Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3]1[CH2:25][O:24][C:5]2([CH2:22][CH2:21][C:20]3[C:19]4[C@H:10]([C@H:11]5[C@@:15]([CH2:17][CH:18]=4)([CH3:16])[C:14](=[O:23])[CH2:13][CH2:12]5)[CH2:9][CH2:8][C:7]=3[CH2:6]2)[O:4]1.CC(C)=O.[Cl-].[Na+]>[OH-].[Na+].CO.C(OCC)(=O)C.O>[CH2:25]1[CH2:3][O:4][C:5]2([CH2:22][CH2:21][C:20]3[C:19]4[C@H:10]([C@H:11]5[C@@:15]([CH2:17][CH:18]=4)([CH3:16])[CH:14]([OH:23])[CH2:13][CH2:12]5)[CH2:9][CH2:8][C:7]=3[CH2:6]2)[O:24]1
Reactant: C[C@]12CC=C3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC1(CC4)OCCO1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC=C3C4=C(CC[C@H]3[C@@H]1CCC2O)CC1(CC4)OCCO1
Temperature: 2 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (MW=37.8; 18.9 g; 500 mmol) in solution in 0.5 N sodium hydroxide (100 ml) is introduced, over approximately 5 min at around 2° C., into a suspension of 3,3-ethylenedioxyestra-5(10), 9(11)-dien-17-one (MW=314.4; 100 g; 318 mmol) in methanol (1 liter). The mixture is stirred for 2 h at around 2° C. and then acetone (100 ml) is introduced over approximately 15 min at around 5° C. The mixture is stirred for 1 h and the medium is run, at around 20° C., into a stirred mixture of water (2 liters), sodium chloride (500 g) and ethyl acetate (400 ml). The mixture is separated by settling out and the aqueous phase is re-extracted with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and concentrated at normal pressure to 500 ml. The distillation is continued while maintaining the volume constant by gradual introduction of 1,2-dimethoxyethane (DME). The temperature at the end of exchange is 83° C. The solution is used as it is in the subsequent stage, but a dry extract results in the expected product (resin). C20H28O3; MW=316.4:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[C:7]([N:11]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20](I)[CH:21]=[CH:22][C:15]=2[NH:14][C:13](=[O:24])[CH2:12]1)([CH3:10])([CH3:9])[CH3:8].C(OCC)(=O)C>C(N(CC)CC)C.[Cu]I.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>[C:7]([N:11]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:21]=[CH:22][C:15]=2[NH:14][C:13](=[O:24])[CH2:12]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)N1CC(=O)Nc2ccc(I)cc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)N1CC(=O)Nc2ccc(C#C[Si](C)(C)C)cc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.8 %

Procedure:
(Trimethylsilyl)acetylene (1.18 mL, 8.4 mmol), copper(I) iodide (0.05 g, 0.28 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.1 g, 0.14 mmol) are added sequentially to a degassed suspension of 4-tert-butyl-3,4-dihydro-7-iodo-1H-1,4-benzodiazepine-2,5-dione (2.5 g, 7.0 mmol) in triethylamine. The reaction mixture is stirred at room temperature for 5 hours and filtered. The filtrate is diluted with ether and concentrated in vacuo to obtain a solid. Chromatography of the solid using silica gel and 15% to 20% ethyl acetate in hexanes solutions gives the title product as a light brown solid (1.33 g, mp 243°-244° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12]C)[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[CH:15]=1.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([C:31]([C:33]2[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=2)=[O:32])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[N:30]=[CH:29][C:28]([C:31]([OH:32])([C:33]2[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=2)[C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[CH:27][CH:26]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)nc1
Reactant: COc1cc(-c2cccc(OC(C)C)c2)c2cc(Br)ccc2n1
Product: CC(C)Oc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1

Procedure:
Following the same procedure as that described in example 1E, 6-bromo-4-(3-isopropoxy-phenyl)-2-methoxy-quinoline (238.4 mg, 0.640 mmol) and (6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (156 mg, 0.705 mmol) generated the title compound of 34C (80 mg, 24% yield).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][CH2:11][C:12]12[CH2:17][CH:16]1[CH2:15][NH:14][CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:25]1([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:39])=[C:35](F)[CH:36]=3)[C:31](=[O:40])[C:30]([C:41]([OH:43])=[O:42])=[CH:29]2)[CH2:27][CH2:26]1>C(#N)C>[C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][CH2:11][C:12]12[CH2:17][CH:16]1[CH2:15][N:14]([C:35]1[CH:36]=[C:37]3[C:32]([C:31](=[O:40])[C:30]([C:41]([OH:43])=[O:42])=[CH:29][N:28]3[CH:25]3[CH2:27][CH2:26]3)=[CH:33][C:34]=1[F:39])[CH2:13]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)CCNCC12CNCC1C2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCNCC12CC1CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 30.6 %

