Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:36][CH2:35]2)=[O:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: COc1ccc(C)cc1N1CCNCC1
Product: COc1ccc(C)cc1N1CCN(C(=O)Nc2cc3ccccc3nc2C)CC1
Yield: 80 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)carbamate and 1-(2-methoxy-5-methylphenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[CH3:14][C:15]1[CH:16]=[C:17]([P:22]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=2)Cl)[CH:18]=[C:19]([CH3:21])[CH:20]=1>C1COCC1.CC(OC)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:22]([C:24]1[CH:25]=[C:26]([CH3:31])[CH:27]=[C:28]([CH3:30])[CH:29]=1)[C:17]1[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=1
Reactant: Brc1ccccc1I
Reactant: Cc1cc(C)cc(P(Cl)c2cc(C)cc(C)c2)c1
Agent: CC(C)[Mg]Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2ccccc2Br)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 9.67 g (34.2 mmol) of 1-bromo-2-iodobenzene in 30 ml of THF are added dropwise, at −78° C., 17.6 ml (37.6 mmol) of an isopropylmagnesium chloride solution (2 molar in THF). The mixture is stirred at a temperature between −30° C. and −40° C. for a further 1 hour, then cooled again to −78° C., and a suspension of 10.4 g (37.6 mmol) of bis(3,5-dimethylphenyl)chlorophosphine in 10 ml of THF and 10 ml of TBME are added. The cooling is removed and the reaction mixture is stirred at room temperature overnight. The resulting solution is admixed with 50 ml of water and extracted with water/TBME. The organic phases are collected and dried over sodium sulphate, and the solvent is distilled off under reduced pressure on a rotary evaporator. The solid white crude product is purified by chromatography (silica gel 60; eluent=methylene chloride). The desired product is obtained as a white solid in a yield of 56%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=2[N:16]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)=[N:11][CH:12]=1.C([N:27]([CH:31]([CH3:33])C)[CH:28]([CH3:30])C)C.N1CCCC1>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:27]3[CH2:28][CH2:30][CH2:33][CH2:31]3)=[CH:19][CH:18]=2)=[N:11][CH:12]=1
Reactant: OCc1ccc(CCC#Cc2ccc(Br)cn2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: Brc1ccc(C#CCCc2ccc(CN3CCCC3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.24 mL (3.04 mmol) methanesulphonic acid chloride are added to a solution, cooled to 0° C., of 800 mg (2.53 mmol) {4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-phenyl}-methanol in 17 mL DCM and then a solution of 0.52 mL ethyldiisopropylamine in 3 mL DCM is added dropwise. The mixture is stirred for a further 30 min at 0° C., 0.51 mL (6.08 mmol) pyrrolidine is added, the reaction mixture is heated to RT and kept at this temperature for 5 h. To complete the reaction another 0.26 mL (3 mmol) pyrrolidine are added and stirred for 1 h at RT. The mixture is evaporated down i.vac., combined with 10 mL water and 20 ml EtOAc, acidified with 1 M HCl and the organic phase is separated off. The aqueous phase is made alkaline with 2 M Na2CO3 solution, extracted with 20 mL EtOAc, the organic phase is separated off and dried over Na2SO4. After the desiccant and solvent have been eliminated the desired product is obtained.
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[CH:15]=1)([CH3:3])[CH3:2].[I:22]N1C(=O)CCC1=O.O>C(#N)C>[I:22][C:15]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:16]([CH3:18])[CH3:17])[CH:19]([CH3:21])[CH3:20]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)[Si](OCc1cn2ccccc2n1)(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CC(C)[Si](OCc1nc2ccccn2c1I)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
1.85 g (6.08 mmol) of 2-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine were solubilised in 25 ml of acetonitrile with magnetic stirring, to this solution were added 1.409 g (6.08 mmol) of N-iodosuccinimide. The mixture was stirred at r.t. for 16 h before being treated with 100 ml of water. The aqueous phase was extracted with 3×50 ml of dichloromethane. The combined organic phases were washed with 100 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. 2.29 g (yield=83%) of 3-iodo-2-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine were obtained as a pale yellow solid. LC-MS: m/z=431 (MH+); UV purity at 254 nm=95%.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[F:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:20])[CH2:18]Br)=[CH:15][CH:14]=1>C(O)C.O.CCOC(C)=O>[F:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:20])[CH2:18][S:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: COc1cccc(S)c1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1cccc(SCC(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 104.5 %

Procedure:
14.27 ml (115.0 mmol) 3-mercaptoanisole were added to a solution of 7.3 g (115.0 mmol) KOH in 120 ml ethanol and 50 ml water. 25.0 g (115.2 mmol) 4-fluorophenacyl bromide in 120 ml EtOAc were added slowly at 0° C. and the solution was stirred at RT over night. The suspension was concentrated and dissolved in EtOAc and water. The inorganic phase was extracted with EtOAc, the combined organic phases were washed with water and brine and dried over Na2SO4. Evaporation yielded 33.2 g crude 1-(4-Fluoro-phenyl)-2-(3-methoxy-phenylsulfanyl)-ethanone as light yellow liquid.
