Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:13]=[C:12]([NH:14]C(=O)C(C)C)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:20]2[CH2:24][C@H:23]([CH2:25][OH:26])[CH:22]=[CH:21]2)[CH2:3][CH2:2]1.[OH-].[Na+].COC(C)(C)C>C(O)(C)C>[CH:8]1[N:9]([C@H:20]2[CH:21]=[CH:22][C@@H:23]([CH2:25][OH:26])[CH2:24]2)[C:10]2[N:11]=[C:12]([NH2:14])[N:13]=[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)[C:6]=2[N:7]=1
Reactant: CC(C)C(=O)Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 22.5 °C
Yield: 77.3 %

Procedure:
N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide (1.0 g, 2.80 mmol) was slurried in a mixture of isopropanol (2 ml) and 10% solution of NaOH (1.1 ml, 2.80 mmol). The mixture was refluxed for 1 h. The resulting solution was cooled to 20-25° C. and tert-butyl methyl ether (2 ml) was added. The aqueous layer was discarded, the organic phase was cooled to 0-5° C. and the resulting slurry filtered off. The solid was dried under vacuum at 40° C. Abacavir (0.62 g, 77%) was obtained as a white powder.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].C(O)C.Cl[C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:24]2[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=2)[N:16]=1
Reactant: COc1ccnc(Cl)n1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccnc(-c2ccc(C=O)cc2)n1
Yield: 41.9 %

Procedure:
1 M aq. Na2CO3 (20 mL) and ethanol (10 mL) were added to a solution of 2-chloro-4-methoxypyrimidine (2.90 g, 20.06 mmol, prepared as described in Tetrahedron 1997, 53, 11595), 4-formylphenylboronic acid (3.90 g, 26.01 mmol) and [1,4-bis(diphenylphosphino)butane]palladium(II) dichloride (0.60 g, 0.99 mmol) in toluene (40 mL) and the mixture was heated to reflux for 18 h. The cooled reaction mixture was diluted with ethyl acetate, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 1.80 g (42%) of the title compound. MS 215 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][C@H:32]([C:36](O)=[O:37])[CH:33]([CH3:35])[CH3:34])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1.C[Si](C)(C)[O:41][NH2:42].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[OH:41][NH:42][C:36]([CH:32]([NH:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][NH:14][C:12]([C:4]3[NH:3][C:2](=[O:1])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)=[O:13])[CH:17]=2)=[CH:23][CH:24]=1)(=[O:29])=[O:30])[CH:33]([CH3:34])[CH3:35])=[O:37]
Reactant: C[Si](C)(C)ON
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
A suspension of N-{[3′-({[(4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl]amino}methyl)biphenyl-4-yl]sulfonyl}valine obtained in Example 77 (0.080 g, 0.150 mmol), O-(trimethylsilyl)hydroxylamine (0.055 mL, 0.449 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (0.086 g, 0.449 mmol) and 1-hydroxybenzotriazole (0.061 g, 0.449 mmol) in DMF (5 mL) was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate, and washed successively with 0.05N hydrochloric acid, aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol-diethyl ether to give the title compound as a white powder (0.058 g, 71%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:16])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 4-(1-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (18.24 g, 79.54 mmol) in dichloromethane (400 mL) and triethylamine (12.20 mL, 87.49 mmol) at 0° C. is added methanesulfonyl chloride (9.23 mL, 119.30 mmol). The reaction is allowed to warm to room temperature over 16 h. The mixture is washed with 0.1 M hydrochloric acid, saturated aqueous sodium bicarbonate, water, and brine. The material is dried over magnesium sulfate, filtered, and concentrated to dryness. The crude material is purified by flash chromatography over silica gel to afford 22.65 g of the title compound as a colourless oil. 1H NMR (CDCl3) δ (ppm): 1.19-1.30 (m, 2H), 1.39 (d, 3H), 1.44 (s, 9H), 1.6-1.8 (m, 3H), 2.66 (m, 2H), 2.99 (s, 3H), 4.16 (m, 2H), 4.62 (t, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12]C)[CH:7]=1.[BrH:14]>C(O)(=O)C>[BrH:14].[BrH:14].[NH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([OH:12])[CH:7]=1
Reactant: COc1cc(CCN)ccn1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: NCCc1ccnc(O)c1
Yield: 50 %

