Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)[C:21](Cl)=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)[C:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1)=[O:22])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: N#Cc1ccc(N)nc1
Product: N#Cc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1

Procedure:
The title compound was prepared as described in Example A (route 1), starting from 2-amino-5-cyanopyridine and 3,5-bis(benzyloxy) benzoyl chloride, 1H NMR δ (d6-DMSO): 5.19 (4H, s); 6.89 (1H, m); 7.26-7.46 (12H, m); 8.27 (1H, dd); 8.33 (1H, d); 8.84 (1H, s); 11.23 (1H, br s); m/z (LCMS; ESI+) 436 (MH+).
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])(C)(C)C.[C:18]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CO.CN(C=O)C>[C:21]([O:20][C:18](=[O:19])[NH:25][CH2:26][CH2:27][CH2:28][C:29](=[O:31])[NH:8][CH2:9][CH2:10][CH2:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCNC(=O)CCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CCNC(=O)CCCNC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrochloric acid (12%, 64 ml) was added to a cold solution of Boc-derivative 3 (21.1 g, 91.7 mmol) in MeOH (190 ml) and stirred overnight at room temperature. The next day additional acid (30 ml) was added and stirring was continued for another 10 h. The reaction mixture was filtered, washed with CHCl3, concentrated and dried in vacuo overnight. The product was suspended in DMF (300 ml) with DIEA (42 ml), cooled to 0° C. and a solution of Bt-derivative 2 (29 g, 90.5 mmol) in DMF (100 ml) was added into the reaction mixture. The cooling bath was removed and the stirring was continued overnight. The solvent and DIEA were removed in vacuo at 45° C., the residue was suspended in CHCl3/H2O mixture, washed with H2O, aq. KHSO4 (20%), H2O, aq. NaHCO3 (2 times with each), dried (Na2SO4), concentrated in vacuo, and triturated with petr. ether. Yield 22.32 g (78%). mp: 134-1350. 1H (CDCl3): 1.15 (t, J=7.27, 3H), 1.44 (s, 9H), 1.65-1.95 (m, 4H), 2.20-2.26 (m, 4H), 3.19 (q, J=6.15, 2H), 3.23-3.35 (m, 4H), 4.82 (bs, 1H), 6.40 (bs, 1H), 6.68 (bs, 1H). 13C (CDCl3): 14.77, 24.92, 25.66, 26.43, 28.38, 33.59, 33.84, 33.92, 34.35, 38.83, 39.66, 79.35, 156.56, 172.65, 173.12. ESI-MS: 338.2 (MNa+), 316.0 (MH+), 216.0 (MH+-Boc).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:6]#[CH:7])[CH2:3][CH2:4][OH:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:5][CH2:4][CH2:3][C:2]([CH3:8])([CH3:1])[C:6]#[CH:7])=[CH:12][CH:11]=1
Reactant: C#CC(C)(C)CCO
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CC(C)(C)CCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of 5.0 g (44.6 mmol) of 3,3-dimethyl-4-pentyn-1-ol and 5.7 g (44.6 mmol) of 4-chlorophenol in 125 ml of tetrahydrofuran cooled to 0° C. is added 11.7 g (44.6 mmol) of triphenyl phosphine followed by 7.8 g (7.0 ml, 44.6 mmol) of diethyl azodicarboxylate. The reaction mixture is allowed to warm to room temperature and stirred overnight. The solvent is evaporated and the residue triturated with hexane. The solid is filtered, washed with hexane and the resulting filtrate evaporated. The residue is subjected to flash chromatography (silica gel) using hexane as eluting solvent to afford 5.0 g of colorless crystalline solid: m.p. 42°-45° C.; NMR (CDCl3) δ1.3 (6H, s), 1.9 (2H, t, J=6.5 Hz), 2.12 (1H, s), 4.15 (2H, t, J=6.6 Hz), 6.8 (2H, d, J=9.0 Hz), 7.2 (2H, d, J=9.0 Hz).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54]O)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54][O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CO[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@H]1O[C@H](COS(=O)(=O)C(F)(F)F)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of dry pyridine (0.46 ml) in methylene chloride (17.5 ml) cooled to -15° C. was added trifluoromethanesulfonic anhydride (0.87 ml). The mixture was stirred during 15 min at -10° C. then methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (1.2 g, 2.58 mmol) in methylene chloride (5 ml) was added (P. Kovac, V. Sklenar and C. Glaudemans, Carbohydr. Res., 175, 201 (1988)). The mixture was stirred during 1.5 h at -10° C. The reaction mixture was washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 7:3 mixture of hexane and ethyl acetate afforded the expected compound methyl 2,3,4-tri-O-benzyl-6-O-trifluoromethylsulfonyl-α-D-glucopyranoside which was crystallized from hexane (1.43 g, 93%); m.p. 44°-45° C.
Reaction SMILES: C[O:2][CH2:3][CH:4]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34])[CH2:9][CH2:10][N:11]([CH:20]([C:24]([OH:26])=[O:25])[CH2:21][O:22]C)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[C:5]([OH:7])=[O:6].C[Si](I)(C)C.N1C=CC=CC=1>C(Cl)(Cl)Cl>[OH:22][CH2:21][CH:20]([N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[CH2:10][CH2:9][N:8]([CH:4]([C:5]([OH:7])=[O:6])[CH2:3][OH:2])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34])[C:24]([OH:26])=[O:25]
Reactant: COCC(C(=O)O)N(CCN(Cc1ccccc1O)C(COC)C(=O)O)Cc1ccccc1O
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(O)C(CO)N(CCN(Cc1ccccc1O)C(CO)C(=O)O)Cc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.7 g N,N'-bis-(2-methoxy-1-carboxy-1-ethyl)-N,N'-bis-(2-hydroxy-phenylmethyl)-ethylenediamine (Example 17), 16 g trimethyl silyl iodide (0.08 mol), 6.32 g pyridine (0.08 mol) in 10 ml of chloroform is stirred at room temperature overnight, under nitrogen. The reaction mixture is filtered and the solvent evaporated in vacuo. The residue is poured in water giving a solid that after purification by chromatography furnishes N,N'-bis-(2-hydroxy-1-carboxy-1-ethyl)-N,N'-bis-(2-hydroxy-phenylmethyl)-ethylene diamine.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][C:25]2[N:26]=[C:27]3[CH:33]=[CH:32][N:31]([S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)(=[O:36])=[O:35])[C:28]3=[N:29][CH:30]=2)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.[Br:43]C(Cl)(Cl)C(Br)(Cl)Cl>O1CCCC1>[Br:43][C:32]1[N:31]([S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:28]2=[N:29][CH:30]=[C:25]([CH2:24][CH2:23][C:17]3[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:15]([O:14][CH3:13])[CH:16]=3)[N:26]=[C:27]2[CH:33]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: COc1cc(CCc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a stirred solution of N,N-diisopropylamine (0.610 mL, 4.25 mmol) in tetrahydrofuran (2.0 mL) at −78° C., n-butyllithium (2.5 M in hexanes, 1.70 mL, 4.25 mmol) was added dropwise. After the white precipitate formed, the mixture was warmed up to 0° C. for 10 minutes. The resulting resulted solution was added to a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (1.30 g, 3.07 mmol) in tetrahydrofuran (10 mL) at 78° C. After 30 min, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (1.10 g, 3.38 mmol) in tetrahydrofuran (6 mL) was added dropwise. After another 1 hour, the reaction mixture was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was purified on silica gel (eluting with 0 to 50% EtOAc in hexanes) to give the desired product (1.30 g, 84%). LCMS calculated for C22H21BrN3O4S (M+H)+: m/z=502.0. Found: 502.0; 1H NMR (400 MHz, CDCl3): δ 8.15-8.12 (m, 3H), 7.68-7.58 (m, 1H), 7.51-7.47 (m, 2H), 6.88 (s, 1H), 6.31 (d, J=2.0 Hz, 2H), 6.28 (t, J=2.5 Hz, 1H), 3.72 (s, 6H), 3.16-3.12 (m, 2H), 2.99-2.96 (m, 2H) ppm.
Reaction SMILES: C(O)(=O)/C=[CH:3]/[C:4](O)=[O:5].[N:9]1([CH2:14][CH2:15][CH2:16][NH:17][C:18]2[C:26]3[CH:27]=[CH:28][CH:29]=[C:24]4[C:25]=3[C:20](=[CH:21][CH:22]=[CH:23]4)[N:19]=2)[CH:13]=[N:12][CH:11]=[N:10]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[N:19]1[C:20]2[C:25]3[C:24](=[CH:29][CH:28]=[CH:27][C:26]=3[C:18]=1[N:17]([CH2:16][CH2:15][CH2:14][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:4](=[O:5])[CH3:3])[CH:23]=[CH:22][CH:21]=2
Reactant: c1cc2c3c(cccc3c1)C(NCCCn1cncn1)=N2
Reactant: O=C(O)/C=C/C(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(CCCn1cncn1)C1=Nc2cccc3cccc1c23
Temperature: -10 °C

