Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1>[N:13]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: c1ccc2c(c1)CCN2
Agent: c1ccc2ncncc2c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Ic1ccc2ncnc(N3CCc4ccccc43)c2c1
Yield: 85 %

Procedure:
0.60 g of 4-chloro-6-iodoquinazoline, 0.31 ml of 2,3-dihydro-1H-indole and 0.50 ml of triethylamine in 5.00 ml of dioxane are heated at 80° C. in a flask until the quinazoline has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is purified by means of column chromatography (gradient EA: methanol 0-20% in 16 min.), giving 0.60 g of 4-(2,3-dihydroindol-1-yl)-6-iodoquinazoline as yellowish solid (yield 85%, content 97%); MS-FAB (M+H+)=373.8; Rf (polar method): 2.21 min.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][CH2:28][C@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].Cl.[CH2:36](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][CH2:28][C@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][N:30]2[CH3:36])=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OCC[C@H]2CCCCN2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OCC[C@H]2CCCCN2C)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-((R)-2-piperidin-2-yl-ethoxy)-pyridazine dihydrochloride (0.065 mmol, 0.033 g) and aqueous formaldehyde (37%, 0.323 mmol, 0.03 mL) in dry DCM (2 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.39 mmol, 0.165 g). The mixture was shaken for 12 hours. The reaction was filtered and the resin was washed with DCM (5 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-[2-((R)-1-methyl-piperidin-2-yl)-ethoxy]-pyridazine (0.02 g, 73%). The neutral amine was treated with 2N HCl in diethyl ether (1 mL) and DCM (1 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.025 g). LCMS: m/z 453 [M+1]. 1H NMR (400 MHz, CD3OD) δ 6.97-7.45 (5H, m), 4.55-4.72 (2H, m), 4.35-4.46 (1H, m), 3.46-3.82 (1H, m), 3.05-3.19 (1H, m), 2.79-3.06 (5H, m), 2.44-2.74 (2H, m), 2.10-2.36 (2H, m), 1.74-2.06 (9H, m), 0.79 (3H, t).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18]>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[O:13][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrCc1ccc2ccccc2c1
Product: COc1ccc(C=O)cc1OCc1ccc2ccccc2c1
Yield: 50 %

Procedure:
2-Bromomethylnaphthalene was reacted with 3-hydroxy-4-methoxybenzaldehyde using the conditions described in Example 1 to give 4-methoxy-3-(naphth-2-ylmethoxy)benzaldehyde in 50% yield, m.p. 80° C. Following the procedure described in Note k. above the product so obtained was reacted with thiazol-2-yl-lithium to give 2-[4-methoxy-3-(naphth-2-ylmethoxy)-α-hydroxybenzyl]thiazole as an oil in 62% yield; that product was oxidised with sodium dichromate to give 4-methoxy-3-(naphth-2-ylmethoxy)phenyl 2-thiazolyl ketone in 58% yield, m.p. 149°-150° C.; and the product so obtained was reacted with ethylmagnesium iodide to give the required starting material in 45% yield, m.p. 80° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([P:16](=[O:19])([OH:18])[OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:24][O:25][C:26](=[O:53])[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[N:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:30]=1)O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:24][O:25][C:26](=[O:53])[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[N:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:30]=1)[O:19][P:16]([C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:13]([CH3:15])[CH3:14])([OH:18])=[O:17]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)P(=O)(O)O
Reactant: COC(=O)C(O)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(OP(=O)(O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Temperature: -5 °C
Reaction time: 0.67 h
Yield: 55.4 %

