Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.[H-].[Na+].[O:11]=[C:12]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]1[CH2:18][CH2:19]OS(C)(=O)=O>CN(C=O)C.CN(C)C1C=CN=CC=1>[Br:8][C:5]1[N:4]=[CH:3][C:2]([O:1][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[CH2:15][CH2:16][C:12]2=[O:11])=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)OCCN1C(=O)CCC1=O
Reactant: Oc1ccc(Br)nc1
Agent: CN(C)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1CCOc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
10 g (58 mmol) of 3-hydroxy-6-bromopyridine were dissolved in 40 ml of DMF and treated with 2.76 g (69 mmol) of sodium hydride (60% suspension in mineral oil). After stirring at room temperature for 1 h, 20 mg of 4-dimethylaminopyridine were added and the mixture was treated with 16.53 g (74.8 mmol) of methanesulfonic acid 2-(2,5-dioxopyrrolidin-1-yl)ethyl ester and heated to 100° C. for 3 h. Subsequently, the solvent was evaporated and the residue was taken up in water and extracted 4 times with ethyl acetate. The combined organic phases were dried and evaporated to dryness. The remaining material was purified by chromatography (silica gel, dichloromethane/methanol 98:2) followed by preparative HPLC (RP18, acetonitrile/water containing 0.1% TFA) to yield 10.8 g of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]2[C:16]([O:17]CC3C=CC=CC=3)=[CH:15][CH:14]=[C:13]([CH3:25])[C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[CH2:1]([C:8]1[NH:9][C:10]2[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([CH3:25])[C:11]=2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1ccc(OCc2ccccc2)c2[nH]c(Cc3ccccc3)nc12
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(O)c2[nH]c(Cc3ccccc3)nc12
Yield: 85 %

Procedure:
A solution of 2-benzyl-4-benzyloxy-7-methylbenzimidazole (3.0 g) in ethanol (400 ml) and 10% palladium-carbon (1.5 g) was hydrogenated at room temperature and pressure until uptake of hydrogen ceased. The mixture was filtered (celite), and the filtrate was evaporated to dryness in vacuo and recrystallized from ethanol-ether to afford the title compound (1.85 g), m.p. 204°-205° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]2([OH:26])[CH2:25][CH2:24][C:16]3([O:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][O:17]3)[CH2:15][CH2:14]2)[CH3:9])=[CH:4][CH:3]=1.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][C:13]3([CH2:14][CH2:15][C:16]4([O:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][O:21]4)[CH2:24][CH2:25]3)[O:26][C:28]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][C:13]3([CH2:14][CH2:15][C:16](=[O:21])[CH2:24][CH2:25]3)[O:26][C:28]2=[O:30])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(Br)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccc(Br)cc1)N1CCC2(CCC(=O)CC2)OC1=O
Product: C[C@@H](c1ccc(Br)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Yield: 36 %

Procedure:
The title compound is prepared from 9-{2-[(S)-1-(4-bromo-phenyl)-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; besides the title compound 3-[(S)-1-(4-bromo-phenyl)-ethyl]-1-oxa-3-aza-spiro[5.5]undecane-2,9-dione (36% of theory) is obtained. Yield: 40% of theory; Mass spectrum (ESI+): m/z=452/454 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][OH:10])[N:6]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1>[F:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][O:10][C:37](=[O:38])[NH:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:6]=1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
A solution of 2-fluoro-4-(3-hydroxypropyl)-1-triphenylmethylimidazole in pyridine was treated with phenylisocyanate at ambient temperature. Work up as for the starting materials of Example 9 gave 2-fluoro-4-(3-phenylcarbamoyloxypropyl)-1-triphenylmethylimidazole, having the following n.m.r. spectrum in d6DMSO: 1.87 (m, 2H); 2.48 (t, 2H); 4.08 (t, 2H); 6.31 (s, 1H); 7.0-7.5 (m, 20H); 9.34 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH2:34]([S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH3:36]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([S:37]([CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])[CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NC1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCC[C@@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine, 5c, (0.40 g, 1.15 mmol) in 10:1 mixture of CH2Cl2/DMF (8 mL) was added iPr2NEt (0.60 mL, 3.46 mmol) followed by 1-propanesulfonyl chloride (0.13 mL, 1.15 mmol). The reaction mixture was stirred at room temperature for 5 hours. The resulting residue was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 316.
Reaction SMILES: [C:1]1(C(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]O.[C:12]1([CH:18]([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)(C1C=CC=CC=1)[OH:23]>CC(C)=O>[C:1]1([OH:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:19]
Reactant: CC(C)(O)c1ccccc1
Reactant: CC(C)c1ccccc1
Agent: [O-]O
Solvent: CC(C)=O
Product: C=C(C)c1ccccc1
Product: Oc1ccccc1

