Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]=1[C:23]([F:26])([F:25])[F:24].[NH2:27][C:28]1[C:29]([C:37]#[N:38])=[N:30][C:31](Cl)=[CH:32][C:33]=1[NH:34][CH3:35].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl.O.O1CCOCC1>[NH2:27][C:28]1[C:29]([C:37]#[N:38])=[N:30][C:31]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:9]([C:23]([F:24])([F:25])[F:26])[CH:10]=2)=[CH:32][C:33]=1[NH:34][CH3:35]
Reactant: CNc1cc(Cl)nc(C#N)c1N
Reactant: COCCOCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1cc(-c2ccc(OCOCCOC)c(C(F)(F)F)c2)nc(C#N)c1N
Temperature: 110 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
2-(4-((2-Methoxyethoxy)methoxy)-3-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.83 g), 3-amino-6-chloro-4-(methylamino)-picolinonitrile (1.55 g), tris(dibenzylideneacetone)dipalladium (0) (0.389 g), tricyclohexylphosphine (0.286 g) and potassium phosphate (3.60 g) were charged to a 100 ml flask. Dioxane (30 ml) and water (12 ml) were added and the mixture placed under a nitrogen atmosphere. The reaction was heated to 110° C. for 3 hours and allowed to stand at room temperature for 2 hours. The mixture was diluted with EtOAc (200 ml) filtered through celite, washed with water (3×200 ml), dried over sodium sulphate and then solvent was evaporated under reduced pressure to yield crude product as a brown oil. DCM was added to the residue causing a pale brown solid to crash out of solution. The mixture was filtered and the solid washed with a small amount of DCM followed by ether to afford 3-amino-6-(4-((2-methoxyethoxy)-methoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)picolinonitrile (28% yield). The liquors were purified by flash chromatography (340 g silica column; 2:1, 1:1, 0:1 heptane/EtOAc mobile phase) to afford further 3-amino-6-(4-((2-methoxyethoxy)-methoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)picolinonitrile (49% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>CN(C=O)C>[CH2:15]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: OCCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
2-[4-Fluorophenyl]ethanol (7.0 g) was added slowly to a stirred suspension of sodium hydride (1.25 g, 60% as dispersion in oil prewashed with petroleum ether bp 60°-80°) in DMF (50 ml). The mixture was stirred for 30 min at room temperature. Allyl bromide (6.0 g) was then added slowly and the whole allowed to stir overnight. The reaction was partitioned between water and ether. The aqueous layer was further extracted with ether and the combined ethereal extracts were washed with water and dried (MgSO4). The ether was removed under reduced pressure to yield the crude subtitled compound as a colourless oil (8.7 g, 96%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:17](O)[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=[CH:15][CH:16]=1>>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]([F:7])[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=[CH:15][CH:16]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Product: CC(C)(C)OC(=O)NCCC(F)c1cccc(Br)c1
Temperature: -78 °C

Procedure:
Diethylaminosulphur trifluoride (DAST) is added under an inert atmosphere to a cold (−78° C.) solution of alcohol 39. The reaction mixture is stirred at −78° C. until no starting material is seen by TLC. The reaction mixture is partitioned between water and EtOAc, and aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine and dried over anhydrous MgSO4. Purification by flash chromatography gives tert-butyl 3-(3-bromophenyl)-3-fluoropropylcarbamate.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[C:7]([C:9]([CH3:20])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH3:10])[N:8]=1)([CH3:3])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[CH:1]([C:4]1[N:5]([CH3:21])[CH:6]=[C:7]([C:9]([CH3:10])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH3:20])[N:8]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1nc(C(C)(C)c2cccc([N+](=O)[O-])c2)c[nH]1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)c1nc(C(C)(C)c2cccc([N+](=O)[O-])c2)cn1C
Temperature: 50 °C
Yield: 54.4 %

