O.C(O)C.[Pd]>[C:1]([O:4][C:5]1([CH3:29])[CH2:7][N:6]1[C:8]1[CH2:9][C@@H:10]2[CH2:27][C:26](=[O:28])[N:11]2[C:12]=1[C:13]([O-:15])=[O:14])(=[O:3])[CH3:2].[Na+:34]
Reactant: CC(=O)OC1(C)CN1C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OC1(C)CN1C1=C(C(=O)[O-])N2C(=O)C[C@H]2C1

Procedure:
A solution of p-nitrobenzyl 2-(2-acetoxy-2-methyl-aziridin-1-yl)-carbapen-2-em-3-carboxylate (0.9 mg, 2.3 micromol) in dioxane (100 microliter), deionized water (60 microliter), absolute ethanol (8 microliter), and 0.5M aqueous sodium bicarbonate (5 microliter) was shaken with 10% (w/w) palladium on charcoal (1.1 mg) under hydrogen (50 psig) for 30 min. The mixture was centrifuged and the pellet washed with deionized water (3×100 microliter). The combined supernate and washes were extracted with ethyl acetate (3×0.5 ml) and concentrated under vacuum to provide 420 microliter of a solution of sodium 2-(2-acetoxy-2-methylaziridin-1-yl)-carbapen-2-em-3-carboxylate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(O)c(C=O)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (115 mg), 2-hydroxy-5-methoxybenzaldehyde (385 mg), and 4-dimethylaminopyridine (321 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 4 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the organic layer was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to quantitatively obtain 180 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([NH:8][CH2:9][C:10](=[O:12])[CH3:11])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([N:8]([CH2:9][C:10](=[O:12])[CH3:11])[C:29](=[O:30])[CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:6])[CH3:7]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)CNC(C)(C)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CN(C(=O)Cc1ccccc1)C(C)(C)c1cccc(Cl)c1
Temperature: 0 °C
Yield: 62.5 %

Procedure:
22.6 g (0.1 mol) of 1-(3-chloro-α,α-dimethylbenzylamino)-2-propanone prepared by the method of Reference Example 5, was dissolved in 200 ml of acetone, and 14.0 g (0.11 mol) of potassium carbonate was added thereto. The mixture was cooled with ice water, and then 15.5 g (0.1 mol) of phenylacetyl chloride was gradually dropwise added thereto under stirring. After completion of the dropwise addition, the reaction mixture was returned to room temperature and stirred for 3 hours. Then, the solvent was distilled off under reduced pressure, and then water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from n-hexane to obtain 21.5 g (yield: 62.5%) of the desired compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][NH2:7])=[S:5])[CH3:2].[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[CH2:19][C:20]1[N:24]2[N:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1>>[CH2:1]([NH:3][C:4]([NH:6]/[N:7]=[C:29](/[C:26]1[CH:27]=[CH:28][C:23]2[N:24]([C:20]([CH2:19][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][C:9]=3[F:8])[N:16]=[CH:15][CH:14]=[CH:13]4)=[CH:21][N:22]=2)[N:25]=1)\[CH3:30])=[S:5])[CH3:2]
Reactant: CCNC(=S)NN
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Product: CCNC(=S)N/N=C(\C)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 53 %

Procedure:
The title compound was prepared from N-ethylhydrazine carbothioamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 53% yield. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.83 (d, 1H), 8.30 (d, 1H), 8.24 (d, 1H), 7.93 (m, 2H), 7.69 (m, 2H), 7.48 (q, 1H), 4.67 (s, 2H), 3.74 (q, 2H), 2.39 (s, 3H), 1.26 (t, 3H). LCMS (method A): [MH]+=422, tR=5.43 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:26])[C:8]2=O)[C:4]([CH3:28])=[N:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:26])[C:8]2=[S:38])[C:4]([CH3:28])=[N:3]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccnc4)cc3c21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1nn(C)cc1-n1c(=S)n(C)c2cnc3ccc(-c4cccnc4)cc3c21
Temperature: 100 °C
Reaction time: 28 h

Procedure:
A mixture of a new batch of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 10.2, 8 mg, 0.219 mmol) and Lawesson's reagent (98 mg, 0.242 mmol) in dioxane (1 ml) was stirred in a seal vial for 28 h at 100° C. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was taken in NMP and purified by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 65:35). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: tR 2.32 min (Method A); M+H=387 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.21 (s, 1H), 8.72-8.68 (m, 1H), 8.62-8.58 (m, 1H), 8.23-8.16 (m, 2H), 8.08-8.04 (m, 1H), 7.93-7.88 (m, 1H), 7.56-7.48 (m, 2H), 3.97-3.93 (m, 6H), 1.92 (s, 3H))
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[CH:19]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1cc([N+](=O)[O-])ccc1-c1cccc(C)c1

