Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]3[CH2:21][CH:20]([C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=4)[O:19][N:18]=3)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:34][CH3:35].[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]3[CH2:21][CH:20]([C:22]4[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)[O:19][N:18]=3)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:34][CH3:35]
Reactant: COC(=O)c1ccc(C2CC(c3cc(C(=O)NCc4ccc(F)c(OC)c4)nc(C)n3)=NO2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccc(C(=O)O)cc4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cold stirred solution of methyl 4-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)benzoate (0.3 g, 0.62 mmol, G.1.29) in THF/water (1:1) was added lithium hydroxide (0.03 g, 1.2 mmol, Sd Fine Chem). The reaction mixture was stirred for about 3 h at RT and excess solvent was removed under reduced pressure. The aqueous layer was acidified with 10% HCl solution. The solid was collected by filtration, washed with water and dried under vacuum to afford 4-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)benzoic acid. (0.2 g), (69%).
Reaction SMILES: F[C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=[O:5].[NH2:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][N:31]=[CH:32]2)=[CH:27][CH:26]=1.C(O)(C(F)(F)F)=O>CC(O)(C)C>[CH:32]1[C:33]2[C:28](=[CH:27][CH:26]=[C:25]([NH:24][C:2]3[N:23]=[CH:22][CH:21]=[CH:20][C:3]=3[C:4]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)=[O:5])[CH:34]=2)[CH:29]=[CH:30][N:31]=1
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cccnc1F
Reactant: Nc1ccc2ccncc2c1
Solvent: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cccnc1Nc1ccc2ccncc2c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a mixture of 2-fluoro-N-(4-pentafluoroethyl-phenyl)-nicotinamide (112 mg) and 7-aminoisoquinoline (40 mg) in t-BuOH (0.5 mL) was added TFA (94 μL). The resulting mixture was stirred for 24 h at 90° C., cooled to RT and purified by flash chromatography (4:1:0.1; MeOH/CH2Cl2/MeOH) to give the title compound as a yellow solid. MS (ES+): 459 (M+H)+. Calc'd for C23H15F5N4O—458.12.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.C(N(CC)CC)C>CC(O)C>[C:31]([O:30][C:28]([N:25]1[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][NH:19][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:27][CH2:26]1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NCCN4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (500 mg, 1.79 mmol) in 2-propanol (40 mL) was added tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (613 mg, 1.97 mmol) followed by triethylamine (200 mg, 1.98 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-{2-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester. (Yield 600 mg, crude).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][CH3:7].[C:8](#[N:11])[CH2:9]O.CCN(CC)CC>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:9][C:8]#[N:11])[CH3:7]
Reactant: CNCCCOC
Reactant: N#CCO
Solvent: CCN(CC)CC
Product: COCCCN(C)CC#N
Yield: 73 %

