Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]([F:34])([F:33])[C:14]1[C:22]2[N:21]=[C:20]([S:23][CH2:24][C:25]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][N:26]=3)[NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[F:34][C:13]([F:33])([F:12])[C:14]1[C:22]2[N:21]=[C:20]([S:23]([CH2:24][C:25]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][N:26]=3)=[O:6])[NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccnc(CSc2nc3c(C(F)(F)F)cccc3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3c(C(F)(F)F)cccc3[nH]2)c1
Reaction time: 1 h

Procedure:
2.3 g of commercially available 85% strength m-chloroperoxybenzoic acid, dissolved in 30 ml of methylene chloride, are added dropwise to a solution, cooled to -30° C., of 3.0 g (0.0088 mole) of 4-trifluoromethyl-2-[(4-methoxy-2-pyridylmethyl)thio]-(1H)-benzimidazole in 50 ml of methylene chloride over the course of 45 minutes. The resulting mixture is then stirred for a further 60 minutes, and the temperature is subsequently allowed to rise to 0° C. After the mixture is washed with saturated aqueous sodium carbonate solution (30 ml), it is dried over sodium sulfate, and the solvent is stripped off in vacuo. The solid residue which remains is recrystallized successively from isopropanol and acetonitrile. Yield: 1.6 g of title compound, m.p. 150° to 151° C.
Reaction SMILES: CO[C:3](=[O:11])[CH:4]([N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH3:5].O.[NH2:13][NH2:14]>C(O)CCC>[N:6]1([CH:4]([CH3:5])[C:3]([NH:13][NH2:14])=[O:11])[CH:10]=[N:9][CH:8]=[N:7]1
Reactant: COC(=O)C(C)n1cncn1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: CC(C(=O)NN)n1cncn1
Yield: 91 %

Procedure:
As described for example 112a, (rac.)-2-[1,2,4]triazol-1-yl-propionic acid methyl ester in butanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 16 h. The mixture was concentrated and triturated with toluene to afford the title compound as a white solid (yield: 91%). MS: m/e=155.0 [M]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[CH:28]([N:31]1[CH2:36][CH2:35][N:34]([C:37](=[O:43])[CH2:38][CH2:39][CH2:40][C:41]#[CH:42])[CH2:33][CH2:32]1)([CH3:30])[CH3:29]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH:28]([N:31]1[CH2:32][CH2:33][N:34]([C:37](=[O:43])[CH2:38][CH2:39][CH2:40][C:41]#[C:42][C:2]2[CH:3]=[CH:4][N:5]3[C:10]=2[C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])[CH3:19])=[N:6]3)[CH2:35][CH2:36]1)([CH3:30])[CH3:29]
Reactant: C#CCCCC(=O)N1CCN(C(C)C)CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC(C)N1CCN(C(=O)CCCC#Cc2ccn3nc([C@H](C)NC(=O)OC(C)(C)C)n(-c4ccccc4)c(=O)c23)CC1
Temperature: 60 °C
Yield: 72.9 %

