Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]([CH2:9][CH:10]([CH2:21][N:22]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])[CH3:23])[CH:11]([O:13][Si](C(C)(C)C)(C)C)[CH3:12])[CH3:8])=[O:6])[CH:2]=[CH2:3].Cl.[OH2:31]>C(OCC)(=O)C>[CH2:27]([O:26][C:24]([N:22]([CH2:21][CH:10]([CH2:9][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH3:8])[C:11]([OH:13])([OH:31])[CH3:12])[CH3:23])=[O:25])[CH:28]=[CH2:29]
Reactant: O
Reactant: C=CCOC(=O)N(C)CC(CN(C)C(=O)OCC=C)C(C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N(C)CC(CN(C)C(=O)OCC=C)C(C)(O)O
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1-(N-allyloxycarbonyl-N-methylamino)-2-(N-allyloxycarbonyl-N-methylaminomethyl)-3-(t-butyldimethylsilyloxy)butane (123 g) in ethyl acetate (1.2 l) was added 6N-aqueous hydrochloric acid (240 ml) at ambient temperature. After stirring at the same temperature for 2.5 hours, to the mixture was added water (1 l) and the organic layer was separated. The organic layer was washed successively with 1N-aqueous sodium hydroxide (1 l), saturated aqueous ammonium chloride (500 ml), and brine (500 ml). After the solution was dried over magnesium sulfate, removal of the solvents gave a residue. The residue was chromatographed on silica gel (1 l) eluting with a mixture of n-hexane and ethyl acetate (95:5-40:60, V/V) to give 1-(N-allyloxycarbonyl-N-methylamino)-2-(N-allyloxycarbonyl-N-methylaminomethyl)-3-hydroxybutan-3-ol (83.18 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[N:13]1([C:4]([C:3]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=2[F:1])=[O:5])[CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1F)N1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 2,4-difluorobenzoyl chloride (1.14 g, 6.46 mmol) in CH2Cl2 was added azetidine hydrochloride (1.46 g, 15.6 mmol) and Et3N (2.70 mL, 19.4 mmol). The reaction mixture was stirred at room temperature for 1 hr, quenched with H2O (100 mL), and extracted with CH2Cl2 (2×100 mL). The organic layers were dried over MgSO4 and concentrated to give an off-white solid (896 mg, 76% yield) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.52-7.59 (m, 1 H) 6.91-6.98 (m, 1 H) 6.81-6.87 (m, 1 H) 4.21 (t, J=7.71 Hz, 2 H) 4.11 (t, J=7.71 Hz, 2 H) 2.30-2.38 (m, 2 H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([NH:25][C@H:26]3[CH2:31][CH2:30][C@@H:29]([CH3:32])[CH2:28][CH2:27]3)[N:8]=2)[CH2:2]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[CH3:33][S:34]([N:1]1[CH2:2][CH:3]([CH2:5][O:6][C:7]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[CH:17][CH:18]=3)=[CH:11][N:10]=[C:9]([NH:25][C@H:26]3[CH2:31][CH2:30][C@@H:29]([CH3:32])[CH2:28][CH2:27]3)[N:8]=2)[CH2:4]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(N4CCOCC4)cc3)c(OCC3CNC3)n2)CC1
Product: CS(=O)(=O)N1CC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)C1

Procedure:
Using the procedure of Example 1 Step 5, 4-((azetidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine was reacted with methanesulfonyl chloride to provide the title compound in 87% yield. 1H NMR (CDCl3, 400 MHz) 8.09 (s, 1H), 7.34 (d, 2H), 6.93 (d, 2H), 5.17 (sb, 1H), 4.50 (d, 2H), 4.08 (m, 1H), 4.01 (m, 2H), 3.87 (m, 4H), 3.82 (m, 2H), 3.17 (m, 4H), 3.05 (m, 1H), 2.66 (s, 3H), 1.85-1.55 (m, 6H), 1.80-1.40 (m, 3H), 0.94 (d, 3H); MS (ESI) m/z: Calc: 515.3 (M). Found. 516.3 (M+1).
Reaction SMILES: C(OC(N1CCN([CH2:14][CH2:15][NH:16][C@:17]23[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20]2)CC1)=O)(C)(C)C.[CH3:55][S:56]([CH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)(=[O:58])=[O:57]>>[CH3:35][C@:32]12[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:37])([CH3:38])[C:26]([C:39]3[CH:40]=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[CH:46][CH:47]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20][C@@H:19]1[C@H:18]1[C@H:49]([C:52]([CH3:54])=[CH2:53])[CH2:50][CH2:51][C@:17]1([NH:16][CH2:15][CH2:14][N:62]1[CH2:63][CH2:64][CH:59]([S:56]([CH3:55])(=[O:58])=[O:57])[CH2:60][CH2:61]1)[CH2:34][CH2:33]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(=O)(=O)C1CCNCC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-(methylsulfonyl)piperidine as the alkylating reagent in Step 3. The product was isolated as a white solid (200 mg, 84%). LCMS: m/e 719.58 (M+H)+, 2.31 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.6 Hz, 1H), 4.87 (s, 1H), 4.75 (s, 1H), 3.76-3.70 (m, 2H), 3.68-3.54 (m, 4H), 3.48-3.29 (m, 1H), 3.18-3.03 (m, 2H), 3.02 (s, 3H), 2.84 (td, J=11.8, 4.7 Hz, 1H), 2.46-1.03 (m, 26H), 1.77 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1cnc(Cl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cnc(NCc2ccc(OC)cc2OC)cc1OC
Temperature: 120 °C
Reaction time: 19 h
Yield: 64.6 %

