Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:10][C:11]1[N:15]([CH2:16][CH2:17][O:18][CH2:19][CH3:20])[C:14]2[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=2[N:12]=1>>[CH2:19]([O:18][CH2:17][CH2:16][N:15]1[C:14]2[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=2[N:12]=[C:11]1[CH2:10][N:5]1[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]1)[CH3:20]
Reactant: CCOCCn1c(CCl)nc2ccccc21
Reactant: CN1CCCNCC1
Product: CCOCCn1c(CN2CCCN(C)CC2)nc2ccccc21
Yield: 69.7 %

Procedure:
In the same manner as described in Example 3, N-methylhomopiperazine (2.6 g) and 2-chloromethyl-1-(2-ethoxyethyl)benzimidazole (2.38 g) obtained in the same manner as described in Reference Example 3 are reacted to give 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)methylbenzimidazole (2.2 g) as a pale yellow liquid. This liquid is treated with fumaric acid (1.63 g), and the crude crystal thus obtained is recrystallized from a mixed solvent of ethyl acetate-ethanol to give 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)methylbenzimidazole 3/2 fumarate semihydrate (2.2 g) as colorless prisms, m.p. 119°-121.5° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31](O)=[O:32])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][C@H:36]1[OH:48]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37][C@H:36]4[OH:48])=[O:32])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:14]=23)[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)O)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Product: Cc1c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c3) and commercially available tert-butyl (3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)[NH:16][N:17]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:28][C:29]1([CH3:35])[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([N:33]4[CH2:32][CH2:31][NH:30][C:29]([CH3:35])([CH3:28])[CH2:34]4)=[CH:22][CH:21]=3)[NH:16][N:17]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CC1(C)CNCCN1
Reactant: COc1cc(CCc2cc(NC(=O)c3ccc(F)cc3)[nH]n2)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCNC(C)(C)C4)cc3)[nH]n2)cc(OC)c1
Temperature: 120 °C
Reaction time: 384 h
Yield: 4.8 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-fluorobenzamide (0.1 g, 0.27 mmol) and 2,2-dimethylpiperazine (0.124 g, 1.04 mmol) were stirred at 60° C. for 20 mins. Potassium carbonate (0.033 ml, 0.54 mmol) and DMSO (1 ml) were added and the reaction stirred at 120° C. in a sealed tube for 16 days. The reaction mixture was cooled and evaporated. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (6.00 mg, 2.000%) as a colourless gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].C([N:28]([CH2:31][CH3:32])CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:15][CH:3]1[CH2:2][CH2:7][CH2:6][CH2:32][CH:31]1[NH2:28])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: NC1CCCCC1NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.900 g, 2.47 mmol), (DL)-trans-1,2-diaminocyclohexane (0.282 g, 2.47 mmol), triethylamine (0.250 g, 2.47 mmol) and benzene (20 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the resulting crude product was recrystallized from hexane to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-aminocyclohexyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.340 g, 28.8% yield).
Reaction SMILES: ClCCl.Br[C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:8]2=[N:9][CH:10]=1.[C:24](O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:8]2=[N:9][CH:10]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In a round bottom flask, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.04 g, 0.05 mmol) is combined with 10 mL of toluene under an atmosphere of nitrogen, and 5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (5, 0.3 g, 0.8 mmol) in 1 mL of toluene is added dropwise. The reaction is stirred at 60° C. for 1 hour, then at 90° C. for 30 minutes. The reaction is cooled to room temperature, an ice/water solution of 0.1 N citric acid at pH 4 is added, and the mixture extracted with ethyl acetate. The organic layer is washed with brine, de-colored with charcoal, filtered through celite and the filtrate dried over sodium sulfate. The sodium sulfate is removed by filtration and the filtrate concentrated under vacuum to provide the desired compound (6, 218 mg).
Reaction SMILES: [CH2:1]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CS(O)(=O)=O.O.[CH2:32]([C:38]1([CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[C:50]2[CH:49]=[C:48]([C:51]3(O)[C:63]4[CH:62]=[C:61]([Br:64])[CH:60]=[CH:59][C:58]=4[C:57]4[C:52]3=[CH:53][C:54]([Br:65])=[CH:55][CH:56]=4)[CH:47]=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>ClCCl>[CH2:20]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:19]2[CH:18]=[C:17]([C:51]3([C:48]4[CH:47]=[CH:46][C:45]5[C:44]6[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=6)[C:38]([CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:50]=5[CH:49]=4)[C:63]4[CH:62]=[C:61]([Br:64])[CH:60]=[CH:59][C:58]=4[C:57]4[C:52]3=[CH:53][C:54]([Br:65])=[CH:55][CH:56]=4)[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2ccc(C3(O)c4cc(Br)ccc4-c4ccc(Br)cc43)cc21
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2ccccc21
Agent: CS(=O)(=O)O
Solvent: O
Solvent: ClCCl
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2ccc(C3(c4ccc5c(c4)C(CCCCCC)(CCCCCC)c4ccccc4-5)c4cc(Br)ccc4-c4ccc(Br)cc43)cc21

