Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[C:16]([F:17])=[CH:15][C:14]([C:18](=[O:38])[CH:19]([N:21]2[CH2:26][CH2:25][C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)([OH:27])[CH2:23][CH2:22]2)[CH3:20])=[CH:13][C:12]=1[F:39])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([O:10][C:11]1[C:12]([F:39])=[CH:13][C:14]([C@@H:18]([OH:38])[C@H:19]([N:21]2[CH2:22][CH2:23][C:24]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:32][CH:33]=3)([OH:27])[CH2:25][CH2:26]2)[CH3:20])=[CH:15][C:16]=1[F:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C(=O)c1cc(F)c(OCc2ccccc2)c(F)c1)N1CCC(O)(c2ccc(C(F)(F)F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H]([C@H](O)c1cc(F)c(OCc2ccccc2)c(F)c1)N1CCC(O)(c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
A mixture of sodium borohydride (0.085 g, 2.25 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(4-benzyloxy-3,5-difluorophenyl)-2-(4-(4-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (1.02 g, 1.96 mmol in 30 mL of ethanol) was added. The reaction was stirred at ambient temperature overnight. The white solid which precipitated was collected by filtration and dried to yield 0.66 g (65%) of (1R*,2R*)-1-(4-benzyloxy-3,5-difluorophenyl)-2-(4-(4-trifluormethylphenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol which was suitable for use without further purification and had: mp 201-202° C. Analysis calculated for C28H28F5NO3.0.25 H2O: C, 63.93; H, 5.46; N, 2.66. Found: C, 63.98; H, 5.49; N, 2.70.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C@:9]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)([CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:8]>CS(C)=O>[C:7]([C:9]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)([CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:8]
Reactant: COC(=O)CC[C@@](C#N)(c1ccc(OC)c(OC)c1)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)CCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Potassium tert-butoxide (27.5 mg, 0.25 mmol) was added to a solution of methyl (S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoate (150 mg, 0.491 mmol; 97% ee by chiral HPLC analysis) in anhydrous dimethyl sulphoxide (4 ml). The resulting golden yellow solution was stirred at room temperature for five minutes and then heated at 100° C. for 1 hour. The reaction mixture was then worked up by quenching with acetic acid and evaporation of solvent under high vacuum, followed by partitioning of the residue between methyl tert-butyl ether and water. The washed and dried organic extract was concentrated to provide methyl 4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoate as an oil (60 mg; 40% recovery). Chiral HPLC analysis of a sample removed prior to heating the reaction mixture at 100° C. showed methyl (S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoate of substantially reduced enantiomeric purity (ca. 10% ee).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](C=C([N+]([O-])=O)C)=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:17].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:8][CH:9]([CH3:10])[CH3:5])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:17]
Reactant: CC(=Cc1c[nH]c2cc(Cl)c(F)cc12)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Nc1c[nH]c2cc(Cl)c(F)cc12
Temperature: 0 °C
Yield: 211.3 %

Procedure:
A solution of 6-chloro-5-fluoro-3-(2-nitro-propenyl)-1H-indole (5.0 g, 19.63 mmol) in tetrahydrofuran (10 mL) was added to the suspension of lithium aluminium hydride (2.92 g, 78.54 mmol) in tetrahydrofuran (20 mL) at 0° C. and then refluxed for 3 hours. The reaction mixture was cooled to 0° C., and quenched according to the Fischer method. The reaction mixture was filtered through celite and the filtrate concentrated to give 2-(6-chloro-5-fluoro-1H-indol-3-yl-1-methyl-ethylamine (4.7 g crude) as a viscous brown liquid. The residue was used without further purification. 1H NMR (500 MHz, CDCl3): δ 8.13 (s, 1H), 7.37 (d, 1H, 6 Hz), 7.32 (d, 1H, J=10 Hz), 7.08 (s, 1H), 3.23-3.26 (m, 1H), 2.77-2.81 (m, 1H), 2.58-2.63 (m, 1H), 1.15 (d, 3H, J=6.5 Hz).
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:9]([CH:20]=1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11].Cl>C1COCC1.O.C(OCC)(=O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:9]([CH:20]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Br)ccc1OCc1ccccc1

