Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].N[C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]=2[CH:21]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].Cl>C(O)C.O>[Cl:1][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]=2[CH:21]=1
Reactant: Cl
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(N)cc21
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(Cl)cc21
Reaction time: 3 h
Yield: 18 %

Procedure:
A mixture of 0.41 g of ethyl 6-amino-2,2-bis(fluoromethyl)-2H-1-benzopyran-4-carboxylate hydrochloride, 0.13 g of sulfuric acid, 0.10 g of sodium nitrite and 12 ml of H2O was stirred under ice-cooling for 1 hour. The reaction mixture was added dropwise to a mixture of 0.30 g of cuprous chloride and 10 ml of concentrated HCl under ice-cooling, then the mixture was stirred at room temperature for 3 hours followed by 3 hours at 70° C. with heating. Added 2N HCl to the reaction mixture and extracted with ethyl acetate. The resultant organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. To the residue thus obtained added a mixture of 50 ml of ethyl alcohol and 2 ml of sulfuric acid and refluxed with heating for 2 hours. The reaction mixture was concentrated in vacuo to half a volume, added water to the residue and extracted with methylene chloride. The resultant organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue thus obtained was purified with silica gel column chromatography (developing solution, ethyl acetate:hexane=1:10) to obtain 0.07 g of ethyl 6-chloro-2,2-bis(fluoromethyl)-2H-1-benzopyran-4-carboxylate with a melting point of 76°-78° C.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:5]=1)([O-])=O>C(Cl)Cl.[Pd]>[O:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:7]3[S:8][C:4]([NH2:1])=[CH:5][N:6]=3)=[CH:14][CH:13]=2)[CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1cnc(-c2ccc(N3CCOCC3)cc2)s1
Agent: [Pd]
Solvent: ClCCl
Product: Nc1cnc(-c2ccc(N3CCOCC3)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-(5-nitrothiazol-2-yl)phenyl)morpholine (0.70 g, 2.44 mmol) in CH2Cl2 (20 mL) was added Pd/C (70 mg). The reaction mixture was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo to give the title compound as an offwhite solid (0.20 g, 32%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@@H:5]1[CH2:9][CH:8](OS(C)(=O)=O)[CH2:7][N:6]1[CH2:15][CH3:16])[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+].CN(C=O)C>O>[CH2:1]([O:3][C:4](=[O:17])[C@@H:5]1[CH2:9][CH:8]([N:18]=[N+:19]=[N-:20])[CH2:7][N:6]1[CH2:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)CN1CC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CC(N=[N+]=[N-])CN1CC
Yield: 73.2 %

Procedure:
A mixture of 3.50 g of N-ethyl-4-mesyloxy-L-proline ethylester, 1.54 g of sodium azide and 10 ml of DMF was reacted at an inner temperature of 90° C. for 4 hours and after cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to obtain an oily product. This was purified by means of silica column chromatography to obtain 2.05 g of 4-azido-N-ethyl-L-proline ethylester.
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]2)[CH2:5][O:4][O:3]1.[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:5]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][C:13]([NH:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[CH:25][CH:26]=3)=[O:19])=[O:15])[CH2:10][CH2:11]2)[CH2:2][O:3][O:4]1
Reactant: O=C(O)CN1CCC2(CC1)COOC2
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCC2(CC1)COOC2)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 48.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,3-dioxa-8-azaspiro[4.5]decan-8-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 219, (2S)-2-(2-(2,3-dioxa-8-azaspiro[4.5]decan-8-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (21.7 mg, 48.1%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 8.00 (d, 1H), 7.60 (d, 2H), 7.27-7.33 (m, 5H), 7.20-7.23 (m, 2H), 6.98-7.04 (m, 4H), 4.68-4.70 (m, 1H), 4.52 (s, 2H), 3.88 (s, 4H), 3.69-3.79 (m, 2H), 3.00 (s, 2H), 2.51-2.54 (m, 4H), 2.63-2.65 (m, 4H). MS (EI) for C31H34FN3O6. found 564.6 (MH+).
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[C:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:27]=[C:26]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]3[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=3[CH3:13])=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Product: CC(=O)c1cccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)c1

