Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH:16]([C:20](N)=[O:21])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:23][C@@H:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])[CH3:25].[BH4-].[Na+].B(F)(F)F.CCOCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][OH:21])[CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:23][C@@H:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])[CH3:25]
Reactant: C[C@@H](Nc1cc(N2CCN(C3CCCC(C(N)=O)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](Nc1cc(N2CCN(C3CCCC(CO)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
To a solution of 3-(4-(4-chloro-3-((R)-1-(2,4-dichlorophenyl)ethylamino)phenyl)piperazin-1-yl)cyclohexanecarboxylic acid (prepared as illustrated in Example 15, 0.077 g, 0.15 mmol) in THF (1 mL) at 0° C. was added sodium borohydride (NaBH4) (0.017 g, 0.5 mmol) and boron trifluoride diethyl etherate (BF3.Et2O) (0.1 mL, 0.8 mmol). The reaction mixture was then stirred at room temperature for 2 h. The reaction was quenched with aqueous saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude was purified by flash chromatography (SiO2, 10-40% ethyl acetate in hexanes) to afford the desired product as a white solid (0.0074 g, 0.015 mmol, 10%). 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 2H), 7.17 (dd, J=2.0, 8.0 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.17 (dd, J=2.8, 8.8 Hz, 1H), 5.78 (d, J=2.4 Hz, 1H), 4.90 (dd, J=5.6, 6.4 Hz, 1H), 4.65 (d, J=5.2 Hz, 1H), 3.54 (d, J=7.2 Hz, 2 μl), 3.03-2.99 (m, 3H), 2.59 (m, 3H), 2.39-2.36 (m, 1H), 2.05-1.95 (m, 1H), 1.75-1.34 (m, 14H); MS: (ES) m/z calculated for C25H33Cl3N3O [M+H]+ 496.2. found 496.3.
Reaction SMILES: [CH3:1][C:2](Cl)([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH2:9])[C:3]([O:5]CC)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[CH2:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:2]([CH3:1])[C:3]1=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: C=C(c1ccccc1)C(C)(Cl)C(=O)OCC
Product: CC1=C(c2ccccc2)CN(Cc2ccccc2)C1=O

Procedure:
Generally following the procedures of the preceding examples, ethyl 2-methyl-2-chloro-3-phenyl-3-butenoate (R=phenyl, R1 =methyl) was reacted with benzylamine to yield N-benzyl-3-methyl-4-phenyl-3-azoline-2-one (R=phenyl, R1 =methyl).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:10][C@H:11]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:37][CH2:38][F:39].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:10][C@H:11]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:37][CH2:38][F:39])=[CH:24][CH:23]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](CCCc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: FCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](CCCc1ccc(OCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-[3-(4-hydroxyphenyl)propyl]-L-glutamate (80 mg, 0.16 mmol), 1-bromo-2-fluoroethane (103 mg, 0.81 mmol), and caesium carbonate (158 mg, 0.49 mmol) were dissolved in 8 ml N,N-dimethylformamide and the solution was stirred at 60° C. for 4 h. The reaction was then poured into 1 N aqueous hydrochloric acid (50 ml) and extracted with dichloromethane (3×75 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by pHPLC on a reversed phase (RP-18) column with an acetonitrile/water gradient. The appropriate fractions were collected, the acetonitrile evaporated under reduced pressure and the remaining aqueous solution was lyophilized.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20]C(C)(C)C)=O)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:25][C@@H:26]([CH:30]([CH3:32])[CH3:31])C(O)=O>>[NH2:25][C@@H:26]([CH:30]([CH3:32])[CH3:31])[C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[C:11]1[NH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][N:10]=1)=[O:20]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
The title compound was prepared from (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate and (S)-2-amino-3-methylbutanoic acid by the procedures detailed in Examples 1 and 2. 1HNMR (300 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.68 (d, J=5.9 Hz, 1H), 7.65 (d, J=5.9 Hz, 1H), 7.46-7.58 (m, 3H), 5.14, 5.05 (dd, J=7.0, 3.0 Hz, 1H, rotamers, 1:1 ratio), 3.66 (app t, J=6.5 Hz, 1H), 3.53-3.61 and 3.38-3.47 (m, 1H, rotamers, 1:1 ratio), 3.28 (s, 2H), 1.70-2.21 (m, 6H), 0.75-0.88 (m, 6H). LCMS: Anal. Calcd. for C18H23BrN4O: 390, 392; found: 391, 393 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[N:7]=[N:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=4)=[CH:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]1=2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 45.7 %