Procedure:
A process of decomposing a cumene oxidation product mixture containing cumene hydroperoxide (CHP) and dimethylphenylcarbinol (DMPC) to produce phenol, acetone and alpha-methyl styrene (AMS) with reduced by-product formation which comprises the steps:
Reaction SMILES: CO[C:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]=1.[Cl-:11].[NH4+:12]>CO>[ClH:11].[CH3:9][C:8]1([CH3:10])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[NH:12]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COC1=NCCCC1(C)C
Solvent: CO
Product: CC1(C)CCCNC1=N
Product: Cl

Procedure:
The product of EXAMPLE 160 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[C:44]([C:50]#[N:51])=[CH:45][CH:46]=[C:47]([CH3:49])[CH:48]=4)=[CH:39][CH:38]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[C:47]([CH3:49])[CH:46]=[CH:45][C:44]=4[C:50]4[NH:3][C:4](=[O:7])[O:5][N:51]=4)=[CH:39][CH:38]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4cc(C)ccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4cc(C)ccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
A mixture of hydroxylammonium chloride (2.2 g), sodium hydrogencarbonate (3.3 g) and dimethyl sulfoxide (40 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-5-methylbiphenyl-2-carbonitrile (2.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (20 mL). N,N′-Carbonyldiimidazole (1 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (1.1 g, 45%).
Reaction SMILES: B(F)(F)F.CCOCC.[OH:10][C:11]1[C:20]([CH3:21])=[C:19]2[C:14]([CH:15]=[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17](=[O:22])[O:18]2)=[CH:13][C:12]=1[O:34][CH:35]([CH3:37])[CH3:36].ClC(Cl)(Cl)C(=N)O[C@H:42]1[C@@H:47]2[O:48][C:49](=[O:51])[O:50][C@@H:46]2[C@@H:45]([O:52][CH3:53])[C:44]([CH3:55])([CH3:54])[O:43]1.C(N(CC)CC)C>C(Cl)Cl>[CH:35]([O:34][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([CH3:21])[C:11]=1[O:10][C@H:42]1[C@@H:47]3[O:48][C:49](=[O:51])[O:50][C@@H:46]3[C@@H:45]([O:52][CH3:53])[C:44]([CH3:55])([CH3:54])[O:43]1)[O:18][C:17](=[O:22])[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:15]2)([CH3:37])[CH3:36]
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Reactant: Cc1c(O)c(OC(C)C)cc2cc(NC(=O)OCc3ccccc3)c(=O)oc12
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](Oc2c(OC(C)C)cc3cc(NC(=O)OCc4ccccc4)c(=O)oc3c2C)OC1(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
Boron trifluoride etherate (1.30 μL, 0.010 mmol) was added to 23c (13.0 mg, 0.034 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (83.0 mg, 0.23 mmol) in anhydrous CH2Cl2 (1.30 mL). After stirring at room temperature for 1.5 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to give 25c as a colorless foam (19.0 mg, 95%): 1H NMR (CDCl3, 500 MHz) 8.17 (s, 1H), 7.51 (s, 1H), 7.35 (s, 1H), 7.34-7.33 (m, 4H), 6.74 (s, 1H), 5.54 (dd, J=9.2, 1.2 Hz, 1H), 5.16 (s, 2H), 4.87-4.84 (m, 1H), 4.73 (dd, J=7.9, 1.9 Hz, 1H), 4.51 (quintet, J=6.0 Hz, 1H), 3.52 (s, 3H), 3.28 (d, J=4.8 Hz, 1H), 2.33 (s, 3H), 1.80-1.77 (m, 6H), 1.30 (s, 3H), 1.27 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 161.6, 158.6, 153.2 153.1, 147.1, 146.8, 142.5, 135.5, 128.7, 128.6, 128.3, 123.3, 121.4, 121.1, 116.2, 108.6, 99.4, 83.1, 79.9, 76.1, 74.7, 72.2, 68.0, 60.5, 27.1, 25.6, 21.9, 21.6, 21.0, 10.1; IR (film) νmax 2955, 2922, 2853, 2359, 2339, 1819, 1711, 1520, 1464, 1375, 1171, 1111, 1034, 962, 822, 766 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C30H33NO11, 584.2132; found, 584.2111.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CN(C)C1C=CN=CC=1.ClCCl>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][O:1][C:17](=[O:19])[CH3:18]
Reactant: O=C(CO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-hydroxyaceto-phenone (10 g, 73.4 mmol), pyridine (17.4 g, 220.2 mmol), dichloromethane (734 mL), 3 crystals of 4-dimethylaminopyridine is cooled to −78° C. To this solution is added acetic anhydride (13.9 mL, 146.9 mmol) then warmed to room temperature and stirred for 18 h. The mixture is washed with water (200 mL) and brine (200 mL) then dried over sodium sulfate. The mixture is filtered and concentrated in vacuo to yield the title compound, 13 g (99%), as a colorless liquid.
Reaction SMILES: S(C)C.[CH3:4][C@@:5]12[O:13][B:12](C3C=CC=CC=3C#N)[O:11][C@@H:10]1[CH2:9][C@@H:8]1[CH2:22][C@H:6]2[C:7]1([CH3:24])[CH3:23]>>[CH3:4][C@:5]12[O:13][BH:12][O:11][C@H:10]1[CH2:9][C@H:8]1[CH2:22][C@@H:6]2[C:7]1([CH3:24])[CH3:23].[BH3:12]
Reactant: CC1(C)[C@@H]2C[C@H]3OB(c4ccccc4C#N)O[C@@]3(C)[C@H]1C2
Solvent: CSC
Product: B
Product: CC1(C)[C@H]2C[C@@H]3OBO[C@]3(C)[C@@H]1C2

