Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:8](=[O:15])[N:7]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)[C:6]1=[O:28].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[O:28]=[C:6]1[N:7]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:26])([F:25])[F:27])[CH:17]=2)[C:8](=[O:15])[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]1[CH2:4][C:3]1[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=1[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Nc1ccccc1
Reactant: N#Cc1ccc(N2C(=O)N(Cc3ccccc3Br)C3(CCCCC3)C2=O)cc1C(F)(F)F
Product: N#Cc1ccc(N2C(=O)N(Cc3ccccc3Nc3ccccc3)C3(CCCCC3)C2=O)cc1C(F)(F)F

Procedure:
To prepare the compound of example 28, the procedure may be according to process “A”. Analogously to the process described in example 1.2, 28.2 and aniline were reacted. 28: Molecular weight 518.19 (C29H25F3N4O2); retention time Rt=3.19 min. [C]; MS (ESI): 519.24 (MH+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[CH:17]([C:19]1[CH:20]=[CH:21][C:22]2[N:26]=[N:25][N:24]([CH3:27])[C:23]=2[CH:28]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:37])=O>C(Cl)Cl>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[CH:17]([C:19]1[CH:20]=[CH:21][C:22]2[N:26]=[N:25][N:24]([CH3:27])[C:23]=2[CH:28]=1)[Cl:37])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cn1nnc2ccc(C(O)c3ccc(Cl)cc3CO[Si](C)(C)C(C)(C)C)cc21
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1nnc2ccc(C(Cl)c3ccc(Cl)cc3CO[Si](C)(C)C(C)(C)C)cc21
Reaction time: 0.5 h

Procedure:
To the solution of α-[2-(t-butyldimethylsilyloxy)methyl-4-chlorophenyl]-1-methyl-1H-benzotriazole-6-methanol (0.5 g) from Example 75 and pyridine (0.11 ml) in methylene chloride (5 ml) was added thionyl chloride (0.1 ml) at 0° C. the mixture was stirred for 30 minutes. The reaction solution was diluted with methylene chloride (5 ml),and sequentially washed with water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, to give the crude 6-[2-(t-butyldimethyl-silyloxy)methyl-α,4-dichlorobenzyl]-1-methyl-1H-benzotriazole.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][C:3]=1[CH:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1.C([N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[C:23](F)[CH:24]=2)[C:19](=[O:28])[C:18]([C:29]([OH:31])=[O:30])=[CH:17]1)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][C:3]=1[CH:8]1[NH:9][CH2:10][CH2:11][N:12]([C:23]2[CH:24]=[C:25]3[C:20]([C:19](=[O:28])[C:18]([C:29]([OH:31])=[O:30])=[CH:17][NH:16]3)=[CH:21][C:22]=2[F:27])[CH2:13]1
Reactant: Cc1cc(C)c(C2CNCCN2)o1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: Cc1cc(C)c(C2CN(c3cc4[nH]cc(C(=O)O)c(=O)c4cc3F)CCN2)o1
Reaction time: 4 h
Yield: 21.9 %

Procedure:
The 1.4 g of 2-(3,5-dimethyl-2-furanyl)piperazine was dissolved in 5 ml of pyridine, 0.66 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid added and the mixture heated at 95°-100° C., under argon, :n a pressure bottle for 4 hours, then cooled. The solvent was removed in vacuo, the residue evaporated twice from toluene and the residue chromatographed, giving 700 mg of crude product. This product was recrystallized from methanol, giving 220 mg of the desired product, mp 230°-232° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][C:18]=1[O:32][CH3:33]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:19][C:18]=2[O:32][CH3:33])=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1coc(-c2ccc(N)c(OC)c2)n1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2OC)nc1Cl
Yield: 85.6 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.13 g, 0.75 mmol), thionyl chloride (2 mL), methyl 2-(4-amino-3-methoxyphenyl)-1,3-oxazole-4-carboxylate obtained in Example (102d) (0.25 g, 1.01 mmol) and pyridine (5 mL), to obtain 0.26 g of the title compound as a colorless solid (86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc(OC)c2)c1
Yield: 82.8 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of 3-methoxyphenylamine (0.189 g, 1.53 mmol) in dioxane (1 ml) and NaHCO3 (0.25 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.44 g, 82%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.60 (3H, s), 3.71 (3H, s); 6.52-6.74 (3H, m); 6.63 (1H, d, J=16.0 Hz); 7.07 (1H, m); 7.43-8.05 (5H, m); 10.27 ppm (1H, br s).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18](C)=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)[CH2:4][O:3]1.O[C:23]1C=CC(C#N)=C(C)C=1>>[CH3:21][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[C:17]([CH3:23])[CH:18]=2)[CH2:4][O:3]1
Reactant: Cc1cc(O)ccc1C#N
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Product: Cc1cc(OC[C@@H]2COC(C)(C)O2)ccc1C(=N)NO

