Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11].[CH3:12][S:13][C:14](=[N:17][C:18]#[N:19])SC>>[CH3:12][S:13][C:14](=[N:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11])[NH:17][C:18]#[N:19]
Reactant: Cc1[nH]cnc1CCCCN
Reactant: CSC(=NC#N)SC
Product: CSC(=NCCCCc1nc[nH]c1C)NC#N
Yield: 75.3 %

Procedure:
Reaction of 4-(4-aminobutyl)-5-methylimidazole (see Example 7 (ii), 2.71 g, 0.012 mol) with dimethylcyanodithioimidocarbonate (1.75 g 0.013 mol), gave S-methyl-N-cyano-N'-[4-(5-methyl-4-imidazolyl)butyl]isothiourea (2.27 g) which was treated directly with methylamine to yield N-cyano-N'-methyl-N"[4-(5-methyl-4-imidazolyl)butyl]guanidine (1.35 g), m.p. 152°-154° C. (from acetonitrile).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: O=C(O)CC(=O)O
Reactant: Cc1ccc(C=O)cc1F
Product: Cc1ccc(C=CC(=O)O)cc1F

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 2h30) between 3-fluoro-4-methyl-benzaldehyde (10.519 g; 76.154 mmol) and malonic acid (15.056 g; 144.694 mmol) gave the product 3-(3-fluoro-4-methyl-phenyl)-acrylic acid as a colorless solid (11.860 g; 86%). LC-MS: tR=0.84 min; [M+H]+: no ionisation.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[NH2:11][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc([N+](=O)[O-])c2N)cc1

Procedure:
0.1 mol (15.3 g) of 3-nitro-ortho-phenylenediamine is dissolved in 50 ml of pyridine, and 0.11 mol (21 g) of para-toluenesulphonyl chloride is then added gradually, whilst stirring, at between 40° and 45° C. When the addition has ended, the stirring is maintained for 15 minutes and the reaction medium is then poured into 250 ml of iced water. The expected product precipitates. It is filtered off, washed with water and recrystallised from acetic acid. It melts at 195° C.
Reaction SMILES: C(O[CH2:5][C:6]1[C:15]2[C:10](=[C:11]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:9]([OH:23])=[C:8]([C:24]([O:26][CH3:27])=[O:25])[N:7]=1)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C(OCC)(=O)C>[OH:23][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]([CH3:5])=[N:7][C:8]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1nc(COC(C)=O)c2cccc(Oc3ccccc3)c2c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C)c2cccc(Oc3ccccc3)c2c1O
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A glass lined Parr pressure reactor vessel equipped with a 4-blade impeller can be charged with 1c, Pd/C (about 0.4 to 0.5 molar equivalents), anhydrous Na2CO3 (about 0.5 molar equivalents), and ethyl acetate. The flask can then be vacuum-purged with nitrogen (3×) and vacuum-purged with hydrogen (3×). The flask can then be pressurized with hydrogen to set point 60 psi and stirred at 60° C. for 6-8 hrs until completion of reaction (1c <0.5%). The flask can then be cooled to 20-25° C., the pressure released to ambient, the head space purged with nitrogen three times and filtered through glass microfiber filter paper. The filtrate can be concentrated and precipitated from cold methanol and dried under vacuum at 50±5° C.
Reaction SMILES: [CH:1]([O:4][P:5]([CH2:11]Br)(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2].[OH:13][CH2:14][C:15]([CH2:38][CH3:39])=[CH:16][CH2:17][C:18]1[C:26]([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[C:25]2[C:21]([CH2:22][O:23][C:24]2=[O:34])=[C:20]([CH3:35])[C:19]=1[O:36][CH3:37].CC(C)([O-])C.[Li+].[Cl-].[Li+]>CN(C=O)C>[CH:1]([O:4][P:5]([CH2:11][O:13][CH2:14][C:15]([CH2:38][CH3:39])=[CH:16][CH2:17][C:18]1[C:26]([O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])=[C:25]2[C:21](=[C:20]([CH3:35])[C:19]=1[O:36][CH3:37])[CH2:22][O:23][C:24]2=[O:34])(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2]
Reactant: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CO
Reactant: CC(C)OP(=O)(CBr)OC(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)COCP(=O)(OC(C)C)OC(C)C
Temperature: 70 °C
Yield: 34.7 %

