Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@H:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[C:20]([OH:22])=[O:21])(=[O:4])=[O:3].[Li+].CC([N-]C(C)C)C.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.OS([O-])(=O)=O.[K+].CCOC(C)=O>C1COCC1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:10][C@H:8]2[CH2:9][N:5]([S:2]([CH2:1][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:3])=[O:4])[C@H:6]([C:20]([OH:22])=[O:21])[CH2:7]2)=[CH:13][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)O)N(S(C)(=O)=O)C2)cc1
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@@H]2C[C@@H](C(=O)O)N(S(=O)(=O)CCc3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 138.9 %

Procedure:
A solution of 138 mg (0.4 mmol) (2S,4R)-1-Methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-2-carboxylic acid in 8 ml THF was treated at −78° C. with 0.83 ml (1.24 mmol, 1.5 M THF solution) of LDA. After 30 min 0.17 ml (1.4 mmol) benzylbromide were added and warmed up to RT over night. The reaction was poured into aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous 10% NaCl solution and dried over Na2SO4 to give 242 mg (quantitativ) crude (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(2-phenyl-ethanesulfonyl)-pyrrolidine-2-carboxylic acid.
Reaction SMILES: ClC(OCC(C)C)=O.O[C:10](=[O:27])[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CCN(CC)CC.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=1>C(Cl)Cl.O>[C:42]([C:39]1[CH:40]=[CH:41][C:36]([NH:35][C:10](=[O:27])[CH2:11][N:12]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:37][CH:38]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1ccc(NC(=O)CN(Cc2ccccc2)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 61.9 %

Procedure:
Isobutyl chloroformate (35.1 g, 0.26 mol) was added (15 min) to an ice-cold solution of tert-butyl N-(2-hydroxy-2-oxoethyl)-N-(phenylmethyl)carbamate (65.0 g, 0.24 mol), described in preceding section a), and Et3N (31.0 g, 0.31 mol) in CH2Cl2 (610 mL). The mixture was stirred at 0° for 45 min. Solid 4′-aminoacetophenone (34.8 g, 0.26 mol) was added portion wise to the reaction mixture. The reaction mixture was stirred at 0° for 1.5 h and then at room temperature for 16 h. H2O (10 mL) was added. The resulting solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (1 L). The solution was washed successively with 1 N aqueous HCl (2×300 mL), a saturated aqueous solution of NaHCO3 (2×300 mL) and brine (200 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting brownish solid was crystallized (EtOAc: Hex) to give the title compound (56.8 g, 61% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ9.72 (broad s, 1H), 7.90 (d, J=8.6 Hz, 2H), 7.40-7.54 (m, 2H), 7.26-7.39 (m, 5H), 4.55 (s, 2H), 3.96 (s, 2H), 2.56 (s, 3H), 1.51 (s, 9H); MS (FAB) m/z383 (MH)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=O)C.[OH-].[Na+]>CO.O>[OH:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc2cccc(COC(C)=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2cccc(CO)c2c1

Procedure:
0.1 mole of the preceding 1-acetoxymethyl-7-methoxynaphthalene is saponified at room temperature, under argon, with a solution of 0.2 mole of sodium hydroxide diluted in 200 cm3 of methanol and 40 cm3 of water.
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].C([O-])(=O)C.[K+].[S:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>CC(N(C)C)=O.C(OCC)(=O)C.O.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>[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:22]1[S:18][CH:19]=[N:20][CH:21]=1
Reactant: c1cscn1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-c1cncs1
Yield: 59 %

