Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:23]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:23]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(Cc2ccccc2)c(=O)n(CCO)c1C
Solvent: ClC(Cl)Cl
Product: Cc1nc(Cc2ccccc2)c(=O)n(CCCl)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.5 %

Procedure:
Thionylchloride (0.42 ml, 6.0 mM) was added dropwise under ice-cooling to a compound 112 (1.29 g, 5 mM) dissolved in chloroform (6 ml), and stirred at room temperature for 5 hours. Chloroform (70 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K2CO3, the resulting aqueous layer being twice extracted with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g), packed with chloroform, and eluted with chloroform to obtain compound 613 (1.00 g, yield: 87.5%).
Reaction SMILES: [F:1][C:2]([CH3:12])([CH3:11])[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[BH4-].[Na+]>CO>[F:1][C:2]([CH3:12])([CH3:11])[CH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4]
Reactant: CC(C)(F)C(=O)c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(F)C(O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
In methanol (30.0 mL) was dissolved 2-fluoro-2-methyl-1-(pyridin-3-yl)propan-1-one (1.73 g, 10.3 mmol) obtained in Step 3. Sodium borohydride (584 mg, 15.4 mmol) was added and the mixture was stirred at 0° C. for 30 minutes. The solvent was evaporated under reduced pressure and water was added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) and further purified by preparative thin-layer chromatography (hexane/ethyl acetate=3/7) to give Compound A11 (1.54 g, 89% yield).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:34][C:33]=1[Cl:47]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:31][C:32]1[C:33]([Cl:47])=[CH:34][C:35]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:36][C:37]=1[Cl:38])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -75 °C
Yield: 86 %

Procedure:
Stir a mixture of (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (345 g, 1.33 mol) and THF (1.8 L) in a 12 L 3-neck round bottom flask, with internal temperature probe/nitrogen inlet and addition funnel, under a nitrogen atmosphere and cool to −75° C. Transfer 1 M LiHMDS (1.6 L) to the addition funnel and add at a rate such that the internal temperature does not reach above −60° C. After the addition is complete, allow the reaction to stir at −25° C. for 30 min then cool to about −60° C. At this point add solid 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzene portionwise over 5 min. When the addition is complete, transfer the reaction vessel to a −10° C. acetone bath and maintain the internal reaction temperature below 10° C. for 1 hr. Cool the mixture to 0° C. then quench with 2 L aqueous 1N hydrochloric acid. Transfer the mixture to a 22 L separatory funnel and dilute with 2.5 L water and 2 L ether. Separate the layers and extract the aqueous layer with ether. Dry the combined organic phase over anhydrous magnesium sulfate, filter and concentrate to 800 g of a thick oil. Purify by silica gel chromatography using hexanes:ethyl acetate to obtain 597 g, (86%) of a colorless oil.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[C:19]2[N:23]([CH:24]=1)[CH:22]=[CH:21][S:20]2>CN(C=O)C.O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[C:19]2[N:23]([C:24]=1[I:8])[CH:22]=[CH:21][S:20]2
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2cn3ccsc3n2)c(F)c1
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3sccn3c2I)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
NIS (5.56 g, 24.7 mmol) was added to 6-(2,4-difluorophenyl)imidazo[2,1-b]thiazole (5.84 g, 24.7 mmol) in DMF (60 mL) then stirred at ambient temperature for about 30 min. The mixture was diluted with water (about 500 mL), filtered, and washed with Et2O to give the title compound (5.17 g, 57.8%): LC/MS (Table 1, Method a) Rt=2.13 min; MS m/z: 363.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:44][CH2:45][CH2:46][CH2:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[Cl:44][CH2:45][CH2:46][CH2:47][S:48]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)(=[O:50])=[O:49]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(CCCCl)Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Reaction time: 2 h

Procedure:
To a solution of 3-(4-[4-(4-aminophenyl)piperazin-1-yl]phenoxy)-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 1) (0.2 g, 0.37 mmole) and pyridine (0.1 g, 1.2 mmole) in methylene chloride (15 ml) at 0° was added, dropwise, a solution of 3-chloropropanesulphonyl chloride (0.072 g, 0.4 mmole) in methylene chloride (1 ml). The resulting mixture was stirred at 0° for 2 hours, an additional portion of 3-chloropropanesulphonyl chloride (0.036 g, 0.2 mmole) was added and stirring was continued overnight at room temperature, the reaction mixture was quenched by the addition of aqueous citric acid, the organic phase separated and washed with water. After drying over magnesium sulphate, the organic phase was concentrated under reduced pressure and the resulting gum purified by flash chromatography on silica gel eluting with ethyl acetate to yield, after collection and evaporation of appropriate fractions, the desired product as a foam, m.p. 80°- 81° (0.24 g, 96%).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][N:14]=[C:15]([CH3:16])[C:10]3=[CH:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>CO.O.C(O)C>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][NH:14][CH:15]([CH3:16])[C:10]3=[CH:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=NCCn2c1cc(-c1ccccc1)c2-c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC1NCCn2c1cc(-c1ccccc1)c2-c1ccccc1
Yield: 86 %

