Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[CH:12]=[C:13]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=2)[CH:14]=[C:15]2[C:23]=1[NH:22][C:21]1[CH:20]=[C:19]([C:24]([N:26]3[CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[O:25])[CH:18]=[CH:17][C:16]2=1)(=[O:10])[NH2:9]>C(Cl)Cl>[N:26]1([C:24]([C:19]2[CH:20]=[C:21]3[C:16]([C:15]4[CH:14]=[C:13]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=5)[CH:12]=[C:11]([C:8]([NH2:9])=[O:10])[C:23]=4[NH:22]3)=[CH:17][CH:18]=2)=[O:25])[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCCN(C(=O)OC(C)(C)C)CC5)ccc4c3c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCCNCC5)ccc4c3c2)c1
Reaction time: 4 h
Yield: 95 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl 4-(8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazole-2-carbonyl)-1,4-diazepane-1-carboxylate (11 mg, 0.020 mmol) in DCM (5 mL). After 4 hr at RT, the solvents were removed and the residue was taken up in MeOH and applied onto a SCX cartridge. This was washed with MeOH and released 2 N NH3 in MeOH to leave 7-(1,4-diazepane-1-carbonyl)-3-(3-methoxyphenyl)-9H-carbazole-1-carboxamide (8.5 mg, 0.019 mmol, 92% yield) as a solid. MS (ESI) m/z 443.23 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.57 (1H, s), 8.28 (1H, d, J=8.24 Hz), 8.24 (1H, s), 7.71 (1H, s), 7.34-7.44 (3H, m), 7.29 (1H, d, J=7.93 Hz), 6.94 (1H, dt, J=7.55, 2.02 Hz), 3.92 (3H, s), 3.81-3.89 (2H, m), 3.55-3.65 (2H, m), 3.10-3.18 (1H, m), 2.94-3.04 (2H, m), 2.87-2.95 (1H, m), 1.96-2.08 (1H, m), 1.77-1.89(1H, m).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:15][C:10]1([CH3:16])[C:11](=[O:14])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)CNCCC1=O
Yield: 98.6 %

Procedure:
1-Benzyl-3,3-dimethyl-4-piperidone 275 g (1.26 mol), was dissolved in 1.0 L. methanol. The solution was transferred to a Parr reactor after adding 10% palladium on carbon (25 g). The reaction mixture was stirred under 300 psi hydrogen pressure at 60° C. until chromatography showed complete conversion. The reaction mixture was filtered and the residue washed with methanol (200 ml). The filtrate was concentrated to dryness to afford 3,3-dimethyl-4-piperidone (158 g) which was used as such for the preparation of either 4-benzyloxycarbonylamino-3,3-dimethylpiperidine or 4-t-butyloxycarbonylamino-3,3-dimethylpiperidine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH2:23][CH3:24])[CH:4]=1.[OH:25][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:23]([O:22][C:5]1[CH:4]=[C:3]([CH:21]=[CH:20][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[O:12][C:13]=1[CH3:14])[CH2:2][O:25][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1)[CH3:24]
Reactant: CCOc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a mixture of 4-(4-chloromethyl-2-ethoxyphenoxy)methyl-5-methyl-2-(2-furyl)-1,3-oxazole (0.56 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.25 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.06 g) at room temperature. After stirring the reaction mixture at room temperature for 30 min, the mixture was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.56 g, yield 86%) from a fraction eluted with tetrahydrofuran-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 149-150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[I:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([I:25])[CH:27]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1cccc(I)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc(I)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 92.9 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-iodophenol (58 mg, 0.26 mmol) to give the title compound (68 mg, 85%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:30](O)(=[O:33])[CH:31]=[CH2:32]>>[C:30]([O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:7])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)(=[O:33])[CH:31]=[CH2:32]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=CC(=O)Oc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
