Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][C:28]([OH:30])=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.[C:50]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)(=[O:53])[NH:51][NH2:52]>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][C:28]([NH:52][NH:51][C:50]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:53])=[O:30])[CH2:24][CH2:25]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)NNC(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (380 mg) was added to a mixture of the product of step (a) (0.5 g), diisopropylethylamine (0.34 ml), 1-hydroxybenztriazole (333 mg) and DMF (10 ml) at ambient temperature. The mixture was stirred for 5 minutes and benzyl carbazate (325 mg) in DMF (2 ml) was added. The mixture was stirred for 18 hours at ambient temperature. The solvent was removed by evaporation and the residue was partitioned between ice-water (25 ml) containing 1M sodium hydroxide (2 ml) and ethyl acetate (50 ml). The ethyl acetate extract was washed with water (20 ml), 0.25M citric acid solution (20 ml), water (20 ml) and saturated sodium chloride solution (10 ml) and dried (MgSO4). The solvent was removed by evaporation to give benzyl 3-[3-(1-t-butoxycarbonylpiperidin-4-yl)propanoyl]carbazate as a foam (790 mg); NMR Spectrum (d6 -DMSO) 0.8-1.1 (m, 2H), 1.3-1.5 (m, 12H), 1.6 (br d, 2H), 2.1 (br t, 2H), 2.62 (m, 2H), 3.9 (br d, 2H), 5.07 (s, 2H), 7.32 (s, 5H), 9.08 (s, 1H), 9.6 (s, 1H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C:11](=[O:21])[C:10]2[CH:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[NH:24][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([CH:8]1[CH2:13][NH:12][C:11](=[O:21])[C:10]2[CH:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[NH:24][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(Cc2ccccc2)c2[nH]c(-c3cccc4cccnc34)cc2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC(Cc2ccccc2)c2[nH]c(-c3cccc4cccnc34)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
A mixture of rac-tert-butyl 7-benzyl-4-oxo-2-(quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-5(4H)-carboxylate (200 mg, 0.441 mmol), DCM (10 mL), and TFA (2 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo, and the residue was suspended in 1N aq. HCl (10 mL) and washed with EtOAc (5 mL). The aq. layer was neutralized with sat. aq. NaHCO3 (5 mL) and extracted with EtOAc (2×10 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by preparative TLC (80% EtOAc/petroleum ether) afforded rac-7-benzyl-2-(quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (30 mg, 0.085 mmol, 19% yield) as a pale green solid: 1H NMR (400 MHz, DMSO-d6) δ 12.29 (1H, br s), 8.92 (1H, dd, J=1.6 Hz & 2.8 Hz), 8.47 (1H, dd, J=1.6 Hz & 6.8 Hz), 8.21 (1H, d, J=7.2 Hz), 7.86 (1H, d, J=8 Hz), 7.67-7.62 (2H, m), 7.43-7.40 (4H, m), 7.33-7.30 (1H, m), 7.18 (1H, d, J=2 Hz), 7.06 (1H, br s), 3.48-3.40 (1H, m), 3.20-3.10 (2H, m), 2.92-2.86 (2H, m). m/z (ESI, +ve) 353.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][CH2:25]OS(C)(=O)=O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH2:25][CH2:24][C:14]1[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:17][C:13]=1[CH3:12])[CH:5]=[O:6]
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: Cc1cc(C=O)cc(C)c1O
Product: Cc1cc(C=O)cc(C)c1OCCc1nc(-c2ccccc2)oc1C

Procedure:
In analogy to the procedures described in examples 114 b], c] and d], 3,5-dimethyl-4-hydroxy-benzaldehyde was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002] to give 3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde. Treatment of 3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde with (benzyloxycarbonyl-methoxy-methyl)-triphenyl-phosphonium chloride then gave 3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2(Z,E)-methoxy-acrylic acid benzyl ester, which was hydrogenated to yield [rac]-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methoxy-propionic acid as light yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[NH2:20][C:21]1[CH:25]=[C:24]([CH:26]2[CH2:28][CH2:27]2)[NH:23][N:22]=1>C1COCC1>[CH:26]1([C:24]2[CH:25]=[C:21]([NH:20][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[C:4]([CH2:12][O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:3]=3)[NH:22][N:23]=2)[CH2:28][CH2:27]1
Reactant: Clc1nc(COc2ccccc2)nc2ccccc12
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: C1CCOC1
Product: c1ccc(OCc2nc(Nc3cc(C4CC4)n[nH]3)c3ccccc3n2)cc1
Temperature: 65 °C