Procedure:
To a solution of 2-isopropyl-4-[1-methyl-1-(3-nitro-phenyl)-ethyl]-1H-imidazole (0.35 g, 1.28 mmol) in THF (2 mL) was added potassium carbonate (0.21 g, 1.5 mmol) and iodomethane (0.12 mL, 1.92 mmol). The mixture was heated at 50° C. for 5 h then concentrated in vacuo. The residue was partitioned between water and DCM then the organic phase was dried over sodium sulfate and evaporated to afford 2-isopropyl-1-methyl-4-[1-methyl-1-(3-nitro-phenyl)-ethyl]-1H-imidazole (0.2 g, 56%) as colourless semisolid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][S:14][C:15]1[N:20]=[C:19]([C:21]2[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=2)[CH:18]=[CH:17][N:16]=1>>[CH3:13][S:14][C:15]1[N:20]=[C:19]([C:21]2[S:25][C:24]([S:26]([NH:1][C:2]3[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=3)(=[O:28])=[O:27])=[CH:23][CH:22]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(-c3ccnc(SC)n3)s2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 5-[2-(methylthio)pyrimidin-4-yl]thiophene-2-sulfonyl chloride as described in the synthetic METHOD B to give a white solid (34.5 mg) with purity >90%. MS (pos) m/z 475.3.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([CH2:26][CH3:27])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:28].CO>>[ClH:28].[CH2:26]([C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[O:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)[CH:21]=[N:20][CH:19]=1)[CH3:27]
Reactant: CCc1cncc2cccc(O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Product: CCc1cncc2cccc(O[C@H]3CC[C@H](N)CC3)c12

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 2 hours) by using Intermediate 126 (41.1 mg) and 10% hydrogen chloride/methanol solution (2 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (0.5 ml) and diethyl ether (1.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (32.7 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:20][O:19][C:14]1[CH:13]=[C:12]([O:21][CH3:22])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:18])[NH:17][C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:3][CH:4]=1)=[N:9]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(Br)cc3)nc2c1
Reactant: Nc1ccncc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(Nc4ccncc4)cc3)nc2c1
Temperature: 105 °C

Procedure:
A mixture of compound 2-(4-bromophenyl)-5,7-dimethoxyquinazolin-4(3H)-one) (0.200 g, 0.554 mmol), 4-aminopyridine (0.0573 g, 0.609 mmol), Pd2(dba)3 (0.0025 g, 0.0028 mmol), Xantphos (0.0018 g, 0.0031 mmol), and Cs2CO3 (0.253 g, 0.776 mmol) in 1,4-dioxane (2.22 mL) under nitrogen was heated at 105° C. for 2 days. The mixture was cooled to room temperature, diluted with EtOAc (200 mL), washed with water (3×75 mL), then brine (75 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under vacuum. The resulting residue was purified over silica gel (12 g, EtOAc/CHCl3/MeOH/NH4OH), to provide the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.90 (s, 1H), 9.19 (s, 1H), 8.29 (d, J=6.29 Hz, 2H), 8.17 (d, J=8.75 Hz, 2H), 7.30 (d, J=8.75 Hz, 2H), 7.05 (d, J=6.29 Hz, 2H), 6.72 (d, J=2.26 Hz, 1H), 6.51 (d, J=2.26 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H). MS (ESI) m/z 375 [C21H18N4O3+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[CH:29][CH:28]=[CH:27]2)=[CH:22][CH:21]=1>>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][N:16]3[CH:11]([C:4]4[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]3=[O:17])=[CH:21][CH:22]=2)[CH:27]=[CH:28][CH:29]=[CH:30]1
Reactant: BrCc1ccc(-n2cccc2)cc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(-n2cccc2)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(4-(bromomethyl)phenyl)-1H-pyrrole. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.80 min.; [M+H]+: 391.18 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([CH:17]=O)[CH:3]=1.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:13]#[N:14])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[C:4](/[CH:17]=[C:24]2\[C:25](=[O:29])[NH:26][C:27]3[C:23]\2=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=3)[CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: N#CC1(COc2ccc(Cl)cc2C=O)CCCC1
Solvent: CO
Solvent: C1CCNC1
Product: N#CC1(COc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CCCC1
Yield: 90.1 %