Procedure:
4-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (60 mg, 0.25 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (90 mg, 0.25 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (60 mg, 46%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.66 (d, J=7.0 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.38 (d, J=1.3 Hz, 1H), 7.26-7.24 (m, 2H), 7.10 (d, J=7.8 Hz, 1H), 4.66 (s, 2H), 3.66 (t, J=3.3 Hz, 2H), 3.86 (s, 3H), 2.84 (t, J=3.3 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[Li]CCCC.[CH:35](=O)[CH2:36][CH2:37]/[CH:38]=[CH:39]/[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>>[CH2:7]([C:6]1[CH:5]=[CH:4][C:3]([CH3:2])=[CH:29][CH:28]=1)[CH:8]=[CH:35][CH2:36][CH2:37]/[CH:38]=[CH:39]/[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: Cc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC/C=C/CCC=O
Agent: [Br-]
Agent: [Li]CCCC
Product: CCCCC/C=C/CCC=CCc1ccc(C)cc1
Yield: 57 %

Procedure:
Starting from p-methylphenethyltriphenylphosphonium bromide (2.90 g, 6.29 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 3.9 mL, 6.29 mmol, 1.0 equiv.) and (E)-dec-4-enal (1.45 g, 9.43 mmol, 1.5 equiv.), 0.92 g (57%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O>>[Br:11][C:12]1[CH:13]=[C:14]([CH2:15][C:7]2[S:6][C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[CH:8]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Cc1ccc2sccc2c1
Product: Cc1ccc2sc(Cc3cccc(Br)c3)cc2c1

Procedure:
5-Methylbenzo[b]thiophene and 3-bromobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[C:5]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:4]=1.[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28][S:29](Cl)(=[O:31])=[O:30])=[CH:24][CH:23]=1>>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([N:16]2[CH2:17][CH2:18][N:19]([S:29]([CH2:28][C:25]3[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=3)(=[O:31])=[O:30])[CH2:20][CH2:21]2)[CH:4]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1N1CCNCC1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Product: O=C(O)COc1ccc(Cl)cc1N1CCN(S(=O)(=O)Cc2ccccc2)CC1

Procedure:
Prepared from the product from Example 38 step c) and benzenemethanesulfonyl chloride according to the procedure described in Example 38 step d) to give the sub-title compound as a white solid.
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][CH:6]([N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[CH2:7]2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Product: O=[N+]([O-])c1ccc(N2CCC(n3ccnc3)C2)cc1
Temperature: 0 °C
Yield: 73.2 %

Procedure:
22 g (0.0767 mol) of 1-(4-nitrophenyl)pyrrolid-3-yl methanesulphonate (2) were heated at 95° C. for 2 hours in 170 g of imidazole (2.5 mol), This mixture was poured into 1 l of ice-cold water until crystallization takes place. After filtration and drying, the yellow powder obtained was chromatographed, eluting with dichloromethane, and 14.5 g of derivative (3) were recovered (73.2% yield).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH3:16])[CH:9]=[C:8]2[C:17]1[N:26](S(C2C=CC(C)=CC=2)(=O)=O)[C:20]2=[N:21][CH:22]=[CH:23][C:24]([CH3:25])=[C:19]2[CH:18]=1>CO.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH3:16])[CH:9]=[C:8]2[C:17]1[NH:26][C:20]2=[N:21][CH:22]=[CH:23][C:24]([CH3:25])=[C:19]2[CH:18]=1
Reactant: COc1cc2c(-c3cc4c(C)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(-c3cc4c(C)ccnc4[nH]3)cn(C)c2cc1OC