Procedure:
To a solution of the above 4-chloro-2-phenoxymethylquinazoline (0.5 g, 1.85 mmol) in THF (30 mL) is added 3-amino-5-cyclopropylpyrazole (0.47 g, 3.69 mmol) and the reaction mixture is heated at 65° C. for 24 hours. Solvent is evaporated and ethanol is added. A white solid forms and is collected by filtration and dried under vacuum to give (5-cyclopropyl-2H-pyrazol-3-yl)-(2-phenoxymethyl-quinazolin-4-yl)-amine.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]([F:19])([F:18])[F:17])[C:5](O)=[O:6])=[N+]=[N-].[NH2:27][C:28]1[CH:58]=[CH:57][CH:56]=[C:55]([F:59])[C:29]=1[CH2:30][CH2:31][C@H:32]1[O:37][CH2:36][C@@H:35]([CH2:38][O:39][C:40](=[O:47])[NH:41][CH2:42][C:43]([F:46])([F:45])[F:44])[N:34](C(OC(C)(C)C)=O)[CH2:33]1>>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:18])([F:19])[F:17])[C@@H:4]([C:5]([NH:27][C:28]2[CH:58]=[CH:57][CH:56]=[C:55]([F:59])[C:29]=2[CH2:30][CH2:31][C@H:32]2[O:37][CH2:36][C@@H:35]([CH2:38][O:39][C:40](=[O:47])[NH:41][CH2:42][C:43]([F:44])([F:46])[F:45])[NH:34][CH2:33]2)=[O:6])[NH:1][C:40]([O:39][CH3:38])=[O:47])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(F)cc1)c1ccccc1OC(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(F)cc1)c1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=763 (M+H)+.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B:9](OC)([O:12]C)[O:10]C.Cl>C1COCC1>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[B:9]([OH:12])[OH:10]
Reactant: COc1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccccc1B(O)O
Temperature: -78 °C
Yield: 93.9 %

Procedure:
Part B: Anisole (1.0 g, 9.25 mmol) was dissolved in dry THF (40 ml) in a dry 100 ml flask flushed with nitrogen and cooled to -78° C. n-Butyl lithium (5.8 ml of a 1.9M solution in hexanes, 11.1 mmol) was added then the cooling bath was exchanged for an ice-water bath. The reaction was stirred for an hour at 0° C. then trimethyl borate (1.26 ml, 10 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was treated with 2N aqueous HCl to pH 3 and mixed well for 30 minutes, then extracted with ether (3×15 ml). The organic materials were combined, dried (MgSO4) then concentrated under reduced pressure which gave 1.32 g (87%) of 2-methoxybenzeneboronic acid as a clear oil.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH2:8][CH3:9])[C:4](=[O:7])[CH2:5][Cl:6].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:22](Cl)=[O:23].C(OCC)(=O)C>C(Cl)Cl.O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[C:22]([NH:2][C:3]([CH2:8][CH3:9])([CH3:10])[C:4](=[O:7])[CH2:5][Cl:6])=[O:23]
Reactant: CCC(C)(N)C(=O)CCl
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CCl
Temperature: 25 °C
Yield: 62 %

Procedure:
To a well-stirred mixture of 0.62 g (3.3 mmol) of 3-amino-1-chloro-3-methyl-2-pentanone hydrochloride and 25 mL of methylene chloride in a 50 mL round-bottomed flask, placed in an ice bath, was added dropwise 0.91 g (9 mmol) triethylamine. After 15 minutes 0.44 g (3 mmol) 3,5-dichlorobenzoyl chloride in methylene chloride (approximately 5 mL) was added dropwise. The mixture was stirred while the temperature was maintained between 0° C. to 5° C. for 1 hour. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was then poured into a mixture of ethyl acetate and water. The mixture separated into phases, an organic and an aqueous phase. The organic phase was washed sequentially with saturated aqueous sodium bicarbonate (1×50 mL), water (1×50 mL), 2.5% aqueous hydrochloric acid (1×50 mL), and water (1×50 mL). The organic layer was dried over anhydrous magnesium sulfate, treated with charcoal and filtered through Celite™ and the solvent was removed in a rotary evaporator yielding 0.6 g of 3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)benzamide as a white solid (mp 159-161° C.).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[C:31]([O:35][C:36](=[O:45])[NH:37][CH:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36](=[O:45])[NH:37][CH:38]1[CH2:39][CH2:40][CH:41]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:42][CH2:43]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(NC(=O)OC(C)(C)C)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[CH3:2].[CH:11](OCC)(OCC)[O:12][CH2:13][CH3:14].C(OC(=O)C)(=O)C>>[CH2:1]([O:3][C:4](=[O:10])[C:5]([S:6]([CH3:9])(=[O:8])=[O:7])=[CH:11][O:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCOC(=O)CS(C)(=O)=O
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)S(C)(=O)=O
Temperature: 135 °C