Procedure:
In a microwave vial, a mixture of 2-bromo-5-nitroanisole (300 mg, 1.27 mmol), potassium acetate (188 mg, 1.90 mmol) and tetrakis(triphenylphosphine)palladium(0) (74 mg, 0.634 mmol) in 4 ml dimethyl acetamide was flushed with argon. Thiazole (459 uL, 6.34 mmol) was added, the tube was sealed, and the mixture was heated for 1 h to 160° C. in a microwave oven. The mixture was diluted with ethyl acetate and water, the layers were separated and the aqueous layer was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residual material was subjected to column chromatography on silica gel using heptane/ethyl acetate (7:3) as eluent to afford the title compound as yellow solid (177 mg, 59%). Mp 125-128° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][C:12]([F:15])([F:14])[F:13])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)C(C)C)(C)C.C([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(OC(C)(C)C)=O>Cl.O1CCOCC1>[N:32]1([C:2]2[C:3]3[CH:10]=[C:9]([CH2:11][C:12]([F:15])([F:14])[F:13])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: FC(F)(F)Cc1cc2c(Cl)ncnc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: FC(F)(F)Cc1cc2c(N3CCNCC3)ncnc2s1
Yield: 66.2 %

Procedure:
190 mg of 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (0.75 mmol) was added to a stirred solution of 290 mg of N,N-diisopropylethylamine (2.25 mmol) and 168 mg of 1-Boc-piperazine (0.9 mmol) in 20 mL and was heated at reflux overnight. Solvent was removed under reduced pressure and the residue was loaded on silica gel column. Elution with DCM:MeOH produced 215 mg of Boc-intermediate as a pale yellow solid. Later it was dissolved in 20 mL of 4M HCl in dioxane and stirred for 2 hs. Solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and saturated sodium carbonate solution. Organic layer was washed with brine, dried over MgSO4 and evaporated to afford 150 mg of 4-(piperazin-1-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine, which was used in the next step without purification.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=[CH:7][N:6]=1>CN(C=O)C>[CH3:1][S:2][C:5]1[C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: OCCOc1cccnc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncccc1OCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
To a suspension of sodium thiomethoxide (3.01 g, 42.9 mmol) in dry DMF (30 mL) was 2-[(2-chloro-3-pyridinyl)oxy]ethanol (7.82 g, 45.1 mmol, from Example 193, Step 1) added and the reaction mixture was stirred at ambient temperature for 1 h.. The solvent was removed under reduced pressure and the residue was partitioned between brine/1 M aqueous NaOH and CHCl3. The aqueous phase was extracted with an additional portion of CHCl3 and the combined organic layers were dried (MgSO4) and concentrated. The resulting red oil was purified by column chromatography on silica using toluene/Et3N/MeOH (96:2:2) as eluent to give 3.0 g (36%) of the title compound as brownish crystals: mp 80° C. Anal. (C7H11NO2S) C, H, N.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:5]([N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3([CH3:35])[CH2:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)[CH3:8])=[O:6].C1(P([CH:53]2[CH2:58][CH2:57]CCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O>[Cl:39][C:38]1[CH:37]=[CH:36][C:4]([C:5]([N:7]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH2:12][N:11]([C:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C:32]4([CH3:35])[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25]3)=[O:23])[CH2:10]2)[CH3:8])=[O:6])=[CH:3][C:2]=1[CH:57]1[CH2:58][CH2:53]1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C(=O)c1ccc(Cl)c(C2CC2)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 821.9 %

Procedure:
To a solution of 3-bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzamide (78 mg, 0.12 mmol) in toluene (1 mL) and water (0.048 mL) was added under an atmosphere of nitrogen potassium phosphate, tribasic mono hydrate (88 mg, 0.42 mmol), tricyclohexylphosphine (4 mg, 0.014 mmol) palladium(II) acetate (2 mg, 0.009 mmol). The reaction mixture was stirred for 18 h at 80° C. under an atmosphere of nitrogen. It was concentrated and purification by chromatography (SiO2, ethyl acetate:methanol=100:0 to 85:15) afforded the title compound (71 mg, 97%) as a light brown foam. MS m/e: 616.2 [M]+.
Reaction SMILES: C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O[C:13]1([C:22]#[C:23][CH:24]([OH:26])[CH3:25])[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][C:14]1([OH:21])[CH3:20].[OH-].[Na+]>O>[OH:21][C:14]1([CH3:20])[CH2:15][CH2:16][C:17]([CH3:18])([CH3:19])[C:13]1=[C:22]=[CH:23][CH:24]([OH:26])[CH3:25]
Reactant: CC(O)C#CC1(O)C(C)(C)CCC1(C)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)C=C=C1C(C)(C)CCC1(C)O
Reaction time: 15 h
Yield: 64.9 %

