Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH3:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[S:13]([N:23]1[CH2:27]C[C@@H:25](O)[CH2:24]1)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[S:13]([N:23]1[CH2:24][CH2:25][C@H:11]([O:10][S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH2:27]1)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)N2CC[C@@H](O)C2)cc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCN(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Methyl para-toluenesulphonate (54 g) was added in portions to a solution of 1-tosyl-3-(R)-(-)-hydroxypyrrolidine (49 g-see Preparation 2) and triphenylphosphine (76 g) in anhydrous tetrahydrofuran (700 ml) at 0° C. The mixture was cooled to -20° C. and diethyl azodicarboxylate (58 g-"DEAD") was added, dropwise, over 30 minutes. During this time, the temperature of the mixture was not allowed to rise above -10° C. When the addition was complete the mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo to give a solid which was purified by column chromatography on silica eluting with hexane containing dichloromethane (50%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from 1-propanol to give the title compound as a colourless solid, yield 56 g, m.p. 110° C., [α]D25 -5.2°(c 1.0, CH2Cl2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14].[C:20](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:20][O:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][C:13]([N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:14]
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1O)N1CCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1CCC(=O)N1CCCC1
Reaction time: 5 h
Yield: 94.1 %

Procedure:
This amide (900 mg, 3.4 mmol) was dissolved in dimethylformamide (100 ml) and potassium carbonate (516 mg) added, followed by iodomethane (0.6 ml, 3.7 mmol). The solution was stirred for 5 hours, then concentrated in vacuo. The residual oil was partitioned between ethyl acetate (50 ml) and H2O (50 ml), the aqueous layer extracted with ethyl acetate (3×50 ml), the combined organic phases washed with brine (20 ml), dried (MgSO4) and evaporated to yield 3-(2-methoxy-4-nitrophenyl)-1-pyrrolidin-1-yl-propan-1-one as a black oil (900 mg, 3.2 mmol);
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]1C[O:11]1.[C:13]([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH3:13])[CH:10]=[O:11]
Reactant: Cc1cccc(CC2CO2)c1C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(C(C)C=O)c1C
Reaction time: 2 h

Procedure:
2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXII), prepared according to example 1 (158 mg, 0.97 mmol), was dissolved in toluene (1.57 mL) and BF3OEt2 (0.006 ml, 0.05 mmol) was added at room temperature. After 2 h at room temperature, a sample was mixed with solid NaHCO3, filtered, concentrated under reduced pressure, and the residue was analyzed by 1H NMR. The crude product consisted essentially of pure 2-(2,3-dimethylphenyl)propanal.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14])([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CO)cc1[N+](=O)[O-]
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
240 g of manganese dioxide were added to a solution of 30 g (0.14 mol) of 2-t-butyl-5-hydroxymethyl-1-nitrobenzene (prepared as described in Preparation 10) in 450 ml of chloroform, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was filtered to remove manganese dioxide, and the filtrate was freed from the solvent by distillation under reduced pressure . The resulting residue was purified by column chromatography through silica gel, using a 1:5 by volume mixture of ethyl acetate and hexane as the eluent, to give 27.4 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][O:13][CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:7]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2].C([Li])CCC.Cl>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@@H:8]([CH2:11][CH2:12][O:13][CH2:14][O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:7]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H](CCOCOCc2ccccc2)CCN1C(=O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCO
Product: CCOC(=O)[C@H]1[C@H](CCOCOCc2ccccc2)CCN1C(=O)OCC

