Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH2:11][CH:10]([CH2:18][OH:19])[CH2:9]2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[CH3:25]I>CN(C=O)C.C(OCC)(=O)C.[Ag]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH2:11][CH:10]([CH2:18][O:19][CH3:25])[CH2:9]2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: COC(=O)C1=CCC(CO)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CI
Agent: O=[Ag]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC1CC=C(C(=O)OC)C(C)(c2ccc(Cl)c(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 41.5 h
Yield: 59.6 %

Procedure:
A solution of methyl (4RS,6RS)-6-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-6-methylcyclohex-1-enecarboxylate (Example 7, Step 9; 32.2 mg, 0.089 mmol) in DMF (0.25 mL) was diluted with methyl iodide (0.75 mL, 11.99 mmol) and treated with silver oxide (103 mg, 0.444 mmol). The resulting suspension was protected from ambient light and stirred at rt for 41.5 h. After this time, the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel, eluting with 10-30% ethyl acetate-hexanes, to provide methyl (4RS,6RS)-6-(4-chloro-3-(trifluoromethyl)phenyl)-4-(methoxymethyl)-6-methylcyclohex-1-enecarboxylate as a colorless gum (20 mg, 60%). Mass spectrum m/z 394.1 (M+NH4+). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=2.2 Hz, 1 H), 7.38 (d, J=8.4 Hz, 1 H), 7.31 (dd, J=8.4, 2.2 Hz, 1 H), 7.27 (m, 1 H), 3.64 (s, 3 H), 3.24 (s, 3 H), 3.15 (d, J=5.7 Hz, 2 H), 2.44 (m, 1 H), 2.00 (ddd, J=19.5, 10.4, 2.4 Hz, 1 H), 1.74 (m, 1 H), 1.65 (s, 3 H), 1.61 (m, 1 H), 1.56 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][OH:7])=[NH:5].N1C=CC=CC=1.[C:36]1([O:42]C(Cl)=O)C=CC=CC=1.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])[CH:9]=[CH:8][C:3]=1[C:4]1[NH:5][C:36](=[O:42])[O:7][N:6]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C(=N)NO)c(F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(F)c1
Temperature: 25 °C

Procedure:
138 mg of 2-Fluoro-N-hydroxy-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-benzamidine were dissolved in 2 ml dichloromethane. 35 μl pyridine and 53 μl phenylchloroformate were added and the mixture stirred at room temperature for thirty minutes. The mixture was diluted by the addition of 20 ml ethyl acetate, washed with brine and dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was dissolved in 2 ml acetonitrile and 105 μl 1,8-Diazabicyclo[5.4.0]undec-7-ene was added. The mixture was stirred at room temperature for 10 minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by reversed phase HPLC to obtain 70 mg 3-{2-Fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazole-5-one as an amorphous lyophilisate.
Reaction SMILES: [C:1]([C:11]1[CH:35]=[CH:34][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:16]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])[CH2:15][C:14]1[CH:34]=[CH:35][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=1)(=[O:38])[CH3:37]
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)c(C(=O)OC)c2)cc1
Reactant: CC(=O)Cl
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(OCC(=O)OC)c(C(=O)OC)c2)C(C)=O)cc1