Procedure:
To a solution of bromomethylphosphonate diisopropyl ester (680 mg, 2.62 mmol) and 6-(3-hydroxymethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (688 mg, 1.75 mmol) in DMF (3 mL) was added lithium t-butoxide (1.0M in THF; 2.6 mL). The reaction was heated at 70° C. for 2 hours. After cooling to ambient temperature, more bromomethylphosphonate diisopropyl ester (680 mg, 2.62 mmol) and lithium t-butoxide (1.0M in THF; 2.6 mL) were added. The reaction mixture was heated at 70° C. for a further hour, cooled, poured into a solution of lithium chloride (5% aqueous) and extracted with ethyl acetate. The organic extract was dried and the product was purified by chromatography on silica gel, eluting with hexane-ethyl acetate to provide 347 mg (35%) of the product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 1.09 (t, 3H, J=7.5 Hz), 1.20-1.26 (m, 2H), 1.31 (t, 12H, J=6 Hz), 2.18 (s, 3H), 2.29 (q, 2H, J=7.5 Hz), 3.5 (m, 2H), 3.59 (d, 2H, J=8.7 Hz), 3.78 (s, 3H), 3.98 (s, 2H), 4.28-4.35 (m, 2H), 4.6-4.8 (m, 2H), 5.13 (s, 2H), 5.4 (t, 1H, J=7 Hz) ppm; 31P (121.4 MHz, CDCl3) δ 20.26 ppm; MS (m/z) 593.3 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:6]([N+:10]([O-])=O)=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:13]1(=O)[C:26]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][C:14]1=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6](=[CH:7][C:8]=1[Cl:9])[N:10]=[C:25]1[C:24]([C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:26]=31)=[N:5]2
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: O=C1C=Cc2c(ccc3ccccc23)C1=O
Solvent: CN(C)C=O
Product: Clc1cc2nc3c4ccccc4c4ccccc4c3nc2cc1Cl
Yield: 99.9 %