Procedure:
A mixture of methanesulfonyl-acetic acid ethyl ester (example 61b) (90 g, 0.547 mol), triethyl orthoformate (242.9 g, 0.641 mol), and acetic anhydride (227 mL) was heated at 130-140° C. for three hours. After cooling the reaction to room temperature, solvent was removed under reduced pressure to give 3-ethoxy-2-methanesulfonyl-acrylic acid ethyl ester (purity 50%). The crude compound was used in the following reaction without further purification. LC-MS m/e 223 (MH+).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][C:16]([NH:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([O:30][C:31]([F:34])([F:33])[F:32])[CH:8]=1)(=[O:5])=[O:4].C(O)(=[O:39])C.C(O)(=O)C.IC1C=CC=CC=1>CC(O)=O.CC(OC(C)=O)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:36][C:2]([F:35])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]([O:30][C:31]([F:32])([F:33])[F:34])[C:10]([C:13]2[N:14]=[N:15][C:16]([NH:19][CH:20]3[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:26])([CH3:27])[CH2:25]3)=[CH:17][CH:18]=2)=[C:11]([OH:39])[CH:12]=1)(=[O:4])=[O:5]
Reactant: CC(=O)O
Reactant: CC1(C)CC(Nc2ccc(-c3ccc(OS(=O)(=O)C(F)(F)F)cc3OC(F)(F)F)nn2)CC(C)(C)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Ic1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CC(Nc2ccc(-c3c(O)cc(OS(=O)(=O)C(F)(F)F)cc3OC(F)(F)F)nn2)CC(C)(C)N1
Temperature: 75 °C
Reaction time: 4 h
Yield: 35.8 %

Procedure:
A mixture of 4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenyl trifluoromethanesulfonate (86 mg, 0.16 mmol), iodobenzene diacetate (71.5 mg, 0.222 mmol) and Pd(OAc)2 (3.6 mg, 0.016 mmol) in AcOH (0.6 mL) and Ac2O (0.6 mL) was heated at 75° C. for 3 hours. The mixture was then heated at 80° C. overnight after addition of another 40 mg of iodobenzene diacetate. The reaction mixture was cooled to room temperature and concentrated. The residue was loaded onto an SCX column, washed with MeOH and diluted with 2 M NH3 in MeOH. The product-containing fractions were concentrated. The residue was treated with 7 M NH3/MeOH and stirred at 40° C. for 4 h. The crude material was purified via flash column chromatography to give the title compound as a beige solid (32 mg, 36.1%). MS (M+1)=559.4.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[S:10](Cl)(=[O:12])=[O:11].[OH-].[NH4+:15]>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[S:10]([NH2:15])(=[O:12])=[O:11]
Reactant: COCCc1ccsc1S(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COCCc1ccsc1S(N)(=O)=O
Reaction time: 8 h

Procedure:
Six grams of crude 3-(2-methoxyethyl)thiophene-2-sulfonyl chloride was dissolved in 25 mL of acetone and added dropwise with stirring at ambient temperature to 25 mL of concentrated aqueous ammonium hydroxide. The reaction mixture was allowed to stand overnight and the acetone removed by evaporation. The aqueous residue was extracted with three 100 mL portions of methylene chloride which were combined, dried over magnesium sulfate, filtered and evaporated to yield a residue which was a mixture of an oil and a solid. The sulfonamide was isolated by passing the residue through a 30 cm high by 80mm diameter column of silica gel using 1:1 ethyl acetate mixed hexanes solvent system and taking 100 mL fractions. The desired product came off in fractions 4 to 12. After evaporation of the solvent 1.84 grams was obtained, m.p. 64°-73° C. Analysis by mass spectroscopy showed a molecular weight of 221 AMU in agreement for the desired sulfonamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][O:14][CH3:15])[CH:7]=1)[CH3:2].[H-].[Na+].I[CH3:20]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][O:14][CH3:15])[CH:7]=1)[CH3:20])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(OCOC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1cccc(OCOC)c1
Reaction time: 20 h

