Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][CH:4]1[C:36](=[O:37])[N:6]2[C:7]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:9][S:10][C@H:5]12)=O.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.O>[NH2:3][CH:4]1[C:36](=[O:37])[N:6]2[C:7]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:9][S:10][C@H:5]12
Reactant: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Yield: 79.1 %

Procedure:
To a suspension of benzhydryl 7-formamido-3 -[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (69.8 g) in methanol (350 ml) was added conc. hydrochloric acid (40.7 ml). The mixture was heated at 30°-35° C. for 2 hours. The mixture was poured into a mixture of ethyl acetate (2 l) and water (1 l) and adjusted to pH 6.5 with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with water and saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and concentrated in vacuo to a crystal. The crystal was washed with diethyl ether to give benzhydryl 7-amino-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (52.3 g).
Reaction SMILES: [Na].Cl[CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[S:7][CH:8]=1.[CH2:13]([OH:15])[CH3:14]>>[CH2:13]([O:15][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[S:7][CH:8]=1)[CH3:14]
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: CCO
Agent: [Na]
Product: CCOCc1csc(NC(C)=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
The sodium metal (16 mg, 0.681 mmol) was dissolved in 2 ml of anhydrous ethanol. To this solution was added a suspension of N-(4-(chloromethyl)thiazol-2-yl)acetamide (100 mg, 0.521 mmol) in ethanol (1 ml). The reaction was stirred at room temperature for 1 hour and then heated at 63° C. for 1 hour. The reaction was concentrated and the residue was purified via preparative HPLC to afford N-(4-ethoxymethyl-thiazol-2-yl)-acetamide as a yellow amorphous solid (44 mg, 42%). LC/MS m/z 199.16 (M-1)+; HPLC Rt: 1.79 min.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[CH:18]([C:20]1[N:25]2[CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=[C:24]2[CH:23]=[CH:22][CH:21]=1)=[O:19]>C1(C)C=CC=CC=1>[CH2:3]([O:2][P:1]([CH:18]([OH:19])[C:20]1[N:25]2[CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=[C:24]2[CH:23]=[CH:22][CH:21]=1)([O:5][CH2:6][CH3:7])=[O:8])[CH3:4]
Reactant: CCOC(=O)c1cn2c(C=O)cccc2n1
Reactant: CCOP([O-])OCC
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2c(C(O)P(=O)(OCC)OCC)cccc2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
Diethyl phosphite (1.7 g, 12.3 mmol, Aldrich), N,N-diisopropylethylamine (1.63 g, 12.4 mmol, Aldrich) and toluene (60 mL) were combined in a 100 mL flask equipped with a N2 inlet and condensor. After warming this solution to 60° C., the product from Example 54 was added. After stirring at 75°-80° C. for 3 h, all solvent was removed from this mixture and the residue was chromatographed (7.5/92.4/0.1 isopropanol/CH2Cl2 /HOAc) to give 1.2 g (66%) of the title product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]#[C:11][CH2:12][C@H:13]([OH:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:33][O:34][CH2:35][CH2:36][O:37][CH2:38]Cl>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]#[C:11][CH2:12][C@H:13]([O:23][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCCl
Reactant: O[C@@H](CC#CCOCc1ccccc1)COc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCO[C@@H](CC#CCOCc1ccccc1)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To an ice cooled solution of (2S)-6-benzyloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (2 g, 6.4 mmol) in dry CH2Cl2 (8 ml) was added N-ethyldiisopropylamine (1.7 ml, 9.5 mmol) and stirred for 10 minutes MEM-chloride (1.1 ml, 9.5 mmol) was added to the solution at 0° C. and stirred for 3 h at room temperature. The solvent was concentrated and the residue purified on a silica gel column using EtOAc-light petroleum (1:4) as eluent to yield (2S)-6-benzyloxy-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hex-4-yne (2.2 g, 85%) as a yellow colour liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.5 1H NMR (CDCl3, 200 MHz): δ 2.65-2.75 (m, 2H), 3.39 (s, 3H), 3.55 (t, J=4.8 Hz, 2H), 3.78 (t, J=4.8 Hz, 2H), 4.11 (s, 2H), 4.16 (m, 3H), 4.56 (s, 2H), 4.89 (s, 2H), 6.8-7.02 (m, 4H), 7.3-7.35 (m, 5H).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH3:51])=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([C:3]1[S:4][C:5]([CH3:51])=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(CC)sc4C)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)c(OC)c2)c(C)s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a mixture of ethyl {4-[4-({4-[({4-[(E)-2-(2-ethyl-5-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.30 g), tetrahydrofuran (6 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 2 hrs. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the precipitated crystals were collected by filtration to give {4-[4-({4-[({4-[(E)-2-(2-ethyl-5-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as crystals (0.19 g, yield 66%). Recrystallization from tetrahydrofuran-hexane gave pale-yellow prism crystals. melting point: 198-199° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](I)=[C:8]([CH3:12])[C:6]=2[N:7]=1.[OH:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1)(=[O:25])=[O:24].[NH:35]1[C:43]2[C:38](=[CH:39][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:41][N:42]=2)[CH:37]=[CH:36]1>>[CH3:12][C:8]1[C:6]2[N:7]=[C:2]([C:40]3[CH:39]=[C:38]4[CH:37]=[CH:36][NH:35][C:43]4=[N:42][CH:41]=3)[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:5]=2[S:10][C:9]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([S:23]([NH:22][CH2:21][CH2:20][OH:19])(=[O:25])=[O:24])[CH:27]=1
Reactant: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: O=S(=O)(NCCO)c1cccc(B(O)O)c1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: Cc1c(-c2cccc(S(=O)(=O)NCCO)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12

