Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[C:14](=[O:19])[CH2:15][CH:16]([OH:18])[CH:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([O:18][CH:16]1[CH2:15][C:14](=[O:19])[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:17]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C2=CC(O)CC2=O)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C2=CC(OC(C)=O)CC2=O)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(3,4,5-trimethoxyphenyl)-4-hydroxy-cyclopent-2-en-1-one (3 gm, 11.36 mmol) in dichloromethane (30 ml) was cooled to 0° C. using ice-salt bath. To the cold solution dry pyridine (1.70 gm, 1.73 ml; 26.0 mmol) was added and stirred at 0° C. for 10 min. To the stirred solution, acetic anhydride (1.63 gm, 1.50 ml, 16.0 mmol) was added dropwise while maintaining the temperature below 0° C. The reaction mixture was stirred at room temperature for 15 h (monitored by TLC) then quenched by adding cold, dilute hydrochloric acid. The organic layer was washed three times with water, 10% sodium bicarbonate solution and finally brine. The organic layer was dried over sodium sulfate and concentrated to dryness under reduced pressure using a rotary evaporator. The crude residue was purified by column chromatography using silica gel (petroleum ether: acetone as eluent) to collect the pure 4-acetoxy-2-(3,4,5-trimethoxy-phenyl)-cyclopent-2-en-1-one (2.56 gm, 73.47%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][CH:36]([CH3:41])[CH2:37][C:38](Cl)=[O:39]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:38](=[O:39])[CH2:37][CH:36]([CH3:41])[CH3:35])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CC(=O)Cl
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)CC(C)C

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with 3-methyl-butyryl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H41N2O2Cl2 [(M+H)+] 579.2540, observed 579.2543.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[O:23][CH3:24])[N:3]=1.[CH2:25](B(O)O)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[O:23][CH3:24])[N:3]=1)[CH3:26]
Reactant: COc1cc(OC(F)(F)F)ccc1-c1nc(Cl)c([N+](=O)[O-])cc1C
Reactant: CCB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(C)cc1[N+](=O)[O-]

Procedure:
Tetrakistriphenylphosphinepalladium(0) (0.03 g, 0.03 mmol) is added to 2-chloro-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine (0.10 g, 0.27 mmol) in toluene (5 mL). Ethyl boronic acid (0.1 g, 1.1 mmol) and potassium carbonate (0.07 g, 0.55 mmol)) are added to this solution, and the reaction is heated to reflux for 17 hours. The product is extracted with ethyl acetate (20 mL). Combined extracts are washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography (5% EtOAC-hexane) yields 2-ethyl-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine as a yellow solid TLC Rf 0.55 (elution with 10% ethyl acetate-hexane)
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:14][CH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][C:10]=1[Cl:13])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Cl)c(C)c1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(CBr)c1Cl
Yield: 95.4 %

Procedure:
1.0 g of azobisisobutyronitrile was added to a solution of 84.0 g (0.38 mol) of methyl 2,4-dichloro-3-methylbenzoate and 67.6 g (0.38 mol) of N-bromosuccinimide in 380 ml of carbon tetrachloride. The reaction mixture was refluxed for 3.5 hours and then cooled, and the precipitate which had formed was filtered off with suction. The filtrate was concentrated under reduced pressure and the resulting residue was triturated with methyl t-butyl ether. 108.0 g of methyl 3-bromomethyl-2,4-dichlorobenzoate were obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl:24][C:25]1[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:24][C:25]1[N:30]=[CH:29][C:28]([C:31]([N:15]([CH3:16])[C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:6]3[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@@H:2]([CH3:1])[CH2:7]3)=[CH:14][CH:13]=2)=[O:32])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
1,1-Dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazine-carboxylate (D3) (0.4 g, 1.254 mmol) was taken up in DCM (4 mL) under argon. 6-Chloro-3-pyridinecarbonyl chloride (0.243 g, 1.379 mmol) in DCM (4 mL) and triethylamine (0.348 mL, 2.508 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM (×2) and the combined organics dried and concentrated to a pale yellow oil. The crude product was purified by column chromatography. Elution with a 0-50% EtOAc/petroleum ether gradient yielded the title compound as a white foam/gum (0.601 g). δH (CDCl3, 400 MHz) 8.21 (1H, d), 7.61 (1H, dd), 7.25 (2H, d), 7.16 (1H, d), 6.99 (2H, d), 4.18 (1H, br.s), 3.80 (1H, d), 3.50 (3H, s), 3.47 (1H, d), 3.34 (1H, d), 3.10 (1H, td), 2.70 (1H, d), 2.49 (1H, d), 2.10 (1H, dd), 2.00 (1H, m), 1.46 (9H, s), 1.20 (3H, d). MS (ES): MH+ 459.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)([OH:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:35][S:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.O>CN(C)C=O.O>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([C:9]([OH:11])([CH3:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[S:36][CH3:35])=[CH:3][CH:4]=2)[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Reactant: CSc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccccc3SC)cc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (61 mg, 0.075 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 11) (354 mg, 0.75 mmol), sodium carbonate (239 mg, 2.25 mmol) and [2-(methylthio)phenyl]boronic acid (252 mg, 1.5 mmol) in N,N-dimethylformamide/water (2:1) (22.5 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[2′-(methylthio)biphenyl-4-yl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [Na+].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11](=O)(=[O:13])[O-:12])=[C:6]([O:15][CH3:16])[CH:5]=1)#[N:3].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>O=P(Cl)(Cl)Cl>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([Cl:18])(=[O:13])=[O:12])=[C:6]([O:15][CH3:16])[CH:5]=1)#[N:3]
Reactant: COc1cc(C#N)ccc1NS(=O)(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C#N)ccc1NS(=O)(=O)Cl