Procedure:
A solution of amine hydrochloride 272 (2.6 g, 18.7 mmol), aqueous glycolonitrile (55%, 2.4 mL, 24.7 mmol) and Et3N (4.0 mL, 28.1 mmol) was stirred at 50° C. for 3 h. The solution was cooled and partitioned between water (50 mL) and Et2O (50 mL). The organic fraction was washed with water (2×50 mL) and brine (50 mL), dried and the solvent evaporated to give nitrile 273 (1.94 g, 73%) as a colourless oil; 1H NMR δ 3.53 (s, 2H, CH2CN), 3.42 (t, J=6.3 Hz, 2H, CH2N), 3.33 (s, 3H, OCH3), 2.54 (t, J=7.1 Hz, 2H, CH2), 2.36 (s, 3H, NCH3), 1.73 (tt, J=7.1, 6.3 Hz, 2H, CH2); MS (APCI) m/z 143 (MH+, 100%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].[F:27][C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([C:34](=[N:36]O)[NH2:35])[CH:33]=1.CCN(C(C)C)C(C)C>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([C:34]2[N:35]=[C:18]([C:17]3[CH:21]=[CH:22][C:14]([N:9]4[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]4[CH3:7])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[O:20][N:36]=2)[CH:33]=1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (106 μL; 1.25 mmol; 3 eq.), Intermediate 24 (120 mg; 0.42 mmol; 1 eq.), Intermediate 23 (77 mg; 0.42 mmol, 1 eq.) and DIEA (2164; 1.25 mmol; 3 eq.) were reacted according to general procedure 2. Purification by preparative HPLC (increasing amount of 0.1% TFA in CH3CN, in 0.1% TFA in water) afforded the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].B(F)(F)F.[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl.[OH-].[Na+]>CCOCC.O>[CH2:1]([O:5][CH2:10][CH:12]1[O:14][CH2:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCC1CO1
Reactant: CCCCO
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCOCC1CO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
370 g (5 mol) of n-butanol and 3 ml of BF3.(C2H5)2O catalyst were heated to 45° C. and stirred for 4 h. An amount of 466 g (5 mol) of epichlorohydrin was added dropwise at 40°-50° C. The mixture was cooled down to room temperature and 6.25 mol of a 50% aqueous solution of sodium hydroxide (250 g of sodium hydroxide dissolved in 250 ml of water) was added dropwise. The mixture was stirred for 1 h. Water was added until complete dissolution of the inorganic salt. The organic phase was separated and 0.5 l of ethyl acetate was added thereto. The organic phase was rinsed twice with water, dried over sodium sulphate, filtered, and concentrated by evaporation. Fractionation was carried out then at normal pressure. Yield: 290 g of 1-butoxy-2,3-epoxypropane boiling at 170°-174° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:24]1([CH2:30][CH2:31][S:32][CH:33]([C:37](O)=[O:38])[C:34](O)=[O:35])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[OH:38][C:37]1[CH:2]=[C:1]([C:4]2[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=2)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:3][C:34](=[O:35])[C:33]=1[S:32][CH2:31][CH2:30][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CCOC(=O)COc1cccc(C(C)=O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using ethyl (3-acetylphenoxy)acetate (2.00 g, 9.00 mmol), trimethyl silyltriflate (4.18 mL, 21.62 mmol), triethylamine (5.01 mL, 36.00 mmol), methylene chloride (23 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 116°-119° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.22 (t, 3H), 2.77 (t, 2H), 3.05 (t, 2H), 4.89 (d, 2H), 6.80 (s, 1H), 7.20 (m, 7H), 7.44 (m, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2cccc(F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (76 mg, 95%), MS (ISP) m/z=320.5 [(M+H)+], mp 210.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:36](=[O:38])[CH3:37])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=3[CH2:33][CH2:34][CH3:35])=[CH:11][CH:12]=2)[CH:7]=1.[OH-].[Na+]>CO>[C:36]([C:9]1[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=2[CH2:33][CH2:34][CH3:35])=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[C:6]([O:5][CH2:4][C:3]([OH:39])=[O:2])[CH:15]=[CH:14]2)(=[O:38])[CH3:37]
Reactant: CCCc1c(OCCOCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCOCCOc2ccc3ccc(OCC(=O)O)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 84.8 %

Procedure:
A suspension of 2.3 g of [[8-acetyl-7-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester and 43 ml of 1N sodium hydroxide in 86 ml of methanol was stirred at reflux for 1 hour. The methanol was removed and aqueous solution was acidified to pH 3. The precipitate was extracted with methylene chloride, washed with water, dried (magnesium sulfate) and concentrated in vacuo to give an oil. The oil was triturated with ether to yield 1.9 g, mp 121°-122° C. (84%) of [[8-acetyl-7-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=[CH:3]1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O>[CH3:12][N:7]1[C:2](=[O:1])[CH:3]=[CH:4][CH:5]=[C:6]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc(=O)[nH]1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: COC(=O)c1cccc(=O)n1C
Yield: 28.5 %