Procedure:
A mixture of 1-[N-(tert-butoxycarbonyl)ethylaminomethyl]-3-azabicyclo[3.1.0]hexane (45.3 mg, 0.18 mmol) and triethylamine (50 μl, 0.36 mmol) in acetonitrile (5 ml) was treated with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (50.0 mg, 0.18 mmol) and heated to 80° for 18 hours. Filtratation of the reaction mixture provided the title product as a white solid (26.8 mg, 0.055 mmol, 31% yield). 1H NMR (CDCl3):8.67 (s, 1H), 7.90 (d, J=15 Hz, 1H), 6.89 (d, J=7 Hz, 1H), 3.87 (bs, 2H), 3.5 (m, 5H), 3.3 (bs, 2H), 1.6 (m, 1H), 1.49 (s, 9H), 1.33 (m, 2H), 1.14 (m, 5H), 0.83 (m, 1H), 0.68 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][NH2:11].[I:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15](F)[C:14]=1[CH:20]=O>CN1C(=O)CCC1>[I:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[N:10]([C:3]3[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=3[F:1])[N:11]=[CH:20][C:14]=12
Reactant: NNc1ccc(F)c(F)c1F
Reactant: O=Cc1c(I)ccnc1F
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncc3c(I)ccnc32)c(F)c1F
Temperature: 185 °C
Yield: 19.6 %

Procedure:
To a dry 15 mL ChemGlass pressure bottle under N2 was added (2,3,4-trifluorophenyl)hydrazine (359 mg, 2.212 mmol), 4-iodo-2-fluoro-3-formylpyridine (555.1 mg, 2.212 mmol), and anhydrous NMP (5 mL). The reaction mixture was flushed with argon, securely capped, and heated at 185° C. for 3 h. The reaction mixture was worked up according to the procedure described in Intermediate 69A. The product was purified by Biotage Silica gel chromatography using a 25 g Thompson Single Step™ silica cartridge with a linear gradient from 100% hexanes to 100% CH2Cl2 over 12 column volumes gave 162.9 mg (20.4%) of the title compound as a yellow solid. LC/MS (Condition B): ret. T=4.0 min, (M+H)+ 375.93.
Reaction SMILES: [Si](OC1C=CC(B(O)O)=CC=1)(C(C)(C)C)(C)C.BrC1C(CC(OC)=O)=C(C2C=CC(O[Si](C(C)(C)C)(C)C)=CC=2)SC=1.ClC1C=CC=CC=1B(O)O.[Si]([O:60][C:61]1[CH:66]=[CH:65][C:64]([C:67]2[S:68][CH:69]=[C:70]([C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=3[Cl:83])[C:71]=2[CH2:72][C:73]([O:75][CH3:76])=[O:74])=[CH:63][CH:62]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:83][C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][C:77]=1[C:70]1[C:71]([CH2:72][C:73]([O:75][CH3:76])=[O:74])=[C:67]([C:64]2[CH:65]=[CH:66][C:61]([OH:60])=[CH:62][CH:63]=2)[S:68][CH:69]=1
Reactant: COC(=O)Cc1c(-c2ccccc2Cl)csc1-c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COC(=O)Cc1c(Br)csc1-c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1c(-c2ccccc2Cl)csc1-c1ccc(O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
This compound was prepared in a fashion similar to Example 1 with the following modifications: 4(t-Butyldimethylsilyloxy)phenylboronic acid (2.53 g, 10.0 mmol) was used in Step 5 to synthesize methyl [4-bromo-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)thien-3-yl]acetate (2.71 g). This material was reacted as in Example 1 Step 6 with 2-chlorophenylboronic acid (1.93 g, 12.31 mmol) to synthesize methyl [2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(2-chlorophenyl)thien-3-yl]acetate (2.12 g). Methyl [2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(2-chlorophenyl)thien-3-yl]acetate (2.00 g, 4.22 mmol) was dissolved in THF and a solution of tetrabutylammonium fluoride in THF (4.65 mL, 1 M, 4.65 mmol) was added dropwise. The solution was heated to 60° C. and stirred for 3 h. The solvent was removed and the mixture was partitioned between EtOAc and 1N HCl. The EtOAc was washed with H2O, dried (MgSO4), and the solvent removed to yield methyl [4-(2-chlorophenyl)-2-(4-hydroxyphenyl)thien-3-yl]acetate (1.34 g) which was used without further purification.
Reaction SMILES: C[O:2][S:3]([CH2:6][C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][N:8]=1)(=O)=[O:4].C1(C)C=CC=CC=1.C[N:24](C=O)C.C(Cl)(=O)C(Cl)=O>O>[CH:13]1[CH:14]=[CH:15][C:10]2[O:9][N:8]=[C:7]([CH2:6][S:3]([OH:2])(=[O:4])=[NH:24])[C:11]=2[CH:12]=1
Reactant: COS(=O)(=O)Cc1noc2ccccc12
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: N=S(=O)(O)Cc1noc2ccccc12
Temperature: 10 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A 250 ml three necked flask, equipped with mechanical stirrer, Dean-Stark trap and condenser, was charged with 1,2-benzisoxazole-3-methanesulfonic acid methyl ester (10 grams, 0.044 mole, obtained from a commercial vendor) and toluene (100 ml). The suspension was heated to reflux while azeotropic distillation of water was performed, during 2 hours. The mixture was thereafter cooled under nitrogen atmosphere to 10° C. and DMF (0.36 ml, 0.0044 mole, 0.1 molar equivalent) was added to the mixture. Oxalyl chloride (4.1 ml, 0.047 mole, 1.07 molar equivalent) was then added drop-wise at 10-15° C. during 30 minutes and the reaction mixture was heated to 40° C. and was kept at this temperature for 4 hours. Ammonia (gas) (3.0 grams, 4 molar equivalents) was then bubbled into the reaction mixture at 10-18° C. during 2 hours and the reaction mixture was kept at ambient temperature overnight. The obtained precipitate was collected by filtration and slurried in 25% ammonium hydroxide (40 ml) at ambient temperature for 2 hours. The obtained solid was collected by filtration, washed with water and dried under reduced pressure at 50° C., overnight to obtain crude zonisamide (7.4 grams, 80.4% yield) having a purity of 98.7%, as determined by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[CH3:33])=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.S(Cl)(Cl)=O.[CH3:40]OC(=O)C1C=CC(N)=C(C)C=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:40][O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:34][CH3:35])(=[O:10])=[O:9])[C:16]=3[CH:17]=2)=[O:22])=[C:25]([CH3:33])[CH:26]=1
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=O)O)cc3C)cc21
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)c(C)c1