Procedure:
The title compound was prepared following the procedure G using the hydrochloride salt of methyl 5-{[(4-dec-1-ynylbenzyl)amino]methyl}-2-(2-methoxy-2-oxoethoxy)benzoate and acetyl chloride (purification by flash chromatography on SiO2, chloroform/MeOH 99:1 to 90:10) as a colorless oil (72%). M+ (ESI): 521.9. HPLC, Rt: 5.4 min (purity: 100%). 1H NMR (CDCl3) δ: 7.62 (m, 1H), 7.41-7.05 (m, 5H), 6.85 (m, 1H), 4.75 (s, 1H), 4.73 (s, 1H), 4.55 (s, 1H), 4.53 (s, 1H), 4.41 (s, 1H), 4.38 (s, 1H), 3.92 (s, 1.5H), 3.90 (s, 1.5H), 3.82 (s, 1.5H), 3.81 (s, 1.5H), 2.41 (m, 2H), 2.21 (s, 1.5H), 2.20 (s, 1.5H), 1.62 (m, 2H), 1.45 (m, 2H), 1.31 (brs, 8H), 0.90 (t, J=6.6 Hz, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=O.[F:21][C:22]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1)(=[O:27])=[O:26])([F:24])[F:23]>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[F:23][C:22]([F:21])([F:24])[S:25]([C:28]1[CH:29]=[C:30]([NH:34][C:14]([CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:17][C:18]([OH:20])=[O:19])=[O:16])[CH:31]=[CH:32][CH:33]=1)(=[O:26])=[O:27]
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Reactant: Nc1cccc(S(=O)(=O)C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)Cc1ccccc1CC(=O)Nc1cccc(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (0.285 mL) was added to a solution of 1,2-phenylenediacetic acid (100 mg, 0.515 mmol) in dichloromethane, followed by 5 drops of DMF. The mixture was stirred at room temperature for 1.5 hours and cooled to 0° C. To the cooled mixture was added DMAP (63 mg, 0.62 mmol) and 3-aminophenyl trifluoromethyl sulfone (116 mg, 0.515 mmol). The mixture was allowed to warm to room temperature and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and purified to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.31 (br s, 1H), 8.51 (s, 1H), 8.04 (m, 1H), 7.75 (d, J=5.1 Hz, 2H), 7.28 (m, 1H), 7.19 (m, 3H), 3.75 (s, 2H, CH2), 3.62 (s, 2H, CH2). MS 401.9 [M++1].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1Br)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:23]1([CH:29]2[NH:34][C:33](=[O:35])[CH2:32][O:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>[Cu]I.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[N:34]1[C:33](=[O:35])[CH2:32][O:31][CH2:30][C@H:29]1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:4]
Reactant: O=C1COCC(C2CCCCC2)N1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)COC[C@H]1C1CCCCC1
Temperature: 110 °C
Reaction time: 48 h
Yield: 63.7 %

Procedure:
A heavy wall flask was charged with trans-cyclohexane diamine (623 mg, 5.5 mmol, 0.5 equiv), 3-bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (4.27 g, 14.2 mmol, 1.3 equiv), K2CO3 (3.02 g, 21.8 mmol, 2.0 equiv), CuI (1.04 g, 5.5 mmol, 0.5 equiv), 5-cyclohexyl-morpholin-3-one (2.0 g, 10.9 mmol, 1.0 equiv) and 1,4-dioxane (10.0 mL). The mixture was flushed with N2 and stirred at 110° C. for 48 hours. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel, EtOAc/heptane 50% to give product 2.8 g (yield 50%).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[N:8]2)=[C:4]([NH2:22])[N:3]=1.C1C(=O)N([Cl:30])C(=O)C1>CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[CH:13]=[C:14]([O:20][CH3:21])[C:15]([O:18][CH3:19])=[CH:16][C:17]=3[Cl:30])=[N:8]2)=[C:4]([NH2:22])[N:3]=1
Reactant: COc1ccc(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC

Procedure:
A solution of 2-Fluoro-8-(3,4-dimethoxy-benzyl)adenine (40 mg, 0.132 mmol), NCS (77.8 mg, 0.58 mmol) in anhydrous DMF (0.7 mL) was stirred at room temperature for 5.5 h. Following solvent removal, the product (22 mg, 49.4%) was collected through silica gel column purification (CHCl3:EtOAc at 8:2 to 4:6). MS m/z 338.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([C:37]([CH3:46])([CH3:45])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:36]=2)[N:33]=1.CN(C)[CH:49]=[O:50]>>[C:49]([OH:50])(=[O:10])/[CH:35]=[CH:37]/[C:38]([OH:40])=[O:39].[C:49]([OH:50])(=[O:10])/[CH:35]=[CH:37]/[C:38]([OH:40])=[O:39].[C:21]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([C:37]([CH3:46])([CH3:45])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:36]=4)[N:33]=3)[CH2:13][CH2:12]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: CN(C)C=O
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)C(C)(C)c1cn2nc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
70 mg of 60% sodium hydride dispersion in mineral oil was dissolved in 5 ml of N,N-dimethylformamide; 570 mg of 4-(diphenylmethoxy)-1-piperidinepropanol was added, followed by stirring at room temperature under reduced pressure for 30 minutes. After 520 mg of t-butyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate was added, followed by stirring at room temperature for 8 hours. Ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (195:5:1). The desired fraction was collected and dissolved in 5 ml of ethyl acetate; a solution of 233 mg of fumaric acid in 10 ml of methanol was added, followed by concentration. The crystal precipitated was collected by filtration, washed with acetone and dried to yield 631 mg of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([F:20])[CH:13]=[C:14]([F:19])[CH:15]=2)[CH2:10]1)[CH2:5][CH2:6][CH3:7].[Li+].[OH-]>C1COCC1.O>[F:19][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([F:20])[CH:13]=1)[CH2:10][CH:9]([NH:8][CH:4]([CH2:5][CH2:6][CH3:7])[C:3]([OH:21])=[O:2])[CH2:18][CH2:17]2
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid methyl ester (1 equiv) is dissolved in THF:water (5:1) and LiOH (1.2 equiv) is added. The reaction is stirred overnight at rt, the solvent is removed, water added, and the pH is adjusted to 7 using 1N hydrochloric acid. The solid is filtered, washed with water and diethyl ether, and dried to afford 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid; Acid derived from diasteromer 1: H1 NMR (400 MHz, CD3OD) 0.99 (t, 3H, J=7.5), 1.48 (m, 2H), 1.82 (m, 3H), 2.36 (m, 1H), 2.65 (m, 1H), 2.95 (m, 2H), 3.28 (s, 1H), 3.42 (m, 1H), 3.74 (m, 1H), 6.80 (m, 2H); (MS m/z 284.3 (M+1). Acid derived from diasteromer 2: H1 NMR (400 MHz, CD3OD) 0.94 (t, 3H, J=7.6), 1.42 (m, 2H), 1.56 (m, 3H), 1.96 (m, 1H), 2.25 (m, 1H), 2.85 (m, 3H), 3.15 (m, 1H), 3.25 (m, 1H), 6.64 (m, 2H); MS m/z 284.2 (M+1).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[C:10]([O:12]C)[CH:9]=[C:8]([O:14]C)[CH:7]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([OH:14])[CH:7]=1
Reactant: COc1cc(Cl)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(O)cc(Cl)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 207.5 %

Procedure:
BBr3 (26 mL; 0.275 mmol) was added to a solution of chloro-3,5-dimethyoxybenzene (10 g; 30 mmol) in CH2Cl2 (100 mL) at −70° C. The cooling bath was removed and the solution was stirred at room temperature for 4 days. After re-cooling to −70° C., MeOH was added (150 mL). After evaporation of the solvent, toluene was added and removed in vacuo. Purification by kugelrohr distillation afforded 9 g (100%) of the sub-title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:35])[C:32](Cl)=[O:33].[CH2:37]([OH:39])[CH3:38]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([C:27]([F:30])([F:28])[F:29])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:31](=[O:35])[C:32]([O:39][CH2:37][CH3:38])=[O:33])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCO
Reactant: FC(F)(F)c1cc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc(C(F)(F)F)c1
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Yield: 56 %

