Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][N:5]1[C:9](=[O:10])[C:8]2([CH2:15][CH2:14][N:13]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:6]1.[OH-].[Na+].ClCCl.Cl>C(O)C>[C:17]1([CH2:16][N:13]2[CH2:14][CH2:15][C:8]3([N:7]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:6][N:5]([CH2:4][C:3]([OH:33])=[O:2])[C:9]3=[O:10])[CH2:11][CH2:12]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CN1CN(c2ccccc2)C2(CCN(Cc3cccc4ccccc34)CC2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)CN1CN(c2ccccc2)C2(CCN(Cc3cccc4ccccc34)CC2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.8 %

Procedure:
(8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl)-acetic acid methyl ester (44.40 g, 0.1 mol, prepared as described above) was dissolved in a mixture of 2 N sodium hydroxide (165 ml, 0.33 mol) and ethanol (500 ml) and stirred at room temperature for 16 h. Dichloromethane (700 ml) was added and pH was adjusted to 5 by the addition of 6 N hydrochloric acid. The organic phase was separated, washed with water (2×200 ml and concentrated to 300 ml in vacuo. Water (300 ml) and dichloromethane (100 ml) were added and the slurry was stirred overnight. The product was collected by filtration, washed successively with water (4×100 ml, dichloromethane (2×50 ml) and acetone (2×50 ml) and dried, affording the title compound as a powder (44.6 g, 97% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:24]=4[C:25]([OH:27])=[O:26])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[C:33](OCC)(=[O:35])C.Cl>C[O-].[Na+].CO>[CH3:33][O:35][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:24]=4[C:25]([OH:27])=[O:26])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(CO[C@H]2CCC[C@@H](OCc3coc(-c4ccc(F)cc4)n3)C2)c1C(=O)O
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc(CO[C@@H]3CCC[C@H](OCc4cccc(C)c4C(=O)O)C3)co2)cc1

Procedure:
170 mg (0.39 mmol) of 6b were heated in 4 ml of 5.6 M NaOMe/MeOH solution at an oil bath temperature of 120° C. for 20 hours. Ethyl acetate and 2 N HCl were added, and the mixture was then worked up analogously to the synthesis of 6b. This gave 7b as a colorless amorphous solid. TLC: (methylene chloride/methanol/conc. ammonia, 30/5/1). Rf˜0.3. C26H29NO6 (451.52) MS(ESI): 452 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:27])[C:12]([CH3:26])=[C:13]([CH2:15][NH:16][C:17]3[C:18]([F:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=3[F:23])[CH:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:27])[C:12]([CH3:26])=[C:13]([CH2:15][NH:16][C:17]3[C:18]([F:25])=[C:19]([CH:20]=[CH:21][C:22]=3[F:23])[O:24][CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(-c2cc(F)cc(F)c2)cc(CNc2c(F)ccc(O)c2F)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 3-[[5-(3,5-difluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2,4-difluoro-phenol (20 mg, 0.05 mmol, 1.0 eq) in DMF (3 mL) was added Cs2CO3 (26 mg, 0.075 mmol, 1.5 eq). The mixture was stirred at room temperature for 30 min then isopropyl bromoacetate (11 mg, 0.06 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for a further 1 h then diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 30:1) to give the title compound as a colorless oil (23 mg, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9](N)[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4].C(#N)C.N([O-])=[O:28].[Na+].[OH-].[Na+]>OS(O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([OH:28])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1OC
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(O)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methoxypyrimidine-4-carboxylic acid methyl ester (200 mg, 0.61 mmol) was dissolved in 20 mL of 9 molar H2SO4 plus 5 mL acetonitrile and treated in portions with NaNO2 (150 mg, 2.2 mmol). After the addition was complete, the mixture was stirred for 30 minutes at 25° C., cooled in ice-salt and treated carefully with 50% NaOH to bring the pH to ca 0.8. The precipitate was taken up by extracting with two 15 mL portions of EtOAc and the combined extracts were washed with 10 mL sat. NaCl, dried (Na2SO4) and evaporated to give the title product 150 mg (75%). Mp: 177-179° C. MS m/z 342; 1H NMR (DMSO-d6): δ 7.81 (m, 1H), 7.31 (m, 1H), 4.05 (s, 3H), 4.01 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].N[C@@H]([C:12]([OH:14])=O)[C@H](C)O.[NH2:15][C@@H](C(O)=O)C(C)C>>[NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH2:3][C:12](=[O:14])[NH2:15]
Reactant: CC(C)[C@@H](N)C(=O)O
Reactant: C[C@@H](N)C(=O)O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Product: NC(=O)C[C@H](N)C(=O)O