Procedure:
To 15 ml of an anhydrous THF suspension containing 717 mg of lithium aluminum hydride was slowly added 20 ml of an anhydrous THF solution containing 2.0 g of 4-(1,2-dihydroxy-2,5,5-trimethylcyclopentyl)but-3-yn-2-ol under ice-cooling in a nitrogen atmosphere over 10 minutes. After the addition, the mixture was placed under refluxing conditions and stirred for 15 hours. After completion of the reaction, the reaction mixture was cooled, and 0.7 ml of water, 0.7 ml of a 15% sodium hydroxide aqueous solution, and 2.1 ml of water were carefully added thereto in this order, followed by vigorously stirring for 20 minutes. Any insoluble matter was removed by filtration with suction, and the filtrate was concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography to obtain 1.2 g (yield: 63%) of 4-(2-hydroxy-2,5,5-trimethylcyclopentylidene)but-3-en-2-ol.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:20]([O:22]C)=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.[OH-].[Na+].O1CCOC[CH2:27]1>>[CH3:27][C:2]1[CH:3]=[C:4]([C:20]([OH:22])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1
Reactant: C1COCCO1
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(Cl)cc2C1=O
Agent: [Na+]
Agent: [OH-]
Product: CCCC(CCC)N1CCc2c(C(=O)O)cc(C)cc2C1=O

Procedure:
33 mg of methyl 7-chloro-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are dissolved in 6 cm3 of dioxane at a temperature close to 20° C. 1.8 cm3 of a 1N aqueous solution of sodium hydroxide are added, then the reaction mixture is heated at a temperature close to 60° C. for 1 h. The mixture is then concentrated to dryness under reduced pressure (5 kPa), taken up by 10 cm3 of ethyl ether and 10 cm3 of water. The aqueous phase is decanted, acidified with 1 cm3 of a 2N aqueous solution of hydrochloric acid. The reaction medium is washed two times with 10 cm3 of dichloromethane. The organic liquors are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). 215 mg of 7-methyl-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid are obtained in the form of yellow crystals that are used directly in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6](N)[CH:7]=1.N([O-])=O.[Na+].[BrH:14]>O>[Br:14][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH3:9]
Reactant: Cc1ccc(Cl)cc1N
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Cl)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Chloro-2-methylbenzenamine (50 g, 0.355 mol) was dissolved in HBr solution (1.5 M, 100 mL) and cooled to 0° C., a solution of NaNO2 (27.6 g, 0.4 mol) in water (200 mL) was added dropwise. After addition, the mixture was stirred for 1 hr. In another flask CuBr (30 g, 0.21 mol) was added to HBr solution (1.5 M, 30 mL) and heated to 60° C., then the mixture was added to the above solution. The mixture was heated to reflux for 1 hr then cooled to rt. The reaction was quenched with water (500 mL), the aqueous layer was extracted 3 times with CH2Cl2, dried over Na2SO4, solvent removal and purification by column chromatography afforded 2-bromo-4-chloro-1-methylbenzene (53 g, 0.26 mol). 1H NMR (CDCl3, 400 MHz) δ 7.53 (s, 1H), 7.20-7.10 (m, 2H), 2.36 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9][C:10]([O:13][CH2:14][CH:15]([OH:18])[CH:16]=[CH2:17])=[CH:11][CH:12]=1)(=O)=O.[C:28]([C:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].C(N(C(C)C)CC)(C)C>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.CN(C)C=O>[CH2:19]([C:8]1[C:7]([C:29]#[C:28][C:30]2([OH:38])[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[CH:12][CH:11]=[C:10]([O:13][CH2:14][CH:15]([OH:18])[CH:16]=[CH2:17])[N:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: C=CC(O)COc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CC(O)COc1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 22.9 %