Reaction SMILES: Cl[C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12.[F:30][C:31]1[CH:32]=[C:33]([OH:38])[CH:34]=[CH:35][C:36]=1[F:37].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O.C(OCC)(=O)C>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[F:37])[O:38][C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12
Reactant: Oc1ccc(F)c(F)c1
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(Oc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
A mixture of ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (2000 mg), 3,4-difluorophenol (655 mg), potassium carbonate (1989 mg) and DMF (10 mL) was stirred at 90° C. for 30 min, and the mixture was allowed to cool to room temperature. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1240 mg).
Reaction SMILES: [C:1]([S:5][S:6][CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:53]([N:60]1[CH2:65][CH2:64][CH:63]([NH2:66])[CH2:62][CH2:61]1)([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54]>CN(C=O)C>[C:1]([S:5][S:6][CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:9]([NH:66][CH:63]1[CH2:62][CH2:61][N:60]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:65][CH2:64]1)=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)COC(=O)NC(CSSC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)COC(=O)NC(CSSC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the acid from Example 59 (6.98 g, 22.6 mmol) in DMF (50 ml was added HATU (8.58 g, 22.6 mmol). After 30 min, Hunig base (4.71 ml, 27.1 mmol) and 1-Boc-4-amino piperidine (5.43 g, 27.1 mmol) were added to the mixture. The reaction was continued stirring at RT for another 3 h. DMF was removed at high vacuum, the crude residue was dissolved in EtAc (300 ml), washed with H2O (50 ml×3). The title compound was obtained after ISCO purification (5% MeOH/DCM).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:6][C:7]1=[N:8][C:9](=[O:19])[S:10]/[C:11]/1=[CH:12]\[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:4]#[CH:5].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:53]1[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[CH:55]=[C:54]1[C:62](O)=[O:63]>CN(C=O)C.O>[O:53]1[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[CH:55]=[C:54]1[C:62]([N:16]1[CH2:17][CH2:18][CH:13](/[CH:12]=[C:11]2/[C:7]([NH:6][CH2:3][C:4]#[CH:5])=[N:8][C:9](=[O:19])[S:10]/2)[CH2:14][CH2:15]1)=[O:63]
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)c2cc3ccccc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a solution of (5Z)-4-(prop-2-yn-1-ylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added N-ethyl-N-(1-methylethyl)propan-2-amine (0.56 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (283 mg), and benzofuran-2-carboxylic acid (124 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/heptane to give the title compound (167 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:41]([NH:40][CH2:38][CH3:39])=[O:42])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CCN=C=O
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@H]4CCCNC4)ncnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCC[C@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 87.1 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3S)-piperidin-3-yl]-9H-purin-6-amine (16 mg, 0.036 mmol, 1 eq.) in 2 mL of THF was added triethylamine (0.015 mL, 0.109 mmol, 3 eq.) and ethyl isocyanate (0.004 mL, 0.055 mmol, 1.5 eq). The reaction is stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 16 mg (86%) of (3S)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}-N-ethylpiperidine-1-carboxamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06-1.34 (m, 3 H) 1.53-1.95 (m, 4 H) 2.12-2.29 (m, 1 H) 3.07 (br. s., 2 H) 3.32 (br. s., 1 H) 3.72-4.41 (m, 3 H) 5.06 (br. s., 1 H) 6.02 (d, J=6.12 Hz, 1 H) 7.08-7.66 (m, 8 H) 8.45 (br. s., 1 H), [M+H]+ 510.3.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[CH2:9]([O:11][P:12]([O-:16])[O:13][CH2:14][CH3:15])[CH3:10].C[Si](C)(C)Cl>>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][P:12](=[O:16])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])=[CH:4][CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: CCOP([O-])OCC
Agent: C[Si](C)(C)Cl
Product: CCOP(=O)(CCc1ccncc1)OCC
