Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH2:19]([O:18][P:17]([CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8])([O:21][CH2:22][CH3:23])=[O:24])[CH3:20]
Reactant: COC(=O)c1ccc(CBr)cc1C(=O)OC
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(C(=O)OC)c(C(=O)OC)c1)OCC
Yield: 77 %

Procedure:
65.7 g (229 mmol) of dimethyl 4-bromomethylphthalate are placed in 100 ml (583 mmol) of triethyl phosphite in a round-bottomed flask. The mixture is refluxed for 4 hours. The medium is then distilled to remove the triethyl phosphite. 60.7 g (77%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11].O[N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[O:24]=[C:19]1[CH2:20][CH2:21][C:22](=[O:23])[N:18]1[O:15][C:14](=[O:16])[CH2:13][NH:12][C:10](=[O:11])[CH2:9][N:3]1[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1]
Reactant: O=C1CCC(=O)N1O
Reactant: CC1CCCC(C)N1CC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1CCCC(C)N1CC(=O)NCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.54 g (20 mMol) [2-(2,6-Dimethyl-piperidin-1-yl)acetylamino]-acetic acid (30) were added to 2.30 g (20 mMol) N-Hydroxysuccinimide and 4.12 g (20 mMol) N,N′-Dicyclohexyl-carbodiimide dissolved in 150 ml dichloromethane. The reaction mixture was stirred for 16 h at room temperature. The solution was filtered and the filtrate was evaporated in vacuo to dryness. The residue was dissolved in 50 mL dichloromethane and treated with charcoal. After filtration, the solution was evaporated in vacuo to dryness and the product was recrystallised from ethyl acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:25])=[CH:11][C:12]([NH:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:37])[C:27]1[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[C:29]([O:30][CH3:31])[CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([F:25])=[CH:11][C:12]([NH:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:13]([CH:17]=1)[C:14]([NH:37][CH2:26][C:27]1[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[C:29]([O:30][CH3:31])[CH:28]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(O)c1cc(OCc2ccccc2)c(F)cc1NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(OCc3ccccc3)c(F)cc2NC2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A mixture of 14 g of the compound obtained in Step 4.4, 7.46 g of veratrylamine, 19.99 g of HBTU and 13.1 g of DIEA in 300 ml of DMF is stirred for 2 hours at room temperature. The solvent is evaporated off under reduced pressure and the residue is taken up in DCM. The resulting solution is washed twice with saturated aqueous NaHCO3 solution. The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/EtOAc mixture from (90/10, v/v) to (40/60, v/v) to give 16 g of the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][S:23][C:24]2[S:25][C:26]([CH3:29])=[N:27][N:28]=2)[CH:7]=1)[CH3:2].[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:32]([Cl:31])=[CH:33][CH:34]=3)=[CH:17][C:16]=2[CH2:22][S:23][C:24]2[S:25][C:26]([CH3:29])=[N:27][N:28]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSc2nnc(C)s2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSc2nnc(C)s2)c1

Procedure:
As described for Example 10, [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and 5-methyl-1,3,4-thiadiazole-2-thiol were reacted to form {4-methoxy-3-[2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-4-nitro-phenoxy]-phenyl}-acetic acid ethyl ester, which was reduced to {3-[4-amino-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and then treated with 4-chlorobenzoyl chloride to provide {3-[4-(4-chloro-benzoylamino)-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester to the acid provided Compound 19.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:40])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])=[CH:18][C:17]=1[O:38][CH3:39])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:6]([OH:7])=[O:5])=[O:40])=[C:17]([O:38][CH3:39])[CH:18]=1)([OH:33])=[O:32]
Reactant: COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)ccc1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)O)ccc1OCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A solution of 250 mg (0.44 mmol) (R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 188 mg (94%) of the title compound as a white powder.
