Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:11]3[S:16][C:15]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]4)=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH3:35]>>[CH3:27][S:24]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:15]2[S:16][C:11]3[C:10]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:9][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH2:35])[CH:7]=4)=[N:13][C:12]=3[CH:14]=2)[CH2:19][CH2:20]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccnc(F)c4)nc(N4CCOCC4)c3s2)CC1
Reactant: N
Agent: [OH-]
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccnc(N)c4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-(2-Fluoro-pyridin-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (107 mg) was heated in ammonia hydroxide (90 ml) in a sealed stainless steel pressurized vessel at 150° C. for 5 days. Extraction into chloroform and purification on silica afforded 418 (57 mg). NMR (CDCl3): 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 4.55 (2H, br s), 7.36 (1H, s), 7.54 (1H, s), 7.65 (1H, d, J=5.3), 8.21 (1H, d, J=5.3) MS (ESI+): MH+ 490.16 (74%)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1.[H][H]>[Ni].C(O)C>[CH3:1][NH:2][CH:3]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4]1
Reactant: [H][H]
Reactant: CNC1=CC(=O)c2ccccc2OC1
Agent: [Ni]
Solvent: CCO
Product: CNC1COc2ccccc2C(O)C1

Procedure:
18.8 g (0.1 mole) 3-methylamino-1-benzoxepin-5(2H)-one is stirred with 40 g Raney Nickel in 400 ml ethanol for five hours at an hydrogen pressure of 55 bar. Subsequently, the catalyst is filtered out, the solvent is distilled off and one obtains 7.7 g (40% of the theoretical yield) racemic-2,3,4,5-tetrahydro-3-methylamino-1-benzoxepin-5-ol as an oil. The compound can be further separated as described earlier and further identified.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([OH:13])=O)[CH:8]=2)[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:26]1([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl.CN(C)C=O>[CH:26]1([CH2:31][NH:32][C:11](=[O:13])[CH2:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)Cc1ccc2cc[nH]c2c1
Reactant: NCC1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2cc[nH]c2c1)NCC1CCCC1
Yield: 81 %

Procedure:
A solution of indole-6-acetic acid (0.70 g) and 1,1'-carbonyldiimidazole (0.83 g) in methylene chloride (20 ml) and N,N-dimethylformamide (5 ml) was heated at reflux for 20 min, treated with cyclopentylmethylamine (0.59 g), and heated at reflux for an additional 3 hr. The solution was diluted with methylene chloride; washed successively with 10% v/v hydrochloric acid, water and brine; dried (MgSO4); and evaporated. The residue was purified by flash chromatography, eluting with 1:19 ethyl acetate: hexane, to give N-cyclopentylmethylindole-6-acetamide (0.83, 81%) as a white powder; partial NMR (80 MHz, CDCl3): 3.13(t, 2H, NHCH2), 3.69(s, 2H, ArCH2), 6.55(m, 1H, H3 -indole), 6.98(dd, 1H, H5 -indole), 7.62(d, 1H, H4 -indole).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.[CH3:24][C:25]([CH3:27])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[ClH:1].[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][CH:25]([CH3:27])[CH3:24])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 150 mg (0.40 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride and 48 μl (0.65 mmol) of acetone in 1.5 ml of 1,2-dichloroethane is adjusted to pH 4 using acetic acid. 254.8 mg (1.20 mmol) of sodium triacetoxyborohydride are added, and the mixture is stirred at RT for 6 h. The contents of the flask are concentrated under reduced pressure and purified by preparative HPLC. The product fractions are concentrated and the residue is dissolved in a 5:1 mixture of acetonitrile and 1N hydrochloric acid, then again concentrated and dried under high vacuum. 49 mg (29.4% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>>[F:17][C:16]1([F:18])[CH2:15][O:14][C:13]([NH2:19])=[N:12][C@@:11]21[C:4]1[C:5](=[CH:6][CH:7]=[C:2]([C:30]3[CH:31]=[N:26][CH:27]=[N:28][CH:29]=3)[CH:3]=1)[O:8][CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10]2
Reactant: OB(O)c1cncnc1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(-c4cncnc4)cc32)C(F)(F)CO1
Yield: 22 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (2RS,4R)-6-bromo-5′,5′-difluoro-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.3) with pyrimidin-5-ylboronic acid yielded the title compound (22% yield) as a white solid. MS (ISP): m/z=409.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.C[O:17][B:18](OC)[O:19]C.Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([B:18]([OH:19])[OH:17])[CH:3]=1
Reactant: COB(OC)OC
Reactant: CCc1ccc(Br)cc1I
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCc1ccc(Br)cc1B(O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
To a solution of 4-bromo-1-ethyl-2-iodobenzene (10.00 g, 32.20 mmol) in anhydrous tetrahydrofuran (60 ml) at −78° C. is added a solution of isopropylmagnesium chloride (16.90 ml, 33.80 mmol, 2M solution in tetrahydrofuran) dropwise, maintaining a temperature below −60° C. After stirring for 20 minutes the reaction mixture is allowed to slowly warm to room temperature followed by an additional hour of stirring. The solution is re-cooled to −78° C. and trimethylborate (7.18 ml, 64.32 mmol) is added dropwise, after which the mixture is again allowed to warm to room temperature with further stirring for 2 hours. Dilute aqueous hydrochloric acid (30 ml) is added, and the crude product is extracted into ethyl acetate (100 ml). The aqueous phase is washed with ethyl acetate (2×100 ml), and all organics are combined, dried over anhydrous magnesium sulfate then concentrated in vacuo to give a light brown solid which is triturated with hexanes to afford 5-bromo-2-ethylphenylboronic acid (6.46 g) as a cream powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([C:11]3[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[C:6]([O:8][CH3:9])=[O:7])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: COC(=O)c1cc(OC)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cc(OC)cc(-c2ccc3[nH]ccc3c2)c1
Temperature: 85 °C
Reaction time: 13 h

