Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]2[N:40]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:39]3[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=3[N:37]=2)[CH2:31]1)=[O:29])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CC#N.CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]2[N:40]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:39]3[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=3[N:37]=2)[CH2:31]1)=[O:29])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(-c4ccc(C(=O)OC)cc4)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(-c4ccc(C(=O)O)cc4)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21

Procedure:
Methyl 4′-((R)-2-(tert-butoxycarbonylamino)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)biphenyl-4-carboxylate (53A) (prepared by the procedure for Example 53, Step A) (0.815 mmoles, 0.545 g) was added to a 25 mL round-bottomed flask equipped for stirring under nitrogen. Tetrahydrofuran (2 mL), methanol (1 mL), and LiOH (2.0 mmoles, 1.0 mL of 2N in H2O) were then added and the resultant solution was allowed to stir at room temperature for 16 hrs. Citric acid (2.09 mmoles, 0.403 g) in H2O (1 mL) was then added and the resultant solution was concentrated in-vacuo, filtered, and then purified by preparative LC/MS. The resultant fractions were collected and the solvent was removed in-vacuo affording a brown colored oil. This oil was re-dissolved in CH3CN (1 mL) and water (2 mL). The resultant solution was frozen and lyophilized to afford 4′-((R)-2-(tert-butoxycarbonylamino)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)biphenyl-4-carboxylic acid (86A) as a tan flocculent solid (0.637 mmoles, 0.417 g, 78% yield). ESI-MS: m/z 655.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH:26]=[O:27].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:26]([C:25]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH3:1])[CH:9]=1)=[O:27]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C#N
Reactant: O=Cc1ccncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cnccc2C=O)ccc1C#N
Temperature: 100 °C
Yield: 78.4 %

Procedure:
A mixture of 1a (430 mg, 1.769 mmol), 3-bromo-4-pyridinecarboxaldehyde (299 mg, 1.608 mmol), sodium carbonate (2N in water, 1.608 mL, 3.22 mmol), bis(triphenylphosphine)palladium(II) chloride (28.2 mg, 0.040 mmol) in DMF (6.432 mL) was heated to 100° C. for 2 hrs. The mixture was quenched with saturated NaHCO3 and extracted with EtOAc two times, dried over magnesium sulfate, filtered and concentrated. The residue was purified via Biotage (0-50% EtOAc/heptane; 25M column) giving compound 1b as white solid (280 mg, 78%). LC-MS (M+1) 223.1, t=1.28 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Whilst carrying out external cooling with ice water a solution of 44.3 g (0.2 mol) of 2-nitrobenzenesulphonyl chloride in 250 ml of chloroform was added dropwise to a solution of 38.0 g (0.2 mol) of 4-amino1-(phenylmethyl)piperidine and 22.0 g (0.22 mol) of triethylamine in 250 ml of chloroform. After the cooling was stopped the mixture was stirred for a further 30 minutes at room temperature, the reaction mixture was then extracted twice with 1 l water. The aqueous extracts were extracted once more with 100 ml of dichloromethane, the combined organic phases were then dried over sodium sulphate and evaporated down in vacuo. The highly viscous light-brown substance obtained in a yield of 75.0 g (99.9% of theory) was further processed without any more purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3([CH3:26])[C:18]4[CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=[CH:22][C:17]=4[O:16][CH2:15]3)[CH:5]=[CH:4][C:3]1=2.ON1C2C=CC=CC=2N=N1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.O>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3([CH3:26])[C:18]4[CH:19]=[C:20]([C:23]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[O:24])[CH:21]=[CH:22][C:17]=4[O:16][CH2:15]3)[CH:5]=[CH:4][C:3]1=2
Reactant: C1COCCN1
Reactant: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(C(=O)O)cc43)ccc21
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(C(=O)N5CCOCC5)cc43)ccc21