Procedure:
A mixture of (S)-tert-butyl (1-(5-bromo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (140 mg, 0.32 mmol), 1-(4-isopropylpiperazin-1-yl)hex-5-yn-1-one (88 mg, 0.36 mmol), bis(triphenylphosphine)palladium(II) chloride (23 mg, 0.03 mmol) and copper iodide (6 mg, 0.03 mmol) in diethylamine (6 ml) was heated at 60° C. for 3 days. The solvent was removed and the crude purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give 134 mg (72% yield) of the title compound. Purity 100%.
Reaction SMILES: CN(C)/[CH:3]=[C:4]1/[C:5](=O)[CH:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:8][CH2:9]/1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH:40][C:41]([NH2:43])=[NH:42])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1>>[CH:10]1([CH:6]2[C:5]3[N:43]=[C:41]([NH:40][C:30]4[CH:31]=[CH:32][C:33]([N:34]5[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]5)=[C:28]([O:27][CH3:26])[CH:29]=4)[N:42]=[CH:3][C:4]=3[CH2:9][CH2:8][CH2:7]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)/C=C1\CCCC(C2CCCCC2)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(C2CCCCC2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 3-[1-dimethylamino-meth-(E)-ylidene]-bicyclohexyl-2-one (84 mg, 0.36 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (111 mg, 0.30 mmol) using in analogous manner the procedure described in example 45b). Obtained as yellow crystals (61 mg, 49%). MS ISP (m/e): 418.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.57 (s, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 7.39 (d, 1H), 7.21 (d, 1H), 7.03 (s, 1H), 3.82 (s, 3H), 2.51-2.65 (m, 2H), 2.14 (s, 3H), 1.72-1.94 (m, 3H), 1.52-1.70 (m, 5H), 1.02-1.35 (m, 7H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8](OC)=[O:9].[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17].O1CCOCC1>O>[CH3:23][C:22]1[C:13]2[NH:12][C:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[C:8](=[O:9])[C:14]=2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1
Reactant: COC(=O)C1CCCCC1=O
Reactant: COC(=O)c1ccc(C)c(N)c1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(C)c2[nH]c3c(c(=O)c12)CCCC3
Temperature: 130 °C
Yield: 31.7 %

Procedure:
A mixture of methyl 2-oxocyclohexanecarboxylate (1.0 g, 6.4 mmol), methyl 3-amino-4-methylbenzoate (1.06 g, 6.4 mmol), polyphosphoric acid (4 mL) and dioxane (6 mL) was heated at 130° C. for 2 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and the resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (100 mL) and SOCl2 (10 mL) was added. The mixture was stirred at reflux for 5 hours, concentrated and treated with water (80 mL), extracted with ethyl acetate (3×80 mL). The organic layer was separated, concentrated to give the crude product. Then the mixture was purified by chromatography column on silica gel (eluted with CH2Cl2/MeOH) to afford crude product, and the final product (0.55 g) was obtained from recrystallization using MeOH as solvent. 1H NMR (DMSO-d6) δ 10.3 (s, 1H), 7.41 (d, 1H, J=7.8 Hz), 6.99 (d, 1H, J=7.8 Hz), 3.73 (s, 3H), 2.78-2.81 (m, 2H), 2.50 (s, 3H), 2.35-2.37 (m, 2H), and 1.64-1.73 (m, 4H). MS (ESI) m/e [M+1]+272.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([N:17]([CH2:19][CH2:20][O:21][CH3:22])[CH3:18])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]2[OH:32])=[O:15])=[CH:6][CH:7]=1
Reactant: COCCN(C)c1ncc(C(=O)O)cc1-c1ccc(Cl)cc1
Reactant: NC[C@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COCCN(C)c1ncc(C(=O)NCC2CCCCC2O)cc1-c1ccc(Cl)cc1

Procedure:
In analogy to example 1f, 5-(4-chloro-phenyl)-6-[(2-methoxy-ethyl)-methyl-amino]-nicotinic acid was coupled with cis-2-aminomethyl-1-cyclohexanol hydrochloride using TBTU and N,N-diisopropyl ethyl amine in N,N-dimethylacetamide to give racemic 5-(4-chloro-phenyl)-N-((1RS,2RS)-2-hydroxy-cyclohexylmethyl)-6-[(2-methoxy-ethyl)-methyl-amino]-nicotinamide as an off-white solid. MS (ISP) 432.4 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH2:19])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>>[CH:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: O=C(O)c1cccnc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1)c1cccnc1
Yield: 43.1 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 8b) (100 mg, 0.36 mmol) and nicotinic acid (40.6 mg, 0.33 mmol) as starting materials. The title compound (54 mg, 39.9%) was isolated as off white solid; MS (ESI): 380 [M+H]+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([C:13]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]([CH3:31])[CH3:30])[N:23]=4)=[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][N:15]4[N:14]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:38]>>[Cl:38][C:20]1[N:15]2[N:14]=[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:12]=3)[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]([CH3:31])[CH3:30])[N:23]=3)=[C:16]2[CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)Nc1nccc(-c2c(-c3ccnc(NC4CCCC4)c3)nn3ccccc23)n1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Li]CCCC
Product: CC(C)Nc1nccc(-c2c(-c3ccnc(NC4CCCC4)c3)nn3c(Cl)cccc23)n1