Procedure:
A solution of (1R)-(+)-(1-benzyloxycarbonylamino-2-methylpropyl)phosphonic acid (4.27 g, 14.9 mmol) in 50 mL of DMF was cooled to −20° C. using a dry ice/methanol bath. To this was added thionyl chloride (1.20 mL, 16.5 mmol) and the reaction mixture was stirred at −5° C. for 40 minutes. 2-(3-(N′,N″-Di(t-butoxycarbonyl)guanidino)phenyl)-2-hydroxyethanoic acid methyl ester (5.60 g, 13.2 mmol) was added to the reaction mixture as a solution in 15 mL of DMF and the reaction was allowed to warm to ambient temperature. After stirring for 3 days, 20 mL of saturated NaHCO3 was added. The solution was washed with ether (2×), combined and concentrated in vacuo to give a mixture of product and starting material. The product was purified by flash column chromatography (10%-100% ethyl acetate/methylene chloride), followed by methanol to give 5.07 g (55%) of 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:36])[C@H:24]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[NH2:25].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CO.C(N(CC)CC)C.CN(C)C=O>[CH3:21][O:22][C:23](=[O:36])[C@H:24]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[NH:25][C:17](=[O:19])[C@H:12]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Nα -Benzyloxycarbonyl-L-isoleucine, 2.65 g., and 2.54 g. of L-tryptophan methyl ester hydrochloride are dissolved in 30 ml. of dimethylformamide and cooled in an ice bath. Triethylamine, 1.4 ml., is added and then 1.5 g. of 1-hydroxy-benzotriazole. Lastly 2.3 g. of dicyclohexylcarbodiimide is added and the reaction let warm to room temperature with stirring continued for 40 hours. The mixture is filtered and the solvent evaporated. The residue is dissolved in 150 ml. of ethyl acetate and washed with 0.5 N hydrochloric acid, saturated sodium chloride solution, 5% sodium bicarbonate solution and finally with saturated sodium chloride solution. The ethyl acetate solution is dried over magnesium sulfate, filtered and the solution evaporated. The product is crystallized from methanol-ether-hexane to give 2.58 g. of the above named product, mp. 152°-155° C; [α]D23 -16.6° (c 1.95, methanol).
Reaction SMILES: [C:1]([CH:4]1[C:9](=O)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)(=[O:3])[CH3:2].[NH2:18]O.Cl.O>CCO>[CH3:2][C:1]1[O:3][N:18]=[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=12
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1onc2c1CNCC2
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A mixture of tert-butyl 3-acetyl-4-oxopiperidine-1-carboxylate (1.50 g) and NH2OH.HCl (0.50 g) in anhydrous EtOH was heated to reflux for 0.5 h. The reaction mixture was cooled to rt, and then poured into 20 mL of water. The resulted mixture was extracted with CH2Cl2 (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo, the residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) DCM/MeOH) to give the title compound as yellow oil (0.45 g, 52.00%), HPLC: 90.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 139.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.31 (s, 3H), 2.86 (t, J=8.0 Hz, 2H), 3.15 (t, J=8.0 Hz, 2H), 3.92 (s, 2H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:33][CH:34]=2)=[N:3]1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)Cc1cn(C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 59.3 %

Procedure:
A mixture of methyl 3-hydroxy-1-methyl-1H-pyrazol-4-ylacetate (245 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (452 mg), potassium carbonate (398 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 6 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 1-methyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-ylacetate (382 mg, yield 59%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11]1>>[OH:3][C:1]([CH:11]1[CH2:12][CH2:13][O:14][C:10]1=[O:15])([CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCCO1
Reactant: CC(=O)c1ccccc1
Product: CC(O)(c1ccccc1)C1CCOC1=O

Procedure:
Using the same procedure as described above, acetophenone is reacted with γ-butyrolactone to produce 2-(1-hydroxy-1-methyl-1-phenylmethyl)-γ-butyrolactone.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16]O)[C:13]([F:18])=[CH:12][C:10]=3[N:11]=2)=[C:5]([CH3:19])[NH:4][N:3]=1.[Br-].[CH3:21][NH:22][CH3:23]>>[CH3:21][N:22]([CH2:16][C:14]1[C:13]([F:18])=[CH:12][C:10]2[N:11]=[C:7]([C:6]3[C:2]([NH2:1])=[N:3][NH:4][C:5]=3[CH3:19])[S:8][C:9]=2[CH:15]=1)[CH3:23]
Reactant: CNC
Reactant: Cc1[nH]nc(N)c1-c1nc2cc(F)c(CO)cc2s1
Agent: [Br-]
Product: Cc1[nH]nc(N)c1-c1nc2cc(F)c(CN(C)C)cc2s1

Procedure:
The title compound (28 mg) was prepared in two steps starting from 30 mg (0.1 mmol) of [2-(3-amino-5-methyl-1H-pyrazol-4-yl)-5-fluorobenzothiazol-6-yl]methanol. The reaction of the bromide was carried out with excess dimethylamine. MS (m/z, ES+): 306.1 (M+1, 43%), 261.1 (60%), 153.5 (100%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:30])=[C:8]2[C:14]([C:15]#[N:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+].CO>>[C:15]([C:14]1[C:8]2[C:9](=[CH:10][N:11]=[C:6]([C:4]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:5])[C:7]=2[OH:30])[N:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]=1[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)#[N:16]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(-c2ccc(F)cc2)n(-c2ccccc2)c2cnc(C(=O)NCC(=O)O)c(O)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 3-cyano-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 431 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=O.Cl.[CH3:8][C:9]1[CH:13]=[C:12]([NH2:14])[S:11][N:10]=1.C(N(CC)CC)C>ClCCl.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:14][C:12]1[S:11][N:10]=[C:9]([CH3:8])[CH:13]=1
Reactant: Cc1cc(N)sn1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCNc1cc(C)ns1