Procedure:
When 0.14 mole each of 3,4-dichloro-6-nitroaniline and phenanthrenequinone were reacted by the method of Example 1, 48.8 g. (99.9 percent yield) of 11,12-dichlorodibenzo[a,c]phenazine, mp = 263°-264° C. (DMF), were obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][N:12]=[C:13]=[O:14]>C1COCC1>[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][NH:12][C:13]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7])=[O:14]
Reactant: O=C=NCc1ccccc1Cl
Reactant: OC[C@@H]1CCCN1
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1Cl)N1CCC[C@H]1CO
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution of (S)-pyrrolidin-2-ylmethanol (110 mg, 1.1 mmol) in THF (2.0 mL) was added 2-chlorobenzyl-isocyanate (167 mg, 1.0 mmol). The reaction mixture was stirred for 1 h and concentrated under reduced pressure to give (S)—N-(2-chlorobenzyl)-2-(hydroxymethyl)pyrrolidine-1-carboxamide as an oil (277 mg), which was used without further purification. LRMS (M+H+) m/z 269.0.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:18][CH2:19][CH2:20]O>>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:20][CH2:19][CH2:18][C:17]([F:26])([F:16])[C:22]([F:25])([F:24])[F:23])(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCCCC(F)(F)C(F)(F)F
Product: O=S(=O)(OCCCC(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
At 0° C., 18.6 g of trifluoromethanesulfonic anhydride was added dropwise to 10.7 g of 4,4,5,5,5-pentafluoropentanol. The mixture was stirred at room temperature for an hour and then at 80° C. for 2 hours. Thereafter, the reaction mixture was poured into ice water and then extracted with t-butyl methyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 6.2 g of 4,4,5,5,5-pentafluoropentyl trifluoromethanesulfonate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.Cl[S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH2:46])=[O:45])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>ClCCl>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[N:18]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([NH:43][C:44]([NH2:46])=[O:45])=[CH:41][CH:42]=3)(=[O:36])=[O:35])[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:11])[F:12]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: NC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(NC(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (185 mg) dissolved in 30 ml of dichloromethane and 0.4 ml of triethylamine was added to 128 mg of N-[4-(chlorosulfonyl)phenyl]urea. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water and 0.1N sodium bicarbonate solution.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([Cl:21])[CH:15]=2)[N:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(-c3cc(CNC(=O)C(C)(C)C)ccc3Cl)[nH]c2=O)cc1Cl
Yield: 46.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-93, 0.350 g, 1.00 mmol), pivaloyl chloride (0.128 g, 1.0 mmol), DIPEA (2.0 mL), dry THF (10 mL) to afford 0.200 g of the desired product. 1H NMR (300 MHz, DMSO c/6): δ 1.13 (s, 9H), 2.34 (s, 3H), 4.29 (d, J=6.3 Hz, 2H), 7.39-7.47 (m, 2H), 7.58-7.61 (m, 2H), 7.82 (d, J=8.7 Hz, 1H), 8.01 (s, 1H), 8.18 (t, 1H), 12.58 (s, 1H); MS (m/z): 433.19 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:20][C:21]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24]>C(Cl)Cl.CN1CCOCC1.ClC(OCC(C)C)=O>[C:11]1([CH2:10][C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:17]2[O:19][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([F:31])([F:32])[F:33])[C:21]=3[N:20]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Yield: 44.5 %

