Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:22]=[N:23][N:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:25]=2[CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:38](O)=[O:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]1[N:24]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:23]=[N:22][C:21]=1[C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]1[CH2:11][C@@H:10]([C:38]([N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:39])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13]1)=[O:20]
Reactant: C1CCNC1
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1

Procedure:
A solution of (3R,5S)-1-(tert-butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (279 mg), pyrrolidine (42 μl), WSC.HCl (144 mg), HOBt (107 mg), diisopropylethylamine (255 μl) and DMF (3 ml) was stirred at room temperature for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the liberated oil was extracted with ethyl acetate (20 ml). The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (245 mg) as an amorphous compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][C@H:11]([CH3:22])[O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:23])[N:4]=[C:3]1[N:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CO>[Pd].C(OCC)(=O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][C@@H:11]([CH3:22])[CH2:10][C@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:39])([CH3:1])[C:3]([N:24]([C:25]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:31])[C:32](=[O:33])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[N:4][C@:5]3([CH3:23])[C:14]=2[CH:15]=1
Reactant: C[C@H]1C[C@@H]2[C@](C)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc([N+](=O)[O-])ccc2O1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@@H]2[C@](C)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc(N)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Tert-butyl N-[(4aR,6S,11bR)-3,3,6,11b-tetramethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (7.3 g, 12.86 mmol) and palladium on carbon (10%), wet (1 g, 0.470 mmol) were combined in ethyl acetate (60 ml) with 5 ml of MeOH under hydrogen atmosphere and stirred at room temp for 1 h. The solution was filtered thru celite, the Pd solids were washed with DCM and MeOH, then the organics were concentrated to afford tert-butyl N-[(4aR,6S,11bR)-10-amino-3,3,6,11b-tetramethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (6.5 g, 12.09 mmol, 94% yield) as a white solid. MS m/z=560 [M+Na].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1.[C-]#N.[Na+].C[N:16]([CH2:18][C:19]1C2C(=NC=C(F)C=2)NC=1C)C>O>[C:18]([CH2:19][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:8][C:9]=1[CH3:11])#[N:16]
Reactant: Cc1cc2cc(F)cnc2[nH]1
Reactant: Cc1[nH]c2ncc(F)cc2c1CN(C)C
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: Cc1[nH]c2ncc(F)cc2c1CC#N
Temperature: 0 °C
Yield: 67 %

Procedure:
Mannich reagent (0.8 ml, prepared according to Liebigs (1971) Ann. Chem., 743, 95-111) was added under stirring to pre-cooled (-78° C.) 5-fluoro-2-methylpyrrolo[2,3-b]pyridine (0.33 g, 2.2 mmol) under argon. The flask containing the reaction mixture was then placed in an ice bath and stirring was continued to give a white suspension. The ice lumps melted within 2 h and the resulting water bath was allowed attain room temperature. After 24 h almost all suspension had dissolved. The reaction mixture was cooled in an ice bath, diluted with deinionized water (8 ml) and extracted with diethyl ether (2×5 ml) to remove some remaining starting material and a by-product (propably the corresponding Mannich dimer). Sodium cyanide (1.08 g, 0.022 mol) was added to the water phase, assumed to contain 3-(dimethylaminomethyl)-5-fluoro-2-methylpyrrolo[2,3 -b]pyridine, and the resulting solution was refluxed for 2 h to afford a suspension which was isolated by filtration. Purification by flash chromatography (SiO 2 /CH2Cl2 :MeOH 19:1) gave 0.28 g (67%, two steps) of 3-(cyanomethyl)-5-fluoro-2-methylpyrrolo[2,3-b]pyridine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22](OCC)=[O:23])[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C(OCC)C>[O:7]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][OH:23])[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C=Cc1cccc(Oc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a stirred mixture of 7.4 grams (0.196 mole) of lithium aluminum hydride in 300 mL of dry diethyl ether under a nitrogen atmosphere was added 26.2 grams (0.098 mole) of ethyl 3-(3-phenoxyphenyl)acrylate in 300 mL of dry diethyl ether. The addition required 90 minutes to complete, and the reaction mixture was stirred overnight at ambient temperature. It was then cooled in an ice/water bath, and sequentially 14 mL of water, 14 mL of a 15% aqueous solution of sodium hydroxide, and 42 mL of water were all added dropwise. This mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate. After being filtered, the solvent was evaporated under reduced pressure, leaving 21.9 grams of 3-(3-phenoxyphenyl)propanol as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH:42]1([CH2:48][S:49](Cl)(=[O:51])=[O:50])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[CH:42]1([CH2:48][S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)CC3CCCCC3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 80.3 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0843 g, 0.183 mmol) was dissolved in dichloromethane (3.0 mL), and the solution was treated with triethylamine (0.127 mL, 0.913 mmol) and cyclohexylmethanesulfonyl chloride (0.108 g, 0.548 mmol) to obtain 4-cyclohexylmethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0914 g, yield 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[CH3:11][O:12][C:13]([C:15]1[CH:20]=[N:19][C:18](Cl)=[CH:17][N:16]=1)=[O:14].O>CN(C=O)C>[CH3:11][O:12][C:13]([C:15]1[CH:20]=[N:19][C:18]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:17][N:16]=1)=[O:14]
Reactant: Oc1ccccc1F
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(Oc2ccccc2F)cn1
Temperature: 0 °C