Procedure:
A mixture of methyl 3-methoxy-5-trifluoromethanesulfonyloxybenzoate (314 mg, 1.00 mmol), 5-indoleboronic acid (193 mg, 1.20 mmol), tetrakis(triphenylphosphine)palladium(0) (57.8 mg, 0.050 mmol), potassium phosphate (318 mg, 1.50 mmol) and 1,2-dimethoxyethane (5.0 ml) was stirred in a nitrogen atmosphere at 85° C. for 13 hours. After left cooled, the reaction mixture was diluted with ethyl acetate, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain the title compound as a colorless oil.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[C:7]([O:12][CH2:13][CH2:14][OH:15])(=[O:11])[C:8]([CH3:10])=[CH2:9].C(N(CC)CC)C.COC1C=CC(O)=CC=1>C(OCC)(=O)C>[C:7]([O:12][CH2:13][CH2:14][O:15][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)OCCO
Reactant: CC(Br)C(=O)Br
Agent: COc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCOC(=O)C(C)Br
Reaction time: 8 h
Yield: 63.9 %

Procedure:
2-Bromopropionyl bromide (18 g, 0.083 mol, 1 m.e) in ethyl acetate (30 mL) was added dropwise to a mixture of 2-hydroxyethyl methacrylate (HEMA) (16.26 g, 0.125 mol, 1.5 m.e) and triethylamine (9.26 g, 0.091 mol, 1.1 m.e) in ethyl acetate (80 mL) at 0° C. under a N2 environment. Hydroquinone monomethyl ether (MEHQ) was added as an inhibitor at this stage (−15 mg, 1.2×10−4 mol). The reaction mixture was stirred overnight, then filtered, further treated with more MEHQ (˜15 mg) and then evaporated to dryness to give a clear colourless oil (14 g, 0.053 mol, 63% yield). 1H NMR (200 MHz, CDCl3) δ 1.82 (d, J=8 Hz, 3H, CH3CH—), 1.95 (s, 3H, (CH3CCO—), 4.36-4.46 (m, 5H, 2× —CH2O— and —CHBr), 5.60 (br. s, 1H, vinyl), 6.13 (s, 1H, vinyl) ppm.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([C@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.C(O)(=O)C>[Zn].C1C=CC=CC=1>[CH3:1][C@H:2]1[C@@:19]2([CH3:20])[C:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])=[CH:5][C:4](=[O:22])[CH2:3]1
Reactant: C[C@@]12C(=CC(=O)[C@H]3C[C@H]31)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Zn]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C