Procedure:
According to a particularly advantageous further development of the invention X is replaced by the D-amino acids: D-alanine, D-threonine or D-valine.
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:35][C:36]1[S:37][C:38](SCCCl)=[CH:39][CH:40]=1.[C:45](#N)[CH3:46]>CO.C(OCC)(=O)C>[OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:45][CH2:46][C:38]2[S:37][C:36]([Cl:35])=[CH:40][CH:39]=2)[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Reactant: ClCCSc1ccc(Cl)s1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H]1CN(CCc2ccc(Cl)s2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A solution of 1 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 40 cm3 of acetonitrile and 10 cm3 of methanol was stirred at a temperature. in the region of 20° C. and then 1.16 g of potassium carbonate and 0.5 g of potassium iodide were added. 1 g of 2-chloro-5-(2-chloroethylthio)thiophene and 10 cm3 of acetonitrile were added to the suspension obtained. The mixture was stirred for 72 hours at a temperature in the region of 80° C. The reaction mass was poured onto 75 cm3 of ethyl acetate and then washed with 3 times 70 cm3 of water. The organic phase was dried over sodium sulfate, filtered, and evaporated under reduced pressure (5 kPa) at a temperature in the region of 45° C. The residue obtained was purified by chromatography under a nitrogen pressure of 40 kPa on a column of silica gel (particle size 20-40 μm; diameter 3.5 cm; silica height 31 cm), elution was carried out with ethyl acetate, and 30-cm3 fractions were collected. Fractions 24 to 52 were combined and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.48 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(5-chlorothien-2-yl)ethyl]piperidine-3-carboxylate was obtained in the form of an oil with a brown color.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[NH:34][C:33]([CH:35]=O)=[C:32]([CH3:37])[CH:31]=2)=[O:29])[CH2:24][CH2:23]1)[CH3:21]>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:33]4[NH:34][C:30]([C:28]([N:25]5[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:27][CH2:26]5)=[O:29])=[CH:31][C:32]=4[CH3:37])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN1CCN(C(=O)c2cc(C)c(C=O)[nH]2)CC1
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN1CCN(C(=O)c2cc(C)c(C=C3C(=O)Nc4ncnc(Nc5ccc(F)c(Cl)c5)c43)[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-(4-ethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrole-2-carbaldehyde (74.8 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 93 mg (73%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.40 (br s, 1H, NH), 11.81 (br s, 1H, NH), 9.28 (br s, 1H), 8.33 (s, 1H), 7.72 (m, 1H), 7.33-7.45 (m, 3H), 6.58 (m, 1H), 3.68 (m, 4H, 2×CH2), 2.31-2.42 (m, 6H), 2.22 (s, 3H, CH3), 1.01 (t, J=7.2 Hz, 3H, CH2CH3). MS 510 [M++1].
Reaction SMILES: [N+:1](C1C2C(=CC=CC=2)CCN1)([O-:3])=[O:2].[F:14][C:15]([F:32])([F:31])[C:16]([N:18]1[CH2:27][CH2:26][CH:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH2:24]2)C1[N+]([O-])=O)=[O:17]>>[N+:1]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][NH:18][C:16](=[O:17])[C:15]([F:14])([F:31])[F:32])([O-:3])=[O:2].[CH2:16]=[O:17]
Reactant: O=C(N1CCC2CC=CC=C2C1[N+](=O)[O-])C(F)(F)F
Reactant: O=[N+]([O-])C1NCCc2ccccc21
Product: C=O
Product: O=C(NCCc1ccccc1[N+](=O)[O-])C(F)(F)F