Procedure:
A solution of 6.2 g of cis ethyl 1-ethoxycarbonyl-3-[2-(benzyloxymethoxy)-ethyl]-pyrrolidine-2-carboxylate in 75 ml of anhydrous ethanol containing 1 ml of butyllithium (1.6M) is refluxed under nitrogen for 6 days. After cooling, 1.7 ml of 1N hydrochloric acid is added, the solution is concentrated in vacuo, cold water added and mixture extracted with methylene chloride. The extract is dried over sodium sulfate, filtered, concentrated and purified by high pressure liquid chromatography using ethyl acetate/hexane (15:85) to yield trans ethyl 1-ethoxycarbonyl-3-[2-(benzyloxymethoxy)-ethyl]-pyrrolidine-2-carboxylate.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH:3]2[CH2:7][CH2:8][CH2:9][CH:2]12.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:20](Br)[CH:21]=[CH2:22]>C1COCC1>[CH2:22]([CH:4]1[C:5](=[O:6])[O:1][CH:2]2[CH2:9][CH2:8][CH2:7][CH:3]12)[CH:21]=[CH2:20]
Reactant: O=C1CC2CCCC2O1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1C(=O)OC2CCCC21

Procedure:
Analogously to the procedure of Example 1, the title compound is was prepared from 1.2 g (9.5 nmuol) of hexahydro-cyclopenta[b]furan-2-one, 10 ml of 1 molar lithium bis-(trimethylsilyl)-amide solution in THF and 1.29 g (9.5 mmol) of allyl bromide in 20 ml of THF. Yield: 1.25 g (79%) of a colourless oil. 1H-NMR(200 MHz; [d6]-DMSO): δ[ppm]: 1.47-1.89 (br m,6H), 2.15-2.55 (br m,4H), 4.41 (m,1H), 5.12 (dd,1H), 5.18 (dd,1H), 5.76 (ddt,1H)
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:12])=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cl-:13].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:13][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:12])=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cncc2cc(O)ccc12
Reactant: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cncc2cc(Cl)ccc12

Procedure:
A mixture of 15.9 g. (0.1 mole) of 7-hydroxy-4-methylisoquinoline and 41.7 g. (0.125 mole) of triphenylphosphine dichloride is heated to 230° C. for four hours, cooled, and partitioned between chloroform and concentrated hydrochloric acid. The aqueous phase is neutralized with ammonium hydroxide and extracted with chloroform to yield 7-chloro-4-methylisoquinoline.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C:7]([CH3:15])([CH3:14])[C:8]([F:13])([F:12])[CH2:9][CH2:10][OH:11])[CH3:5])[CH3:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:11][CH2:10][CH2:9][C:8]([F:12])([F:13])[C:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])([CH3:15])[CH3:14])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CCOC(C)OC(C)(C)C(F)(F)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(C)OC(C)(C)C(F)(F)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 1.00 g (0.0044 mol) of 4-(1-ethoxyethoxy)-3,3-difluoro-4-methyl-1-pentanol, 4 mL of pyridine and 1.27 g (0.0066 mol) of p-toluenesulfonyl chloride was stirred at 0° C. for 18 hr. The mixture was quenched with ice chips. The mixture was then poured into water and extracted with methylene chloride. The organic phase was sequentially washed with 10% aqueous sulfuric acid and saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to yield oily 4-(1-ethoxyethoxy)-3,3-difluoro-4-methyl-1-pentanol 1-(4-methylbenzenesulfonate). NMR (CDCl3) δ4.93 (quartet, 1, J=7 Hz), 4.27 (triplet, 2, J=7 Hz), 3.45 (quartet, 2, J=7 Hz), 2.45 (singlet, 3), 2.36 (multiplet, 2), 1.27 (triplet, 6, J=1 Hz), 1.24 (doublet, 3 J=7 Hz), and 1.15 ppm (triplet, 3, J=7 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH:9]([CH3:10])[CH2:8][C:7]2([CH3:12])[CH2:11][CH:3]1[CH2:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=12.BrC#[N:19]>C(Cl)Cl>[CH3:10][CH:9]1[N:2]([C:1]#[N:19])[CH:3]2[CH2:11][C:7]([CH3:12])([C:6]3[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=3[CH2:4]2)[CH2:8]1
Reactant: N#CBr
Reactant: CC1CC2(C)CC(Cc3ccccc32)N1C
Solvent: ClCCl
Product: CC1CC2(C)CC(Cc3ccccc32)N1C#N
Temperature: 45 °C
Reaction time: 2 h