Procedure:
The borane (1R,2R,6S,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane was synthesised from the diol and BH3.SMe2 and reacted with aryl halides by the procedure described in Example 26. The reaction products were identified by gc/ms. (i) 2-[(1R,2R,6S,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]benzonitrile
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:21]#[N:22])[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:8]=1[C:9]#[N:10].C(=O)([O-])O.[OH:29][CH2:30][CH2:31][N+:32]([CH3:35])([CH3:34])[CH3:33]>C(O)C>[C:21]([C:6]1[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:8]([C:9]#[N:10])=[C:3]([CH:2]([F:1])[F:24])[N-:4][C:5]=1[CH3:23])#[N:22].[OH:29][CH2:30][CH2:31][N+:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)F)N1
Agent: C[N+](C)(C)CCO
Agent: O=C([O-])O
Solvent: CCO
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)F)[N-]1

Procedure:
To a suspension of 67 mg (0.21 mmol) 2-(difluoromethyl)-6-methyl-4-(3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile (Enantiomer 2; Example 3) in ethanol (1.4 ml) under argon atmosphere was added 28.9 μl (0.21 mmol) 2-hydroxy-N,N,N-trimethylethanaminium hydrogencarbonate solution (choline bicarbonate, 80% in water), and the mixture was stirred at reflux temperature for 1 h. Subsequently, the solution was evaporated, and the residue was dried in vacuo. The precipitate was stirred in 1.5 ml THF for 3 days and then centrifuged to yield 48 mg (54% of th.) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:3].[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>C(O)(=O)C>[F:15][C:7]1[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1ccnn1C(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)c1c(F)cnn1C(C)C
Temperature: 100 °C