Procedure:
The nitro-tetrahydroisoquinoline of formula (IV) may be prepared by hydrolysis of 2-trifluoroacetyl-nitro-tetrahydroisoquinoline obtained by reaction of an N-(nitrophenyl)ethyl-trifluoroacetamide and paraformaldehyde in acidic conditions using the procedure of Stokker, Tet. Lett., 1996, 37, 5453. N-(nitrophenyl)ethyl-trifluoroacetamides can be prepared from readily available materials by reaction of trifluoracetic anhydride with lutidine and nitrophenethylamine hydrochloride, as illustrated in the Descriptions below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:25]3[NH:29][C:28](=[O:30])[N:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:26]=3)=[O:24])[CH2:16][C@@H:17]([OH:21])[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:37](=[O:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39]Cl.N1C(C)=CC=CC=1C.[Na+].[I-]>CN(C=O)C>[CH2:42]([O:41][C:37]([O:38][CH2:39][O:19][C:18](=[O:20])[C@H:17]([OH:21])[CH2:16][C@H:15]([NH:22][C:23]([C:25]1[NH:29][C:28](=[O:30])[N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:26]=1)=[O:24])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:13][CH:12]=1)=[O:44])[CH3:43]
Reactant: CCOC(=O)OCCl
Reactant: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)OCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1nn(-c2ccccc2)c(=O)[nH]1
Yield: 4.3 %

Procedure:
A solution of (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-4-[(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)amino]pentanoic acid (253 mg, 0.5 mmol), chloromethyl ethyl carbonate (69 mg, 0.5 mmol), 2,6-lutidine (165 mg, 1.5 mmol) and NaI (150 mg, 1 mmol) in DMF (20 mL) was stirred for 15 hours at 50° C. The mixture was quenched with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were collected and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc=3:1) to yield the title compound as a white solid (13 mg). LC-MS: 608.8 [M+H]+. 1H NMR: (CDCl3, 400 MHz) δ 1.27 (t, J=8.0 Hz, 3H), 2.03-2.33 (m, 2H), 3.02-3.05 (m, 2H), 4.18 (q, J=8.0 Hz, 2H), 4.49 (br, 1H), 4.85 (br, 1H), 5.57-5.76 (m, 2H), 7.03 (d, J=12 Hz, 1H), 7.25-7.40 (m, 4H), 7.42-7.51 (m, 3H), 7.53-7.61 (m, 3H), 7.93 (d, J=8.0 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11].Cl>C(OCCO)C.[Cl-].[Na+].O.O>[CH3:8][C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=2)[CH:5]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCCO
Product: Cc1cc(Nc2cccc([N+](=O)[O-])c2)nc(N)n1
Temperature: 25 °C

Procedure:
To a suspension of 2-amino-4-chloro-6-methyl-pyrimidine (A8) [10.04 g, 69.93 mmol] and 3-nitroaniline 99.95 g, 72.02 mmol) in 2-ethoxyethanol (300 mL) was added c.HCl (30 mL), and the resulting solution was refluxed for ˜16 h. After this time, the reaction mixture was allowed to cool to room temperature, and then diluted with brine and H2O. The resulting suspension was filtered through a Celite pad, and the solid material thus collected re-dissolved in MeOH, and filtered through a pad of Celite. Solvent was removed under reduced pressure to give diamine E1 as an amorphous beige solid, which was used without further purification: 1H NMR (400 MHz, DMSO): δ 12.97 (br s, 1H, pyrimidinyl-N+—H), 11.03 (s, 1H, ArNHAr), 8.52 (s, 1H, ArH), 8.31 (d, J=7.83 Hz, 1H, ArH), 7.97 (ddd, J=8.20, 2.19, 0.72 Hz, 1H, ArH), 7.83 (v br s, 2H, ArNH2), 7.66 (t, J=8.21 Hz, 1H, ArH), 6.25 (s, 1H, ArH), 2.31 (s, 3H, ArCH3); LCMS (APCl+): 246 (100%).
Reaction SMILES: C1C=CC(C(NC2C3NC=NC=3N=CN=2)=[O:8])=CC=1.C(N[C:23]1[CH:44]=[CH:43][N:26]([C@@H:27]2[O:42][C@H:36]([CH2:37][O:38]C(=O)C)[C@@H:31]([O:32]C(=O)C)[C@H:28]2[O:29]C)[C:25](=[O:45])[N:24]=1)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C.ClCCl>[C@@H:27]1([N:26]2[CH:43]=[CH:44][C:23](=[O:8])[NH:24][C:25]2=[O:45])[O:42][C@H:36]([CH2:37][OH:38])[C@@H:31]([OH:32])[C@H:28]1[OH:29]
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Reactant: CO[C@@H]1[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1n1ccc(NC(C)=O)nc1=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 75 °C
Yield: 50 %

