Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:20]([NH2:23])[CH:21]=[CH2:22].C(=O)([O-])O.[Na+]>>[CH2:20]([NH:23][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:21]=[CH2:22]
Reactant: CCCCCCCNc1nc(Cl)nc2c(C)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCCCCCCC)c2scc(C)c2n1
Yield: 68.3 %

Procedure:
In a sealed tube were heated 82 mg (1.2 mmol) of 2-chloro-4-heptylamino-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 261 mg (yield: 68.3%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20]([C:22]1[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=1)=[O:21])(C)(C)C.CCN(CC)CC.[CH2:37]1[C:40]2([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][N:38]1C(OC(C)(C)C)=O>CS(C)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:21])[C:22]1[CH:27]=[CH:26][C:25]([N:43]2[CH2:44][CH2:45][C:40]3([CH2:37][NH:38][CH2:39]3)[CH2:41][CH2:42]2)=[N:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(N2CCC3(CC2)CNC3)nc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
tert-Butyl[2-{[(6-chloropyridin-3-yl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamate F (20 mg, 0.088 mmol) was dissolved in 1 mL of DMSO and treated with Et3N(0.010 mL) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (20 mg, 0.047 mmol). The mixture was stirred at 90° C. for 18 h, partitioned between EtOAc and saturated NaHCO3, dried (MgSO4), filtered and concentrated), concentrated and the residue was purified by chromatography on SiO2 (EtOAc/CH2Cl2, 0% to 100%). The residue was dissolved in 1 mL of 1:1 TFA/CH2Cl2, stirred for 1 h and concentrated. Neutralization with EtOAc/sat'd NaHCO3 extraction and drying (MgSO4) gave desired product, N-[2-amino-5-(2-thienyl)phenyl]-6-(2,7-diazaspiro[3.5]non-7-yl)nicotinamide, which was confirmed by MS (ESI+): cal'd [M+H]+ 420.2, obs'd 420.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:22]I>>[F:1][C:2]1[CH:3]=[C:4]([N:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[N:12]=2)[CH3:22])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(Nc2nc(C)nc3ccccc23)cc1F
Reactant: CI
Product: COc1ccc(N(C)c2nc(C)nc3ccccc23)cc1F

Procedure:
The title compound was prepared from (3-fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (250 mg, 0.88 mmol) and methyl iodide (0.39 ml, 6.18 mmol) by a procedure similar to example 36. 1H NMR (CDCl3): 7.76 (d, J=8.4 Hz, 1H), 7.59-7.53 (m, 1H), 7.09-6.82 (m, 5H), 3.91 (s, 3H), 3.58 (s, 3H), 2.73 (s, 3H).
Reaction SMILES: C(S[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[C:8]([CH3:26])=[C:7]2[C:27]([O:29][CH3:30])=[O:28])C.Cl[C:32]1C=C(C=C[CH:41]=1)C(OO)=O.C([O-])(O)=O.[Na+].[O-:47][S:48]([O-:51])(=S)=O.[Na+].[Na+]>ClCCl>[CH2:32]([S:48]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=1)[C:8]([CH3:26])=[C:7]2[C:27]([O:29][CH3:30])=[O:28])(=[O:51])=[O:47])[CH3:41]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cc2c(C(=O)OC)c(C)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)c1cc2c(C(=O)OC)c(C)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of methyl 6-(ethylthio)-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (7.05 g, 11.33 mmol) and 3-chloroperoxybenzoic acid (5.11 g, 22.7 8 mmol) in dichloromethane (50 mL) was stirred overnight. Saturated aqueous NaHCO3 and Na2S2O3 were added slowly, and the mixture was stirred for 30 min and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-15% ethyl acetate/methylene chloride) to give methyl 6-(ethylsulfonyl)-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (3.4 g, 64% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.98-8.05 (m, 2H), 7.92 (d, J=8.03 Hz, 1H), 7.76-7.85 (m, 2H), 4.10 (s, 3H), 4.09 (s, 3H), 3.54 (q, J=7.53 Hz, 2H), 2.37 (s, 3H), 1.15 (t, J=7.40 Hz, 3H); MS (m/z) 468.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:20]=1[C:21](OC)=[O:22]>C1C=CC=CC=1.ClCCl>[CH3:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21](=[O:22])[N:1]([C:2]1[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1)[CH2:29]2
Reactant: COC(=O)c1c(C)cccc1CBr
Reactant: CCOC(=O)Cn1ccc2ccc(N)cc21
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCOC(=O)Cn1ccc2ccc(N3Cc4cccc(C)c4C3=O)cc21
Yield: 64 %

