Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1Br)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnccc1Br
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnccc1-c1cccnc1

Procedure:
By carrying out the operation analogously to example 1, starting from 4-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation II, and 3-pyridineboronic acid, the desired product is obtained in the form of an ecru solid (yield=57%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[C:18]([CH3:20])[C:17]([CH2:21][OH:22])=[CH:16][N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.O=[Mn]=O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[C:18]([CH3:20])[C:17]([CH:21]=[O:22])=[CH:16][N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1CO
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1C=O
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
A mixture of {2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}methanol (1.75 g) and MnO2 (5.1 g) in AcOEt (30 ml) was refluxed under stirring for 1.5 hours. After removal of the insoluble material, and the solvent was evaporated in vacuo to give 2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarbaldehyde (1.58 g).
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:30])[N:13]([CH3:29])[C:14]([CH:23]([OH:28])[C:24]([O:26]C)=[O:25])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:10]=3[C:9]3[CH2:31][O:32][CH2:33][CH2:34][C:8]2=3)=[CH:4][CH:3]=1.C(O[C:41]([CH3:44])([CH3:43])[CH3:42])(=O)C.Cl(O)(=O)(=O)=O.[Li+].[OH-].Cl>CO>[C:41]([O:28][CH:23]([C:14]1[N:13]([CH3:29])[C:12](=[O:30])[C:11]2[N:7]([CH2:6][C:5]3[CH:35]=[CH:36][C:2]([F:1])=[CH:3][CH:4]=3)[C:8]3[CH2:34][CH2:33][O:32][CH2:31][C:9]=3[C:10]=2[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:24]([OH:26])=[O:25])([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2c3c(n(Cc4ccc(F)cc4)c2c(=O)n1C)CCOC3
Reactant: CC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2c2c(n3Cc3ccc(F)cc3)CCOC2)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 52.8 %

