Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[C:19]([C:21](=[O:31])[NH:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:24])[CH:18]=[CH:17][C:16]=3[S:32][C:33]3[CH:38]=[CH:37][C:36]([NH:39]C(=O)OC(C)(C)C)=[CH:35][CH:34]=3)=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(Cl)Cl.FC(F)(F)C(O)=O>>[NH2:39][C:36]1[CH:35]=[CH:34][C:33]([S:32][C:16]2[CH:17]=[CH:18][C:19]([C:21]([NH:22][C@H:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH3:24])=[O:31])=[CH:20][C:15]=2[NH:14][C:8]2[C:7]3[C:12](=[CH:13][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[N:11]=[CH:10][N:9]=2)=[CH:38][CH:37]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(N)cc3)ncnc2c1
Yield: 72.5 %

Procedure:
The product of Example 431G (36 mg, 0.0568 mmol) was treated with 1:1 v/v methylene chloride/trifluoroacetic acid (3 mL) at room temperature for one hour then concentrated by rotary evaporation. The residue was dissolved in ethyl acetate (50 mL), washed with saturated aqueous sodium hydrogencarbonate (25 mL), water (25 mL), and brine (25 mL) then dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification by silica gel flash chromatography eluting with 3:97 methanol/methylene chloride afforded the title compound as a white solid (22 mg, 0.0412 mmol, 73%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.31 (d, J=6.99 Hz, 6 H) 1.45 (d, J=7.35 Hz, 3 H) 3.01-3.20 (m, 1 H) 5.07-5.26 (m, 1 H) 5.57 (s, 2 H) 6.61 (d, J=8.46 Hz, 2 H) 6.83 (d, J=8.46 Hz, 1H) 7.11 (d, J=8.82 Hz, 2 H) 7.17-7.43 (m, 5 H) 7.54-7.64 (m, 2 H) 7.69 (dd, J=8.46, 1.10 Hz, 1 H) 7.89 (d, J=1.47 Hz, 1 H) 8.43 (t, J=4.23 Hz, 2 H) 8.74 (d, J=7.72 Hz, 1 H) 9.88 (s, 1 H); MS (ESI+) m/z 534 (M+H)+, 1067 (2M+H); MS (ESI−) m/z 532 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][C:22]1[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:25]3[O:26][C:22]([CH3:21])=[CH:23][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: Cc1ccc(C=O)o1
Product: Cc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Br)cnc3[nH]2)o1
Yield: 30 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 5-Methyl-2-furancarboxaldehyde (17.9 mg, 0.163 mmol) were reacted to produce 19 mg (30%) of the title compound. mp: 200-201° C., 1H NMR (300 MHz, DMSO-d6): 13.17 (s, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.20 (s, 1H), 7.06 (s, 1H), 6.36 (s, 1H), 6.33 (s, 1H), 5.16 (t, J=8 Hz, 1H), 3.32 (s, 1H), 2.87 (s, 1H), 2.73 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.40 (s, 3H), 2.23 (d, J=8 Hz, 1H), 1.37 (d, J=8 Hz, 1H). MS: 428, 430 (M+H), HPLC: 2.39 (G method).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:41][C:38]3[C:39]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc2[nH]c(-c3cccc(Br)c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 588.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8](=[O:28])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](I)=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F-:31].[Cs+].O1[CH2:38][CH2:37]OCC1>O.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>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8](=[O:28])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:5]4[C:6]([F:31])=[N:7][CH:8]=[CH:37][CH:38]=4)=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: C1COCCO1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Solvent: O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3cccnc3F)c3ccccc32)cc1
Yield: 50 %

Procedure:
Combine N-(4-Fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide (300 mg, 0.56 mmol), 2-Fluoro-3-boronic acid-pyridine (140 mg, 1.12 mmol), CsF (170 mg, 1.12 mmol) and Dichlorobis(triphenylphosphine)palladium (100 mg, 0.14 mmol) in dioxane (2.0 mL) and water (0.200 mL). Evacuate the reaction and place under a nitrogen atmosphere. Heat the resulting reaction in an 80 degree oil bath for 15 h. Cool the reaction and filter through a short pad of silica gel with additional ethyl acetate. Evaporate and purify by flash column chromatography (EtOAc/Hexanes) to yield 141 mg of an off white foam (50%) LRMS: MH+ 503.92.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]([CH2:10][CH3:11])[C:8]#[N:9])=[CH:3][CH:2]=1.[CH2:13](N)[CH2:14][NH2:15]>>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([CH:7]([C:8]2[NH:9][CH2:13][CH2:14][N:15]=2)[CH2:10][CH3:11])=[CH:5][CH:6]=1
Reactant: CCC(C#N)c1ccc(C)cc1
Reactant: NCCN
Product: CCC(C1=NCCN1)c1ccc(C)cc1

Procedure:
rac-2-(1-p-Tolyl-propyl)-4,5-dihydro-1H-imidazole was prepared from rac-2-p-tolyl-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 203.0 ((M+H)+.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2Br)=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>COCCO.O.[Cu]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:17]3[S:18][CH:19]=[CH:20][C:21]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=NO)c2sccc2Br)CC1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: CC(C)(C)OC(=O)N1CCC(c2noc3ccsc23)CC1
Temperature: 65 °C
Reaction time: 6 h
Yield: 49.5 %

Procedure:
Add to a stirring solution of 4-[(3-bromo-thiophen-2-yl)-hydroxyimino-methyl]piperidine-1-carboxylic acid tert-butyl ester (Example 21b) (25 g., 64.2 mmol) in 2-methoxyethanol (200 mL), a solution of potassium hydroxide (7.2 g, 128.4 mmol) in water (20 mL). Heat the reaction to 60° C. and then add copper powder (1.25 g). Stir at 60-70° C. for 6 h and then at ambient temperature overnight. Pour the reaction mixture into water (500 mL) and extract with EtOAc (3 times). Concentrate to a dark residue and purify by column chromatography over silica gel (heptane/EtOAc, 4:1) to provide 9.8 g (50%) of a white solid.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@@H:4]1[NH2:5].C[O-].[Na+].Cl[CH2:18][C:19]([O:21]C(=O)CCl)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CO.CN(C=O)C>[N:26]([CH2:18][C:19]([NH:5][C@H:4]1[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@@H:10]([CH2:12][OH:13])[O:11][CH:3]1[OH:2])=[O:21])=[N+:27]=[N-:28]
Reactant: O=C(CCl)OC(=O)CCl
Reactant: N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: [N-]=[N+]=[N-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: [N-]=[N+]=NCC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A solution of mannosamine hydrochloride (250 mg, 1.16 mmol) and sodium methoxide (1.16 ml of a 1 M methanolic solution) in dry MeOH (10 ml) was stirred for 1 h at room temperature, after which chloroacetic anhydride (991 mg, 5.80 mmol) was added. The resulting solution was stirred overnight at room temperature under an atmosphere of N2 and then quenched with H2O (5 ml) for 1 hour. The solution was neutralized with saturated NaHCO3 and concentrated, and the residue was filtered through a plug of silica gel eluting with 5:1 CHCl3/MeOH. The crude product obtained was dissolved in DMF (10 ml) and NaN3 (78 mg, 1.39 mmol) was added. After heating at reflux overnight, the solution was cooled and concentrated. Purification by silica gel chromatography eluting with a gradient of 50:1 to 6:1 CHCl3/MeOH afforded 179 mg of compound 20 (59% over two steps). The compound was peracetylated prior to incubation with cells as follows. A solution of 20 (25 mg, 0.095 mmol), acetic anhydride (1.0 ml, 11 mmol) and a catalytic amount of DMAP in pyridine (2 ml) was cooled to 0° C. The mixture was stirred overnight, warmed to rt, then diluted with CH2Cl2 (100 ml) and washed with 1 N HCl (3×50 ml), sat. NaHCO3 (1×50 ml), water (1×50 ml) and saturated NaCl (1×50 ml). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 1:10 to 1:2 EtOAc/hexanes to afford 39 mg (95%) of acetylated 20 (compound 36).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([C:17]2[C:18]([NH:34][C:35]3[C:36]4[CH:37]=[N:38][N:39](C5CCCCO5)[C:40]=4[CH:41]=[CH:42][CH:43]=3)=[N:19][CH:20]=[C:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:22]=2)[N:3]=1.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(Cl)Cl>[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[CH3:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([C:17]2[C:18]([NH:34][C:35]3[C:36]4[CH:37]=[N:38][NH:39][C:40]=4[CH:41]=[CH:42][CH:43]=3)=[N:19][CH:20]=[C:21]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=3)[CH:22]=2)[N:3]=1
Reactant: Cc1nc(-c2cc(Cc3ccc(S(C)(=O)=O)cc3)cnc2Nc2cccc3c2cnn3C2CCCCO2)c2ncn(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2cc(Cc3ccc(S(C)(=O)=O)cc3)cnc2Nc2cccc3[nH]ncc23)c2nc[nH]c2n1
Reaction time: 2 h
Yield: 8.22 %

Procedure:
A solution of N-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (111 mg, 0.164 mmol) in DCM (3.0 mL) was treated with TFA (1.0 mL) and allowed to stand for 2 h. The mixture was concentrated, azeotroped with toluene, purified by prep HPLC, and the pure fractions were concentrated and triturated with MeOH to give pure N-(3-(2-methyl-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-yl)-1H-indazol-4-amine trifluoroacetate (8.4 mg, 0.013 mmol, 8.22% yield) as an orange crystalline solid. 1H NMR (400 MHz, d6-DMSO) δ 13.12 (br. s., 1H); 12.61 (br. s., 1H); 9.68 (br. s., 1H); 8.63 (s, 1H); 8.36 (d, J=2.15 Hz, 1H); 8.26 (s, 1H); 8.08 (d, J=7.63 Hz, 1H); 7.87 (d, J=8.22 Hz, 2H); 7.59 (d, J=8.22 Hz, 2H); 7.31 (t, J=8.02 Hz, 1H); 7.16 (d, J=8.41 Hz, 1H); 4.17 (s, 2H); 3.16 (s, 3H); 2.93 (s, 3H). m/z (ESI, +ve ion) 511.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CCc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(CCc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(2-phenylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:18]#[C:19][CH2:20][CH2:21][CH2:22][OH:23].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[C:18]#[C:19][CH2:20][CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33]
Reactant: OCCCC#Cc1cc2ccn(-c3ccc(F)cc3)c2cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC#Cc1cc2ccn(-c3ccc(F)cc3)c2cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A solution of 87 mg (0.28 mmol) 5-[6-Fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol in 3 ml CH2Cl2 was treated with 0.14 ml (1 mmol) NEt3 and 80 μl (0.33 mmol) MsCl, stirred at room temperature for one hour, poured into icy 0.5 M aqueous HCl and extracted three times with Et2O. Drying of the combined organic layers with Na2SO4 and evaporation of the solvent gave (93 mg) Methanesulfonic acid 5-[6-fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester as a light brown oil. 31 mg of this oil were dissolved in DMF, treated with 0.2 ml Allylmethylamine and the mixture stirred at 80° C. during 2 hours. Pouring the mixture into 0.5 M NaOH, extraction with CH2Cl2, drying of the organic layers with MgSO4, and flash chromatography with CH2Cl2/MeOH 19:1 gave 24 mg (89%) Allyl-{5-[6-fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-methyl-amine as a light yellow oil, MS: 365 (MH+).