Procedure:
4-(2-Aminoethyl)-2-methoxypyridine dihydrochloride (225 mg, 1.00 mmol) synthesized in Reference Example 12 was mixed with 48% hydrobromic acid (3.0 mL) and acetic acid (3.0 mL), and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure to give 4-(2-aminoethyl)-2-hydroxypyridine dihydrobromide (150 mg, yield 50%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[C:12]([OH:21])[C:11]=2[C:22]([F:25])([F:24])[F:23])=[CH:6][CH:5]=1.[CH3:28][N:29]1[CH:33]=[C:32]([C:34](O)=[O:35])[N:31]=[CH:30]1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O>[OH:21][C:12]1[C:11]([C:22]([F:23])([F:24])[F:25])=[C:10]([CH:15]=[CH:14][C:13]=1[C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:34]([C:32]2[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=2)=[O:35])=[CH:27][CH:26]=1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: CC(C)C(=O)c1ccc(OCc2ccc(CN)cc2)c(C(F)(F)F)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)c1ccc(OCc2ccc(CNC(=O)c3cn(C)cn3)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 148.3 %

Procedure:
Mechanically stir suspensions of 1-[4-(4-aminomethyl-benzyloxy)-2-hydroxy-3-trifluoromethyl-phenyl]-2-methyl-propan-1-one hydrochloride (244 g, 604 mmol), 1-methyl-imidazole-4-carboxylic acid (95 g, 753 mmol), and 1-hydroxybenzotriazole hydrate (118 g, 770 mmol) in tetrahydrofuran (8 L) in two separate 22-L Morton flasks. Treat each solution with diisopropylethylamine (269 mL, 1.54 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (145 g, 756 mmol) in single portions and stir overnight at room temperature. Dilute each with 4 L of water and extract twice with 4 L of ethyl acetate. Wash organic layers with saturated sodium chloride solution, dry with magnesium sulfate, filter, and evaporate the filtrates to tan foams. Combine the foams and recrystallize from isopropanol (6 L) to afford the title compound (426 g, 74% yield). m.p. 164.7° C.; HPLC Rt=4.86 min; 1H NMR (DMSO-d6) δ 13.95 (s, 1H), 8.45 (t, J=8.0 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.63 (d, J=12.0 Hz, 2H), 7.33 (ABq, J=12.0, 8.0 Hz, 4H), 6.89 (d, J=8.0 Hz, 1H), 5.32 (s, 2H), 4.39 (d, J=8.0 Hz, 2H), 3.71 (hept, J=8.0 Hz, 1H), 3.67 (s, 3H), 1.12 (d, J=8.0 Hz, 6H); 19F NMR (DMSO-d6) δ-54.10; MS (m/z): 476.0 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[CH3:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:21]=2[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]5[CH2:16][CH2:15]5)=[O:13])[N:10]=4)[N:7]=3)[CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)cc2s1
Yield: 43.9 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (309 mg, 0.942 mmol), 2-methyl-1,3-benzothiazole-6-ol (250 mg, 1.51 mmol), potassium carbonate (390 mg, 2.83 mmol) and N,N-dimethylformamide (4.0 mL) as starting materials and in the same manner as in Example 95, the title compound (151 mg, 44%) was obtained as a pale-yellow powder.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[N:6][CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:9]1[CH2:10][CH:11]=[C:12]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][N:6]=2)[CH2:13][CH2:14]1
Reactant: Fc1nccnc1I
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1nccnc1C1=CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a glass microwave vial was added 2-fluoro-3-iodopyrazine (1.6485 g, 7.36 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.319 g, 11.04 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.413 g, 0.589 mmol), and sodium carbonate (3.90 g, 36.8 mmol) in DME (19.63 mL) and water (4.91 mL) to stir at 80° C. overnight. Reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide 2-(3,6-dihydro-2H-pyran-4-yl)-3-fluoropyrazine. [M+H]=181.1.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:19]#[N:20])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:21][C@H:22]([C:24]([OH:26])=[O:25])[CH3:23].CO[Na].CO>>[C:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:21][C@@H:22]([CH3:23])[C:24]([OH:26])=[O:25])=[O:7])[N:9]=1)#[N:20]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccccc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: CO[Na]
Solvent: CO
Product: C[C@H](NC(=O)c1nc(C#N)c2ccccc2c1O)C(=O)O
Temperature: 120 °C
Reaction time: 0.67 h
Yield: 70.8 %