Procedure:
A solution of methyl 2-(5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridin-8-yl)-2-hydroxyacetate (26 mg, 0.053 mmol) was dissolved in tert butyl acetate (618 μl, 5.30 mmol), cooled to 0° C. and treated with perchloric acid (7.21 μl, 0.053 mmol) and the reaction vessel was transferred to the fridge. After 72 h (weekend), the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in THF (0.2 mL) and MeOH (0.2 mL), treated with 2M LiOH (133 μl, 0.265 mmol) and heated to 50° C. After 2 h, The reaction mixture was poured into 1M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by reverse phase HPLC to afford 2-(tert-butoxy)-2-(5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridin-8-yl)acetic acid (15 mg, 0.028 mmol, 53.1% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d)=7.50-7.43 (m, 1H), 7.17 (none, 5H), 7.03-6.95 (m, 2H), 5.95-5.86 (m, 1H), 5.77-5.69 (m, 1H), 5.29 (s, 1H), 4.08 (s, 1H), 3.94-3.86 (m, 1H), 3.79-3.70 (m, 1H), 3.66 (s, 3H), 3.60 (d, J=14.1 Hz, 1H), 2.70-2.53 (m, 2H), 2.42 (s, 3H), 1.05 (s, 9H). LCMS (m/z) ES+=533 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1B(O)O.[CH3:13][C:14]1([CH3:30])[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](OS(C(F)(F)F)(=O)=O)=[CH:15]1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:16]1[CH2:17][C:18]([CH3:21])([CH3:20])[CH2:19][C:14]([CH3:30])([CH3:13])[CH:15]=1
Reactant: COc1ccc(C)cc1B(O)O
Reactant: CC1(C)C=C(OS(=O)(=O)C(F)(F)F)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C)cc1C1=CC(C)(C)CC(C)(C)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
To a mixture of 2-methoxy-5-methylphenylboronic acid (1 g, 6.02 mmol), trifluoromethanesulfonic acid 3,3,5,5-tetramethylcyclohex-1-enyl ester (1.9 g, 6.62 mmol) produced in Example (4a) and 1,2-dimethoxyethane (30 mL) were added tetrakis(triphenylphosphine)palladium(0) (0.35 g, 0.30 mmol) and 2N aqueous solution of sodium carbonate (9.0 mL, 18.0 mmol), followed by stirring for 3 hours at an external temperature of 90° C. under a nitrogen atmosphere. Brine was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtrated, the resultant filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate/heptane) to give 1.0 g of the title compound as a light yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([Cl:19])=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC.O.[F-].[K+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:3]1[C:2]([C:25](=[O:27])[CH3:26])=[CH:7][N:6]=[C:5]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[N:10][C:4]=12
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)c(Br)cnc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc2c(ncn2COCC[Si](C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
6-Bromo-7-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine (379 mg, 1.05 mmol) in toluene (6 mL) was stirred with bis(triphenylphosphine)palladium(II) dichloride (106 mg, 0.151 mmol) and tributyl(1-ethoxyvinyl)tin (435 mg, 1.21 mmol) at 120° C. 4 hours. The reaction mixture was allowed to cool to room temperature and stirred with water (20 mL) and potassium fluoride (0.5 g) at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was stirred with hydrogen chloride-methanol solution (10 wt %, 4 mL) at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→3/1 (v/v)) to give the title compound as a yellow solid (89.6 mg, yield 26%).
Reaction SMILES: Cl.NO.C([N:7](CC)C(C)C)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23]C(OCC)=O)=S)=[N:18][CH:19]=1>CCO.CO>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([N:7]=[C:21]([NH2:23])[N:20]=2)[CH:19]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Br)cn1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2ccc(Br)cn2n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a suspension of hydroxylamine hydrochloride (409.2 g, 5.888 mol) in EtOH/MeOH (1:1, 2.5 L) was added N,N-diisopropylethylamine (606.1 mL, 3.480 mol), the mixture was stirred at room temperature (20° C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (352.8 g, 1.160 mol) was then added and the mixture slowly heated to reflux (Note: bleach scrubber required to quench H2S evolved). After 2 h at reflux the mixture was allowed to cool and filtered to collect the precipitated solid. The collected solid was washed successively with water (1.0 L), EtOH/MeOH (1:1, 1.0 L) and diethyl ether (500 mL) then air-dried to afford the title compound as a white solid (169.2 g, 69%). No further purification was required.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH3:10])=[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:28]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:6]1=[O:34])[CH:2](C)[CH3:3].[C:35](N1C(C)=C(CCCCC)N(CC2C=CC(C3C=NC=CC=3C3NN=NN=3)=CC=2)C1=O)(C)(C)C>>[CH:1]([N:5]1[C:9]([CH3:10])=[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:28]=3[C:29]3[NH:30][N:31]=[N:32][N:33]=3)=[CH:21][CH:22]=2)[C:6]1=[O:34])([CH2:2][CH3:3])[CH3:35]
Reactant: CCCCCc1c(C)n(C(C)(C)C)c(=O)n1Cc1ccc(-c2cnccc2-c2nnn[nH]2)cc1
Reactant: CCCCCc1c(C)n(CC(C)C)c(=O)n1Cc1ccc(-c2cnccc2-c2nnn[nH]2)cc1
Product: CCCCCc1c(C)n(C(C)CC)c(=O)n1Cc1ccc(-c2cnccc2-c2nnn[nH]2)cc1