Procedure:
2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (50 mg) was coupled to N-(2-hydroxyethyl)-3-boronobenzene sulfonamide, and then reacted with 7-azaindole-5-boronic acid pinacol ester via General Procedure F. The product was purified by reverse phase HPLC to yield 17.7 mg of 423. MS (Q1) 551.1 (M)+
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].[C:21](Cl)(=[O:26])[CH2:22][C:23](Cl)=[O:24].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:16]([C:15]1[CH:14]=[C:13]([N:12]2[C:23](=[O:24])[CH2:22][C:21](=[O:26])[NH:1][C:2]3[C:11]4[C:6]([CH:5]=[CH:4][C:3]2=3)=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:20]=[CH:19][CH:18]=1)#[N:17]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: N#Cc1cccc(Nc2ccc3ccccc3c2N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 27.4 %

Procedure:
To an ice-cold solution of 3-(1-amino-2-naphthylamino)benzonitrile (968 mg, 3.73 mmol) in toluene (10 mL) was added malonyl chloride (436 μL, 4.48 mmol). The mixture was stirred at 80° C. for 20 minutes, then at 110° C. for 10 minutes. After the reaction mixture was cooled to room temperature, the solution part of the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, and was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. While The precipitated solid in the reaction mixture was dissolved in chloroform, was washed with a saturated aqueous sodium bicarbonate solution, and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residues were combined, and Each product purified by silica gel column chromatography (hexane/ethyl acetate=1/4), and the residue was recrystallized from ethyl acetate to give the titled compound as a pale yellow crystal (335 mg, yield 27%). mp: 220-222° C.
Reaction SMILES: Cl[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[C:10](=[S:15])([O:12]CC)[NH2:11]>O>[O:9]=[C:3]1[C:2]2[S:15][C:10](=[O:12])[NH:11][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: O=C1CCCC(=O)C1Cl
Reactant: CCOC(N)=S
Solvent: O
Product: O=C1CCCc2[nH]c(=O)sc21
Temperature: 140 °C
Yield: 36.1 %

Procedure:
A mixture of 29.3 g of 2-chloro-1,3-cyclohexanedione [Muehlstaedt et al, J. Prakt Chem., Vol. 20 (1963), p. 285] and 21 g of ethyl thiocarbamate was heated at 140°C for 15 minutes and was then poured into water. The precipitate formed was recovered by vacuum filtering and was crystallized from isopropyl alcohol to obtain 12.2 g of 7-oxo-2,3,4,5,6,7-hexahydrobenzothiazoline-2-one melting at 262°C.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1>[C:28]1([N:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:16][CH:17]=3)=[CH:22][CH:23]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccccc1
Reactant: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.6 %

Procedure:
A 0.66 weight % toluene solution 100 μl of tri-t-butylphosphine was added to a toluene 100 ml solution of 4-bromo-4′-(N,N-diphenylamino)biphenyl 4.00 g, aniline 1.11 g, tris(benzylideneacetone)-dipalladium (0) 183 mg and t-butoxysodium 1.35 g, and the mixture was stirred at room temperature for 5 hours. After finishing the reaction, the mixture was filtered through celite, and the filtrate was extracted with toluene. This was concentrated under reduced pressure, and the resulting crude product was subjected to column refining to obtain 3.20 g of pale yellow powder of N,N,N′-triphenylbenzidine.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:28]([O:30]C)=[O:29])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21](=[O:23])[CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:28]([OH:30])=[O:29])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21](=[O:23])[CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 90 °C
Yield: 92.7 %