Procedure:
3,4,6-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine (from Example LVI, 1.7 g) dissolved in CH2Cl2 (40 mL) is added to a solution of BrCN (1.17 g) in CH2Cl2 (10 mL) chilled in an ice bath. The cooling bath is removed and the mixture is stirred at ambient temperature for 1 h and at 45° C. for 2 h. After cooling to ambient temperature, the solution is washed with water, 2 M hydrochloric acid, and 10% aqueous K2CO3 solution. The solution is dried (MgSO4), the solvent is removed, and the residue is triturated with little acetone to give the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]([O:26]CC)=[O:25])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc([C@H]2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc([C@H]2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)cc1C(=O)O
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A mixture of (R)-3-(3-ethoxycarbonyl-4-methyl-phenyl)-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester (2.12 g, 4.72 mmol), potassium carbonate (1.30 g, 9.43 mmol), methanol (25 mL) and water (6 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (150 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 1.98 g (99%) (R)-3-(3-carboxy-4-methyl-phenyl)-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@@H:7]([CH3:10])[CH2:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@@H:7]([CH3:10])[CH2:8][NH:9][S:23]([CH:20]([CH3:22])[CH3:21])(=[O:25])=[O:24])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C[C@@H](CN)Oc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NC[C@H](C)Oc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
The above prepared (2S)-2-(4-bromophenoxy)propylamine was combined in a 500 mL 3-neck round bottomed flask with triethylamine (5.7 mL) and methylene chloride (110 mL), fitted with a thermometer, stirbar, and in a nitrogen system. The reaction mixture was cooled to 0° C. in an ice bath, with stirring, and isopropylsulfonyl chloride (2.75 mL, 24.585 mmol) was added by syringe. The mixture was stirred overnight, gradually becoming room temperature. The reaction was quenched with 100 mL water, and extracted two times with 100 mL methylene chloride. The organic extractions were combined, and washed with 200 mL brine, dried with sodium sulfate, filtered and concentrated in-vacuo, yielding 2.08 g viscous brown oil. This material was further purified using one Waters Prep-Pak® on a Waters Prep 2000 HPLC, in a 3:1 hexanes:ethyl acetate solvent system to provide the final title compound (1.63 g, 30%) as a viscous yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14]>O>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:12][C:13](=[O:14])[NH:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c(=O)c2ccc(Br)cc2[nH]1
Temperature: 195 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a 250 mL round bottom flask, 2-amino-4-bromo-benzoic acid (10 g, 0.0463 mol) and urea (27.78 g, 0.4629 mol) were added. The reaction mixture was stirred at 195° C. for 3 h. The reaction mixture was allowed to reach 80° C. and water was added. The aqueous reaction mixture was stirred at 80° C. for 5-10 min then allowed to reach room temperature. The solid was filtered, dried and azeotroped with toluene to afford the title compound [10 g, 90%]. This material was taken to the next step without any further purification.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([NH2:45])=[N:43][CH:44]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:45][C:42]5[CH:41]=[CH:40][C:39]([Cl:38])=[CH:44][N:43]=5)=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Cl)cn3)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.5 %