Procedure:
LiOH.H2O (222 mg, 5.29 mmol) was added to a stirred solution of phenylmethyl 5-bromo-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 4, method A; 700 mg, 1.76 mmol) in THF (15 ml) and water (5.00 ml). The mixture was refluxed for 12 h and then diluted with ethyl acetate (50 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a yellow solid. 400 mg.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C1C2C(COC([NH:62][CH2:63][C:64](O)=[O:65])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][CH2:63][C:64]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:65]
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: NCC(=O)O[C@H]1c2ccccc2C[C@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.9 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (220 mg, 0.57 mmol), DCC (142 mg, 0.69 mmol) and DMAP (7 mg, 0.059 mmol) in ethyl acetate (10 mL), was added N-[(9H-fluoren-9-ylmethoxy)carbonyl]glycine (171 mg, 0.57 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (8 mL) and cooled to 0° C. Dimethylamine (8 mL, 20% in THF) was added drop wise at N2 atmosphere and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 130 mg (56%) of the title compound as an off white solid.
Reaction SMILES: ClC1C=C([N:8]2N=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)C=CC=1.[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([F:27])[CH:26]=1)[NH2:23].N1C=CC=CC=1C=O>>[F:19][C:20]1[CH:21]=[C:22]([N:23]2[N:8]=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:11]2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: Nc1cc(F)cc(F)c1
Agent: O=Cc1ccccn1
Product: Fc1cc(F)cc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3,5-difluoroaniline (131 mg, 1.0 mmol) and pyridine-2-carboxaldehyde (109 mg, 1.0 mmol) were employed to obtain 2-[2-(3,5-difluorophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H-].[Na+].[CH2:11](I)[CH3:12]>C1COCC1>[CH2:11]([O:8][CH2:7][C@@H:2]([NH2:1])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH3:12]
Reactant: CCI
Reactant: CC(C)C[C@H](N)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@@H](N)CC(C)C
Reaction time: 20 h

Procedure:
(S)-leucinol (6.4 mL, 5 mmol) was added over 30 minutes to a well stirred slurry of 6% sodium hydride (2.2 g, 55 mmol) in THF (50 mL) at room temperature under N2. After all of the sodium hydride had reacted, a solution of ethyl iodide (4 mL, 50 mmol) in THF (50 mL) was added and the reaction stirred at 20°-25° C. for 20 hours. THF was removed under reduced pressure and the residue partitioned between diethyl ether and brine. The ether extract was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was flash chromatographed over silica gel and pure aminoether eluted with a mixture of 10% isopropanol and 90% chloroform.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].S.[OH:10][CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:17][CH:18]([N:20]1[C:33]2[CH:32]=[C:31]([C:34](=S)N)[CH:30]=[CH:29][C:28]=2[S:27][C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19].C(OC(C)C)(C)C>C(OCC)(=O)C>[NH:1]1[CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[N:8]=[C:34]1[C:31]1[CH:30]=[CH:29][C:28]2[S:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH:18]([CH3:19])[CH2:17][N:13]3[CH2:14][CH2:15][CH2:16][C@@H:12]3[CH2:11][OH:10])[C:33]=2[CH:32]=1
Reactant: CC(CN1CCC[C@@H]1CO)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: NC1CCCCC1N
Agent: S
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: CC(CN1CCC[C@@H]1CO)N1c2ccccc2Sc2ccc(C3=NC4CCCCC4N3)cc21
Temperature: 150 °C