Procedure:
4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-3-methyl-benzoic acid, MS (ISP): m/e=515.3 (M−H), was prepared as described in example 1, steps 1 to 6. Step 5 was performed using thionyl chloride in toluene and dimethyl-formamide for the formation of the acyl chloride, and 4-amino-3-methyl-benzoic acid methyl ester was used for the coupling, yielding 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-3-methyl-benzoic acid methyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([CH2:10][C:11]([O:13]CC)=[O:12])=[CH:9][N:4]2[CH:3]=1.[ClH:16]>>[ClH:16].[CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]([CH2:10][C:11]([OH:13])=[O:12])=[CH:9][N:4]2[CH:3]=1
Reactant: CCOC(=O)Cc1cn2cc(C)sc2n1
Agent: Cl
Product: Cc1cn2cc(CC(=O)O)nc2s1
Yield: 59 %

Procedure:
Ethyl 4-bromo-3-oxobutanoate (92 g, 0.35 mol) was added to a solution of 5-methylthiazol-2-amine (40 g, 0.35 mol) in acetone (400 mL). The mixture was left to stand overnight and then evaporated to give 2-amino-3-(4-ethoxy-2,4-dioxobutyl)-5-methylthiazol-3-ium bromide in 82% yield, 101 g. 2-amino-3-(4-ethoxy-2,4-dioxobutyl)-5-methylthiazol-3-ium bromide (101 g, 0.28 mol) was then refluxed in ethanol (250 mL) for 2 hours. The solvent was then evaporated to give ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate hydrobromide as yellow crystals in 97% yield, 85 g. Solid K2CO3 was added to a solution of ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate hydrobromide (85 g, 0.28 mol) in water (300 mL) to pH ˜8. The product was extracted with chloroform (3×100 mL), and the combined extracts were dried over Na2SO4 and evaporated to give ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate in 84% yield 52 g. Ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate (52 g, 0.23 mol) was refluxed in 10% aqueous HCl (150 mL) for 2 hours. The solution was evaporated to dryness to give the title compound as brown crystals in 59% yield 32.3 g; m/z 197 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH:5]1[CH2:10][CH:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C:7]([CH3:20])([CH3:19])[O:6]1>[OH-].[Na+].CO>[CH3:19][C:7]1([CH3:20])[O:6][C@@H:5]([CH2:4][C:3]([OH:21])=[O:2])[CH2:10][C@@H:9]([CH:11]=[CH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:8]1
Reactant: COC(=O)CC1CC(C=Cc2ccccc2)OC(C)(C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)O[C@@H](CC(=O)O)C[C@@H](C=Cc2ccccc2)O1
Yield: 89 %