Reaction SMILES: C(OC(=O)N[C@@H](CC1C=CC=CC=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)(C)(C)C.[CH3:31][C:32]1([CH3:39])[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1.[CH:40]([O:43][C:44]1[CH:45]=[C:46]([CH:65]=[C:66]([N:68]2[CH2:72][CH2:71][CH2:70][C:69]2=[O:73])[CH:67]=1)[C:47]([NH:49][C@H:50]([C@@H:58]1[CH2:62][C@@H:61]([CH3:63])[C:60](=[O:64])[O:59]1)[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:48])([CH3:42])[CH3:41]>>[CH2:51]([C@H:50]([NH:49][C:47](=[O:48])[C:46]1[CH:65]=[C:66]([N:68]2[CH2:72][CH2:71][CH2:70][C:69]2=[O:73])[CH:67]=[C:44]([O:43][CH:40]([CH3:42])[CH3:41])[CH:45]=1)[C@@H:58]([OH:59])[CH2:62][C@H:61]([C:60](=[O:64])[NH:38][CH:35]1[CH2:36][CH2:37][C:32]([CH3:39])([CH3:31])[CH2:33][CH2:34]1)[CH3:63])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC1(C)CCC(N)CC1
Reactant: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H]2C[C@@H](C)C(=O)O2)cc(N2CCCC2=O)c1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Product: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CCC(C)(C)CC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D1 from 4,4-dimethylcyclohexylamine (D53) and 3-isopropoxy-N-[(S)-1-((2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl)-2-phenylethyl]-5-(2-oxopyrrolidin-1-yl)benzamide (D49).
Reaction SMILES: Br[C:2](Br)=[CH:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Li]CCCC.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[O:27][CH2:28][C:29](N(OC)C)=[O:30].[NH4+].[Cl-]>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[O:27][CH2:28][C:29](=[O:30])[C:2]#[C:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: COc1ccc(OCC(=O)N(C)OC)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(Br)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(OCC(=O)C#C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Yield: 50.2 %

Procedure:
To a THF (120 mL) solution of (S)-t-butyl 2-(2,2-dibromovinyl)pyrrolidine-1-carboxylate (5.326 g), n-BuLi (11.6 mL, 2.64 N hexane solution) was added dropwise at −78° C. and the mixture was stirred at the same temperature for an hour; thereafter, a THF (50 mL) solution of the compound (4.00 g) obtained in Example 14-(1) was added dropwise and temperature was raised to room temperature over an hour. The reaction mixture was added to a saturated aqueous solution of NH4Cl (400 mL) and the organic layer extracted with AcOEt (400 mL×2) was dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by neutral silica gel chromatography (AcOEt/hexane) to give the titled compound (2.934 g, pale yellow oil.)
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccccc4)cc3OCC)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccccc4)cc3OCC)CC1)CC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (5 mL)-THF (5 mL) solution of methyl 6-(1-((2-cyclopropyl-5-ethoxybiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (460 mg), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (DMSO/ethanol/hexane) to obtain the title compound (397 mg).
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13](F)[N:12]=2)[N:9]=[CH:8][C:7]=1[C:23]#[N:24].Cl>C(OC)(C)(C)C>[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([O:2][CH3:1])[N:12]=2)[N:9]=[CH:8][C:7]=1[C:23]#[N:24]
Reactant: CO
Reactant: N#Cc1cnn(-c2nc(F)c(C(F)(F)F)cc2Cl)c1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COc1nc(-n2ncc(C#N)c2N)c(Cl)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