Procedure:
Three and three-tenths grams of the free base of Example 69 and 10 ml of acetic anhydride were added to 5 ml of pyridine, and the mixture then refluxed for 15 minutes. The volatiles were removed in vacuo and the residue partitioned between 100 ml of dichloromethane and 100 ml of saturated NaHCO3 solution. The dichloromethane layer was dried over MgSO4. The dichloromethane solution was heated to boiling and hexane added until turbidity resulted (about 300 ml). The mixture was then cooled at -10° C. The precipitate of the title compound was collected, washed with hexane, and dried; yield, 1.9 grams; mp 128° C.-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[OH:23]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: OO
Reactant: O=C1CC2CSc3ccccc3C2=NN1c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC2CS(=O)c3ccccc3C2=NN1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a mixture of 11.5 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one in 200 ml of acetic acid is added 66 ml of 35% hydrogen peroxide dropwise with stirring at room temperature. After the completion of addition, the mixture is stirred at room temperature for 3 hours, poured into an excess amount of water and extracted with chloroform. The extract is washed with water, dried over magnesium sulfate anhydride and the chloroform is distilled off under reduced pressure. To the precipitated crystals is added diisopropyl ether. The crystals are collected by filtration and recrystallized from isopropyl alcohol to give 7.7 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one 6-oxide, melting at 181°-183° C., as colorless needles.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([Cl:16])=[C:10]([Cl:17])[CH:9]=3)[CH3:2].CC(O)=[O:20].OO>O>[CH2:1]([C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:20])[C:6]2=[N:5][N:4]=1)=[CH:12][C:11]([Cl:16])=[C:10]([Cl:17])[CH:9]=3)[CH3:2]
Reactant: CCc1nnc2cnc3cc(Cl)c(Cl)cc3n12
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: CCc1nnc2c(=O)[nH]c3cc(Cl)c(Cl)cc3n12
Temperature: 50 °C