Procedure:
Ethyl 2-(6-amino-1H-indol-1-yl)acetate (intermediate B) (7.66 mmol, 1 equiv.) was dissolved in benzene (30 ml), and methyl 2-(bromo-methyl)-6-methylbenzoate (8.42 mol, 1.1 equiv.) and TEA (9.19 mmol, 1.2 equiv.) were added at 25° C. and the mixture was refluxed for 12 h. The reaction mixture was reduced under reduced pressure and the residue was taken up in dichloromethane (30 ml), washed with water and sat. NaCl solution (5 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (10% ethyl acetate in hexane). Yield: 64%
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.[H-].[Na+].O>CN(C)C=O>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:17][CH:16]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(CN(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
In an argon atmosphere, diphenylamine (338 mg, 2.00 mmol) and 4-bromobenzyl bromide (500 mg, 2.00 mmol) were dissolved in dimethylformamide (8 mL), and to the solution was added sodium hydride (88 mg, 2.2 mmol) under ice -cooling, followed by stirring at room temperature for 4 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (14:1 hexane/acetone) to obtain N-(4-bromobenzyl)diphenylamine (478 mg, 71%).
Reaction SMILES: [CH2:1]([C:3]([C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH:18]([OH:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:14]([CH3:26])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2].CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])(=O)=O>ClCCl>[CH2:1]([C:3]([C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH:18]([O:23][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C:19]([CH3:21])([CH3:20])[CH3:22])=[C:14]([CH3:26])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)cs1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of 1-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-ol (7.5 g, 20 mmol) in dichloromethane (100 ml) at −78° C. is added 2,6-dimethylpyridine (5.8 ml, 50 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (6.0 ml, 26 mmol). After stirring at RT for 2 h, the reaction diluted with dichoromethane and washed successively with 1N HCl followed by satd NaHCO3. The organic layer is dried over MgSO4 and concentrated to give the title product (9.5 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2.[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:14])([F:15])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Br)c(C(F)(F)F)cc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(C(F)(F)F)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C
Reaction time: 30 h
Yield: 73.9 %

Procedure:
To a solution of 6-bromo-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (40 mg, 0.13 mmol) in concentrated H2SO4 (0.5 mL) at 25° C. was added KNO3 (16 mg, 0.15 mmol, Baker). The mixture was stirred at 25° C. for 30 h and poured into ice water (2 g). The yellow precipitate was collected by filtration and the solid was dissolved in 1N KOH (10 mL). It was filtered and the filtrate was acidified to pH=5 with 4N HCl (2.5 mL) to give a yellow precipitate. The precipitate was collected and dried in the air at 50° C. for 4 h, affording the title compound (34 mg, 74%) as a yellow powder. Recrystallization from DMSO/H2O gave 18 mg (40%) of the title compound as yellow needles. Mp: 333°-5° C. (dec.); IR (KBr, cm-1): 3428, 3308, 3251, 3207, 1761, 1698, 1537, 600. 1H NMR (DMSO-d6): δ12.601 (br, 1H), 12.341 (s, 1H), 7.606 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][CH2:25][CH3:26])[N:14]([CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[K+].C(Cl)(=O)C(Cl)=O.[NH3:35]>CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][CH2:25][CH3:26])[N:14]([CH2:15][C:16]([CH3:21])([CH3:22])[C:17]([NH2:35])=[O:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)C(=O)OC
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)C(N)=O
Reaction time: 8 h