Procedure:
To a stirred solution of (3-Methoxymethoxy-phenyl)-acetic acid ethyl ester (31.2 g) in DMF (200 mL) was slowly added sodium hydride (6.21 g) and iodomethane (22.3 g) at 0°. After stirred for 20 h at 0°, this reaction mixture was quenched with water. This mixture was extracted with EtOAc, and combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=10:1) to afford the product as colorless oil.
Reaction SMILES: CC1SC=CC=1.BrBr.[Br:9][C:10]1[CH:14]=[C:13](Br)[S:12][C:11]=1[CH3:16].CC1(C)C(C)(C)OB([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)O1.C(OB1OC(C)(C)C(C)(C)O1)(C)C.BrC1C=CC(OC)=CC=1>>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:13]2[S:12][C:11]([CH3:16])=[C:10]([Br:9])[CH:14]=2)=[CH:29][CH:28]=1
Reactant: Cc1sc(Br)cc1Br
Reactant: CC1(C)OB(COc2ccccc2)OC1(C)C
Agent: BrBr
Agent: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: COc1ccc(Br)cc1
Product: COc1ccc(-c2cc(Br)c(C)s2)cc1

Procedure:
The synthesis starts from commercially available 2-methylthiophene, which is brominated in the 3 and 5 position with bromine. The 3,5-dibromo-2-methylthiophene reacts in a Suzuki coupling with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) methoxybenzene, made from 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 4-bromoanisole in a grignard reaction to obtain 5-(4′-methoxyphenyl)-3-bromo-2-methylthiophene. This compound is reacts with butyl lithium and octafluorocyclopentene to obtain the reaction product. Another example synthesizes 1,2-bis(2-methyl-5-phenyl-3-thienyl) perfluorocyclopentene, while 1,2-bis(5′-(4″-hydroxyphenyl)-2′-methylthien-3′-yl) perfluorocyclopentene is obtained from 1,2-bis(5′(4″methoxyphenyl)-2′-methylthien-3′-yl) perfluorocyclopentene via reaction with BBr3.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[C:10]([F:12])[CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:13])[CH:2]=[CH2:3]>C1(SC2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>[F:12][C:10]1[CH:11]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]([OH:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C=CCc1cc(F)cc(C=O)c1O
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCCc1cc(F)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a round-bottom flask were added aldehyde 47d (1.10 g, 6.11 mmol, 1.0 equiv.), 5% Pd/C (220 mg, 20 wt % of 47d), diphenyl sulfide (10 μL, 0.061 mmol, 0.010 equiv.), and EtOAc (25 mL, 0.25 M). The reaction mixture was stirred overnight at room temperature under an atmosphere of H2 (balloon pressure). The reaction mixture was filtered through Celite and washed thoroughly with EtOAc. The filtrate was concentrated to afford aldehyde 47e (991 mg, 89.3%) as a yellow oil. 1H-NMR (500 MHz, CDCl3) δ 11.06 (br s, 1H), 9.80 (s, 1H), 7.12 (dd, 1H, J=3.0, 9.0 Hz), 7.06 (dd, 1H, J=3.0, 7.5 Hz), 2.62 (t, 2H, J=7.5 Hz), 1.63 (sext, 2H, J=7.5 Hz), 0.96 (t, 3H, J=7.5 Hz). 13C-NMR (125 MHz, CDCl3) δ 195.9 (d, JC-F=2.5 Hz), 156.3 (d, JC-F=1.0 Hz), 155.5 (d, JC-F=238.1 Hz), 133.9 (d, JC-F=6.3 Hz), 124.7 (d, JC-F=23.1 Hz), 119.6 (d, JC-F=6.5 Hz), 115.4 (d, JC-F=22.4 Hz), 31.2, 22.4, 14.0. 19F-NMR (470 MHz, CDCl3) δ −127.3. HRMS (EI): 182.07392 (M+); calcd. for C10H11FO2: 182.07431.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH2:10])[CH2:4][CH2:3]1.C1C(O)=CC=CC=1C.[CH3:23][N:24]([CH3:27])[C:25]#[N:26].[OH-].[Na+]>O>[CH3:23][N:24]([CH3:27])[C:25]([NH2:26])=[N:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[N:5]1[CH2:4][CH2:3][O:2][CH2:7][CH2:6]1
Reactant: CN(C)C#N
Reactant: Nc1ccccc1N1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(O)c1
Solvent: O
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1
Temperature: 100 °C