Procedure:
Sodium hydroxide (0.2 mL of 1 N, 0.2 mmol) was added to a solution of the Methyl 13-cyclohexyl-6,7-dihydro-6-oxo-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (20 mg, 0.052 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) in a microwave vial. The vial was sealed and the contents heated at 90° C. for 5 min in a microwave apparatus. The solution was acidified with dilute hydrochloric acid to precipitate the crude acid. The solid was collected and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (18 mg, 92%). ESI-MS m/z 374 (MH+); 1H NMR (500 MHz, ACETONE-D6) δ 1.22-1.35 (m, 1 H) 1.41-1.58 (m, 2 H) 1.59-1.70 (m, 1 H) 1.73-1.85 (m, 2 H) 1.92-2.00 (m, 1 H) 2.11-2.26 (m, 3 H) 3.04 (m, 1 H) 3.60 (d, J=14.04 Hz, 1 H) 3.97 (d, J=13.73 Hz, 1 H) 4.56 (d, J=18.31 Hz, 1 H) 5.19 (d, J=18.31 Hz, 1 H) 7.51 (m, 2 H) 7.57 (t, J=7.32 Hz, 1 H) 7.66 (d, J=7.63 Hz, 1 H) 7.81 (dd, J=8.39, 1.37 Hz, 1 H) 8.03 (d, J=8.24 Hz, 1H 8.23 (s, 3 H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[NH:37][N:36]=1.O[C@H:51]1[CH2:55][O:54][CH2:53][C@@H:52]1[NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60]>C1COCC1>[C:59]([O:58][C:57]([NH:56][C@@H:52]1[CH2:53][O:54][CH2:55][C@@H:51]1[N:37]1[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([I:34])=[N:36]1)=[O:63])([CH3:62])([CH3:60])[CH3:61]
Reactant: CCOC(=O)c1[nH]nc(I)c1C(=O)OCC
Reactant: CC(C)(C)OC(=O)N[C@H]1COC[C@@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn([C@H]2COC[C@H]2NC(=O)OC(C)(C)C)c1C(=O)OCC
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
To a solution of PPh3 (2.72 g, 10.35 mmol) in THF (10 mL) at 0° C. was added DIAD (2.013 mL, 10.35 mmol) dropwise and stirred for 15 min. A solution of Intermediate 104C (1.4 g, 4.14 mmol) in THF (10 mL) was added to the above reaction mixture and was stirred at 0° C. for 45 min. A solution of tert-butyl ((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamate (1.683 g, 8.28 mmol) in THF (10 mL) was added dropwise at 0° C. and the reaction mixture was stirred at RT for 12 h. The reaction mixture was then concentrated and the crude compound was purified by silica gel chromatography (24 g REDISEP® column, eluting with 30% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 352A (1.7 g, 81%) as a white solid. MS(ES): m/z=522 [M−H]+; The crude product was taken to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=3[O:16][CH3:17])[NH:8][C:4]=2[CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][C:10]=3[O:16][CH3:17])[NH:8][C:4]=2[CH:3]=1
Reactant: COc1cc(O)ccc1-c1nc2ccc(F)cc2[nH]1
Reactant: CS(=O)(=O)Cl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(F)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 5-fluoro-2-(2'-methoxy-4'-hydroxy-phenyl)-benzimidazole and methanesulfonic acid chloride.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:21]2[CH2:26][CH:25]([CH2:27][OH:28])[CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C1COCC1.O>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:21]2[CH2:26][CH:25]([CH2:27][O:28][S:48]([CH3:47])(=[O:50])=[O:49])[CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)C1CC(CO)CN(C(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)C1CC(COS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate (570 mg) and triethylamine (0.25 ml) in THF (10 ml) was added methanesulfonyl chloride (0.1 ml) under ice-cooling, and the mixture was stirred at room temperature 1 hr. Triethylamine (0.25 ml) and methanesulfonyl chloride (0.1 ml) were further added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the object compound (624 mg).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])(=[O:4])=[O:3].[C:12](=[S:14])=[S:13].[OH-].[K+].Cl[CH:18](Cl)[CH2:19]Cl>O.C(Cl)(Cl)Cl.CN(C)C=O>[S:13]1[CH:19]=[CH:18][S:14][C:12]1=[CH:1][S:2]([CH2:5][C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])(=[O:3])=[O:4]
Reactant: ClCC(Cl)Cl
Reactant: S=C=S
Reactant: CC(C)OC(=O)CS(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)CS(=O)(=O)C=C1SC=CS1
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a mixture of 18 g of isopropyl methylsulfonylacetate, 7.6 g of carbon disulfide and 200 ml of dimethylformamide, 22.4 g of potassium hydroxide was added under ice-cooling. The resultant mixture was stirred for 2 hours. Thereafter, 13.3 g of 1,1,2-trichloroethane was added, followed by stirring at 80° C. for 3 hours. After cooling the reaction mixture, chloroform and water were added and the resulting organic layer was separated. Upon removal of the solvent by distillation under reduced pressure, 24.1 g of the title compound was obtained as pale yellow crystals. Upon recrystallization from isopropanol, they turned to white crystals. Melting point: 127°-127.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Cl[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1.C(N(CCCC)CCCC)CCC>>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Reactant: Clc1ccc(Cl)nc1
Solvent: CCCCN(CCCC)CCCC
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(c4ccc(Cl)cn4)CC3)cc2)C1