Procedure:
A modification of the methods described in Part C of Example 60 was used to treat methyl 3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate (7.6 g, 21 mmol) with potassium hydroxide (44 mL of 0.5 M); additional potassium hydroxide (22 mL) was added after refluxing for four hours. After the reaction was heated at reflux for five days, additional potassium hydroxide (11 mL) was added, and the reaction was heated for four more hours. After the reaction with oxalyl chloride (3.7 mL, 42 mmol) was stirred overnight, additional oxalyl chloride (1.0 mL) was added, and then the reaction was stirred for two hours. After the addition of ammonia in methanol (35 mL), the reaction was stirred for one hour and then concentrated. The residue was stirred with saturated aqueous sodium bicarbonate for 30 minutes, isolated by filtration, and recrystallized three times from methanol/water. During the first recrystallization, a solution in methanol was filtered through a 20 micron filter prior to the addition of water. The resulting crystals were dried overnight in a vacuum oven at 70° C. to provide 1.60 g of 3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanamide as light tan crystals, mp 231-233° C.
Reaction SMILES: Cl.BrCCC[NH2:6].C(N(CC)CC)C.Cl[S:15]([C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20](OC)=[O:21])(=[O:17])=[O:16]>ClCCl>[OH:16][S:15]1([OH:17])[C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20](=[O:21])[NH:6]1
Reactant: NCCCBr
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NS(O)(O)c2ccccc21
Temperature: 25 °C
Reaction time: 66 h
Yield: 33.3 %

Procedure:
3-Bromopropylamine hydrochloride (2.189 g, 10 mmol) was suspended in 15 ml of dry dichloromethane, and to the suspension were added triethylamine (7 ml, 50 mmol) and methyl 2(chlorosulfonyl)benzoate (2.738 g, 10.5 mmol). The mixture was stirred at room temperature for 66 hours, poured into ice water, extracted with dichloromethane, washed with water, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel to give 617 mg of 1,1-Dihydroxy-3-oxo-3H-benzo[d]isothiazole (20%). The isothiazole was etherified with Deg. B-Bh-Ester by the NaH/DMF method described above, and the compound was subjected to deprotection to remove the Bh group by the TFA/Anisole method described above, providing 309 mg of the desired compound 120 (97%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:18](=[S:20])=[S:19]>[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[Fe+3].C(N(CC)CC)C.C(O)C.O>[CH:1](=[N:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([S:20][S:20][C:18]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][N:9]=[CH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:14]2)=[S:19])=[S:19])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: O=Cc1ccccc1
Reactant: NCCN1CCNCC1
Agent: [Fe+3]
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: S=C(SSC(=S)N1CCN(CCN=Cc2ccccc2)CC1)N1CCN(CCN=Cc2ccccc2)CC1

Procedure:
10.6 parts of benzaldehyde are added to a solution of 12.9 parts of 1-(2-aminoethyl)piperazine in 24 parts of water and 24 parts of ethanol. 7.6 parts of carbon disulfide are then slowly added dropwise with ice cooling, whereby a precipitate forms. This is again dissolved after dilution with 100 parts each of water and of ethanol by addition of 10.1 parts of triethylamine and oxidized with 33 parts with potassium hexacyanoferrate(III). The product that now precipitates is filtered, washed repeatedly with water and finally with methanol, and dried at 30° C. in vacuum. Obtained are 26 parts of a substance with 56.4% C, 6.3% H, 14.5% N, and 21.5% S (calculated: 57.5% C, 6.2% H, 14.4% N, 21.9% S), which corresponds to the title compound of this Example according to IR and 1H-NMR.
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:27]1[N:31]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)[N:30]=[CH:29][CH:28]=1)CCC>>[CH3:21][C:3]1[C:2]([C:27]2[N:31]([C:32]3[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=3)[N:30]=[CH:29][CH:28]=2)=[CH:7][N:6]2[CH:8]=[CH:9][N:10]=[C:5]2[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Reactant: Cc1c(Br)cn2ccnc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2ccnc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (Int. 9, 30 mg, 0.085 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 62 mg, 0.135 mmol) using a similar method to that used in Example 1 (Step 4) (28 mg).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[OH:16].CN([CH:20]=[O:21])C.[OH-].[Na+].OS([O-])(=O)=O.[Na+]>O.CCOCC>[OH:16][C:9]1[C:8]([O:7][CH3:6])=[CH:13][C:12]([CH:20]=[O:21])=[C:11]([O:14][CH3:15])[CH:10]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(OC)c(O)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cc(C=O)c(OC)cc1O
Reaction time: 48 h
Yield: 9.4 %