Yield: 54.7 %

Procedure:
A dry r.b. flask was loaded with 108 ml of 4-vinylpyridine (1 mole) and 129 ml of diethylphosphite (1 mole) under nitrogen. Dropwise addition of 25 ml of trimethylchlorosilane (0.2 mole) gave exothermic reaction to 53° C. with intermittent ice bath colling. Once the exotherm subsided the reaction mixture was fitted for vacuum distillation. A possible exotherm was noted during distillation with deposition of solids in the lines. The distillation was shut down, the traps cleaned, and distillation recommenced giving 133 g diethyl 2-(4-pyridyl)ethylphosphonate b0.2 =129-134° C. as a greenish fluid that turned light yellow on standing. Portion NMR in CDCl3 /TMS showed a 6H absorption at 1.3 ppm, 1.9H quintet at 2.1 ppm, 2H multiplet at 2.9 ppm, 4.2H triplet at 4.1 ppm, 2.1H 1:1 doublet at 7.2 ppm, and a 2.1H singlet at 8.5 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:12](=[O:23])[C:11]=2[C:10]([CH3:24])=[CH:9]1.C1C(=O)N([Br:32])C(=O)C1.O>CN(C=O)C>[Br:32][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:16]2[CH2:15][CH2:14][N:13]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:12](=[O:23])[C:11]=2[C:10]=1[CH3:24]
Reactant: Cc1cn(-c2ccccc2Cl)c2c1C(=O)N(N1CCCCC1)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c2c(n(-c3ccccc3Cl)c1Br)CCN(N1CCCCC1)C2=O
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To as solution of 1-(2-chlorophenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-4-one (0.93 g, 2.70 mmol) in DMF (30 ml) was added NBS (0.50, 2.84 mmol) at 0° C. The reaction mixture was stirred at this temperature for one hour and then water was added. The mixture was extracted with ether (×3). The combined ether extracts were dried (Na2SO4), filtered and concentrated to give 0.92 g (84%) of the title compound after flash chromatography (heptane:EtOAc gradient).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.C(N(CC)CC)C.[I-].C([NH3+])(C)(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1
Reactant: COC(=O)CCCCCBr
Reactant: Sc1ccc(Cl)cc1
Agent: CC(C)(C)[NH3+]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCCCCSc1ccc(Cl)cc1

Procedure:
To a solution of 6-bromohexanoic acid methyl ester (2.1 g, 10 mmol), triethylamine (1.6 mL, 11 mmol) and tert-butylammonium iodide (200 mg, 0.54 mmol) in freshly distilled THF (30 mL) was added 4-chlorothiophenol (1.45 g, 10 mmol) under an atmosphere of argon. The mixture was stirred at reflux for 2 hours after which it was concentrated under reduced pressure. The oil was dissolved in ethyl acetate (100 mL) and then washed successively with saturated aqueous sodium hydrogen carbonate (50 mL), distilled water (50 mL) and brine (50 mL). The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an yellow oil that was purified by flash chromatography (1:9 diethyl ether:40-60° C. petroleum ether). The title compound was obtained as a colourless oil (2.5 g, 93%).
Reaction SMILES: C(OC([NH:11][CH2:12][C@H:13]([NH:17]C(OC(C)(C)C)=O)[C:14]([OH:16])=O)=O)C1C=CC=CC=1.[CH3:25][S:26]([Cl:29])(=[O:28])=[O:27].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:29].[NH2:17][C@H:13]([C:14](=[O:16])[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:12][NH:11][S:26]([CH3:25])(=[O:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCNC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NC[C@H](N)C(=O)N1CCCC1
Product: Cl

Procedure:
Starting from (S)-3-[(benzyloxycarbonyl)-amino]-2-[(tert-butyloxycarbonyl)-amino]-propanoic acid, methanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26].C(Cl)[Cl:30]>[OH-].[Na+].[Cu]I>[ClH:30].[ClH:30].[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[C:26][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1
Reactant: ClCCl
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CN1CCC[C@H]1COc1cncc(C#CC(C)(C)C)c1
Product: Cl

