Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)(=[O:8])=[O:7].[NH2:16][C:17]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[CH3:18].CCN(CC)CC>CC#N>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([C:17]([NH:16][CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)(=[O:8])=[O:7])([C:19]2[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=2)[CH3:18])=[CH:26][C:27]=1[F:33])#[N:30]
Reactant: O=S(=O)(NCCCBr)c1cccc(O)c1
Reactant: Cn1cncc1C(C)(N)c1ccc(C#N)c(F)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1cncc1C(C)(NCCCNS(=O)(=O)c1cccc(O)c1)c1ccc(C#N)c(F)c1

Procedure:
N-(3-Bromo-propyl)-3-hydroxy-benzenesulfonamide (0.23 g, 0.782 mmol), (+)-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-fluoro-benzonitrile (Example 1, Step I) (0.191 g, 0.78 mmol), and Et3N (0.218 mL, 1.56 mmol) were dissolved in CH3CN (5 mL) and heated at reflux for 16 h. The reaction mixture was concentrated in vacuo, azeotroped with toluene, and dried to give the title compound. MS (M+1) 458.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:23]([O-])=O)=[N:11][CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.ClCCl.[Zn]>[CH2:1]([O:8][C:9]1[C:10]([NH2:23])=[N:11][CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 98.5 %

Procedure:
Zinc (1.34 g, 20.5 mmol) was added slowly to a solution of 3-(benzyloxy)-5-(2-chlorophenoxy)-2-nitropyridine (0.730 g, 2.05 mmol) in acetic acid (20 mL) in a water bath. The reaction mixture was stirred 2 hours, then diluted with dichloromethane (100 mL) and filtered through Celite. The pad was washed several times with dichloromethane, and the combined filtrates were concentrated. The residue was partitioned between ethyl acetate and 2N NaOH, and the organic layer was washed with brine, dried, and concentrated to afford 3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-amine (0.66 g, 98.7% yield) as a light yellow oil. 1H NMR (CDCl3) δ 4.85 (bs, 2H), 5.03 (s, 2H), 6.79-6.83 (m, 2H), 7.02 (t, 1H), 7.14 (t, 1H), 7.37-7.47 (m, 7H).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([O:39][C:40]([F:43])([F:42])[F:41])=[C:34](B(O)O)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([O:39][C:40]([F:41])([F:42])[F:43])=[C:34]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[CH:25][CH:26]=3)=[O:12])[C:4](=[O:28])[CH:3]=2)[CH:35]=1
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1Br
Reactant: OB(O)c1cc(Cl)ccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)(F)F
Reaction time: 8 h

Procedure:
Under argon (in a flask dried by heating), 125 mg (0.28 mmol) of tert-butyl 4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate), 80 mg (0.33 mmol, 1.2 eq.) of 5-chloro-2-trifluoromethoxyphenylboronic acid, 115 mg (0.83 mmol, 3.0 eq.) of potassium carbonate and 23 mg (0.03 mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxane and stirred overnight in an oil bath already preheated to 110° C. The reaction mixture was filtered through Celite and the residue was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The residue was triturated with water, filtered off, washed with water and dried under reduced pressure. Yield: 155 mg (purity 83%, 82% of theory)
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:24](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.CO>CC(C)=O>[CH3:24][O:22][C:21]([C:19]1[O:20][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1)=[O:23]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Solvent: CO
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)o1

