Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][C:3]=1[F:19].[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].O>CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[F:19])[CH2:6][C:7]1([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]1)[C:8]2=[N:26][S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25]
Reactant: CC(C)(C)S(N)=O
Reactant: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=NS(=O)C(C)(C)C
Temperature: 25 °C
Yield: 57 %

Procedure:
6′-Bromo-5′-fluoro-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 8, 2.0 g, 6.11 mmol), 2-methylpropane-2-sulfinamide (1.11 g, 9.17 mmol) and titanium ethoxide (2.52 mL, 12.2 mmol) were dissolved in 2-Me THF (31 mL) and heated to reflux for 48 h. The reaction was allowed to cool to r.t. whereafter it was diluted with EtOAc (75 mL). Water (25 mL) was added dropwise over 10 min under vigorous stirring and then the mixture was left standing without stirring for 1.5 h. The solids were filtered off and the organics were concentrated. The was purified by silica gel chromatography using a stepwise gradient of heptane/EtOAC (5:1-4:1-3:1-1:1), to give the title compound (1.5 g, 57% yield) as a diasteromer mixture in the ratio ˜4:1 (established by HPLC and NMR analysis) (1.50 g, 57% yield). The was used in the next step. 1H NMR (500 MHz, CDCl3, signals for both isomers) δ ppm 1.20-1.29 (m, 1 H) 1.30-1.41 (m, 14 H) 1.50-1.60 (m, 4 H) 1.60-1.68 (m, 1 H) 1.97-2.08 (m, 1 H) 2.08-2.20 (m, 2.5 H) 2.24-2.32 (m, 0.3 H) 2.95-3.02 (m, 2.5 H) 3.22-3.32 (m, 1 H) 3.35 (s, 0.9 H) 3.40 (s, 3 H) 3.48-3.53 (m, 0.3 H) 7.09-7.11 (m, 0.3 H) 7.13 (d, 1 H) 8.64-8.88 (m, 1 H); MS (ES+) m/z 430, 432 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:38])([F:37])[C:5]1[CH:6]=[C:7]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:8][NH:9][CH2:10][C:11]1[C:12]([N:21]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:22][CH3:23])=[N:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2.[C:39](=[S:41])=[S:40].[CH3:42]I>C1COCC1.O>[CH3:42][S:40][C:39](=[S:41])[N:9]([CH2:8][C:7]1[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=[C:5]([C:4]([F:37])([F:3])[F:38])[CH:6]=1)[CH2:10][C:11]1[C:12]([N:21]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:22][CH3:23])=[N:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: S=C=S
Reactant: CCN(CC1CCCC1)c1nc2ccccc2cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC1CCCC1)c1nc2ccccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=S)SC
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
To a suspension of sodium hydride (0.023 g, 0.98 mmol) in dry THF (15 mL) at 0° C., in a 25 mL round bottom flask, was added {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-quinolin-2-yl }-cyclopentylmethyl-ethyl-amine (0.25 g, 0.44 mmol), obtained in step (iv) of Example 35. This reaction mixture was stirred for 10 minutes at the same temperature; carbon disulphide (0.112 g, 0.98 mmol) was added dropwise, followed by the addition of methyl iodide (0.208 g, 1.47 mmol). The reaction was allowed to reach RT and stirring was continued for 0.5 h. Water was then added to the reaction, which was then extracted with ethyl acetate. The combined organic layer was washed with brine solution and dried over sodium sulfate. The solvent was evaporated to afford the title compound (0.250 g, yield: 87%).
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:50]([OH:53])([CH3:52])[CH3:51])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([C:50]([OH:53])([CH3:52])[CH3:51])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of 2-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]propan-2-ol 2c (155 mg, 0.21 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 5 mL) were added o-dichlorobenzene (155 mg, 1.06 mmol) and 10% Pd/C (22 mg, 0.02 mmol) in turn at room temperature. The mixture was stirred at room temperature under H2 for 1 hour and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/2 to give the title compound 2 as a white solid (90 mg, 91.8%, HPLC: 96.8%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 509[M+HCOO]−; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.35 (s, 2H), 7.30 (dd, 1H), 7.08 (d, 2H), 6.81 (d, 2H), 5.46 (t, 1H), 5.01 (d, 1H), 4.95 (d, 1H), 4.21 (s, 1H), 3.95 (d, 5H), 3.78 (d, 1H), 3.68 (dd, 1H), 3.43 (dd, 1H), 3.35 (m, 1H), 1.28 (t, 3H), 1.18 (s, 3H), 1.13 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1([CH2:18][CH2:19][Cl:20])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[Cl-].[Cl-].IC1C=CC=CC=1.Cl.[OH2:31]>N1C=CC=CC=1>[Cl:20][CH2:19][CH2:18][C:4]1([CH2:3][CH2:2][Cl:1])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:31])[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: ClCCC1(CCCl)c2ccccc2Sc2ccccc21
Reactant: O
Agent: Cl
Agent: [Cl-]
Solvent: Ic1ccccc1
Solvent: c1ccncc1
Product: O=S1c2ccccc2C(CCCl)(CCCl)c2ccccc21
Reaction time: 0.25 h