3,5-di tert.butyl-4-hydroxyphenyl acrylate was prepared by stirring a mixture of 22 grams of 2,6-di tert.butyl hydroquinone, 25.2 grams of trifluoroacetic acid anhydride, and 9.4 grams of acrylic acid for 4 hours at room temperature. The product was precipitated by adding 100 milliliters of water to the reaction mixture and was then filtered off and dried. After recrystallizing twice from hexane, there was obtained 13.3 grams of product of melting point 100° C. to 102° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:12]([N+:17]([O-:19])=[O:18])=[CH:13][N:14]=2)=[CH:8][CH:9]=1)[CH3:16]
Reactant: CCN(CC)c1ccc(-c2nccs2)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCN(CC)c1ccc(-c2ncc([N+](=O)[O-])s2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
To a mixture of N,N-diethyl-4-(thiazol-2-yl)aniline (1.39 g, 6.00 mmol) and concentrated sulfuric acid (10 mL) was added concentrated nitric acid (0.45 mL) at −10° C. The reaction mixture was stirred at 0° C. for 3 h, then poured into ice water and extracted with CH2Cl2 (30 mL×3). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=1:1) to give the title compound as a yellow solid (0.73 g, 44%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.C[CH2:39][N:40](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>CN1C(=O)CCC1>[O:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:8]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH:40][CH3:39])=[O:34])=[CH:30][CH:29]=4)=[CH:23][CH:24]=3)[N:10]=2)[CH2:18][CH2:17]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: CNC(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1
Yield: 76.6 %

Procedure:
To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with methylamine (594 μL, 2M solution. in THF) to give the product as a white solid (118 mg, 77% yield); MS (ESI) m/z=519.3.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29](O)=[O:30])=[CH:23]2>>[OH:12][CH:9]1[CH2:8][CH2:7][N:6]([C:4](=[O:5])[C@@H:3]([NH:2][C:29]([C:24]2[NH:25][C:26]3[C:22]([CH:23]=2)=[CH:21][C:20]([Cl:19])=[CH:28][CH:27]=3)=[O:30])[CH2:13][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH2:11][CH2:10]1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC(O)CC1
Agent: Cl
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-1-(4-hydroxy-piperidin-1-yl)-3-(1H-imidazol-4-yl)-propan-1-one hydrochloride (0.7 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.7 mmol) were coupled according to Procedure A (120 hour reaction time, acid wash omitted). The crude product was triturated twice with ether, with 1:1 ether-hexanes and the residue purified by chromatography on silica gel eluted with 5-20% ethanol in dichloromethane containing 0.5% ammonium hydroxide. Yield 232 mg, 81%; HPLC (40/60) 2.57 minutes (98%); PBMS 416/418 (MH+, 100%);
Reaction SMILES: [C:1]([C:3]1C=C(C=CC=1)N)#N.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[N:18]=2)[CH:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12]1=[O:38].CC1C=CC(S(O)(=O)=O)=CC=1>>[CH2:10]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[N:18]=2)[CH:13]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:12]1=[O:38])[CH:1]=[CH2:3]
Reactant: N#Cc1cccc(N)c1
Reactant: CN1CCN(c2ccnc(Nc3cccc(C#N)c3)n2)C(c2ccccc2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCN1CCN(c2ccnc(Nc3cccc(C#N)c3)n2)C(c2ccccc2)C1=O
Yield: 57 %

Procedure:
Intermediate 6, (0.10 g, 0.30 mmol) and 3-cyanoaniline (0.05 g, 0.45 mmol) were reacted together following the procedure detailed for the compound of Example 2, with the addition of an equivalent of tosic acid which eventually gave the title compound as a white solid (0.07 g, 57%).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH2:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[Cl-].[CH3:23][C:24]([NH:27][SiH:28]([CH3:30])[CH3:29])([CH3:26])[CH3:25]>>[CH:1]1([CH2:7][C:8]2[CH:16]([Si:28]([CH3:30])([CH3:29])[NH:27][C:24]([CH3:26])([CH3:25])[CH3:23])[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1=C(CC2CCCCC2)Cc2ccccc21
Reactant: C[SiH](C)NC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Product: CC(C)(C)N[Si](C)(C)C1C(CC2CCCCC2)=Cc2ccccc21