Procedure:
A mixture of 10.0 g of (0.031 mole) of 5-tetradecyloxy-2-furoic acid, 200 ml of acetone and 4.3 g (0.031 mole) of potassium carbonate is stirred at room temperature after which 3.9 g (0.031 mole) of dimethylsulfate is added. The mixture is stirred with heating for about two and one-half hours during which time 10 ml of methanol is added. The mixture is then diluted with 100 ml of acetone, and filtered. The filtrate is evaporated to dryness and recrystallized from methanol to give 5-tetradecyloxy-2-furoic acid methyl ester, M.P. 56°-58° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([O:8]C(C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:4][N:3]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].[OH-].[Na+].O>C1COCC1.CO>[OH:8][C@H:5]1[CH2:4][N:3]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C@H:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: C[C@@H]1CC[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@H](O)CN1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of benzyl (2R,5R)-2-methyl-5-{[(4-nitrophenyl)carbonyl]oxy}piperidine-1-carboxylate (54.3 g, 136 mmol) in THF (850 mL) and MeOH (138 mL) was added 1 N NaOH (204 mL) and water (30 mL). The solution was stirred overnight, then concentrated in vacuo. The residue was diluted with minimal brine and water and extracted twice with EtOAc. The organics were washed with brine, dried over MgSO4, filtered, and concentrated to give the titled compound as a crude, orange-yellow oil which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.28-7.36 (m, 5H), 5.14 (d, J=3.5 Hz, 2H), 4.50 (t, J=6.8 Hz), 1H), 4.09 (d, J=8.8 Hz, 1H), 3.94 (s, 1H), 3.09 (dd, J=14.3, 1.9 Hz, 1H), 2.06-2.15 (m, 1H), 1.96 (br s, 1H), 1.75-1.83 (m, 1H), 1.66-1.72 (m, 1H), 1.24-1.32 (m, 2H), 1.16 (d, J=7.0 Hz, 2H) ppm. LRMS m/z (M+H) 250.1 found, 250.1 required.
Reaction SMILES: [CH:1]([Si:4]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([C:16]([O:18]CC)=[O:17])=[CH:14][N:15]=2)[CH:12]=1)([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO.O>[CH:24]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:21]([CH3:23])[CH3:22])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=2)[CH:12]=1)([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1cnc2ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc2ncc(C(=O)O)n2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude ethyl 6-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (60) obtained above was dissolved in THF/MeOH/H2O (3:2:1, 5 mL). 6N LiOH (2.27 mL, 13.6 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. All solvents were removed and 6N HCl was added until pH 5-6. EtOAc (5 mL) was added and the mixture was stirred for 1 hour. The precipitate was filtered and dried to give 6-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid (61). 1H NMR (400 MHz, d6-DMSO) δ 9.37 (s, 1H), 8.21 (s, 1H), 7.76 (dd, J=1.2, 9.2 Hz, 1H), 7.46 (dd, J=2.0, 9.2 Hz, 1H), 4.94 (s, 2H), 1.20 (m, 3H), 1.08 (d, J=6.8 Hz, 18H). MS m/z 349.2 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=[O:31])[NH:16][CH:17]([C:25]2[S:26][CH:27]=[C:28](Br)[CH:29]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])[NH2:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=[O:31])[NH:16][CH:17]([C:25]2[S:26][CH:27]=[C:28]([C:39]3[CH:40]=[CH:41][C:36]([C:33](=[O:35])[NH2:34])=[CH:37][CH:38]=3)[CH:29]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(Cc2ccccc2)c2cc(Br)cs2)CC1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(Cc2ccccc2)c2cc(-c3ccc(C(N)=O)cc3)cs2)CC1
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1B (522 mg, 1.0 mmol) and 4-carbamoylphenylboronic acid (248 mg, 1.5 mmol) was dissolved in DMF (15 mL). Under N2, potassium phosphate (530 mg, 2.5 mmol) and bis(tri-t-butylphosphine) palladium (25 mg, 5 mol %) were added to the mixture. The resulting mixture was stirred at 85° C. for 2.5 h. The reaction mixture was cooled to rt, filtered and concentrated. Reverse-phase HPLC purification afforded IC as a light yellow solid. LC/MS m/z 561.2 (M+H)+. 1H NMR (400 MHz, CD3OD) δ: 0.91-0.95 (m, 2H), 1.29-1.42 (m, 4H), 1.55-1.63, (m, 1H), 1.75-1.78 (m, 2H), 1.98-2.09 (m, 1H), 2.85 (d, J=7.9 Hz, 2H), 3.30-3.33 (m, 2H), 5.45-5.48 (m, 1H), 7.19-7.20 (m, 1H), 7.25, (s, 4H), 7.35 (s, 1H), 7.61 (s, 1H), 7.69 (d, J=7.6 Hz, 2H), 7.87 (d, J=7.6 Hz, 2H), 7.97 (s, 1H), 8.41 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][Cl:24]>CN(C)C=O>[Cl:24][CH2:23][CH2:22][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1
Reactant: ClCCBr
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(CCCl)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-methoxyphenyl)piperazine was dissolved in N,N-dimethylformamide, and potassium carbonate and 1-bromo-2-chloroethane were added. The resulting mixture was stirred at room temperature overnight, the solid material filtered off, and the solvent removed from the filtrate under reduced pressure. The residue was purified by biotage chromatography eluting with 3:7 ethyl acetate:hexanes, to provide 1-[4-(2-chloroethyl)piperazinyl]-4-methoxybenzene.
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.O=S(Cl)[Cl:17].CN(C=O)C>>[Cl:17][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1ccc2nc(S)oc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(Cl)oc2c1