Procedure:
3,4-Dihydro-6,7-diphenyl-1-methylpyrrolo[1,2-a]pyrazine (2.0 g) was dissolved in a mixture of 100 ml of methanol and 10 ml of water under argon. The solution was treated portionwise with 0.8 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 150 ml of methylene chloride and washed with 100 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 60 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude produce, 2.0 g of yellow resin, was dissolved in a 20-fold amount of ethanol and boiled briefly with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 2.1 g (86%) of 6,7-diphenyl-1,2,3,4-tetrahydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (2:1); m.pt.: 187°-190° C. (dec.).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].[C:43]([C:46]1[CH:53]=[C:52]([Cl:54])[C:49]([C:50]#[N:51])=[C:48]([I:55])[C:47]=1O)(=[O:45])[CH3:44]>O1CCCC1.C(OCC)(=O)C>[C:43]([C:46]1[C:47]([O:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[C:48]([I:55])[C:49]([C:50]#[N:51])=[C:52]([Cl:54])[CH:53]=1)(=[O:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC(=O)c1cc(Cl)c(C#N)c(I)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(C#N)c(I)c1OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
Diethyl azodicarboxylate (2.3 mL, 14 mmol) was added slowly to a solution of triphenylphosphine (3.79 g, 14.5 mmol) and tert-butyl (2-hydroxyethyl)carbamate (2.3 g, 14 mmol) in tetrahydrofuran (93 mL) and cooled in an ice bath. After stirring for 15 minutes, the 4-acetyl-6-chloro-3-hydroxy-2-iodobenzonitrile (3.1 g, 9.6 mmol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with water, 1 N HCl, and brine, then dried over magnesium sulfate and concentrated to give a dark oil. The product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give tert-butyl [2-(6-acetyl-4-chloro-3-cyano-2-iodophenoxy)ethyl]carbamate as a tan solid (3.2 g, 71%). LCMS calculated for C16H18ClIN2O4Na (M+Na)+: m/z=487.1; found: 486.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([O:34][CH3:35])[C:23]([NH:26]C(=O)OC(C)(C)C)=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([O:34][CH3:35])[C:23]([NH2:26])=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cnc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cnc1N
Yield: 28 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl (5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxypyridin-2-yl)carbamate (120 mg, 0.233 mmol) was deprotected in TFA/DCM (1/5 ml). This afforded 27 mg (21.9% yield) of the titled compound. 1H NMR (DMSO-d6, 400 MHz): δ 8.577-8.572 (d, 1H), 8.417-8.413 (d, 1H), 8.37 (s, 1H), 8.03 (s, 2H), 7.956-7.953 (d, 1H), 7.86-7.79 (s, 1H), 7.799-7.793 (d, 1H), 7.40-7.39 (q, 1H), 7.12-7.07 (m, 3H), 5.40 (s, 2H), 4.06 (s, 3H). MS: m/z=415.6 (M+1), HPLC: 93.86% in method A.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Fc1cc(F)c2c(c1)NCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(F)cc(F)cc21
Yield: 59.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 310 mg of 4,6-difluoro-2,3-dihydro-1H-indole, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 225 mg of 2-[2-(4,6-difluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[C:10](OCC)(OCC)(OCC)[CH3:11].C1(C)C(S(O)(=O)=O)=CC=CC=1>>[CH2:4]([C:3]12[CH2:8][O:9][C:10]([CH3:11])([O:7][CH2:6]1)[O:2][CH2:1]2)[CH3:5]
Reactant: CCOC(C)(OCC)OCC
Reactant: CCC(CO)(CO)CO
Agent: Cc1ccccc1S(=O)(=O)O
Product: CCC12COC(C)(OC1)OC2
Temperature: 25 °C

Procedure:
Trimethylolpropane (268.0 g, 2.0 mol), triethyl orthoacetate (356.4 g, 2.20 mol) and toluene sulfonic acid (4.0 g) were charged into a oven dried round bottom flask equipped with a stirring bar, distillation head and under nitrogen. The resulting solution was heated until the theoretical amount od ethanol was collected. The reaction was cooled to room temperature. Fractional vacuum distillation afforded the product as a water clear liquid, boiling point 62.8-71.2° C. at 0.78-1.80 torr. Yield: 276.0 g (87.3%)
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][C:18]#[C:19][CH2:20][CH2:21][CH3:22].C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:26]/[C:27]([NH:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22]
Reactant: CCCC#COc1cc(C=O)ccc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C#CCCCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 75.3 %