Procedure:
Ethyl 2-{1-benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1H-indol-3-yl}-2-oxoacetate was prepared from 1-benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1H-indole (1.07 g, 2.56 mmol), oxalyl chloride (1.3 mL, 15 mmol), and ethanol (6 mL) following the procedure described in Step 3 of Example 1. Purification by HPLC (reverse phase column) using 85% acetonitrile and 0.1% trifluoroacetic acid in water as the mobile phase yielded the title compound as a light yellow solid (0.746 g, 56%). 1HNMR (300 MHz, DMSO-d6): δ 8.8 (s, 1H), 8.5 (s, 1H), 8.3 (s, 2H), 8.1 (s, 1H), 7.75 (s, 2H), 7.25-7.4 (m, 5H), 5.65 (s, 2H), 4.35 (q, 2H, J=7.5 Hz), and 1.35 ppm (t, 3H, J=7.5 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10]C)=O)[CH2:6][S:5][C:4]2[S:12][CH:13]=[CH:14][C:3]1=2.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[O:1]=[C:2]1[CH:7]([C:8]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:10])[CH2:6][S:5][C:4]2[S:12][CH:13]=[CH:14][C:3]1=2
Reactant: COC(=O)C1CSc2sccc2C1=O
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)C1CSc2sccc2C1=O
Yield: 89.8 %

Procedure:
A mixture of methyl 5,6-dihydro-4-oxo-4H-thieno[2,3-b]-thiopyran-5-carboxylate (5.7 g, 0.025 mole), aniline (3.5 g, 0.0375 mole) and xylene (180 ml) is refluxed for 2.5 hrs. in a Soxhlet apparatus, the thimble of which contains 20 g of Linde type 4A molecular sieve. The mixture is cooled in an ice bath, and the resulting crystalline precipitate (m.p. 155°-158° C.) is collected, dried and recrystallized from methylene chloride and isopropyl ether to give 6.5 g (90%) of off-white crystalline material, m.p. 155°-158° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(O)(C(F)(F)F)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](O)([CH3:21])[CH3:20])=[CH:15][C:14]=1[CH3:23].N>C(Cl)(Cl)Cl.O>[N:1]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([CH3:23])[CH:15]=1)([CH3:21])[CH3:20])=[N+:2]=[N-:3]
Reactant: Cc1cc(C(C)(C)O)ccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(C(C)(C)N=[N+]=[N-])ccc1Cl
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A flask was charged with sodium azide (4.22 g, 65 mmol) and chloroform (250 mL). The mixture was cooled in an ice-salt bath to −5° C. TFA (12.52 mL, 162 mmol) was added over 3 minutes, followed by a solution of the alcohol INT 20 (6 g, 32.5 mmol) in chloroform (10 mL) while the temperature was kept below 0° C. The formed slurry was stirred for one hour, then allowed to warm up to room temperature overnight. After that time, the thick slurry had turned into a cloudy solution. The mixture was treated with concentrated ammonia (25 mL) and water (50 mL). The chloroform layer was separated and the aqueous layer was extracted once more with chloroform. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[O:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.Cl.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C(Cl)Cl>[F:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][N:39]([C:8](=[O:10])[CH2:7][C@H:5]3[O:6][C:2]([CH3:1])([CH3:12])[O:3][C:4]3=[O:11])[CH2:38][CH2:37]2)=[CH:34][CH:35]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1(C)OC(=O)[C@@H](CC(=O)N2CCN(c3ccc(F)cc3)CC2)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.1 %

