Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([C:4]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)c1ccc2cnccn12
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(Cl)c2cnccn12
Yield: 82.3 %

Procedure:
0.5 g of 6-acetylpyrrolo[1,2-a]pyrazine prepared in Preparation Example 15 was dissolved in 5 ml of chloroform; and 0.5 g of N-chlorosuccinimide was added threrto. The reaction mixture was refluxed for 2 hours and then concentrated. The residue was chromatographed over silica gel to yield 0.5 g of title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:3]1[CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]=1>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)[CH:9]=2)[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:3]1[CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(O)cc2n1C
Reactant: BrCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 315 mg of the ester from Step B in 3 mL of DMF were added 225 mg of milled K2CO3 and 272 mg of 2-(bromomethyl)quinoline. The mixture was stirred at R.T. for 18 h, poured into 25% aq. NH4OAc, and extracted with ethyl acetate. The organic extract was dried over Na2SO4 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to give the title compound as a foam.
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.[S:21]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22]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:26]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=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: O=Cc1ccsc1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccsc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 26.7 %

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 3-Thiophenecarboxaldehyde (18.2 mg, 0.163 mmol) were reacted to produce 17 mg (27%) of the title compound. mp: 238-241° C., 1H NMR (300 MHz, DMSO-d6): 13.21 (s, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.75 (s, 1H), 7.72 (s, 2H), 7.22 (s, 1H), 7.13 (d, J=8 Hz, 1H), 6.40 (br s, 1H), 6.35 (br s, 1H), 5.19 (t, J=8 Hz, 1H), 3.31 (s, 2H), 3.29 (s, 1H), 2.88 (s, 1H), 2.76 (s, 1H), 2.61 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS: 430, 432 (M+H), HPLC: 2.44 min (G method).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:22])=[C:5]2[C:10]=1[C:9]([CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])=[N:8][NH:7][C:6]2=[O:21].[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C=O)C>[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:15]([C:14]2[CH:13]=[C:12]([CH:20]=[CH:19][CH:18]=2)[CH2:11][C:9]2[C:10]3[C:5](=[C:4]([CH3:22])[NH:3][C:2]=3[CH3:1])[C:6](=[O:21])[NH:7][N:8]=2)=[O:16])[CH2:27][CH2:26]1
Reactant: COC1CCNCC1
Reactant: Cc1[nH]c(C)c2c(=O)[nH]nc(Cc3cccc(C(=O)O)c3)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4c(C)[nH]c(C)c34)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.179 g, 0.47 mmol) was added to 3-((5,7-dimethyl-1-oxo-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-4-yl)methyl)benzoic acid (51) (0.100 g, 0.34 mmol), 4-methoxypiperidine (0.043 g, 0.37 mmol) and triethylamine (0.117 mL, 0.84 mmol) in DMF (2 mL). The resulting solution was stirred at room temperature for 5 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.054 g, 40.9% yield). 1H NMR (400.132 MHz, DMSO) δ 1.18-1.93 (4H, m), 2.24 (3H, s), 2.51 (3H, s), 3.02-3.19 (2H, m), 3.25 (3H, s), 3.40 (2H, m), 3.76-3.97 (1H, m), 4.09 (2H, s), 7.14 (1H, s), 7.20 (1H, d), 7.27 (1H, d), 7.36 (1H, t), 11.08 (1H, s), 11.92 (1H, s); m/z (LC-MS, ESI+), RT=1.38 min (M+H=395.09).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][N:7]=1)=[O:5])C.[OH-].[Li+:22]>O.C1COCC1>[C:17]([O:16][C:14]([NH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([O-:5])=[O:3])=[N:7][CH:8]=1)=[O:15])([CH3:20])([CH3:18])[CH3:19].[Li+:22]
Reactant: CCOC(=O)c1ccc(CNC(=O)OC(C)(C)C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)[O-])nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 118.1 %