Procedure:
In a 2 L round-bottom flask, 50 g of the compound (1) and 200 g of 9,9-dihexylfluorene were dissolved in 1000 ml of dichloromethane, and then the temperature was decreased to 0° C. The reaction solution was slowly added with a s olution of 10 ml of methane sulfonic acid dissolved in 100 ml of dichloromethane with stirring, followed by further stirring for 2 hours. The resulting reaction solution was poured into water, after which an extraction was performed using diethyl ether. The solvent was evaporated using a rotary evaporator. A column chromatography separation resulted in 60 g (58%) of (9,9-di(9,9-dihexylfluoren-2-yl)-2,7-dibromofluorene) (2).
Reaction SMILES: [CH:1]12[NH:9][CH:5]([C:6](=[O:8])[CH2:7]1)[CH2:4][O:3][CH2:2]2.C([O-])([O-])=O.[K+].[K+].[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17]>CC#N>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:9]1[CH:5]2[C:6](=[O:8])[CH2:7][CH:1]1[CH2:2][O:3][CH2:4]2)(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: O=C1CC2COCC1N2
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC2COCC1N2S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of compound 108b (100 mg), TEA (102 mg), K2CO3 (207 mg, 1.5 mmol, 3.0 eq) and 2-nitro-benzenesulfonyl chloride (222 mg) in MeCN (10 mL) was stirred at room temperature for 10 h. Then the solvent was removed in vacuo, the residue was purified by silica gel (EA/PE=1:3) to give 8-(2-nitrophenyl)sulfonyl-3-oxa-8-azabicyclo[3.2.1]octan-6-one 108c as a white solid, 100 mg. MS: calc'd (MH+) 313, measured (MH+) 313.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C[O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1
Reactant: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CC1Cc2ccc(O)cc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Anhydrous AlCl3 (1.38 g, 10.35 mmol) was added all at once to a solution of ethyl (±)-10,11-dihydro-3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate (643.6 mg, 2.07 mmol) in anhydrous CH2Cl2 (21 mL) at 0° C. under argon. The yellow solution was warmed to RT and stirred for 3 h, then was cooled to 0° C. and quenched with cold 3 N HCl (10 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated. Silica gel chromatography (25% EtOAc/hexanes) gave the title compound as a nearly colorless oil (611.7 mg, 100%): TLC Rf 0.26 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl13) δ 7.03-7.22 (m, 4H), 6.93 (d, J=8.1 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 6.58 (dd, J=8.1, 2.6 Hz, 1H), 5.00 (s, 1H), 4.25 (d, J=14.9 Hz, 1H), 4.11-4.25 (m, 2H), 3.73-3.88 (m, 1H), 3.79 (d, J=14.9 Hz, 1H), 3.28 (dd, J=15.0, 4.1 Hz, 1H), 2.91 (dd, J=15.0, 9.3 Hz, 1H), 2.65 (dd, J=15.6, 4.9 Hz, 1H), 2.53 (dd, J=15.6, 9.5 Hz, 1H), 1.27 (t, J=7.2 Hz, 3H); FTIR (CCl4) 3611 (sharp), 3447 (broad), 1734, 1504, 1291, 1272, 1176, 1152 cm-1 ; MS (ES) m/e 314.2 (M+NH4)+, 297.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](=[NH:20])[NH:4][C:5](=[O:19])[N:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([N:4]1[C:3](=[NH:20])[C:2]([F:1])=[CH:7][N:6]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[C:5]1=[O:19])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(F)c(=N)[nH]c2=O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)n2cc(F)c(=N)n(Cc3ccccc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 20 mL microwave vial, 5-fluoro-4-imino-1-(4-methoxyphenylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one (111 mg, 0.37 mmol) was stirred at room temperature in dimethyl formamide (3 mL) together with anhydrous potassium carbonate (210 mg, 0.55 mmol). Benzylbromide (89 μL, 0.75 mmol) was added. The reaction was capped and placed on a Biotage Initiator microwave reactor for 20 min at 130° C., with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (EtOAc; 250 mL), and washed with water (H2O; 3×100 mL). The organic phase was dried over magnesium sulfate (MgSO4), filtered, and the solvent evaporated under reduced pressure. Purification by flash chromatography (SiO2, EtOAc/Hexanes gradient) afforded 3-benzyl-5-fluoro-4-imino-1-(4-methoxyphenylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one as a pale yellow oil (15 mg; 11%): 1H NMR (400 MHz, CDCl3) δ 8.09-8.02 (m, 3H), 7.38-7.27 (m, 6H), 7.00-6.96 (m, 2H), 4.65 (d, J=5.7 Hz, 2H), 3.87 (s, 3H). ESIMS m/z 391 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C@@H:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][C:35]([NH:19][C@H:11]([C:7]1[N:6]([CH2:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=2[O:2][CH3:1])[CH:10]=[CH:9][N:8]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:36]
Reactant: COc1ccccc1Cn1ccnc1[C@@H](N)Cc1ccccc1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1Cn1ccnc1[C@H](Cc1ccccc1)NC(=O)Cc1c[nH]c2ccc(O)cc12
Reaction time: 0.5 h