Procedure:
To a soultion of N-(4-cyano-2-methoxyphenyl)-sulfamic acid sodium salt (1 mmol) at 0° C. in POCl3 (1 mL) is added phosphorous pentachloride (1.2 mmol). Upon reaction completion, the reaction mixture is concentrated and the crude material will be carried onto the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[O:15][CH2:14][CH2:13][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1

Procedure:
33.03 g (200 mmol) of 4-nitroacetophenone, 12.30 mL (220 mmol) of ethylene glycol, and 1.00 g (5 mmol) of p-toluenesulfonic acid are placed in 250 mL of toluene, then refluxed for 16 hours using the water separator. Then the reaction mixture is cooled and extracted with water. The organic phase is dried and evaporated to dryness. The residue is extracted with diisopropyl ether and suction filtered. Yield: 34.45 g (82%).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[H][H]>>[C:1]([O:20][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: [H][H]
Product: CCCCCCCC/C=C\CCCCCCCCO
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
As in the preceeding examples, 200 grams of oleic acid and 10 grams of the catalyst system prepared according to the above paragraph were treated in a manner similar to that set forth in Example I above, that is, by reaction at a temperature of 300° C. and a pressure of 1000 psi of hydrogen for a period of 4 hours. After the 4 hour reaction period had elapsed, heating was discontinued, the autoclave was allowed to return to room temperature, and the excess pressure was vented. Analysis of the reaction product after separation from the catalyst disclosed that there had been a 94% reduction of the carboxyl moieties to form oleyl oleate, oleyl alcohol as well as geometric and positional isomers thereof with an 83% reduction of the double bond.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[C:29]([CH3:30])=[CH:28][CH:27]=[C:26]3[CH3:31])[N:20]=2)[CH:3]=1.C[Si]([N-:36][Si](C)(C)C)(C)C.[Na+].[CH2:42]1[CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C.CCOC(C)=O.O>[CH2:10]([C:9]1[C:8](=[O:17])[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[C:26]([CH3:31])=[CH:27][CH:28]=[C:29]3[CH3:30])[N:20]=2)[C:43]=1[C:44]1[O:45][CH:46]=[CH:42][N:36]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C1CCOC1
Reactant: Cc1ccc(C)n1-c1cccc(Nc2cc(Cl)ccc2C(=O)CCc2ccccc2)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C)n1-c1cccc(-n2c(-c3ncco3)c(Cc3ccccc3)c(=O)c3ccc(Cl)cc32)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of oxazole-2-carboxylic acid (147 mg) and DMF (2 drops) in DCM (1 mL) was treated with oxalyl chloride (127 μL). Gas evolution ceased after 2 h. CHCl3 (2 mL) was added, the volatiles removed in a vacuum oven (40° C., 200 mbar), and the residual oil dissolved in THF (2 mL) to form “solution A”. A mixture of 1-{4-chloro-2-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-2-ylamino]-phenyl}-3-phenyl-propan-1-one (430 mg) in THF (2 mL) was treated with DMF (2 drops) and NaHMDS solution (2.5 mL, 1 M in THF) was added dropwise. Solution A (2 mL) was added dropwise, and the mixture stirred at RT for 12 h. The product was worked up in EtOAc/H2O and chromatographed (DCM/MeOH 100:0 to 70:30) to provide 3-benzyl-7-chloro-1-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-2-yl]-2-oxazol-2-yl-1H-quinolin-4-one.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:20][C:12]1[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([CH3:19])=[N:17]2
Reactant: Cc1ccc2cccc(O[Si](C)(C)C(C)(C)C)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(Br)ccc(O[Si](C)(C)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 138.1 %