Procedure:
To a solution of [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (3.48 g; 20.0 mmol; 1.0 eq.), TEA (6.07 g; 60.0 mmol; 3.0 eq.) in DCM (60 mL) was added HOBt (2.97 g; 22.0 mmol; 1.1 eq.) and the mixture was chilled to 0° C. EDC (4.6 g; 24.0 mmol; 1.2 eq.) was then added and the resulting reaction mixture was stirred for 15 min at 0° C. 1-(4-fluorophenyl)piperazine dihydrochloride (5.57 g; 22.0 mmol; 1.1 eq.) was added and the resulting reaction mixture was stirred at RT over night. Purification by flash chromatography (AcOEt/c-Hex: 50/50) gave the title compound as a colorless oil (5.12 g, 76%). M+ (ESI): 337.2. HPLC (Condition A): Rt: 2.5 min (HPLC purity: 97.4%).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[OH-].[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Na+].[Cl-]>[CH2:16]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCOCCOCCOCCO
Reactant: ClCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: OCCOCCOCCOCCOCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To the oil of monodispersed tetraethylene glycol (19.4 g, 0.10 mol) was added a solution of NaOH (4.0 g in 4.0 mL) and the reaction was sired for 15 mm. Then benzyl chloride (3.54 mL, 30.8 mmol) was added and the reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature, diluted with sat NaCl (250 mL), and washed CH2Cl2 (2×200 mL). The organic layers were combined, washed sat. NaCl, dried MgSO4, and chromatographed (silica, ethyl acetate) to afford the monodispersed compound 23 as a yellow oil (6.21 g, 71% yield).
Reaction SMILES: [BrH:1].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[OH2:13].[BrH:1].[CH:14]1([NH:20][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: Oc1ccc2nccc(Cl)c2c1
Agent: Br
Product: O
Product: Oc1ccc2nccc(NC3CCCCC3)c2c1
Yield: 40 %

Procedure:
A solution of 245 mg (0.94 mmol) of 4-chloroquinolin-6-ol hydrobromide and 1.0 mL of cyclohexylamine was heated under reflux overnight. Excess volatile components of the reaction mixture were evaporated under reduced pressure. The residue was slurried with isopropyl ether and then filtered. The solids were recrystallized from hot acetic acid to afford 129 mg (40%) of the title compound: m.p. 280°-285° C. (dec.).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH2:8]([O:15][C@@H:16]1[C@@H](CO)[O:19][C@@H:18]([N:23]2[CH:30]=[C:29]([F:31])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([O:15][C@@H:16]1[C@@H:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:19][C@@H:18]([N:23]2[CH:30]=[C:29]([F:31])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A 3.33 ml quantity of acetic anhydride was added to a solution of 3.95 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 30 ml of pyridine, and the mixture was left to stand at 40° C. overnight. The solvent was distilled off and the residue was dissolved in 30 ml of ethyl acetate. The solution was washed twice with 15 ml of water. The ethyl acetate layer was dried on anhydrous sodium sulfate and concentrated The concentrate was placed on a silica gel column and eluted with chloroform, giving 3.62 g of the title compound in a yield of 81.5%.
Reaction SMILES: CN(C)[CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:5]=1.[Cl:24]C(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:24][CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:5]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(CN(C)C)c2cccnc21
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCl)c2cccnc21
Reaction time: 2 h

Procedure:
Into a round bottom flask was added compound 4 (500.0 mg, 1.51 mmol) and toluene (5.0 mL, 0.047 mol) under an atmosphere of nitrogen. Into the reaction mixture 1.0 M isopropyl chloroformate in toluene (1.6 mL) was added slowly at room temperature. The reaction mixture was stirred for another 2 hours to give desired compound 5 used for next step without purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][OH:14].[H-].[Na+].[H][H].Cl[C:20]1[CH:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][N:21]=1>O1CCCC1.O.CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:20]1[CH:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][N:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1CO
Reactant: [H][H]
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (5-methyl-2-phenyl-4-oxazolyl)methanol (9.46 g) and N,N-dimethylformamide (0.50 mL) was added sodium hydride (60%, oil, 2.40 g) at room temperature and the reaction mixture was stirred at room temperature until generation of hydrogen ended. The mixture was added to a solution of methyl 2-chloropyridine-4-carboxylate (8.58 g) in tetrahydrofuran (50 ml) at room temperature and the resulting mixture was further stirred at room temperature for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals of methyl 2-(5-methyl-2-phenyl-4-oxazolyl)methoxy-4-pyridinecarboxylate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless needle crystals (2.19 g, 14%). melting point: 106-107° C.