Procedure:
A mixture of 1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (135 mg, 0.5 mmol, see Example 1(a)), (S)-alanine (225 mg, 2.5 mmol) and a 0.5 N solution of MeONa in methanol (5 mL, 2.5 mmol) was heated in a microwave oven with stirring for 40 min at 120° C. before the mixture was concentrated in vacuo. To the residue was added water (10 mL) and the mixture was washed with diethyl ether (4×40 mL). The pH of the purified solution was adjusted to about 2 by the addition of aqueous 6 N HCl. The resulting suspension was extracted with ethyl acetate (1×40 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a yellowish solid (101 mg); MS-(−)-ion: M−1=284.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:18]=1[O:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:21]1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:18]=3[O:19][C@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:31])[C:27]([F:30])([F:28])[F:29])[CH2:21]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: Cc1ccc(N)c(O[C@H]2CCCN(C(=O)C(F)(F)F)C2)c1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3ccc(C)cc3O[C@H]3CCCN(C(=O)C(F)(F)F)C3)c2c1C

Procedure:
Prepared analogously to example 65.1. from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and (S)-1-(3-(2-amino-5-methylphenoxy)piperidin-1-yl)-2,2,2-trifluoroethanone
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH:20]3[CH2:22][CH2:21]3)[N:8]=2)[CH:6]=1.[NH2:23][C:24]1[N:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([CH:20]3[CH2:22][CH2:21]3)[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:27]4[CH:26]=[N:25][C:24]([NH2:23])=[N:29][CH:28]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(-c2cc(C3CC3)nc(-n3cnc(Br)c3)n2)cc1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C4CC4)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-cyclopropyl-pyrimidine (example E.14) (0.30 g, 0.8 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.18 g, 0.8 mmol) according to the general procedure VI. Obtained as a white solid (0.093 g, 37%). MS (ISP) 390.3 [(M+H)+]; mp 238-240° C.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.S(=O)(=O)(O)O.[N+]([O-])(O)=O>[Ni].C(O)C>[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:4][CH:5]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Ni]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: CC(=O)c1ccccc1