Procedure:
2-Fluorophenol (21.6 g, 233 mmol) was dissolved in DMF (250 mL) under a calcium chloride drying tube. The solution was cooled to 0° C., and then 60% NaH in paraffin oil (9.3 g, 233 mmol) was added in small portions. After the main portion of NaH had dissolved, 5-chloro-pyrazine-2-carboxylic acid methyl ester (Preparation 41, 40.2 g, 233 mmol) was added. The mixture was refluxed for 1 hour and then poured into water (1 L). The aqueous mixture was extracted with ether (3×300 mL), and the combined organic layers were washed with 2% sodium hydroxide aqueous solution (400 mL) and filtered through a layer of silica gel (40/60 μm). The filtrate was concentrated in vacuo to yield the title compound which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:20]([C:22]4([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]4)=[O:21])=[CH:15][C:14]=3[F:34])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:35][CH3:36].CS(O[CH2:42][CH2:43][CH2:44][C:45]1([OH:48])[CH2:47][CH2:46]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:48][C:45]1([CH2:44][CH2:43][CH2:42][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:18]=[CH:17][C:16]([N:19]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:20]([C:22]5([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]5)=[O:21])=[CH:15][C:14]=4[F:34])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:35][CH3:36])[CH2:47][CH2:46]1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1O
Reactant: CS(=O)(=O)OCCCC1(O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1OCCCC1(O)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 9 by using N-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide (300 mg, 0.616 mmol), 3-(1-hydroxycyclopropyl)propyl methanesulfonate (155 mg, 0.80 mmol), and Cs2CO3 (602.5 mg, 1.848 mmol) in 3 mL of DMA. The residue was purified by a silical gel column chromatography (6:1 (v/v) EtOAc/n-hexane). The title compound was obtained as a white solid (263 mg, 73%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32](O)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2>>[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:1][CH2:2][C@@H:3]4[CH2:7][CH2:6][CH2:5][N:4]4[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 57.7 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 11, tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (142 mg, 0.71 mmol) was reacted with 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 7), and the product purified by column chromatography, eluting with methanol/methylene chloride (1/9) containing 0.1% triethylamine to give tert-butyl (2S)-2-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)methyl]pyrrolidine 1-carboxylate (178 mg, 58%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:25]>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][S:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:25])=[O:2])=[CH:9][CH:10]=1
Reactant: COC(=O)CC(=O)Nc1ccc(SCc2cccc(F)c2)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(SCc2cccc(F)c2)cc1
Yield: 47 %

Procedure:
Prepared in analogy to example 3 from N-[4-(3-fluoro-benzylsulfanyl)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=47%. Colorless solid. MS: m/e=319.3 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:26])[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([F:27])[CH:5]=1.[H][H]>CO.C(OCC)(=O)C.[Pt](=O)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:26])[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([F:27])[CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)c(F)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCC(=O)c2cccnc2Nc2ccccc2)c(F)c1
Yield: 96.3 %

Procedure:
A solution of 3-fluoro-4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (890 mg, 2.36 mmol) in methanol (59.1 mL) and ethyl acetate (59.1 mL) at 25° C. was treated with platinum(IV) oxide (26.8 mg, 118 μmol). The reaction was stirred under a balloon of hydrogen gas for 18 h. At this time, the reaction was filtered through a pad of Celite® and was rinsed with a solution of 10% methanol/methylene chloride (3×75 mL). The filtrate was concentrated in vacuo to afford 3-fluoro-4-[3-oxo-3-(2-phenylamino-pyridin-3-yl)-propyl]-benzoic acid methyl ester (860 mg, 96.2%) as a dark green solid. The material was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[C:30]([O:34][C:35](=[O:44])[NH:36][CH:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:44])[NH:36][CH:37]1[CH2:38][CH2:39][CH:40]([NH:43][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[CH:16]=[C:8]([O:7][C:6]3[CH:28]=[CH:29][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:9]=2)[CH2:41][CH2:42]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: N#Cc1ccc(Oc2cc(OCc3cccc([N+](=O)[O-])c3)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3cccc([N+](=O)[O-])c3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 72.8 %