Procedure:
A solution of 2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-acetic acid methyl ester (8.5 g, 29.3, mmol) in 1N NaOH (32 mL) and methanol (64 mL) was heated to reflux for 45 minutes. After evaporation under reduced pressure, the aqueous solution was washed once with diethyl ether and acidified with 1N HCl (33 mL). The precipitate was collected and recrystallized from ethyl acetate/isopropyl ether to afford 7.2 g (90%) of the title compound as a colorless solid; m.p.=153-155° C.
Reaction SMILES: O.[OH-].[K+:3].[CH2:4]([C:6]1[S:10][C:9](=[N:11][C:12]([C:14]2[CH2:18][CH2:17][CH2:16][C:15]=2[C:19]([OH:21])=[O:20])=[O:13])[N:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[N:7]=1)[CH3:5]>C(O)C>[CH2:4]([C:6]1[S:10][C:9](=[N:11][C:12]([C:14]2[CH2:18][CH2:17][CH2:16][C:15]=2[C:19]([O-:21])=[O:20])=[O:13])[N:8]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:27][CH:28]=2)[N:7]=1)[CH3:5].[K+:3].[K+:3].[CH2:4]([C:6]1[S:10][C:9](=[N:11][C:12]([C:14]2[CH2:18][CH2:17][CH2:16][C:15]=2[C:19]([O-:21])=[O:20])=[O:13])[N:8]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:27][CH:28]=2)[N:7]=1)[CH3:5]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)[O-])CCC2)s1
Reaction time: 8 h

Procedure:
In a mixed solution containing 15 ml of water and 16 ml of a 0.5N potassium hydroxide solution in ethanol, 2.0 g of 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazolin-2-yliden]aminocarbonyl]-1-cyclopentenecarboxylic acid was dissolved. From the resulting solution, the solvent was distilled off. To the residue, 50 ml of ethanol was added, and the resulting mixture was allowed to stand overnight. The crystals so precipitated were collected by filtration and dried, whereby 2.24 g of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1ccc(Br)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1ccc(Br)cc1)S(C)(=O)=O
Temperature: 25 °C

Procedure:
A solution of N-(4-bromophenyl)methanesulfonamide (200 mg, 0.80 mmol), potassium carbonate (2 eq) and methyl iodide (2 eq) in DMF (2 mL) was heated at 60° C. for 18 h. After cooling to rt the mixture was diluted with EtOAc and washed with water. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give N-(4-bromophenyl)-N-methylmethanesulfonamide.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[CH:7]=[C:8]([C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH:27]1[CH:31]=[C:30]([CH2:32][CH2:33][N:34]2[C:38](=[O:39])[CH2:37][NH:36][C:35]2=[S:40])[N:29]=[CH:28]1.N1CCCCC1>ClCCl>[NH:27]1[CH:31]=[C:30]([CH2:32][CH2:33][N:34]2[C:38](=[O:39])/[C:37](=[CH:17]/[C:15]3[O:16][C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=4)=[CH:13][CH:14]=3)/[NH:36][C:35]2=[S:40])[N:29]=[CH:28]1
Reactant: O=C1CNC(=S)N1CCc1c[nH]cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(C=O)o2)c1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(/C=C3\NC(=S)N(CCc4c[nH]cn4)C3=O)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
5-(3-(Tributylstannyl)phenyl)furan-2-carbaldehyde (65 mg, 0.14 mmol) synthesized by the same method as in Example 4 and 3-(2-(1H-imidazol-4-yl)ethyl)-2-thioxoimidazolidin-4-one (32 mg, 0.15 mmol) synthesized by the same method as in Example 3 were dissolved in dichloromethane (7 mL), piperidine (20 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) overnight. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform/methanol (9/1 (volume ratio)) as an eluent, to give labeling precursor 3 in a yield of 42 mg (yield 45.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Mg]Br.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18](=[O:21])[CH2:19][CH3:20])[CH:15]=[CH:16][CH:17]=1.[Cl-].[NH4+].Cl>C1COCC1.O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])([OH:21])[CH2:19][CH3:20])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccccc1[Mg]Br
Reactant: CCC(=O)c1cccc(OC)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)(c1cccc(OC)c1)c1ccccc1C
Reaction time: 8 h
Yield: 438.6 %

