Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[CH2:5]([O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][C:12]=1[OH:20])[CH3:6].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=1.CC(C)([O-])C.[K+]>O.C(OCC)(=O)C>[CH2:5]([O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][C:12]=1[O:20][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=1)[CH3:6]
Reactant: CCOCCOc1cc2[nH]ccc2cc1O
Reactant: CC(=O)Nc1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOCCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Dimethylsulfoxide (20 mL) was added to a mixture of 6-(2-ethoxyethoxy)-1H-indol-5-ol described in Production Example 24-5 (3.28 g, 14.8 mmol), N-(4-chloropyridin-2-yl)acetamide described in Production Example 1-5 (2.78 g, 16.3 mmol), and potassium tert-butoxide (1.83 g, 16.3 mmol) under nitrogen atmosphere at room temperature. The liquid mixture was stirred at 150° C. overnight. The reaction liquid was allowed to stand to cool to room temperature and then diluted with water and ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and then the drying agent was separated by filtration. The filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=99:1-19:1) to obtain the title compound (2.5 g, 48%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[H-].[Na+].[S:11]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][OH:27])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>CN(C=O)C>[Br:8][C:6]1[CH:7]=[C:2]([O:27][CH2:26][C@@H:22]2[CH2:23][CH2:24][CH2:25][N:21]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=2)(=[O:13])=[O:12])[CH:3]=[N:4][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CO)cc1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2COc2cncc(Br)c2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a suspension of 3,5-dibromopyridine (1.5 g, 6.05 mmol) and 60% NaH (307 mg, 7.7 mmol) in DMF (6 mL) was added 1-tosyl-2-(S)-pyrrolidinemethanol (1.4 g, 5.5 mmol), and the reaction mixture was stirred for 4 hours at room temperature and 1 hour at 60° C. The DMF was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane 6:1 to afford the title compound (1.2 g).
Reaction SMILES: [I-].C[S+](C)C.[Li]CCCC.[CH3:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CC.[OH2:21].[CH2:22]1[CH2:26]O[CH2:24][CH2:23]1>>[OH:21][C:22]([CH3:26])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:23]=[CH2:24]
Reactant: CCCCCCCC(C)=O
Reactant: O
Reactant: C1CCOC1
Agent: C[S+](C)C
Agent: [I-]
Agent: [Li]CCCC
Product: C=CC(C)(O)CCCCCCC
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
BK1114. Trimethylsulfonium iodide (23.53 g, 115.3 mmol) was suspended in anhydrous THF (250 mL) under argon and the slurry cooled to −20° C. A pre-cooled (−20° C.) solution of n-BuLi (2.14M in hexanes, 51.2 mL, 109 mmol) was added slowly via cannulating needle and the solution stirred for 10 minutes at −20° C. A pre-cooled (−20° C.) solution 2-nonanone (5.0 mL, 28.8 mmol) was then added slowly via cannulating needle and the resultant solution was stirred at −20° C. for 1 hour. The reaction was allowed to warm to room temperature over 2 hours. Water (200 mL) was added and the mixture was extracted with Et2O (3×100 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford an oily residue. This material was chromatographed on silica gel (eluting with 10% EtOAc/hexanes) to afford 3-hydroxy-3-methyl-1-decene (3.56 g, 72% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8].C[Si]([C:19]([Si](C)(C)C)(C([O-])=O)[C:20]([O-:22])=[O:21])(C)C.[Li+].[Br-].OS(O)(=O)=O.[C:37]([O:40][C:41]([CH3:43])=[CH2:42])(=[O:39])[CH3:38]>CC#N.CCN(CC)CC>[O:8]=[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=1)[CH2:19][C:20]([OH:22])=[O:21].[CH3:42][C:41]1([CH3:43])[O:40][C:37](=[O:39])[CH:38]=[C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=2)[O:8]1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: C=C(C)OC(C)=O
Reactant: C[Si](C)(C)C(C(=O)[O-])(C(=O)[O-])[Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)OC(=O)C=C(c2cccc(OC(F)(F)F)c2)O1
Product: O=C(O)CC(=O)c1cccc(OC(F)(F)F)c1

Procedure:
The 3-oxo-3-(3-trifluoromethoxy-phenyl)-propionic acid was prepared from 3-trifluoromethoxybenzoyl chloride and bis(trimethylsilyl)malonate with Et3N and LiBr in CH3CN at 0° C. according to general procedure H (method c1). The crude material was transformed into the title compound by stirring in isopropenyl acetate and conc. H2SO4 according to general procedure J (method a). Obtained as an orange solid (2.27 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][S:12][C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)=[C:9](Br)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1)=[O:5])[CH3:2].CN(C)CC(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl>[C:19]1([N:8]2[C:9]3[N:17]4[CH:16]=[CH:15][N:14]=[C:13]4[S:12][CH2:11][C:10]=3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(Br)c1CSc1ncc[nH]1
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2ccccc2)c2c1CSc1nccn1-2
Temperature: 180 °C