Procedure:
Piperidine (0.45 mL, 4.6 mmol) was added to a suspension of 4-methoxy-3-(pent-1-ynyloxy)benzaldehyde (1.0 g, 4.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.93 g, 4.2 mmol) in toluene (10 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(4-methoxy-3-(pent-4-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (1.2 g, 77%) as a yellow crystalline solid; mp 154-156° C.; δH (400 MHz, DMSO-d6) 1.91 (p, 7.6 Hz, 2H, CH2), 2.34 (dt, J=7.6, 2.4 Hz, 2H, CH2CCH), 2.82 (t, J=2.4 Hz, 1H, CCH), 3.80 (s, 3H, OCH3), 4.10 (t, J=7.6 Hz, 2H, OCH2), 6.78 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.26 (s, 1H, NH), 13.56 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 14.5, 27.8, 55.6, 66.8, 71.6, 83.8, 111.7, 111.8, 116.6, 119.9, 120.3, 122.6, 122.8, 127.2, 131.1, 134.0, 141.1, 141.6, 148.1, 150.9, 164.1, 169.4; HRMS (ESI) calculated for C22H21NO5 [M+H]+ 380.1492. found 380.1490; vmax 754, 1257, 1510, 1584, 1659, 2944, 3250, 3512 cm−1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]45[CH2:30][CH:25]6[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]6)[CH2:22]4)[CH2:28]5)=[CH:17][CH:16]=3)=[N:10][C:9]=2[CH:31]=1)=[O:4].[Br-].[Al+3].[Br-].[Br-].O.Cl>CSC.ClCCl>[C:21]12([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:11]4[O:12][C:8]5[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:31][C:9]=5[N:10]=4)=[CH:16][CH:17]=3)[CH2:28][CH:27]3[CH2:29][CH:23]([CH2:24][CH:25]([CH2:26]3)[CH2:30]1)[CH2:22]2
Reactant: COC(=O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Solvent: CSC
Solvent: O
Product: O=C(O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65.9 %

Procedure:
To a solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid methyl ester (100 mg, 0.24 mmol) in dimethyl sulfide (5 ml) and dichloromethane (5 ml) was added aluminum bromide (1.02 g, 3.84 mmol). The reaction mixture was stirred at room temperature for 2.5 h, after which water and 10% HCl were added. After stirring at room temperature for 1 h, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2Cl2:MeOH=4:1) to give 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid as a white solid (63.8 mg, 66.0% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:16]=[C:15]([CH3:17])[C:14]([N:18]3[CH:22]=NC=N3)=[N:13][C:12]2=[O:23])[CH2:8][C@@H:7]1[N:24]=[N+:25]=[N-:26])(=[O:3])[CH3:2].[CH2:27](N)[CH2:28]C>CC#N>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:16]=[C:15]([CH3:17])[C:14]([NH:18][CH2:22][CH2:27][CH3:28])=[N:13][C:12]2=[O:23])[CH2:8][C@@H:7]1[N:24]=[N+:25]=[N-:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(-n3cncn3)nc2=O)C[C@@H]1N=[N+]=[N-]
Reactant: CCCN
Solvent: CC#N
Product: CCCNc1nc(=O)n([C@H]2C[C@H](N=[N+]=[N-])[C@@H](COC(C)=O)O2)cc1C