Procedure:
N-bromosuccinimde (14 g) was added in one portion to a stirred solution of 8-t-butyldimethylsilyloxyquinaldine (15 g) in chloroform at -40° C. under an inert atmosphere. The reaction was warmed to room temperature and then heated to reflux for 6 h. Further N-bromosuccinimide (6 g) was added to the reaction at room temperature and stirring continued for 3 days. The reaction mixture was poured into 5% aqueous sodium metabisulphite solution (300 ml) and extracted with chloroform (3×300 ml). The combined organic phases were dried over magnesium sulphate and concentrated in vacuo to afford the title compound as an orange oil (16.4 g).
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH2:33](I)[CH3:34].O>ClCCl>[CH2:33]([N:30]1[CH2:31][CH2:32][N:27]([C:24]2[CH:23]=[CH:22][C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:2]([CH3:1])[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:9])[CH3:10])[CH:16]=3)=[CH:26][CH:25]=2)[CH2:28][CH2:29]1)[CH3:34]
Reactant: CN(Cc1cccc(-c2ccc(N3CCNCC3)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: CCI
Solvent: O
Solvent: ClCCl
Product: CCN1CCN(c2ccc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
tert-Butyl (2-{methyl[(4′-piperazin-1-ylbiphenyl-3-yl)methyl]amino}-2-oxoethyl)carbamate (180 mg) was dissolved in dichloromethane (3.6 ml), and TEA (125 mg) was added thereto under ice-cooling. Subsequently, ethyl iodide (128 mg) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with CHCl3. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl3) to obtain tert-butyl {2-[{[4′-(4-ethylpiperazin-1-yl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (137 mg).
Reaction SMILES: C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.[C:45]([O:49][C:50](=[O:59])[C:51]1[CH:56]=[CH:55][C:54]([C:57]#[CH:58])=[CH:53][CH:52]=1)([CH3:48])([CH3:47])[CH3:46]>C(#N)C.[Cu]I>[C:50]([C:51]1[CH:56]=[CH:55][C:54]([C:57]#[C:58][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:53][CH:52]=1)([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:59]
Reactant: C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2ccc(C#Cc3ccc(C(=O)OC(C)(C)C)cc3)cc2)cc1
Reaction time: 8 h

Procedure:
100 ml of triethylamine, 6.3 g of triphenylphosphine, 2.81 g of (Pφ3)2PdCl2 and 0.77 g of copper(I)iodide are added under nitrogen to 61 g of 4-bromo-4'-carbethoxybiphenyl in 300 ml of absolute acetonitrile. 44.3 g of 4-ethinyl-benzoic acid tert.-butyl ester dissolved in 300 ml of absolute acetonitrile are slowly added dropwise at the reflux temperature and the reaction mixture is boiled overnight. It is then suction filtered while hot and stirred up in water and again suction filtered and the residue is dissolved in CH2Cl2 and filtered after the addition of Tonsil.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15](O)([CH2:17][CH2:18][C:19]([CH3:22])(O)[CH3:20])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:14][C:15]1([CH3:16])[C:2]2[CH:1]=[C:13]3[C:5]([C:6]4[CH:7]=[C:8]5[C:19]([CH3:22])([CH3:20])[CH2:18][CH2:17][C:15]([CH3:16])([CH3:14])[C:9]5=[CH:10][C:11]=4[CH2:12]3)=[CH:4][C:3]=2[C:19]([CH3:22])([CH3:20])[CH2:18][CH2:17]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(O)CCC(C)(C)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CCC2(C)C
Temperature: -8 °C
Yield: 53 %

