Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([N:18]2[CH:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[C:19]2=[O:36])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.[I-].[Na+]>C(#N)C>[CH2:1]([C:8]1[CH:9]=[C:10]([N:18]2[CH:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[C:19]2=[O:36])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc(OCCBr)c(Cc2ccccc2)c1
Reactant: C1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc(OCCN2CCCC2)c(Cc2ccccc2)c1

Procedure:
A solution of 1-[3-benzyl-4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (60 mg) in acetonitrile (1 ml) was mixed with pyrrolidine (0.2 ml) and sodium iodide (5 mg) and boiled under reflux for 2 hours. The cooled solution was filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 531.66 (C34H33N3O3); MS (ESI): 532 ([M+H]+), was obtained as hydroformate in this way.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)CCl>C1COCC1.CN(C1C=CN=CC=1)C>[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:22])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cccc(C)c1O
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1cccc(C)c1OC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 1 °C
Reaction time: 17 h
Yield: 76.4 %

Procedure:
2,6-Dimethylphenol (0.257 g, 2.1 mmol) and 4-[(tert-butoxycarbonyl)amino]butanoic acid (0.427 g, 2.1 mmol) were dissolved in THF (10 ml, dry) and DMAP (0.005 g, 0.04 mmol) was added. After cooling down to 0-2° C., EDC (0.483 g, 2.52 mmol) was added portionwise under nitrogen atmosphere. The ice bath was removed and stirring was continued over night at rt. After 17 h, the mixture was diluted with DCM (50 ml) and extracted with water (20 ml), HCl (2N, 20 ml) and water (20 ml) again. The organic layer was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel, using DCM/MeOH (95:5) as eluent, to give the title compound (0.493 g, 76%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 1.45 (s 9H), 1.94-2.01 (m, 2H), 2.14 (s, 6H), 2.66 (t, 2H), 3.24-3.29 (m, 2H), 4.66 (bs, 1H), 7.05 (s, 3H); Mass Spectrum: M-tert-Bu+H+ 252.1
Reaction SMILES: ClC1C=C(C2C=C(C([N:22]3[CH2:27][CH2:26]N[C:24](=[O:28])[CH2:23]3)=O)OC=2C2C=CC(F)=CC=2)C=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42](O)=[O:43])=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36].N1CCOCC1>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42]([N:22]3[CH2:23][CH2:24][O:28][CH2:26][CH2:27]3)=[O:43])=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccc(F)cc3)o2)CCN1
Solvent: C1COCCN1
Product: O=C(c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1)N1CCOCC1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 6 starting with the compound from Example 21A. 1.5 equivalents of morpholine are used. 205 mg (59% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[N:11]3[CH:15]=[CH:16][N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O.C(N(CC)C1C=CC=CC=1)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([Cl:20])[N:11]3[CH:15]=[CH:16][N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cc2nccn12
Solvent: CC#N
Solvent: CCN(CC)c1ccccc1
Product: Clc1nc(-c2ccc(Br)cc2)cc2nccn12
Temperature: 50 °C
Yield: 39 %

Procedure:
To a flask charged with 7-(4-bromophenyl)imidazo[1,2-c]pyrimidin-5(6H)-one (25.00 g, 86.173 mmol), phosphoryl trichloride (31.554 mL, 344.69 mmol), and N,N-diethylaniline (27.420 mL, 172.35 mmol) was added acetonitrile (200 mL) and the mixture was heated to 50° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue diluted with water and DCM. The aqueous was neutralized with potassium carbonate and the bi-phasic mixture passed through a pad of celite to remove the insoluble material. The layers were separated and the aqueous extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude material was triturated with hexanes and the solids were collected by filtration to afford 7-(4-bromophenyl)-5-chloroimidazo[1,2-c]pyrimidine (10.369 g, 33.604 mmol, 38.997% yield). MS (apci) m/z=310.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[F:21])[CH:7]=1)[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:19]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=[CH:16][C:15]=2[F:21])=[O:22])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(-c3ccccc3)ccc2F)c1
Temperature: 80 °C