Procedure:
1.3 cm3 of aqueous 5N potassium hydroxide solution are added to a solution of 0.13 g of 2-[5,6-dimethoxy-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-4-methyl-1H-pyrrolo[2,3-b]pyridine in 15 cm3 of methanol, at a temperature in the region of 20° C. The reaction medium is refluxed for about 18 hours. The reaction mixture is evaporated under reduced pressure and the residue thus obtained is dissolved in 100 cm3 of ethyl acetate, transferred into a separating funnel and washed with 50 cm3 of distilled water. The aqueous phase is re-extracted with twice 50 cm3 of ethyl acetate, and the combined organic phases are washed successively with 50 cm3 of saturated aqueous sodium chloride solution and 50 cm3 of distilled water. The organic extract is dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the crude compound, which is purified by chromatography on a Flash Chromabond RS 6 SiOH cartridge (3 g of silica). The elution was performed at a flow rate of 10 cm3/min with a heptane/isopropanol mixture (70/30 by volume). The fractions containing the expected compound are combined and evaporated to give 2-[5,6-dimethoxy-1-methyl-1H-indol-3-yl]-4-methyl-1H-pyrrolo[2,3-b]pyridine in the form of a pasty yellow solid (0.008 g, 8%), the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].Cl.[CH3:21][O:22][C:23](=[O:31])[C@H:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[NH2:25].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:30][O:29][C:27](=[O:28])[CH2:26][CH:24]([NH:25][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]([F:19])([F:18])[F:17])[CH:4]=1)[C:23]([O:22][CH3:21])=[O:31]
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC(NC(=O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1)C(=O)OC

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[O:13])[C:9]([OH:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([Cl:22])[CH:19]=1)[CH2:15][NH:14][C:12]([C:10]1[C:9]([OH:24])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:11]=1)=[O:13]
Reactant: C1COCCN1
Reactant: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Cl)c2cccnc2c1O
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(N2CCOCC2)c2cccnc2c1O
Temperature: 25 °C

Procedure:
A solution of the chloride from Example 44 Step 5 (14 mg, 0.037 mmol) in morpholine (0.5 ml) was heated at 120C for 36 hrs under argon. The resulting solution was cooled to room temperature and the solvent evaporated in vacuo. The residue was dissolved in hot DMF (0.5 ml) and purified by preparative HPLC. (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[CH:7]=1)=[O:5].S(=O)(=O)(O)O>>[CH2:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[S:10][C:6]=2[C:4](=[O:5])[CH2:3]1
Reactant: O=C(CCCl)c1cc2c(s1)CCCC2
Agent: O=S(=O)(O)O
Product: O=C1CCc2c1sc1c2CCCC1
Temperature: 95 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
A 50-mL single-necked round-bottomed flask equipped with a magnetic stirrer was charged with 105b (800 mg, 3.51 mmol) and 98% sulfuric acid (8 mL). After stirring at 95° C. for 16 h, the reaction mixture was poured into ice (50 g), and the resulting suspension was extracted with ethyl acetate (3×50 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 105c in 47% yield (320 mg) as an off-white solid: mp 75-76° C.; 1H NMR (500 MHz, CDCl3) δ 2.89 (m, 2H), 2.87-2.83 (m, 4H), 2.56 (t, 2H, J=6.5 Hz), 1.84 (m, 4H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33](=[O:50])[CH2:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:50])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)[CH:20]=3)[OH:15])=[CH:6][CH:7]=2)=[CH:37][CH:36]=1)[CH3:31]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(O)c3cn(Cc4ccc(Cl)c(Cl)c4)nn3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3,4-dichloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)O)[CH:16]=3)[N:11]3[N:33]=[N:34][N:35]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(=[N:39]C(N)=O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[NH2:39])[CH:16]=3)[N:11]3[N:33]=[N:34][N:35]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Reactant: NC(=O)N=S(=O)=O
Product: Cn1cncc1C(N)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 160 °C
Reaction time: 5 h
Yield: 26106.5 %