Procedure:
Using the procedure of Step A of Example 7, a solution of 19.9 g of BOC-L-phenylalanine in 150 ml of methylene chloride and 20.6 ml of N-methyl-morpholine, 19.5 ml of isobutyl chloroformate in 75 ml of methylene chloride and 15.4 g of 2-amino-3-trifluoromethyl benzoic acid in 150 ml of methylene chloride and 8.3 ml of N-methyl-morpholine were reacted to obtain 14.5 g of 1,1-dimethylethyl N-[(S) 2-phenyl-1-[4-oxo-8-(trifluoromethyl)-4H-3,1-benzoxazin-2-yl]-ethyl]-carbamate melting at 145° C. and having a specific rotation of [α]D =-33.5°±2° (c=0.5% in CH3COOH).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([Br:21])=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]([O:47][C:48]([NH:50][CH2:51][CH2:52]CO)=[O:49])([CH3:46])([CH3:45])[CH3:44].CCOC(/N=N/C(OCC)=O)=O>ClCCCl>[C:1]([O:4][C@H:5]([CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:52][CH2:51][NH:50][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])[C:16]([Br:21])=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2CCNC(=O)OC(C)(C)C)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a stirring suspension of (R)-1-(5-acetoxyhexyl)-8-bromo-3-methylxanthine (5.10 g, 13.2 mmol), triphenylphosphine (5.24 g, 20.0 mmol) and 3-(tert-butoxycarbonylamino)-1-propanol (3.2 g, 20.0 mmol) in anhydrous 1,2-dichloroethane (100 ml) at room temperature was added diethylazodicarboxylate (3.48 g, 20.0 mmol) dropwise. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (1:1) to provide (R)-1-(5-acetoxyhexyl)-8-bromo-7-(2-(N-tert-butoxycarbonylamino)ethyl)-3-methylxanthine (6.10 g, 85% yield) as a beige oil.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].Cl[C:6]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH2:14]2)[N:9]=[C:8]([C:23]([F:26])([F:25])[F:24])[N:7]=1.[H-].[Na+]>O1CCCC1>[O:20]1[C:16]2([CH2:21][CH2:22][CH:13]([O:12][C:10]3[N:9]=[C:8]([C:23]([F:26])([F:25])[F:24])[N:7]=[C:6]([O:3][CH2:2][CH2:1][OH:4])[CH:11]=3)[CH2:14][CH2:15]2)[O:17][CH2:18][CH2:19]1
Reactant: OCCO
Reactant: FC(F)(F)c1nc(Cl)cc(OC2CCC3(CC2)OCCO3)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
1,2-Ethanediol (60 μL, 1.1 mmol) and 4-chloro-6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine (described in Example 1, Step 1) (91 mg, 0.27 mmol) were dissolved in tetrahydrofuran (1.4 mL) and cooled to 0° C. Sodium hydride (60%/mineral oil, 22 mg, 0.56 mmol) was added and stirred for 30 minutes at 0° C., then at 22° C. for 20 hours. LCMS analysis showed no remaining starting material, and as the main component, formation of the product, M+H 365. The reaction was quenched with aqueous bicarbonate. The aqueous solution was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (Na2SO4) and the solvent removed in vacuo. The product was purified by preparative LCMS using a Waters Fraction-Linx instrument and a 30 mm×100 mm Sunfire C18 column; 38% CH3CN—H2O (0.1% TFA), 0.5 min, 4.5 min gradient to 56%; 60 mL/min; detector set at M+H 365; retention time, 5.7 min. HPLC found the UVmax as 240 nm. The solvent was removed by rotary evaporation to give 56 mg of product (57% yield). The compound of Example 56 was then obtained by following the steps described for Example 45.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[CH:18]OC)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](=O)(O)[O-:22].[Na+]>O1CCCC1.Cl>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][CH:21]=[O:22])[CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CCC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 1-benzhydryl-3-methoxymethylene-azetidine (0.19 g, 0.88 mmol) in tetrahydrofuran (20 mL) and 1N hydrogen chloride (10 mL) was refluxed overnight. The mixture was neutralized with saturated sodium bicarbonate and extracted with methylene chloride (3×50 mL). The combined organic extracts were washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford 0.17 g of the title compound as a light yellow oil. 1H NMR (400 MHz, DMSO-D6): δ 3.2 (br, 4H), 4.42 (s, 1H), 7.13–7.18 (m, 2H), 7.23–7.27 (m, 4H), 7.37–7.40 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][S:7][CH:8]1[CH:16]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9]1.O.[OH-].[Li+]>C1COCC1.O>[C:18]1([CH2:17][CH:16]2[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[N:9][CH:8]2[S:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CCCSC1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCSC1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 50 mg (0.13 mmol) of 4-(3-naphthalen-1-ylmethyl-2,3-dihydro-imidazo[1,2-a]pyridin-2-ylsulfanyl)-butyric acid methyl ester in 2 mL of THF is treated with a solution of 11 mg (0.26 mmol) of lithium hydroxide monohydrate in 1 mL of water at room temperature. The resulting mixture is heated to 40° C., and stirred at this temperature for 3 h. Then the reaction mixture is cooled to room temperature and concentrated in vacuo. The residue is diluted with water and neutralized with 1N HCl solution. The product is extracted with ethyl acetate, and the organic layer is separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography eluting with 3˜10% methanol in dichloromethane solution to give the title compound. LCMS (ESMS): m/z 377 (M+H+)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].CS(O[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O.O>CN(C)C=O>[CH:6]([C:4]1[N:3]=[CH:2][N:1]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:5]=1)=[O:7]
Reactant: O=Cc1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(C=O)c2)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 23.1 %