Procedure:
Dissolve 5-aminomethyl-2-chloro-pyridine (2 g, 14 mmol) and di-tert-butyl-dicarbonate (3.37 g, 15.4 mmol) in DCM (30 mL) and stir at room temperature for 2 h. Concentrate the reaction mixture and purify by chromatography on silica gel eluting with hexane/EtOAc (10:1 and 5:1) to give 5-(tert-butoxycarbonylamino-methyl)-2-chloro-pyridine as a yellow solid (3.6 g, 100%). MS (ES+) m/z: 243 (M+H)+. Dissolve 5-tert-butoxycarbonylamino-methyl)-2-chloro-pyridine (1 g, 4.12 mmol) in a mixture of ethanol (15 mL) and DMF (5 mL), and add potassium carbonate (427 mg, 3.09 mmol), palladium(II) acetate (92 mg, 0.4 mmol) and diphenylphosphinoferrocene (240 mg, 0.44 mmol). Pressurize the mixture 25 to 15 psi with carbon monoxide gas and heat the reaction mixture to 90° C. for 16 h. Filter the reaction mixture, concentrate the filtrate, and partition the residue between water and hexane/EtOAc (1:1). Dry the organic layer over Na2SO4, filter, and concentrate in vacuo. Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (3:2) to give 5-(tert-butoxycarbonylamino-methyl)-pyridine-2-carboxylic acid ethyl ester as a brown oil (920 mg, 80%). MS (ES+) m/z: 281 (M+H)+. Dissolve 5-(tert-butoxycarbonylamino-methyl)pyridine-2-carboxylic acid ethyl ester (920 mg, 3.28 mmol) in a mixture of water/THF (1:2, 15 mL) and add lithium hydroxide (87 mg, 3.61 mmol). Stir the mixture at ambient temperature for 4 h and concentrate to a solid. Dry the material by azeotrope distillation with toluene to give the desired intermediate as a brown solid (1 g, 100%). MS (ES+) m/z: 253 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[O:16][CH2:17][CH2:18][O:19][CH:20]=3)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=2[N:10]=1)[CH3:2].[H][H]>O1CCOCC1.C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[S:7][C:8]2[C:14]([CH:15]3[CH2:20][O:19][CH2:18][CH2:17][O:16]3)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=2[N:10]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)Nc1nc2c(OC)ccc(C3=COCCO3)c2s1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)Nc1nc2c(OC)ccc(C3COCCO3)c2s1
Yield: 62.1 %

Procedure:
To a stirred solution of 12.0 g (35.7 mmol) [7-(5,6-dihydro-[1,4]dioxin-2-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid ethyl ester in 600 ml dioxane and 12 ml acetic acid was added 12 g of 10% palladium on charcoal and the mixture was then stirred for 48 h at room temperature under a 10 bar atmosphere of hydrogen. The mixture was then filtered, washing with dioxane, and the filtrate concentrated in vacuo. Flash chromatography (1/1 acetone/dichloromethane) followed by trituration in ether and hexane afforded 7.50 g (62%) (±)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid ethyl ester as a white solid. ES-MS m/e (%): 339 (M+H+, 100).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[CH:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:25][CH:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([CH2:7][N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:5][CH:4]=2)=[CH:29][CH:28]=1)[CH3:24]
Reactant: CC(C)Oc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(OCc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Reaction time: 48 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 4-[4-(chloromethyl)benzyl]piperazine-1-carboxylate (4.00 g) in DMF (25 mL) were added 4-isopropoxyphenol (2.81 g) and K2CO3 (3.40 g) at room temperature, then the reaction mixture was stirred for 2 days. The reaction mixture was diluted with H2O, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/1 to 1/1) to afford tert-butyl 4-(4-{[4-(propan-2-yloxy)phenoxy]methyl}benzyl)piperazine-1-carboxylate as a colorless solid (5.42 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[N:10][CH:11]=1.[CH3:16][NH2:17]>CO>[CH3:16][NH:17][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([O:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: CC(C)Oc1cncc(OCCCCl)c1
Reactant: CN
Solvent: CO
Product: CNCCCOc1cncc(OC(C)C)c1
Temperature: 100 °C