Procedure:
To a solution of methyl 6-chloro-4-methoxypyridine-3-carboxylate (1.09 g) in N,N-dimethylacetamide (12 mL), 2,4-dimethoxybenzylamine (1.35 g) and potassium carbonate (2.24 g) were added at room temperature, and the mixture was stirred at 120° C. for 19 hours. The reaction solution was cooled to room temperature, then diluted with ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (Biotage Ltd., elution solvent: hexane/ethyl acetate) to obtain the title compound (1.16 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].[CH3:33][N:34]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41])=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][CH:45]=[C:37]([C:35]([N:34]([CH3:33])[CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)=[O:36])[CH:38]=3)=[C:3]([C:13]3[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=4)[CH:30]=[CH:31][N:32]=3)[CH:4]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ccc(OC2CCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A mixture of 26 mg of 2-(2-amino-5-cyclobutoxyphenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide, 21 mg of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid, 27 mg of HATU, and 63 μL of DIEA in 0.2 mL of DMF was stirred at 60° C. for 2 h. The product was isolated by reverse phase chromatography eluting with 0.05% TFA in a water/acetonitrile gradient. This procedure gave 24 mg of a yellow solid. 1H NMR (400 MHz, CD3OD, ppm): δ 9.46 (t, J=5.8 Hz, 1H), 8.85 (d, J=5.3 Hz, 1H), 8.26 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 8.05 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.85-7.80 (m, 1H), 7.80-7.47 (m, 6H), 7.31 (d, J=2.7 Hz, 1H), 7.00 (dd, J=8.9, 2.6 Hz, 1H), 4.83-4.71 (m, 1H), 4.67 (s, 2H), 4.09 (s, 2H), 3.96 (m, 2H), 3.77 (m, 4H), 3.52 (t, J=4.9 Hz, 2H), 3.24 (s, 2H), 3.07 (s, 3H), 2.59-2.39 (m, 2H), 2.25-2.04 (m, 2H), 1.93-1.60 (m, 2H). MS (ESI, m/z) 716.26 [M+H]+.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.Cl[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.O>CN(C)C=O>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)=[CH:14][CH:15]=1)#[N:18]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2cnc3ccccc32)cc1
Temperature: 130 °C

Procedure:
Sodium hydride (60% strength in mineral oil; 24.0 g, 0.60 mol) is placed in a flask and admixed with N,N-dimethylformamide (80 ml). A solution of benzimidazole (73.3 g, 0.60 mol) in N,N-dimethylformamide (250 ml) is added dropwise to the suspension over a period of 1 hour. After H2 evolution has ceased 4-chlorobenzonitrile (55.6 g, 0.40 mol) is added and the mixture is subsequently heated at 130° C. for 10.5 hours. After cooling to room temperature, the reaction mixture is poured into water (4 I) and the residue formed is filtered off with suction, washed with water and dried under reduced pressure. This gives 90.6 g of 1-(4-cyanophenyl)benzimidazole which still comprises mineral oil as contaminant.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:28]([O:30][C:31](=[O:37])[CH2:32][C@@H:33]([C:35]#[CH:36])[NH2:34])[CH3:29].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:28]([O:30][C:31](=[O:37])[CH2:32][C@@H:33]([C:35]#[CH:36])[NH:34][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])/[CH:15]=[CH:14]/[CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25])[CH3:29]
Reactant: C#C[C@@H](N)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C#C[C@H](CC(=O)OCC)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a mixture of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidinecarboxylic acid (1 g), 3(S)-ethynyl-β-alanine ethyl ester hydrochloride (0.48 g) and 1-hydroxybenzotriazole (0.37 g) in dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.5 ml) at 0° C. The reaction mixture was stirred overnight at room temperature, and then poured into water. The whole was extracted with ethyl acetate, washed with aqueous saturated NaHCO3, water, and brine, dried over MgSO4, and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with CHCl3-MeOH (99:1) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine ethyl ester as a pale yellow oil (1.34 g).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1.C(Cl)(Cl)Cl.[Cl-].[Na+]>C(O)(=O)C>[C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9]([N:14]3[CH:17]=[CH:21][CH:20]=[CH:19]3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c(N)cccc21
Reactant: COC1CCC(OC)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1CCc2c1cccc2-n1cccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.2 %