Procedure:
To 137 mg of imidazole-4-carboxaldehyde diluted in 2 ml of anhydrous dimethylformamide under argon are added portionwise at 0° C. 63 mg of sodium hydride (60% in mineral oil). The reaction mixture is stirred for 45 min at 0° C. then 400 mg of tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate are added portionwise, and the solution is brought to 100° C. for 15 h. Water is added and the product is extracted several times with ethyl acetate. The organic phases are combined, washed with sodium chloride saturated aqueous solution, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 2:8 to 100% ethyl acetate) to yield 92 mg of tert-butyl 4-(4-formyl-1H-imidazol-1-yl)piperidine-1-carboxylate in the form of a colourless oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:15]2[NH:16][C:17]([N:19]3[CH2:24][CH2:23][NH:22][C@H:21]([CH3:25])[CH2:20]3)=[N:18][C:14]=2[CH:13]=[C:12]([C:26]([F:29])([F:28])[F:27])[CH:11]=1.C(N(CC)C(C)C)(C)C>>[Cl:9][C:10]1[C:15]2[NH:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:2]4[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=4)[C@H:21]([CH3:25])[CH2:20]3)=[N:18][C:14]=2[CH:13]=[C:12]([C:26]([F:29])([F:28])[F:27])[CH:11]=1
Reactant: Clc1cccnc1Cl
Reactant: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CCN1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CCN1c1ncccc1Cl

Procedure:
A mixture of 2,3-dichloro-pyridine (44 mg, 0.3 mmol, Aldrich), 7-chloro-2-[(3R)-3-methylpiperazin-1-yl]-5-(trifluoromethyl)-1H-benzoimidazole (80 mg, 0.25 mmol, Example 48a) and N,N-diisopropylethylamine (0.1 mL, 0.58 mmol, Aldrich) reacted under the conditions of Example 48b to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 430 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH:10]3[CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12][CH2:11]3)[CH2:7][C:6]=2[CH:22]=1.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][CH:8]([CH:10]4[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]4)[CH2:7][C:6]=3[CH:22]=2)=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: O=C(N1CCC(C2Cc3cc(Br)ccc3O2)CC1)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCNCC2)O3)cc1
Temperature: 90 °C

Procedure:
To a mixture of 1-[4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidin-1-yl]-2,2,2-trifluoro-ethanone (2.50 g) and 4-(methanesulfonyl)phenyl boronic acid (1.45 g) in N,N-dimethylformamide (25 mL) a 2 M aqueous Na2CO3 solution (8.26 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene].CH2Cl2 complex (540 mg) is added. The resulting mixture is stirred over night at 90° C. After cooling to room temperature, water (50 mL) and ethyl acetate (100 mL) are added and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4), and the solvent is evaporated. The residue is chromatographed on silica gel [dichloromethane/(methanol/NH4OH 9:1) 90:10-80:20] to give the title compound, since the trifluoroacetyl group is removed under the reaction conditions. LC (method 1): tR=0.88 min; Mass spectrum (ESI+): m/z=358 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][CH:16]=3)[N:11]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C1COCC1.CO>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)[C:9]([CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:10]1)([OH:28])=[O:27]
Reactant: COC(=O)CCCCn1cc(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCCn1cc(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 100 °C
Yield: 99.3 %

Procedure:
2N NaOH solution (2.0 mL) was added to a solution of methyl 3-cyclohexyl-1-(5-methoxy-5-oxopentyl)-1H-indole-6-carboxylate (410 mg, 1.1 mmol) in THF/Methanol mixture (2.0 mL/2.0 mL). The reaction mixture was heated at 100° C. under microwave condition for 15 min, after which it was concentrated and the pH was adjusted to 4–5 with 1N HCl solution. A precipitate formed which was collected by filtration to give the product as a white powder, (375 mg, 99% yield). MS m/z 344(MH+). 1H NMR (300 MHz, CD3OD) δ ppm 1.24–1.98 (m, 10 H) 2.00–2.15 (m, 2 H) 2.25–2.39 (m,2H) 2.84 (m, 1 H) 4.16–4.30 (m, 2 H) 4.56–4.72 (m, 2 H) 7.22 (m, 1H) 7.58–7.78 (m, 2H) 8.10 (m, 1H).