Procedure:
To Compound 4 (2 g, 9.5 mmol), SOCl2 (9.8 ml, 134 mmol) and DMF (0.8 mL, 10 mmol) was added at room temperature. The reaction mixture heated to reflux for 15 min. The solvent was removed under reduced pressure. The crude oil was azeotroped with xylene twice.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].Cl.[OH:8][CH:9]([CH2:15][C:16](=[O:18])[O-:17])[CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12].C(OCC)C>FC(F)(F)C(O)=O>[C:1]([C:9]([CH2:15][C:16](=[O:17])[O-:18])([CH2:10][N+:11]([CH3:12])([CH3:13])[CH3:14])[OH:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: C/C=C/C(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: C/C=C/C(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
8 cc (0.08 moles) of crotonyl chloride were added to a solution of carnitine hydrochloride (8 grams; 0.04 moles) in trifluoroacetic acid. The reaction mixture was kept under stirring at 50° C. overnight. Subsequently, ethyl ether was added to the mixture and a precipitate formed. The precipitate was filtered off and used as such in the subsequent reaction.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[N:3]=1.[NH2:22][C:23]1[S:24][C:25]([CH3:28])=[CH:26][N:27]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:28][C:25]1[S:24][C:23]([NH:22][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])=[CH:12][CH:11]=3)[N:3]=2)=[N:27][CH:26]=1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)C1CC1
Reactant: Cc1cnc(N)s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cnc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CC4)cc3)n2)s1
Temperature: 100 °C
Yield: 70.3 %

Procedure:
A suspension of N-(4-(4,6-dichloropyrimidin-2-ylthio)phenyl)cyclopropane-carboxamide (5.0 g, 14.7 mmol), amino-5-methylthiazole (1.85 g, 16.2 mmol), tris(dibenzylideneacetone)dipalladium (0.673 g, 0.74 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene (0.636 g, 1.10 mmol) and sodium carbonate (2.18 g, 20.58 mmol) in dioxane (120 ml) was heated at 100° C. for 2 h. The reaction mixture was then allowed to cool to room temperature before the tan precipitate was collected by filtration, washed with ethyl acetate (50 ml) water (3×30 ml) and then diethyl ether (50 ml) and dried to give title compound as a tan solid (4.32 g, 70%). 1H NMR (DMSO) 0.81 (4H, d), 1.83 (1H, m), 2.09 (3H, s), 6.35 (1H, br s), 6.88 (1H, s), 7.53 (2H, d), 7.74 (2H, d), 10.48 (1H, s). MS(ES+): 418.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.O.[Pd]>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=[O:19])=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cccc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 70 °C