Reaction SMILES: [Na].[CH3:2][C@H:3]([NH:11][C:12]1[N:17]=[C:16](Cl)[N:15]=[C:14]2[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:21][C:13]=12)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:28]([OH:31])[CH2:29][CH3:30]>[Na+].[Cl-]>[CH3:2][C@H:3]([NH:11][C:12]1[N:17]=[C:16]([O:31][CH2:28][CH2:29][CH3:30])[N:15]=[C:14]2[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:21][C:13]=12)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCCO
Reactant: C[C@@H](Cc1ccccc1)Nc1nc(Cl)nc2c1cnn2-c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Product: CCCOc1nc(N[C@@H](C)Cc2ccccc2)c2cnn(-c3ccccc3)c2n1
Temperature: 90 °C

Procedure:
Next, 324 mg sodium was reacted with 10 ml of n-propanol. To this, 640 mg of (S)-N-(1-methyl-2-phenylethyl) -1-phenyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine in 5 ml of n-propanol was added with stirring and the reaction was heated to 90° C. for 2 hours. It was then cooled, diluted with 200 ml saturated NaCl, and extracted with 200 ml CHCl3. The organic layer was dried over MgSO4, filtered, and concentrated to yield an oil which was purified by radial chromatography (30-50% Et2O/hexane) to yield after recrystallization from 30% Et2O/hexane 382 mg of product (m.p. 134°-136° C.). Proton NMR indicated ether was still present. The compound was then oven dried under vacuum for 6 hours to yield 318 mg of (S)-N-(1-methyl-2-phenylethyl)-1-phenyl-6-propoxy-1H-pyrazolo[3,4-d]pyrimidin-4-amine (m.p. 134°-136° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([O:25]C)=[O:24])=[CH:13][C:12]=2[N:11]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=[O:24])=[CH:13][C:12]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2nc(C)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(F)cccc3Cl)[nH]c12
Yield: 74.2 %

Procedure:
The title compound was prepared following the procedure described for Step-5 of Intermediate-55 using methyl 7-[(2-chloro-6-fluorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylate (0.190 g, 0.508 mmol), MeOH (3.0 mL) and sodium hydroxide (0.101 g, 2.52 mmol) to afford 0.136 g of the desired product. 1HNMR (DMSO-d6): δ 2.60 (s, 3H), 7.35 (s, 2H), 7.44 (s, 1H), 7.64 (s, 1H), 12.0-13.0 (s, 3H); MS [M+H]+: 360.2.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:37])([C:33]([F:36])([F:35])[F:34])[C:30](O)=[O:31]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30](=[O:31])[C:29]([F:37])([F:28])[C:33]([F:36])([F:35])[F:34])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C(F)(F)C(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and 2,2,3,3,3-pentafluoro-propionic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=425.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C(#N)C.[CH2:25]([OH:28])[CH:26]=[CH2:27]>C(N(CC)CC)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([O:28][CH2:25][CH:26]=[CH2:27])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)Cl)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: C=CCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCOC(=O)C(C)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
0.5 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionyl chloride is dissolved in 25 ml. of acetonitrile containing 0.5 ml. of allyl alcohol and 0.5 ml. of triethylamine. After 16 hours the mixture is evaporated to dryness and partitioned between ethyl acetate and water. The organic solution is washed, dried, passed through a short (10 g.) silica gel column, then evaporated to give allyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate as an oil [nmr spectrum in deuterochloroform relative to tetramethylsilane: 1.54 (doublet, CH3), 2.84 (quartet, CH), 4.55 (doublet, OCH2), 5.1-6.0 (multiplet, CH=CH2) and 7.00 ppm (singlet, 10, 11-H); mass spectrum: 318(M+) 233,205].