Procedure:
(S)-1-(1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethanamine (75 mg, 0.2 mmol), 2-(5-hydroxy-1H-indol-3-yl)acetic acid (47 mg, 0.25 mmol) and HATU (97 mg, 0.26 mmol) were combined in DMF (2 mL) and treated with diisopropylethylamine (70 μL). The reaction was stirred for 30 min and the purified by RP HPLC to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ 10.53 (d, 1H), 8.67 (d, 1H), 7.58 (s, 1H), 7.38-7.28 (m, 2H), 7.20-7.12 (m, 3H), 7.12-6.98 (m, 4H), 6.91-6.79 (m, 3H), 6.72 (d, 1H), 6.57 (dd, 1H), 5.38-5.31 (m, 1H), 5.17 (d, 2H), 3.71 (s, 3H), 3.40-3.22 (m, 3H), 3.16 (dd, 1H). MS (m/z) 481.2 [M+H]+.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)(=[O:32])=[O:31])[C:20]1=[O:39])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:18][CH:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)(=[O:31])=[O:32])[C:20]1=[O:39]
Reactant: CC(C)(C)[Si](OC1CCN(c2ccccc2S(=O)(=O)Nc2nccs2)C1=O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1C(O)CCN1c1ccccc1S(=O)(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of (R)-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide (5.5 gm, 9.53 mmol) in THF (40 mL) under N2, was added a solution of tetrabutyl ammonium fluoride in THF (1 M, 40 mL, 38.12 mmol). Upon completion of addition, the mixture was stirred at RT overnight. The reaction mixture was poured into water and extracted with CH2Cl2 (2×50 mL), dried over magnesium sulfate, and concentrated. Purification via silica gel chromatography using 2-10% MeOH in CH2Cl2 gave (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide (2.6 gm, 76%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=340.0; tR=0.54 min.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:9].Cl[C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([CH3:35])[N:29]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:35][C:30]1[N:29]=[C:28]([N:24]2[CH2:25][CH2:26][CH:21]([N:10]([CH2:8][CH3:9])[C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:22][CH2:23]2)[CH:33]=[C:32]([CH3:34])[N:31]=1
Reactant: CCN(C(=O)OCc1ccccc1)C1CCNCC1
Reactant: Cc1cc(Cl)nc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)OCc1ccccc1)C1CCN(c2cc(C)nc(C)n2)CC1
Reaction time: 14 h
Yield: 63 %

Procedure:
A mixture of benzyl ethyl(piperidin-4-yl)carbamate trifluoroacetate (4.14 mmol, 1.0 eq), 4-chloro-2,6-dimethylpyrimidine (0.706 g, 4.97 mmol, 1.2 eq) and K2CO3 (1.14 g, 8.28 mmol, 2.0 eq) in acetone (20 ml) was stirred for 14 hours at boiling temperature. After monitoring by TLC, the mixture was concentrated, diluted with DCM (200 ml), washed with water (80 ml) and sat. NaCl solution (80 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 2.0% MeOH in DCM). Yield: 63% (960 mg, 2.60 mmol)
Reaction SMILES: [CH2:1]([S:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Mg].II.[C:22](=[O:24])=[O:23].Cl>O1CCCC1.O>[CH2:1]([S:11][C:12]1[CH:17]=[CH:16][C:15]([C:22]([OH:24])=[O:23])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCSc1ccc(Br)cc1
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCSc1ccc(C(=O)O)cc1
Temperature: -70 °C