Procedure:
A stirred solution of 10.0 g (0.052 mole) of 4-amino-1-indanyl acetate (prepared as in Example 1, step F) and 7.5 g (0.056 mole) of 2,5-dimethoxytetrahydrofuran in 21.2 mL of acetic acid was heated under reflux for 3.5 hours. The reaction mixture was then allowed to cool to ambient temperature, and was stirred for 16 hours. The reaction mixture was poured into 200 mL of chloroform. An aqueous saturated solution of sodium chloride (200 mL) was added, and the mixture was stirred for 10 minutes. The aqueous layer was separated and washed with 50 mL of chloroform. The combined organic phases were washed with two portions of 50 mL each of an aqueous saturated solution of sodium chloride. The organic layer was dried over potassium carbonate, filtered, and the filtrate concentrated under reduced pressure to give 13.2 g of 4-(1-pyrrolyl)-1-indanyl acetate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS([O:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47]C[CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:45][CH2:44][N:43]4[CH2:42][CH2:41][O:40][CH2:47][CH2:48]4)[CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(O)c3)nn3ccnc23)n1
Reactant: CS(=O)(=O)OCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(OCCN4CCOCC4)c3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 40 %

Procedure:
To a mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, then dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica, EtOAc) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(2-morpholinoethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.65 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.59-7.54 (m, 3H), 7.45-7.40 (m, 2H), 7.04-7.02 (m, 2H), 6.22 (d, 1H, J=7.5 Hz), 6.04 (d, 1H, J=7.8 Hz), 4.25-4.20 (m, 3H), 3.79-3.76 (m, 4 h), 3.68 (brs, 1H), 3.51-3.48 (m, 1H), 2.87 (t, 2H, J=5.7 Hz), 2.64 (brs, 4 h), 2.14-2.06 (m, 3H), 1.78 (brs, 1H), 1.67-1.62 (m, 4 h), 1.50-1.48 (m, 2H), 1.25 (d, 3H, J=6.3 Hz). LC/MS: 500 [M+H]+, tR=1.13 min. HPLC: 95.85% at 214 nm, 95.41% at 254 nm, tR=5.12 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[CH3:26]I>C1COCC1>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CI
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(C(C)(C)C)cc1
Yield: 101 %

Procedure:
23.3 mL of lithium bis(trimethylsilyl)amide (1.0 M, 23 mmols) was added dropwise to 4.75 g (23 mmols) of methyl 4-tert-butylphenylacetate in 100 mL of dry THF at −78° C. while stirring under nitrogen. The mixture was stirred at this temperature for 45 minutes, then 1.5 mL (24 mmol) methyl iodide was added dropwise and the solution was stirred for an additional 1 hour at −78° C. The mixture was poured into 200 mL of H20 and the desired product was extracted with 500 mL diethyl ether. The organic layer was backwashed once with 500 mL H2O, dried over K2CO3, and concentrated under reduced pressure to yield 5.12 g of a dark oil. The oil was purified via silica gel chromatography eluting with a solvent gradient of hexane to hexane/ethyl acetate 19:1. The fractions containing the desired product were combined and concentrated under reduced pressure to yield the title compound 2.65 g (53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].CCOC(C)=O.[NH3:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH2:35])(=[O:27])=[O:26]
Reactant: N
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(S(N)(=O)=O)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Through a 0° C. solution of the product from Example 1, Step C (96 mg, 0.21 mmols) in 5 mL of CH2Cl2, ammonia gas was bubbled for 3 minutes. The reaction was sealed, stirred for 30 minutes, warmed to room temperature and stirred 20 minutes more. This was poured into EtOAc and washed with water and brine. The solution was dried over Na2SO4 and concentrated in vacuo to give the titled compound. ESI+MS: 443 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][O:23][C:24]1[C:25]2[C:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[CH:37]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)(=O)=O>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH2:22][O:23][C:24]2[C:25]3[C:30]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=4[CH:37]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)OCCOc1cc2ccccc2c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3c3ccccc23)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with 2-(9-phenanthrenyloxy)ethyl methanesulfonate (1.26 g). The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and the solids were filtered off, dissolved in dichloromethane, dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from dichloro-methane-diethyl ether provided 0.8 g of alpha-oxo-4-[[2-(9-phenanthrenyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a yellow solid, mp 147°-148° C.
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH:8]=[CH:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]([O:25][CH3:26])(=[O:24])[C:22]#[CH:23]>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:23][C:22]([C:21]([O:25][CH3:26])=[O:24])=[C:6]2[N:7]1[CH:8]=[CH:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=12
Reactant: C#CC(=O)OC
Reactant: Oc1c(-c2ccccc2)sc2c3sccc3cc[n+]12
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12
Reaction time: 1 h