Procedure:
In a manner similar to the method described in Example 1b, 1-(4-chloro-2-formyl-phenoxymethyl)-cyclopentanecarbonitrile (17.4 g, 66 mmol) was reacted with 6-chlorooxindole (8.5 g, 51 mmol) and pyrrolidine (4.69 g, 66 mmol) in methanol to give the title compound as a yellow solid (19 g).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[CH:14][N:13]=1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.O.[OH-].[Na+]>C(Cl)Cl>[F:1][CH2:2][CH2:3][NH:4][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[CH:14][N:13]=1
Reactant: COc1ccc2nc(-c3ccc(N(CCF)C(=O)OC(C)(C)C)nc3)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc2nc(-c3ccc(NCCF)nc3)oc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.8 %

Procedure:
tert-Butyl (2-fluoroethyl)[5-(6-methoxy-1,3-benzoxazol-2-yl)pyridin-2-yl]carbamate (0.65 mmol) was dissolved in CH2Cl2 (20 mL), trifluoroacetic acid (0.5 mL) was added and the reaction mixture was stirred for 4 hours at r.t. Water (20 mL), NaOH (1.5 mL, 5M aq., pH adjusted to 12) and CH2Cl2 (20 mL) was added and the layers separated. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried (Na2SO4) filtered and concentrated. Purification using reverse phase HPLC afforded the title compound (78.0 mg). 1H NMR δ ppm 8.74 (d, 1H) 8.03 (dd, 1H) 7.60-7.64 (m, 1H) 7.58 (d, 1H) 7.35 (d, 1H) 6.95 (dd, 1H) 6.70 (d, 1H) 4.60-4.66 (m, 1H) 4.47-4.54 (m, 1H) 3.82 (s, 3H) 3.67-3.74 (m, 1H) 3.60-3.67 (m, 1H); ESI-MS m/z 288 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]3)=[N:5][CH:6]=[N:7]2.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)[N:17]=[CH:16]3)=[N:5][CH:6]=[N:7]2
Reactant: Fc1cccc2ncnc(Nc3ccc4[nH]ncc4c3)c12
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
To a stirred partial solution of 5-fluoro-N-1H-indazol-5-ylquinazolin-4-amine (3.35 g, 12 mmol) and 2-picolyl chloride hydrochloride (2.07 g, 12.6 mmol) in DMF (60 ml) was added portion-wise, sodium hydride (60% dispersion in mineral oil, 1.01 g, 25.2 mmol). The reaction was maintained at ambient temperature by slight cooling and stirred for 18 hours. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (5 ml) and evaporated under high vacuum. The residue was partitioned between 2.5M aqueous NaOH and DCM and the organic phase was dried over anhydrous Na2SO4 and evaporated. The product was purified by chromatography (5% methanol/ethyl acetate) and the crystallized by trituration with ether to give 5-fluoro-N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]quinazolin-4-amine (1.8 g, 41%); NMR spectrum (300 MHz) 5.75 (s, 2H), 6.97 (d, 1H), 7.27 (m, 1H), 7.41 (dd, 1H), 7.54-7.75 (m, 4H), 7.84 (q, 1H), 8.12 (d, 2H), 8.50 (m, 2H), 9.23 (d, 1H); Mass spectrum MH+ 371.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH3:15]>>[CH2:17]([N:16]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14][CH3:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC1CO1
Reactant: CCCNCCCCCCNCCC
Product: CCCCCCCCCC(O)CN(CCC)CCCCCCN(CCC)CC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and N,N'-dipropylhexamethylenediamine affords N,N'-(1,6-hexylene)-bis[N-propyl-2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = CH3 (CH2)2, X = (CH2)6, Z = H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7]Br)[CH3:2].C([O-])=[O:12].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][OH:12])[CH3:2]
Reactant: O=C[O-]
Reactant: CCOC(=O)CC(=O)CBr
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CC(=O)CO

Procedure:
To a solution of 4-bromo-3-ketobutyric acid ethyl ester (2a) (21 g, 0.10 moles) in methanol dried prior to use with Molecular Sieves is added sodium formate (10.2 g, 0.15 moles), and the mixture is refluxed for 1 hour. The reaction mixture is concentrated under reduced pressure to remove the solvent. The residue is extracted with chloroform. The extract is purified by silica gel column chromatography (eluting solvent=benzene/ethyl acetate (2:1)) to give the title compound (3a). Yield: 7.34 g, 50%.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([OH:24])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH:21]1([CH2:20][O:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][C@@H:10]([OH:24])[CH2:9][OH:8])[CH2:23][CH2:22]1
Reactant: O[C@@H](COCc1ccccc1)COc1ccccc1OCC1CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OC[C@H](O)COc1ccccc1OCC1CC1

