Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:20]([N:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[C:17]4[C:21]([OH:23])=O)=[N:12]3)=[C:7]2[CH:6]=[CH:5][CH:4]=1.[C:24](N1C=CN=C1)([N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1)=O.CN(C)CCN>CN(C)C=O>[CH3:24][N:26]([CH3:27])[CH2:30][CH2:29][NH:28][C:21]([C:17]1[C:18]2[C:13](=[N:12][C:11]3[C:20]([N:19]=2)=[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]2=[CH:9][CH:10]=3)[CH:14]=[CH:15][CH:16]=1)=[O:23]
Reactant: COc1cccc2c1ccc1nc3cccc(C(=O)O)c3nc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: CN(C)C=O
Product: COc1cccc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
A mixture of 4-methoxy-benzo[a]phenazine-11-carboxylic acid (II.1) (129 mg) and 1,1′-carbonyldiimidazole (138 mg) was stirred in dry N,N-dimethylformamide (8 mL) at room temperature for 4 hours. To this mixture was added N,N-dimethylethylenediamine (commercially available)(0.5 mL) and the reaction mixture was stirred at room temperature for a further 30 minutes. The volatiles were then removed in vacuo. The residue was dissolved in dichloromethane, washed with water, dried (MgSO4) and the solvent removed in vacuo to provide crude product. This was purified using flash chromatography (5% methanol in dichloromethane) to yield the title compound as a bright yellow solid (120 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].[F-].[Cs+]>C(COC)OC.C(O)C>[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:12]2[CH:11]=[CH:10][C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:32][CH:31]=1)=[O:29]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc(C=O)cc2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (5 g, 12 mmol) was dissolved in dimethoxyethane (70 mL) and ethanol (7 mL). 4-Formylbenzeneboronic acid (2.0 g, 13 mmol) was added and argon was bubbled in the mixture, for 15 minutes. Cesium fluoride (4 g, 26 mmol) and tetrakistriphenylphosphine palladium (0.69 g, 0.6 mmol) were added and the mixture was brought to reflux under an argon atmosphere for 4 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate/water (100 mL/100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 9/1) to yield 3.42 g (76%) of the desired product as a yellow oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3ccc(F)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(F)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is dropped to a solution of 4.07 g of 4,5-bis(4-methoxyphenyl)-2-(4-fluorophenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus obtaining 3.86 g of 4,5-bis(4-methoxyphenyl)-2-(4-fluorophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=1[CH:10]([OH:11])[C:8](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)cc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1ccc(C)c(C(O)C(=O)c2ccccc2)c1

Procedure:
Phenylglyoxal monohydrate (500 mg, 3.29 mM) and p-xylene (0.56 ml, 4.79 mM) were dissolved in dichloroethane (5 ml), titanium tetrachloride (0.9 ml, 8.2 mM) was added, and reacted at room temperature for 30 minutes. Using the same procedure as in Example 1, 2',5'-dimethylbenzoin was obtained as crystal (587.7 mg, 73.9% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[O:15])[C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([Cl:35])[CH:34]=1.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:28][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)=[O:15])[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[N:6][CH:7]=2)[CH:32]=[C:33]([Cl:35])[CH:34]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(CNC(=O)c2cc(Cl)cnc2-c2cccnc2)cc1OC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C1CCC(CNCC2CCCCC2)CC1
Solvent: C1COCCO1
Product: COc1ccc(CNC(=O)c2cc(-c3cc(Cl)cc(Cl)c3)cnc2-c2cccnc2)cc1OC
Temperature: 110 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 5-chloro-2,3′-bipyridine-3-carboxylate (1-2, 0.500 g, 2.01 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added potassium hydroxide (0.200 g, 3.61 mmol) and water (1.25 mL) and the system was stirred at room temperature overnight. The reaction mixture was then neutralized with 6N HCl to a pH of 2.0 and then concentrated in vacuo to afford 5-chloro-2,3′-bipyridine-3-carboxylic acid as a bone powder in the form of a bis HCl salt. ESI+ MS [MH]+C11H7ClN2O2=234.9. To a solution of the bis HCl salt form of 5-chloro-2,3′-bipyridine-3-carboxylic acid (0.613 g, 2.00 mmol) and 3,4-dimethoxybenzylamine (0.367 g, 2.2 mmol) in dimethylformamide (10 mL) was added EDC (0.764 g, 4.00 mmol), HOBt (0.612 g, 4.00 mmol) and triethylamine (0.6 mL, 10 mmol) and the system was stirred in an oil bath at 100° C. for 3 h. The system was cooled to room temperature, extracted with EtOAc, washed with water and dried over magnesium sulfate. The crude reaction mixture was then tritirated with ether to afford 5-chloro-N-(3,4-dimethoxybenzyl)-2,3′-bipyridine-3-carboxamide as a bone powder. ESI+ MS [MH]+ C20H18ClN3O3=234.9. To a solution of 5-chloro-N-(3,4-dimethoxybenzyl)-2,3′-bipyridine-3-carboxamide (0.600 g, 1.56 mmol) in dioxane (5.2 mL) was added 3,5-dichlorophenyl boronic acid (1.50 g, 7.82 mmol), N,N-dicylohexylmethylamine (0.368 mL, 1.72 mmol), and bis(tri-t-butylphosphine)palladium (0.023 g, 0.047 mmol) and the system was stirred at 110° C. for 20 minutes in the microwave. The reaction was then cooled to room temperature, and partitioned between ethyl acetate and water. The reaction mixture was filtered and purified via normal phase chromatography (0→6% MeOH in DCM) followed by reverse phase chromatography (10%→65% 0.1% TFA in water: 0.1% TFA in ACN) followed by free basing with saturated sodium carbonate afforded the title compound (2-1) as a white powder. 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.95 (s, 1H), 8.66-8.68 (m, 1H), 8.15 (s, 1H), 7.98-8.00 (m, 1H), 7.53-7.54 (m, 2H), 7.46-7.47 (m, 1H), 7.28-7.30 (m, 1H), 6.77 (d, J=5 Hz, 1H), 6.39-6.66 (m, 2H), 5.69 (br s, 1H), 4.42 (d, J=5.5 Hz, 2H), 3.85 (s, 3H), 3.88 (s, 3H). HRMS [M+H] C26H21Cl2N3O3 calc'd 494.1033, found 494.1023.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[C@@H:18]([CH2:24][OH:25])[C@@H:17]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[C:35]([O:23][CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([O:15][C@@H:13]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=2)[CH3:14])[C@@H:17]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C@@H:18]1[CH2:24][OH:25])(=[O:37])[CH3:36]
Reactant: C[C@@H](O[C@H]1CC[C@H](CO)[C@@H](CO)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)[C@@H]1CO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of [(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]dimethanol (3.3 g, 6.7 mmol, intermediate step J) in dichloromethane (50 mL) were added acetyl chloride (0.52 mL, 7.4 mmol) and TEA (1.1 mL, 7.9 mmol) at room temperature. The resulting mixture was stirred at r.t. for 6 hr. The solvent was removed under vacuum and the residue was separated by column chromatography on silica gel eluting with 3:1 hexane:ethyl acetate. The less polar mono-alcohol on TLC was collected (0.75 g). MS: (MH)+ 536.2.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:25])(=[O:24])=[O:23])=[CH:11][CH:10]=1)C1C=CC=CC=1.B(F)(F)F.CCOCC>C(S)(S)C.C(OCC)C.O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:25])(=[O:24])=[O:23])=[CH:13][CH:14]=1
Reactant: O=S(=O)(F)CCCCCCCc1ccc(OCc2ccccc2)cc1
Agent: CC(S)S
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: O=S(=O)(F)CCCCCCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 13.1 (0.182 g, 0.5 mmol) in ethanedithiol (10 mL), at room temperature, under an argon atmosphere was added BF3.Et2O (0.282 g, 2.0 mmol). The reaction mixture was stirred at room temperature for 1 hour and then diluted with diethyl ether (20 mL) and water (10 mL). The organic layer was separated and the aqueous phase extracted with diethyl ether. The combined organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue obtained was chromatographed through a column of silica gel eluting with 50% diethyl ether-hexane to give 14.1 (0.096 g, 70% yield) as a white solid (m p 47-51° C.).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:38]=[S:39]1(=[O:50])[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:47]3[CH2:48][CH2:49][N:44]([CH:41]4[CH2:42][CH2:43][S:39](=[O:50])(=[O:38])[CH2:40]4)[CH2:45][CH2:46]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCC(N2CCNCC2)C1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)C2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-piperazine to give the title compound as a mixture of diastereomers.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][SH:6].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>CN(C=O)C.CCOCC>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1
Reactant: OCCCCS