Procedure:
A solution of the product of Example 19C (471 mg, 0.861 mmol) in anhydrous tetrahydrofuran (8 mL) was treated with 5-chloro-2-aminopyridine (125 mg, 0.972 mmol) and diisopropylethylamine (0.232 mL, 1.332 mmol), and stirred at room temperature under a nitrogen atmosphere for 18 hours. The solvent was removed by rotary evaporation in vacuo, the residue taken up in ethyl acetate (250 mL) and washed with saturated aqueous sodium bicarbonate (50 mL), water (2×50 mL), and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with methylene chloride provided the title compound as a yellow solid (373 mg, 61%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][F:15])[NH:11][CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(#N)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][F:15])[N:11]([CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: C[C@@H]1CN[C@@H](CF)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN(CC(=O)OCc2ccccc2)[C@@H](CF)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
A mixture of (2R,5R)-5-fluoromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.371 g, 1.27 mmol), potassium carbonate (0.70 g, 5.1 mmol), benzyl bromoacetate (0.38 g, 1.65 mmol) and acetonitrile (10 mL) was stirred at 20° C. for 18 h. Mixture was poured into water (50 mL) and extracted with DCM (3×30 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-100% Et2O in 40-60 petroleum ether) gave the title compound (0.424 g, 87%) as an oil. MS [M+H]+=381.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1)[CH3:2].[CH3:15][CH:16](O)[CH:17]=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:15]([CH:8]1[C:7]([CH3:13])([CH3:14])[C:6]2[C:10](=[CH:11][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:16]=[CH:17][CH3:18]
Reactant: CCc1ccc2c(c1)C(=O)CC2(C)C
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(CC)ccc2C1(C)C
Yield: 70 %

Procedure:
A solution of 9.1 g of 6-ethyl-3,3-dimethyl-1-indanone, 9.98 ml of 3-buten-2-ol and 250 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxypropane was boiled under reflux for 88 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 6:1). In addition to 2.0 g of educt, there were obtained 8.2 g (70%) of (RS)-2-(2-buten-1-yl)-6-ethyl-3,3-dimethyl-1-indanone as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC2C=CC=CC=2)=[O:19])=[CH:13][C:12]=1[O:28][CH3:29].[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[O:28][CH3:29]
Reactant: COc1cc(CC(=O)OCc2ccccc2)ccc1NC(=O)Nc1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a stirred solution of benzyl 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetate (2.04 g, 5 mmol) in THF (40 mL) was added 0.25 N NaOH (40 mL). The resulting mixture was stirred overnight. The mixture was poured into 1 N HCl (10 mL), and the resulting precipitate was collected with suction. The residue was recrystallized from CHCl3—EtOH to give 1.04 g (66%) 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetic acid as a white crystalline powder. mp 185-188 (d); 1H-NMR (DMSO-d6) δ3.50 (2H, s), 3.82 (3H, s), 6.78 (1H, dd, J=1.4 and 8.3 Hz), 6.92 (1H, d, J=1.4 Hz), 6.95-7.01 (1H, m), 7.10-7.14 (1H, m), 7.19-7.24 (1H, m), 8.01 (1H, d, J=8.3 Hz), 8.14-8.18 (1H, m), 8.72 (1H, s), 9.17 (1H, s); MS (FAB) m/z 319 (M++1); Anal. Calcd. for C16H15N2O4F: C, 60.37; H, 4.75; N, 8.80. Found: C, 60.20; H, 4.82; N, 8.67.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][C:19]=1[CH:24]=O.N1CCCC1>C(O)C>[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][C:19]=1[CH:24]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: C1CCNC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]1
Temperature: 90 °C

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol), 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (29 mg, 0.23 mmol) and pyrrolidine (0.006 mL) in ethanol (0.5 mL) was refluxed for 2 hours at 90° C. The reaction was cooled and the precipitate which formed was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([S:14][CH3:15])[CH:12]=[CH:13][C:7]=2[NH:6][S:5]1(=[O:17])=[O:16])[CH3:3].[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.C(OCC)(=O)C>[CH3:3][CH:2]([N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([S:14][CH3:15])[CH:12]=[CH:13][C:7]=2[N:6]([CH2:22][CH:21]=[CH2:20])[S:5]1(=[O:17])=[O:16])[CH3:1]
Reactant: CSc1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCN1c2ccc(SC)cc2CN(C(C)C)S1(=O)=O

