Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccc(-c2ncc[nH]2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccnc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-bromophenyl)-1H-imidazole (15.0 g, 67.2 mmol) in DMF (150 ml) at 0° C. was added NaH (60% dispersion in mineral oil, 3.90 g, 97.5 mmol). The mixture was stirred at 0° C. for 1 hour and (2-(chloromethoxy)ethyl)trimethylsilane (14.8 mL, 84.0 mmol) was added. The resulting solution was allowed to warm from 0° C. to ambient temperature while stirring over 24 hours. The reaction mixture was diluted with 1:1 brine:H2O (500 mL), extracted with EtOAc (3×200 mL), dried over sodium sulfate, filtered and concentrated to an oil. Purification of the oil by column chromatography, eluting with 10-50% EtOAc/Hexane, afforded 2-(4-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole as a light orange oil, (17.1 g, 70%). LCMS (APCI+) m/z 353, 355 [M+H]+.
Reaction SMILES: [CH:1]([Si:4](OS(C(F)(F)F)(=O)=O)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Br:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH3:39])([CH3:38])[CH2:34][NH:35]2)=[CH:31][C:30]=1[F:40]>C(Cl)Cl>[Br:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH3:38])([CH3:39])[CH2:34][N:35]2[Si:4]([CH:1]([CH3:2])[CH3:3])([CH:5]([CH3:6])[CH3:7])[CH:8]([CH3:9])[CH3:10])=[CH:31][C:30]=1[F:40]
Reactant: CC1(C)CNc2cc(Br)c(F)cc21
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)N1CC(C)(C)c2cc(F)c(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
Triisopropylsilyltrifluoromethanesulfonate (3.5 mL, 13.0 mmol) and DIPEA (3.2 mL, 19.5 mmol) were added to a solution of 6-bromo-5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole (1.5 g, 6.5 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature overnight then quenched with saturated aqueous NaHCO3 and extracted with DCM (×3). The organic phase was dried (MgSO4), filtered and concentrated. The crude material was purified by SiO2 chromatography (10% EtOAc in petrol) to give the title compound (1.8 g) as a white solid. 1H NMR (DMSO-d6): 7.07 (1H, d), 6.65 (1H, d), 3.44 (2H, s), 1.64-1.33 (3H, m), 1.33-1.17 (6H, m), 1.10 (18H, d).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:22][O:21][C:19]([CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16])=[O:20]
Reactant: CCC(=O)N1CCC(=O)c2cc(O)ccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)N1CCC(=O)c2cc(OCC(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 119.1 %

Procedure:
A mixture of 6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.314 g), methyl bromoacetate (1.01 g), and potassium carbonate (0.828 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 24 hours, poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (15 g) with chloroform as an eluent to give 6-methoxycarbonylmethoxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.08 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[CH3:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:13]2[N:12]=1>N1C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[C:18]([S:20]([NH:4][C:3]3[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=3[F:9])(=[O:22])=[O:21])[N:19]=[C:13]2[N:12]=1
Reactant: Cc1ccn2nc(S(=O)(=O)Cl)nc2n1
Reactant: Nc1c(F)cccc1F
Solvent: c1ccncc1
Product: Cc1ccn2nc(S(=O)(=O)Nc3c(F)cccc3F)nc2n1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 72.5 %