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(SCCCCO)cc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-hydroxybutanethiol (5.0 g, 47 mmol) in DMF (100 mL) was added NaH (60% dispersion in mineral oil, 2.1 g). After the effervescence had ceased, p-chloroacetophenone (4.3 mL, 33 mmol) was added. The solution was then stirred at 110° C. for 3 h. The mixture was cooled to RT and then diluted with ether (200 mL). The ethereal suspension was washed with 5% HCl (aq, 2×100 mL), water (100 mL), and then brine (50 mL). The ether extract was dried (MgSO4), filtered and concentrated to afford crude 1-[4-(4-hydroxybutylsulfanyl)phenyl]ethanone, which was used without purification. 1-[4-(4-hydroxybutylsulfanyl)phenyl]ethanone was taken up in dimethylformamide dimethylacetal (100 mL) and stirred at reflux for 12 h. The mixture was cooled and then concentrated to about one half of the original volume. Hexane was added to precipitate 3-Dimethylamino-1-[4-(4-hydroxybutylsulfanyl)phenyl]propenone. The mixture was filtered, washed with hexanes (50 mL), and dried to afford 3-Dimethylamino-1-[4-(4-hydroxy-butylsulfanyl)phenyl]propenone (6.4 g, 23 mmol). HPLC Retention Time; 5.58 min. (Method B) M+1; 279.8.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH3:32][O:33][CH2:34][C:35]1[N:39]=[C:38]([CH2:40][NH2:41])[O:37][N:36]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:41][CH2:40][C:38]1[O:37][N:36]=[C:35]([CH2:34][O:33][CH3:32])[N:39]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: COCc1noc(CN)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCc1noc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)n1
Reaction time: 1 h
Yield: 37 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), (3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)methanamine (9.96 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were dissolved in DMF (1 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-((3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (9.7 mg, 0.017 mmol, 37.6% yield): LCMS=557.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.53 Hz), 7.50-7.76 (8 H, m), 5.21 (1 H, s), 4.69 (2 H, d, J=7.53 Hz), 4.54 (2 H, s), 3.43 (3 H, s); HPLC peak RT=2.7 min (Method E).
Reaction SMILES: [C:1](=[O:14])(OC1C=CC=CC=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22].C(Cl)Cl>CCO>[C:3]([O:2][C:1]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:14])([CH3:4])([CH3:5])[CH3:6]
Reactant: NCCCCCCN
Reactant: CC(C)(C)OC(=O)Oc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCCN
Temperature: 78 °C

Procedure:
tert-Butyl phenyl carbonate (25.60 mL, 138.0 mmoles) was added to a stirred solution of 1,6-diaminohexane (15.30 g, 131.7 mmoles) in absolute EtOH (150 mL) in a 250 mL RB flask. The apparatus was fitted with a condenser and heated to 78° C. overnight under a blanket of nitrogen and then allowed to cool to room temperature. The solvent was stripped off the reaction mixture in vacuo (rotary evaporator) yielding a pale pink oily residue. CH2Cl2 (200 mL) was added to the residue and the resultant solution extracted with 3×200 mL portions of de-ionised water. For each extraction the pH of the aqueous phase was monitored and adjusted with HCl (aq, 2M) such that the pH of the aqueous layer was 3<pH<7 [only required for 1st extraction, needing ca. 60-70 mL HCl (aq, 2M)]. The aqueous phases were collected in a Erlenmeyer flask containing aqueous NaOH (aq, 100 mL, 3M). Ensuring that the pH of the collected aqueous extracts was ≧14 the resulting aqueous phase was extracted with CH2Cl2 (3×150 mL). These organic phases were recombined, evaporated to a volume of ca. 200 mL and subjected to the above pH modulated purification protocol for a second time by first extracting with water [3×200 mL, 3<pH<7 modulation with HCl (aq, 2M), again only required for 1st extract needing ca. 45-55 mL HCl (aq, 2M)], basicifying these aqueous extracts with NaOH (100 mL, 3M) and extracting with CH2Cl2 (3×150 mL). The CH2Cl2 extracts were combined, reduced in volume to 200 mL and then dried over anhydrous MgSO4, filtered, and stripped to dryness on a rotary evaporator for a period of 20 minutes to yield 6-(tert-butoxycarbonylamino)hexylamine as a peach oil. This peach oil was then subjected to a short path distillation using a Kugelrohr apparatus with an oven temperature of 180° C. and at a vacuum pressure of 0.160 torr, the receiver bulb was cooled by means of a dry-ice/acetone bath. Yield: 13.1 g (46%, colourless oil). 1H NMR (CDCl3) δ 1.14 (s, 2H, —NH2), 1.26-1.37 (m, 4H, —CH2—), 1.37-1.52 (s+m, 9H+4H, t-Bu+—CH2—), 2.67 (t, 2H, >NCH2—), 3.09 (q, 2H, —C(═O)NCH2—), 4.60 (bs, 1H, —C(═O)NH—).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[O:16][CH2:17][CH2:18][NH2:19].CO>C(Cl)Cl>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:19][CH2:18][CH2:17][O:16][C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=3[O:13][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: COc1ccccc1OCCN