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a mixture of 2-(cyclohexylmethyl)indene (2.0 g, 9.4 mmol) in 40 mL of hexanes were added 6.0 mL of butyl lithium (1.6 M hexane; 9.6 mmol). The mixture was stirred overnight, the mother liquor decanted and the solid dissolved in THF. To this was added N-(1,1-dimethylethyl)dimethylsilanamine chloride (1.64 g, 9.9 mmol) and the solution stirred for 1 hour. The volatiles were removed in vacuo, the residue extracted with hexane, filtered and the volatiles removed in vacuo to give 2.85 g (90 percent) of a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][CH:28]([CH2:32][OH:33])[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34]>C(OCC)(=O)C>[ClH:34].[NH:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][CH:28]([CH2:32][OH:33])[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)NCC(CO)C(=O)O)C2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)C(CO)CNC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-2-hydroxymethyl-β-alanine (0.24 g) in ethyl acetate (2 ml) was added 4N HCl in ethyl acetate (1.3 ml) at 0° C., and the reaction mixture was stirred for 2 hours at room temperature. The precipitates were filtered and washed with diethyl ether to give N-[(R)-1-[3-(4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-2-hydroxymethyl-β-alanine hydrochloride (0.17 g, 82.0%).
Reaction SMILES: [Li+].[OH-].Br[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]=[C:17]([O:19][C@H:20]4[C@H:24]5[O:25][CH2:26][C@@H:27]([OH:28])[C@H:23]5[O:22][CH2:21]4)[NH:18][C:13]3=[CH:12][C:11]=2[Cl:29])=[CH:6][CH:5]=1.[C:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])[CH3:31]>O1CCOCC1.O>[OH:28][C@@H:27]1[CH2:26][O:25][C@@H:24]2[C@H:20]([O:19][C:17]3[NH:18][C:13]4[C:14]([N:16]=3)=[N:15][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:36]5[CH:37]=[CH:38][C:33]([C:30](=[O:32])[CH3:31])=[CH:34][CH:35]=5)=[CH:5][CH:6]=3)=[C:11]([Cl:29])[CH:12]=4)[CH2:21][O:22][C@H:23]12
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(Br)cc3)c(Cl)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)[nH]c4cc3Cl)cc2)cc1
Temperature: 80 °C

Procedure:
LiOH (0.41 ml, 1.230 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (41.8 mg, 0.051 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[[5-(4-bromophenyl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (225.2 mg, 0.497 mmol) and 4-acetylphenylboronic acid (100.3 mg, 0.612 mmol) in dioxane (4.0 ml) and water (0.59 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. for 18 h. The reaction mixture was then partitioned between EtOAc (50 ml) and water (50 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×50 ml), dried over Na2SO4, filtered, and evaporated under reduced pressure to give a yellow solid. The solid was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush. The desired fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a light yellow solid. LC-MS: calculated for C26H22ClN3O5 491.12 observed m/e: 492.10 (M+H)+ (Rt 1.14/2 min); 1H NMR δ (ppm) (CD3OD): 8.11 (d, J=8.5 Hz, 2H), 7.85 (d, J=8.5 Hz, 2H), 7.83 (s, 1H), 7.77-7.82 (m, 4H), 5.55 (qt, J=5 Hz, 1H), 4.97 (t, J=5.3 Hz, 1H), 4.47 (t, J=4.8, 1H), 4.27-4.30 (m, 1H), 4.17 (dd, J=5.8, J=10.3, 1H), 4.11 (dd, J=4.8 Hz, J=10.3, 1H), 3.90 (t, J=7.5 Hz, 1H), 3.60 (t, J=8.8 Hz, 1H) 2.65 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:31][NH2:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31]/[N:32]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NOCc1ccccc1
Product: C/C(=N\OCc1ccccc1)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 43 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and O-benzylhydroxylamine (intermediate H) in 43% yield using the same procedure as described in the synthesis of example 22 1H-NMR (400 MHz, CDCl3), δ ppm 9.43 (s, 1H), 8.93 (d, 1H), 8.13 (m, 2H), 7.91 (s, 1H), 7.83 (d, 1H), 7.42 (m, 6H), 6.10 (s, 2H), 5.36 (s, 2H), 2.40 (s, 3H). LCMS (method A): [MH]+=410, tR=5.94 min.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:15]C)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1.C1(=O)[O:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.O>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[O:15])[CH:9]=1