5 ml of methanol were added in the course of 10 minutes at 20° C. to a suspension of 0.23 g (0.0092 mol) of 95% sodium hydride in 75 ml of methyl tert-butyl ether and the mixture was stirred for 25 minutes until a clear solution was obtained. 3 g (0.0098 mol) 10 of 5-amino-4-cyano-1-(3-chloro-6-fluoro-5-trifluoromethylpyrid-2-yl) pyrazole (Example IV.1.) in 50 ml of methyl tert-butyl ether were subsequently added with stirring and the mixture was stirred for 2 hours at 25 C. Approximately 50 g of ice and 100 ml of hydrochloric acid were added and the phases were separated. The organic phase was washed using saturated sodium chloride solution, dried and filtered through silica gel. After concentration, stirring with ether/pentane, filtration with suction and drying, 2.4 g (77% of theory) of the title compound of m.p. 135°-139° C. were obtained (active ingredient example No. 5.003).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.O>CN(C=O)C>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[O:10][C:11]3[C:3]([CH2:2][N:20]4[CH:24]=[CH:23][N:22]=[CH:21]4)=[CH:4][C:5]([OH:19])=[CH:6][C:7]=3[CH:8]=2)=[CH:13][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(-c2cc3cc(O)cc(Cn4ccnc4)c3o2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of benzyl bromide 4 (0.070 g, 0.215 mmole) in 10 mL DMF was added imidazole (0.030 g, 0.437 mmole). After stirring at 60° C. for 3 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 0.059 g (88%) of imidazole 16 as a light tan solid: Mp=269–271° C.; 1H NMR (DMSO-d6) δ 9.88 (s, 1 H), 9.24 (s, 1 H), 7.88 (s, 1 H), 7.72 (d, 2 H, J=8.6 Hz), 7.26 (s, 1 H), 7.04 (s, 1 H), 6.93 (s, 1 H), 6.88 (d, 2 H, J=8.7 Hz), 6.83 (d, 1 H, J=2.3 Hz), 6.50 (d, 1 H, J=2.3 Hz), 5.46 (s, 2 H); MS 305 (M−H)−
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6]([CH3:14])([C:12]#[N:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[SH2:15].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6]([CH3:14])([C:12](=[S:15])[NH2:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: S
Reactant: Cc1cnc2c(c1)CCCC2(C)C#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cnc2c(c1)CCCC2(C)C(N)=S

Procedure:
3,8-dimethyl-8-cyano-5,6,7,8-tetrahydroquinoline is treated with H2S in pyridine in the presence of triethylamine following the general procedure of Example 5 and the title compound is isolated and recrystallised from benzene as the quarter hydrate, colourless meedles m.p. 164° C. This was converted to the hydrochloride by treatment in isopropanol with a solution of dry HCl gas in ether. The title compound hydrochloride crystallised as colourless needles m.p. 277° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=3)=[N:6][CH:7]=[CH:8][N:9]=2)[CH2:3][CH2:2]1.[Cl-].[Cl-].[NH3+:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][NH+:26]=1)[CH3:24].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([C:4]2[C:5]([C:10]3[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:22][C@@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:34])[F:35])=[CH:27][N:26]=4)[CH3:24])=[O:19])=[CH:14][CH:15]=3)=[N:6][CH:7]=[CH:8][N:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)Cc1ccc(-c2nccnc2C2CC2)cc1
Reactant: C[C@@H]([NH3+])c1ccc(OCC(F)(F)F)c[nH+]1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)Cc1ccc(-c2nccnc2C2CC2)cc1)c1ccc(OCC(F)(F)F)cn1
Reaction time: 12 h
Yield: 73.8 %

Procedure:
To a solution of 0.080 g (0.32 mmol) of ([4-(3-cyclopropylpyrazin-2-yl)phenyl]acetic acid in 1.00 ml DMF was added 0.11 g (0.38 mmol) of 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.056 g (0.41 mmol) of HOAt, 0.078 g (0.41 mmol) of EDC, and 0.17 mL (0.94 mmol) of DIEA. After 12 h at room temperature, the reaction mixture was purified by reverse-phase preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) to afford 0.13 g (73.8%) of 2-[4-(3-cyclopropylpyrazin-2-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CDCl3, 400 MHz) δ 8.36 (s, 2H); 8.27 (d, J=2.74 Hz, 1H); 7.68 (d, J=8.15 Hz, 2H); 7.40 (d, J=8.06 Hz, 2H); 7.34 (m, 2H); 7.20 (d, J=5.95 Hz, 1H); 5.15 (m, 1H); 4.41 (dd, J=7.88, 15.84 Hz, 2H); 3.65 (s, 2H); 2.22 (m, 1H); 1.46 (d, J=6.95, 3H); 1.19 (m, 2H); 0.99 (m, 2H). HRMS (ES) [M+1]+calcd for C24H24F3N4O2: 457.1851, Found: 457.1831. FLIPR alpha1I IP=47 nM.