Procedure:
1-isobutyl-4-pentyl-5-methyl-1,3-dihydro-3-[[4-[4-(1H-tetrazol-5-yl)-3-pyridinyl]phenyl]methyl]-2H-imidazol-2-one, 1-tertbutyl-4-pentyl-5-methyl-1,3-dihydro-3-[[4-[4-(1H-tetrazol-5-yl)-3-pyridinyl]phenyl]methyl]-2H-imidazol-2-one;
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:13])=[C:7]([C:10]([OH:12])=[O:11])[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[Li][CH2:15]CCC.IC>C1COCC1>[CH2:13]([C:6]1[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:9][S:8][C:7]=1[C:10]([OH:12])=[O:11])[CH3:15]
Reactant: Cc1c(CC(C)C)csc1C(=O)O
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCc1c(CC(C)C)csc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a solution of 4-isobutyl-3-methyl-thiophene-2-carboxylic acid (991 mg, 5.0 mmol) in THF (30 mL), tert.-BuLi (7.3 mL, 11 mmol, 1.5 M in pentane) is slowly added at −78° C. The mixture is stirred at −78° C. for 1 h, then iodomethane (1.6 mL, 25.7 mmol) is added. The mixture is stirred and is allowed to warm to rt over a period of 15 h before the reaction is quenched with 1 N aq. HCl (50 mL) and extracted with DCM (1×100 mL, 2×50 mL). The combined organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by CC on silica gel eluting with a gradient of EA in hexane to give 3-ethyl-4-isobutyl-thiophene-2-carboxylic acid (325 mg) as a yellow solid; LC-MS: tR=0.98 min, 1H NMR (CD3OD): δ 7.22 (s, 1H), 2.94 (q, J=7.6 Hz, 2H), 2.42 (d, J=7.0 Hz, 2H), 1.86 (hept, J=7.0 Hz, 1H), 1.11 (t, J=7.6 Hz, 3H), 0.93 (d, J=7.0 Hz, 6H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:14])[C:6](=[O:13])[C:7]=1[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])C.[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.[K+].[Br-]>>[C:9]([NH:8][C:7]1[C:6](=[O:13])[C:5](=[O:14])[C:4]=1[NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][C:16]([F:15])([F:26])[F:27])=[CH:19][CH:20]=1)([CH3:10])([CH3:11])[CH3:12]
Reactant: CCOc1c(NC(C)(C)C)c(=O)c1=O
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)Nc1c(NCc2ccc(OC(F)(F)F)cc2)c(=O)c1=O
Yield: 66 %

Procedure:
The title compound was prepared according to the procedure for example 1-step 2 except that 3-ethoxy-4-(tert-butylamino)-cyclobut-3-ene-1,2-dione was used in place of (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione and 4-trifluoromethoxy-benzylamine was used in place of 4-fluoro-benzylamine. Yield: 66%; mp: 292°-294° C.; 1H NMR (300 MHz, DMSO-d6): δ1.36 (m, 9H), 4.73-4.79 (m 2H), 7.39 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.2 Hz, 2H), 7.81 (brs, 1H), one N--H proton not seen; IR (KBr, cm-1): 3293s, 3242s, 3061w, 2980m, 1794m, 1655s, 1569s, 1542s, 1472s, 1447s, 1280-1160brs; MS (ES) m/z (relative intensity): 365 (M+ +Na, 100), 343 (M+ +H, 75); Anal. Calcd. for C16H17 F3N2O3 : C, 56.14; H, 5.01; N, 8.18. Found: C, 56.28; H, 5.05; N, 7.97.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:18][CH:19]([F:36])[O:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][CH:19]([F:36])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Reactant: O=C(O)c1ccc(Nc2ncc(Br)cn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1
Temperature: 90 °C

Procedure:
To 4-(5-bromopyrimidin-2-ylamino)benzoic acid 53 (0.25 mmol) in 1,4-dioxane (2.0 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.28 mmol), 1.8M K2CO3 (0.5 mmol) and Pd(PPh3)4 (0.017 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 90° C. for 8 h. The reaction mixture is diluted with water (10 mL) neutralized with 2M HCl and extracted with DCM (3×20 mL). Purification by preparative HPLC (ACN gradient 20-70%) affords 4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoic acid 54 as white solid. MS (m/z) (M+1)+: 358.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8][C:7]=1[NH:15][C:16](=[O:18])[CH3:17])=[O:5])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][C:7]=1[NH:15][C:16](=[O:18])[CH3:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1c(NC(C)=O)sc2ccccc12
Yield: 35.8 %