Procedure:
The starting 2,6-difluoroaniline (18.1 g, 0.140 mol) was dissolved in 45 ml of pyridine and 36.1 g (0.155 mol) of 5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride was added. After an exothermic reaction subsided the reaction mixture was stirred at room temperature for 15.5 hours. The pyridine was removed by evaporation at reduced pressure, and the residue was treated with 600 ml of 0.5N naOH. After stirring to dissolve all soluble material the mixture was filtered through celite and the filtrate was acifified with 3N HCl. The precipitate which separated upon acidification was collected by filtration and dried to yield 33.0 g (73%) of the desired product as a pale red solid, m.p. 245°-247° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].F[C:19]1[CH:20]=[N+:21]([O-:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26].O>CN(C=O)C>[N+:25]([C:24]1[CH:23]=[CH:22][N+:21]([O-:28])=[CH:20][C:19]=1[O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)([O-:27])=[O:26]
Reactant: Oc1cccc2c1CCCC2
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 5,6,7,8-tetrahydro-1-naphthol (6.0 g) in DMF (100 ml) was added Na2CO3 (10 g) portionwise at room temperature. Then a solution of 3-fluoro-4-nitropyridine-N-oxide (6.0 g) in 20 ml of DMF was added dropwise and the mixture was stirred at room temperature for four hours. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat NaCl, anhy. MgSO4).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH:11]=[O:12])[NH:8][C:7]=12.[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOCC.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:12])[NH:8][C:7]=12
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cc2ccnc(Cl)c2[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccccc1)c1cc2ccnc(Cl)c2[nH]1
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (Example 138) (1.0 g, 5.5 mmol) in THF (27.7 mL) was added 3.0 M phenylmagnesium bromide in Et2O (3.8 mL, 11.3 mmol) at −78° C. under a nitrogen atmosphere. After stirring for ca. 2 h, additional 3.0 M phenylmagnesium bromide in Et2O (0.92 mL, 2.7 mmol) was added. The reaction mixture was stirred for another 1.5 h. The reaction mixture was poured into a saturated NH4Cl solution and extracted with EtOAc (3×). The combined organic extracts were washed with saturated NaCl, and dried over Na2SO4. Filtration and concentration provided the crude material, which was purified by flash chromatography to provide (7-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanol (0.97 g, 67%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ5.99 (1H, s), 6.42 (1H, s), 7.25-7.48 (6H, m), 7.82 (1H, d, J=5.4 Hz); ESI MS m/z 259 [C14H11ClN2O+H]+; HPLC (Method A) >99% (AUC), tR=13.8 min.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Cl)[CH:34]=1.O>CN(C)C=O>[C:20]1([C:18]2[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16][N:15]([CH2:14][C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH2:39][C:35]5[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=5)[CH:5]=4)[CH:10]=3)[CH:19]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(O)ccc3c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4cccnc4)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propionate (599 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 3-Picolyl chloride (230 mg) was added to the mixture, which was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[4-phenyl-1-[6-(3-pyridylmethoxy)-2-naphthylmethyl]-3-pyrrolyl]propionate (647 mg, yield: 88%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.C(N(CC)CC)C.[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1>CN(C)C=O>[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][N:20]1[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCc3ccccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A suspension of 0.80 g (0.0041 2 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 17 ml of dimethylformamide was treated with 1.7 ml (0.0123 mol) of triethylamine and 0.67 g (5.3 mol) of 1,2,3,4-tetrahydroisoquinoline and the mixture was stirred at room temperature under argon for 3 hours. The mixture was completely freed from the solvents and the residue was chromatographed over silica gel with dichloromethane/methanol 9:1 as the eluent and recrystallized from ethyl acetate/diethyl ether. 0.72 g (69%) of 5-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2-methyl-pyrimidin-4-ylamine was obtained as beige crystals; m.p. 150°-153°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[Br:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42](Cl)=[O:43]>CCCCCC>[Br:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]3)=[CH:6][CH:7]=1)=[O:43]
Reactant: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1)c1cccc(Br)c1
Reaction time: 1 h
Yield: 29.2 %

Procedure:
To a 200 mL three-neck flask was added 5.0 g (12 mmol) of 9-(4-bromophenyl)-10-phenylanthracene. The air in the flask was replaced with nitrogen. Then, 65 mL of tetrahydrofuran was added thereto, and the temperature of the mixture was set to −80° C. Into this solution was dripped 8.1 mL (13 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) with a syringe. After that, this solution was stirred at the same temperature for 1 hour. Then, 2.8 g (13 mmol) of 3-bromobenzoyl chloride was added to this solution, and the mixture was stirred for 18 hours while its temperature was returned to room temperature. Then, an organic substance was extracted from the aqueous layer of this mixture with ethyl acetate, and the solution of the extract and the organic layer were combined and washed with a saturated aqueous sodium chloride solution. The organic layer was dried with magnesium sulfate. Then, this mixture was gravity filtered. The obtained filtrate was concentrated to give a solid. The obtained solid was purified by silica gel column chromatography (with a developing solvent of hexane and toluene in a 5:1 ratio) to give 1.8 g of a light-yellow solid in a yield of 28%. A reaction scheme of the above synthesis method is illustrated in the following (H-1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12]O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11].N1C=CC=CC=1.S(Cl)([Cl:22])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][Cl:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: COCOc1ccc(CO)cc1Br
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCOc1ccc(CCl)cc1Br
Reaction time: 1 h