Procedure:
POCl3 was added dropwise (T<20° C.) to a solution of intermediate 57, 2,5-Dimethoxyphenol (10.8 g, 0.07 mol) in DMF (22 mL, 0.28 mol) under vigorous stirring and cooling with an ice bath. The reaction mixture was stirred at room temperature for 72 h, then at 50° C. for 48 h, cooled, and diluted with H2O and ether (50 mL each). The solution was alkalized to pH 6 with a 10 N solution of NaOH. The aqueous layer was separated and subjected to extraction with ether. The combined extracts were dried and evaporated. The residue was recrystallized from ether. The obtained crystals were dissolved under argon in MeOH (20 mL). NaOH (0.5 g, 12 mmol) was added, and the mixture was stirred for 12 h. Then pH was brought to 6 with a 5 M solution of NaHSO4 (2.4 mL), and the mixture was evaporated. The residue was dissolved in CHCl3. The solution was washed with H2O, dried, and evaporated to give the title compound (1.2 g, 10%) as yellow crystals. 1H NMR data (DMSO-d6): 10.37 (s, 1H, —COH), 10.14 (s, 1H, Ar—OH), 7.17 (s, 1H, Ar—H), 6.60 (s, 1H, Ar—H), 3.81 (s, 3H, —OCH3), 3.76 (s, 3H, —OCH3).
Reaction SMILES: [Br-].[Li+].C(P(=[O:16])(CCCC)CCCC)CCC.[C:17]([O:22][CH2:23][C@@H:24]1[O:26][CH2:25]1)(=[O:21])[CH2:18][CH2:19][CH3:20].[F:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=O)[CH:31]=[CH:32][CH:33]=1>CC1C=CC=CC=1C>[C:17]([O:22][CH2:23][C@@H:24]1[O:26][C:25](=[O:16])[N:34]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=2)[CH2:35]1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCP(=O)(CCCC)CCCC
Reactant: O=C=Nc1cccc(F)c1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: [Br-]
Agent: [Li+]
Solvent: Cc1ccccc1C
Product: CCCC(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1

Procedure:
A mixture of lithium bromide (0.181 g, 2.08 mmol), tri-n-butylphosphine oxide (0.454 g, 2.08 mmol), and dry o-xylene (10 ml) is azeotropically dried for 1 hr. After cooling below the reflux point, a mixture of (R)-glycidyl butyrate (5.000 g, 34.68 mmol) and 3-fluorophenyl isocyanate (4.755 g or 3.96 ml, 34.68 mmol) in dry o-xylene (10 ml) is added over 10 min to the hot mixture (some refluxing observed during the addition). When the addition is complete, the mixture is heated to reflux for 2 hr and then allowed to cool to 20-25o. The solvent is removed under reduced pressure and the residue chromatographed over silica gel, eluting with hexane/ethyl acetate (6:1, 4:1, and then 2:1), to give the title compound, [α]25D -46.7° (c 1.0, CHCl3); IR (mineral oil mull) 1758, 1615, 1591, 1498, 1229, 1197, 1169 cm-1 ; NMR (CDCl3, 300 MHz) δ 7.44, 7.34, 7.23, 6.86, 4.88, 4.39, 4.32, 4.13, 3.82, 2.33, 1.63, 0.92; MS (m/z) 281, 193, 180, 150, 148, 137, 123, 95, 43; HRMS (m/z)281.1068 (calc'd for C14H16FNO4 =281.1063).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH:6](=[O:8])[CH3:7].[O:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH3:1][CH2:2][CH2:3][CH:6]([CH3:7])[CH3:10].[C:10]([O:9][CH2:13][CH3:12])(=[O:8])[CH3:11]
Reactant: [Li]CCCC
Reactant: CC=O
Reactant: C1CCOC1
Product: CCCC(C)C
Product: CCOC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (4R,9aR)-6-bromo-4-methyl-1,2,3,4,9,9a-hexahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (1.0 g) in dry tetrahydrofuran (30 mL) at −78° C. under argon was added dropwise a solution of butyl lithium in hexanes (2.5M, 1.2 mL). The mixture was stirred for 1 h then acetaldehyde (0.31 mL) was added dropwise. The mixture was warmed to room temperature, stirred for 30 minutes then partitioned between ethyl acetate (50 mL) and aqueous ammonium chloride solution (50 mL). The organic layer was washed (water), treated with di-tert-butyl dicarbonate (0.5 g), left to stand for 30 minutes then concentrated in vacuo. The residue was purified by flash column chromatography [SiO2; isohexane-ethyl acetate (9:1)→>(1:1)] to give (4R,9aR)-6-(1(RS)-ethanol)-iodo-4-methyl-1,2,3,4,9,9a-hexahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester as a clear oil (0.43 g), NMR δH (400 MHz, CDCl3) 7.13 (1H, dd, J 7.5, 1 Hz), 6.33 (1H, d, J 7.5 Hz), 4.69 (1H, q, J 6.5 Hz), 4.36 (1H, m), 4.29–3.81 (4H, m), 3.06 (1H, m), 3.01 (1H, dd, J8.5, 8.0 Hz), 2.66 (1H, m ), 2.51 (1H, dd, J 16, 6 Hz), 1.48 (9H, s), 1.44 (3H, d, J 6.5 Hz) and 1.24 (3H, dt, J 6.5, 4 Hz); m/z M+ 334 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].C1(=O)O[CH2:14][CH2:13][O:12]1>[Br-].C([N+](CC)(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([O:10][CH2:14][CH2:13][OH:12])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Product: O=Cc1cc(Cl)ccc1OCCO