Procedure:
A solution of N6 -benzoylaminopurine (Lancaster) (1.23 g, 5.16 mmol) stirring in anhydrous acetonitrile under an argon atmosphere was treated with BSA (3.82 ml, 15.48 mmol) at reflux for 3 hours. Upon cooling, a solution of N4 -acetyl-5',3'-di-O-acetyl-2'-O-methyl cytidine (2) (see above) (0.66 g, 1.72 mmol) in 20 ml anh. acetonitrile was added to the reaction mixture followed by TMStriflate (1.03 ml, 5.16 mmol). The reaction mixture was then heated to 75° C. for 16 hours while stirring under positive pressure argon. Upon cooling, an additional 1.03 ml (5.16 mmol) of TMStriflate was added, and the reaction heated to 75° C. for an additional 20 hours. Once cool, the reaction mixture was diluted with two volumes of dichloromethane and washed with sat. NaHCO3. The organic layer was then dried over Na2SO4 and evaporated in vacuo. Flash chromatography employing a gradient of 10 to 80% ethyl acetgate/hexanes afforded (1) as a white foam; 0.403 g, 50% yield. 1H NMR (CDCl3): 8.88 (br s, 1H, NH), 8.81 (s, 1H, H8), 8.31 (s, 1H, H2), 8.11-7.53 (m, 5H, benzoyl), 6.18 (d, J1'2,' =4.8, 1H, H1'), 5.41 (t, J3',2' =4.8, J3',4' =4.8, 1H, H3'), 4.75 (t, J2',1' =4.8, J2',3' =4.8, 1H, H2'), 4.50-4.34 (m, 3H, H4', H5', H5"), 3.44 (s, 3H, OCH3), 2.19 (s, 3H, OAc), 2.14 (s, 3H, OAc).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:28])[NH:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[C:19]([Cl:26])[C:18]=1[F:27])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:26][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([CH2:16][NH:15][C:14]([C@@H:9]2[CH2:10][C@@H:11]([F:13])[CH2:12][NH:8]2)=[O:28])[C:18]=1[F:27])[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Cl)c(F)c(CNC(=O)[C@@H]2C[C@@H](F)CN2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (2S,4R)-2-(5-carboxy-3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (146 mg, 0.3 mmol) in CH2Cl2 (4 mL) was added TFA (1 mL). The reaction mixture was stirred for 1 h at ambient temperature and the solvent was removed in vacuo to give the title compound which was used without further purification. tR (HPLC conditions c): 3.11 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[S:26][C:14]3[N:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:21])[N:17]([CH3:20])[C:18](=[O:19])[C:13]=3[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[S:26][C:14]3[N:15]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:16](=[O:21])[N:17]([CH3:20])[C:18](=[O:19])[C:13]=3[CH:12]=2)=[CH:6][CH:5]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3ccc([N+](=O)[O-])cc3)sc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3ccc(N)cc3)sc21
Temperature: 90 °C
Yield: 7.9 %

Procedure:
To a solution of 6-(4-nitrophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (275 mg) in ethanol (15 ml) and water (1 ml) was added iron powder (82 mg) and ammonium chloride (78 mg). The mixture was heated at 90° C. for 6 h. and then allowed to cool to room temperature. The reaction was filtered and then evaporated before being partitioned between ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate, and then evaporated. The resultant oil was purified by normal phase HPLC (isohexane:ethyl acetate 80-0:20-100) to give the title compound (20 mg).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCC(=O)OC(C)(C)C