Procedure:
The title compound is obtained as a beige oil (0.65 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 4-hydroxy-2-methyl-benzonitrile and L-alpha-beta-isopropyliden glycerol; LC-MS: tR=0.62 min, [M+H]+=281.0.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=O)=[CH:24][C:23]=4OC)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=CC2[N:38](C)[C:39](=[O:52])C(F)(F)CN(C3CCCC3)C=2N=1.NC1C=C2C(CC(=O)N2)=CC=1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[C:29]5[C:25]([CH2:26][C:39](=[O:52])[NH:38]5)=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Nc1ccc2c(c1)NC(=O)C2
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc4c(c3)NC(=O)C4)ncc21

Procedure:
The title compound was synthesized using an analogous procedure to that described in connection with 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid from 2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one and 6-aminoindolin-2-one. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45-1.86 (m, 6H) 1.92-2.16 (m, 2H) 3.39 (s, 3H) 3.54 (s, 2H) 3.87 (t, J=13.39 Hz, 2H) 4.74 (quin, J=8.27 Hz, 1H) 6.81 (d, J=8.34 Hz, 1H) 7.00 (br. s., 1H) 7.26 (s, 1H) 7.50 (br. s., 1H) 7.58 (s, 1H) 7.97 (s, 1H). [M+H] calc'd for C21H22F2N6O2, 429. found 429.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([N:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][CH2:20]2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([N:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][CH2:20]1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: NCC(CC1CC1)N1C=CC(C(F)(F)F)=NC1
Product: O=C(NCC(CC1CC1)N1C=CC(C(F)(F)F)=NC1)c1c(Cl)cccc1Cl

Procedure:
From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS (MH+): m/z=418.1, tR (minutes, Method D)=0.79
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:36]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O.C(N(CC)CC)C>[CH2:36]([N:43]1[CH2:48][CH2:47][CH:46]([NH:49][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=3)=[O:13])[CH2:45][CH2:44]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1cc2cc(O)ccc2[nH]1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
To a stirred mixture of 5-hydroxy-1H-indole-2-carboxylic acid (1.85 g, 10.43 mmol) in anhydrous dimethylformamide (15 mL) was added triethylamine (1.73 mL), 1-hydroxybenzotriazole (1.64 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.39 g) and 1-benzylpiperidin-4-ylamine (2.39 g, 12.54 mmol). The reaction mixture was stirred at room temperature over-night and then solvents were removed under reduced pressure, poured into water, filter the solid and washed with water. The solid was purified by silica gel column chromatography, eluted with CH2Cl2:MeOH (93:7) to afford 0.87 g (24%) of N-(1-benzylpiperidin-4-yl)-5-hydroxy-1H-indole-2-carboxamide as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 11.17 (s, 1H), 8.72 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.7.29 (m, 6H), 6.91 (s, 1H), 6.82 (s, 1H), 6.68 (m, 1H), 3.75 (br s, 1H), 3.46 (s, 2H), 2.81 (d, J=11.4 Hz, 2H), 2.02 (t, J =10.8 Hz, 2H), 1.77 (m, 2H), 1.56 (m, 2H); LCMS (m/z): 350 (MH+).
Reaction SMILES: C([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])(OC(C)(C)C)=O.F[C:19]1[CH:20]=[C:21]([CH3:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26]>[OH-].[Na+].C(O)C.Cl.C(O)(=O)C>[NH2:8][C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:19]1[CH:20]=[C:21]([CH3:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:15]([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(NCCCC[C@H](N)C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.7 %