Procedure:
Crude 5-(3-chloropropoxy)-3-isopropoxypyridine (0.92 g, 4.01 mmol) was dissolved in methanol (10 mL) and added to a 40 wt % aqueous solution of methylamine (10 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the solution was concentrated by rotary evaporation. Saturated NaCl solution (50 mL) was added, and the mixture was basified with 10% NaOH solution to pH 11. The mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered and concentrated by rotary evaporation to give 1.98 g of a brown oil. The product was purified by column chromatography on silica gel (60 g) eluting with hexane to remove impurities, followed by CHCl3—CH3OH-Et3N (50:50:2, v/v/v) to collect the product. Selected fractions containing the product were combined and concentrated by rotary evaporation. The resulting brown oil was dissolved in CHCl3 (25 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to give 0.64 g (71.6%) of a brown oil.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.[CH:18]1([NH:22][S:23](Cl)(=[O:25])=[O:24])[CH2:21][CH2:20][CH2:19]1>N1C=CC=CC=1>[CH:18]1([NH:22][S:23]([N:4]2[C:3]3([CH2:1][CH2:2]3)[CH2:8][N:7]([C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:6][CH2:5]2)(=[O:25])=[O:24])[CH2:21][CH2:20][CH2:19]1
Reactant: O=S(=O)(Cl)NC1CCC1
Reactant: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Solvent: c1ccncc1
Product: O=S(=O)(NC1CCC1)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-(4,7-diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (6.55 mmol) (intermediate 21) in dry pyridine (25 mL) was added N-cyclobutylsulfamoyl chloride (7.86 mmol) (Intermediate 29). The reaction mixture was stirred at rt for 16 h. After evaporation of the solvent in vacuo the crude mixture was purified by flash chromatography on silica using heptane→MeOH:EtOAc affording the title compound as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:31])[CH:21]=[CH:22][C:23]1[CH:28]=[C:27](Br)[CH:26]=[C:25](Br)[CH:24]=1.Cl>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:18][O:19][C:20](=[O:31])/[CH:21]=[CH:22]/[C:23]1[CH:28]=[C:27]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH:26]=[C:25]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH:24]=1
Reactant: COC(=O)C=Cc1cc(Br)cc(Br)c1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cc(-c2ccc(OCc3ccccc3)cc2)cc(-c2ccc(OCc3ccccc3)cc2)c1
Reaction time: 8 h

Procedure:
4.00 g (14.4 mmol) sodium metaborate-octahydrate and 250 mg (0.349 mmol) bis(triphenylphosphine)palladium(II)chloride are stirred for 15 min in 50 ml THF and 50 ml water, and 5.00 g (21.3 mmol) 4-benzyloxybenzene boronic acid, 3.00 g (9.37 mmol) 3,5-dibromo cinnamic acid methyl ester are added and the mixture is stirred overnight at reflux. The mixture is acidified with 2 M hydrochloric acid, the precipitated product is filtered off, suspended in hot ethanol, filtered off and used in the next step without further purification.
Reaction SMILES: C(=O)([O-])O.[K+].[I:6][C:7]1[CH:8]=[C:9]([C:14](=[NH:16])[NH2:15])[CH:10]=[CH:11][C:12]=1[CH3:13].Cl[CH2:18][C:19](=O)[CH3:20]>O1CCCC1.O>[I:6][C:7]1[CH:8]=[C:9]([C:14]2[NH:15][C:19]([CH3:20])=[CH:18][N:16]=2)[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: CC(=O)CCl
Reactant: Cc1ccc(C(=N)N)cc1I
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccc(C)c(I)c2)[nH]1
Yield: 80.8 %

Procedure:
Potassium hydrogen carbonate (0.204 g, 2.0 mmol) was added to a solution of 3-iodo-4-methylbenzenecarboximidamide (preparation 59a, 0.53 g, 0.54 mmol) in tetrahydrofuran (5 mL) and water (1 mL) and the mixture was heated to reflux. Then 1-chloropropan-2-one (0.16 mL, 2.1 mmol) in tetrahydrofuran (2.50 mL) was added dropwise over 20 min and the mixture was refluxed overnight. The mixture was evaporated and the residue purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (0.13 g, 22%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10][CH2:11][C:12](Cl)=[O:13].CCN(C(C)C)C(C)C>ClCCl>[Br:10][CH2:11][C:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:13]
Reactant: O=C(Cl)CBr
Reactant: Nc1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(F)cc1F
Reaction time: 4 h