Procedure:
A solution of (S)-1-benzyloxy-3-[o-(cyclopropylmethoxy)phenoxy]-2-hydroxypropane (10.97 g) in 100 ml ethanol, to which is added 3.5 g of 10% palladium on carbon, is hydrogenated at 45 lbs. pressure at room temperature until the uptake of hydrogen ceases (about 10 minutes). The catalyst is filtered off, washed with ethanol and the filtrate concentrated under reduced pressure leaving a crystalline residue that is recrystallized from 35 ml of ethanol; (S)-3-[o-(cyclopropylmethoxy)phenoxy]-1,2-propanediol, m.p. 95°-97°, [α]D25 =5.32° (c=0.99, CH3OH) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:5][N:6]1[C:10](=[O:11])[N:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=2)[C:15](O)=[O:16])[CH:8]=[N:7]1.C(N(C(C)C)CC)(C)C.O.[OH:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=C[C:39]=2[N:38]=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CC1ON=C(CN)C=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:5][N:6]1[C:10](=[O:11])[N:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=2)[C:15]([NH:38][CH2:39][C:40]2[CH:41]=[C:42]([CH3:43])[O:35][N:36]=2)=[O:16])[CH:8]=[N:7]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccnc(-n2cnn(Cc3ccc(F)c(F)c3)c2=O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cc(CN)no1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CNC(=O)c2ccnc(-n3cnn(Cc4ccc(F)c(F)c4)c3=O)c2)no1
Temperature: 25 °C
Reaction time: 23 h
Yield: 71.1 %