Procedure:
A solution of 9,9-bis(2'-chloroethyl)thioxanthene in pyridine (25 ml.) and water (5 ml.) is cooled in an ice/salt bath to -5° to 0° C. and a solution of iodobenzene dichloride (2.7 g.) in dry pyridine (10 ml.) is added slowly during 15 minutes with stirring. Stirring at 0° C. is continued for a further 15 minutes, the reaction mixture is poured into water, acidified with concentrated hydrochloric acid and extracted with chloroform. The product is crystallised from cyclohexane to give 9,9-bis(2'-chloroethyl)-thioxanthene 10-oxide, m.p. 126°-127° C.
Reaction SMILES: [CH2:1]([N:3]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)C=O)[CH3:2].[CH2:22]=O.Cl.[CH3:25][NH:26][CH3:27]>C(O)(=O)C>[CH3:25][N:26]([CH2:22][C:19]1[O:18][C:17]([CH2:16][CH2:15][C:13]2[CH:12]=[CH:11][C:9]3[N:10]=[C:6]([NH:3][CH2:1][CH3:2])[O:7][C:8]=3[CH:14]=2)=[CH:21][CH:20]=1)[CH3:27]
Reactant: CNC
Reactant: CCN(C=O)c1nc2ccc(CCc3ccco3)cc2o1
Reactant: C=O
Agent: Cl
Solvent: CC(=O)O
Product: CCNc1nc2ccc(CCc3ccc(CN(C)C)o3)cc2o1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 2-(N-ethylformamido)-6-[2-(2-furyl)ethyl]benzoxazole (1.25 g), 36% formalin (1.83 ml) and dimethylamine hydrochloride (1.79 g) in acetic acid (8.3 ml) was stirred at 80° C. for 6 hours. The solvent was evaporated in vacuo, the residue was mixed with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel by eluting with chloroform-methanol (20:1, V/V). The pure base was converted to the maleate in a usual way and the salt was recrystallized from ethyl acetate to give 6-[2-(5-dimethylaminomethylfuran- 2-yl)ethyl]-2-ethylaminobenzoxazole 3/2 maleate (0.38 g).
Reaction SMILES: [N:1]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:34])[CH2:25][NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[N:16]=1.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:34])[CH2:25][N:26]([S:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:9])=[O:8])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:19][CH:18]=2)[N:16]=1
Reactant: Nc1nc(-c2ccc(NC(=O)CNCc3ccccc3)cc2)cs1
Reactant: O=S(=O)(Cl)N1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1nc(-c2ccc(NC(=O)CN(Cc3ccccc3)S(=O)(=O)N3CCOCC3)cc2)cs1
Temperature: 25 °C
Reaction time: 37 h
Yield: 38 %

Procedure:
4-Morpholinesulfonyl chloride (213 mg, 1.15 mmol) was added (5 min) to an ice-cold solution of N-{4-(2-amino-4-thiazolyl)phenyl}-2-{(phenylmethyl)-amino}acetamide.2HCl (450 mg, 1.09 mmol), the corresponding free base has been described in example 2) and Et3N (443 mg, 4.38 mmol) in CH2Cl2 (10.9 mL). The reaction mixture was allowed to warm to room temperature and DMAP (14.0 mg, 0.11 mmol) was added. After standing for 37 h at room temperature, the mixture was dissolved in EtOAc (125 mL). The solution was washed successively with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography (SiO2, EtOAc) gave the title compound (200 mg, 38% yield) as a white solid: M.p. 193-194°; 1H NMR (400 MHz, DMSO-d6) δ10.02 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.7 Hz, 2H), 7.30-7.41 (m, 5H), 7.01 (s, 2H), 6.89 (s, 1H), 4.59 (s, 2H), 3.91 (s, 2H), 3.58 (t, J=4.6 Hz, 4H), 3.18 (t, J=4.6 Hz, 4H); MS (FAB) m/z 488 (MH)+; Anal. Calcd for C22H25N5O4S2: C, 54.19; H, 5.17; N, 14.36. Found: C, 53.63; H, 5.07; N, 14.34.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11](=O)[CH2:12]2)=[CH:7][CH:6]=1>CCOCC.CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:12]=1
Reactant: CN
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCC
Solvent: CCOCC
Product: CNC1=Cc2cc(OC)ccc2CC1
Reaction time: 0.5 h