Procedure:
Following the procedure of Example 5(c) 3-(4-cyano phenoxy)-5-(3-nitro benzyloxy)benzoic acid 1.1 g (2.81 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.6 g, 2.81 mmol) were used to afford 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.35 (2H, s), 6.78 (1H, d), 7.04 (1H, s), 7.12 (2H, d), 7.22 (1H, s), 7.46 (1H, s), 7.72 (1H, t), 7.9 (3H, d), 8.2 (1H, d), 8.34 (2H, m).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:14][C@H:13](CS([O-])(=O)=O)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]([CH2:23][C:24]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[CH:26][CH:25]=1)=[N+:21]=[N-:22].[F:32][C:33]1[C:34](=[O:40])[NH:35][C:36](=[O:39])[NH:37][CH:38]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O.CCOC(C)=O.CN(C=O)C>[N:20]([CH2:23][C:24]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[CH:26][CH:25]=1)=[N+:21]=[N-:22].[F:32][C:33]1[C:34](=[O:40])[NH:35][C:36](=[O:39])[N:37]([C@H:13]2[CH2:12][C@@H:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14]2)[CH:38]=1
Reactant: O=S(=O)([O-])C[C@H]1C[C@H](CCOCc2ccccc2)C1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: COc1ccc(CN=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n([C@H]2C[C@@H](CCOCc3ccccc3)C2)cc1F
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
In a 50 mL three-neck flask with trans-3-(benzyloxyethyl)cyclobutyl-mesylate (0.34 g, 1.2 mmol), N3-PMB-5-fluoro-uracil (0.36 g, 1.44 mmol), K2CO3 (0.2 g, 1.44 mmol) and 18-crown-6 (0.38 g, 1.44 mmol) inside, dry DMF 10 mL was added under argon to give a light yellow solution with some white solids at the bottom of the flask. After 5 min, start to heat to 120° C. After 24 hr, add 30 mL EtOAc and 20 mL H2O. The organic phase was separated and washed with brine once. The organic phase was dried over MgSO4 and the solvents were evaporated to give the crude product, which was purified by silica gel flash chromatography (Hexane: EtOAc=3:1) to give an off-white solid (0.27 g, 50.9%) combined with some three-membered ring by-products. 1H NMR (CDCl3, 300 MHz): δ 1.72-1.79 (m, 4H), 2.16-2.24 (m, 1H), 2.51-2.60 (m, 2H), 3.43-3.48 (m, 2H), 3.77 (s, 3H), 4.48 (s, 2H), 4.64-4.75 (m, 1H), 5.05 (s, 2H), 6.81-6.84 (d, J=9.0, 2H), 7.29-7.36 (m, 6H), 7.44-7.47 (d, J=9.0, 2H). MS (FAB): expected for C25H27FN2O4 (M+H)+ 439.49. Found 439.20320. IR (neat) νmax 2926, 2854, 1712, 1458, 1377, 1265, 895, 740, 705.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:16](=O)[CH:17]=[CH2:18].[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[N:1]1[C:2]2[C:15](=[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]3=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C=CC=O
Reactant: Nc1cc2ccccc2c2ccccc12
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: c1ccc2c(c1)c1ccccc1c1ncccc21
Yield: 33.6 %