Procedure:
[3-(5-Bromo-2-fluoro-benzoylamino)-phenyl]-acetic acid ethyl ester (78) (209 mg, 0.55 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. The crude reside was purified by column chromatography using 20% EtOAc in heptane to give the title compound.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[C:4]([CH3:14])[N:3]=1.C1COCC1.[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:7][N:6]1[C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[C:4]([CH3:14])[N:3]=[C:2]1[C:27]#[C:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1noc(-c2c(C)nc(Br)n2C)n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1noc(-c2c(C)nc(C#Cc3ccccc3)n2C)n1
Reaction time: 16 h
Yield: 55.1 %

Procedure:
To a stirred solution of 5-(2-bromo-3,5-dimethyl-3H-imidazol-4-yl)-3-methyl-[1,2,4]oxadiazole (0.52 g, 2.02 mmol) in THF (10 mmol) was added at RT bis(triphenyl-phosphin)palladium(II)chloride (71 mg, 0.1 mmol), phenylacetylene (0.31 g, 3.03 mmol), triphenylphosphine (27 mg, 0.1 mmol) and triethylamine (0.61 g, 6.07 mmol). Through the reaction mixture was bubbled argon for 10 min and stirring was continued at 55° C. for 16 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (40 ml), dried (MgSO4) and evaporated to give the crude product as yellow oil (0.81 g). Purification by column chromatography on silica gel (ethyl acetate/toluene 5:1) gave the title compound (0.31 g, 55%) as a light yellow solid, m.p. 137° C. and MS: m/e=278.1 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C(O)C>[CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1cccc(N)c1OC
Solvent: CCO
Product: CCOC(=O)C(=CNc1cccc(OC)c1OC)C(=O)OCC
Temperature: 80 °C
Yield: 90.1 %

Procedure:
To a mixture of 2,3-dimethoxyaniline (20 g, 131 mmol) in Ethanol (50 mL) was added diethyl 2-(ethoxymethylene)malonate (26.2 mL, 131 mmol). The mixture was heated at 80° C. for 1 h. LCMS indicated completion of the reaction. The mixture was concentrated in vacuo to remove ethanol, and washed with hexane to afford diethyl 2-(((2,3-dimethoxyphenyl)amino)methylene)malonate (38 g, 118 mmol, 90% yield) as a white solid. This crude mixture was directly used in next step. LCMS: (M+H)+: 324.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH:9]=O.[OH-].[K+].O.Cl.[CH2:15]1C[O:18][CH2:17][CH2:16]1>>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:9]=[C:17]([OH:18])[C:16]([CH3:15])=[N:1]2)=[CH:4][N:5]=1
Reactant: C1CCOC1
Reactant: Nc1cc(Cl)ncc1C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cc(Cl)ncc2cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Treat a mixture of 4-amino-6-chloro-pyridine-3-carbaldehyde (39 g, 0.25 mol) and 2-hydroxy acetone (28 g, 0.375 mol) in THF (400 mL) with KOH (52.5 g, 0.75 mol), stir at RT for 1 h, add water and acidify with 1N HCl. Collect the resulting solids by filtration, wash with water (3×), then EtOAc (2×) and dry to afford the title compound (45 g, 93%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 2.54 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30](C)(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:34]>O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([NH2:34])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(-c2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)ccc1F
Reactant: N
Solvent: O
Product: Cc1cc(-c2c(-c3ccc(S(N)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)ccc1F

Procedure:
The title compound was prepared according to the method of procedure Example 384, substituting 2-(3,4-difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 105 mg, 27%). mp 243-245° C. 1H NMR (300 MHz, DMSO-d6) δ 2.2 (s, 3H), 7.01 (m, 2H), 7.25 (m, 1H), 7.45 (s, 1H), 7.47 (bs, 2H), 7.6 (m, 2H), 7.77 (d, J=9 Hz, 2H), 7.85 (m, 1H), 8.26 (s, 2H). MS (DCI/NH3) m/z 472 (M+H)+, 489 (M+NH4)+. Anal. calc. for C24H17F3N2O3S.0.5 H2O: C, 58.59; H, 3.42; N, 8.91. Found: C, 57; H, 4.23; N, 8.89.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[C:8](Cl)(=[O:10])[CH3:9].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[CH3:7][C:6]1[CH:5]=[C:4]([C:8]([CH3:9])=[O:10])[S:3][C:2]=1[CH3:1]
Reactant: Cc1ccsc1C
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)c1cc(C)c(C)s1
Temperature: -5 °C
Yield: 99.9 %