Procedure:
Vanillin was alkylated with t-butyl bromoacetate in DMF in the presence of potassium carbonate the usual way to give a waxy solid. (quant.) mp 86.8°-90° C. MS(NH3): 284 (base, M+NH4).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][N:51]1[C:59]2[C:54](=[CH:55][C:56]([NH2:60])=[CH:57][CH:58]=2)[CH:53]=[N:52]1>ClCCCl.C(#N)C>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:60][C:56]1[CH:55]=[C:54]3[C:59](=[CH:58][CH:57]=1)[N:51]([CH2:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=1)[N:52]=[CH:53]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CC#N
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)N(C)C
Temperature: 45 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A mixture of (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (783 mg, 3 mmol), triphenylphosphine (2.35 g, 9 mmol) and carbon tetrachloride (8.62 ml, 90 mmol) in 1,2-dichloroethane (20 ml) was stirred at 45° C. for 2 hours. The mixture was cooled and the solvents were evaporated under vacuum. 1-(Pyridin-2-ylmethyl)-1H-indazol-5-amine (706 mg, 3.15 mmol) and acetonitrile (15 ml) were added. The mixture was stirred at 75° C. for 1 hour. After cooling, the solvents were evaporated under vacuum. The residue was diluted in DCM and extracted with 2N hydrochloric acid. The aqueous layer was neutralised by addition of 6N aqueous ammonia and extracted with DCM. The DCM layer was dried over magnesium sulfate and the solvents were evaporated under vacuum. The residue was purified twice by chromatography on silica gel (first eluant: 3% 6N methanolic ammonia in DCM; second eluant: 3% methanol in DCM) to give the title compound as a white foam (600 mg, 43%); NMR Spectrum (CDCl3) 1.72 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.75 (s, 2H), 6.81 (m, 2H), 7.17 (m, 1H), 7.41 (d, 1H), 7.48 (d, 1H), 7.62-7.53 (m, 2H), 7.81 (dd, 1H), 8.10 (s, 1H), 8.44 (d, 1H), 8.58 (d, 1H), 8.62 (s, 1H); Mass spectrum 468.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](=O)[CH3:11])[CH:6]=[CH:7][CH:8]=1.[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:15][NH2:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH3:11])[CH:6]=[CH:7][CH:8]=1.[ClH:23].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COc1cccc(CC(C)=O)c1
Product: COc1cccc(CC(C)NCC(O)c2cccc(Cl)c2)c1
Product: Cl

Procedure:
N-[2-(3-methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine was prepared from 1-(3-methoxyphenyl)propan-2-one (3.81 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (3.99 g) by an analogous procedure to that described in Example 1 and purified by column chromatography on silica gel using 2-5% methanol in dichloromethane as eluent. The purified amine was converted to its hydrochloride salt by addition of ethereal hydrogen chloride and crystallised from ethyl acetate-diethyl ether to give N-[2-(3-methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride, m.p. 101°-4° C. as u a 60:40 mixture of diastereoisomers.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[N:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][C:9]=1[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])(=[O:3])[CH3:2].[BH4-].[Na+].O.C(Cl)(Cl)Cl>CO>[CH3:14][N:12]([CH3:13])[CH2:11][CH2:10][C:9]1[N:8]=[C:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:6]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:4]=1[CH:1]([OH:3])[CH3:2]
Reactant: CC(=O)c1c(CCN(C)C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CC(O)c1c(CCN(C)C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 19.9 %

Procedure:
A mixture of 5-acetyl-6-(2-dimethylaminoethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine (1 g) and sodium borohydride (0.1 g) in methanol (40 ml) was stirred for 1 hour. The reaction mixture was poured into a mixture of water and chloroform and adjusted the pH to 9. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (20:1). The fractions containing the desired product were combined and concentrated in vacuo. The residue was recrystallized from diethyl ether to afford 6-(2-dimethylaminoethyl)-5-(1-hydroxyethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine (0.2 g).