Procedure:
A solution of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-3-methyl-2H-1-benzofuran-5-carboxylic acid (100 mg, 0.275 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol) 1,3-dicyclohexylcarbodiimide (112 mg, 0.55 mmol) and morpholine (0.024 ml, 0.255 mmol) in 5 ml of THF and 2 ml of DMF is stirred at room temperature for 6 hours. 30 ml of water and 30 ml of ethyl acetate are added. After stirring and separation of the phases by settling, the aqueous phase is extracted with 2×30 ml of ethyl acetate. The organic phases are then combined and washed twice with 30 ml of water and then dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is then purified by flash chromatography on a column of silica (50% heptane/50% ethyl acetate).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCc1cc2c(OC)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc2c(OC)cccc2n1Cc1ccccc1
Reaction time: 1.5 h
Yield: 48.7 %

Procedure:
2-Ethyl-4-methoxy-1H-indole (4.2 g, 24 mmol) is dissolved in 30 mL of DMF and 960 mg (24 mmol) of 60% NaH/mineral oil is added. After 1.5 hours, 2.9 mL(24 mmol) of benzyl bromide is added. After 4 hours, the mixture is diluted with water extracting twice with ethyl acetate. The combined ethyl acetate is washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue is chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 3.1 g (49% yield) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole.
Reaction SMILES: Cl[C:2](=[N:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH2:17][C:18]#[N:19])[C:3]([O:5][CH3:6])=[O:4].O1CCOCC1>[Sn].C(=O)([O-])[O-].[Ag+2]>[N:7]1[N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH2:16][CH2:17][C:18]2=[N:19][C:2]=1[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)=NNc1ccccc1OCCC#N
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [Sn]
Solvent: C1COCCO1
Product: COC(=O)c1nc2n(n1)-c1ccccc1OCC2
Reaction time: 4 h
Yield: 7 %

Procedure:
To chlorohydrazone 85 (2.87 g, 10.2 mmol) in a 200 mL flask was added 1,4-dioxane (100 mL) and silver carbonate (4.22 g, 15.3 mmol) under nitrogen (FIG. 18). The flask was fitted with a reflux condenser, and wrapped in tin foil (to keep in the dark). Next, the reaction was refluxed while stirring for 4 hours. Then, the reaction was filtered, concentrated, and purified by silica gel chromatography to provide ester 86 in 7% yield over two steps. 1H NMR (500 MHz, CDCl3) δ 8.19 (dd, J=8.2, 1.4 Hz, 1H), 7.31 (td, J=8.0, 1.6 Hz, 1H), 7.25-7.20 (m, 1H), 7.18 (dd, J=8.1, 1.3 Hz, 1H), 4.50 (t, J=5.7 Hz, 2H), 4.03 (s, 3H), 3.50 (t, J=5.7 Hz, 2H). LRMS m/z Calcd. for C12H11N3O3: 245.08004, found: 246.1 [M+1].
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:16]1([C:22](=[O:24])[CH3:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CN(C)C=O.CCOC(C)=O>[C:22]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)(=[O:24])[CH3:23]
Reactant: CC(=O)N1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Temperature: 130 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
To a solution of 4-fluorobenzaldehyde (5 g, 40.2 mmol) in N,N-dimethylformamide (130 mL) was added potassium carbonate (8.35 g, 60.4 mmol) and 1-piperazin-1-ylethanone (10.3 g, 80.5 mmol) and the reaction was stirred at 130° C. for 16 hours. The reaction was then cooled to ambient temperature, diluted with EtOAc and washed with water (×2) and brine. The organic layer was then dried with MgSO4, concentrated and purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give 4-(4-acetylpiperazin-1-yl)benzaldehyde (5.96 g, 64% yield). LCMS (m/z) ES+ 233 [M+1]+.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39].O>C(Cl)Cl>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:12]1[N:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[CH:20][CH:21]=2)[C:14]([CH3:15])=[C:10]([C:8](=[O:9])[NH:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)Oc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc(C(=O)NN3CCCCC3)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide, from Ex. 2, Step 1 (321 mg, 0.72 mmol) in 10 ml CH2Cl2 was cooled to 0° C. Triethylamine (101 μl, 0.72 mmol) was added followed by ethanesulfonyl chloride (69 μl, 0.72 mmol) and the reaction mixture was stirred at room temperature overnight. Water was added, the mixture extracted with CH2Cl2 (3×20 ml), dried (Na2SO4), filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:3) afforded 230 mg (60%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[C:35]([F:43])[CH:34]=1.N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:40])=[O:41])=[C:35]([F:43])[CH:34]=1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(Cl)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 4-chloro-2-fluorobenzenesulfonyl chloride (16 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 26 mg of the target compound, 4-chloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2-fluorobenzenesulfonamide (percentage yield: 91%), was obtained.
Reaction SMILES: Cl[CH2:2][Si:3]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I-:16].[Na+].[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC>C(O)C>[CH2:11]([O:10][Si:3]([O:13][CH2:14][CH3:15])([CH2:2][I:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:12]
Reactant: CCO[Si](CCl)(OCC)c1ccccc1
Reactant: [I-]
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCO[Si](CI)(OCC)c1ccccc1
Yield: 49.8 %

