Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[Si:18]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
20.0 g (115 mmol) of tert-butyl 3-hydroxyazetidine-1-carboxylate and 9.43 g (139 mmol) of imidazole were initially charged in 200 ml of anhydrous DMF, and 34.91 g (127 mmol) of tert-butyl(diphenyl)silyl chloride were added at RT. After the reaction mixture had been stirred at RT for 18 h, it was poured into 3.2 liters of water and then extracted three times with approx. 1 liter each time of diethyl ether. The combined organic extracts were washed successively with saturated sodium hydrogencarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the solvent was removed on a rotary evaporator. The remaining residue was stirred with 100 ml of pentane for a few minutes. Subsequently, the solid was filtered off with suction and dried under high vacuum. 29.18 g (61% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N+:7]([O-])[C:8]([CH3:11])=[CH:9][CH:10]=[C:5]2[O:4][N:3]=1.O=P(Cl)(Cl)[Cl:15].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:15][C:10]1[CH:9]=[C:8]([CH3:11])[N:7]=[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=12
Reactant: Cc1noc2ccc(C)[n+]([O-])c12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)c2onc(C)c2n1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
3,5-dimethylisoxazolo[4,5-b]pyridine 4-oxide (0.650 g, 3.96 mmol) in chloroform (5 mL), was added POCl3 (1.45 mL, 15.8 mmol) and the mixture was heated at 80° C. for 2 hours. The solution was cooled and poured onto ice water. The solution was neutralized with saturated NaHCO3 and the solution was then extracted with EtOAc, dried, and concentrated. The solid was triturated with ether and filtered twice to obtain two crops of the title compound (0.417 g, 57.7% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=2)[N:16]([CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][C:29]([Cl:35])=[CH:30][CH:31]=3)[N:26]=2)[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7].CN1CCOCC1.[CH:43]1([O:48][C:49](Cl)=[O:50])[CH2:47][CH2:46][CH2:45][CH2:44]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:49]([O:48][CH:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:50])[CH:21]=2)[N:16]([CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][C:29]([Cl:35])=[CH:30][CH:31]=3)[N:26]=2)[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C(Cl)OC1CCCC1
Reactant: COC(=O)c1ccc(Cc2cn(Cc3ccc4ccc(Cl)cc4n3)c3ccc(N)cc23)c(OC)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(Cc2cn(Cc3ccc4ccc(Cl)cc4n3)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Reaction time: 0.25 h

Procedure:
To the solution of the amine from Step 2 in CH2Cl2 (4 ml) at r.t. was successively added N-methylmorpholine (130 μl, 3 eq.) followed by cyclopentylchloroformate (176 μl, 3 eq.). After 15 mins, the mixture was quenched with aq NH4Cl and worked up in the usual manner. Chromatography on silica gel (EtOAc/toluene, 1:9) afforded the title carbamate (170 mg).
Reaction SMILES: [CH2:1]([C:5]1[C:13]([C:14]([C:16]2[CH:23]=[CH:22]C(C#N)=[CH:18][CH:17]=2)=[O:15])=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[C:29]([OH:32])(=[O:31])[CH3:30]>O>[CH2:1]([C:5]1[C:13]([C:14]([C:16]2[CH:23]=[CH:22][C:30]([C:29]([OH:32])=[O:31])=[CH:18][CH:17]=2)=[O:15])=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2ccccc2c1C(=O)c1ccc(C#N)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCc1nn2ccccc2c1C(=O)c1ccc(C(=O)O)cc1

Procedure:
A mixture of 845 mg of the product of Example 2 and 15 ml of a mixture in equal proportions of sulfuric acid, acetic acid and water was refluxed for 2 hours and the mixture was cooled down, taken up in water, filtered, washed with water and dried at 80° C. under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([OH:41])([C:39]#[CH:40])[CH3:38])[CH:32]=1>>[C:26]([O:25][C@@H:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:40]#[C:39][C:37]([OH:41])([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[CH3:38])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:29])[CH3:27]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC(C)(O)c1cccnc1
Product: Cc1cc2ccc(C#CC(C)(O)c3cccnc3)cc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-(pyridin-3-yl)but-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate and 2-(pyridin-3-yl)but-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 9.05 (s, 1H), 8.86 (d, J=8 Hz, 1H), 8.80 (s, 1H), 8.08 (m, 1H), 7.80 (d, J=8 Hz, 1H), 7.72 (s, 1H), 7.56 (m, 3H), 7.49 (d, J=8 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J=8 Hz, 1H), 5.16 (s, 1H), 2.61 (s, 3H), 1.87 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H30ClNO4: 528.2. found: 528.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[N:14]=[C:15]2[C:20](=[O:21])[NH:19][NH:18][CH:17]=[C:16]2[N:22]=1.[CH3:23][NH2:24]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([NH:24][CH3:23])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[N:14]=[C:15]2[C:20](=[O:21])[NH:19][NH:18][CH:17]=[C:16]2[N:22]=1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Reactant: CN
Product: CNS(=O)(=O)c1ccc(-c2nc3c[nH][nH]c(=O)c-3n2)c(OC)c1