Reactant: COC(=O)c1cccnc1
Reactant: O=C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCCO)c1cccnc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A solution of potassium tert-butoxide (83.55 g) in tetrahydrofuran (500 ml) at 22° C. is treated, dropwise, with a solution of methyl nicotinate (68.5 g) and delta-valerolactone (75.0 g) in tetrahydrofuran (125 ml) during a period of 1 hour. The solution is then stirred at 23° C. for 2 hours. The reaction mixture is diluted with water and washed with toluene (125 ml). The organic phase is discarded and the aqueous phase is treated dropwise with concentrated hydrochloric acid (400 ml; 37% w/v). The solution is stirred for a further 2 hours. The solution is then washed with dichloromethane (250 ml). The organic phase is discarded and the aqueous phase is treated with aqueous sodium hydroxide solution to bring it to between pH8 and pH9. The aqueous phase is then washed with toluene (125 ml) and the organic phase is back washed with water (3×100 ml). The two aqueous phases are combined and extracted with dichloro- methane. The dichloromethane extract is dried over magnesium sulphate, and evaporated to dryness, to give 4-hydroxybutyl 3-pyridyl ketone (61.1 g) in the form of an oil which crystallises to form a pale brown solid, m.p. 36°-38° C. [NMR (CDCl3): 1.7(m,2H), 1.9(m,2H), 3.1(t,2H), 3.7(t,2H), 7.4(m,1H), 8.2(dt,1H), 8.8(m, 1H), 9.2(m, 1H)].
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[Br:12][CH2:13][CH:14](OC)OC.OS(O)(=O)=O>C1COCC1>[Br:1][C:2]1[C:3]([F:11])=[CH:4][C:5]2[CH2:9][O:10][CH:14]([CH2:13][Br:12])[O:8][C:6]=2[CH:7]=1
Reactant: OCc1cc(F)c(Br)cc1O
Reactant: COC(CBr)OC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: Fc1cc2c(cc1Br)OC(CBr)OC2
Yield: 45.7 %

Procedure:
Preparation according to Preparation 9. 5-bromo-4-fluoro-2-(hydroxymethyl)phenol (2.3 g, 10.4 mmol), 2-bromo-1,1-dimethoxyethane (9.9 ml, 83 mmol), dry THF (30 ml) and concentrated H2SO4 (4 ml) were heated at 55° C. for 2 h. Purification by flash column chromatography (isooctane/EtOAc 10:1) gave the title compound (1.55 g). MS m/z (rel. intensity, 70 eV) 328 (M+, 11), 326 (M+, 23), 324 (M+, 12) 204 (98), 202 (bp), 176 (41), 174 (43), 95 (59).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[N:9][N:10]=2)[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])=[N:9][N:10]=3)[N:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: N#Cc1cccc(-c2nnc3ccc(Cl)nn23)c1
Reactant: C1CCNCC1
Product: N#Cc1cccc(-c2nnc3ccc(N4CCCCC4)nn23)c1

Procedure:
A mixture of 3-(6-chloro-1,2,4-triazolo[4,3-b]pyridazin-3-yl)benzonitrile (450 mg) and piperidine (5 ml) was stirred with heating under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the resultant residue was extracted with chloroform. The extract was washed with saturated aqueous solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant crude crystals were recrystallized from ethanol to obtain 3-[6-(piperidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl)benzonitrile (435 mg) as slightly yellowish crystals.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:27]1([CH2:33][CH:34]([OH:36])[CH3:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:36][CH:34]([CH3:35])[CH2:33][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: CC(O)CN1CCCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(CN1CCCCC1)Oc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.54 g (7.00 mmol) iodobenzene and 2.75 g (10.5 mmol) triphenylphosphane are added successively to a solution of 1.00 g (6.98 mmol) 1-piperidin-1-yl-propan-2-ol in 20 mL DCM. 2.19 mL (10.5 mmol, 95%) diisopropyl azodicarboxylate is added dropwise at RT and the reaction is stirred for 2 h at RT. It is diluted with water, the organic phase is washed with water and dried over MgSO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, DCM/MeOH 9:1). The oily residue is triturated with diisopropylether, filtered off from the insoluble residue and the filtrate is evaporated to dryness i.vac.