Procedure:
A microwave vial was charged with ethyl 1-(1-methylethyl)-1H-pyrazole-5-carboxylate (0.15 g) and Selectfluor™ (0.38 g) followed by acetonitrile (3 ml) and acetic acid (1 ml). The mixture was heated at 100° C. under microwave irradiation for 180 min. Selectfluor™ (0.076 g) was added and the mixture heated at 100° C. under microwave irradiation for 60 min. Further Selectfluor™ (0.15 g) was added and the mixture heated at 100° C. under microwave irradiation for 60 min. Further Selectfluor (0.38 g) was added and the mixture heated at 100° C. under microwave irradiation for 60 min. The solvent was removed in vacuo and the residue was partitioned between DCM (15 ml) and water (15 ml) and separated using a hydrophobic frit. The aqueous layer was extracted with dichloromethane (2×5 ml) and the combined organic layers were concentrated in vacuo. Purification by chromatography on silica gel (20 g silica cartridge), eluting with a gradient of 0-50% DCM in cyclohexane over 20 minutes gave the title compound (100 mg) as a colourless oil.
Reaction SMILES: Cl[C:2]1[N:3]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4](=[O:13])[C:5]2[N:6]=[CH:7][N:8]([CH2:11]C)[C:9]=2[N:10]=1.[F:21][C:22]1[CH:23]=[C:24]([OH:30])[CH:25]=[C:26]([F:29])[C:27]=1[F:28]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:3]2[C:4](=[O:13])[C:5]3[N:6]=[CH:7][N:8]([CH3:11])[C:9]=3[N:10]=[C:2]2[O:30][C:24]2[CH:23]=[C:22]([F:21])[C:27]([F:28])=[C:26]([F:29])[CH:25]=2)=[CH:15][CH:16]=1
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: CCn1cnc2c(=O)n(-c3ccc(F)cc3)c(Cl)nc21
Product: Cn1cnc2c(=O)n(-c3ccc(F)cc3)c(Oc3cc(F)c(F)c(F)c3)nc21
Temperature: 140 °C

Procedure:
A mixture of 2-chloro-1-(4-fluorophenyl)-9-ethyl-1,9-dihydro-6H-purin-6-one (55.6 mg, 0.20 mmol) and 3,4,5-trifluorophenol (0.40 mmol) is heated to 140° C. for 36 h. After cooling to RT, the crude mixture is purified by preparative HPLC to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) 7.98 (1H, s), 7.55 (2H, m), 7.45 (2H, m), 7.34 (2H, m), 3.53 (3H, S). m/z=391.05 (M+1); RT=0.78 min.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:17][C:16]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)=[N:15][CH:14]=2)=[CH:9][CH:8]=1>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:17][C:16]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)=[N:15][CH:14]=2)=[CH:11][CH:12]=1.[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:17][C:16]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)=[N:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(-c2ncc(-c3ccc(OC)cc3)s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Product: O=C(O)c1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 211.3 %