Procedure:
The title compound was prepared by reaction of 1-bromo-2-methoxy4-nitrobenzene with 3-methylphenylboronic acid in the presence of palladium acetate.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][O:18][C:17]3=[O:22])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Br[Zn][CH2:25][CH:26]([CH3:28])[CH3:27].O.C(OCC)(=O)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:25]([C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][O:18][C:17]3=[O:22])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[Zn]Br
Reactant: O=C1COC(=O)N1CCC1CCN(c2cccc(Br)n2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)Cc1cccc(N2CCC(CCN3C(=O)COC3=O)CC2)n1
Reaction time: 17 h

Procedure:
2 g (5.43 mmol) of 3-{2-[1-(6-bromo-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, prepared in step 13.3, and 0.20 g (0.271 mmol) of dichlorobis(triphenylphosphine)palladium (Pd(PPh3)2Cl2) suspended in 10 ml of tetrahydrofuran are introduced under an inert atmosphere. 22 ml (10.80 mmol) of a solution (0.5 M) of bromo(isobutyl)zinc in tetrahydrofuran are then added. Stirring is continued at room temperature for 17 hours. The reaction mixture is poured into water and ethyl acetate. The phases are separated by settling, the aqueous phase is extracted twice with ethyl acetate, the combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 20/80 mixture of ethyl acetate and cyclohexane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[N:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]1[CH:11]=[C:10]([Br:12])[N:9]=[C:8](Br)[C:7]=1[N+:14]([O-:16])=[O:15])[CH3:2].[NH3:25].C(OCC)(=O)C.O>CC1CCCO1>[CH2:1]([O:3][C:4](=[O:24])[N:5]([C:6]1[CH:11]=[C:10]([Br:12])[N:9]=[C:8]([NH2:25])[C:7]=1[N+:14]([O-:16])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(Br)c1[N+](=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Benzyl-(2,6-dibromo-3-nitro-pyridin-4-yl)-carbamic acid ethyl ester (7.50 g) was dissolved in 2-methyl-tetrahydrofuran (15 ml) and the solution placed in a sealable vessel. Concentrated aqueous ammonia solution (15 ml) was added and the vial was then sealed and the bi-phasic mixture left to stir vigorously at room temperature for 36 hours. The reaction mixture was then transferred to a separating funnel and ethyl acetate (120 ml) and water (120 ml) were added. The phases were separated, and then the organics washed with brine (100 ml), dried (MgSO4), and evaporated to a yellow oil. Upon standing, a yellow solid crystallised. This was collected by filtration and washed with pentane, providing the title compound (6.64 g) as a yellow solid.
Reaction SMILES: C(S[CH2:9][CH2:10][Cl:11])CCCCCC.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](OO)=O)[CH:14]=1.[S:23](S([O-])=O)([O-:26])(=O)=[O:24].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:14]([S:23]([CH2:9][CH2:10][Cl:11])(=[O:26])=[O:24])[CH2:13][CH2:18][CH2:17][CH2:16][CH2:15][CH3:19]
Reactant: CCCCCCCSCCCl
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCS(=O)(=O)CCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 2-chloroethyl heptyl sulfide (1.0 g, 5.13 mmol) in methylene chloride (50 mL). Add metachloroperbenzoic acid (3.2 g, 15 mmol) portionwise and stir at room temperature for 1 hour. Add addition metachloroperbenzoic acid (1.0 g) and stir at room temperature for 2 hours. Treat with saturated sodium meta bisulfite (until negative starch-iodide test) and basify with saturated sodium hydrogen carbonate. Extract with methylene chloride (2×25 mL), dry (MgSO4) and evaporate in vacuo to yield 1.23 g 2-chloroethyl heptyl sulfone as a white solid; MS (CI/CH4) m/z 227(M+1).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:21]([OH:23])=O)[CH2:11][S:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH:28][C@H:29]([C:40]([OH:42])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)(C)(C)C>>[C:1]([NH:9][C@H:10]([C:21]([NH:28][C@H:29]([C:40]([OH:42])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:23])[CH2:11][S:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(NC(CSC(=O)c1ccccc1)C(=O)O)c1ccccc1
Product: O=C(N[C@@H](CSC(=O)c1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)c1ccccc1

Procedure:
N-(N,S-Dibenzoyl-D,L-cysteinyl)-tryptophan was obtained as a diastereomer mixture (melting point 175°-178° C., petroleum ether; Rf=0.19 and 0.16 in system II) by a procedure similar to that described in Example 16, using N,S-dibenzoyl-D,L-cysteine and tert.-butyl tryptophan as starting materials. Recrystallization from diethyl ether gave N-(N,S-dibenzoylcysteinyl)-tryptophan (melting point 210°-213° C., Rf=0.19 in system II) in a form which was pure according to thin-layer chromatography. N-(N,S-dibenzoyl-D-cysteinyl)-tryptophan (melting point 157°-160° C., Rf=0.16 in system II) which was pure according to thin-layer chromatography was obtained from the mother liquor after crystallization from petroleum ether.