Procedure:
(ca) 22.9 g of 3-hydroxy-2-phenylthiazolo[3,2-a]thieno-[2,3-c]pyridinium hydroxide (internal salt) and 13.6 ml of methyl propiolate were heated together under argon in 1000 ml of toluene until the starting material was completely taken up. The solvent was removed in vacuo and the residue was stirred in 500 ml of ether/methanol (9:1) for 1 hour. The yellow crystals obtained were removed by filtration under suction. There was obtained methyl 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate of m.p. 153°-154° (dec.). An additional portion of product of m.p. 151°-152° (dec.) can be obtained by chromatography of the filtrate on silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([N+]([O-])=O)[CH:11]=1>C(O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)[CH:15]=1
Reactant: Cc1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1cccc(Nc2cc(Cl)ccc2[N+](=O)[O-])c1
Reaction time: 72 h

Procedure:
81 ml of m-toluidine is added to a solution of 50 g of 1-chloro-3,4-dinitrobenzene in 250 ml of ethanol, and the solution was allowed to stand for 72 hours. The reaction mixture was filtered, and the crystallizate was washed with cold ethanol and 2N aqueous hydrochloric acid. It was purified by chromatography on silica gel.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[N:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][N:4]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)[N:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:17][C:18]1[N:19]=[C:20]([C:24]2[N:28]([CH2:2][C:3]3[C:8]([O:9][CH3:10])=[N:7][C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:5][N:4]=3)[CH:27]=[CH:26][N:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Reactant: COc1nc(-c2ccccc2)cnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2)cnc1Cn1ccnc1-c1cccc(F)n1
Temperature: 45 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A mixture of 2-chloromethyl-3-methoxy-5-phenyl-pyrazine (70 mg, 0.30 mmol), 2-fluoro-6-(1H-imidazol-2-yl)-pyridine (48 mg, 0.294 mmol) and K2CO3 (123 mg, 0.9 mmol) in DMF (5 mL) is stirred at 45° C. for 16 hours. On cooling, the reaction is quenched with saturated NH4Cl (2 mL) and extracted with DCM (3×10 mL). The combined organic layers are dried and solvent removed. PTLC separation (10% MeOH in DCM) gives 91 mg of 2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-3-methoxy-5-phenyl-pyrazine as an oil. 1H NMR (CDCl3) 8.41 (s, 1H), 8.08 (dd, 1H), 7.95–7.99 (m, 2H), 7.80 (dd, 1H), 7.42–7.49 (m, 3H), 7.22 (s, 1H), 7.15 (s, 1H), 6.77 (dd, 1H), 5.98 (s, 2H), 4.08 (s, 3H). B. 3-Methoxy-5-phenyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-pyrazine (Compound 2) 1. Synthesis of 2-(1H-imidazol-2-yl)-thiazole
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:20])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[C:24]([NH2:29])[N:23]=1.Cl.[OH-].[Na+]>O>[NH2:29][C:24]1[N:25]=[C:26]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:20])[CH:3]=2)[CH:27]=[C:22]([Cl:21])[N:23]=1
Reactant: N#Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(Cl)nc(N)n4)cc3F)c12

Procedure:
49.0 mg (0.18 mmol) of 4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 33.0 mg (0.20 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 5 ml of water. 0.12 ml (0.24 mmol) of 2N hydrochloric acid is added, and the mixture is heated at reflux overnight. Using concentrated aqueous sodium hydroxide solution, the mixture is made alkaline, and the product is purified by preparative HPLC.