Procedure:
A mixture of intermediate (3) (0.0061 mol) and sodium azide (0.0079 mol) in N,N-dimethylacetamide (DMA)(20 ml) was stirred at 50° C. for 18 hours. The mixture was cooled to room temperature and poured out into ice water. The precipitate was filtered off, washed with H2O thoroughly and taken up in CH2Cl2. The organic solution was dried, filtered and the solvent was evaporated. The residue was crystallized from CH3CN DIPE. The precipitate was filtered off and dried yielding 2.3 g (75%) of (±)-5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol (intermediate 4); mp. 232-233° C. d) A mixture of intermediate (4) (0.0573 mmol) and sulfonylurea (300 g) was stirred at 160° C. for 5 hours and then cooled. Ice water was added, then methylene chloride and the mixture was filtered over celite. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue was purified by column chromatography over silica gel. The pure fraction were collected and the solvent was evaporated yielding 7.5 g (26%) of (±)-5-(3-chlorophenyl)-α-(4-chloro-phenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine (intermediate 5). e) Intermediate (5) was separated into its enantiomers and purified by column chromatography over Chiralpak AD® (eluent: hexane/EtOH 50/50; 15-35 μm). The pure first (A) fractions were collected and the solvent was evaporated yielding 3.3 g of residue which was crystallized from CH3CN/DIPE. The precipitate was filtered off and dried, yielding 2.55 g of (−)-5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine (compound 1)[α]D20=−7.16°(c=5 mg/ml MeOH); mp.=178-180° C.; 1H-NMR (DMSO, 400 MHz) δ in ppm:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=2)[NH:9]1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.O>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])[CH2:17][C:16]2([CH3:18])[CH3:19])#[N:21]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C#N)cc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-aminophenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (500 mg, 1.8 mmol) in pyridine (3 mL) was added benzenesulfonyl chloride (230 μL, 1.8 mmol) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by HPLC to give N-[2-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide. LC/MS m/e obsd. (ESI+) [(M+H)+] 418.2.
Reaction SMILES: [CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9](=[O:17])[CH:8]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:32][CH2:33][CH3:34]>CN(C)C=O>[CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:32][CH2:33][CH3:34])[C:9](=[O:17])[CH:8]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1N=C(C2CCCC2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCC2)c2ccccc21
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 5-cyclopentyl-1,3-dihydro-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one [Example 5, Step 3] (1.48 g, 3.93 mmol) in anhydrous dimethylformamide (40 ml), cooled in an ice bath, was added sodium hydride (60% dispersion in oil, 173 mg, 4.33 mmol) and the resulting mixture stirred under nitrogen for 1 h. Iodopropane (0.46 ml, 4.72 mmol) was then added and the mixture stirred at room temperature for 3 h. The solvent was evaporated and the residue partitioned between dichloromethane (100 ml) and water (100 ml). The aqueous layer was re-extracted with more dichloromethane (100 ml), the organic extracts were combined, dried (MgSO4) and evaporated. The residue was then triturated with ether to afford the title compound (1.36 g, 83%) as a white solid. mp 138°14 140° C. 1H NMR (360 MHz, CDCl3) δ 0.80 (3H, t, J=7.4 Hz), 1.26-1.79 (8H, m), 1.94 (1H, m), 2.12 (1H, m), 3.30 (1H, m), 3.55 (1H, m), 4.29 (1H, m), 5.10 (2H, m), 5.13 (1H, d), 6.52 (1H, d, J=8.1 Hz), 7.23-7.34 (5H, m), 7.48 (1H, t of d, J=8.0 and 1.4 Hz), 7.56 (1H, dd, J=7.8 and 1.4 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][S:10]([CH3:12])=[O:11].[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:18]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH2:9][S:10]([CH3:12])=[O:11])[CH2:15][CH2:16][CH3:17]
Reactant: CS(=O)CC(=O)c1ccccc1O
Reactant: CCCCN
Product: CCCCN=C(CS(C)=O)c1ccccc1O
Yield: 95 %

Procedure:
A solution of 2'-hydroxy-2-(methylsulfinyl)acetophenone (15 g, 0.076 mole) in n-butylamine (75 ml) was stirred at room temperature for 16 hrs. The reaction mixture was poured into petroleum ether (500 ml) and the product, which precipitated, was filtered off. Recrystallization from ethylacetate-cyclohexane gave yellow crystals (18.2 g, 95%), mp 128°-129°.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:33][CH:32]=1>>[C:1]1([C:7]2[N:8]=[C:9]([N:12]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][O:29][C:31]4[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:33][CH:32]=4)=[CH:26][CH:27]=3)[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc(CN(CCc2ccccn2)c2nc(-c3ccccc3)cs2)cc1
Reactant: COC(=O)CCc1ccc(O)cc1
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccn3)c3nc(-c4ccccc4)cs3)cc2)cc1
Yield: 57 %

Procedure:
The title compound was synthesized in the same manner as in Example 8 from (4-{[(4-phenyl-1,3-thiazol-2-yl)(2-pyridin-2-ylethyl)amino]methyl}phenyl)methanol and methyl 3-(4-hydroxyphenyl)propanoate by Mitsunobu reaction (yield 57%). Yellow oil.