Procedure:
A mixture of 2.37 g (10 mmol) of Nα -BOC-L-lysine and 1.65 g (11.0 mmol) of 3-fluoro-4-nitrotoluene in 10 mL of 1N NaOH and 10 mL of ethanol were heated at reflux for 48 hours, then cooled to room temperature. A precipitate was filtered off and discarded. Removal of the solvent/n vacuo gave an oil which was dissolved in 50 % ethanol/3M NH3 and taken to dryness. The residue was dissolved in 12 mL of 4N HCl in 33% acetic acid and stirred for four hours, then concentrated to dryness and purified by flash chromatography (eluting with 12:1:1 acetonitrile/water/HOAc). The resulting oil was recrystallized from water/methanol to afford 470 mg (42% yield) of the title product as bright orange prisms.: mp 234°-235° (dec.); MS M/Z (DCl/NH3): 282 [M+H]+ ; 1H NMR (300 MHz, D2O) δ: 1.1-1.45 (m, 6H), 2.78 (t, J=6.6 Hz, 2H), 2.99 (t, J=6.0 Hz, 1H), 5.88 (d, J=7.8 Hz, 1H), 6.07 (s, 1H), 7.32 (d, J=7.8 Hz, 1H). 13C NMR (75.5 MHz, D2O) δ: 185.73, 151.31,148.37, 131.02, 119.60, 116.09, 58.83, 45.20, 37.87, 31.19, 25.86; Analysis calc'd for C13H19N3O4 : C, 55.51;H, 6.81;N, 14.94; found: C, 55.25;H, 6.94; N, 14.75.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[C:17](=O)[CH3:18])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=[C:9]2[CH:17]([NH2:26])[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc2cccnc2n1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc2cccnc2n1-c1cccc(F)c1
Temperature: 65 °C
Yield: 133.3 %

Procedure:
A mixture of 1-[1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]ethanone (0.24 g, 0.94 mmol) and ammonium acetate (0.73 g, 9.5 mmol) in methanol (3.0 mL) and acetonitrile (3.0 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, sodium cyanoborohydride (0.18 g, 2.8 mmol) was added to the resultant mixture. The reaction was heated at 65° C. overnight. The reaction was then cooled to room temperature and quenched with saturated NaHCO3 solution and then extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the crude amine (0.32 g), which was used directly in the next step. LCMS calculated for C15H15FN3(M+H)+: m/z=256.1. Found: 256.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].C(N(CC)CC)C.[CH2:27]([C:34]1[CH:38]=[CH:37][NH:36][C:35]=1[CH2:39]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCOCC>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH2:39][C:35]1[NH:36][CH:37]=[CH:38][C:34]=1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:15]
Reactant: OCc1[nH]ccc1Cc1ccccc1
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)OCc1[nH]ccc1Cc1ccccc1
Reaction time: 18 h

Procedure:
To the acid chloride of 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid (2.5 mmol) in ether is added 1.3 ml of triethylamine followed by 3-benzylpyrrolylmethyl alcohol (2.0 mmol) in ether over about 2 minutes. The reaction mixture is stirred for about 18 hours and then quenched with saturated aqueous sodium bicarbonate. The organic phase is washed with aqueous sodium bicarbonate, water and brine, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a circular chromatograph eluting with 20% ether/hexane to give 3-benzylpyrrolylmethyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:17])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].[C:18](Cl)(=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(Cl)(=O)OCC>C(Cl)Cl>[CH2:30]([C:31]1[O:16][C:8](=[O:17])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: Nc1ccccc1C(=O)O
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCc1nc2ccccc2c(=O)o1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Triethylamine (1.76 ml) was added to a suspension of anthranilic acid (823 mg) in methylene chloride (20 ml). Then, myristoyl chloride (1.63 ml) was dropwise added to the mixture while being cooled with ice. After being stirred for 2.5 hour at room temperature, the reaction mixture was cooled with ice. Triethylamine (0.92 ml) and ethyl chlorocarbonate (0.63 ml) were dropwise added to the reaction mixture successively. After being stirred for 1 hour at 0° C. and for 1.5 hours at room temperature successively, the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with water, neutralized with diluted hydrochloric acid, and washed with saturated brine. The organic layer was dried over magnesium sulfate anhydride and then concentrated. The residue was purified by silica gel column chromatography (silica gel 60 g, chloroform-hexane), thereby yielding 1.663 g of the aimed compound as colorless crystals.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6]O.[CH2:8]([O:15][C:16]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:17]=1[CH:18]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(O)(=O)C>[CH2:8]([O:15][C:16]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:17]=1[C:18]#[N:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(C=O)c(OCc2ccccc2)c1OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C#N)c(OCc2ccccc2)c1OC