Procedure:
To a solution of boron tribromide (1.0M in dichloromethane, 97.7 ml) was added dropwise methyl 4-[5-(4-methoxyphenyl)thiazol-2-yl]benzoate (3.18 g) in dichloromethane (50 ml) at −78° C. The reaction mixture was allowed to warm to room temperature, and stirred for 2 hours. The reaction mixture was poured into ice-water (1000 ml), and stirred for 30 minutes at room temperature. The precipitate was collected by filtration, washed with water, and dried overnight to give in the proportion of 37:63 mixture of methyl 4-[5-(4-hydroxyphenyl)thiazol-2-yl]benzoate and 4-[5-(4-hydroxyphenyl)thiazol-2-yl]benzoic acid (3.07 g), and those were used without purification in the next reaction.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([N:18]1[CH2:25][CH:24]2[CH:20]([C:21](=O)[C:22]3[C:28]([CH3:29])=[CH:27][S:26][C:23]=32)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C(Cl)Cl>[CH2:11]([N:18]1[CH2:25][CH:24]2[CH:20]([C:21](=[CH2:1])[C:22]3[C:28]([CH3:29])=[CH:27][S:26][C:23]=32)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1csc2c1C(=O)C1CN(Cc3ccccc3)CC21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C1c2c(C)csc2C2CN(Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (9.6 g, 26.8 mmol) was dissolved in THF (67 ml), cooled to 0° C. and treated with potassium bis(trimethylsilyl)amide (KHMDS) (5.33 g, 26.8 mmol) producing a clear yellow solution. Next, a solution of the product from step f) (1.9 g mg, 6.70 mmol) in THF (33 ml) was added and the reaction was warmed to 22° C. After 1 hour, the reaction was diluted with CH2Cl2 (300 ml) and washed with brine (100 ml). The organic layer was dried (MgSO4) and the solvent evaporated in vacuo to give the crude subtitle product (3.1 g) that was used without further purification.
Reaction SMILES: [CH:1]1([C:6]2[C:10]([NH:11][C:12](=O)[CH2:13][C:14]3[CH:19]=[CH:18][C:17](OC)=[CH:16]C=3)=[C:9]([C:23]([NH2:25])=[O:24])[O:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:26].[K+].[CH3:28]O>>[CH:1]1([C:6]2[C:10]3[N:11]=[C:12]([C:13]4[CH:14]=[CH:19][C:18]([O:26][CH3:28])=[CH:17][CH:16]=4)[NH:25][C:23](=[O:24])[C:9]=3[O:8][N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CO
Reactant: COc1ccc(CC(=O)Nc2c(C3CCCC3)noc2C(N)=O)cc1
Reactant: [OH-]
Agent: [K+]
Product: COc1ccc(-c2nc3c(C4CCCC4)noc3c(=O)[nH]2)cc1

Procedure:
2.56 g (7.45 mmol) of 3-cyclopentyl-4-{[2-(4-methoxyphenyl)acetyl]amino}-isoxazole-5-carboxamide (example X) are heated under reflux for 16 hours, together with 4.3 g of potassium hydroxide, in 170 ml of methanol. The solvent is removed in vacuo and the residue is taken up in dichloromethane; the solution is washed with 1N hydrochloric acid and water, after which the organic phase is dried over sodium sulfate and the solvent is removed. The residue is purified by chromatography (cyclohexane/ethyl acetate=2:1).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([N:55](CC3C=CC(OC)=CC=3)[C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[C:50]([F:54])[CH:49]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.C(OC([NH:87][C@@H:88]([CH3:92])[C:89](O)=[O:90])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:87][C@H:88]([C:89]([NH:28][C@H:29]1[CH2:30][CH2:31][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[C:50]([F:54])[CH:49]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:33][CH2:34]1)=[O:90])[CH3:92]
Reactant: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](N)C(=O)N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccnc(F)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BOP (68.4 mg, 0.155 mmol) was added to a solution of 62B (30.0 mg, 0.052 mmol), DIEA (0.036 mL, 0.206 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (19.52 mg, 0.103 mmol) in DCM (1 mL). The clear reaction mixture was stirred at room temperature for 30 min, and then concentrated to dryness. TFA (0.238 mL, 3.09 mmol) was added and the reaction solution was stirred at 70° C. for 1 h. The resulting mixture was concentrated and then diluted with MeOH and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 10% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 90% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to afford 6-((trans-4-(L-alanylamino)cyclohexyl)amino)-N-(2-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide (13.7 mg, 0.026 mmol, 49.9% yield) as white solid. HPLC Rt=1.618 minutes (Phenomenex Luna 5 micron C18 4.6×30 mm: 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). [M+H]=533.17.
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C([Li])CCC.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>O1CCCC1.CCCCCC>[O:1]1[CH2:6][C:5](=[O:7])[N:4]([C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C1COc2cccnc2N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1COc2cccnc2N1C(=O)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Under an anhydrous atmosphere, a solution of 10 mmol of 2H-pyrido[3,2-b][1,4]oxazin-3-one in 50 ml of tetrahydrofuran is cooled to −78° C. At that temperature, 11 mmol of a 1.6M solution of n-butyllithium in hexane are added dropwise. After 30 minutes' contact at −78° C., 11 mmol of phenyl chloroformate are added dropwise and stirring is maintained for a further 2 hours. After returning to ambient temperature, the solution is hydrolysed and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated. After purification by chromatography on silica gel (petroleum ether/ethyl acetate: 8/2), the expected product is isolated.