Procedure:
From methoxyacetyl chloride and 3-methyl-isothiazol-5-ylamine hydrochloride with triethylamine in dichloromethane. Then treatment with a borane-dimethyl sulphide complex in tetrahydrofuran.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][NH2:27]>>[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][NH:27][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: NNc1ccccc1Br
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(NNc2ccccc2Br)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and (2-bromo-phenyl)-hydrazine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO at 60° C.) δ 9.19 (br, 1H), 7.66 (brd, 1H), 7.46 (d, 1H), 7.44 (br, 1H), 7.20 (t, 1H), 6.98-6.75 (3H), 6.71 (t, 1H), 6.23 (s, 1H), 3.94 (t, 2H), 3.82 (s, 3H) and 2.93 (t, 2H); MS (ESI) (M+H)+ 413, 415.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]([CH:15]([C:20]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=2[C:22]#N)[C:16]([OH:19])([CH3:18])[CH3:17])[CH:13]=[N:12][CH:11]=1)(C(C)(C)C)(C)C.S(=O)(=O)(O)[OH:30].C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[Cl:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:20]2[C:21]=1[C:22](=[O:30])[O:19][C:16]([CH3:18])([CH3:17])[CH:15]2[N:14]1[C:10]([CH2:9][OH:8])=[CH:11][N:12]=[CH:13]1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(O)C(c1cccc(Cl)c1C#N)n1cncc1CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC(=O)c2c(Cl)cccc2C1n1cncc1CO

Procedure:
2-{1-[5-(tert-Butyldimethylsilanyloxymethyl)-imidazol-1-yl]-2-hydroxy-2-methyl-propyl}-6-chloro-benzonitrile (0.188 g, 0.616 mmol), prepared in a similar fashion as described in Example 6c is dissolved in 1,4-dioxane (5 mL). Concentrated sulfuric acid (0.130 mL, 2.46 mmol) and water (0.130 mL) are added and the mixture is stirred at reflux for 16 h. After cooling down, the mixture is basified to pH 10 using solid sodium bicarbonate and is then diluted with water and extracted with ethyl acetate twice. The combined organic phase is dried over Na2SO4 and concentration in vacuo. The residue obtained is purified by silica gel chromatography (dichloromethane-methanol, 9:1) to give 8-chloro-4-(5-hydroxymethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one; HRMS (ESI) m/z 307.0845 [(M+H)+: Calcd for C15H16N2O3Cl: 307.0849]; 1H NMR (400 MHz, MeOD) δ ppm 1.30 (s, 3 H), 1.56 (s, 3 H), 4.77 (d, J=13.6 Hz, 1 H), 4.83 (d, J=13.6 Hz, 1 H), 5.77 (s, 1 H), 7.02 (s, 1 H), 7.35 (s, 1 H), 7.55 (br. d, J=7.3 Hz, 1 H), 7.68 (dd, J=8.0, 7.3 Hz, 1 H), 7.72 (dd, J=8.0, 1.5 Hz, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.I[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[N:13]([CH:21]([CH3:23])[CH3:22])[N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:21]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C:11]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[N:12]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cncnc1
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cncnc2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of 5-Pyrimidinylboronic acid (15 mg, 0.14 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (15 mg, 0.015 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O) to yield BA53. ESI-MS (M+H)+ m/z calcd 256.1, found 256.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.Cl[CH2:17][C:18]1[O:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:19]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH3:12][C:8]1[C:9]([CH2:17][C:18]2[O:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:14])([CH3:13])[C:6]=2[CH:7]=1
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(CCl)o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cc3c(cc2C)C(C)(C)CCC3(C)C)o1
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution containing 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphtalene 4 (20 g, 99 mmol) and methyl 5-(chloromethyl)-2-furoate 5 (17.28 g, 99 mmol) in methylene chloride (500 mL, 0.2 M), aluminum trichloride (16.46 g, 124 mmol) is added slowly as a solid at the reflux temperature of methylene chloride. The solution is refluxed for an additional two hours. The reaction is monitored by tlc in 10% ethyl acetate/hexanes solution. The reaction is cooled to room temperature and the unreacted aluminum trichloride is quenched with water over 15 minutes. The crude product is extracted with methylene chloride and passed through silica gel (80 g) and eluted with methylene chloride. The solvent is evaporated in vacuo to syrup. The crude product us purified with silica gel (300 g) via a plug filtration column. Methyl 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furoate 6 is eluted with 2% ethyl acetate/hexanes to afford 15.4 g (46% yield). NMR 1.25 (s, 6H), 1.28 (s, 6H), 1.67 (s, 4H), 2.23 (s, 3H), 3.89 (s, 3H), 3.97 (s, 2H), 5.95 (d, 1H), 7.09 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([N+:35]([O-:37])=[O:36])[CH:34]=1)[C:29](Cl)=[O:30])([O-:25])=[O:24]>N1C=CC=CC=1>[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([N+:35]([O-:37])=[O:36])[CH:34]=1)[C:29]([O:21][C@H:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([O:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:22])[CH2:16]1)=[O:30])([O-:25])=[O:24]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1COC1CCCC(O)C1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](OC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)C1
Temperature: 50 °C