Procedure:
A mixture of 12.8 g (0.052 mol) of chloromethyl(diethoxy)phenylsilane, 9.4 g (0.062 mol) of sodium iodide and 0.21 g (0.52 mol) of tricaprylylmethylammonium chloride (Aliquat®336) in 10 of ethyl alcohol was refluxed for 12 hours, cooled, filtered, and evaporated. The filtrate was diluted with water and extracted with ether. The ether solution was washed with brine, dried over magnesium sulfate, evaporated, and distilled to provide 8.7 g (50%) of the title compound as a clear liquid: b.p. 86°-100° (0.15 mm); nD19 1.5204; ir (neat) 2980, 1590, 1480, 1430, 1390, 1290, 1165 cm-1 ; nmr (CDCl3) 1.25 (6H, t, J=7), 2.15 (2H, s), 3.85 (3H, q, J=7) and 7.3-7.9 (5H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([OH:13])=O)[CH:8]=2)[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:26]1([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl.CN(C)C=O>[CH:26]1([CH2:31][NH:32][C:11](=[O:13])[CH2:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NCC1CCCC1
Reactant: O=C(O)Cc1ccc2cc[nH]c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2cc[nH]c2c1)NCC1CCCC1
Yield: 81 %

Procedure:
A solution of indole-6-acetic acid (0.70 g) and 1,1'-carbonyldiimidazole (0.83 g) in methylene chloride (20 ml) and N,N-dimethylformamide (5 ml) was heated at reflux for 20 min, treated with cyclopentylmethylamine (0.59 g), and heated at reflux for an additional 3 hr. The solution was diluted with methylene chloride; washed successively with 10% v/v hydrochloric acid, water and brine; dried (MgSO4); and evaporated. The residue was purified by flash chromatography, eluting with 1:19 ethyl acetate: hexane, to give N-cyclopentylmethylindole-6-acetamide (0.83, 81%) as a white powder; partial NMR (80 MHz, CDCl3): 3.13(t, 2H, NHCH2), 3.69(s, 2H, ArCH2), 6.55(m, 1H, H3 -indole), 6.98(dd, 1H, H5 -indole), 7.62(d, 1H, H4 -indole).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([CH3:12])[C:3]=1[Cl:13].[Cu](C#N)[C:15]#[N:16].O>CN(C=O)C>[Cl:13][C:3]1[C:4]([CH3:12])=[C:5]([CH2:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:7][C:2]=1[C:15]#[N:16]
Reactant: N#C[Cu]C#N
Reactant: Cc1c(CC(N)=O)ccc(Br)c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CC(N)=O)ccc(C#N)c1Cl
Temperature: 150 °C
Yield: 67 %

Procedure:
A suspension of bromide 1B (2.70 g, 10.3 mmol) and copper cyanide (0.92 g, 10.3 mmol) in DMF (30 mL) was heated to 150° C. for 4 h. The suspension was cooled, poured into water with stirring, and the solid was filtered and dried to give 1.44 g (67%) of the desired nitrile. 1H NMR (DMSO-d6) δ 2.12 (s, 3H), 2.29 (s, 3H), 7.72 (d, J=8.8, 1H), 7.75 (d, J=8.2, 1H), 9.73 (s, 1H); 13C NMR (DMSO-d6) δ 15.3, 23.5, 107.7, 116.5, 123.0, 130.1, 131.5, 135.7, 142.3, 168.8; HPLC a) column: Phenominex ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.23 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.13 min retention time (95%); MS (ES) m/z 209 [M+H]+.
Reaction SMILES: C([NH:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[C:8]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[CH:23]=2)[CH:7]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl.CO>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:22]2[CH:23]=[C:18]([C:8]3[CH:7]=[C:6]([NH2:5])[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[CH:9]=3)[CH:19]=[N:20][CH:21]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(-c2cncc(-c3cc(NC(C)(C)C)nc(-c4ccccn4)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1cccc(-c2cncc(-c3cc(N)nc(-c4ccccn4)c3)c2)c1
Temperature: 70 °C