Procedure:
In a 500 ml three-necked flask purged with nitrogen, 9.72 g (58.6 mmol, 1 eq) of fluorene and 19.61 g (134 mmol, 2.3 eq) of 2,5-dimethyl-2,5-hexanediol were placed at room temperature. Then, 85 ml of dehydrated dichloromethane was added. After stirring by a magnetic stirrer, the mixture was cooled to −8° C. with an ice bath (light brown slurry). To the slurry, 38.9 g (292 mmol, 5.0 eq) of pulverized anhydrous aluminum chloride was added over a period of 70 minutes, followed by stirring at 0° C. for 2 hours. The ice bath was removed, and the solution was stirred at room temperature for 19 hours (dark brown solution). After disappearance of fluorene was confirmed by gas chromatography, the dark brown solution was poured into 150 ml of ice water to perform quenching (yellowish brown slurry) After the soluble component was extracted with 500 ml of diethyl ether, the organic phase was neutralized with a saturated sodium hydrogencarbonate aqueous solution and washed with water. The dispensed organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator. The residue was transferred onto a Kiriyama funnel, washed 6 times with 10 ml of hexane and vacuum dried to obtain a white powder (12.0 g, yield: 53%)
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@@:7]23[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[C:8]3=[O:25])=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.CCN(C(C)C)C(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]23[CH2:14][C@@H:13]([O:15][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)[C:8]3=[O:25])=[CH:26][CH:27]=1
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]2(Cc3ccc(Br)cc3)C[C@@H](O)CN12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@]2(Cc2ccc(Br)cc2)C1
Reaction time: 1 h

Procedure:
To a solution of (5S,7R)-5-(4-bromobenzyl)-3-(3,5-dichloro-phenyl)-7-hydroxy-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.81 g) in CH2Cl2 (5 mL) and DIEA (0.50 mL) at 0° C. was added methanesulfonyl chloride (0.19 mL). After 1 hour at 0° C., the mixture was diluted with CH2Cl2, washed with satd. NaHCO3 and brine, dried (Na2SO4) and concentrated to give (5S, 7R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-7-methylsulfonyloxy-1,3-diazabicyclo[3.3.0]octane-2,4-dione. MS (m/z) 494 (MH+). (2) To a solution of the compound obtained above in DMF (4 mL) at 75° C. was added sodium azide (0.54 g). After heating for 2 hours the mixture was diluted with Et2O and water. The organic solution was collected, washed with water and brine, dried (Na2SO4), filtered and concentrated. Purification by chromatography (silica gel: 2% methanol/CH2Cl2, Chromatotron) afforded the titled compound (0.82 g). MS (m/z) 494 (MH+), mp 58.9° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][NH:11][CH3:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][C:15]=1[CH3:24]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:11]([CH3:12])[CH3:10])(=[O:22])=[O:21])=[CH:16][C:15]=1[CH3:24]
Reactant: CNC
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(S(=O)(=O)N(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
Diisopropylethylamine (4.95 mL, 27.8 mmol) was added at 0° C. to a stirred solution of dimethylamine (3.70 mL, 55.6 mmol) in tetrahydrofuran (25 mL) and the reaction mixture was stirred at room temperature for 15 minutes. A 0.1 M solution of 4-bromo-3-methyl-benzenesulfonyl chloride (3.0 g, 11 mmol) in tetrahydrofuran was added at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated off under reduced pressure. The residue was diluted with ethyl acetate, and the inorganic salts were filtered through a celite bed. The filtrate was washed with 2 N aqueous HCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2.90 g (94%) of 4-bromo-3-methyl-N,N-dimethyl-benzenesulfonamide, which was used in subsequent reactions without further purification. MS cald. for C9H12BrNO2S [M+] 278.2, obsd. 280.0.
Reaction SMILES: [N:1]1([S:6]([CH:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH3:10])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([NH:25][C:26](=O)[O:27]C2C=CC=CC=2)[N:18]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([O:16][CH3:15])[N:18]=[C:19]([NH:25][C:26](=[O:27])[NH:14][S:11]([CH:9]([S:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:8])[CH3:10])(=[O:13])=[O:12])[N:20]=1
Reactant: CC(S(N)(=O)=O)S(=O)(=O)N1CCCC1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)C(C)S(=O)(=O)N2CCCC2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3.6 g (0.015 mol) of 1-pyrrolidinosulfonylethanesulfonamide (Example 1a) and 4.0 g (0.019 mol) of phenyl 4,6-dimethoxypyrimidin-2-ylcarbamate in 40 ml of acetonitrile there are added 2.9 g (0.019 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After the mixture has been stirred for five hours at room temperature, it is treated with 250 ml of ice/water and acidified with HCl to pH 2. Extraction with dichloromethane, drying and evaporation give crude 3-(4,6-dimethoxypyrimidin-2-yl)-1-(1-pyrrolidinosulfonylethylsulfonyl)urea, which is purified by trituration with diisopropyl ether (yield: 4.6 g; 73% of theory; melting point 145°-146° C.).