Procedure:
Compound (117) was prepared from compound (26) and (3-acetyl-phenyl)-boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt=1.69 mins, m/z (ES−) 349 (M−H for C21H18O5).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>CO>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNC1
Solvent: CO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (10.0 g 0.037 moles) and 5-Fluoro-1,3-dihydro-indol-2-one (5.41 g; 0.0358 moles) in methanol were reacted in presence of catalytic amount of pyrrolidine (0.16 mL) as base at reflux temperature for 2-8 hours. The resultant Sunitinib base was triturated in methanol at reflux temperature for 1-2 hours and isolated at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)(=O)=O)=CC=1.BrCC1CCCCO1.[O:26]1[CH2:30][C:29]2([C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]2=[O:39])[C:28]2[CH:40]=[C:41]3[C:46](=[CH:47][C:27]1=2)[CH2:45][CH2:44][CH2:43][CH2:42]3>>[O:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[CH2:12][N:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]2([CH2:30][O:26][C:27]3[CH:47]=[C:46]4[C:41](=[CH:40][C:28]2=3)[CH2:42][CH2:43][CH2:44][CH2:45]4)[C:31]1=[O:39]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCCC3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: BrCC1CCCCO1
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)CCCC3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1-[(2R)-tetrahydrofuran-2-ylmethyl]-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1H)-one was obtained (80%) as a colorless solid: mp 139-141° C.; 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 1H), 7.15-7.01 (m, 3H), 6.66 (s, 1H), 6.41 (s, 1H), 4.88 (dd, J=8.9, 0.9 Hz, 1H), 4.63 (dd, J=8.9, 2.5 Hz, 1H), 4.32-4.24 (m, 1H), 4.00-3.69 (m, 4H), 2.75-2.71 (m, 2H), 2.54 (br s, 2H), 2.10-1.86 (m, 3H), 1.78-1.69 (m, 5H); 13C NMR (75 MHz, CDCl3) δ178.0, 158.6, 142.9, 138.8, 132.4, 130.0, 128.6, 126.5, 123.6, 123.4, 123.2, 110.1, 109.5 79.7, 76.9, 68.2, 57.9, 44.6, 29.9, 29.2, 29.0, 25.6, 23.2, 23.0; MS (ES+) m/z 375.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[CH:14][C:13]=1[S:22]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Cl)c(O)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 4-amino-2,6-dichlorophenol (Aldrich, 5.9 g, 33 mmol) in 30 mL of THF was added 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (4.19 g, 15 mmol). The mixture was stirred overnight. The reaction mixture was filtered and washed with EtOAc. The filtrate was washed with 2N HCl, twice with a brine solution, dried over Na2SO4 and concentrated. The residue was purified by chromatography (20%-25% EtOAc/hexanes) to give 5.7 g (90%) of product. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 10.15 (s, 10H), 8.19 (d, J=8.3 Hz, 1H), 8.16 (d, J=1.1 Hz, 1H), 7.92 (dd, J=8.3, 2.2 Hz, 1H), 7.06 (s, 2H). MS (EI): m/z 418 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.C[Si]([C:18]#[N:19])(C)C.N1C=CC=CC=1.O=P(Cl)(Cl)Cl.[OH-].[Na+].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1.[Zn+2].[I-].[I-]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:18]#[N:19])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [I-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc2cccc(C#N)c2c1
Temperature: 45 °C
Yield: 78 %

Procedure:
7-Methoxy-1-tetralone (8.16 g, 46 mmol, 1 eq) and ZnI2 (0.365 g, 1 mmol, 0.025 eq) were dissolved in 25 ml of toluene and heated at 45° C. Trimethylsilylcyanide (TMSCN) (5.0 g, 50 mmol, 1.1 eq) is added over a period of 20 min, and all is refluxed for 3 h. After cooling the mixture at about 35° C., pyridine (5.5 ml, 69 mmol, 1.5 eq) and POCl3 (6.4 ml, 69 mmol, 1.5 eq) are added, and the mixture is boiled under reflux for another 6 h. Thereafter, 80 ml of a 3 N NaOH cooled at 3° C. is added over a period of 15 min. The aqueous phase is extracted with 48 ml of toluene, and the organic phase is washed twice with 40 ml of 1 N NaOH, once with 40 ml of water, three times with 40 ml of 3 N HCl, once with 40 ml of water, once with 40 ml of a saturated NaHCO3 solution and once with a saturated sodium chloride solution. After the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (8.41 g, 37 mmol, 0.8 eq) over 20 min, the organic phase is boiled under reflux for 2 h. After cooling, the precipitate was filtered off and washed twice with 32 ml of 1 N NaOH and once with 32 ml of a saturated sodium chloride solution. Drying of the precipitate yielded the desired product in a yield of 78%, 6.6 g.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1.CCCCCC.C(OCC)C>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]2([C:2]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=3[C:4](=[O:5])[O:6]2)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1cc(Cl)ccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1OC2(CCN(Cc3ccccc3)CC2)c2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
To a solution of 2-bromo-5-chlorobenzoic acid (2.35 g, 10.0 mmol) in tetrahydrofuran (THF) (15 mL) was added, a 1.6 M solution in hexane, n-butyllithium (20 mL, 32.0 mmol) slowly at −78° C. under nitrogen. After addition was complete the reaction mixture was kept on stirring at −78° C. for 3 h. Then a solution of 1-benzylpiperidin-4-one (3.78 g, 20.0 mmol) in THF (10 mL) was added slowly to the reaction mixture at −78° C. After addition was complete the reaction temperature was raised to room temperature and the reaction mixture was kept on stirring at room temperature overnight. The reaction mixture was poured into a mixture of water (60 mL) and diethyl ether (60 mL), layers were separated. The aqueous layer was extracted with diethyl ether (2×20 mL). The aqueous layer was acidified with aqueous 6M hydrochloric acid (HCl) to pH 2 and boiled for 1 h, cooled to 0° C., pH was adjusted to 10.0 by addition of aqueous sodium hydroxide (NaOH) (6M) and rapidly extracted with trichloromethane (CHCl3). The organic layer was washed with water, dried over sodium sulphate (Na2SO4), filtered and concentrated in vacuo to give the subtitled compound (1.22 g) and it was pure enough for the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[CH:3]=1.[CH3:19][NH2:20]>C1COCC1>[CH3:19][NH:20][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[CH:3]=1
Reactant: CN
Reactant: Clc1cc(Oc2ccc3ncccc3c2)ncn1
Solvent: C1CCOC1
Product: CNc1cc(Oc2ccc3ncccc3c2)ncn1