Procedure:
In a similar manner as described in Example 17 from N-cyclopentyl-N-(4-{3-[2-(isopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}-2-pyridinyl)amine (155 mg, 0.375 mmol), n-butyllithium (700 μL 1.6 M in hexanes, 1.12 mmol), and carbon tetrachloride (145 μL, 1.50 mmol) was formed 4-{7-chloro-2-[2-(cyclopentylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-N-isopropyl-2-pyrimidinamine. Flash chromatography (1:1 hexanes:ethyl acetate to 1:2 hexanes:ethyl acetate) provided sample (65 mg, 39%). Rf 0.20 (1:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.40 (d, 1H), 8.14–8.11 (m, 2H), 7.27 (m, 1H), 7.07 (d, 1H), 6.82 (d, 1H), 6.66 (s, 1H), 6.46 (d, 1H), 5.11 (d, 1H), 4.79 (d, 1H), 4.21 (m, 1H), 3.98 (m, 1H), 1.98 (m, 2H), 1.74–1.44 (m, 6H), 1.30 (d, 6H); MS m/z 448 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([CH2:23][CH3:24])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH2:21][CH3:22])[CH:14]=2)=[N:10][CH:11]=1)=[O:4].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:23]([C@H:2]1[NH:1][C:26](=[O:28])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH2:21][CH3:22])[CH:14]=3)=[N:10][CH:11]=2)[C:3]1=[O:4])[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOc1cc(Oc2ncc(NC(=O)[C@H](N)CC)cn2)ccc1C
Solvent: ClCCl
Product: CCOc1cc(Oc2ncc(N3C(=O)N[C@H](CC)C3=O)cn2)ccc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 132 %

Procedure:
To a solution of ((2R)-2-amino-N-(2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)butanamide (Intermediate 94, 62 mg) in dry dichloromethane (4 mL), TEA (158 μl, 1.13 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (25.2 mg, 0.085 mmol) in dry dichloromethane (2 mL) was then added dropwise and the reaction mixture was stirred at 0° C. for 20 minutes. The reaction mixture was evaporated under vacuum. The residue obtained was purified by silica gel chromatography chromatography (Companion system, 12 g silica cartridge) with Cyclohexane/EtOAc as eluents from 100/0 to 50/50 in 20 minutes and then 50/50 during 15 minutes to afford the title compound as a white solid (40 mg).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)=[O:22])=[CH:16][CH:15]=1)#[CH:13].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:13]#[C:12][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=4)=[O:22])=[CH:18][CH:19]=3)=[N:7][N:6]2[CH:8]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: C#Cc1ccc(NC(=O)Nc2cccc(C)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)Nc2ccc(C#Cc3ccc4nc(N)cn4n3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a nitrogen bubbled solution of 6-iodo-imidazo[1,2-b]pyridazin-2-ylamine (260 mg, 1 mmol, 1 eq) and 1-(4-ethynylphenyl)-3-(3-methylphenyl)urea (375 mg, 1.5 eq) in DMF (5 mL) was added triethylamine (0.56 mL, 4 eq), bis(triphenylphosphine)palladium(II) dichloride (70.2 mg, 0.1 eq), and copper(I) iodide (38.1 mg, 0.2 eq). The reaction mixture was stirred at room temperature for 10 minutes and then partitioned between saturated aq NaHCO3 and i-PrOH—CHCl3 (1:4). The aqueous layer was extracted once more with i-PrOH—CHCl3 (1:4). The two organic layers were combined, washed with brine, and dried with anhydrous Na2SO4. The upper clear liquid was decanted, concentrated with silica gel, and the solid mixture was chromatographed (eluted from DCM to MeOH-DCM 1:15). The product fractions were collected and concentrated. The solid residue was triturated with EtOAc-Hex (1:1) and gave 1-{4-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)ethynyl]phenyl}-3-(3-methylphenyl)urea as a brown solid upon filtration in amount of 133 mg.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH:18]O>C(O)(=O)C>[NH2:1][C:2]1[S:6][C:5]([S:7]([C:8]([CH3:11])([CH3:9])[CH3:10])=[O:18])=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OO
Reactant: CC(C)(C)Sc1nc(-c2ccccc2)c(N)s1
Solvent: CC(=O)O
Product: CC(C)(C)S(=O)c1nc(-c2ccccc2)c(N)s1