Procedure:
A solution of 5 (15.16 g, 135 mmole) and acetyl chloride (9.6 mL, 135 mmole) in 60 mL benzene dried over Na was cooled to −5° C. and vigorously stirred during the addition of a solution of tin (IV) chloride in 50 mL benzene over a period of 1 hour. The reaction mixture was removed from the cold bath and stirred for an additional hour at room temperature. The slow addition of 4 mL concentrated HCl in 28 mL water quenched the reaction. The organic layer was separated, washed with 2×10 mL water, dried over Na2SO4 and evaporated to give 20.8 g of crude product. Chromatography on a column of silica eluted with pet. ethenethyl acetate (10:1) and evaporation of relevant fractions gave a viscous yellow oil, 16.42 g, 79%. 1H NMR (CDCl3) δ: 2.08, s, 3H, COCH3; 2.31, s, 3H, CH3; 2.41, s, 3H, CH3; 7.33, s, 1H, H-3. 13C NMR (CDCl3) δ: 13.3, 13.7, 26.1, 134.7 135.3, 139.1, 143.4, 190.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10]1([C:20](O)=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:9]=[C:20]([C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=1)[NH:8]2
Reactant: Nc1ncnc(Cl)c1N
Reactant: O=C(O)c1cccc2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2[nH]c(-c3cccc4ccccc34)nc12
Temperature: 110 °C
Yield: 80.4 %

Procedure:
A mixture of 6-chloro-4,5-diaminopyrimidine (519 mg, 0.00359 mol) and 1-naphthalenecarboxylic acid (618 mg, 0.00359 mol) in phosphoryl chloride (2.0 mL, 0.021 mol) was heated at 110° C. under an atmosphere of nitrogen for 5.5 hours. The reaction was cooled and the residue was washed several times with ether. The residue was dissolved in CH2Cl2 and aqueous NaHCO3. The layers were separated and the aqueous was extracted with EtOAc (1×) and CH2Cl2 (1×). The combined organics were washed with saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered, and collected in vacuo to obtain 810 mg (80%) of an orange solid. LC/MS: Rt=1.68 min, ES+ 261 (FA standard).
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=O)[NH:15][C:12]2=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([NH:36][NH2:37])([NH2:35])=[NH:34].[ClH:38].Cl>C(O)C>[ClH:38].[ClH:38].[CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18](=[N:37][NH:36][C:33]([NH2:35])=[NH:34])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:15][C:12]2=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: N=C(N)NN=C(c1ccccc1)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Yield: 69.3 %