Procedure:
Prepared analogously to Example 11 from 2-(2-methoxy-4-chlorosulfonyl-phenyl)-5-H-imidazo[4,5-d]pyridazin-4-one and aqueous methylamine solution
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8](=O)[CH2:9][CH3:10].[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[OH:20].BrCC=CC>O>[CH2:7]([O:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[F:12])[CH:8]=[CH:9][CH3:10]
Reactant: CCC(C)=O
Reactant: Oc1cccc(F)c1F
Agent: CC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC=CCOc1cccc(F)c1F
Temperature: 25 °C

Procedure:
122 g of anhydrous potassium carbonate was added to a 2-butanone (600 mL) solution containing 77.2 g of 2,3-difluorophenol, and then 90.0 mL of 1-bromo-2-butene (E/Z ratio=92/8) was added thereto. The solution was heated under reflux for 4 hours, then cooled to room temperature, and water was added dropwise thereto to stop the reaction. Extraction was performed with hexane (three times), and the collected organic phase was washed with 3M hydrochloric acid, water, saturated aqueous solution of sodium hydrogencarbonate, and saturated saline in this order, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure (155 to 160° C., 50 kPa), to thereby obtain 106 g of 1-(2-butenoxy)-2,3-difluorobenzene in the form of a colorless and transparent liquid (E/Z ratio=82/18 according to 1H-NM analysis).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([OH:11])=[O:10])([O-])=O>CC(O)=O.CCO.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)COc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cccc(OCC(=O)O)c1

Procedure:
(3-Nitro-phenoxy)-acetic acid (1.978 g; 10.0 mmol) was reduced by catalytic hydrogenation (10% Pd—C; 45 psi H2) in AcOH-EtOH-MeOH then filtered through diatomaceous earth and concd yielding the title aniline. LC-MS 168 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:22][CH2:21][CH2:20][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:10])[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1nc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(C(=O)NCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of 6-methyl-5-nitropyridine-2-carboxylic acid (0.500 g, 3.0 mmol) in DCM (7 mL) were added 2-morpholin-4-ylethanamine (1.0 mL, 7.7 mmol), TBTU (0.992 g, 3.1 mmol), and DIEA (1.34 mL, 7.7 mmol). The reaction mixture was allowed to stir at rt overnight and then quenched with water. The organic solution was separated and the aqueous solution was extracted with DCM. The organic solutions were combined and concentrated. The residue was purified by column chromatography to give 6-methyl-N-(2-morpholin-4-ylethyl)-5-nitropyridine-2-carboxamide (0.27 g, 30%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.C(N(CC)CC)C>>[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([C:6]2[N:2]([CH3:1])[C:3]([CH2:7][C:8]3[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:5]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cn1cccc1Cc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)c2ccc(Cc3cccc([N+](=O)[O-])c3)n2C)cc1
Yield: 28 %

Procedure:
3-(1-Methylpyrrol-2-ylmethyl)nitrobenzene (2.0 g, 9.2 mmol) [prepared as in Example 8, Step (b)], 4-methylbenzoyl chloride (2.84 g, 18.4 mmol), and triethylamine (2.0 ml, 14.3 mmol) were dissolved in xylenes (80 ml) and the reaction mixture was refluxed for 36 h. Purification on a Florisil column (hexane-ethyl acetate, 95:5) gave 3-{5-(4-methyl-benzoyl)-1-methyl-1H-pyrrol-2-ylmethyl}nitrobenzene (0.86 g, 28%) as a solid. ##STR45##
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:4][CH:3]1[O:5][N:6]=[C:7]([C:13]1([O:18][CH2:17][CH2:16][O:15]1)[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][CH:2]1[CH2:4][CH:3]1[O:5][N:6]=[C:7]([C:13]1([O:15][CH2:16][CH2:17][O:18]1)[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=NOC1CC1(Cl)Cl)C1(C)OCCO1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=NOC1CC1Cl)C1(C)OCCO1
Yield: 33.9 %