Procedure:
In Example 22, 0.4006 g (2.611 mmol) of methyl 6-oxo-1,6-dihydropyridine-2-carboxylate and 0.4006 g (2.899 mmol) of potassium carbonate were combined in a 25 mL RBF. 1 mL of DMSO followed by 4 mL (64.25 mmol) of methyl iodide was added and the reaction refluxed for 4 hours. The solvent was removed under reduced pressure and the resulting oil was extracted with hot hexanes (8×25 mL), the extracts were combined and solvent removed to yield a yellow oil. Recrystallization from hexanes yielded the product as white/yellow crystals (0.1245 g, 28.52%). Melting Point: 56-57° C. IR: (Nujol) 3437.61, 1731.13, 1652.94, 1590.77, 1457.45, 1443.48, 1379.43, 1265.53, 1218.08, 1156.78, 1086.06, 900.89, 825.45, 817.06, 765.03, 755.48, 722.85 cm−1. 1H NMR: (500 MHz, CDCl3) 3.67 (s, 3H), 3.91 (s, 3H), 6.71 (dd, J=1.2, 9.1 Hz, 1H), 6.74 (dd, J=1.2, 6.8 Hz, 1H), 7.29 (dd, J=6.7, 9.1 Hz, 1H). 13C NMR: (126 MHz, CDCl3) 33.40, 52.90, 110.42, 124.46, 137.21, 138.21, 162.45, 162.70.
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]1[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=1)=[N+:12]=[N-:13]>>[ClH:1].[ClH:1].[NH:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[CH2:14][N:11]1[CH:4]=[C:3]([CH2:2][C:5]2[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=2)[N:13]=[N:12]1
Reactant: C#CCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1nc2ccccc2[nH]1
Agent: Cl
Product: Nc1nc(Cc2cn(Cc3nc4ccccc4[nH]3)nn2)c[nH]1
Yield: 59 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.091 g, 0.576 mmol) was reacted with 2-azidomethyl-1H-benzimidazole, which was synthesized using previously reported methods (Hiales et al., Synthesis 1978, 4, 313-315), (0.120 g, 0.691 mmol) following the general procedure for click reactions outlined above to produce 4-[1-(1H-Benzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-ylmethyl]1Himidazol-2-ylamine dihydrochloride (0.125 g, 59%) of a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.01 (s, 1H), δ 7.58 (d, 2H), δ 7.31 (t, 2H), δ 6.44 (s, 1H), δ 5.98 (s, 2H) δ 3.84 (s, 2H) ppm; 13C (75 MHz, CD3OD) δ 135.6, 124.7, 123.7, 123.5, 122.8, 112.8, 112.3, 108.4, 83.6, 78.9, 74.0, 73.2, 44.2, 19.3 ppm; HRMS (ESI) calcd for C14H14N8(M+) 295.1414, found 295.1420.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[F:9][C:10]([F:23])([F:22])[O:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C.CCCP(=O)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:8][C:5]1[N:4]=[N:3][C:2]([NH:1][C:19](=[O:20])[CH2:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:10]([F:22])([F:9])[F:23])[CH:13]=2)=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1cccc(OC(F)(F)F)c1
Reactant: Nc1ccc(Cl)nn1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(OC(F)(F)F)c1)Nc1ccc(Cl)nn1
Reaction time: 0.08 h

Procedure:
3-Amino-6-chloropyridazine (55.5 g, 0.428 mol) and 3-(Trifluoromethoxy)phenylacetic acid (1.1 equiv., 0.471 mol, 104 g) were dissolved in DMF (30.0 vol., 1.66 L) in a 3000 mL three neck round-bottom flask. Addition of DIEA (1.1 equiv., 0.471 mol, 82 mL) via addition funnel was done over 5 minutes. Propylphosphonic anhydride solution (300 mL of a 50% solution in DMF, 1.1 equiv., 0.471 mol,) was charged into a 500 mL addition funnel and added dropwise to reaction solution (keeping reaction temperature ≦+30° C.). The reaction usually goes to completion after 3 hours (TLC: 6:4 hexanes-ethyl acetate). Reaction mixture was then poured into 7.5% sodium bicarbonate (80.0 vol., 4.4 L) which was chilled in an ice bath. Off-white crystalline powder was filtered through a Büchner funnel, rinsed with water (20.0 vol., 1.1 L). Dried in a 50° C. vacuum to a constant weight to afford N-(6-chloropyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide 1117: yield of 119.6 g (77%). 1H NMR (300 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.38 (d, J=9.4 Hz, 1H), 7.88 (d, J=9.4 Hz, 1H), 7.52-7.27 (m, 4H), 3.90 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CCN(C(C)C)C(C)C.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=O)=[CH:31][CH:30]=1)[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:14]1([CH2:13][N:12]2[C:3]3=[N:4][CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[C:2]3[N:1]=[C:36]2[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:26][CH3:27])=[CH:30][CH:31]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)c1cnc(NCC2CC2)c(N)c1
Reactant: CCOc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Cc2nc3cc(C(=O)OC)cnc3n2CC2CC2)cc1
Yield: 33.7 %