Procedure:
3,4-Dihydro-3-(1-methylethyl)-6-methylthio-1H-2,1,3-benzothiadiazine-2,2-dioxide (10 g, 0.0367 mol) was added to a suspension of sodium hydride (1.61 g, 60% dispersion) in dry dimethylformamide (200 ml) at room temperature under a nitrogen atmosphere. The pale grey suspension was stirred for ten mins, and then allyl bromide (3.49 ml, 0.0404 mol) was added in one portion. The reaction mixture was stirred at 80° C. for 3 hr. The mixture was then concentrated in vacuo to yield a brown residue. The residue was dissolved in ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was then dried (MgSO4) and concentrated in vacuo to afford 3,4-dihydro-3-(1-methylethyl)-6-methylthio-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. δ(1H NMR, DMSO, ppm): 1.1 (6H, d), 2.5 (3H, s), 4.1 (1H, m), 4.5 (2H, d), 4.7 (2H, s), 5.3 (1H, dd), 5.4 (1H, dd), 6.0 (1H, m), 7.0 (1H, d), 7.3 (2H, m).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([Br:12])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].I[CH2:14][CH2:15][CH3:16]>>[C:1]([C:5]1[CH:6]=[C:7]([Br:12])[CH:8]=[CH:9][C:10]=1[O:11][CH2:14][CH2:15][CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCI
Reactant: CC(C)(C)c1cc(Br)ccc1O
Product: CCCOc1ccc(Br)cc1C(C)(C)C
Yield: 86.7 %

Procedure:
Following the basic procedure of Example 46(a), by reacting 4.58 g (0.02 mol) of 3-tert-butyl-4-hydroxybromobenzene with 2.2 ml (0.022 mol) of 1-iodopropane, 4.7 g (87%) of 3-tert-butyl-4-propyloxybromobenzene were obtained in form of a colorless oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:22])=[CH:6][C:7]([O:20][CH3:21])=[C:8]([NH:10][C:11](=[S:19])OC2C=CC=CC=2)[CH:9]=1)(=[O:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([Cl:30])[CH:29]=1>>[C:1]([C:4]1[C:5]([CH3:22])=[CH:6][C:7]([O:20][CH3:21])=[C:8]([NH:10][C:11]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([Cl:23])[CH:29]=[C:28]([Cl:30])[CH:27]=3)[CH2:36][CH2:35]2)=[S:19])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: COc1cc(C)c(C(C)=O)cc1NC(=S)Oc1ccccc1
Product: COc1cc(C)c(C(C)=O)cc1NC(=S)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 79 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)thiocarbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C@@H:39]1[CH2:56][C:55]2[C@H:50]([CH2:51][CH2:52][C:53](=[O:57])[CH:54]=2)[C@@H:49]2[C@@H:40]1[C@H:41]1[C@@:45]([CH2:47][CH:48]2O)([CH3:46])[C:44](=[O:59])[CH2:43][CH2:42]1>C(OCC)(=O)C>[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C@@H:39]1[CH2:56][C:55]2[C@H:50]([CH2:51][CH2:52][C:53](=[O:57])[CH:54]=2)[C@@H:49]2[C@@H:40]1[C@H:41]1[C@@:45]([CH2:47][C@@H:48]2[F:12])([CH3:46])[C:44](=[O:59])[CH2:43][CH2:42]1
Reactant: C[C@]12CC(O)[C@H]3[C@@H]([C@H](CCCCCCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 2 h

Procedure:
3.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene and, drop by drop, 4 ml of perfluorobutane-1-sulfonic acid fluoride are added to 6.7 g of 7α-(9-chlorononyl)-11-hydroxy-estr-4-ene-3,17-dione in 35 ml of ethyl acetate at 0° C. After 2 hours, it is diluted with ethyl acetate, washed several times with 2N hydrochloric acid and neutralized with saturated sodium bicarbonate solution and water. The crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient. Yield: 6.2 g of 7α-(9-chlorononyl)-11β-fluor-estr-4-ene-3,17-dione as an oil.