Procedure:
A slurry of sodium acetate (17.06 g, 0.208 mol) and hydroxylamine (14.45 g, 0.208 mol) in glacial acetic acid (120 ml) was added to 2-benzyloxy-3,4-dimethoxybenzaldehyde (28.3 g, 0.104 mol) and the resulting suspension stirred at reflux for 18 hours. On cooling, water (250 ml) was added and the mixture extracted with dichloromethane (500 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with hexane:ethyl acetate (80:20 v/v) to give the subtitle compound as an oil that crystallised on standing (21.06 g, 75%). Rf 0.52 (ethyl acetate:hexane, 1:1, v/v). MS m/z 270 (MH)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]3[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=3)[CH:26]=2)[CH:10]=1.Cl[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>C(#N)C.C(Cl)Cl>[CH3:7][NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:35][CH2:36][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH:28]=3)[CH:26]=2)[CH:10]=1
Reactant: CNc1cc(-c2cncc(-c3cccc(O)c3)c2)cc(-c2ccccn2)n1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CNc1cc(-c2cncc(-c3cccc(OCCN4CCCC4)c3)c2)cc(-c2ccccn2)n1

Procedure:
Potassium carbonate (3.0 eq, 0.686 mmol, 95 mg) is added to a suspension of 3-(6′-Methylamino-[2,2′;4′,3″]terpyridin-5″-yl)-phenol (Example 2.189, step 1) (1.0 eq, 0.229 mmol, 81 mg) in dry acetonitrile (2.0 ml) under an inert atmosphere of nitrogen. 1-(2-Chloro-ethyl)-pyrrolidine (3 eq, 0.686 mmol, 92 mg) is added and the reaction is heated using microwave radiation at 150° C. for 2 hours. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated 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]+ 453.
Reaction SMILES: [CH:1]([N:4]([CH3:15])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:12][O:13][CH3:14])[CH2:6]1)([CH3:3])[CH3:2].[CH2:16]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH:1]([N:4]([CH3:15])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:7]([CH2:12][O:13][CH3:14])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N
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: CC#N
Product: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of crude dihydrobromide salt of (1R,3R,4S)-N1-isopropyl-3-(methoxymethyl)-N1-methylcyclohexane-1,4-diamine prepared according to the procedure of Example 4b, Step 2 (423 mg) in acetonitrile (5 mL) was treated with 2-(benzyloxycarbonylamino)acetic acid (259 mg), diisopropylethylamine (0.80 ml) and HATU (516 mg). The mixture was stirred overnight at rt, then was concentrated under vacuum. The residue was purified by reverse phase HPLC followed by lyopholization to provide benzyl 2-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(methoxymethyl)cyclohexylamino)-2-oxoethylcarbamate (192 mg) as a white powder. MS found: (M+H)+=406.3.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]2[CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9][C:2]=12.C([NH2:19])(C)(C)C.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:19][C:6]1[N:1]=[C:2]2[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[C:3]2=[CH:4][CH:5]=1
Reactant: CC(C)(C)N
Reactant: COC(=O)C1CCc2c1ccc[n+]2[O-]
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CCc2nc(N)ccc21
Temperature: 0 °C

Procedure:
To a solution of methyl 6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxylate 1-oxide (700 mg, 3.6 mmol) in CF3-toluene (20 mL) and CHCl3 (20 mL) was added tert-butylamine (3.8 mL, 36 mmol). The solution was cooled to 0° C. in an ice bath. To the solution was added p-toluenesulfonic anhydride (3.5 g, 10.9 mmol) in small portions until all SM was consumed according to LC-MS. The volatiles were removed under reduced pressure, and the residue was redissolved in TFA (20 mL). The dark solution was heated to 70° C. for 2 hours. LC showed mostly product, with a little bit SM remaining. The reaction was stopped at that point. TFA was removed on a rotavapor, and the residue was taken up in saturated sodium carbonate, extracted three times with IPA-CHCl3 (1:3, 50 mL each). The extractions were combined, dried over sodium sulfate, adsorbed onto silica gel, and purified by MPLC (DCM:MeOH with 10% aq NH4OH). After removal of solvent was collected as the desired methyl 2-amino-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxylate. LC-MS (IE, m/z): 193 [M+1]+;
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][O:7][CH2:6][C@H:5]1[NH:10]C(=O)OC(C)(C)C)=[N+:2]=[N-:3].O1CCOCC1.Cl.Cl>C(Cl)Cl>[N:1]([C@H:4]1[CH2:9][CH2:8][O:7][CH2:6][C@H:5]1[NH2:10])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1COCC[C@@H]1N=[N+]=[N-]
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: [N-]=[N+]=N[C@H]1CCOC[C@H]1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Tert-butyl ((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)carbamate (1.5 g, 6.19 mmol) was taken up in DCM (5 ml) and 4N HCl dioxane (4.64 ml, 18.57 mmol) added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed to give (3S,4S)-4-azidotetrahydro-2H-pyran-3-amine (1.1 g, 6.16 mmol, 99% yield) as an HCl salt. MS (ES+) C5H10N4O requires: 142, found: 143 [M+H]+.