Procedure:
Following general procedure 13B: Combined methyl 5-amino-6-[(cyclopropylmethyl)amino]nicotinate (950 mg, 4.3 mmol), DIPEA (1.1 ml), 4-ethoxyphenylacetic acid (850 mg, 4.72 mmol) and HATU (1.80, 4.74 mmol) in DMF (15 mL). The crude product was purified by flash chromatography on silica gel (EtOAc) to produce the desired product (530 mg, 34%).
Reaction SMILES: O[CH:2]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(#N)C>[Br:32][CH:2]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(O)c1ccsc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)C(Br)c1ccsc1
Reaction time: 2 h

Procedure:
A mixture of (RS) methyl 2-hydroxy-2-(thien-3-yl)acetate (see Preparation 24) (4.49 g), triphenylphosphine (8.21 g) and carbon tetrabromide (10.4 g) in acetonitrile (100 ml) was refluxed for 2 hours, cooled, further triphenylphosphine (2.5 g) and carbon tetrabromide (3 g) were added, and refluxing was continued for a further 2 hours. After cooling, the mixture was used directly, without further purification, in Preparation 17.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:32]1([NH2:39])[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[NH:33]1>O1CCOCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:36]4[N:35]=[C:34]([NH2:38])[N:33]=[C:32]([NH2:39])[CH:37]=4)=[CH:18][CH:19]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)[nH]2)cc1
Reactant: NC1=NC=CC(N)(Cl)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4ccc(Cl)c(C(F)(F)F)c4)[nH]3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 46.3 %

Procedure:
4-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H[1,2,4]triazol-3-yl]-phenol (1.3 g, 3.66 mmol) was dissolved in 18 mL of anhydrous dioxane in a 10-20 md microwave vial (Personal Chemistry). Solid Cs2CO3 (1.19 g, 3.66 mmol, 1.0 eq) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 4-chloro-2,4-diaminopyrimidine (0.530 g, 3.66 mmol) was added. The vial was capped and microwaved at 200° C. for 25 min. Then the reaction mixture was diluted with ca. 10 mL of MeOH, transferred into a round-bottom flask and concentrated in vacuo to ca. 20 mL. The resulting reddish solution was loaded on a short pad of silica gel and eluted first with 100% ethyl acetate to remove the unreacted starting material and then with 20% MeOH in EtOAc to elute the product. The product was further purified by ISCO system (80 g pre-packed column, 40 min method, 0% to 10% MeOH gradient in ethyl acetate). Solvent was removed in vacuo to give the title product as an off-white solid (0.785 g). Yield 46.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:39][CH3:40])=[C:5]([CH:36]=[CH:37][CH:38]=1)[C:6]([O:19][CH2:20][C@H:21]1[O:25][C@@H:24]([N:26]2[CH:33]=[CH:32][C:30](=O)[NH:29][C:27]2=[O:28])[C@H:23]([OH:34])[C@@H:22]1[OH:35])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:41]1[CH:45]=[N:44][CH:43]=[N:42]1>>[CH3:1][O:2][C:3]1[C:4]([O:39][CH3:40])=[C:5]([CH:36]=[CH:37][CH:38]=1)[C:6]([O:19][CH2:20][C@H:21]1[O:25][C@@H:24]([N:26]2[CH:33]=[CH:32][C:30]([N:41]3[CH:45]=[N:44][CH:43]=[N:42]3)=[N:29][C:27]2=[O:28])[C@H:23]([OH:34])[C@@H:22]1[OH:35])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccccc2)c1OC
Reactant: c1nc[nH]n1
Product: COc1cccc(C(OC[C@H]2O[C@@H](n3ccc(-n4cncn4)nc3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccccc2)c1OC