Procedure:
This compound was prepared according to the procedure described by Evans, et al., J. Org. Chem. 35, 4122 (1970) as follows. Into a dry, nitrogen purged, 500 ml, 3-neck flask fitted with mechanical stirrer, dropping funnel and nitrogen inlet tube was added a solution of 14.3 g (460 mmole) methylamine in anhydrous ether (100 ml) and a solution of 20.0 g (113.5 mmole) 7-methoxy-2-tetralone in same solvent (100 ml) and the solution was placed under a slow stream of nitrogen and cooled to -18° (ice-methanol). A solution of 11.56 g (61 mmole) titanium tetrachloride in pentane (50 ml) was added dropwise with stirring over 30 min period. After the addition, the reaction mixture was stirred at room temperature for 1 hr and then fast filtered. The solid residue was washed with ether (50 ml) and the filtrate and washings were combined. Removal of the solvent in vacuo gave 20.6 g (96%) of XIId as an oxygen-sensitive oil which crystallized on standing; IR (neat), 3430 (NH), 1630 cm-1 (C=C--N); NMR δ, 2.15 (m, 2, benzylic), 2.55 (m, 2, allylic), 2.70 (s, 3, NCH3), 3.15 (broad, NH), 3.70 (s, 3, OCH3), 5.13 (s, 1, C-1H), 6.25-6.90 (m, 3, ArH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:28]([CH3:27])(=[O:30])=[O:29])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(NS(C)(=O)=O)c1
Yield: 70 %

Procedure:
Starting with [4-(3-amino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester and methanesulfonyl chloride, and using the method analogous to the one described for example 22-1, [4-(3-methanesulfonylamino-benzene-sulfonyl-amino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (15 mg, 70%) was obtained as a white solid. MS cald. for C18H24N4O6S2 456, obsd. (ESI+) [(M+H)+]:457.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: O=C1NCCc2ccc(Br)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cc(Br)ccc2CCN1c1ccc(F)cc1
Temperature: 130 °C
Yield: 47.1 %

Procedure:
A mixture of 7-bromo-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 23-1, 60 mg, 0.265 mmol), 1-fluoro-4-iodobenzene (118 mg, 0.531 mmol), potassium carbonate (36.7 mg, 0.265 mmol) and copper (I) iodide (10.11 mg, 0.053 mmol) in DMF (1.000 mL) was heated at 130° C. for 5 h. The mixture was cooled to rt and filtered through a Celite pad, and the solids were washed with EtOAc. The filtrate was washed with water and brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 to 60:40 hexane-EtOAc) to give 7-bromo-2-(4-fluorophenyl)-3,4-dihydroisoquinolin-1(2H)-one (40 mg, 47%). 1H NMR (400 MHz, chloroform-d) δ 7.15-7.27 (4H, m), 7.04-7.13 (2H, m), 6.48 (1H, d, J=1.94 Hz), 2.96-3.08 (2H, m), 2.73-2.84 (2H, m). Mass spectrum m/z 320, 322 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[H][H].FC1C(F)=C(C#N)C(F)=C(F)C=1[C:14]#[N:15].FC1C(F)=CC(F)=C(F)C=1C#N>[Pd]>[CH3:2][CH:1]([C:14]#[N:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: N#Cc1c(F)c(F)c(C#N)c(F)c1F
Reactant: CCc1ccccc1
Agent: [Pd]
Agent: N#Cc1c(F)c(F)cc(F)c1F
Product: CC(C#N)c1ccccc1
Reaction time: 1 h