Procedure:
A mixture of 2-(1-(3,4-difluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinic acid (0.22 g, 0.66 mmol), diisopropylethylamine (0.6 mL, 9.57 mmol), 1-hydroxybenzotriazole monohydrate (0.20 g, 1.44 mmol) and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.40 g, 1.24 mmol) and (5-methylisoxazol-3-yl)methanamine (0.19 g, 0.99 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature for 23 hours and concentrated in vacuo. The residue was suspended in a mixture of saturated sodium bicarbonate solution (10 mL) and ether (2.5 mL) and stirred at ambient temperature overnight. The solid was collected by filtration, washed with saturated sodium bicarbonate solution, water, ether, hexanes and dried in vacuo to afford 2-(1-(3,4-difluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-((5-methylisoxazol-3-yl)methyl)-isonicotinamide as a colorless solid (0.20 g, 71% yield): mp 160-161° C.; 1H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 8.53 (d, J=5.7 Hz, 1H), 8.46 (s, 1H), 7.70 (dd, J=5.1, 1.4 Hz, 1H), 7.25-7.09 (m, 4H), 6.03 (s, 1H), 4.96 (s, 2H), 4.67 (d, J=5.7 Hz, 2H), 2.41 (s, 3H); MS (ES+) m/z 427.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:17][O:16][C:15](=[O:18])[C@H:14]([CH2:19][C:20]([OH:22])=[O:21])[C@@H:13]([O:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C@H:12]([CH3:29])[O:11][C:10]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](O)([CH3:34])([CH3:33])[CH3:32].C(=NC(C)C)=NC(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:24]([O:23][C@@H:13]1[C@@H:14]([CH2:19][C:20]([O:22][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:21])[C:15](=[O:18])[O:16][CH2:17][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10](=[O:30])[O:11][C@H:12]1[CH3:29])(=[O:28])[CH:25]([CH3:26])[CH3:27]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CC(=O)O
Reactant: CC(C)(C)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 2-((3S,7R,8R,9S)-3-(tert-butoxycarbonylamino)-8-(isobutyryloxy)-9-methyl-2,6-dioxo-1,5-dioxonan-7-yl)acetic acid (400 mg, 0.928 mmol) in CH2Cl2 (2 mL) was added tert-butyl alcohol (3.44 mg, 4.64 mmol) and DMAP (91 mg, 0.744 mmol) at room temperature (about 22° C.). The solution was cooled to 0° C. and N,N′-methanediylidenedipropan-2-amine (172 uL, 1.11 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 2 h, and then loaded directly onto a SiO2 column and purified by flash chromatography (hexanes/EtOAc gradient) to give the title compound (380 mg, 84%) as a white solid: mp 170-172° C.; 1H NMR (400 MHz, CDCl3) δ 5.44-5.15 (m, 2H), 5.08-4.94 (m, 1H), 4.93-4.75 (m, 2H), 3.74-3.54 (m, 1H), 2.98-2.87 (m, 1H), 2.83-2.71 (m, 1H), 2.61 (hept, J=7.0 Hz, 1H), 2.32-2.21 (m, 1H), 1.44 (s, 9H), 1.40 (s, 9H), 1.27 (d, J=6.3 Hz, 3H), 1.21 (dd, J=7.0, 1.6 Hz, 6H); ESIMS m/z 410 ([M+Na]+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1>CCO.O[Pd]O>[CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1
Reactant: Cc1cccc(Cn2nc(C)c3c([N+](=O)[O-])cccc32)n1
Agent: O[Pd]O
Solvent: CCO
Product: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
A suspension of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (54 mg, 0.19 mmol) in absolute EtOH (1.5 mL) was treated at ambient temperature with dihydroxypalladium (27 mg, 0.019 mmol). The mixture was stirred at ambient temperature under a hydrogen atmosphere for 16 hours, then filtered through a Celite® pad and concentrated to afford 36 mg of the desired product as a clear yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:18])[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:18])[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(=O)CCCCCC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)C(O)CCCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
A solution of crude methyl 7-tert-butoxycarbonyl-2-oxoheptanoate (1 g) in 1,2-dichloroethane (10 ml) was treated with sodium triacetoxyborohydride (822 mg, 3.88 mmol). The mixture was stirred at room temperature for 16 hours, quenched with sat. aq. sodium bicarbonate and extracted with ether. The organic phase was washed with aq. sodium bicarbonate, brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane:ethyl acetate=4:1) to give the title compound (554 mg, 43%, 2 steps) as a colorless liquid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]([N:16]=CN(C(C)C)C(C)C)[N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH3:33]>C(O)C>[NH2:16][C:4]1[N:3]=[C:2]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=2[CH3:33])[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:6][N:5]=1
Reactant: Cc1cc(O)ccc1N
Reactant: CC(C)N(C=Nc1ncc(Oc2ccc(Cl)cc2)c(Cl)n1)C(C)C
Solvent: CCO
Product: Cc1cc(O)ccc1Nc1nc(N)ncc1Oc1ccc(Cl)cc1
Temperature: 24 °C
Reaction time: 20 h
Yield: 6.2 %

Procedure:
Nitrogen was bubbled through a suspension of 2 g (9 mmol) of 4-chloro-5-(4-chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidine (see Example 2) in 20 ml of ethanol for 10 minutes. Then 1.15 g (9.34 mmol) of 4-amino-3-methylphenol was added and nitrogen bubbled through the suspension for 5 minutes. The solution was then tightly sealed and stirred at 24° C. for 20 hours. Then 5 ml of concentrated hydrochloric acid was added to the mixture and refluxed for 60 minutes. The mixture was cooled and spin evaporated. The residue was suspended in 100 mL CH2Cl2 and 400 mL water. The pH was adjusted to 12 with 3N NaOH. The organic phase was washed with water (400 mL) twice, brine (200 mL) and then dried over Na2SO4. The salt was removed by filtration and the filtrate applied to a Silica Gel 60 column (2.5×10 cm) preequilibrated with CH2Cl2. The column was eluted with 800 mL CH2Cl2 and then with mixtures of ethylacetate and CH2Cl2. The fractions showing one spot on TLC (EtOAc; Rf0.45) were pooled and concentrated by spin evaporation. The liquor formed crystals on standing. 0.19 g (6% yield) of product, a white solid, was obtained after drying in vacuo at 105° C. for 16 hours, mp 199-201° C.