Procedure:
With the nickel catalyst, if very pure m-nitroacetophenone is used (i.e., 100% by GLC as obtained, for example, by crystallization from ethanol) the hydrogenation will not occur or will occur slowly. Where crude (less than 100% purity) m-nitroacetophenone is used-the impurities present being acidic sulfuric acid, nitric acid, or other acid material contained in the m-nitroacetophenone as obtained directly from the nitration of acetophenone without further purification-the process is operable. Crude m-nitroacetophenone when suspended in water gives a strongly acid system with a pH of 2.6 to 3.2. If very pure m-nitroacetophenone is used and fails to hydrogenate, the addition of a few drops of sulfuric acid to the aqueous suspension will permit hydrogenation to occur to yield the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1COCC1>[C:28]([NH:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A solution of tert-butyl 2-amino-1-(4-chlorophenyl)ethylcarbamate (Intermediate 73) (0.208 g, 0.77 mmol) and N-ethyldiisopropylamine (0.266 mL, 1.54 mmol) in THF (5 mL) was treated with acetic anhydride (0.102 mL, 1.08 mmol). The resulting solution was stirred at ambient temperature for 2 hours. The mixture was partitioned between DCM and sodium bicarbonate solution. The organic layer was concentrated and the residue was purified by flash column chromatography on silica using gradient elution (10% ethyl acetate/DCM to 40% ethyl acetate/DCM). The desired product, tert-butyl 2-acetamido-1-(4-chlorophenyl)ethylcarbamate (0.151 g, 62.7%), was thus isolated as a colourless solid.
Reaction SMILES: [C@H:1]1([CH2:11]N)[C@@H:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].CO>O>[CH3:11][C@H:1]1[C@H:10]2[CH2:9][CH2:8][CH2:7][CH2:6][N:5]2[CH2:4][CH2:3][CH2:2]1
Reactant: NC[C@@H]1CCCN2CCCC[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H]1CCCN2CCCC[C@H]12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The lupinane amine.2HCl (1-[(1S,9aR)-octahydro-2H-quinolizin-1-yl]methanamine, CAS #: 75532-84-2, commercially available from ChemBridge, San Diego) (1.0 eq) was combined with 2,4-dichloro-5-X-pyrimidine (X=H, F, Cl, Me, CF3, CN, CONH2, OMe, NMe2) (1.0 eq) and NaHCO3 (1.2 eq). A mixture of MeOH:H2O (4/1) (concentration of the reaction mixture: ca. 0.1-0.5 M) was added and the resulting suspension was stirred for 1 d at RT. After the completion of the reaction was confirmed by TLC and HPLC, silica gel was added to the reaction mixture and solvents were evaporated under reduced pressure. The resulting solid was loaded on a CombiFlash column and further purified by flash chromatography eluting with DCM/MeOH—NH3 (2M) (gradient 0->10%).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH3:10])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1
Reactant: Oc1ccc(I)nc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(I)nc1Br
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-3-hydroxy-6-iodopyridine (11-2, 40 g, 133 mmol) in DMF (80 ml) was added K2CO3 (16.77 g, 121 mmol) and methyl iodide (66.3 g, 467 mmol). The system was stirred for 45 minutes at 100° C., cooled to room temperature and then treated with water (650 mL) and stirred for 0.5 h. The resulting solids that precipitated from solution were isolated by filtration and dried to give the title compound (11-3) as a pale brown solid. ESI+MS C6H5BrINO: 313.8 found, 313.9 required.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[OH:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]O>O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[OH:6]
Reactant: c1c[nH]cn1
Reactant: OCc1ccccc1O
Solvent: O
Product: Oc1ccccc1Cc1ncc[nH]1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mechanical mixture of imidazole (5 eq., 3.5 g) and 2-hydroxybenzyl alcohol (1.0 eq., 1.24 g) was heated to about 120° C. in a stoppered flask. The melt was stirred for 5 hours at about 120° C., allowed to cool and the fused mass was treated with hot H2O (40 mL) and the resulting suspension was cooled to about 4° C. The white crystalline precipitate was filtered and dried in vacuo to constant mass (1.49 g, 85%; LSIMS m/z 175 (MH+)).
Reaction SMILES: [ClH:1].C([O:4][C:5](=[O:40])[C:6]([CH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([NH:31]C(=O)C1C=CC=CC=1)=[N:26][CH:25]=[CH:24]2)([NH:12]C(OC(C)(C)C)=O)C(OCC)=O)C>C(O)(=O)C>[ClH:1].[ClH:1].[NH2:12][CH:6]([CH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([NH2:31])=[N:26][CH:25]=[CH:24]2)[C:5]([OH:40])=[O:4]
Reactant: CCOC(=O)C(Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nccc2cc(CC(N)C(=O)O)ccc12
Temperature: 100 °C

Procedure:
15 mL of acetic acid and 30 mL of a solution of 6N hydrochloric acid were added to 1.34 g of 1h and heated at 100° C. for 16 h. After cooling to room temperature the aqueous solution was extracted twice with diethyl ether. The aqueous phase was concentrated under reduced pressure giving 0.79 g of amino acid 1i. 1H-NMR 200 MHz (D2O) δ: 3.33-3.56 (2H, m), 4.36 (1H, dd, J=6.5 Hz and J=7.5 Hz), 7.12 (1H, d, J=7 Hz), 7.46 (1H, d, J=7 Hz), 7.62 (1H, dd, J=8 Hz and J=2 Hz), 7.73 (1H, d, J=2 Hz), 8.18 (1H, d, J=8 Hz).
Reaction SMILES: C(CCSSC1C=CC=CN=1)(O)=[O:2].[CH:14]1([N:20]=[C:21]=[N:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1>[CH:23]1([NH:22][C:21]([NH:20][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:2])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CCSSc1ccccn1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 72 h