Procedure:
The triazole (3) (1.5 g, 5.64 mmol) was added to 47 ml of HOAc, and then 14 ml 30% H2O2 added. The mixture was warmed 4 hours at 50° C., then cooled to room temperature and poured into H2O. The precipitate was filtered and dried, yielding 1.09 g of 1-ethyl-7,8-dichloro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one (4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[CH3:21][C:19]1[CH:18]=[CH:17][C:15]2=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=[C:14]2[CH:20]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2ccc(C)cc2n1
Product: Cc1ccc2nn(CCC#Cc3ccccn3)nc2c1
Yield: 36.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (66 mg, 0.42 mmol) and 2-but-3-ynyl-5-methyl-2H-benzo[d][1,2,3]triazole (70 mg, 0.38 mmol, Example 165(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 36 mg (0.14 mmol, 37%) of 5-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:40]([N:47]1[CH2:51][CH2:50][C@@H:49]([C:52](O)=[O:53])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:40]([N:47]1[CH2:51][CH2:50][C@@H:49]([C:52]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:53])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)[C@@H]1CCN(Cc2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)[C@@H]1CCN(Cc2ccccc2)C1
Yield: 33.9 %

Procedure:
This compound was prepared according to method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.181 g; 0.476 mmol), (R)-1-benzylpyrrolidine-3-carboxylic acid hydrochloride (0.119 g; 0.476 mmol), and N,N-diisopropylethylamine (0.189 mL; 1.08 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% of a solution of 5% ammonium hydroxide in methanol, in dichloromethane) to afford 0.056 g (34%) of (R)-1-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)pyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=3[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([O:30]C)=[O:29])[CH:21]=3)[C:9]2=[O:32])[CH2:4][CH2:3]1.[OH-].[Na+].Cl>CO.O1CCCC1>[C:28]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH2:19][N:10]1[C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:12]=2[N:8]([C@H:5]2[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]2)[C:9]1=[O:32])([OH:30])=[O:29]
Reactant: COC(=O)c1cc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ccc(C#N)cc32)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ccc(C#N)cc32)cc1C(=O)O
Temperature: 600 °C