Procedure:
2.52 g of 9-aminophenanthrene (13 mmol) was added into a two-necked bottle and placed in a drying oven. After 2.1 g of ferric chloride (13 mmol) and 1.77 g of zinc chloride (13 mmol) were added, a nitrogen gas was conducted. Next, 25 ml of acetic acid was slowly added. Next, 875 mg of propenal (15.6 mmol) was then added with thermal reflux for three hours. After cooling, 15% of the NaOH aqueous solution was slowly added under an ice bath to neutralize the pH level to 7. Next, the resulting solution was extracted by adding ethyl acetate and a saturated NaHCO3 aqueous solution. Following, water was removed by adding dried magnesium sulfate and solvent was removed by using filtration and concentration processes. The result was next purified using column chromatography using n-hexane/ethyl acetate (4:1) as an eluent. 1.0 g of a white dibenzo[h,f]quinoline (DBQ) solid was obtained, with a yield of 34%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH:17]=[O:18])[CH2:6][CH2:7][CH3:8])[CH3:2].[CH2:20](O)[CH2:21][OH:22]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH:17]1[O:22][CH2:21][CH2:20][O:18]1)[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: OCCO
Reactant: CCCC(Oc1ccc(Cl)cc1C=O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OCC
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A mixture of 2-(4-chloro-2-formyl-phenoxy)-pentanoic acid ethyl ester (15 g, 53 mmol), ethylene glycol (25 mL, 440 mmol) and p-toluenesulfonic acid (0.8 g, 4.65 mmol) in toluene (150 mL) was refluxed with a Dean-Stark trap attached to remove water. After 3 h, the reaction was cooled and washed with water, saturated NaHCO3 solution and water, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow oil (16 g).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])[CH2:17][CH2:16]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:40]([O:42][CH2:43][CH2:44]Cl)[CH3:41].N12CCCN=C1CCCCC2>C(#N)C.C(OCC)(=O)C>[CH3:1][N:2]([CH2:11][CH:12]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]([C:23]2[N:24]([CH2:41][CH2:40][O:42][CH2:43][CH3:44])[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[O:22])[CH2:17][CH2:16]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3[nH]2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: CCOCCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOCCn1c(C(=O)C2CCN(CCC(CN(C)C(=O)c3ccccc3)c3ccc(Cl)c(Cl)c3)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)-benzamide (1.36 mmol), 2-chloroethyl ethyl ether (0.59 g, 5.44 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.66 g, 10.9 mmol) in acetonitrile (16 mL). Heat to reflux. After 18 hours, cool to ambient temperature and dilute the reaction mixture with ethyl acetate. Extract twice with saturated aqueous solution of ammonium chloride, 5% aqueous solution of sodium bicarbonate, water, and saturated aqueous solution of sodium chloride. Dry the organic layer over Na2SO4, filter, and concentrate invacuo to give the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].Cl.N1C=CC=CC=1.[N-:36]=[N+:37]=[N-:38].[Na+].O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21]2[NH:38][N:37]=[N:36][N:22]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: N#Cc1cccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: c1cc(COc2cccc(-c3nnn[nH]3)c2)cc(OCc2ccc3ccccc3n2)c1
Temperature: 100 °C

Procedure:
A mixture of 1.2 g (3.28 mmol) of 3-[3-(2-quinolinylmethyloxy)benzyloxy]benzonitrile, 1.89 g (16.4 mmol) of pyridine hydrochloride, and 1.06 g (16.4 mmol) of sodium azide in 10 ml of DMF is heated at 100° C. for 4 days. The reaction mixture is poured into water. The crude product collected on a filter and recrystallized from ethyl acetate to give 5-[3-(3-(2-quinolinylmethyloxy)benzyloxy)phenyl] tetrazole. (M.P. 169°-172° C.)
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17](OS(C(F)(F)F)(=O)=O)=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:30])[C:11]1=[O:31])(=[O:3])[CH3:2].[CH3:33][NH:34][CH3:35]>O1CCCC1>[C:1]([O:4][C@H:5]([CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([N:34]([CH3:35])[CH3:33])=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:30])[C:11]1=[O:31])(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(OS(=O)(=O)C(F)(F)F)cc(C)nc2n(C)c1=O
Solvent: C1CCOC1
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(N(C)C)cc(C)nc2n(C)c1=O
Temperature: 0 °C

Procedure:
A pressure tube was charged with (R)-3-(5-acetoxyhexyl)-1,7-dimethyl-5-trifluoromethanesulfonyloxypyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.208 mmol) and tetrahydrofuran (1 ml). After cooling to 0° C., dimethylamine gas was introduced until approximately 1 ml had collected. The tube was sealed and heated at 55° C. for 18 hours. After cooling to room temperature, the tube was carefully vented and the dimethylamine was evaporated to provide crude (R)-3-(5-acetoxyhexyl)-1,7-dimethyl-5-(N,N-dimethylamino)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15].P(Br)(Br)[Br:18]>N1C=CC=CC=1>[Br-:18].[Br-:18].[CH2:14]([OH:15])[CH2:13][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:16]
Reactant: BrP(Br)Br
Agent: OCCOCCOCCOCCOCCO
Solvent: c1ccncc1
Product: [Br-]

Procedure:
In a manner similar to that described in Example 2A, treat pentaethylene glycol with phosphorous tribromide in pyridine. Isolate and purify the resultant product in a manner similar to that described to obtain pentaethylene glycol dibromide.