Procedure:
To a stirred solution of 6-(2-propenylhydrazone)nicotinamido-3-propanol (190 mg, 0.8 mmol) and 2-carboxyethyl-2-pyridyldisulphide (163 mg, 1.0 equiv) in THF (10 ml) at 0° C. was added dicyclohexyl-carbodiimide (157 mg, 1.0 equiv) and the mixture was stirred at 0°-5° C. for 72 hours during which time a white solid precipitated. The white solid was filtered off and the filtrate evaporated under reduced pressure. The residue was dissolved in ethyl acetate and cooled, which gave a further precipitate of dicyclohexyl urea ("DCU"). This procedure was repeated once again until all of the urea had been removed. The desired product was purified by column chromatography on silica gel using 5% methanol in dichloromethane as eluent. Re-crystallisation in ethyl acetate/ether gave white solid (85 mg, 25%). 1H NMR (CDCl3) δ1.15 (t, 3H, J=7.5 Hz), 1.95 (pentet, 2H, J=6.0 Hz), 2.36 (dq, 2H, J=5.0, 7.6 Hz), 2.80 (t, 2H, J=7.0 Hz), 3.07 (t, 2H, J=7.0 Hz), 3.50 (m, 2H), 4.04 (t, 2H, J=6.0 Hz), 6.51 (broad triplet, 1H, D2O exchangeable), 7.07-7.12 (m, 1H, 7.17-7.21 (m, 2H), 7.60-7.72 (m, 2H), 7.95-7.99 (dd, 1H, J=8.8, 2.4 Hz), 8.22 (broad s, 1H, D2O exchangeable), 8.42-8.45 (m, 1H), 8.55 (d, 1H, J{32 2.4 Hz); mass spectrum (FAB); m/e relative intensity); 448 (100, M+1), 176 (45).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([NH:6][CH2:7][CH3:8])=[CH:4][CH:3]=1.[C:11]1([S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1.C(N(CC)CC)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH2:7][CH3:8])[C:21]([NH:20][S:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:19])=[O:18])=[O:22])=[CH:4][CH:3]=1
Reactant: CCNc1ccc(Br)cc1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCN(C(=O)NS(=O)(=O)c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution was prepared containing 4.0 g (0.02 mole) of 4-bromo-N-ethylaniline in 25 ml of benzene and one drop each of triethylamine and dibutyltin dilaurate. A solution of 3.7 g (0.02 mole) of benzenesulfonylisocyanate was added to the first solution. The temperature was allowed to rise to 35° C. The mixture was stirred for 2 hours at room temperature and for one-half hour at 40°-45° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[C:29]1([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO>[OH:21][CH:19]([CH2:20][N:38]1[CH2:39][CH2:40][N:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:36][CH2:37]1)[CH2:18][O:17][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:16])[CH:15]=[C:6]([C:5]3[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:7]2)=[CH:12][CH:11]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)cc(OC)c1OC
Solvent: CO
Product: COc1cc(-c2cc(=O)c3ccc(OCC(O)CN4CCN(c5ccccc5)CC4)cc3o2)cc(OC)c1OC

Procedure:
3′,4′,5′-Trimethoxy-7-(2,3-epoxy-propoxy)-flavone, 31 (1.1 g, 3 mmol) and 1-phenyl piperazine (0.5 mL, 3.27 mmol) in dry methanol (130 mL) were reacted in a similar manner to that described under 34 to afford 42. Yield 1.4 g (85%); mp 170-171° C.; MS (FAB) 547 (M++1); IR (KBr) 3406, 1635; 1H NMR (200 MHz, CDCl3) δ 8.13 (d, J=9.5 Hz, 1H), 7.27 (t, J=7.9 Hz, 2H), 7.10 (s, 2H), 7.04-7.01 (m, 2H), 6.95-6.87 (m, 3H), 6.70 (s, 1H), 4.21-4.12 (m, 3H), 3.95 (s, 6H), 3.93 (s, 3H), 3.23 (t, J=4.6 Hz, 4H), 2.87-2.83 (m, 2H), 2.68-2.65 (m, 4H). Analysis Calcd for C31H34N2O7: C, 68.12; H, 6.27; N, 5.12. Found: C, 68.26; H, 6.37; N, 5.41.