Procedure:
A solution of 1a (3.0 g, 11.24 mmol) in benzene (100 mL) was mixed with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.8 g, 16.85 mmol). The resultant mixture was heated at reflux for 2 h, diluted with saturated NaHCO3 solution (300 mL) and extracted with ethyl acetate (300 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 8:1) then provided the title compound (1.06 g, 35%) as a yellow solid: MS (ES) m/z 264 (M+H)+;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([Cl:13])([Cl:12])[CH2:5][NH:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]([Cl:12])([Cl:13])[CH2:5][N:6]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C(Cl)(Cl)CNC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)C(Cl)(Cl)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 143.7 %

Procedure:
A solution of 1.5 g (0.0063 mole) of 2,2-dichloro-3-cyclopentylamino-propionic acid methyl ester in 3 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 0.81 g (0.0042 mole) of 2,4-dichloro-5-nitro-pyrimidine, 1.76 g (0.02 mole) of sodium bicarbonate and 15 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 24 hours at room temperature and then 24 hours at 75 degrees. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 2.4 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dichloro-propanoic acid methyl ester (IV-298) as a yellow thick oil. This material was used directly in the next step without further purification.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH2:12][CH:11]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:23](O)=[O:24])=[CH:18][CH:17]=3)=[O:14])[O:10][N:9]=2)[CH:3]=1>C(Cl)Cl>[Cl:1][C:23]([CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13]([CH:11]2[O:10][N:9]=[C:8]([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)[CH2:12]2)=[O:14])=[CH:17][CH:18]=1)=[O:24]
Reactant: O=C(Nc1ccc(C(C(=O)O)c2ccccc2)cc1)C1CC(c2cccnc2)=NO1
Reactant: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(C(C(=O)Cl)c2ccccc2)cc1)C1CC(c2cccnc2)=NO1

Procedure:
) HCl (gaseous) (excess) was bubbled through a suspension of (±)-4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]-α-phenylbenzeneacetic acid (0.005 mol) in CH2Cl2 (100 ml) for 10 minutes. The solvent was removed under reduced pressure. The white solid was co-evaporated twice with toluene. Thionyl chloride (50 ml) was added. The reaction mixture was heated and refluxed for 1 hour. The solvent was evaporated. The reaction mixture was co-evaporated three times with toluene, yielding N-[4-[(chlorocarbonyl)phenylmethyl]phenyl]4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (compound 493).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](=[O:9])[C:4]2[CH:12]=[CH:11][CH:7]=[CH:6][CH:5]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.67 h
Yield: 182.4 %

Procedure:
A total of 55.7 grams of p-nitrobenzoyl chloride was dissolved in 225 milliliters of benzene and, while stirring, 65 grams of anhydrous aluminum chloride was added thereto over a period of 40 minutes, all of which was done under a nitrogen atmosphere. After addition was completed, the mixture was stirred for 30 minutes on a steam bath and then poured over ice. Extraction of the resulting product with methylene chloride, followed by washing the organic layer with water, drying with anhydrous magnesium sulfate and filtering, resulted in the recovery of 62.2 grams of p-nitrobenzophenone.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:35]1[C:39]2([O:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH2:38][C@@H:37]([C:45]2[NH:46][CH:47]=[C:48]([C:50]3[CH:55]=[CH:54][C:53]([C:56]4[CH:61]=[CH:60][C:59]([C:62]5[N:63]=[C:64]([C@@H:67]6[CH2:71][CH2:70][CH2:69][N:68]6[C:72]([C@@H:74]([NH:78][C:79](=[O:82])[O:80][CH3:81])[CH:75]([CH3:77])[CH3:76])=[O:73])[NH:65][CH:66]=5)=[CH:58][CH:57]=4)=[CH:52][CH:51]=3)[N:49]=2)[NH:36]1>CN(C=O)C>[CH3:7][C@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:8]([N:36]1[C@H:37]([C:45]2[NH:46][CH:47]=[C:48]([C:50]3[CH:51]=[CH:52][C:53]([C:56]4[CH:61]=[CH:60][C:59]([C:62]5[N:63]=[C:64]([C@@H:67]6[CH2:71][CH2:70][CH2:69][N:68]6[C:72](=[O:73])[C@@H:74]([NH:78][C:79]([O:80][CH3:81])=[O:82])[CH:75]([CH3:77])[CH3:76])[NH:65][CH:66]=5)=[CH:58][CH:57]=4)=[CH:54][CH:55]=3)[N:49]=2)[CH2:38][C:39]2([O:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH2:35]1)=[O:10]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)N[C@@H](C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)N[C@@H](C)C(=O)N1CC2(C[C@H]1c1nc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)n5)cc4)cc3)c[nH]1)OCCCO2
Reaction time: 0.05 h
Yield: 29 %