Procedure:
Tert-Butyl-[5″-(3-methoxy-phenyl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (1 eq, 0.073 mmol, 0.030 g) is dissolved in TFA (6 ml)/DCM (1 ml) and the reaction mixture is heated at 70° C. for 5 hours. The reaction mixture is cooled down and reduced in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 355.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH:7]([CH3:25])[N:8]([C:21](=[O:24])[CH2:22][CH3:23])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([CH3:20])[CH:12]=3)[C:4]=2[CH:3]=1.O.NN>CO.ClCCl.[Ni]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=3[CH2:6][CH:7]([CH3:25])[N:8]([C:21](=[O:24])[CH2:22][CH3:23])[N:9]=2)=[CH:12][C:13]=1[CH3:20]
Reactant: CCC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2CC1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCC(=O)N1N=C(c2ccc(N)c(C)c2)c2cc(Cl)ccc2CC1C
Reaction time: 0.75 h
Yield: 55.9 %

Procedure:
3.86 g (10 mmoles) of (±)-4,5-dihydro-8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3-propionyl-3H-2,3-benzodiazepine are dissolved in a mixture of 80 cm3 of methanol and 13 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is purified by chromatography over a column containing silica gel and using a mixture of ethyl acetate and hexane, then the product is recrystallized from acetonitrile. Thus, 1.99 g (56%) of the title compound are obtained in the form of cream coloured solids melting at 152–154° C.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([NH2:35])=[O:34]>>[C:33]([CH:28]1[N:27]([CH2:2][C:3]2[NH:8][C:7]([C:9]3[S:10][CH:11]=[CH:12][N:13]=3)=[N:6][CH:5]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Cl:21])[C:4]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:32][CH2:31][O:30][CH2:29]1)(=[O:34])[NH2:35]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: NC(=O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(N)=O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 45 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2.75 g, 6 mmol) was reacted with morpholine-3-carboxamide (0.78 g, 6 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (1.37 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][CH:28]([CH3:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][CH:28]([CH3:33])[CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CC(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (77 mg, 75%), MS (ISP) m/z=413.5 [(M+H)+], mp 197° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 3-methyl-butyric acid.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.Br[C:15]1[CH:23]=[CH:22][C:18]([N:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=1.[CH3:24][C:25]([OH:29])([C:27]#[CH:28])[CH3:26].[Cl-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.C1(C)C=CC([B-](C2C=CC(C)=CC=2)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1.O1CCCC1>[CH3:20][N:19]([C:18]1[CH:22]=[CH:23][CH:15]=[CH:16][C:17]=1[C:28]#[C:27][C:25]([CH3:26])([OH:29])[CH3:24])[CH3:21]
Reactant: CN(C)c1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: [Pd+2]
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(C)c1ccccc1C#CC(C)(C)O
Yield: 86.1 %

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.034 g (0.15 mmol) of palladium (II) acetate, 0.019 g (0.1 mmol) of copper (I) iodide, 1.088 g (6 mmol) of dicyclohexylamine and 5 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.174 g (0.3 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate obtained in Example B-3 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 30° C. for 30 minutes. 1.000 g (5 mmol) of 4-bromo-N,N-dimethylaniline and 0.505 g (6 mmol) of 2-methyl-3-butyne-2-ol were added, followed by stirring at 30° C. for 17 hours. After the completion of the reaction, 10 ml of tetrahydrofuran, 5 ml of toluene and 15 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.875 g of 4-(N,N-dimethylaminophenyl)-2-methyl-3-butyne-2-ol (yield: 86 mol % based on 4-bromo-N,N-dimethylaniline). The identification of the product was made by mass spectroscopy, 1H-NMR and 13C-NMR.