Procedure:
To 5-amino-2-(tert-butylsulfanyl)-4-phenylthiazole (102 mg, 385 μmol) in acetic acid (5.0 ml) was added aqueous hydrogen peroxide (218 μl, 30% wt, 1.9 mmol) dropwise at ambient temperature. After 5 hr the mixture was partitioned between dichloromethane (50 ml) and water (50 ml). The aqueous phase was separated and extracted with dichloromethane (20 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to yield essentially pure 5-amino-2-(tert-butylsulfinyl)-4-phenylthiazole (110 mg, quant.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:8][C:7](=[O:9])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(Cl)c(Cl)c1

Procedure:
A suspension of 300 g of 3,4-dichlorocinnamic acid (J. Org. Chem., 26:2991 (1961)) and 25 ml of concentrated sulfuric acid in 1.7 liters of methanol is heated to reflux for 24 hours. The solution is concentrated, cooled, and filtered to give as a white solid, 3,4-dichlorocinnamic acid methyl ester, mp 114°-15° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:7](=[O:20])[CH:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[NH:9][C:10](=O)[C:4]=2[CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:43])=O>C1(C)C=CC=CC=1>[Cl:43][C:10]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:31]=[CH:30][C:5]=2[N:6]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:7](=[O:20])[CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)NC(=O)c3cc(Cl)ccc32)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Temperature: 90 °C
Yield: 100.4 %

Procedure:
7-Chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (0.65 g, 1.43 mmol) was suspended in anhydrous toluene (10 mL) under a nitrogen atmosphere. N,N-Dimethylaniline (0.36 mL, 2.9 mmol) was added followed by phosphorus oxychloride (0.20 mL, 2.1 mmol) and the mixture was heated at 90° C. for 4 hours. After cooling to ambient temperature, the mixture was diluted with 40 mL of ethyl acetate:hexanes (1:2), washed with ice water (10 mL), ice cold 1 M hydrogen chloride (2×10 mL), and brine, then dried with sodium sulfate, decanted and concentrated in vacuo. The residue was redissolved in a small amount of ethyl acetate, then poured onto a silica plug. The product was eluted with 100 mL of ethyl acetate:hexanes (1:2) to yield (E)-5,7-dichloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (680 mg, 100%) which was used without further purification.
Reaction SMILES: [OH-].[Na+].C([O:6][C@H:7]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([CH:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:24]2)=[O:22])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)C>CO.C1COCC1>[OH:6][CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C@H:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:24]2)=[O:22])=[CH:18][CH:19]=1
Reactant: CC(=O)O[C@@H](c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(C(O)c2ccccc2)cc1)[C@@H]1CC(c2cccnc2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
) NaOH 1N (1 ml) was added dropwise to a stirred solution of (S)-[4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]phenyl]phenylmethyl acetate (0.001 mol) in methanol (20 ml) and THF (20 ml) and the reaction mixture was stirred for one hour at RT. The solvent was evaporated under reduced pressure. The white solid residue was taken up into methanol. The precipitate was filtered off, washed with methanol and diethyl ether, then dried, yielding 0.2 g (92%) of (S)-4,5-dihydro-N-[4-(hydroxyphenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide (compound 57).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][C@H:14]2[CH3:27])=[O:12])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CN1CCOCC1.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>ClCCl>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:3]([O:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][C@H:14]2[CH3:27])=[O:12])=[N:4][CH:5]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ncc(Cl)cc1N
Reactant: O=C1CCC(=O)O1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ncc(Cl)cc1NC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.2 %