Procedure:
To a solution of 2-methylphenyl magnesium bromide (prepared from 4.9 g magnesium turnings and 24 ml of 2-bromotoluene) in dry THF (300 ml) was added dropwise a solution of 3'-methoxypropiophenone (25.9 g, 0.16 mol) in dry THF (200 ml). When addition was complete the mixture was heated at reflux temperature for 2 h. Water (250 ml) was added followed by a saturated ammonium chloride solution (250 ml) and the mixture was left overnight. A 4 N hydrochloric acid solution was added until a clear solution was obtained and the phases was separated. The organic phase was dried over magnesium sulphate and the solvent evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (690 g) using a gradient of n-heptane in ethyl acetate to give 28.2 g (55%) of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propanol. A mixture of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propanol (26.2 g, 0.10 mol), isopropanol (300 ml) and a 6 N solution of sulphuric acid (150 ml) was stirred at room temperature for 2 h. The reaction mixture was neutralised with a 4 N sodium hydroxide solution and extracted with ethyl acetate (2×200 ml). The combined organic phases was dried over magnesium sulphate and the solvent was evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (800 g) using n-heptane as eluent to give 18.4 g (76%) of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propene.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](I)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:12]([C@@H:14]1[NH:18][C:17](=[O:19])[CH2:16][C@@:15]1([OH:21])[CH3:20])[CH3:13].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:18]2[C:17](=[O:19])[CH2:16][C@@:15]([OH:21])([CH3:20])[C@@H:14]2[CH2:12][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(I)ccc(C#N)c1Cl
Reactant: CC[C@@H]1NC(=O)C[C@]1(C)O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@@H]1N(c2ccc(C#N)c(Cl)c2C)C(=O)C[C@]1(C)O

Procedure:
Using 2-chloro-4-iodo-3-methylbenzonitrile (565 mg), (4S,5S)-5-ethyl-4-hydroxy-4-methylpyrrolidin-2-one (350 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (180 mg), tris(dibenzylideneacetone)dipalladium(0) (93 mg) and cesium carbonate (929 mg), and in the same manner as in Example 62, the title compound was obtained as colorless crystals (yield: 132 mg, 22%).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:22]([N:13]1[C:14]2[C:2]([CH3:1])=[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:4]=[CH:5][C:6]=2[C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1ccc2c([nH]c3ccccc32)c1C
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c3ccccc3n(Cc3ccccc3)c2c1C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A solution of 29 mg of ethyl 1-methylcarbazole-2-carboxylate in 1 ml of N,N-dimethylformamide was added, with ice-cooling, to a suspension of 10 mg of sodium hydride (55% w/w dispersion in mineral oil) in 2 ml of N,N-dimethylformamide. 29 mg of benzyl bromide was then added to the reaction mixture, which was then stirred for 1 hour, with ice-cooling. After this time, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate and the organic extract was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 1 g of silica gel with a 9:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 38 mg of the title compound, melting at 79°-80° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)(C)(C)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:25]Br.Cl>>[ClH:21].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:25][O:14][C@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:27]=[C:28]([Cl:30])[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1c1ccccc1
Reactant: Clc1cc(Cl)cc(CBr)c1
Agent: Cl
Product: Clc1cc(Cl)cc(CO[C@H]2CCCN[C@H]2c2ccccc2)c1

Procedure:
The title compound was prepared from 1-t-butyloxycarbonyl-3-hydroxy-2-phenylpiperidine (Example 2c) and 3,5-dichlorobenzylbromide in an analogous manner to that described in Example 2d, e, m.p.=243°-245° C. 1H NMR (360 MHz, CDCl3) 1.49-1.53 (1H, m, CHH), 1.60-1.70 (1H, m, CHH), 1.82-1.95 (1H, m, CHH), 2.14-2.18 (1H, m, CHH), 2.79-2.87 (1H, m, NCHH), 3.27-3.31 (1H, m, NCHH), 3.60 (1H, s, OCHCHN), 3.82 (1H, s, OCHCHN), 4.02-4.05 (1H, d, J=13 Hz, OCHH), 4.31-4.35 (1H, d, J=13 Hz, OCHH), 6.80 (2H, s, ArH), 7.15 (1H, s, ArH), 7.25-7.35 (5H, m, ArH). Found: C, 58.24; H, 5.38; N, 3.91. Calcd. for C18H19NOCl2.HCl C, 58.01; H, 5.41; N, 3.76%.