Procedure:
A mixture of 46.5 mg of 2-benzyl-6-(2-hydroxy-3-butenyl)oxy-3-pyridyl trifluoromethane sulfonate, 22.7 mg of 3-ethynyl-3-quinuclidinol, 6.6 mg of tetrakis(triphenylphosphine)palladium(0), 0.1 mg of cuprous iodide, 60.1 μl of diisopropylethylamine and 1 ml of N,N-dimethylformamide was stirred at 80° C. for 3 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 5% methanol/ethyl acetate, to give 10.7 mg of the target compound.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1)[C:27]#[N:28]>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:12])[N:28]=2)[CH:29]=[CH:30][C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: N#Cc1ccc(Cc2ccc(Cl)c(Cl)c2)c(Cl)c1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Cc2ccc(Cl)c(Cl)c2)c(Cl)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.00 g), 3-chloro-4-(3,4-dichlorobenzyl)benzonitrile (0.93 g), anhydrous iron (III) chloride (0.50 g) and o-dichtorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 1 hour. After cooling, the reaction mixture is dissolved in chloroform (300 ml), washed with dilute hydrochrolic acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 0.64 g of desired compound (melting point: 179.0°-185.0° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([OH:23])=O)[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[Cl:24]CCl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([Cl:24])=[O:23])[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: ClCCl
Reactant: COc1cccc(NS(=O)(=O)c2cccc(C=CC(=O)O)c2)c1
Solvent: CN(C)C=O
Product: COc1cccc(NS(=O)(=O)c2cccc(C=CC(=O)Cl)c2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a suspension of 3-[3-(3-methoxyphenyl-sulfamoyl)-phenyl]-acrylic acid (5i) (0.38 g, 1.14 mmol) in dichloromethane (4 ml) oxalyl chloride (0.3 ml, 3.43 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.40 g, 100%).
Reaction SMILES: ClC1C(Cl)=C(CC([O-])=O)C=C2C=1C1C(CC)(C2)CCC(=O)C=1.[Cl:23][C:24]1[C:36]([Cl:37])=[C:35]([O:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH:34]=[C:33]2[C:25]=1[C:26]1[C:31]([CH2:47][CH2:48][CH3:49])([CH2:32]2)[CH2:30][CH2:29][C:28](=[O:50])[CH:27]=1>>[Cl:23][C:24]1[C:36]([Cl:37])=[C:35]([O:38][CH2:39][C:40]([OH:42])=[O:41])[CH:34]=[C:33]2[C:25]=1[C:26]1[C:31]([CH2:47][CH2:48][CH3:49])([CH2:32]2)[CH2:30][CH2:29][C:28](=[O:50])[CH:27]=1
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC(=O)OC(C)(C)C)c(Cl)c1Cl)C2
Agent: CCC12CCC(=O)C=C1c1c(cc(CC(=O)[O-])c(Cl)c1Cl)C2
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2

Procedure:
Carrying out a reaction as described in Example 53, Step B, except that the tert.-butyl [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)acetate is replaced by an equimolar amount of tert.-butyl [(5,6-dichloro-3-oxo-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]-acetate, thereby is obtained [(5,6-dichloro-3-oxo-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:25])[NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14]2)=CC=1)([O-])=O.[C:26]([NH:33][C@@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[N-]=C=O>CO.C(Cl)Cl>[C:29]([O:28][C:26](=[O:27])[NH:33][C@@H:34]1[CH2:38][CH2:37][N:36]([C:11](=[O:25])[NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14]2)[CH2:35]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(N[C@@H]1CCN(Cc2ccccc2)C1)Oc1ccc([N+](=O)[O-])cc1
Agent: [N-]=C=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)N[C@@H]2CCN(Cc3ccccc3)C2)C1
Reaction time: 8 h