Procedure:
The method in which 5′-O-(dimethoxytrityl)uridine derivatives are condensed with 1,2,4-triazole to give 1-[5′-O-(dimethoxytrityl)-β-D-ribofuranosyl]-4-(1,2,4-tri azol-1-yl)pyrimidin-2-(1H) -one derivatives, which are then reacted with an amine in dioxane solvent to yield 5′-O-(dimethoxytrityl)cytidine derivatives (Journal of Organic Chemistry, 47, 3623 (1982)).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[NH:14][CH:15]=[C:16]([CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:33]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[N:14]([CH3:33])[CH:15]=[C:16]([CH2:20][C:21]4[CH:26]=[N:25][C:24]([O:27][CH3:28])=[N:23][CH:22]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:31][CH:32]=1
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: COc1ncc(Cc2cn(C)c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Temperature: 50 °C
Yield: 29.1 %

Procedure:
To a solution of 2-(4-(4-fluorophenoxy)benzylthio)-5-((2-methoxypyrimidin-5-yl)methyl) pyrimidin-4(1H)-one (100 mg, 0.222 mmol) and Hunig's base (0.058 mL, 0.333 mmol) in DCM (4 mL) was added MeI (0.021 mL, 0.333 mmol). The mixture was heated at 50° C. for 2 h. Purification via reverse phase flash chromatography then afforded the title compound (30 mg, 29.1% yield). LCMS: rt=3.05 min, [M+H]=465.
Reaction SMILES: [H-].[Na+].[ClH:3].Cl.[NH2:5][C:6]1[N:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]2[CH2:15][NH:14][CH2:13][CH2:12][C:10]=2[N:11]=1.I[CH2:24][CH3:25]>CN(C)C=O>[ClH:22].[ClH:3].[NH2:5][C:6]1[N:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]2[CH2:15][N:14]([CH2:24][CH3:25])[CH2:13][CH2:12][C:10]=2[N:11]=1
Reactant: CCI
Reactant: Nc1nc2c(c(-c3ccc(Cl)cc3)n1)CNCC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2nc(N)nc(-c3ccc(Cl)cc3)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 158.3 %

Procedure:
A suspension of sodium hydride (12.7 g, 320 mmol), washed three times pentanes, in dimethylformamide (200 mL) was treated with 2-amino-4-(4-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride (35.3 g, 110 mmol). The mixture was stirred at room temperature for 2 hours, and iodoethane (8.8 mL, 110 mmol) was added. The mixture was stirred at room temperature overnight, quenched with water and the resulting precipitate was collected by filtration to give 31.5 g (79%) of 2-amino-4-(4-chlorophenyl)-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride. m.p.>260° C. MS: 289 (MH+). IR(KBr): 3224, 2641, 2311, 1623 cm-1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu](I)I>[C:7]1([N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Ic1ccccc1
Reactant: c1c[nH]nn1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-n2ccnn2)cc1
Temperature: 110 °C

Procedure:
1,2,3-Triazole (5 g), iodobenzene (9.72 ml) and copper iodide (0.68 g) was taken in dry DMF under Nitrogen atmosphere. 1,2-(N,N-dimethyl) cyclohexyl diamine (1.02 g) and potassium phosphate (30.73 g) was added into above mixture. The reaction mixture was reflux at 110° C. for over night. TLC was checked no starting material and the reaction mixture was filtered through celite. The filtrate was diluted with water and product was extracted with dichloromethane. The organic layer was evaporated and the crude product was purified by column chromatography using 60-120 silica gel and pet ether \ ethyl acetate as eluent to give 1-phenyl-1H-1,2,3-triazole as white solid.