Procedure:
1,2-Diaminocyclohexane (7.98 g) is added to an ethanolic solution (30 cc), saturated with hydrogen sulphide, of 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbothioamide, L series (2.79 g). The mixture is heated in an autoclave at 150° C. for 17 hours, then diluted with ethyl acetate (250 cc) and washed with distilled water (4×200 cc). The organic phase is separated after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is stirred with boiling acetonitrile (6×30 cc), and the oil obtained is solidified by stirring with isopropyl ether (100 cc). The residue is chromatographed on a column (height: 52 cm; diameter: 2.5 cm) of silica gel (0.2-0.06 mm), eluting with a 60:40 (by volume) mixture (2 liters) of 1,2-dichloroethane and methanol and collecting 120-cc fractions. The first liter is discarded, and fractions 4 to 7 containing the pure product are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 2-(3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}phenothiazine, L series (1.8 g) in the form of a yellow solid.
Reaction SMILES: P(OC(C)C)(OC(C)C)OC(C)C.C([Li])CCC.[N:19]1[C:27]([NH2:28])=[C:26]2[C:22]([N:23]=[CH:24][NH:25]2)=[N:21][CH:20]=1.[O:29]1[CH:35]2[CH:30]1[CH:31]=[CH:32][CH2:33][CH2:34]2>[Pd].CCCCCC.O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.CS(C)=O>[OH:29][CH:30]1[CH2:35][CH2:34][CH:33]([N:23]2[CH:24]=[N:25][C:26]3[C:22]2=[N:21][CH:20]=[N:19][C:27]=3[NH2:28])[CH:32]=[CH:31]1
Reactant: C1=CC2OC2CC1
Reactant: Nc1ncnc2nc[nH]c12
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Nc1ncnc2c1ncn2C1C=CC(O)CC1
Reaction time: 0.25 h
Yield: 26.9 %

Procedure:
The palladium(0) catalyst is prepared by bringing together 179.6 mg of palladium(II) acetate, 2 ml of triisopropyl phosphite and 1.06 ml of a 1.4 molar solution of butyllithium in n-hexane in 60 ml of dry tetrahydrofuran at 0° C. under argon. 60 ml of dry dimethylsulfoxide and 17.32 g (0.128 mol) of adenine are then added. After stirring for 15 minutes, 12.3 g (0.128 mol) of 3,4-epoxycyclohexene, dissolved in 40 ml of dry tetrahydrofuran, are added dropwise (3 hours). The suspension is stirred at room temperature for 24 hours, poured into 650 ml of ethanol and stirred and the precipitate (1 g of adenine) is filtered off with suction. The filtrate is concentrated and the residue is chromatographed over aluminum oxide using methylene chloride/methanol 15/1. 7.96 g (36.9% of theory) of 9-[(1RS,4SR)-4-hydroxycyclohex-2-en-1-yl]adenine of melting point 181° to 183° C. are obtained. 1H NMR (270 MHz, d6 -DMSO); δ[ppm]: 8.15 (s, 1H), 8.04 (s, 1H), 7.22 (s, 2H), 6.09 (m, 1H), 5.84 (m, 1H), 5.06 (m, 1H), 4.93 (d, 1H), 4.09 (m, 1H), 1.99 (m, 2H), 1.81 (m, 1H),, 1.56 (m, 1H).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[F:12].[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][C@H:20]([CH3:29])[C:21](N1CCOCC1)=[O:22].[NH4+].[Cl-]>C1COCC1.O>[F:12][C:6]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[C:21](=[O:22])[C@H:20]([O:19][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1)[CH3:29]
Reactant: Fc1ccc(F)c(Br)c1
Reactant: C[C@@H](OC1CCCCO1)C(=O)N1CCOCC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](OC1CCCCO1)C(=O)c1cc(F)ccc1F
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A mixture of magnesium (7.25 g, 0.298 mol) and iodine (catalytic amount) and 1-bromo-2,5-difluorobenzene (20.0 g, 0.178 mol) in THF (250ml ) was vigously stirred. The color of iodine was disappeared and the inner temperature rose up to 65° C. To this mixture was added additional 1-bromo-2,5-difluorobenzene (30.0 g, 0.267 mol) dropwise to maintain the inner temperature from 50 to 55° C. over 45min. The resulting mixture was stirred at 55° C. for 30min. then at r.t. for 1 hr. The mixture was cooled down to −5° C. To this mixture was added a solution of 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (52.5 g, 0.216 mol ) in THF (150ml) dropwise over 40min. And the resulting mixture was stirred at r.t. for 4hrs. The reaction mixture was cooled down to 5° C. and saturated NH4Cl aq. (100ml) was added carefully. The whole was diluted with H2O (600ml) and extracted with EtOAc (400 ml+200 ml×2). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (n-hexane: EtOAc=10:1˜5:1) to give (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 81% ) as pale yellow syrup.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:57])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH: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.[SH:65][C:66]1[S:67][C:68]2[CH:73]=[CH:72][N:71]=[CH:70][C:69]=2[N:74]=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:57])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:65][C:66]4[S:67][C:68]5[CH:73]=[CH:72][N:71]=[CH:70][C:69]=5[N:74]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH: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
Reactant: Sc1nc2cnccc2s1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4cnccc4s3)CS[C@@H]3C(NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 78.5 %