Procedure:
A mixture of 2-morpholinoaniline hydrochloride (19.2 g), m-cresol (80 ml) and dimethylcyanamide (9.45 g) was heated at 100° C. for five hours, cooled and added to a mixture of 40% aqueous sodium hydroxide solution (300 ml) and ice (300 g). Water (300 ml) was added and the resulting solid separated by filtration, washed with water and dissolved in dichloromethane. The solution was dried and the solvent removed to give a residue which was recrystallised from hexane to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 142°-143° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:39]([C:40]([F:43])([F:42])[F:41])=[C:38]([C:44](Cl)=[O:45])[CH:37]=[N:36]2)=[CH:31][CH:30]=1)([O-:28])=[O:27]>C1COCC1>[C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:44]([C:38]3[CH:37]=[N:36][N:35]([C:32]4[CH:33]=[CH:34][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=4)[C:39]=3[C:40]([F:41])([F:42])[F:43])=[O:45])[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1)(=[O:25])[CH:22]([CH3:23])[CH3:24]
Reactant: O=C(Cl)c1cnn(-c2ccc([N+](=O)[O-])cc2)c1C(F)(F)F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)c3cnn(-c4ccc([N+](=O)[O-])cc4)c3C(F)(F)F)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride: ESMS m/e: 629.2 (M+H)+.
Reaction SMILES: [S:1](=[O:22])(=[O:21])([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[C:19]#[N:20])=[CH:6][CH:5]=1)[NH2:2]>C(O)=O.[C].[Pd]>[S:1](=[O:21])(=[O:22])([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[C:19]#[N:20])=[CH:8][CH:9]=1)[NH2:2]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1-c1ccc(OS(N)(=O)=O)cc1
Agent: [Pd]
Solvent: O=CO
Product: N#Cc1cc(N)ccc1-c1ccc(OS(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.9 %

Procedure:
262 mg of 2′-cyano-4′-nitrobiphenyl-4-yl sulfamate was dissolved in 2.5 ml of formic acid, and 445 mg of 10% palladium-carbon was added thereto, followed by stirring at room temperature for 5 minutes. After the reaction mixture was filtered to remove any insoluble matter and the filtrate was poured into a saturated aqueous solution of sodium chloride, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 10:1 mixture of chloroform and methanol as the developing solvent) to obtain 52 mg of 4′-amino-2′-cyanobiphenyl-4-yl sulfamate.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4](=[N:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18](OC)=[O:19])[CH:17]=2)[N:11]=1)[NH2:5]>O.CO.O1CCCC1>[NH2:3][C:4](=[N:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][OH:19])[CH:17]=2)[N:11]=1)[NH2:5]
Reactant: COC(=O)c1cncc(-c2csc(N=C(N)N)n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NC(N)=Nc1nc(-c2cncc(CO)c2)cs1
Yield: 45.3 %

Procedure:
A solution of sodium borohydride (1.2 g) in water (25 ml) was added slowly to a solution of 2-(diaminomethyleneamino)-4-(5-methoxycarbonylpyridin-3-yl)thiazole (2.8 g) in methanol (70 ml) and tetrahydrofuran (70 ml) under refluxing for 20 minutes. The mixture was refluxed for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in water (100 ml). The mixture was extracted with a mixture of ethyl acetate (300 ml) and tetrahydrofuran (150 ml). The extract was dried with magnesium acetate and then evaporated to afford 2-(diaminomethyleneamino)-4-(5-hydroxymethylpyridin-3-yl)thiazole (1.14 g).
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:25]([OH:26])=[CH:24][C:20]4[CH:21]=[CH:22][S:23][C:19]=4[CH:18]=3)[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:18]=[C:19]5[S:23][CH:22]=[CH:21][C:20]5=[CH:24][C:25]=4[O:26][CH2:34]3)[C:9]2=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C(c2cc3sccc3cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3ccsc3cc12

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(5-hydroxy-1-benzothiophen-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1′H)-one was obtained (54%) as an off-white solid: MS (ES+) m/z 460.2 (M+1).