Procedure:
100 g of ethylbenzene and 3.0 g of 5% palladium/activated carbon were added to a 1000 cc stainless steel autoclave. The gas phase was sufficiently replaced with hydrogen gas, then hydrogen gas was used to apply a pressure of 0.3 MPa and make the temperature 100° C. and catalytic pretreatment was carried out for 1 hour. The gas phase was again sufficiently replaced with nitrogen, then 3.0 g of the reaction material, that is, 2,3,5,6-tetrafluoroterephthalonitrile was added. The nitrogen atmosphere was maintained, the autoclave sealed as it was at atmospheric pressure, and the temperature held at 175° C. After 3 hours, the reaction solution was analyzed by gas chromatography, whereupon the conversion of 2,3,5,6-tetrafluoroterephthalonitrile was found to be 100% and the yield of 2,3,5,6-tetrafluorobenzonitrile (based on 2,3,5,6-tetrafluoroterephthalonitrile) was 95%. At the same time, 13.4 mmol of α-methylbenzylcyanide was produced. This corresponded to 0.95 times molar amount relative to the production of 2,3,5,6-tetrafluorobenzonitrile.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1/[CH:15]=[CH:16]/[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)=[O:18]>CO.[Pd]=O>[C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH2:15][CH2:16][C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: Cc1[nH]cnc1/C=C/C(=O)c1cccc2ccccc12
Agent: O=[Pd]
Solvent: CO
Product: Cc1[nH]cnc1CCC(=O)c1cccc2ccccc12
Product: O=C(O)CCC(=O)O

Procedure:
A suspension of (E)-3-(5-methyl-1H-imidazol-4-yl)-1-(1-naphthalenyl)-2-propen-1-one maleate (0.38 g) in methanol (50 ml) was hydrogenated at room temperature and atmospheric pressure over a stirred suspension of pre-reduced 10% palladium oxide on carbon (50% aqueous paste; 40 mg) in methanol (10 ml) for 2 h. The reaction mixture was filtered, the filtrate was concentrated in vacuo to ca. 5 ml, and diluted with dry ether (ca. 150 ml) to precipitate the title compound (0.28 g) as a solid, m.p. 107°-108°.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5]O.[H-].[Na+].[CH:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH:30]([CH2:33][O:34]S(C)(=O)=O)[O:31][CH3:32])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CCCCCC.C(OCC)(=O)C>CS(C)=O>[CH:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH:30]([CH2:33][O:34][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:7])[O:31][CH3:32])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(COCCCCCCCCCCCCC1CCCCC1)COS(C)(=O)=O
Reactant: OCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(COCCCCCCCCCCCCC1CCCCC1)COCCOCCO
Temperature: 75 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
2.03 g (19.2 millimole) of diethylene glycol was dissolved in 10 ml of dimethylsulfoxide (DMSO), to which 0.576 g (14.4 millimole) of 60% sodium hydride was added, and the mixture was stirred at 75° C. for 1 hour. The mixture was cooled to room temperature, to which 1.93 g (4.62 millimole) of 1-O-(12-cyclohexyl)dodecyl-3-O-mesyl-2-O-methylglycerol in 5 ml of DMSO was added, and the reaction mixture was stirred at 75° C. for 1 hour. After the reaction, 20 ml of ice water and 50 ml of hexane-ethyl acetate (1:1) mixture were added to the reaction mixture, and the upper layer was separated after shaking thoroughly. The aqueous layer was extracted with 20 ml of hexane-ethyl acetate (1:1), and the organic layers were combined, washed with water and dried (MgSO4), followed by evaporation of the solvent. The residue was subjected to silica gel (60 g) column chromatography, and eluted with hexane-ethyl acetate (1:1), to give 1.0 g (49%) of the above-captioned compound as colorless oil.
Reaction SMILES: C(NC1CCNC1)(=O)C.[CH2:10]([O:17][C:18]([NH:20][CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl[C:27]1[N:36]=[C:35]2[C:30]([C:31](=[O:42])[C:32]([C:39]([OH:41])=[O:40])=[CH:33][N:34]2[CH2:37][CH3:38])=[CH:29][C:28]=1[F:43]>>[CH2:10]([O:17][C:18]([NH:20][CH:21]1[CH2:25][CH2:24][N:23]([C:27]2[N:36]=[C:35]3[C:30]([C:31](=[O:42])[C:32]([C:39]([OH:41])=[O:40])=[CH:33][N:34]3[CH2:37][CH3:38])=[CH:29][C:28]=2[F:43])[CH2:22]1)=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: O=C(NC1CCNC1)OCc1ccccc1
Agent: CC(=O)NC1CCNC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NC(=O)OCc4ccccc4)C3)nc21