Procedure:
Ethyl-5-bromo-4-[(1H-imidazol-2ylthio) methyl]-1-phenyl-1H-pyrazole-3-carboxylate (0.3 g, 0.74 mmol, 1 eq), Cul (14 mg, 0.074 mmol, 0.1 eq), N,N-dimethylglycine (15 mg, 0.147 mmol, 0.2 eq), K2CO3 (0.2 g, 1.47 mmol, 2 eq) are taken in DMSO (6 mL) heated at 180° C. for 0.5 h under microwave irradiation. The reaction mixture is diluted with DCM and filtered through a pad of celite. The filtrate is partitioned between DCM and water. The organic layer is washed with brine, dried over Na2SO4 and concentrated. The crude is purified by flash chromatography to afford the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 7.67-7.59 (m, 5H), 6.93 (d, J=1.5 Hz, 1H), 6.48 (d, J=1.4 Hz, 1H), 4.40 (s, 2H), 4.34 (q, J=7.7 Hz, 2H), 1.31 (t, J=7.7 Hz, 3H). MS (ESI+): 313.2. HPLC (max plot) 97.73%; Rt 2.73 min.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NCCN1CCCC1
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(NCCN2CCCC2)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 58 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.54 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using 1-(2-aminoethyl)pyrrolidine instead of thiomorpholine to the title compound (145 mg, 58%) which was obtained as an off-white solid. MS: m/e=464.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[F:17])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+]>[Fe].O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[F:17])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(Oc2ccc(Cl)cc2)c(F)c1
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cc(F)c(Oc2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 114.2 %

Procedure:
A mixture of 4-(4-chlorophenoxy)-3,5-difluoronitrobenzene (10.6 g, 37 mmol), toluene (150 ml), H2O (150 ml), iron powder (6.9 g, 124 mmol), and ammonium acetate (9.3 g, 120 mmol) was heated to reflux with stirring for 2-3 hrs. After cooling to room temperature, the reaction mixture was filtered through Celite with thorough washing with H2O and EtOAc. The filtrate was transferred to a separatory funnel and the phases separated. The aqueous phase was further extracted with EtOAc (2×). The combined organic phases were washed with H2O (1×), sat'd NaCl (1×), dried over Na2SO4, and concentrated in vacuo to give 4-(4-chlorophenoxy)-3,5-difluoroaniline (10.8 g, 113%) which was used in the next step without further purification. 1H NMR (CDCl3): δ 3.81 (s, 2H), 6.27 (d, 2H, J=9.2 Hz), 6.85 (d, 2H, J=9.2 Hz), 7.21 (d, 2H, J=9.2 Hz).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:14]([CH2:28][CH2:29][CH3:30])[C:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25](I)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:16])[CH2:12][CH3:13]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:28]([N:14]([CH2:11][CH2:12][CH3:13])[C:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:16])[CH2:29][CH3:30]
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: c1cocn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[(Dipropylamino)carbonyl]-5-iodobenzoic acid (12 g, 32 mmol) is dissolved in 20% methanol/benzene (480 mL), and 2M trimethylsilyldiazomethane in hexane (19 mL, 38 mmol) is added slowly. Upon completion of the addition, the solution is concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate for use without further purification in the following reaction. To a −70° C. stirred solution of oxazole (120 mg, 1.7 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 1.2 mL, 1.9 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 5.2 mL, 5.2 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (643 mg, 1.6 mmol) in anhydrous tetrahydrofuran (3 mL) followed by palladium(0)tetrakis(triphenylphosphine) (80 mg, 0.07 mmol). The reaction mixture is heated at reflux for 3 h. The reaction mixture is cooled, diluted with ethyl acetate, filtered, washed with saturated sodium bicarbonate, water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides the title compound in pure form. 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H) 7.32 (s, 1H), 3.52 (t, 2H), 3.22 (t, 2H), 1.75 (m, 2H), 1.30 (m, 2H), 0.97 (t, 3H), 0.79 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:12][CH2:11][C:5]2([S:9][CH2:8][C:7](=[O:10])[NH:6]2)[CH2:4][CH2:3]1.C=O.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[C:20]1(C)C=CC=CC=1>C(O)C>[CH3:1][N:2]1[CH2:12][CH2:11][C:5]2([S:9][CH2:8][C:7](=[O:10])[N:6]2[CH2:20][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:4][CH2:3]1
Reactant: CN1CCC2(CC1)NC(=O)CS2
Reactant: Cc1ccccc1
Reactant: C1CCNC1
Agent: C=O
Solvent: CCO
Product: CN1CCC2(CC1)SCC(=O)N2CN1CCCC1
Temperature: 0 °C
Yield: 63 %