Procedure:
To a solution of 1-(trans-4-hydroxycyclohexyl)-3-(4-methoxy-3-methoxycarbonylbenzyl)-5-cyano-2,3-dihydro-1H-benzimidazole-2-one (120 mg) in methanol (10 mL) and tetrahydrofuran (2 mL) was added 1N-aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 600° C. for an hour. After the solution was acidified with 1N-hydrochloric acid, the organic solvent of the solution was removed by evaporation. The aqueous layer was diluted with water and extracted with a mixture of chloroform and methanol (4:1). The separated organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 3-(3-carboxy-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5-cyano-2,3-dihydro-1H-benzimidazole-2-one as a colorless powder (88.8 mg).
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[Br:13][CH2:14][CH2:15][CH2:16][NH2:17].CCN(CC)CC>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][NH:17][S:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NCCCBr
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1ccccc1)NCCCBr
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
A solution of phenylmethanesulfonyl chloride (2.19 g, 10 mmol) was added into a suspension of 3-bromopropan-1-amine hydrobromide (2.19 g, 10 mmol) and Et3N (2.02 g, 20 mmol) in THF (50 mL) at 0° C. The mixture was stirred at 0° C. for 5 min. TLC confirmed the completion of reaction. Solid was filtered out with suction, and the filtrate was concentrated to provide compound N-(3-bromopropyl)(phenyl)methanesulfonamide (2.7 g, quant.) as a pale yellow solid which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 5H), 4.48 (m, 1H), 4.27 (s, 2H), 3.41 (t, J=6.6 Hz, 2H), 3.16 (q, 2H), 2.01 (m, 2H). LCMS (ESI), m/z, 314 and 316 [M+Na]+, Br pattern found.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.[CH:13](=[O:17])[CH:14]([CH3:16])[CH3:15].O>O1CCCC1>[CH3:15][CH:14]([CH3:16])[CH:13]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)[OH:17]
Reactant: Brc1cncnc1
Reactant: CC(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(O)c1cncnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of n-butyl lithium (20 ml of 2.6 M, 52 mmol) in dry tetrahydrofuran (60 ml) at -78° C., was added a cold solution of 5-bromopyrimidine (6.36 g, 40 mmol) in dry tetrahydrofuran (30 ml) over a period of 5 minutes. After 10 minutes a cold solution of iso-butyraldehyde (2.88 g, 40 mmol) in dry tetrahydrofuran (30 ml) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was poured into water and extracted with ether (2×100 ml). The organic layer was collected, washed with brine and dried over magnesium sulphate before removing the solvent. Flash chromatography (silica gel, petrol/ether elution) gave the product as a yellow oil.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:8][C:9]([CH3:13])=[N+:10]([O-:12])[CH:11]=1)([OH:3])=[O:2].[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:17][O:2][C:1]([CH2:4][O:5][C:6]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:8][C:9]([CH3:13])=[N+:10]([O-:12])[CH:11]=1)=[O:3]
Reactant: Cc1cc([N+](=O)[O-])c(OCC(=O)O)c[n+]1[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 59.7 %

Procedure:
The carboxylic acid (c) (8.4 g) in DMF (100 ml) was treated with potassium carbonate (7.6 g) and iodomethane (2.8 ml) and stirred for 3 days. After evaporation of solvent, water (200 ml) was added and the solid filtered off and dried under vacuum to give the product (5.32 g).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]#[N:29].O>CN(C)C=O>[C:28]([CH2:27][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:13][CH2:12][CH2:11]1)#[N:29]
Reactant: c1ccc(C2(c3ccccc3)CCNCCO2)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCN1CCOC(c2ccccc2)(c2ccccc2)CC1

Procedure:
To the solution of 2.5 g of 7,7-diphenyl-hexahydro-1,4-oxazepine in 5 ml of dimethylformamide, 1.5 g of anhydrous potassium carbonate are added while stirring, followed by the dropwise addition of the solution of 0.85 g of chloroacetonitrile in 2 ml of dimethylformamide and the suspension is stirred for 5 hours at room temperature. It is poured onto a mixture of ice and water, the aqueous phase extracted twice with 20 ml of diethyl ether each, the extract dried, filtered and evaporated. The residue is recrystallized from ethanol, to yield the 4-cyanomethyl-7,7-diphenyl-hexahydro-1,4-oxazepine melting at 119°-121° (its hydrochloride melts at 178°-180° with decomposition).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6]Br.[C:17]([NH:24][C@H:25]([C:36]([OH:38])=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[CH3:22][C:20]([CH3:23])([O:19][C:17]([NH:24][CH:25]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[C:36]([O:38][CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=1)=[O:37])=[O:18])[CH3:21]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Following the method of Example 1, 3,5-bistrifluoromethylbenzyl bromide (4.9 g) and N α BOC-L-tryptophan (5 g) gave the title compound after recrystallisation from ethyl acetate/petroleum ether.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].[O:21]=[S:22]1(=[O:38])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[C:24](=[O:32])[N:23]1[CH2:33][CH2:34][CH2:35][CH2:36]Br>>[O:38]=[S:22]1(=[O:21])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[C:24](=[O:32])[N:23]1[CH2:33][CH2:34][CH2:35][CH2:36][N:17]1[CH2:18][CH2:19][CH:14]([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]2=[O:20])[CH2:15][CH2:16]1
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Reactant: CCCCn1c(=O)n(C2CCNCC2)c2ccccc21
Product: CCCCn1c(=O)n(C2CCN(CCCCN3C(=O)c4cc(Cl)ccc4S3(=O)=O)CC2)c2ccccc21

Procedure:
From 4-(3-butyl-2-oxo-1-benzimidazolinyl)piperidine and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one using the procedures described in Example 1 there was obtained a white solid upon formation of the HCl salt (from methanol), melting point 192-195° C. Analysis calculated for C27H334N4O4S.HCl.0.8 H2O: C, 54.41; H, 6.02; N, 9.40; found: C, 54.41; H, 5.82; N, 9.34. The NMR was consistent with the structure.