Procedure:
A solution of ethyl 2-(2,2-dichlorocyclopropyloxy- imino)-3,3-ethylenedioxybutyrate (syn isomer)(312 mg) and tri-n-butyltinhydride (0.55 ml) in toluene (2 ml) was refluxed under nitrogen atmosphere in the presence of catalytic amount of 2,2-azobisisobutyronitrile for hours. The reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography on silica gel (24 g) and eluted with a mixture of diethyl ether and n-hexane (1:2 V/V). The fractions containing the compound, which had higher Rf-value on TLC [development solvent system:diethyl ether and n-hexane (2:1 V/V)], were collected and concentrated in vacuo to give ethyl 2-(2-chlorocyclopropyloxyimino)-3,3-ethylenedioxybutyrate (syn isomer)(94 mg).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:6]=1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:71]=[C:70]([C:72](O)=[O:73])[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)=[CH:58][CH:57]=1>O.CN(C=O)C>[F:55][C:56]1[CH:57]=[CH:58][C:59]([C:62]2[CH:71]=[C:70]([C:72]([NH:1][C:2]3[O:3][C:4]([C:7]4[O:8][CH:9]=[CH:10][CH:11]=4)=[N:5][N:6]=3)=[O:73])[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)=[CH:60][CH:61]=1
Reactant: Nc1nnc(-c2ccco2)o1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)nc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nnc(-c2ccco2)o1)c1cc(-c2ccc(F)cc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
Commercially available 2-amino-5-(2-furyl)-1,3,4-oxadiazole (57 mg, 0.38 mmol), HOAt (51 mg, 0.37 mmol), HATU (143 mg, 0.38 mmol), and N,N-diisopropylethylamine (87 μL, 0.50 mmol) were added to a DMF (2 mL) solution of commercially available 2-(4-fluorophenyl)-4-quinolinecarboxylic acid (67 mg, 0.25 mmol), and the mixture was stirred at room temperature for 3 days. To the reaction solution, water was added, and the deposited solid was collected by filtration, and washed with water and then with methanol and methylene chloride in this order. The obtained solid was dried to obtain the title compound (61 mg, 0.15 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][C@@H:7]1[CH3:49])=[O:5].[OH-].[Na+].[Na+].[Cl-]>O1CCOCC1.CCOC(C)=O>[CH3:50][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][C@@H:7]1[CH3:49])=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)C[C@H](C)N3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)C[C@H](C)N3C(=O)CN(C)C)[nH]c2nccc1-2
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A solution of 2-({2-{[(2S)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (254 mg, 0.362 mmol) in dioxane (10 mL) and a 2M aqueous NaOH solution (2 mL) was heated at 80° C. for 6 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (50 mL) and a saturated NaCl solution (10 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to afford 2-[(2-{[(2S)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide as a pink solid (144 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (d, J=5.49 Hz, 3H), 2.27 (s, 6H), 2.59 (d, J=15.57 Hz, 1H), 2.80 (d, J=4.40 Hz, 3H), 3.08 (d, J=14.28 Hz, 1H), 3.21-3.46 (m, 2H), 3.80 (s, 3H), 4.71-4.85 (m, 1H), 6.27-6.34 (m, 1H), 6.83-7.08 (m, 3H), 7.26-7.44 (m, 1H), 7.54 (s, 1H), 8.33 (d, J=8.06 Hz, 1H), 547.40; Optical rotation −11.4 (1 mg/mL MeOH, rt).
Reaction SMILES: C([O:8][C:9](=[O:36])[CH2:10][C:11]1([OH:35])[CH2:16][CH2:15][CH:14]([N:17]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[C:31]([O:30][C:28]([N:17]([CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:14]1[CH2:13][CH2:12][C:11]([CH2:10][C:9]([OH:36])=[O:8])([OH:35])[CH2:16][CH2:15]1)=[O:29])([CH3:33])([CH3:34])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)C1CCC(O)(CC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)C1CCC(O)(CC(=O)O)CC1
Reaction time: 19 h

Procedure:
A solution of {4-[tert-Butoxycarbonyl-(2-tert-butoxycarbonylamino-ethyl)-amino]-1-hydroxy-cyclohexyl}-acetic acid benzyl ester (0.540 g, 1.07 mmol) in methanol (15 mL) was purged with argon for 5 min. Palladium on carbon (10%, 0.127 g) was added, the flask evacuated, and the reaction stirred under a H2 atmosphere for 19 hr. The reaction was filtered through a Celite-plugged filter frit, washed with methanol and DCM, and concentrated. The crude product was carried forward without purification. ESI-MS m/z 439 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[CH:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=O.S(=O)(O)[O-].[Na+]>CO>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:9]1[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: Nc1ccccc1N
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 19 %