Procedure:
A solution of 7.83 g (30.4 mMol) of 6-chloro-4-(quinolin-6-yloxy)-pyrimidine (step 1.1) and 121 ml of a 1 N MeNH2 in THF is stirred for 7.5 h in a sealed vessel. After addition of 30 g of SiO2, the mixture is concentrated and the resulting powder put on top of a chromatograph column (SiO2; EtOAc). Eluation (EtOAc→EtOAc/EtOH 50:1→20:1→9:1) gives the title compound: m.p.: 173° C.; MS: [M+1]+=253; Anal.: C,H,N.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:34])[C:8]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)=[C:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=3)[S:10]2)=[CH:5][CH:4]=1.[Cl-].[Cl-].[Cl-].[Al+3]>CCOC(C)=O>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:9]2[S:10][C:11]3[C:6]([C:7](=[O:34])[C:8]=2[C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=3)=[CH:19][CH:18]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1ccc(Cc2sc3cc(OC)ccc3c(=O)c2-c2ccc(C(=O)OC)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Cc2sc3cc(O)ccc3c(=O)c2-c2ccc(C(=O)O)cc2)cc1
Temperature: 130 °C
Yield: 21 %

Procedure:
Synthesis: Step 1: Synthesis of methyl 4-(7-methoxy-2-(4-(methoxycarbonyl)benzyl)-4-oxo-4H-thiochromen-3-yl)benzoate. Aluminum trichloride (253 mg, 1.9 mmol) was added to Intermediate E (methyl 4-(2-(3-methoxyphenylthio)-2-oxoethyl)benzoate) (500 mg, 1.58 mmol) and the mixture was heated at 130° C. for 1 hour. After cooling to room temperature, the reaction mixture was dissolved in EtOAc (50 ml) and washed with 1 N icy HCl (25 ml×2), water (25 ml) and brine (25 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Combi-Flash (40 g silica gel, fluent: PE:EtOAc=10:0 to 1:1 by gradient, 40 ml/min, 30 min, 1.2 L total solvent volume) to afford product as a yellow solid (160 mg, 21%). MS (ESI): m/z 475.1 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[O:11]([NH2:14])[CH2:12][CH3:13]>>[CH2:12]([O:11][N:14]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:13]
Reactant: CCON
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Product: CCON=Cc1ccc(F)cc1
Yield: 58 %