Procedure:
(3-Bromo-4-methoxymethoxy-phenyl)-methanol (250 mg) was dissolved in DCM (20 mL), pyridine (0.15 mL) was added followed by thionyl chloride (0.15 mL), and the mixture was stirred for 1 hour. The mixture was partitioned with water and ethyl acetate. The solvent removal gave 2-bromo-4-chloromethyl-1-methoxymethoxy-benzene as a clear oil, which was used directly in next step. The oil was dissolved in acetone, and sodium iodide (300 mg) was added. The mixture was stirred overnight and a yellow precipitate was formed. Extraction with ethyl acetate and water gave 2-iodo-4-chloromethyl-1-methoxymethoxy-benzene as a brown oil that turned into solid after standing. 1HNMR (CDCl3, 300 MHz): 7.58 (d, J=2.0 Hz, 1H), 7.25 (dd, J=2.0, 8.5 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 5.25 (s, 2H), 4.39(s, 2H), 3.51 (s, 3H) ppm. The iodide (170 mg) and trimethylphosphate (0.1 mL) were mixed and stirred at 120° C. for 1 hour. After cooling to room temperature, the reaction mixture was directly applied to silica gel column eluting with 5% MeOH in DCM to yield 150 mg of the corresponding phosphonate.
Reaction SMILES: [C:1]1([C@H:7]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:8]([OH:11])[CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:23]([CH3:25])=[CH2:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH:9]([C@H:8]1[O:11][C:23]([CH3:25])([CH3:24])[N:12]([C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH2:10]
Reactant: C=C(C)OC
Reactant: C=C[C@@H](O)[C@@H](NC(=O)c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C[C@H]1OC(C)(C)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 38 %

Procedure:
32 mg (0.12 mmol) of (1S,2R)-1-phenyl-1-benzoylamino-2-hydroxy-3-butene, in suspension in 0.64 cm3 of anhydrous toluene, are put, under an argon atmosphere, in a 10 cm3 single-necked, round-bottomed flask equipped with a magnetic stirrer system and a reflux condenser. 226 μl (173 mg, 2.4 mmol) of 2-methoxypropene, 6.0 mg (0.024 mmol) of pyridinium p-toluenesulphonate and 8 grains of 4 Å molecular sieve are then added. The resulting reaction mixture is allowed to react at a temperature in the region of 15° C. for 2.5 hours and is then heated at 100° C. for 2 hours. After cooling to a temperature in the region of 15° C., the reaction mixture is diluted in 40 cm3 of dichloromethane. The organic phase is washed once with 5 cm3 of a saturated sodium bicarbonate solution, 3 times with 5 cm3 of water and once with a saturated aqueous sodium chloride solution and is then dried over anhydrous sodium sulphate. After filtration and concentration to dryness under reduced pressure, the residue obtained is purified by chromatography on silica gel, eluting a first time with an ethyl ether/dichloromethane (2/98 by volume) mixture and then a second time with an ethyl acetate/hexane (10/90 by volume) mixture. There are thus obtained, with a yield of 38%, 14 mg (0.0456 mmol) of (4S,5R)-5-vinyl-3-benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.[CH2:10]([S:12](Cl)(=[O:14])=[O:13])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])=[N:6][CH:7]=1
Reactant: NCc1ccc(Br)cn1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
To a solution of (5-bromopyridin-2-yl)methanamine (250 mg, 1.34 mmol) in CH2Cl2 (3 mL) is added ethyl sulfonyl chloride (95 mg, 0.74 mmol) followed by triethylamine (0.3 mL, 2.0 mmol). The reaction is stirred at room temperature for 1.5 hours. The reaction is directly injected onto a 12 g silica gel column and chromatographed eluting from 100% hexanes to 50:50 ethylacetate:hexanes to afford the title compound (158 mg): m/z (Cl) M+H 279+281.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:7]([CH2:15][CH:16]=[CH2:17])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>CN(C)C1C=CN=CC=1.ClCCl.C(=O)([O-])O.[Na+]>[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([O:1][CH2:2][CH:3]([N:7]([C:8]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:14])[CH2:15][CH:16]=[CH2:17])[CH2:4][CH:5]=[CH2:6])=[O:33])=[CH:35][CH:36]=1)([O-:27])=[O:26]
Reactant: C=CCC(CO)N(CC=C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(COC(=O)c1ccc([N+](=O)[O-])cc1)N(CC=C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To a mixture of tert-butyl [1-(hydroxymethyl)but-3-en-1-yl]prop-2-en-1-ylcarbamate (15.0 g) produced above, triethylamine (19.0 g) and dichloromethane (150 mL) was added N,N-dimethylpyridin-4-amine (0.7 g). To the mixture was added dropwise a solution of 4-nitrobenzoyl chloride (14.2 g) in dichloromethane (30 mL), and the mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, the mixture was extracted with dichloromethane, and the extract was dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (14.1 g).
Reaction SMILES: I[C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:23][CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1cccc(C(=O)O)c1I
Reactant: CC(C)(C)c1ccc(N)cc1
Product: CC(C)(C)c1ccc(Nc2c(C(=O)O)cccc2C(=O)O)cc1
Yield: 93 %