Reaction SMILES: C([O:3][C:4](=[O:22])/[C:5](/[CH3:21])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)C.O[Li].O>>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[C:5](\[CH3:21])/[C:4]([OH:22])=[O:3])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)/C(C)=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: [Li]O
Solvent: O
Product: COc1ccc(/C=C(\C)C(=O)O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
A suspension of (E)-3-(3-cyclopentoxy-4-methoxyphenyl)-2-methyl-acrylic acid ethyl ester (30 g, 98.6 mmol) and LiOH.H2O (lithium hydroxide hydrate) (5.0 g, 119.2 mmol, 1.2 equiv.) in methanolwater (4:1, 100 mL) was stirred at room temperature for 24 hours. Methanol wag removed under reduced pressure and the resulting residue was dissolved in water (100 mL), washed with three 100 mL portions of ethyl acetate, neutralized with 1.0 N HCl (hydrochloric acid) (100 mL), and extracted with two 150 mL portions of ethyl acetate. The extract was washed with brine, dried over anhydrous Na2SO4 (sodium sulfate), and concentrated under reduced pressure to afford the desired product as a light yellow powder (18.2 g, 66% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 12.4 (br. s, 1H, COOH), 7.56 (s, 1H, olefinic), 7.04 (m, 1H, aromatic), 4.81 (m, 1H), 3.78 (s, 3H, OCH3), 2.06 (s, 3H, CH3), 1.91-1.57 (m, 8H, cyclopentyl)
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].O[CH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[C:24](=[O:38])[NH:25][C:26](=[O:37])[C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])=[CH:15]1.N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([O:5][CH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[C:24](=[O:38])[NH:25][C:26](=[O:37])[C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])=[CH:15]1)(=[O:4])=[O:3]
Reactant: O=C1NC(=O)C(c2cn(CCCO)c3ccccc23)=C1c1ccccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCn1cc(C2=C(c3ccccc3[N+](=O)[O-])C(=O)NC2=O)c2ccccc21
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
93 mg of methanesulphonic anhydride were added to a solution of 0.46 mmol of the product of Example 55 in 25 ml of dichloromethane. 0.5 ml of pyridine was added and the mixture was stirred for 0.5 hour, then washed with water, dried and concentrated. Chromatography of the residue on silica gel with 10% methanol in dichloromethane gave 160 mg of 3-[1-[3-(methylsulphonyloxy)propyl]-3-indolyl]-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione, m.p. 177°-178° C.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH2:25])(=[O:24])[CH2:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][C:9]=1[NH:25][C:21](=[O:24])[CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)C(=O)CC2
Reactant: CCC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(=O)NC1=C(Cc2ccccc2)c2cc(OC)ccc2CC1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
In a three-necked flask equipped with a Dean-Stark apparatus, heating mantle and magnetic stirrer were charged 1-benzyl-7-methoxy-3,4-dihydronaphthalen-2(1H)-one (120 g, 451 mmol), propionamide (82 g, 1126 mmol) and p-toluenesulfonic acid monohydrate (17.14 g, 90 mmol) followed by toluene (1.8 I). The resulting solution was heated to reflux for 5 days and monitored by HPLC (about 16% of starting material remained). The reaction mixture was cooled to r.t. and washed with 8% aqueous sodium bicarbonate solution (250 ml) and water (250 ml). The layers were separated. The organic layer was concentrated to near dryness and chase distilled with IPA (100 ml). The crude product was transferred to a flask equipped with a mechanical stirrer, heating mantle and nitrogen inlet. IPA (500 ml) was added to the flask and suspension was heated to 62° C. and all the solids were dissolved. The suspension was allowed to cool over 2 hrs to 30° C. then cooled to 5° C. Solids were filtered and washed with mixture of heptane/IPA (4:1, 100 ml). Solids were dried under vacuum to give 93.5 g (yield: 65%) product as a white solid.