Procedure:
5.16 g (40 mmol) of 2,4-difluoroaniline and 6.3 g (40 mmol) of bromoacetyl chloride are treated in 200 ml of dichloromethane with 5.17 g (40 mmol) of Hunig base. After 4 h, the mixture is washed twice with 1N hydrochloric acid and once with water, dried (MgSO4) and concentrated.
Reaction SMILES: [ClH:1].CC(C)([O:5][C:6](=[O:45])[CH2:7][NH:8][C@@H:9]([C:23]([N:25]1[CH2:44][CH2:43][CH2:42][C@H:26]1[C:27]([NH:29][CH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37]([NH2:41])=[N:36][CH:35]=[CH:34]2)=[O:28])=[O:24])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.FC(F)(F)C(O)=O>ClCCl>[ClH:1].[C:6]([CH2:7][NH:8][C@@H:9]([C:23]([N:25]1[CH2:44][CH2:43][CH2:42][C@H:26]1[C:27]([NH:29][CH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37]([NH2:41])=[N:36][CH:35]=[CH:34]2)=[O:28])=[O:24])[CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([OH:45])=[O:5]
Reactant: CC(C)(C)OC(=O)CN[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nccc2cc(CNC(=O)[C@@H]3CCCN3C(=O)[C@H](NCC(=O)O)C(c3ccccc3)c3ccccc3)ccc12

Procedure:
To a solution of N-[2-(1,1-dimethylethoxy)-2-oxoethyl]-β-phenyl-D-phenylalanyl-N-[(1-amino-6-isoquinolyl)methyl]-L-prolinamide hydrochloride c (4.6 g, 7.1 mmol) in dichloromethane (25 ml) was added trifluoroacetic acid (4.6 ml). After standing over-night the solution was evaporated to dryness, dissolved in dichloromethane and excess hydrochloric acid in diethyl ether added. The product was precipitated by addition of anhydrous diethyl ether then collected by filtration and dried under vacuum to give 2.8 g. A further 0.8 g was obtained by precipitation from the mother liquors.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][S:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.O>CC#N>[CH3:17][O:16][CH2:15][CH2:14][N:4]1[C:5](=[O:13])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([S:20][CH3:19])=[CH:22][CH:23]=2)[C:3]1=[O:18]
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Reactant: CSc1ccc(N)cc1
Solvent: CC#N
Solvent: O
Product: COCCN1C(=O)C(Nc2ccc(SC)cc2)=C(c2ccccc2)C1=O
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
3-Chloro-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione (0.26 mmol, 70 mg) and 4-(methylthio)aniline (0.53 mmol, 73 mg) was dissolved in dry CH3CN (2 mL) and the reaction mixture was sequentially subjected to microwave heating single node 140° C. for, 10 min, 140° C. for 10 min, and 140° C. for 20 min. 0.3 mL Water was added and the reaction mixture was purified using HPLC (57% 0.1M ammonium acetate buffer: 43% CH3CN→100% CH3CN, 20 mL/min) to give 49 mg (50%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.22 (bs, 1H), 7.19-7.10 (m, 3H), 7.06-7.00 (m, 2H), 6.95-6.90 (m, 2H), 6.58-6.53 (m, 2H), 3.82 (t, J=5.6 Hz, 2H), 3.63 (t, J=5.6 Hz, 2H), 3.38 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1([NH:15][C:16]2[C:17](=[O:33])[N:18]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:25](OC)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13]1.C([Mg]Cl)(C)C.Cl>C1COCC1.O>[CH:1]1([NH:4][C:25](=[O:26])[C:24]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:12]4([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[OH:5])[CH2:14][CH2:13]4)[C:17]3=[O:33])[CH:23]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To cyclopropylamine (0.60 mL, 8.46 mmol) and Methyl 3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 167c, 0.331 g) in THF (5 mL) at rt was added isopropylmagnesium chloride (0.85 mL of a 2M solution in THF) dropwise. The reaction was stirred for 1 h and then further isopropylmagnesium chloride (0.85 mL of 2M solution in THF) was added and the reaction stirred for 16 h. Water and 2M aqueous HCl were cautiously added and the aqueous layer extracted with dichloromethane (2×). The combined organics were dried (Na2SO4) and the solvent removed in vacuo to give the subtitle product as a yellow solid (0.342 g).
Reaction SMILES: [CH3:1][C:2]1[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[O:8][C:9]([CH3:12])=[N:10][N:11]=1)=[O:5].[C:25]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[CH3:25][N:6]([C:7]1[O:8][C:9]([CH3:12])=[N:10][N:11]=1)[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])[C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1nnc(NC(=O)c2ccc(C(F)(F)F)c(S(C)(=O)=O)c2C)o1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: Cc1nnc(N(C)C(=O)c2ccc(C(F)(F)F)c(S(C)(=O)=O)c2C)o1