Procedure:
Similar reaction of 2-iodoisophthalic acid and 4-tert-butylaniline gave 2-[(4-tert-butyl)phenylamino]isophthalic acid (93%), mp (EtOAc/petroleum ether) 221-222° C. 1H NMR [(CD3)2SO] δ 1.24 (s, 9 H, 3×CH3), 6.84 (d, J=8.7 Hz, 2 H, H-2' and H-6' or H-3' and H-5'), 6.99 (t, J=7.7 Hz, 1 H, H-5), 7.21 (d, J=8.6 Hz, 2 H, H-3' and H-5' or H-2' and H-6'), 7.93 (d, J=7.8 Hz, 2 H, H-4 and H-6), 9.65 (br s, 1 H, NH) and 12.99 (br s, 2 H, 2×COOH Anal. (C18H13NO2) C, H, N.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:21])([F:22])[F:23])[CH2:12][CH2:13]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: FC(F)(F)c1ccccc1C1=CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)cc1
Yield: 48.8 %

Procedure:
Using the procedure from Example 14A, Step 14D, 1-benzyl-4-[2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (Example 14A, Step 14C, 150 mg, 0.65 mmol) was reacted with 4-tert-butylbenzenesulfonyl chloride (182 mg, 0.78 mmol) to afford the title compound (135 mg), a white solid, in 49% yield.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:30])[CH3:29])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:30][N:28]([CH3:29])[C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=2)[CH:14]=1)=[O:31]
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(CCl)cc1

Procedure:
4-Chloromethylbenzoyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide using an analogous procedure to that described in Example 37 except that the reaction product was triturated under water rather than under 2N aqueous hydrochloric acid solution. There was thus obtained the title compound; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.95 (s, 6H), 4.28 (s, 2H), 6.9 (d, 1H), 7.21 (m, 3H), 7.29 (d, 1H), 7.58 (d, 3H), 7.8 (s, 1H), 7.96 (d, 2H), 9.9 (s, 1H), 10.08 (s, 1H); Mass Spectrum: M−H− 420.
Reaction SMILES: [CH:1]1([O:6][C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=[C:18]([CH:26]([NH2:33])[C:27]4[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=4)[C:17]4[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:16]3=4)[CH2:11][CH2:10]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=C1CCC(=O)N1[O:46][C:47](=O)[O:48][C:49]1([CH:52]2[CH2:54][CH2:53]2)[CH2:51][CH2:50]1>ClCCl.C(N(CC)CC)C>[CH:1]1([O:6][C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH:15]3[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=[C:18]([CH:26]([NH:33][C:47]([O:48][C:49]4([CH:52]5[CH2:54][CH2:53]5)[CH2:51][CH2:50]4)=[O:46])[C:27]4[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=4)[C:17]4[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:16]3=4)[CH2:13][CH2:14]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1cncc1C(N)C1=Cc2cccnc2C(N2CCN(C(=O)OC3CCCC3)CC2)c2ccc(Cl)cc21
Reactant: O=C(ON1C(=O)CCC1=O)OC1(C2CC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cncc1C(NC(=O)OC1(C2CC2)CC1)C1=Cc2cccnc2C(N2CCN(C(=O)OC3CCCC3)CC2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
4-{6-[Amino-(3-methyl-3H-imidazol-4-yl)-methyl]-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl}-piperazine-1-carboxylic acid cyclopentyl ester (60 mg, 0.11 mmol) was dissolved in 5 ml of dichloromethane and 0.2 ml of triethyl amine. Carbonic acid bicyclopropyl-1-yl ester 2,5-dioxo-pyrrolidin-1-yl ester (45 mg, 0.19 mmol) was added and the reaction mixture stirred for 18 hours at ambient temperature under a dry nitrogen atmosphere. The reaction mixture was washed with brine and evaporated to a solid. The solid was chromatographed on silica gel using 5% methanol/dichloromethane as eluent to obtain 49 mg of title product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:5][C@H:4]([C:6]([NH2:8])=[O:7])[C:3]1([CH3:10])[CH3:9].Cl[C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[C:18]([C:17]1[C:12]([NH:1][C@@H:2]2[CH2:5][C@H:4]([C:6]([NH2:8])=[O:7])[C:3]2([CH3:10])[CH3:9])=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=1)#[N:19]
Reactant: CC1(C)[C@H](N)C[C@@H]1C(N)=O
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1ncc(C#N)c(N[C@@H]2C[C@H](C(N)=O)C2(C)C)n1
Yield: 78 %

Procedure:
A mixture of (1S,3R)-3-amino-2,2-dimethylcyclobutanecarboxamide. (120 mg, crude), chloro-2-(methylthio)pyrimidine-5-carbonitrile (130 mg, 0.70 mmol) and DIEA (129 mg, 1.0 mmol) in isopropanol (5 mL) was stirred at 80° C. for 2 h. After removal of the solvent, the residue was purified by silica gel column chromatography (10%-30% ethyl acetate in petroleum ether) to afford the title compound (160 mg, 0.55 mmol, 78% yield for two steps). MS (ESI) m/z 292.2 [M+H]+.