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine 270 mg, 1 mmol) in 5 mL of CH2Cl2 was added triethylamine (0.5 mL), Pd(II) (19 mg), CuI (a catalytic amount) and 0.3 mL of 3,3-dimethyl-1-butyne (2 mmol). The reaction mixture was heated at reflux for 40 hours. The mixture was diluted with CH2Cl2, and 2 mL of 10% NaOH were added. The organic layer was separated and dried, and the solvent was removed under reduced pressure. The free base was purified by chromatography, eluting with 1 to 2% MeOH in CH2Cl2. MS (CI/NH3) m/z 273 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.32 (s, 9H), 1.80 (br m, 3H), 2.05 (m, 1H), 2.36 (m, 1H), 2.52 (s, 3H), 2.73 (m, 1H), 3.17 (m, 1H), 3.95 (m, 1H), 4.05 (m, 1H), 7.18 (m, 1H), 8.20 (m, 2H). The salt was prepared by treatment with HCl in Et2O, as described above, to give 100 mg of the title compound. MS (CI/NH3) m/z 273 (M+H)+. 1H NMR (D2O, 300 MHz) δ8.44 (d, J=2.2, 1H), 8.40 (s, 1H), 8.01 (m, 1H), 4.61 (dd, J=2.9, 11.1, 1H), 4.54 (dd, J=5.5, 11.0, 1H), 3.96 (m, 1H), 3.26 (m, 1H), 3.05 (s, 3H), 2.41 (m, 1H), 2.22 (m, 1H), 2.10 (m, 2H). Anal. Calcd for C17H24N2O·2.0 HCl·0.4 H2O: C, 57.92; H, 7.66; N, 7.95. Found: C, 58.10; H, 7.74; N, 7.57. [α]25D=-7.70° (c 1.46, MeOH).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH2:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[C:4]([C:33]([NH:35][NH2:36])=[O:34])[CH:3]=1.[CH:37](OCC)(OCC)OCC.O.N>C(O)(=O)C>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH2:22][CH2:23][C:17]=4[CH:16]=3)[C:6]=2[CH:5]=[C:4]([C:33]2[O:34][CH:37]=[N:36][N:35]=2)[CH:3]=1
Reactant: CCCc1nc2c(C)cc(C(=O)NN)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reactant: CCOC(OCC)OCC
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: CCCc1nc2c(C)cc(-c3nnco3)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 50 °C
Reaction time: 6 h
Yield: 58 %

Procedure:
[step 2] (E)-{2-[4-Methyl-6-(hydrazinocarbonyl)-2-propylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (40 mg, 0.08 mmol) obtained in step 1 was suspended in acetic acid (3 mL), triethyl orthoformate (3 mL) was added, and the mixture was stirred at 50° C. for 6 hr. Water (10 mL) was added to the mixture, and the mixture was neutralized to pH 9 with 30% aqueous ammonia solution, and extracted twice with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give (E)-{2-[4-methyl-6-(1,3,4-oxadiazol-2-yl)-2-propylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (24 mg, 58%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:12]2)=O)(C)(C)C.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[ClH:23].[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:12]2
Reactant: COC(=O)c1cnc2ccc(NC(=O)OC(C)(C)C)cc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cnc2ccc(N)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-[(tert-butoxycarbonyl)amino]quinoline-3-carboxylate (Int-2, 1.28 g, 4.23 mmol) in methylene chloride (38 mL) was added hydrochloric acid in 1,4-dioxane (4.0 M, 10.6 mL, 42.3 mmol). The reaction was stirred at room temperature overnight then concentrated under reduced pressure. The crude reside was dried in vacuo and used as obtained. LC-MS: (FA) ES+ 203; 1H NMR (400 MHz, d6-DMSO) δ ppm 9.14 (s, 1H), 9.08 (d, J=1.8 Hz, 1H), 8.10 (d, J=9.1 Hz, 1H), 7.62 (dd, J=9.1, 2.4 Hz, 1H), 7.33 (d, J=1.7 Hz, 1H), 3.96 (s, 9H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:14]([C:22]([OH:24])=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O:32]1[CH2:37][CH2:36][CH:35]([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([CH2:45][NH2:46])[CH2:41][CH2:40]2)[CH2:34][CH2:33]1.[OH-].[Na+]>ClCCl>[C:28]([O:27][C:25](=[O:26])[NH:13][C@@H:14]([C:22](=[O:24])[NH:46][CH2:45][CH:42]1[CH2:41][CH2:40][N:39]([CH2:38][CH:35]2[CH2:34][CH2:33][O:32][CH2:37][CH2:36]2)[CH2:44][CH2:43]1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: NCC1CCN(CC2CCOCC2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(CC2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
6.7 g of carbonyldiimidazole is added to a solution of 10 g of Boc-D-Phe-OH in 80 ml of dichloromethane, cooled to 0° C. The resulting solution is maintained under stirring at 0° C. for 1 hour. A solution consisting of 8.0 g of (11) in 20 ml of dichloromethane is then dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 2 hours. 100 ml of 1M NaOH is added to the mixture, the two phases are separated, the organic phase is washed with water (2×), and after a low-pressure solvent change with ethyl acetate, compound (12) is crystallised from ethyl acetate to obtain 14.64 g of white solid. Yield 85%.