Procedure:
A mixture of [5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl](phenyl)methanone (Example 55) (129 mg, 0.31 mmol), aminoguanidine hydrochloride (36 mg, 0.32 mmol) and 6 N HCl (0.26 mL) in ethanol (10 mL) was heated to reflux under a nitrogen atmosphere for 2.5 h. TLC analysis showed the remaining ketone, therefore additional aminoguanidine hydrochloride (10 mg, 0.09 mmol) was added. The reaction mixture was refluxed until TLC analysis showed the reaction was completed (2 h). After concentration to dryness, the crude material was triturated with EtOAc. The solid was collected by filtration and dried to provide [[[5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl](phenyl)methylene]amino]guanidine dihydrochloride (60.6 mg, 36%) as a yellow solid: ESI MS m/z 474 [C29H27N7+H]+; HPLC (Method A) 89.3% (AUC), tR=17.5 min.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=5)=[CH:23][CH:22]=4)[C:13](=[O:20])[N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7][N:6]1[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])=[O:4].Cl.[CH3:44][O:45][C:46](=[O:64])[CH:47]([NH2:63])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[CH:40]([O:39][C:37]([N:6]1[CH:5]([C:3](=[O:4])[NH:63][C@H:47]([C:46]([O:45][CH3:44])=[O:64])[CH2:48][C:49]2[CH:50]=[CH:51][C:52]([C:55]3[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][CH:56]=3)=[CH:53][CH:54]=2)[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=5)=[CH:25][CH:26]=4)[C:13](=[O:20])[N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7]1)=[O:38])([CH3:41])[CH3:42]
Reactant: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C
Reactant: COC(=O)C(N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-isopropyl ester 7-methyl ester (204 mg) was hydrolyzed and coupled to 2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester-hydrochloride according to general procedures A and B to provide (S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid isopropyl ester (161 mg, LC/MS: m/z 862).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[CH:12]4[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1.Cl[CH2:20][CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:24].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[CH:12]4[CH2:18][CH2:17][N:16]([CH2:20][CH2:21][CH2:22][C:23]([C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)=[O:24])[CH2:15][CH2:14][CH:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CN1CCN2c3c(cccc31)C1CCNCCC12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN2c3c(cccc31)C1CCN(CCCC(=O)c3ccc(F)cc3)CCC12
Temperature: 96 °C
Reaction time: 18 h
Yield: 30.7 %

Procedure:
3-Methyl-2,3,7,8,9,10,11,11a-octahydro-1H,6bH-azepino[4′,5′:4,5]pyrrolo[1,2,3-de]quinoxaline (72 mg, 0.3 mmol), 4-chloro-4′-flourobutyrophenone (119 mg, 0.6 mmol), KI (49 mg, 0.3 mmol), and DIEA (383 mg, 3 mmol) were added to dioxane (2.5 mL). The suspension was stirred at 96° C. for 18 hrs. The reaction was cooled to rt and then concentrated. The residue was purified by column chromatography (5-10 % MeOH/CH2Cl2), to afford the title compound (37.5 mg, 31%) as an oil. The enantiomers of the title compound were separated on a Chiracel OD column using 8% EtOH-Hexane as the eluent. 1H NMR (CDCl3, 300 MHz) δ 7.9-8.1 (2H, m), 7.1-7.2 (2H, m), 6.6-6.7 (1H, m), 6.3-6.5 (2H, m), 2.7-3.8 (19 H, m), 1.9-2.3 (4H, m) ppm. MS (ESI): 408.3 (base, M+H)
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([CH2:22][N:23]3[C:27]4=[N:28][CH:29]=[C:30]([F:32])[CH:31]=[C:26]4[N:25]=[CH:24]3)[CH:19]=[CH:18][C:16]=2[N:17]=1)(=O)=O.[CH3:33][S-:34].[Na+]>CN(C=O)C>[F:32][C:30]1[CH:31]=[C:26]2[N:25]=[CH:24][N:23]([CH2:22][C:20]3[CH:19]=[CH:18][C:16]4[N:17]=[C:13]([NH:12][C@@H:7]5[CH2:8][CH2:9][CH2:10][CH2:11][C@H:6]5[S:34][CH3:33])[S:14][C:15]=4[CH:21]=3)[C:27]2=[N:28][CH:29]=1
Reactant: C[S-]
Reactant: CS(=O)(=O)O[C@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.8 %