Procedure:
A mixture of 1,2-diaminobenzene (6.59 g), methyl 4-formylbenzoate (10.0 g) and sodium bisulfite (6.60 g) in methanol (500 mL) is stirred at reflux for 6 hours. The mixture is filtered and the solvent evaporated to leave a yellow solid. This solid is recrystallized from ethyl acetate/ethanol to give 2.92 g of the title compound as an oil-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:5]2[N:18]=[CH:19][N:20]([CH:21]([CH3:23])[CH3:22])[C:4]=2[CH:3]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(O)C>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:5]3[N:18]=[CH:19][N:20]([CH:21]([CH3:23])[CH3:22])[C:4]=3[CH:3]=2)[CH:28]=[N:29][CH:30]=1
Reactant: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(Cl)cc21
Reactant: OB(O)c1cncc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(-c3cncc(F)c3)cc21
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A 5 ml microwave reaction vial was charged with 4-(2-(6-chloro-1-isopropyl-1H-imidazo[4,5-c]pyridin-4-ylamino)ethyl)phenol (c): (17 mg, 0.051 mmol), 5-fluoropyridin-3-ylboronic acid (72 mg, 0.51 mmol), and tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol). To this mixture was added toluene (1 ml), ethanol (0.5 ml) and aqueous sodium carbonate solution (2M, 0.5 ml). The vial was sealed and the reaction mixture was stirred at 140° C. under microwave irradiation for 2 hours. Water was added to the cooled mixture, which was extracted with ethyl acetate (5 ml×3). The organic fractions were combined, dried over sodium sulfate, and concentrated. The residue was purified by reverse-phase HPLC (C18 column, eluting with ACN—H2O 0.05% TFA) to afford the title compound as an off-white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCOCC2)C2N=NNC=2N=1)(C)(C)C.BrCC1C=CC([F:55])=CC=1Cl>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:55])=[CH:17][C:16]=3[Cl:21])[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nn(Cc3ccccc3Cl)nc2n1
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCOCC2)c2nn(Cc3ccc(F)cc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-2-(2-chloro-benzyl)-7-morpholin-4-yl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step d), the title compound was prepared from 5-tert-butyl-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-4-fluorobenzene and isolated as white solid (5.1 mg, 30%). MS (m/e): 405.4 (MH+).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([NH:17][C:18]3[CH:32]=[CH:31][C:21]([CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:20][CH:19]=3)=[O:16])=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C>CO>[NH2:23][CH2:22][C:21]1[CH:31]=[CH:32][C:18]([NH:17][C:15]([C:12]2[N:10]3[N:11]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=[CH:8][C:9]3=[N:14][CH:13]=2)=[O:16])=[CH:19][CH:20]=1
Reactant: CCCCNc1ccc2ncc(C(=O)Nc3ccc(CNC(=O)OC(C)(C)C)cc3)n2n1
Solvent: CO
Solvent: CC(=O)Cl
Product: CCCCNc1ccc2ncc(C(=O)Nc3ccc(CN)cc3)n2n1
Reaction time: 8 h
Yield: 13.9 %

Procedure:
To a solution of tert-butyl 4-(6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxamido)benzylcarbamate (230 mg, 0.53 mmol) in methanol (15 mL) was added acetyl chloride (0.37 mL, 5.25 mmol) dropwise. The reaction mixture was stirred for overnight, concentrated and purified by Prep HPLC (neutral) to give N-(4-(aminomethyl)phenyl)-6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxamide (25 mg, 20% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.54 (s, 1H), 8.11 (s, 1H), 7.80 (d, J=8.38 Hz, 2H), 7.77 (d, J=9.92 Hz, 1H), 7.50 (d, J=8.38 Hz, 2H), 6.92 (d, J=9.70 Hz, 1H), 4.12 (s, 2H), 3.48 (t, J=7.17 Hz, 2H), 1.79 (quin, J=7.33 Hz, 2H), 1.55 (dq, J=15.02, 7.41 Hz, 2H), 1.02 (t, J=7.39 Hz, 3H); LRMS (ESI) m/e 339.2 [(M+H)+, calcd for C18H23N6O 339.4].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])[CH2:6][CH3:7])[CH3:2].[CH:18]1([CH:21]([C:23]2[S:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH3:38])O)[CH2:20][CH2:19]1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:21]([CH:18]2[CH2:19][CH2:20]2)[C:23]2[S:27][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=3)=[N:25][C:24]=2[CH3:38])=[CH:11][C:10]=1[CH3:16])[CH2:6][CH3:7])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CC1
Reactant: CCOC(=O)C(CC)Cc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(CC)Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CC2)cc1C

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-(4-hydroxy-2-methyl-benzyl)-butyric acid ethyl ester (example 125 c]) was reacted with [rac]-cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (example 121 a]) in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 2-(4-{cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-benzyl)-butyric acid ethyl ester as a mixture of two diastereomeric racemates as light yellow liquid.