Procedure:
Synthesized from 25 g of 3-chloro-6-hydroxybenzaldehyde, 14 g of ethylene carbonate and 45 g of tetraethylammonium bromide as described in Example XIIa.
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH2:3][OH:4].[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH2:9]Cl>C(O)CO>[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH2:9][O:4][CH2:3][CH2:2][OH:5]
Reactant: CN(C)C(=O)CCl
Reactant: OCCO
Agent: [Na]
Product: CN(C)C(=O)COCCO
Temperature: 50 °C
Reaction time: 1 h

Procedure:
40 ml of ethylene glycol and 8.4 g (0.1 mole) ethylene glycol monosodium salt are weighed into a 100 ml round bottom flask. The reaction mixture is heated to 50° C. with stirring and at this temperature, 12.2 g (0.1 mole) of chloroacetic acid N,N-dimethylamide are added dropwise in 1 hour. The reaction mixture is kept at the same temperature for further 1 hour and subsequently submitted to fractionated distillation. The first fraction (boiling temperature approx. 80° C., 260 Pa) comprises the solvent ethylene glycol. The boiling temperature of the product fraction is 130-135° C. (13 Pa). The purity of the product is higher than 98% as determined by gas chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH2:20][OH:21])=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)[CH:26]=[N:25][N:24]=[N:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C(Cl)=CN=C(N2CCC(C3SC=C(COC4C=CC(N5C=NN=N5)=CC=4)N=3)CC2)N=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH2:20][O:21][C:30]3[CH:31]=[CH:32][C:27]([N:22]4[CH:26]=[N:25][N:24]=[N:23]4)=[CH:28][CH:29]=3)=[C:17]([CH3:19])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccc(-n2cnnn2)cc1
Reactant: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1CO
Agent: Clc1cnc(N2CCC(c3nc(COc4ccc(-n5cnnn5)cc4)cs3)CC2)nc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1COc1ccc(-n2cnnn2)cc1
Reaction time: 4 h

Procedure:
To a solution of 4-(5-Hydroxymethyl-4-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.2 mmol) in THF (6.4 mL) was added, 4-tetrazol-1-yl-phenol (0.52 g, 3.2 mmol), polymer bound triphenylphosphine (3 mmol/g, 1.6 g). To this solution was added ditertierybutylazodicarboxylate (1.1 g, 4 8 mmol), stirred for 4 hours and filtered through a pad of celite. The filtrate was concentrated and purified by silica gel chromatography to provide the desired product. 1H NMR (CDCl3): δ 9.01 (1H, s), 7.66 (2H, d), 7.15 (2H, d), 5.21 (2H, s), 4.19 (2H, m), 3.10 (1H, m), 2.86 (2H, m), 2.45 (3H, s), 2.08 (2H, m), 1.72 (2H, m), 1.47 (9H, s).