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (30 mg), 2,5-dichloropyridine (30 mg) and tributylamine (0.2 ml) were heated at 160° C. for 2 hours. The cooled crude mixture was washed with heptane and purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (3N in methanol)). This resulted in the product with the molecular weight of 427.98 (C23H30ClN5O); MS (ESI): 428 (M+H+).
Reaction SMILES: [CH2:1]([C:5]12[CH2:12][CH2:11][CH:8]([CH:9]=[CH:10]1)[CH2:7][C:6]2=[O:13])[CH2:2][CH2:3][CH3:4].C(C1C=CC=CC=1)(=O)C>C1CCCCC1>[CH2:1]([C:5]12[CH:9]3[CH:8]([CH2:7][C:6](=[O:13])[CH:10]13)[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12C=CC(CC1)CC2=O
Solvent: CC(=O)c1ccccc1
Solvent: C1CCCCC1
Product: CCCCC12CCC3CC(=O)C1C32
Reaction time: 50 h

Procedure:
A 4% solution of (+)-1-butyl-bicyclo[2.2.2]oct-5-en-2-one (1.5 g.) in cyclohexane was irradiated in a Pyrex apparatus under argon and in the presence of 200 mg. of acetophenone with a 250 w. medium pressure mercury lamp. After 50 hours, a conversion of 98% was achieved. The solution was concentrated by evaporation and the residue subjected to chromatography on 100 g. of silica gel (70 to 230 mesh) with toluene to remove the acetophenone and with toluene/1% diethyl ether. Pure (-)-8-butyl-tricyclo[3.3.0.02,8 ]octan-3-one was obtained.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][C:8]([F:11])([F:10])[CH2:7][CH2:6][N:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)[NH2:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([CH:4]1[CH2:9][C:8]([F:11])([F:10])[CH2:7][CH2:6][N:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(F)(F)CC1C#N
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 2-carbamoyl-4,4-difluoro-piperidine-1-carboxylate, 13g, (1.72 g, 6.51 mmol) in CH2Cl2 (50 mL) was added was N,N-triethylamine (2.03 mL, 14.61 mmol) followed by the dropwise addition of (2,2,2-trifluoroacetyl)-2,2,2-trifluoroacetate (1.02 mL, 7.32 mmol). After 15 minutes, the mixture was diluted with aqueous saturated NaHCO3 solution and the layers were separated. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated to dryness. The crude residue was passed through a plug of silica gel and eluted with 10-30% EtOAc/hexanes to afford the desired product, 13h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[NH:15][CH2:14][CH2:13][N:12]([C:16]4[CH:25]=[C:24]5[C:19]([C:20](=[O:31])[C:21]([C:28]([OH:30])=[O:29])=[CH:22][N:23]5[CH2:26][CH3:27])=[CH:18][C:17]=4[F:32])[CH2:11]3)=[CH:7][C:6]=2[CH:33]=1.[CH:34](O)=O>C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[N:15]([CH3:34])[CH2:14][CH2:13][N:12]([C:16]4[CH:25]=[C:24]5[C:19]([C:20](=[O:31])[C:21]([C:28]([OH:30])=[O:29])=[CH:22][N:23]5[CH2:26][CH3:27])=[CH:18][C:17]=4[F:32])[CH2:11]3)=[CH:7][C:6]=2[CH:33]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc5cc(Cl)ccc5o4)C3)cc21
Reactant: O=CO
Agent: C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(c4cc5cc(Cl)ccc5o4)C3)cc21

Procedure:
A 150 mg portion of 7-[3-(5-chloro-2-benzofuranyl)-1-piperazinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was suspended in 0.6 ml of 37% formaldehyde and 0.75 ml of 90% formic acid was added. The mixture was heated on a steam bath for 2 hours, then evaporated to dryness. A 5 ml portion of water was added, the pH adjusted to 7.0 with lN sodium hydroxide and the solid collected, washed with water and dried, giving 113 mg of the desired product, mp 248°-249° C.