Procedure:
1β,2β-Methylene-4-androstene-3,17-dione, zinc powder, and acetic acid are refluxed together for a period of 1 hour. On cooling benzene is added, the suspension filtered and the filtrate taken to dryness under vacuum. The residue is chromatographed on silica gel and eluted with methylenechloride. Recrystallization from acetone-hexane yields 1β-methyl-4-androstene-3,17-dione.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:24]([O:32][C@H:33]1[C@@H:37]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:36](OC(=O)C)[O:35][C@@H:34]1[C:51]([NH:53][CH2:54][CH3:55])=[O:52])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[C@H]1[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C)O[C@@H]1C(NCC)=O)(=O)C1C=CC=CC=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClC(Cl)(Cl)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:39]([O:38][C@@H:37]1[C@H:33]([O:32][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:34]([C:51]([NH:53][CH2:54][CH3:55])=[O:52])[O:35][C@H:36]1[N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[Cl:11])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCNC(=O)[C@H]1O[C@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCNC(=O)[C@H]1O[C@@H](OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A suspension of 2-amino-6-chloropurine (4.60 g, 27.13 mmol) in 1,1,1-trichloroethane (230 ml) was treated with N,O-bis(trimethylsilyl)acetamide (20 ml, 81.4 mmol). The mixture was heated under reflux for 6 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was treated with a solution of (2S,3S,4R,5R)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate and (2S,3S,4R,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (Preparation 18) (14.39 g, 32.6 mmol) in anhydrous toluene (230 ml) and trimethylsilyl trifluoromethanesulfonate (20 ml, 108.5 mmol). The resulting solution was then heated at 90° C. under a nitrogen atmosphere for 90 minutes. The mixture was cooled to room temperature, diluted with ethyl acetate (250 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate (350 ml) and then brine (350 ml). The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2 by volume) to afford the title compound as a foam (8.1 g).
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[C:9]([CH2:10]O)=[CH:8][CH:7]=[CH:6][N:5]=1.S(Cl)([Cl:14])=O>>[Cl:1][CH2:3][C:4]1[C:9]([CH2:10][Cl:14])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: OCc1cccnc1CO
Reactant: O=S(Cl)Cl
Reactant: Cl
Product: ClCc1cccnc1CCl
Temperature: 25 °C

Procedure:
2,3-bis(hydroxymethyl)pyridine hydrochloride (JP 49 020181) (2.7 g, 15.4 mmol) was added portionwise to stirred thionyl chloride (20 mL) at 0° C. under nitrogen. The cooling bath was removed, and the reaction allowed to come to room temperature, then heated at reflux for one hour. The dark mixture was allowed to cool to room temperature, then the thionyl chloride was removed in vacuo. The residue was azeotroped with toluene (x2), the brown solid residue treated with ice, basified with Na2CO3 (sat), then extracted with diethyl ether (x3). The combined extracts were dried (Na2SO4), filtered and evaporated to give 2,3-bis(chloromethyl)pyridine (2.6 g) as a red/brown liquid. This material was used immediately in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:16]Br.C(OCC)(=O)C>ClCCl.CCCCCC>[Br:16][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH2:9]
Reactant: BrBr
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25 %

Procedure:
To a solution of p-anisidine (10 g, 0.08 mol) and sodium carbonate (17.2 g, 0.16 mol) in dichloromethane (400 ml) was added a solution of bromine (3.8 ml), 0.072 mol) in dichloromethane (200 ml) dropwise. The reaction was stirred at ambient temperature for 45 minutes, diluted with dichloromethane (200 ml) and washed with water (2×200 ml). The organic layer was dried over magnesium sulphate, and the solvent was removed in vacuo to yield a dark brown oil. Chromatography on silica eluting with a gradient of ethyl acetate in hexane (10%, 15% and 20%) afforded the title compound as a dark red oil (4 g, 25%), m/z (ES+) 202 (M30 +H, 100%). 1H NMR (250 MHz, CDCl3) δ 3.73 (3H, s), 3.78 (2H, broad s), 6.72 (2H, t, J 1.2 Hz), 7.00 (1H, q, J 1.26 Hz).
Reaction SMILES: [OH-:1].[Na+].O.S([O-])([O-])(=O)=O.O[NH3+:10].O[NH3+].[CH3:13][O:14]/[N:15]=[C:16](/[C:20]1([CH3:25])[O:24][CH2:23][CH2:22][O:21]1)\[C:17](=O)[CH3:18]>C(OC)(C)(C)C>[CH3:13][O:14][N:15]=[C:16]([C:20]1([CH3:25])[O:24][CH2:23][CH2:22][O:21]1)[C:17](=[N:10][OH:1])[CH3:18]
Reactant: CO/N=C(\C(C)=O)C1(C)OCCO1
Reactant: [NH3+]O
Reactant: [OH-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: CON=C(C(C)=NO)C1(C)OCCO1
Temperature: 50 °C
Reaction time: 9 h

Procedure:
24 g (0.03 mol) of 50% strength aqueous sodium hydroxide solution and 200 ml of water were initially charged at 25° C. and admixed a little at a time with a total of 25 g (0.0152 mol) of hydroxylammonium sulfate. 50 g (0.0267 mol) of the ketal (Example 2) were then added dropwise, and the reaction mixture was stirred at 50° C. (pH=7-8) for 9 hours. A pH of 5-6 was then set using aqueous sodium hydroxide solution, and the mixture was stirred at 50° C. for 48 hours. Another 25 g of hydroxylammonium sulfate and 24 g of 50% strength aqueous sodium hydroxide solution were then metered in, and the mixture was stirred at 50° C. for another 20 hours. 300 ml of methyl tert-butyl ether were then added. The solid which is insoluble in the two-phase mixture was filtered off, washed with a little hexane and dried. This gave 9 g of the title compound (phys. data of the E,E-isomers see Tab. 2). The organic phase of the two-phase mixture obtained as mother liquor was dried over sodium sulfate and subsequently concentrated on a rotary evaporator. This gave another 17.5 g of the title compound.
Reaction SMILES: ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=O)[CH:25]=2)[CH:20]=[CH:19]1.[NH:30]1[CH2:34][CH2:33][C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31]1>CN(C=O)C.O>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([N:30]3[CH2:34][CH2:33][C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:31]3)=[O:29])[CH:25]=2)[CH:20]=[CH:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)c2ccc3cc[nH]c3c2)C1
Reaction time: 16 h