Procedure:
A solution of 8-Methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF277 5.13 g, 0.0275 mol), formaldehyde (37% solution, 2.75 ml), and pyrrolidine (2.3 ml, 0.0275 mole) in ethanol (2.3 ml) was refluxed for 4 h, then left at room temperature over night. Toluene (10 ml) was added and the solvent was evaporated. Boiling pentane (100 ml) was added to the residue and the solution was decanted. The trituration with hot pentane was repeated four times, the pentane layers were combined, cooled to 0° C. and the precipitate was collected and identified as AF287 (4.6 gr, 63% yield). 1H-NMR (CDCl3) δ 1.69–1.77 (m, 5H), 2.20–2.29 (s and m, 5H, CH3, and CH2), 2.43–2.58 (m, 6H), 2.82–2.86 (m, 2H), 3.50 (s, 2H), 3.50 (s, 2H, SCH2), 4.14 (s, 2H, NCH2N) ppm. MS (EI) m/e 269(M+); 198; 84; 70.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[C:18]([OH:30])[CH:17]=1.O>CN(C)C(=O)C>[OH:30][C:18]1[CH:17]=[C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH:29]=[CH:28][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2ccccc2)c(O)c1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)c(O)c1)C(F)(F)F
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.78 g, 4.9 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.59 g, 4.9 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4-Amino-2-hydroxybenzophenone (0.70 g, 3.3 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution decanted from an oily precipitate which was dissolved in methylene chloride, dried (MgSO4) and concentrated in vacuo to yield a brown oil. Purification by flash column chromatography (5% v/v ethyl acetate/methylene chloride) yielded the title propanamide as a white solid (0.83 g, 71%); mp 173°-175° C. 1H-NMR (250 MHz, CDCl3): 1.74 (s, 3H, CH3) 3.49 (s, 1H, OH) 7.14 (dd, 1H, J=8.7, 2.2 Hz, aromatic) 7.28 (d, 1H, J=2.1 Hz, aromatic),7.46-7.65 (m, 6H, aromatic) 8.49 (s, 1H, NH) 12.3 (s, 1H, phenolic OH). MS (CI, CH4): (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH:14]([CH3:25])[CH2:13]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([S:36]([Cl:39])(=[O:38])=[O:37])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>>[ClH:39].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([S:36]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N:12]3[CH2:17][CH2:16][NH:15][CH:14]([CH3:25])[CH2:13]3)=[CH:4][CH:3]=2)(=[O:37])=[O:38])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CC1CN(c2ccc(N)c3ccccc23)CCN1C(=O)OC(C)(C)C
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCNC(C)C3)c3ccccc23)cc1OC
Product: Cl

Procedure:
The title compound was prepared from (intermediate 8 after reduction according to Method A) tert-butyl 4-(4-amino-1-naphthyl)-2-methyl-1-piperazinecarboxylate (0.189 g, 0.55 mmol) and 3,4-dimethoxybenzenesulfonyl chloride (0.130 g, 0.55 mmol) by the method described above: yield HCl-salt 0.068 g (26%); 1H NMR (CD3OD)
Reaction SMILES: Br.[OH:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[Si:23]([O:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cccc(-c2ncccc2O)c1
Agent: Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cccnc1-c1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 99.5 %

Procedure:
To a stirred suspension of 3-(3-hydroxypyridin-2-yl)nitrobenzene hydrobromide (0.3 g) and imidazole (165 mg) in N,N-dimethylformamide (3 ml) was added tert-butyldimethylsilyl chloride (183 mg), and the mixture was stirred for 18 hours. The mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 3-(3-tert-butyldimethylsilyloxypyridin-2-yl)nitrobenzene (332 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH2:14])[CH2:6]2.C(N(CC)CC)C.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][C:24](=[O:25])[C:23]([F:30])([F:29])[F:22])[CH2:6]2
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1cc2c(cc1OC)[C@@H](CN)C2
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc2c(cc1OC)[C@@H](CNC(=O)C(F)(F)F)C2
Reaction time: 2 h