Procedure:
A solution of ((R)-1-benzyl-pyrrolidin-3-yl)-carbamic acid 4-nitro-phenyl ester (1 eq.) and (3R)-(+)-3-(Boc-amino)pyrrolidine in MeOH is heated using microwave radiation at 100° C. for 1 hour. The reaction mixture is reduced in vacuo. The resulting oil is dissolved in DCM and isocyanate resin (3 eq.) is added and shaken overnight. The resin was filtered off and the DCM was removed in vacuo to yield the title compound. MS (ES+) m/e 299.21 (MH+).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.C([Li])CCC.[C:19]([O:22][C@@H:23]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:24]([OH:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:21])[CH3:20].[F:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[N:52]=[C:53]([CH:67]([CH3:69])[CH3:68])[N:54](/[CH:63]=[CH:64]/[CH:65]=[O:66])[C:55]=2[C:56]2[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=2)=[CH:47][CH:46]=1.[Cl-].[NH4+]>C1COCC1.O>[F:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]2[N:52]=[C:53]([CH:67]([CH3:69])[CH3:68])[N:54](/[CH:63]=[CH:64]/[C@@H:65]([OH:66])[CH2:20][C:19]([O:22][C@@H:23]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]([OH:37])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:21])[C:55]=2[C:56]2[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=2)=[CH:49][CH:50]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Reactant: CC(=O)O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)CC(=O)O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Yield: 94.4 %

Procedure:
A solution of dry dicyclohexylamine (2.49 ml) in dry THF (30 ml) under nitrogen at 3° was treated dropwise with a solution of n-butyl lithium (1.55M in hexanes, 8.06 ml). After 25 min the solution was cannulated dropwise into a stirred suspension of (S)-1-hydroxy-1,1,2-triphenyleth-2-yl acetate (1.828 g) in dry THF (60 ml) under nitrogen at -40°, plus washings (10 ml). When the addition was complete the mixture was allowed to warm to 3°. After 20 min the solution was cooled to -40° and treated with a solution of (E)-3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenal (1.762 g) in dry THF (35 ml) and washings (5 ml) at 3° dropwise. After 4 h the reaction mixture was treated with saturated aqueous ammonium chloride solution (20 ml) and allowed to warm. Water (200 ml) was then added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were dried and evaporated and purified by FCC eluting with System A (7:3) to give the title compound (3.234 g) as a light brown foam, νmax (CHBr3) 2971 (OH), 1729 cm-1 (C=O) (SS:SR=93.7 as determined by pmr).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:20])[CH:11]([OH:19])[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25]CC)=[O:24].C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CN(C)C=O.C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:11]([OH:19])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:22]([CH3:29])([CH3:28])[C:23]([OH:25])=[O:24])=[CH:14][CH:13]=2)=[O:20])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cc(C)cc(NC(=O)C(O)c2ccc(O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Cc1cc(C)cc(NC(=O)C(O)c2ccc(OC(C)(C)C(=O)O)cc2)c1

Procedure:
The preparation of the ethyl ester was carried out using N-(3,5-Dimethyl-phenyl)-2-hydroxy-2-(4-hydroxy-phenyl) acetamide (4.0 g, 14.8 mmol), ethyl 2-bromoisobutyrate (19.2 g, 19.2 mmol), potassium carbonate (3.0 g, 22.1 mmol) in dimethylformamide (30 mL) to yield 2.9 g after column chromatography purification. Hydrolysis of the ester was carried out with (1.0 g, mmol) in ethanol (40 mL) and lithium hydroxide (1.05 g, 25 mmol) dissolved in water (20 mL). Purification by column chromatography gave 900 mg. m.p.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[CH3:15][C:12]1[CH:13]=[CH:14][C:8]2[S:7][C:6]([N:5]=[C:1]=[O:2])=[N:10][C:9]=2[CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc2sc(N)nc2c1
Solvent: CCOC(C)=O
Product: Cc1ccc2sc(N=C=O)nc2c1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-5-methylbenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about one hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 5-methylbenzothiazol-2-yl isocyanate dimer.