Procedure:
EDCxHCl (17.7 g, 93.00 mmol, 1.5 eq), 1-hydroxy-7-azabenzotriazole (4.2 g, 31.01 mmol, 0.5 eq) followed by triethylamine (28.7 mL, 204 mmol, 3.3 eq) were added at room temperature to a stirred solution of 1H-indole-6-carboxylic acid (10 g, 62.03 mmol, 1.0 eq) in dry DMF (50 mL). (R)-tert-butyl pyrrolidin-3-ylcarbamate (13.86 g, 74.44 mmol, 1.2 eq) was added after 10 min and stirring was continued for 16 h at room temperature. The reaction mixture was diluted with icy water (100 mL), and the precipitating solid was filtered off, washed with water (50 mL) and pet ether (50 mL), and dried under vacuum. White solid. Yield: 11.0 g (55% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Cl)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.BrC1C2N(C(C(NC3C=CN=CC=3F)=O)=CN=2)N=C(Cl)C=1.[CH3:43][O:44][C:45]1[CH:58]=[CH:57][C:48]([CH2:49][NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[CH:47][CH:46]=1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:50]([CH2:49][C:48]2[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:58][CH:57]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Cl)cc(Cl)nn12
Reactant: COc1ccc(CNc2ccccn2)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccccn2)c2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.5 %

Procedure:
To a suspension containing a mixture of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 5A (1.2 g, 3.68 mmol) was added N-(4-methoxybenzyl)pyridin-2-amine (1.183 g, 5.52 mmol) in THF (36.8 mL) at 0° C. This mixture was charged with a 1M solution of potassium tert-butoxide (7.36 mL, 7.36 mmol), slowly via syringe. The dark suspension was stirred for 20 min at room temperature. Volatiles were removed in vacuo and the resulting residue was triturated with MeOH and cooled to 0° C. Filtration, with cold MeOH washes afforded a tan solid which was dissolved in THF and azeotroped with PhMe to remove residual MeOH, then dried in vacuo overnight, which afforded 6-chloro-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (1.31 g, 68.5% yield) as a tan solid. LC/MS, m/z 504.0 (M+1). HPLC Rt=4.265 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.02 (1H, d, J=2.27 Hz), 8.62 (1H, d, J=2.27 Hz), 8.35-8.48 (4H, m), 8.23 (1H, s), 7.67-7.83 (1H, m), 7.32 (2H, dd, J=8.56, 2.27 Hz), 7.24 (1H, dd, J=7.05, 5.29 Hz), 7.00 (1H, s), 6.79-6.89 (2H, m), 5.60 (2H, s), 3.62-3.72 (3H, s).
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][C:24]=2[CH:34]=1.[CH:35]1(O)[CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:3]([O:5][CH:35]4[CH2:38][CH2:37][CH2:36]4)=[O:4])[CH2:32][CH2:33]3)=[N:25][C:24]=2[CH:34]=1
Reactant: OC1CCC1
Reactant: Fc1cc(-n2cnnn2)ccc1-c1ccc2oc(C3CCNCC3)nc2c1
Reactant: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(OC1CCC1)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4F)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
Tert-butyl 4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate (300 mg, 0.65 mmol) dissolved in DCM (15 ml) and added Trifluoroacetic acid (1.5 ml). This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain 5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (300 mg). 5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF (2.6 ml) and added N,N-Carbonyl diimidazole (101 mg, 0.63 mmol) and stirred at rt for 1 h. To this mixture added cyclobutanol (0.05 ml, 0.63 mmol) and TEA (0.13 ml, 0.94 mmol) and stirred at 60° C. for overnight. Work up (EtOAc/H2O) and purification of the crude by combiflash with gradient mixture of ethyl acetate and petether (1:1) as eluent afforded the titled compound (25 mg) as an off-white solid. M.P.: 165-169° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.04 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m, 4H), 7.55-7.50 (m, 1H), 4.96 (septet, J 7.8, 1H), 4.20 (d, J 12.4, 2H), 3.22-3.13 (m, 1H), 3.06 (t, J 9.8, 2H), 2.40-2.30 (m, 2H), 2.24-2.15 (m, 2H), 2.15-2.02 (m, 2H), 2.00-1.90 (m, 2H), 1.78 (q, J 10, 2H).