Procedure:
The Suzuki coupling was carried out according to the method of Dyer et al. (2001) Tetrahedron Letters 42: 1765-1767. Commercially available 4-(trifluoromethyl)phenylboronic acid (15 g, 78.7 mmol) and 3-bromobenzoic acid (15.1 g, 75 mmol) were suspended in 2-propanol:water (1:4, 72 mL). 10% Pd/C (1.5 g) was added and then aqueous Na2CO3 (39 mL, 20% by weight) was added. The resulting mixture was heated at 70° C. for 4 hours. The precipitate was filtered and rinsed with a 20% aqueous Na2CO3 solution. The filtrate was diluted with water and acidified to a pH of 2. The white solid was filtered and dried in vacuo. The crude material (2.1) (19.69 g) was used in the next step without further purification
Reaction SMILES: [CH2:1]([N:19]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:20](=[O:45])[CH2:21][CH2:22][CH:23]([CH:25]1[C:41]2([CH3:42])[CH:28]([CH:29]3[CH:38]([CH2:39][CH2:40]2)[C:37]2([CH3:43])[CH:32]([CH2:33][CH:34]([OH:44])[CH2:35][CH2:36]2)[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:64](=O)([O:73]N1C(=O)CCC1=O)[O:65][N:66]1[C:70](=[O:71])[CH2:69][CH2:68][C:67]1=[O:72].C(N(CC)CC)C.C(#N)C>ClCCl>[O:72]=[C:67]1[CH2:68][CH2:69][C:70](=[O:71])[N:66]1[O:65][C:64](=[O:73])[O:44][CH:34]1[CH2:33][CH:32]2[C:37]([CH3:43])([CH:38]3[CH:29]([CH2:30][CH2:31]2)[CH:28]2[C:41]([CH3:42])([CH:25]([CH:23]([CH3:24])[CH2:22][CH2:21][C:20](=[O:45])[N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:26][CH2:27]2)[CH2:40][CH2:39]3)[CH2:36][CH2:35]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(OC(=O)ON5C(=O)CCC5=O)CCC4(C)C3CCC12C
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.4 %

Procedure:
Referring to scheme 20, amide 82 (15.5 g, 17.6 mmol) was dissolved in anhydrous dichloromethane (150 mL). To the solution were added disuccinimidyl carbonate (6.76 g, 26.4 mmol), triethylamine (10 mL) and acetonitrile (50 mL). The reaction mixture was stirred at room temperature under argon for 6 h and then evaporated dryness. The residue was dissolved in dichloromethane (300 mL). It was washed with saturated NaHCO3 aqueous solution (3×100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Compound 83 (12.3 g, 71%) was obtained as colorless powder after drying in high vacuum, which was directly used for the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][CH:4]=1)=[O:2].CN(C=O)C.[H-].[Na+].[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:36][CH2:37]I)[C:32]([O:34][CH3:35])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C>[C:11]([O:10][C:9]([N:8]([C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)[CH2:37][CH2:36][C@H:31]([NH:30][C:28]([O:27][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:29])[C:32]([O:34][CH3:35])=[O:33])=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: COC(=O)[C@H](CCI)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ncc(C=O)s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCN(C(=O)OC(C)(C)C)c1ncc(C=O)s1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
To a dry 2-5 mL microwave vial under N2 is added tert-butyl (5-formylthiazol-2-yl)carbamate (100 mg, 0.438 mmol) and anhydrous DMF (2.5 mL). The resulting dark solution stirred at room temp for 5 min, treated with sodium hydride (22.13 mg, 0.876 mmol), flushed with N2 for 15 min, then treated with material from Example 115 (301 mg, 0.876 mmol) and securely capped. The resulting dark solution is stirred at room temp for 30 min, then heated in a microwave heating unit for 15 min at 80° C. under high power. The reaction is diluted with ethyl acetate (200 mL), washed with water (6×25 mL), brine (1×25 mL), dried over Na2SO4, filtered, the solvent removed in vacuo and the resulting residue purified by BIOTAGE® Silica gel chromatography on a 25 g Thompson Single Step silica cartridge using 100% CH2Cl2 to 75% EtOAc/CH2Cl2 over 11 column volumes to give 176.7 mg (91%) of the title compound as a thick oil, LC/MS (Condition A): ret. T=3.83 min, (M+Na) 466.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]3[CH2:17][CH2:16][NH:15][CH2:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:25][C:24]1[C:19]([N:15]2[CH2:16][CH2:17][C:9]3[C:8]([NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:14]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccnc1Cl
Reactant: c1ccc(Nc2ncnc3c2CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: Clc1cccnc1N1CCc2c(ncnc2Nc2ccccc2)C1
Temperature: 150 °C
Yield: 25.6 %