Procedure:
180 mg (0.495 mmol) of 2-methyl-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide are dissolved in 6 ml of DMF (abs.), and 68 mg (0.495 mmol) of K2CO3 and 0.047 ml (0.495 mmol) of dimethyl sulfate are added. The reaction mixture is boiled under reflux for 15 hours. Then the mixture is filtered, and the filtrate is concentrated and purified by column chromatography (silica gel; heptane/ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].Cl>C(Cl)Cl>[CH3:36][S:37]([NH:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)N2CCN(CCOc3ccc(N)cc3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(OCCN2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Reaction time: 2 h
Yield: 47.7 %

Procedure:
To the above amine (1.50 g, 3.59 mmol) in CH2Cl2 (30 mL) at 0° C. under nitrogen was added pyridine (0.58 mL, 7.18 mmol) and methanesulfonyl chloride (0.42 mL, 5.38 mmol). After stirring for 2 hours, the mixture was partitioned between 10% aqueous NaHCO3 and 4:1 CH2Cl2 /isopropanol. The organic phase was dried and concentrated to afford a residue which was treated with ethanolic HCl to give 0.85 g (48%) of the title compound as a hydrochloride: mp: 170°-175° C.; 1H NMR (DMSO-d6): δ10.12 (s, 1H), 9.45 (s, 1H), 7.45 (d, J=8.56 Hz, 2H), 7.25 (d, J=8.59 Hz, 2H), 7.16 (d, J=8.96 Hz, 2H), 6.97 (d, J=8.97 Hz, 2H), 4.37 (m, 2H), 3.60-3.25 (m, 10H), 3.05 (s, 3H), 2.87 (s, 3H), IR (KBr): 3010, 2580, 2460, 1640, 1610 cm-1 ; MS (m/z) 497 (MH+, 10 %) 198 (35), 79 (100).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:16]([C:23]1[N:27]=[C:26]([NH2:28])[S:25][N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[N:27]=[C:26]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])[S:25][N:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1nc(Cc2ccccc2)ns1
Product: Cc1cn(-c2ccc(Nc3nc(Cc4ccccc4)ns3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 3-benzyl-[1,2,4]thiadiazol-5-ylamine. The title compound was obtained as a white solid (Yield=21%). MS ISP (m/e): 373.1 (100) [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1
Reactant: O=C1CCCCc2ccc([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)CCCC2

Procedure:
A solution of 3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-one (CAS #7507-93-9, 2 g, 9.75 mmol), palladium (413 mg, 10% on carbon, 0.4 mmol) in methanol (25 ml) under the hydrogen atmosphere (60 PSI) was stirred at room temperature for 16 hrs. The mixture was filtered through a layer of diatomaceous earth, washed with methanol and concentrated under reduced pressure to provide the title compound. 1H NMR (CDCl3) δ 1.77-1.84 (m, 4H), 2.67-2.73 (m, 2H), 2.82 (t, J=6.10 Hz, 2H), 6.75 (dd, J=8.14, 2.71 Hz, 1H), 6.99 (d, J=8.48 Hz, 1H), 7.05 (d, J=2.71 Hz, 1H). MS (M+H)+ m/z 175.