Procedure:
To a solution of 2-(3-amino-5-chloro-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.10 g, 0.26 mmol) in dichloromethane (3 mL) was added N-methylmorpholine (0.028 mL, 0.26 mmol) and succinic anhydride (0.026 g, 0.26 mmol). The reaction was stirred at ambient temperature for 3 days. The reaction was diluted with dichlormethane and washed with 1N hydrochloric acid solution. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.040 g, LRMS: 493.2).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][C:10]2[NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:24].C(=O)(O)[O-].[Na+].C(O)C>C(Cl)(Cl)Cl>[C:1]1([CH2:7][CH2:8][S:9]([C:10]2[NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=2)=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(CCSc2nc3cnccc3[nH]2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=S(CCc1ccccc1)c1nc2cnccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[(2-Phenylethyl)thio]-1H-imidazo[4,5-c]pyridine (2.4 g, 0.0094 mol) was dissolved in 120 mL of chloroform with heating. The reaction solution was cooled in an ice bath to 0°-5° C. m-Chloroperoxybenzoic acid (1.91 g, 0.0094 mol) was added portionwise. The reaction mixture was then stirred at room temperature for 1 hour. 10% aqueous sodium bicarbonate was added and the organic layer was separated and dried over magnesium sulfate. After filtering, the filtrate was evaporated to half the volume in a rotary evaporator. Ether was added to the cloudy point and the reaction mixture was cooled in ice. The crystals that had formed amounted to 0.63 g. An analytical sample, m.p. 171°-174° C., was obtained by recrystallization from ethanol.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH3:15][O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([CH:22]3[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][O:16][CH3:15])[CH2:24][CH2:23]3)=[CH:33][CH:32]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1(N)CCCCC1
Reactant: COCCN1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCN1CCC(c2ccc(C(=O)NC3(C(=O)NCC#N)CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (107 mmol), 4-[1-(2-methoxy-ethyl)-piperidin-4-yl]-benzoic acid hydrochloride (107 mmol), HOBT (107 mmol), WSCD (107 mmol) and triethylamine (107 mmol) are dissolved in DMF (250 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH (with 2N NH3)=9:1 as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether/ethyl acetate and the solid filtered of and dried (vacuum). A pale powder with mp. 160-162° C., Rf=0.42 (CH2Cl2/MeOH (with 3N NH3)=9:1) is obtained.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:31]
Reactant: c1ccc(Nc2ccc3ccccc3n2)nc1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=S([O-])([O-])=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc2ccccc2n1
Reaction time: 0.17 h
Yield: 55 %

Procedure:
NaH (35 mg, 0.91 mmol) was added to II (344 mg, 0.91 mmol) in DMF (5 mL) at rt. After 10 min, KI (227 mg, 1.37 mmol) and ethyl 7-bromoheptanoate (0.267 mL, 1.37 mmol) were added. The reaction mixture was stirred at 90° C. for 19 h after which 0.1 M Na2S2O3 (50 mL) and EtOAc (50 mL) were added; the phases were then separated and the aqueous phase extracted with EtOAc (2×25 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with hexane/EtOAc (90:10 to 85:15), to furnish III as a colourless oil (189 mg, 55%).