Procedure:
0.5 g of 3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol is dissolved in 3 ml of pyridine and, at 0° C., 0.6 g of 3,5-dinitrobenzoyl chloride is added. The reaction mixture is then heated at 50° C. for 10 minutes. The reaction is checked (LCMS) showing the formation of the desired product, in addition to unreacted alcohol cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol. After a further 10 minutes of stirring at room temperature, the reaction is terminated by addition of 5 ml of concentrated hydrochloric acid, and the crude product is filtered off with suction, taken up in ethyl acetate, washed with saturated sodium bicarbonate and sodium chloride solution and dried over magnesium sulfate. Purification by HPLC gives 0.15 g of the compound cis-3-[2-(4-fluorophenyl )-5-methyloxazol4-ylmethoxy]cyclohexyl 3,5-dinitrobenzoate as yellow solid.
Reaction SMILES: CC([N:5]([CH2:9][C:10]1[C:11](=[O:21])[NH:12][C:13]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:14][C:15]=1[CH3:16])C(=O)[O-])(C)C.[ClH:22]>>[NH2:5][CH2:9][C:10]1[C:11](=[O:21])[NH:12][C:13]([CH:17]2[CH2:18][CH2:19][CH2:20]2)=[CH:14][C:15]=1[CH3:16].[ClH:22]
Reactant: Cc1cc(C2CCC2)[nH]c(=O)c1CN(C(=O)[O-])C(C)(C)C
Agent: Cl
Product: Cc1cc(C2CCC2)[nH]c(=O)c1CN
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl[(6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3pyridinyl)methyl]carbamate (2.1 g, 7.2 mmol) in 4 N HCl (in 15 mL 1,4 dioxane) was heated to 60° C. for 1 h. The mixture was cooled to room temperature. The mixture was filtered and dried to give 3-(aminomethyl)-6-cyclobutyl-4-methyl-2(1H)-pyridinone as an HCl salt (1.95 g, 90%). LCMS MH+=193.1 1H NMR (400 MHz, DMSO-d6) δ 11.70 (br s, 1H), 8.01 (s, 3H), 6.04 (s, 1H), 3.74 (d, 2H), 3.32-3.39 (m, 1H), 2.22 (s, 3H), 2.17-2.20 (m, 2H), 2.06-2.11 (m, 2H), 1.85-1.95 (m, 1H), 1.71-1.79 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[CH:7]=[CH:6][C:5]=1[I:15])[CH3:2].[H-].[Na+].I[CH3:19]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH3:19])[CH:7]=[CH:6][C:5]=1[I:15])[CH3:2]
Reactant: CI
Reactant: CCOc1cc(C(C)(C)CO)ccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(C(C)(C)COC)ccc1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
To a solution of 2-ethoxy-4-(2-hydroxy-1,1-dimethylethyl)iodobenzene (1.0 g, 3.123 mmol, example 4) in tetrahydrofuran cooled to 0° C. was added sodium hydride (150 mg, 6.246 mmol, 60% in mineral oil). Iodomethane (0.58 mL, 9.369 mmol) was added after 15 min. The icebath was then removed and the reaction mixture was stirred at room temperature for 12 h. Saturated solution of ammonium chloride was added and the mixture was partitioned between ethyl acetate (20 mL) and water (5 mL). The product was extracted with ethyl acetate (2×). The organic layers were washed with water (1×), brine (1×), dried over anhydrous sodium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of 0-60% ethyl acetate in hexanes) gave 2-ethoxy-4-(2-methoxy-1,1-dimethylethyl)iodobenzene (891 mg, 85% yield) as clear oil.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[OH:11][CH2:12][CH2:13][NH:14][NH2:15].[ClH:16]>C(O)C>[ClH:16].[NH2:6][C:5]1[N:14]([CH2:13][CH2:12][OH:11])[N:15]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: NNCCO
Agent: Cl
Solvent: CCO
Product: Nc1c(N=O)cnn1CCO
Temperature: 76.5 °C
Yield: 91.5 %

Procedure:
To a flask having an inner volume of 200 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 16.86 g (110 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 94.0% by weight synthesized in the same manner as in Example. 1, 8.02 g (100 mmol) of 2-hydroxyethylhydrazine with a purity of 95% by weight, 100 ml of ethanol and 10 ml (120 mmol) of conc. hydrochloric acid, and the mixture was reacted under reflux (76 to 77° C.) for one hour. After completion of the reaction, when the reaction mixture was analyzed by high performance liquid chromatography (absolute calibration curve method), it was found that 17.62 g of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole hydrochloride (Reaction yield: 91.5%) had been formed.