Solvent: CO
Solvent: ClCCl
Product: COc1ccccc1OCCNc1ccc2ncc(Br)n2n1
Temperature: 160 °C
Yield: 44.1 %

Procedure:
A mixture of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine (232 mg, 1 mmol) and 2-(2-methoxy-phenoxy)-ethylamine (2 g, 12 mmol) was heated in a microwave at 160° C. for 30 min. The reaction mixture was subjected to ISCO (40 g column, DCM 3 min. then 0-10% MeOH in DCM over 30 min.) to gave the product (160 mg). LRMS (ESI) m/z 363 and 365.1 [(M+H)]+, calc'd for C15H15BrN4O2: 363.22.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][C@@H:13]([C:17]([NH2:19])=[O:18])[CH:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>C(C#N)(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([CH:14]([CH3:16])[CH3:15])[C:17]([NH2:19])=[O:18])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(Cl)nc1Cl
Reactant: CC(C)[C@@H](N)C(N)=O
Agent: CC(=O)C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.7 %

Procedure:
To a mixture of 3,5-dichloropyrazine-2-carbonitrile (500 mg, 2.84 mmol) and D-valinamide HCl salt (476 mg, 3.12 mmol) in AcCN (10 mL) was added DIPEA (1.11 mL, 6.25 mmol). After stirring at room temperature for 4 h, it was diluted with EtOAc, washed with sat. NaHCO3, organic layer was separated and washed with brine, dried and concentrated to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-methylbutanamide (740 mg). Step 2: To a mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-methylbutanamide (100 mg, 0.394 mmol) in Dioxane (2 mL) was added 3-aminoquinoline (71 mg, 0.492 mmol), Pd(OAc)2 (18 mg, 0.079 mmol), BINAP (49 mg, 0.079 mmol) and K2CO3 (163 mg, 1.18 mmol). After heating at 95° C. for 5 h, the mixture was filtered, the filtrate was concentrated and purified by preparative HPLC to give (R)-2-(5-cyano-6-(quinolin-3-yl)pyrazin-2-ylamino)-3-methylbutanamide (113 mg).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:19]=[N:20][C:21]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:22][CH:23]=2)[C:14]([NH2:17])=[N:15][CH:16]=1>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:19]=[N:20][C:21]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:22][CH:23]=2)[C:14]2[N:15]([CH:16]=1)[CH2:4][CH2:5][S:6](=[O:8])(=[O:7])[N:17]=2
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncc(Cl)cc1-c1ccc(OC2CCCCC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(OC4CCCCC4)nc3)C2=N1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 553 mg) in THF (dry) (30 mL) was added 2-chloroethanesulfonyl chloride (0.582 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 5-chloro-6′-(cyclohexyloxy)-3,3′-bipyridin-2-amine (840 mg) in THF (dry) (30 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. carefully. EtOAc and THF were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane). The residue was crystallized from THF/IPE to give the title compound (336 mg) as colorless crystals.
Reaction SMILES: C(OC(C1C(N)=C(NC2C=CC=CC=2OC)N=C(N[C@H]2CCN(C(OC(C)(C)C)=O)C2)[N:7]=1)=O)C.C(OC([N:42]1[CH2:46][CH2:45][C@H:44]([NH:47][C:48]2[N:56]=[C:55]3[C:51]([NH:52][C:53](=[O:65])[N:54]3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[O:63][CH3:64])=[C:50]([C:66]([O:68]CC)=O)[N:49]=2)[CH2:43]1)=O)(C)(C)C>ClCCl>[CH3:64][O:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[N:54]1[C:53](=[O:65])[NH:52][C:51]2[C:55]1=[N:56][C:48]([NH:47][C@H:44]1[CH2:45][CH2:46][NH:42][CH2:43]1)=[N:49][C:50]=2[C:66]([NH2:7])=[O:68]
Reactant: CCOC(=O)c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CCNC3)nc21
Yield: 132.1 %

Procedure:
(S)-Ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (S)-Ethyl 5-amino-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.357 g, 0.756 mmol) and carbonyldiimidiazole (1.22 g, 7.56 mmol) in dichloromethane (20 mL) were reacted according to general procedure F and purified using biotage chromatography (0-100% ethyl acetate in hexanes) to afford a mixture of the title product (0.369 g, 98%). MS (ESI) m/z 499.5 [M+1]+.