Procedure:
1-(5-O-Acetyl-3-azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-5-methyl-4-(1,2,4-triazol-1-yl)-2-(1H)-pyrimidinone (0.5 g, 1.4 mMol) was dissolved in dry CH3CN (50 mL) and treated with n-propylamine (0.6 mL, 7 mMol) at ambient temperature for 48 hours. The reaction was evaporated to an oil and chromatographed on silica gel eluted with 20:1 CHCl3/MeOH (v/v). The appropriate fractions were combined and evaporated to give the title compound as a solid: mp=138°-140° C.; UV(nm): at pH 1 λmax=285,217(ε=14900,12200), λmin=246(ε=2500); at pH 13 λmax=274(ε=12500), λmin=250(ε=9000), λsh=236(ε=10000); H NMR(DMSO-d6) δ7.32(s,1H,H6), 7.24-7.18(m,1H,--NH--), 6.13(t,1H,H1',J=6.44 Hz), 4.45-4.40(m,1 H,H3'), 4.23-4.21(m,2H,--NH--CH2--), 4.00-3.92(m,1H,H4'), 3.26-3.19(m,2H,H5'), 2.33-2.26(m,2H,H2'), 2.05(s,3H,acetyl), 1.85(s,3H,5-CH3), 1.57-1.46(m,2H,--CH2--CH3), 0.88-0.81(t,3H,--CH2--CH3).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[C:4]2[CH2:13][S:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:5]=2[O:6][C:7]=1[C:8]#[N:9].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][C:2]1[C:3](=[O:18])[C:4]2[CH2:13][S:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:5]=2[O:6][C:7]=1[C:8]1[NH:21][N:20]=[N:19][N:9]=1
Reactant: Cc1c(C#N)oc2c(c1=O)CSc1ccccc1-2
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2nnn[nH]2)oc2c(c1=O)CSc1ccccc1-2
Temperature: 110 °C
Yield: 68.1 %

Procedure:
A mixture of 3-methyl-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-2-carbonitrile (3.14 g, 12.3 mmoles, described in Example 6), sodium azide (0.884 g, 13.6 mmoles) and ammonium chloride (0.130 g, 2.4 mmoles) in dimethylformamide (18 ml) is heated at 110° C. for 18 hr. The dark solution is evaporated and the residue is dissolved in water (50 ml). The aqueous solution is washed with ethyl acetate and acidified with 10% hydrochloric acid. The precipitate is collected, washed with water and crystallized from acetone-water to give the title compound (2.5 g), mp 247°-248° C.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[O:12])[CH2:7][CH2:6]1.O.[OH-].[Na+]>C1COCC1.ClCCl>[O:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[C:11]([N:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]2[CH2:2][O:18]2)[CH2:6][CH2:7]1)=[O:12]
Reactant: O=C([C@H]1CCCO1)N1CCN(C[C@H](O)CCl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C([C@H]1CCCO1)N1CCN(C[C@H]2CO2)CC1
Reaction time: 1 h

Procedure:
To a cold solution of (S)-1-chloro-3-(4-[(R)-tetrahydro-2-furoyl]-1-piperazinyl)-2-propanol (2.4 g, 8.67 mmol) in THF (25 mL) in an ice bath was added water (7 mL), and then sodium hydroxide (0.416 g, 10.41 mmol) as solid pellets. The mixture was stirred vigorously at the same temperature for 1 h, and diluted with dichloromethane (200 mL). The mixture was washed with 1 M sodium hydroxide and brine solution, then dried and concentrated, to provide the title intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:6]=[N:7][CH:8]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cncc(Nc2ncccc2-c2nc(C)nc3[nH]cnc23)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A suspension of N-(5-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (60 mg, 0.144 mmol) in DCM (3 mL) was cooled to 0° C., treated with trifluoroacetic acid (3 mL, 40.4 mmol), and the yellow solution was stirred at 0° C. for 1 h. The mixture was concentrated in vacuo, the residue was neutralized with 2 M NH3 in MeOH and then concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 2% to 10% 2 M NH3-MeOH in DCM to give N-(5-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (30 mg, 0.090 mmol, 62.6% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.66 (s, 1H); 13.09 (s, 1H); 9.84 (dd, J=7.82, 1.56 Hz, 1H); 8.63 (s, 1H); 8.46 (d, J=1.76 Hz, 1H); 8.41 (dd, J=4.69, 1.76 Hz, 1H); 8.20 (s, 1H); 7.95 (d, J=2.54 Hz, 1H); 7.10 (dd, J=7.82, 4.69 Hz, 1H); 3.87 (s, 3H); 2.89 (s, 3H). m/z (ESI, +ve ion) 334 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Product: O=C/C=C/c1ccc(-c2ccccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyridinyl)-benzaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].Cl.[CH3:11]O>>[NH2:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:11])=[O:4]
Reactant: CC(C)CC(N)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)CC(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
2-Amino-4-methylpentanoic acid (5.0 g 38.2 mmol) was slowly added to sat. HCl/MeOH (50 mL). The mixture was stirred (RT, 5 h) then heated to reflux (16 h). After the reaction, the solvent was removed under reduced pressure. The residue was diluted with water (50 mL), then NaHCO3 was added to adjust pH=7. The mixture was then extracted with DCM (3×50 mL), the combined organic layers were dried over MgSO4, concentrated under reduced pressure to afford methyl 2-amino-4-methylpentanoate as a colorless liquid (5.3 g, 96%). Mass calculated for C7H15NO2=145.20. found: [M+H]+=145.9. The product was used in next step without further purification.