Procedure:
To a stirred solution of N-[(methyloxy)carbonyl]-L-alanine (22.5 mg, 0.153 mmol, prepared according to the procedure provided in WO2003055474) in DMF (2 mL) were added TEA (15.5 mg, 0.153 mmol) and HATU (58.2 mg, 0.153 mmol). After ˜3 min stirring, methyl [(1S)-1-({(2S)-2-[4-(4′-{2-[(3S)-6,10-dioxa-2-azaspiro[4.5]dec-3-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate (Example 19) (100 mg, 0.153 mmol) was introduced. After stirred for additional 2 hrs at rt, the reaction mixture was directly loaded to RP HPLC, eluting with 5 to 80% acetonitrile/water (0.2% NH3H2O(conc.)), to give methyl ((1S)-1-methyl-2-{(3S)-3-[4-(4′-{2-[(2S)-1-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2-pyrrolidinyl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-6,10-dioxa-2-azaspiro[4.5]dec-2-yl}-2-oxoethyl)carbamate (Example 5) as solid (36 mg, yield: 29%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.04-11.11 (m, 2H) 7.37-8.02 (m, 8H) 7.18-7.36 (m, 2H) 5.60 (br. s., 2H) 5.17-5.40 (m, 2H) 3.17-4.73 (m, 14H) 2.79-3.19 (m, 1H) 2.45-2.81 (m, 1H) 2.29-2.45 (m, 1H) 1.49-2.29 (m, 8H) 1.22-1.47 (m, 3H) 0.73-1.16 (m, 6H). HRMS: (M+H)+ calcd: 783.3830; found: 783.3832.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([N:11]1[C:19]2[C:18]([F:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:13]([C:21]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:39])[CH2:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH:26]=[N:27][CH:28]=2)=[O:22])=[CH:12]1)([CH3:10])[CH3:9])(C)(C)C>C1COCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C:30]([NH:29][C:25]2[CH:26]=[N:27][CH:28]=[C:23]([C:21]([C:13]3[C:14]4[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=4[N:11]([C:8]([CH3:10])([CH3:9])[CH2:7][OH:6])[CH:12]=3)=[O:22])[CH:24]=2)=[O:39])=[CH:33][CH:34]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncc(F)c21
Solvent: C1CCOC1
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a solution of N-(5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridine-3-carbonyl}-pyridin-3-yl)-2-(4-chloro-phenyl)-acetamide (Preparation 2, 35 mg, 70 μmol) in THF (2 mL) 4M dioxane-HCl (0.2 mL) was added and stirred at room temperature for 4 hours. The reaction was evaporated in vacuo and triturated with pentane-ether to afford the title compound as a white solid in 88% yield, 25 mg.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10](Cl)[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20]([OH:23])[CH2:21][OH:22]>>[NH2:2][C:3]1[N:11]=[C:10]([O:22][CH2:21][CH2:20][OH:23])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: OCCO
Agent: [Na]
Product: Nc1nc(OCCO)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 70 %

Procedure:
To sodium (74 mg, 3.2 mmol) in 5 ml of ethylene glycol were added 6-amino-9-benzyl-2-chloropurine (157 mg, 0.58 mmol). The mixture was heated at 100° C. for 4 hours and concentrated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (3% methanol/chloroform) to give the subject compound (121 mg, yield 70%).