Procedure:
Reaction of 4-fluorobenzaldehyde with ethoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution toluene-ethyl acetate 95:5) and distillation (58% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.35 (3H, t, J=7.07 Hz, CH3), 4.24 (2H, q, J=7.07 Hz, OCH2), 7.08 (2H, m, aromatics), 7.59 (2H, m, aromatics), 8.07 (1H, s, CH).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:35]#[N:36])=[N:18][C:19]=3[NH:23][CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[O:7][C@@H:6]1[CH2:37][O:38]C(=O)C)(=O)C.N>C(O)C>[OH:10][C@@H:9]1[C@H:5]([OH:4])[C@@H:6]([CH2:37][OH:38])[O:7][C@H:8]1[N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([C:35]#[N:36])=[N:18][C:19]=2[NH:23][CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CCO
Product: N#Cc1nc(NCc2cccc3ccccc23)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.5 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-{2-cyano-6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}tetrahydro-3-furanyl acetate (3.5 g, 6.27 mmol) (Preparation 13) in ethanol (120 ml) was saturated with ammonia gas and stirred at room temperature for 4 days. The solvent was removed under reduced pressure and the residue was triturated with water (100 mls), filtered and dried to afford the title compound as a solid (2.4 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1.Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.[I-].[Li+]>O1CCCC1.C(OCC)(=O)C.O>[CH2:12]([O:11][C:9]([C:7]1[CH:8]=[C:4]([CH3:3])[N:5]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:6]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)n(CCOC2CCCCO2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium hydride (934 mg, 23.4 mmol) in tetrahydrofuran (50 mL) was treated with ethyl 3-methylpyrazole-5-carboxylate (3.00 g, 19.5 mmol) and the reaction mixture stirred at room temperature for 30 minutes. 2-(2-Bromoethoxy)tetrahydro-2H-pyran (3.5 mL, 19.5 mmol) and lithium iodide (50 mg, 0.39 mmol) were added and the reaction mixture refluxed for 16 hours. The reaction mixture was cooled and taken up in ethyl acetate and water. The organics were separated and washed with 10% citric acid solution, water, saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol 99:1 to 95:5 to yield the title product, 4.47 g.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10]C)=[O:8])=[CH:4][CH:3]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][O:9][C:7]([C:5]1[N:6]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:15])[C:2]([Br:1])=[CH:3][CH:4]=1)=[O:8]
Reactant: CCOC(=O)c1ccc(Br)[nH]1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)n1CC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A mixture of ethyl 5-bromo-1H-pyrrole-2-carboxylate (0.13 g, 0.64 mmol), 2-bromo-1-(4-methoxyphenyl)ethanone (160 mg, 0.69 mmol) and potassium carbonate (132 mg, 0.95 mmol) in N,N-dimethylformamide (4 mL) was stirred at room temperature overnight. At this time, the light brown reaction mixture was quenched with water. The resulting precipitate was collected by filtration and dried in vacuo. The resulting solid was dissolved in methylene chloride, concentrated in vacuo and then triturated with diethyl ether. The resulting solid was collected by filtration and dried in vacuo to afford 5-bromo-1-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester (155 mg, 69%) as light brown solid. 1H NMR (chloroform-d) δ ppm 8.00 (d, J=8.8 Hz, 2H), 6.96-7.07 (m, 3H), 6.85 (d, J=1.8 Hz, 1H), 5.71 (s, 2H), 3.91 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:48][N:49]2[CH:53]=[N:52][CH:51]=[N:50]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[C:38](=[O:39])[N:37]([CH:40]([CH3:47])[CH:41]([NH:43]C(=O)[O-])[CH3:42])[N:36]=[CH:35]5)=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:43][CH:41]([CH3:42])[CH:40]([N:37]1[C:38](=[O:39])[N:34]([C:31]2[CH:30]=[CH:29][C:28]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:12]5[CH2:11][O:10][C:9]([C:3]6[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=6[F:1])([CH2:48][N:49]6[CH:53]=[N:52][CH:51]=[N:50]6)[O:13]5)=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)=[CH:33][CH:32]=2)[CH:35]=[N:36]1)[CH3:47]
Reactant: CC(NC(=O)[O-])C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of compound (28)(0.0038 mol) in CF3COOH (10 ml) and CH2Cl2 (50 ml) was stirred at room temperature for 4 hours and neutralized with a NaHCO3 solution. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in 2-propanol, filtered off and dried, yielding 2.4 g (92%) of [2S-[2α,4α(S*,R*)]]-2-(2-amino-1-methylpropyl)-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]-phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (compound 37; mp. 168.5° C.).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[NH:32][CH2:31][N:30]([CH:34]([CH3:36])[CH3:35])[C:29]2=[O:37].N1C=CC=CC=1.C1CN2C(=NCCC2)NC1>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([N:32]2[C:33]3[C:28](=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:23])[C:29](=[O:37])[N:30]([CH:34]([CH3:36])[CH3:35])[CH2:31]2)=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: Cc1cccc2c1NCN(C(C)C)C2=O
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: C1CN=C2NCCCN2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc2c1N(C(=O)c1cc(Br)nn1-c1ncccc1Cl)CN(C(C)C)C2=O
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (787 mg, 2.45 mmol) (i.e. the product of Example 1, Step D) in dichloromethane (10 mL) was added dimethylformamide (20 μL) and oxalyl chloride (235 μL). The mixture was stirred for 1 hour, at which point it had become clear. After removing volatiles under reduced pressure, the residue was dissolved in dichloromethane (5 mL) and one half of the solution was added to a mixture of the product of Step A (0.25 g, 1.2 mmol) and pyridine (148 μL, 1.8 mmol) in methylene chloride (10 mL). After stirring at ambient temperature overnight, 1,5,7-triazabicyclo[4.4.0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (1 g) (Fluka Chemie AG catalog number 90603) was added and the mixture was stirred for an additional 15 minutes. The mixture was then filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel to give the title compound, a compound of the invention, as a white solid (0.18 g).