Reaction SMILES: C1C(=O)N(Br)C(=O)C1.[CH:9]1[C:13]2=[C:14]([NH2:18])[N:15]=[CH:16][N:17]=[C:12]2[N:11]([C@@H:19]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[CH2:20]2)[CH:10]=1.C[C:28]([O-:30])=[O:29].[Na+]>CN(C=O)C>[NH2:18][C:14]1[C:13]2[C:9]([C:28]([OH:30])=[O:29])=[CH:10][N:11]([C@@H:19]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[CH2:20]3)[C:12]=2[N:17]=[CH:16][N:15]=1
Reactant: Nc1ncnc2c1ccn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: CC(=O)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(C(=O)O)cn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reaction time: 0.17 h

Procedure:
NBS (1.42 g, 8.0 mmol, dissolved in 4 ml of dried DMF) is added, at room temperature, to a solution of 2′-deoxytubercidin (1.0 g, 4.0 mmol) and NaOAc (0.78 g, 8.0 mmol) in dried DMF (10 ml). The red solution is stirred for 10 minutes and then evaporated. Title compound (38) is obtained as colorless crystals (400 mg, 25%) following flash chromatography (column: 20×5 cm, CH2Cl2/MeOH, 9:1), evaporation of the more rapidly migrating zone and subsequent recrystallization from isopropanol. Isolation of the more slowly migrating zone yields 5-bromo-2′-deoxytubercidin (130 mg, 10%). Method B: a solution of NBS (1.42 g, 8.0 mmol, dissolved in 4 ml of dried DMF) is added to a solution of 5-bromo-2′-deoxytubercidin (1.3 g, 4.0 mmol) and NaOAc (0.785 g, 8.0 mmol) in dried DMF (10 ml). Purification, see method A. Yield: 490 mg, 30% of 21. Melting point: 181° C. TLC (silica gel, CH2Cl2/MeOH, 9:1): Rf 0.40. 1H-NMR (D6-DMSO): δ=2.12 (m, Hα-2′); 2.50 (m, Hβ-2′); 3.51 (m, 2H, H-5′); 3.84 (m, 1H, H-4′); 4.44 (m, 1H, H-3′); 5.20, (br, 2H, 5′-OH, 3′-OH); 6.42 (“t”, J=6.2 Hz, 1H, H-1′); 6.93 (br, 2H, NH2); 8.10 (s, 1H, H-2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]O)[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:23])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][F:23])[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NCc1nc(CO)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1nc(CF)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of 1.0 g of the above-obtained 2-(tert-butoxycarbonylamino)methyl-4-hydroxymethylthiazole in 20 ml of dichloromethane was added 0.6 ml of diethylaminosulphur trifluoride with ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To this reaction solution was added 20 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (10 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a 50:1 mixture of chloroform and methanol to give 0.535 g (yield 47%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[C:5]([C@@H:10]([NH:21]C(=O)OC(C)(C)C)[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)#[C:2][CH3:3].[ClH:29]>C(Cl)Cl>[ClH:29].[C:1]([C:4]1[C:5]([C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[NH2:21])=[N:6][CH:7]=[CH:8][CH:9]=1)#[C:2][CH3:3]
Reactant: CC#Cc1cccnc1[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Product: CC#Cc1cccnc1[C@@H](N)c1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 0.03 h

Procedure:
To a 500 mL round bottom flask containing (S)-tert-butyl ((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate (400 mg, 1.025 mmol) was added DCM (8 mL) and the mixture was stirred at 23° C. for 2 min. At this time, hydrogen chloride (4N in 1,4-dioxane) (37.4 mg, 1.025 mmol) (4 mL) was added via syringe. The reaction was stirred for 3 h then the volatiles were removed via rotoryevaporator. The solid was placed on high vacuum overnight to give (S)-(3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)-methanamine hydrochloride as a white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[C:17](=[O:22])[NH:18][CH2:19][CH2:20][CH:21]=1.[CH3:24]Br>C1COCC1>[CH3:11][O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[C:17](=[O:22])[N:18]([CH3:24])[CH2:19][CH2:20][CH:21]=1