Procedure:
A solution of 4-(decylthio)bromobenzene (32.9 g) in dry tetrahydrofuran (100 ml) was added over about 30 minutes to a stirred, refluxing suspension of magnesium turnings (2.64 g) and one crystal of iodine in dry tetrahydrofuran (100 ml). The mixture was then stirred at reflux for 2 hours after which it was cooled to -70° C. Carbon dioxide was passed through the stirred solution at -70° C. for about 2 hours. The solution was warmed to room temperature and was then poured into a mixture of ice and water (1.251). Hydrochloric acid was added to bring the pH to 1, the precipitate was collected and washed with water, dried and then crystallized from cyclohexane to yield 4-(decylthio)benzoic acid (20.29 g) in the form of white crystals, m.p. 108°-109° C. [Elemental analysis: C,69.2; H,8.9; S,11.1%; calculated: C,69.34; H,8.9; S,10.88%].
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1[O:13][C:14](=[O:16])[CH3:15])(=[O:3])[CH3:2].[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]=[CH:26][C:25](=[O:32])[C:24]=2[C:23]2([S:36][CH2:35][CH2:34][S:33]2)[CH2:22]1)(=[O:19])[CH3:18]>>[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]3[CH:26]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:8]4[C:7]([CH:6]3[O:13][C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:25](=[O:32])[C:24]=2[C:23]2([S:36][CH2:35][CH2:34][S:33]2)[CH2:22]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC1(C(C)=O)CC2=C(C(=O)C=CC2=O)C2(C1)SCCS2
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Product: CC(=O)OC1c2ccccc2C(OC(C)=O)C2C(=O)C3=C(CC(OC(C)=O)(C(C)=O)CC34SCCS4)C(=O)C12
Yield: 78.8 %

Procedure:
A solution of 220 mg (1.0 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 234 mg (0.66 mmol) of rac-3'-acetoxy-3'-acetyl-1',2',3',4',5',8'-hexahydro-5',8'-dioxospiro[1,3-dithiolane-2,1'-naphthalene] [prepared as described in Example 5(A)] in 15 ml of dry xylane was stirred and heated under reflux under an atmosphere of nitrogem for 30 minutes. The pale orange solution was evaporated and the resulting yellow oil was triturated with 15 ml of diethyl ether to yield 298 mg (79%) of rac-3',6',11'-triacetoxy-3'-acetyl-1',2',3',4',5',5a',6',11',11a',12'-decahydro-5',12'-dioxospiro[1,3-dithiolane-2,1'-naphthacene] in the form of a yellow solid of melting point 135°-145° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].[Br:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CS(C)=O>[Br:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])=[CH:21][CH:20]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: BrCc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Br)nc1
Yield: 30.2 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (3.6 g), dimethylsulfoxide (20 ml), potassium carbonate (3.0 g) and 6-bromo-3-(bromomethyl)pyridine (5.5 g) according to the similar method described in Production Example 4 was obtained 2.2 g of 2-((6-bromo-3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (10)).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:8][C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:10][N:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:8][C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[CH:10][N:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2ncc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1ncc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-5-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[N:7]=[C:6]([C:12]([OH:14])=O)[CH:5]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[N:7]=[C:6]([C:12]([Cl:24])=[O:14])[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 75 °C
Reaction time: 7 h
Yield: 117.4 %

Procedure:
A 500 mL three neck round bottom flask with thermowell was fitted with a condenser which vented to a trap and then an aqueous 10% NaOH scrubber, magnetic stir bar, two stoppers and a thermometer. To the vessel was added 4,5,6-trichloropicolinic acid (86 g which contained 8.6 g water, 77.4 g active, 0.32 mol), toluene (160 mL), thionyl chloride (85 mL, 1.12 mol) and DMF (0.3 mL). The slurry was heated to 70-80° C., held there for 7 h and then cooled to room temperature and allowed to stir overnight. Approximately 0.2 mL of the pale yellow solution was placed in a vial and concentrated to a solid under a stream of N2. The solid was treated with a mixture of triethylamine/methanol (0.3 mL/2 mL) and then warmed with a heat gun for ca. 1 min. HPLC analysis indicated that less than 1% of the carboxylic acid remained as compared to the methyl ester derivative. The solution was concentrated on a rotary evaporator leaving a pale yellow solid. The solid was dried (40° C./20 mmHg) for about 1 h providing the title compound (92 g): mp 68-70° C.; 1H NMR (CDCl3, 400 MHz) δ 8.12 (s), the solid contained about 4 wt % toluene as determined by integration of the proton signals; 13C NMR (CDCl3, 101 MHz) δ 167.3, 151.0, 145.82, 145.8, 135.7, 125.5.