Procedure:
In place of 3-acetylaminopyrrolidine, 3-benzyloxycarbonylaminopyrrolidine was allowed to react with 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid in the same manner as described in Example 1 to give 7-(3-benzyloxycarbonylamino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, which was used in the next step:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][C:3]=1[NH2:4].Cl[C:20]([O:22][C:23]([CH3:25])=[CH2:24])=[O:21]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][C:3]=1[NH:4][C:20](=[O:21])[O:22][C:23]([CH3:25])=[CH2:24]
Reactant: C=C(C)OC(=O)Cl
Reactant: Cc1cc(F)c(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Add 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.0 g, 19.91 mmol) and isopropenyl chloroformate (2.40 mL, 21.90 mmol) in EtOAc (60 mL) and saturated aqueous NaHCO3 (60 mL) and stir at RT for 6 h. Separate the layers, extract the aqueous layer with EtOAc (2×), wash the combined organics with brine, dry over Na2SO4 and concentrate to obtain the title compound. Use for the next reaction without further purification (assuming 100% yield). MS (m/z): 336.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[O:30]1[CH2:32][C@H:31]1[CH2:33][O:34][C:35]1[CH:43]=[CH:42][C:38]2[O:39][CH2:40][O:41][C:37]=2[CH:36]=1>>[CH2:22]([NH:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:32][C@H:31]([OH:30])[CH2:33][O:34][C:35]3[CH:43]=[CH:42][C:38]4[O:39][CH2:40][O:41][C:37]=4[CH:36]=3)=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:14][CH2:15]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: c1cc2c(cc1OC[C@@H]1CO1)OCO2
Reactant: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCN)cc2)CC1
Product: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc4c(c3)OCO4)cc2)CC1
Yield: 31.1 %

Procedure:
4-{[4-(2-Aminoethyl)phenyl]sulfonyl}-N-octyl-1-piperidinecarboxamide (0.920 g, 2.172 mmol) was reacted with 5-[(2S)oxiranylmethoxy]-1,3-benzodioxole(0.211 g, 1.086 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.209 g, 0.338 mmol).
Reaction SMILES: O.P([O-])([O-])(O)=O.[K+:7].[K+].C(O)C.[CH3:12][C:13]([C@@H:29]1[C:35](=[O:36])[N:34]2[C@@H:30]1[CH2:31][C:32]([S:50][CH2:51][CH2:52][NH:53]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[C:33]2[C:37]([O:39]CC1C=CC([N+]([O-])=O)=CC=1)=[O:38])([O:15]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:14]>O1CCOCC1.[Pt]=O>[NH2:53][CH2:52][CH2:51][S:50][C:32]1[CH2:31][C@H:30]2[N:34]([C:35](=[O:36])[C@H:29]2[C:13]([OH:15])([CH3:14])[CH3:12])[C:33]=1[C:37]([O-:39])=[O:38].[K+:7]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Agent: O=[Pt]
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(O)[C@@H]1C(=O)N2C(C(=O)[O-])=C(SCCN)C[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of platinum oxide (60.0 mg), water (4.2 ml), aqueous dipotassium hydrogen phosphate (1.0M, 0.385 ml) and ethanol (0.6 ml) was shaken for 30 minutes under a hydrogen atmosphere (50 psi) at ambient temperature. The mixture was added to a solution of 4-nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-[2-(4-nitrobenzyloxycarbonylamino)-ethylthio]-7-oxo-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylate (60.0 mg) in dioxane (7.2 ml) and shaken for 2 hours under a hydrogen atmosphere (50 psi) at ambient temperature. The reaction mixture was filtered using diatomaceous earth and the filter-cake was washed with water (20 ml). The combined filtrates (32 ml) were lyophilized over a period of 4 hours. The residue was chromatographed on non-ionic adsorption resin, Diaion HP-20-AG (trade mark, made by Mitsubishi Chemical Industries) (13×230 mm) eluting with water (120 ml) and then a mixture of water and isopropanol (19:1, 60 ml). The fractions showing UV maxima at 296 nm were collected, concentrated and lyophilized to give potassium (5R,6R)-3-(2-aminoethylthio)-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (10.4 mg) as pale yellow powder.