Reactant: CBr
Reactant: COC(=O)CCC1=CCCNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCC1=CCCN(C)C1=O
Reaction time: 0.5 h
Yield: 72 %

Procedure:
0.22 ml of 1.0M NaHMDS solution in THF (0.22 mM) was added to 0.5 ml of THF solution containing 80 mg 3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl ester (f) prepared from the step 1 in Example 3 (0.44 mM) in a dropwise manner at −79° C. and then stirred for 30 min. After 0.48 ml of methyl bromide (0.48 mM) was added to the reaction mixture, the solution was stirred at 0° C. for 3 hrs. The reaction mixture was quenched by 2 ml of sat. NH4Cl solution and then the organic layer was extracted with ethyl acetate (7 ml). The combined organic layer was washed with 2 ml of sat. NH4Cl solution (2 ml) and 2 ml of sat. NaCl solution subsequently. Then the organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with EtOAc solvent as an eluant to give 62 mg of the title compound (i2) (yield: 72%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:15])=[C:9]([C:33]3[CH:38]=[C:37]([NH:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=4)[N:36]=[CH:35][N:34]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClC(Cl)C>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:33]3[CH:38]=[C:37]([NH:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=4)[N:36]=[CH:35][N:34]=3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-((3-((4-(piperidin-1-yl)-2-(6-((3-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)phenyl)carbamoyl)benzyl)thio)propanoate in 1 mL of dichloroethane was added 1 mL of TFA. The mixture was stirred 1 h, and then the solvent was evaporated. The residue was purified by chromatography on silica gel to give 100 mg of a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 7.82 (s, 1H), 7.78-7.60 (m, 4H), 7.59-7.50 (m, 4H), 7.45 (t, J=7.6 Hz, 1H), 7.34-7.15 (m, 2H), 6.97 (s, 1H), 4.76 (s, 2H), 3.84 (s, 2H), 3.26 (s, 4H), 2.64-2.54 (m, 2H), 2.53-2.45 (m, 2H), 1.73-1.62 (m, 4H), 1.62-1.50 (m, 2H). MS (ES, m/z): 650.28 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](SC)=[N:6][C:5](=[O:10])[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[N:3]1.[CH3:18][O-:19].[Na+]>CO>[CH3:1][N:2]1[C:7]([O:19][CH3:18])=[N:6][C:5](=[O:10])[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[N:3]1
Reactant: C[O-]
Reactant: CSc1nc(=O)c(-c2cccc(C)c2)nn1C
Agent: [Na+]
Solvent: CO
Product: COc1nc(=O)c(-c2cccc(C)c2)nn1C
Yield: 90.9 %

Procedure:
To a solution of 2-methyl-3-methylthio-6-(m-methylphenyl)-5-oxo-2,5-dihydro-1,2,4-triazine (1.0 g) in methanol (10 ml), sodium methoxide (0.5 g) was added, and the resultant mixture was stirred at room temperature for 2 hours. After stirring, the resulting mixture was evaporated to dryness to give a crude product. Recrystallization of the crude product from acetone gave 0.85 g of 2-methyl-3-methoxy-6-(m-methylphenyl)-5-oxo-2,5-dihydro-1,2,4-triazine in 91% yield. M.P., 110° C.
Reaction SMILES: [NH2:1][OH:2].[C:3]([OH:7])(=[O:6])[CH:4]=[CH2:5]>CO>[C:3]([CH2:4][CH2:5][N:1]([OH:2])[CH2:5][CH2:4][C:3]([OH:7])=[O:6])([OH:7])=[O:6]
Reactant: NO
Reactant: C=CC(=O)O
Solvent: CO
Product: O=C(O)CCN(O)CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
Methanol (200 ml) was added to a mechanically stirred aqueous solution of hydroxylamine (13.24 g of 50% solution, 0.2 moles). Acrylic acid (27.4 ml, 0.4 moles) was added dropwise to the solution at 25° C. over thirty minutes. After a few hours of reaction, a white precipitate began to form. The reaction mixture was stirred overnight at room temperature, and the resulting white solid was filtered out, washed with cold water, and dried in vacuum overnight to give 30.4 g (85%) of the desired compound.