Reaction SMILES: CN1CCOCC1.[CH3:8][O:9][C:10](=[O:54])[NH:11][C@@H:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]1[NH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[NH:41][C:42]([CH2:45][N:46]5[CH2:51][CH2:50][CH2:49][CH:48]([NH2:52])[C:47]5=[O:53])=[N:43][CH:44]=4)=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:26][N:27]=1)=[O:17])[CH:13]([CH3:15])[CH3:14].Cl[C:56]([O:58][CH3:59])=[O:57]>ClCCl>[CH3:59][O:58][C:56](=[O:57])[NH:52][C@@H:48]1[CH2:49][CH2:50][CH2:51][N:46]([CH2:45][C:42]2[NH:41][C:40]([C:37]3[CH:38]=[CH:39][C:34]([C:31]4[CH:30]=[CH:29][C:28]([C:25]5[NH:24][C:23]([CH:19]6[CH2:20][CH2:21][CH2:22][N:18]6[C:16](=[O:17])[CH:12]([NH:11][C:10]([O:9][CH3:8])=[O:54])[CH:13]([CH3:15])[CH3:14])=[N:27][CH:26]=5)=[CH:33][CH:32]=4)=[CH:35][CH:36]=3)=[CH:44][N:43]=2)[C:47]1=[O:53]
Reactant: COC(=O)N[C@@H](C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(N)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCC[C@@H](NC(=O)OC)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Yield: 319 %

Procedure:
4-Methylmorpholine (71 μL, 0.64 mmol) was added to a suspension of (R)-{1-[2-(5-{4′-[2-(3-amino-2-oxo-piperidin-1-yl methyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (137 mg, 0.21 mmol) in dichloromethane (5 mL). Methyl chloroformate (16.5 μL, 0.21 mmol) was added to the resulting solution. After 20 minutes the solvent was removed under reduced pressure. The residue was taken up in tetrahydrofuran (4 mL) and methanol (2 mL) and an aqueous solution of sodium hydroxide (2 N, 1 mL) was added. After 2 hours the organic solvents were removed under reduced pressure and the aqueous phase was decanted. The residue was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1% TFA in water and 0.1% TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide (R)-{1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid methyl ester (46.7 mg, 0.67 mmol, 32%). C37H44N8O6 calculated 696.3 observed [M+1]+ 697.4; rt=1.58 min. 1H (DMSO-d6,): δ=8.05 (s, 1H), 7.87 (m, 8H) 7.30 (m, 1H), 5.10 (t, J=7.2 Hz, 1H), 4.85 (d, J=15.6 Hz, 1H), 4.53 (d, J=16.0 Hz, 1H), 4.08 (m, 2H), 3.81 (m, 2H), 3.51 (s, 3H), 3.50 (s, 3H), 2.14 (m, 1H), 2.05-1.78 (series m, 8H), 0.78 (m, 6H).