Procedure:
Using 369 mg of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido}-3-chloromethyl-3-cephem-4-carboxylate in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 74 mg of 2-mercaptothiazolo[4,5-c]pyridine, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 331 mg of the title compound in a yield of 79%.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1>>[C:19]1([CH3:23])[CH:20]=[CH:21][CH:22]=[CH:17][C:18]=1[C:2]#[C:1][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1cccc(I)c1
Reactant: C#Cc1ccc(OCC(=O)OCC)cc1
Product: CCOC(=O)COc1ccc(C#Cc2ccccc2C)cc1

Procedure:
The title compound was prepared from ethyl (4-ethynylphenoxy)acetate (42 mg, 0.21 mmol) and iodo-3-methylbenzene (0.03 mL, 0.20 mmol) according to the general procedure ID to give 43 mg (72%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:10). Rf: 0.22 (EtOAc:hexanes, 1:10); 1HNMR (CDCl3) δ 7.49-7.46 (m, 3H), 7.26-7.12 (m, 3H), 6.90-6.87 (m, 2H), 4.64 (s, 2H), 4.30-4.27 (dq, 2H, J=7.2 Hz, 2.1 Hz), 2.50 (s, 3H), 1.33-1.28 (tt, 3H, J=7.2 Hz, 1.5 Hz); 13CNMR (CDCl3) δ 168.6, 157.7, 140.0, 133.0, 131.7, 129.4, 128.1, 125.5, 123.2, 116.9, 114.7, 93.0, 87.4, 65.4, 61.5, 20.7, 14.1; EI-MS m/z 294 (M+).
Reaction SMILES: C([Mg]Cl)=C.CO[CH:7]([Si:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH:13]=[CH2:14])[CH:11]=[CH2:12])OC.O>C1COCC1>[CH3:7][Si:10]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH:11]=[CH2:12])[CH:13]=[CH2:14]
Reactant: C=C[Si](C=C)(c1ccccc1)C(OC)OC
Agent: C=C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: C=C[Si](C)(C=C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
158 ml of a solution of vinylmagnesium chloride in THF is added dropwise using a dropping funnel in 1 h at room temperature under nitrogen to 13.1 ml of a solution of dimethoxymethylphenyldivinylsilane in 36 ml of anhydrous THF. The temperature is controlled with a water bath. After addition, the mixture is stirred at room temperature for 16 h and then refluxed for 2 h. 40 ml of H2O is then added and the mixture is stirred for 30 min. The white precipitate that forms is filtered and is then rinsed with ethyl acetate. The filtrate is extracted with ethyl acetate twice. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under vacuum. 12.56 g of methyl-phenyl-divinyl-silane is obtained in the form of a clear yellow oil, which is then used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:28]([NH:35][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 120.8 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), benzylamine (18.2 μL, 0.17 mmol), triethylamine (58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 45.2 mg (76%) of the title compound as a TFA salt (1.5 H2O, 2.1 TFA, effective MW=711.98). 1H NMR (DMSO-d6): δ 9.86 (1H, s), 9.14 (1H, t, J=5.4), 8.73 (1H, d, J=4.8), 8.29 (4H, m), 7.56 (1H, d, J=7.0), 7.74 (2H, m), 7.89 (2H, m), 7.31 (5H, m), 7.16 (1H, d, J=7.8), 6.93 (1H, t, J=7.3), 4.46 (2H, d, J=6.1). ESIMS (M+H+): 446.5.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[N:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[S:16][CH:17]=2)=O)=[C:8]([Cl:22])[C:7]([O:23][CH3:24])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].ClC1C(OC)=CC=C2C=1N=C(C1SC=C(C#C)N=1)C=C2O>>[Cl:22][C:8]1[C:7]([O:23][CH3:24])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([C:13]1[N:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[S:16][CH:17]=1)[CH:2]=[C:1]2[OH:3]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2csc(C(F)(F)F)n2)c1Cl
Agent: C#Cc1csc(-c2cc(O)c3ccc(OC)c(Cl)c3n2)n1
Product: COc1ccc2c(O)cc(-c3csc(C(F)(F)F)n3)nc2c1Cl
Yield: 26 %