Procedure:
A mixture of (1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl methanesulfonate (100 mg, 0.2 mmol) and sodium thiomethoxide (74 mg, 1.0 mmol) in DMF (1.0 mL) was stirred at rt for 2 h. The mixture was purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-((1R,2R)-2-(methylthio)cyclohexyl)benzo[d]thiazol-2-amine (5 mg, 4%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.41 (t, J=1.8 Hz, 1H), 8.04-8.11 (m, 2H), 7.67 (s, 1H), 7.30 (m, 1H), 7.23 (m, 1H), 5.48 (s, 2H), 3.72 (m, 1H), 2.56 (m, 1H), 1.99-2.08 (m, 5H), 1.63-1.71 (m, 2H), 1.41-1.51 (m, 1H), 1.21-1.36 (m, 3H); LCMS (ESI) m/z 428 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:23]1CCOCC1.C(OC(Cl)=O)C(C)C.N>C1COCC1>[C:18]([O:17][C:15](=[O:16])[NH:14][C@H:10]([C:11](=[O:12])[NH2:23])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(N)=O
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
To a solution of (S)-3-benzyloxy-2-(tert butoxycarbonylamino)propionic acid (0.98 g, 3.3 mmol) in anhydrous THF (13 mL) at −15° C. was added N-methylmorpholine (0.4 mL, 3.3 mmol) and isobutylchloroformate (0.4 mL, 3.3 mmol) under a nitrogen atmosphere. After 2 minutes, 33% aqueous ammonia (0.3 mL, 5 mmol) was added and the resulting mixture stirred at −15° C. for 2 h. The reaction mixture was allowed to warm to RT and was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The combined organic fractions were washed with aqueous 5% NaHCO3, water, dried (MgSO4) and concentrated in vacuo. The resulting white solid was used without further purification (quant. yield). 1H NMR (CDCl3, 300 MHz): δ 7.41-7.25 (5H, m), 6.42 (1H, br s), 5.48 (2H, br s), 4.55 (2H, dd, J=22., 12 Hz), 4.30 (1H, br s), 3.95-3.85 (1H, dd, J=9.5, 3.9 Hz), 3.55 (1H, dd, J=9.5, 6.7 Hz), 1.42 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:22]=3[F:29])=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[NH4+].[Cl-].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[NH:40][N:39]=[N:38][N:28]=4)=[CH:23][C:22]=3[F:29])=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2nnn[nH]2)cc1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Temperature: 120 °C
Yield: 34 %

Procedure:
To a stirred solution of [rac]-2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-N-(4-cyano-2-fluoro-phenyl)-2-cyclohexyl-acetamide (110 mg, 0.22 mmol) in dry DMF (3 ml) was added NH4Cl (48.39 mg, 0.88 mmol) and NaN3 (57.2 mg, 0.88 mmol) at room temperature. The reaction mixture was then heated at 120° C. for 12 h. After cooling, TLC shows formation of new spot, filtered the solid material by sintered funnel and washed the solid residue by EtOAc (3×5 ml). Combined organic layers were reduced under pressure at 50° C. and diluted the residue with EtOAc (15 mL). Organic layer was washed with H2O (10 ml), brine (10 ml) and dried over Na2SO4; which was then concentrated under reduced pressure to give crude material (90 mg). Crude product was then purified by column chromatography [SiO2 (230-400 mesh), MeOH:DCM 0:95/5:95] to give the title compound (40 mg, 33.3%) as brown solid. MS: m/e=534.0 [M+H+].
Reaction SMILES: [NH2:1][CH:2]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4][CH2:3]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[C:21]1([NH:27][C:28]([NH:1][CH:2]2[CH2:20][C:6]3[C:7]4[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=4[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=3[CH2:4][CH2:3]2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1

Procedure:
The product of Example 15 (0.15 g, 0.5 mmol), phenylisocyanate (0.1 g, 1 mmol) and triethylamine (0.1 g) in 5 mL dimethylformamide were stirred at room temperature for 18 h. The solvent was removed by rotoevaporation and the residue suspended in methanol/dimethylformamide. After heating, the solid was collected by filtration and dried in vacuo. CHN calc'd for C19H17N5O5.0.5H2O.HCON(Me)2 : C, 55.34; H, 5.27: N, 17.60 found-C, 55.38: H, 4.95; N, 17.04. H-NMR (400 MHz, dmso) 1H, s, 12.1; 1H, s, 11.45; 1H, s, 8.4; 1H, s, 7.95; 1H, s, 7.7; 2H, d, 7.4; 2H, t, 7.23; 1H, t, 6.9 1H, d, 6.35; 1H, t, 4.1; +ring protons.