Procedure:
5,6,7,8-Tetrahydro-N-phenylpyrido[3,4-d]pyrimidin-4-amine (500 mg, 2.2 mmol) was dissoled in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added 2,3-dichloropyridine (423 mg, 2.86 mmol) and N,N-diisopropylethylamine (0.38 mL, 2.2 mmol). The mixture was heated at 150° C. in a microwave (Emrys Optimizer model, Personal Chemistry) for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (190 mg, 27%).
Reaction SMILES: Cl[CH2:2][C:3]([OH:16])([CH2:14][OH:15])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH:17]12[CH2:25][CH:21]([CH2:22][NH:23][CH2:24]1)[CH2:20][N:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18]2.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:29]([O:28][C:26]([N:19]1[CH2:18][CH:17]2[CH2:25][CH:21]([CH2:22][N:23]([CH2:2][C:3]([OH:16])([CH2:14][OH:15])[CH2:4][O:5][C:6]3[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=3)[CH2:24]2)[CH2:20]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Reactant: N#Cc1ccc(OCC(O)(CO)CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)(CO)COc3ccc(C#N)cc3)C2)C1
Yield: 31 %

Procedure:
A mixture of 4-(3-chloro-2-hydroxy-2-hydroxymethylpropoxy)benzonitrile (180 mg; 0.74 mmol; from step (b) above), tert-butyl 3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate (230 mg; 1.0 mmol; see Example F above) and K2CO3 (140 mg; 1.0 mmol) in MeCN (5 mL) was refluxed for 48 hours. The reaction mixture was filtered and the filtrate concentrated. The residue was dissolved in diethyl ether and the solution was acidified with KHSO4 (aq.). The aqueous layer was collected and NaHCO3 (satd.) was added followed by ether extraction. The organic layer was collected, dried, concentrated and subjected to column chromatography (DCM:MeOH; 20:1) to give the title compound in a 31% yield.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:10])[CH:8]=O.C([O:13][CH:14](OCC)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)C.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[O:16][C:15](=[CH:8][N:7]([CH3:10])[CH3:6])[CH:14]=[O:13]
Reactant: CN(C)C=O
Reactant: CCOC(COc1ccc(Cl)c(Cl)c1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN(C)C=C(C=O)Oc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 51.7 %

Procedure:
Phosphorus oxychloride (18.4 g, 120 mmol) was added to dimethylformamide (8.8 g, 120 mmol), maintaining the temperature below 25° C. by an external ice-bath. Upon completion of the addition the reaction mixture was heated to 50° C. for 45 minutes and then cooled to room temperature. Chloroform (35 ml) was added and the resulting solution was brought to reflux. 3,4-Dichlorophenoxyacetaldehyde diethylacetal (9.61 g, 40.0 mmol) was added in portions. After heating for 3 hours at reflux the solution was cooled to room temperature and poured carefully onto a solution of potassium carbonate (115 g) in water (100 ml). The mixture was cooled in an ice-bath to around room temperature and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo yielding a brown oil, which was purified by flash column chromatography (SiO2, ethyl acetate) yielding the title compound (5.38 g, 52% yield) as a brown solid.