Procedure:
To 2.9 g (15 mmol) of {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}amine in 7.5 mL of methanol, at ambient temperature, there are added, all at once, 2.1 mL (15 mmol/1 eq.) of triethylamine, and then, dropwise, over 20 minutes, 2.3 mL (19 mmol/1.25 eq.) of ethyl trifluoroacetate. Stirring is carried out at ambient temperature for 2 hours, followed by evaporating to dryness. The residue is taken up in 100 mL of dichloromethane, and washing with 50 mL of 1N hydrochloric acid and then 50 mL of water and drying over magnesium sulphate are carried out. After filtration and concentration, the desired product is collected.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6](Cl)[CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].CC(C)([O-])C.[K+].[C@H:35]1([NH2:42])[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37][CH2:36]1>C1COCC1.CO>[NH2:41][C@H:38]1[CH2:39][CH2:40][C@H:35]([NH:42][C:6]2[CH:7]=[C:2]([NH:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[C:3]3[N:4]([C:9]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=4[F:21])=[O:13])=[CH:10][N:11]=3)[N:5]=2)[CH2:36][CH2:37]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: Nc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C

Procedure:
A suspension of 5A (20 mg, 0.061 mmol) in THF (1 mL) was treated with pyridin-2-amine (11.54 mg, 0.123 mmol). A solution of potassium t-butoxide (0.123 mL, 0.123 mmol) in THF was added and the reaction was stirred at room temperature. After two hours the solvent was removed under a stream of nitrogen. (trans)-cyclohexane-1,4-diamine (200 mg, 1.751 mmol) was added and the reaction mixture was heated to 160° C. for 3 hours. The solution was cooled to room temperature and diluted with MeOH. The solid residue was filtered and dried. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=28.731 minutes) was isolated and lyophilized to dryness to afford 6-((trans-4-aminocyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide (1.5 mg, 4.25%). HPLC Rt=3.343 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=462.1.
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8]3.C([O-])([O-])=O.[K+].[K+].[CH3:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](F)=[CH:29][CH:28]=1)=[O:26].O>CS(C)=O>[CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[N:8]3[C:30]1[CH:31]=[CH:32][C:27]([C:25](=[O:26])[CH3:24])=[CH:28][CH:29]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: c1ccc2c(c1)ccc1c3ccccc3[nH]c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1ccc(-n2c3ccccc3c3ccc4ccccc4c32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 11H-benzo[a]carbazole (2.00 g, 9.22 mmol) in DMSO (20 mL) is added K2CO3 (3.85 g, 27.9 mmol) at 180° C., and then the mixture is stirred for 1 hour. To the mixture is added 4-fluoroacetophenone (1.28 g, 9.228 mmol). After stirring for 8 hours, the reaction mixture is cooled to room temperature, and poured into water. The crude product is extracted with ethyl acetate, and it is washed with water and brine. The organic layer is dried over MgSO4. After concentration, the crude product is purified by column chromatography on silica gel eluting with CH2Cl2 to obtain an off-white solid (160 mg; 5%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 2.75 (s), 7.20 (d), 7.23 (t), 7.34-7.46 (m), 7.65 (d), 7.75 (d), 8.00 (d), 8.19 (d), 8.22 (d), 8.25 (d).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:14]=[CH:13][O:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([N:8]([CH2:9][C:10]1[CH:14]=[CH:13][O:12][CH:11]=1)[CH2:16][CH2:17][OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: c1ccc(CNCc2ccoc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN(Cc1ccccc1)Cc1ccoc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 0.641 g (3.423 mmol) of N-benzyl-3-furylmethylamine and 0.64 g (5.1 mmol) of 2-bromoethanol in 30 ml of N,N-dimethylformamide, 0.95 g of potassium carbonate was added, followed by stirring at 80° C. for 2 hours. 0.64 g (5.1 mmol) of 2-bromoethanol was further added, followed by overnight stirring at 80° C. The reaction mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield 2-[benzyl-(3-furylmethyl)amino]ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][OH:11])[CH2:7][C:6]=2[CH:12]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][O:11][CH3:15])[CH2:7][C:6]=2[CH:12]=1
Reactant: CI
Reactant: OCC1Cc2cc(F)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1Cc2cc(F)ccc2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
To a solution of (5-fluoro-2,3-dihydrobenzofuran-2-yl)methanol (854) (1.0 g, 6.0 mmol) in dimethylformamide (130.0 mL) was added 60% NaH in mineral oil (0.480 g, 12.0 mmol) and MeI (1.12 mL, 18.0 mmol). The suspension was stirred at room temperature for 24 h and diluted with water (50 mL), and extracted with ethyl acetate (2×25 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-10% EtOAc in hexanes) to provide the desired 5-fluoro-2-(methoxymethyl)-2,3-dihydrobenzofuran (855) (0.650 g, 59.5%) as a colorless oil.