Procedure:
Compound 255a (white solid) was synthesized from compound 254a (1 g, 1 eq.) in 26% yield, following the procedure as described for compound 209a. 1H NMR (CDCl3, 400 MHz): δ (ppm) 4.07 (s, 3H), 6.78 (s, 1H), 7.09 (d, J=9.13 Hz, 1H), 8.14 (s, 1H), 8.30 (d, J=9.13 Hz, 1H), 9.93 (s, 1H); 19F NMR (CDCl3, 376 MHz): δ (ppm) −61.14 (s, 3F); MS (ESI, EI+): m/z=360.91 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].[B-](F)(F)(F)F.[CH3:17][CH2:18][O+](CC)CC.C(Cl)(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[NH:6])[O:5][CH2:17][CH3:18]
Reactant: NC(=O)c1c(F)cccc1F
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1c(F)cccc1F
Reaction time: 24 h

Procedure:
2,6-Difluorobenzamide (1.56 g) in methylene chloride was added to triethyloxonium fluoborate (1.9 g) in methylene chloride and the mixture stirred for 24 hours. The solution was then washed three times with cold sodium carbonate solution and dried over sodium sulphate. The methylene chloride solution was evaporated to yield an oil. This was mixed with chloroform and the solution filtered from insoluble material. Evaporation of the chloroform gave the ethyl 2,6-difluorobenzimidate as a mobile oil.
Reaction SMILES: [N:1]#CBr.C(N(C(C)C)CC)(C)C.C(Cl)(Cl)Cl.[CH3:17][N:18]1[C:22]2[CH2:23][CH2:24][C:25]3[C:32]4([CH3:35])[CH:33]([CH3:34])[CH:19]1[CH2:20][C:21]=2[C:26]=3[CH:27]=[CH:28][CH2:29][N:30]=[CH:31]4>C(=O)(O)[O-].[Na+]>[C:17]([N:18]1[C:22]2[CH2:23][CH2:24][C:25]3[C:32]4([CH3:35])[CH:33]([CH3:34])[CH:19]1[CH2:20][C:21]=2[C:26]=3[CH:27]=[CH:28][CH2:29][N:30]=[CH:31]4)#[N:1]
Reactant: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2C
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2C#N
Temperature: 25 °C
Yield: 94.5 %

Procedure:
To a stirred solution of 6.81 g of cyanogen bromide, 4.7 ml of diisopropylethylamine, and 142 ml of chloroform was added, at room temperature with stirring, a solution of 13.7 g of 1,2,3,4,5,6-hexahydro-3,6,12-trimethyl-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 414 ml of chloroform. The mixture was heated at reflux for 2.6 hr, cooled to room temperature, diluted with aqueous sodium bicarbonate solution, and the layers were separated. The organic layer was washed with sodium bicarbonate solution. The combined aqueous layers were extracted with ether. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate, and filtered. Concentration of the filtrate followed by purification by flash chromatography (silica gel, 2% triethylamine/ethyl acetate) afforded 13.5 g (95%) of 3-cyano-6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine.