Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:31])[CH2:15]/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35](=[O:55])[CH2:36][C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)[CH3:33]>>[CH2:32]([O:34][C:35](=[O:55])[CH2:36][C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:31])[CH2:15]/[CH:16]=[CH:17]/[C:18]4[CH:19]=[CH:20][C:21]([O:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:22][CH:23]=4)=[CH:6][CH:7]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)[CH3:33]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccc(Oc5ccccc5)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 28, Step 1, using (E)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-(4-phenoxy-phenyl)-but-3-en-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:26]1SC2CCC(C)CC=2C=1C(OCC)=O.C1(S(Cl)(=O)=O)C=CC=CC=1>>[CH3:26][CH:18]1[CH2:17][CH2:16][C:14]2[S:15][C:11]([NH:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])=[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[CH2:19]1
Reactant: CCOC(=O)c1c(N)sc2c1CC(C)CC2
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CC(C)CC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-5-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (prepared according to Pinkerton et al., Bioorg. Med. Chem. Lett., 2007, 17, 3562-3569) and benzenesulphonyl chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C@@H:12]3[C@@H:8]([CH2:9][C:10](=[O:19])[NH:11]3)[CH2:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27](=O)([O:33]C(C)(C)C)[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>ClCCl>[O:19]=[C:10]1[CH2:9][C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]3([CH2:7]2)[CH2:3][CH2:2][N:1]([C:27]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33])[CH2:6][CH2:5]3)[NH:11]1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C1C[C@H]2CC3(CCNCC3)c3ccccc3[C@H]2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C[C@@H]1CC(=O)N[C@@H]1c1ccccc12
Yield: 55.9 %

Procedure:
A solution of the (3aR,9bS)-1,3a,4,9b-tetrahydrospiro[benzo[g]indole-5,4′-piperidin]-2(3H)-one (900 mg, 3.51 mmol) in dichloromethane (100 ml) was treated with triethylamine (3 ml) and di-tert-butyl carbonate (1.5 g, 6.8 mmol) at room temperature for 1 h. The reaction mixture was diluted with dichloromethane, washed with aqueous saturated NH4Cl. The organic phase was separated and the aqueous phase was re-extracted with dichloromethane (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified by flasj chromatography (40 g silica gel, CH2Cl2/CH3CN up to 0:100%) to give (3aR,9bS)-tert-butyl 2-oxo-1,2,3,3a,4,9b-hexahydrospiro[benzo[g]indole-5,4′-piperidine]-1′-carboxylate 12 (700 mg). LC-MS: m/e=301.5 (M−t-Bu+H, 100%). Rt=3.04 min. 1H NMR (300 MHz, CDCl3): 7.36 (d, 1H), 7.25 (td, 1H), 7.21-7.13 (m, 2H), 6.32 (s, 1H, NH), 4.71 (d, J=5.8 Hz, 1H, CHN), 4.02 (br. d, 1H), 3.90 (br. d, 1H), 3.01 (td, J=13.4, 2.8 Hz, 1H), 2.89 (td, J=13, 3.1 Hz, 1H), 2.73-2.62 (m, 1H), 2.29 (td, J=12.7, 5.0 Hz, 1H), 2.23-2.44 (m, 3H), 1.66-1.59 (m, 1H), 1.51 (dd, J=13.2, 4.3 Hz, 1H), 1.41 (s, 9H), 1.37-1.30 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[N:10]([C:12](=[O:14])[CH3:13])[CH2:11][C:4]=2[CH:3]=1.[F-].[K+].[C:23]1(OB=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:23]1([C:2]2[CH:20]=[CH:19][C:5]3[O:6][CH2:7][C:8]4[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=4[N:10]([C:12](=[O:14])[CH3:13])[CH2:11][C:4]=3[CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)N1Cc2cc(Cl)ccc2OCc2ccccc21
Reactant: O=BOc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)N1Cc2cc(-c3ccccc3)ccc2OCc2ccccc21
Temperature: 80 °C

Procedure:
To a stirred mixture of 1-(2-Chloro-6H,12H-5-oxa-11-aza-dibenzo[a,e]cycloocten-11-yl)-ethanone Example 348D (21.5 mg, 74.7 umol), KF (14.3 mg, 0.25 mmol), phenylboranic acid (10.0 mg, 82.2 umol) and tri-t-butyl phosphine (4.54 mg, 22.4 umol) in dioxane (0.40 mL) under argon was added Pd2(dba)3 (6.84 mg, 7.47 umol). This mixture was heated at 80° C. for 19 hours and cooled to room temperature. To this cooled mixture under argon was added more Pd2 (dba)3 and tri-t-butyl phosphine. This mixture was then heated at 100° C. for 24 h upon which time some more Pd2 (dba)3 and tri-t-butyl phosphine were added. The mixture was heated at 80° C. for another 24 h and cooled to room temperature. This mixture was concentrated in vacuo and purified by a ISCO auto CombiFlash with a RediSep 4 g column, eluted with CH2Cl2-EtOAc, detected at 220 nM to give 4.3 mg of impure 1-(2-Phenyl-6H,12H-5-oxa-11-aza-dibenzo[a,e]cycloocten-11-yl)-ethanone Example 348. This was further purified by a Shimadzu auto prep HPLC, employing 30% to 100% 10 min gradient elution with 0.1% TFA in MeOH-water solvent system, 220 nM detection, 20 mL/min elution with a YMC ODS S5 20×100 mm column to give 3.3 mg of 1-(2-Phenyl-6H,12H-5-oxa-11-aza-dibenzo[a,e]cycloocten-11-yl)-ethanone Example 348 in 13% yield. HPLC Rt=3.53 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=330
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([NH:19][C:20]([C@@H:22](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39](=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@@:23]([OH:30])([CH2:27][CH2:28][OH:29])[C:24]([O-:26])=[O:25])=[O:21])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)[C:3]#[C:4][CH3:5].[K+:48].[BH4-].[Na+]>CO>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([NH:19][C:20]([C@@H:22](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([OH:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@@:23]([OH:30])([CH2:27][CH2:28][OH:29])[C:24]([O-:26])=[O:25])=[O:21])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)[C:3]#[C:4][CH3:5].[K+:48]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)[O-])C(=O)OC)cc1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(O)CCCCCCC)[C@@](O)(CCO)C(=O)[O-])C(=O)OC)cc1
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a mixture of No. 5214357, a mixture of sodium and potassium (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (100 mg, 0.147 mmol) and methanol (5 mL) was added NaBH4 (5.5 mg, 0.146 mmol) at room temperature. After stirring for 1.5 hours, NaBH4 (5.5 mg, 0.146 mmol) was added again. After stirring for 30 minutes, the consumption of the starting materials was confirmed by LCMS. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure to obtain the title compound (100 mg, yield 99% or more, white solid).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]1[CH2:13][CH:14]3[NH:19][CH:18]([C:7]2=1)[CH2:17][CH2:16][CH2:15]3.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[CH2:30]>>[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][N:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:12][CH:11]=2)[C:7]2[CH:18]3[NH:19][CH:14]([CH2:13][C:8]1=2)[CH2:15][CH2:16][CH2:17]3
Reactant: FC(F)(F)Oc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Reactant: C=Cc1ccccc1C
Product: Cc1ccccc1CCn1c2c(c3cc(OC(F)(F)F)ccc31)C1CCCC(C2)N1

Procedure:
The coupling of 2-trifluoromethoxy-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (148 mg, 0.500 mmol; Example 140A) and 1-methyl-2-vinylbenzene (118 mg, 1.00 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 1.09-1.21 (m, 1H), 1.29-1.43 (m, 2H), 1.80 (d, J=13 Hz, 1H), 2.02-2.10 (m, 4H), 2.27 (tt, J=14, 5 Hz, 1H), 2.41 (tt, J=14, 4 Hz, 1H), 3.00 (dt, J=14, 5 Hz, 1H), 3.05-3.14 (m, 1H), 3.35 (dd, J=18, 7 Hz, 1H), 4.21 (ddd, J=15, 9, 6 Hz, 1H), 4.28-4.33 (m, 1H), 4.37 (ddd, J=15, 5, 5 Hz, 1H), 5.29 (s, 1H), 6.92 (d, J=7 Hz, 1H), 7.06 (t, J=7 Hz, 1H), 7.09-7.12 (m, 1H), 7.15 (t, J=7 Hz, 1H), 7.30 (d, J=10 Hz, 1H), 7.54 (d, J=9 Hz, 1H), 7.63 (s, 1H); MS (DCI/NH3) m/z 415 (M+H)+.
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[N:2].FC(F)(F)C(O)=O.[CH2:22]([N:29]([CH2:33][Si](C)(C)C)[CH2:30]OC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:22]([N:29]1[CH2:30][C@@H:3]([C:1]#[N:2])[C@H:4]([C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:33]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccccc1C=CC#N
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccccc1[C@@H]1CN(Cc2ccccc2)C[C@H]1C#N

Procedure:
In a 50 mL round bottom flask were combined methyl 2-(2-cyanovinyl)benzoate (Example 1A, 11.03 g, 58.9 mmol) trifluoroacetic acid (0.045 mL, 0.589 mmol) and dichloromethane (100 mL). N-Benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (64.8 mmol) was added as a solution in dichloromethane (100 mL) dropwise over 15 minutes while stirring under argon. The reaction was stirred at room temperature for 20 hours, then quenched with aqueous sodium bicarbonate and extracted with dichloromethane. The organic washes were combined and washed with brine, dried over Na2SO4, filtered, and the solvent was removed in vacuo to provide the crude product. The mixture of isomers was added to a silica gel column and was eluted with ethyl acetate/hexanes (gradient 0-20%, 40 minutes) to provide the title compound as the faster eluting (less polar) isomer. 1H NMR (500 MHz, CDCl3) δ ppm 2.82 (dd, 1H, J=9.09 Hz, J=7.81 Hz), 2.88 (dd, 1H, J=9.74 Hz, J=4.27 Hz), 2.99-3.03 (m, 1H), 3.05-3.09 (m, 1H), 3.29 (t, 1H, J=8.37 Hz), 3.71 (m, 2H), 3.94 (s, 3H), 4.51 (ddd, 1H, J=8.29 Hz, J=6.36 Hz, J=4.35 Hz), 7.25-7.40 (m, 6H), 7.50 (dt, 1H, J=7.65 Hz, J=1.45 Hz), 7.62 (d, 1H, J=7.24 Hz), 7.81 (dd, 1H, J=7.89 Hz, J=1.29 Hz); MS (DCI+) m/z 321.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17](=[O:27])[C@H:18]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH3:19]>CS(C)=O>[O:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[O:20][C@@H:18]([C:17]1([C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[F:9])[CH2:4][O:27]1)[CH3:19]
Reactant: C[C@@H](OC1CCCCO1)C(=O)c1ccc(F)cc1F
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H](OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Temperature: 15 °C
Yield: 91.2 %

Procedure:
To dimethyl sulfoxide (50 ml) was added 60% sodium hydride (0.833 g) in mineral oil. While stirring the mixture at about 15° C., trimethylsulfoxonium iodide (4.80 g) was added thereto, which was stirred for 15 minutes at room temperature. The reaction mixture was cooled with ice, to which was added a dimethyl sulfoxide solution (10 ml) of (2R)-2',4'-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (4.90 g). The resultant mixture was stirred for two hours at room temperature. The reaction mixture was poured into ice-water (120 ml), followed by extraction with ethyl acetate (150 ml, 100 ml, 100ml). Ethyl acetate layers were combined and washed with water (50 ml) and a saturated aqueous solution of sodium chloride (50 ml), followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel chromatography (eluent: hexane-ethyl acetate=10:1) to afford 2-[(1R)-1-(3,4,5,6 -tetrahydro-2H-pyran-2-yloxy)ethyl]-2-(2,4-difluorophenyl)oxirane (4.70 g) as a pale yellow oily product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)[CH:28]=1
Reactant: Brc1cccnc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cccnc4)c3n2)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (355 mg, 1.0 mmol) and commercially available 3-bromo-pyridine (158 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (211 mg, 49%). MS (EI) 432.2 [(M)+]; mp 173° C.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].Cl.C(O[C:10](=N)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])C>>[NH2:5][C:3]1[S:4][C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:1][N:2]=1
Reactant: CCOC(=N)CC(=O)OCC
Reactant: NNC(N)=S
Agent: Cl
Product: CCOC(=O)Cc1nnc(N)s1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
Thiosemicarbazide (1.0 g, 11.0 mmol) and ethyl 3-ethoxy-3-iminopropionate hydrochloride (2.0 g, 10.0 mmol) were mixed in glacial acid (2 mL) for 10 min at 55° C. and then boiled for 1.5 h. The reaction mixture was evaporated, diluted with cold water, carefully neutralized with NaHCO3, and cooled to 5° C. The precipitate was collected and crystallized from water to yield 0.88 g (4.70 mmol, 47%) of the product, mp 149-150° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.19 (t, 3H, J=7.2 Hz), 3.96 (s, 2H), 4.10 (q, 2H, J=6.9 Hz), 7.11 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 14.0, 35.4, 60.9, 150.4, 168.9, 169.6.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:20]([O:22]C(C)(C)C)=[O:21])=[C:14]([CH2:18][Br:19])[CH2:15][S:16](=[O:17])[C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[C:1]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:20]([OH:22])=[O:21])=[C:14]([CH2:18][Br:19])[CH2:15][S:16](=[O:17])[C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.9 %

Procedure:
6.25 g of t-butyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide were added to 25 ml of trifluoroacetic acid at room temperature and after stirring for 15 minutes at room temperature, the trifluoroacetic acid was evaporated under vacuo. After addition of 20 ml of dichloromethane, evaporation to dryness was repeated. 25 ml of ether were added to the residue and the formed crystals were vacuum filtered, washed with ether and dried under vacuo to obtain 5.77 g of 7-benzamido-3-bromomethyl-3-cephem-4-carboxylic acid-1-oxide as a slightly yellowish colored solid having the following characteristics:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:42]=[CH:41][C:13]([CH2:14][NH:15][C:16](=[O:40])[C@H:17]([C@@H:19]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH:32]C(OC(C)(C)C)=O)=[CH:27][CH:26]=2)=[O:22])[OH:20])[OH:18])=[CH:12][CH:11]=1)=O)(C)(C)C.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[NH2:8][CH2:9][C:10]1[CH:42]=[CH:41][C:13]([CH2:14][NH:15][C:16](=[O:40])[C@H:17]([C@@H:19]([C:21]([NH:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][NH2:32])=[CH:29][CH:30]=2)=[O:22])[OH:20])[OH:18])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)[C@@H](O)[C@H](O)C(=O)NCc2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(CNC(=O)[C@@H](O)[C@H](O)C(=O)NCc2ccc(CN)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.594 g of N,N'-bis-(4-tert.-butoxycarbonylaminomethyl-benzyl)-D-tartaramide was dissolved in 0.8 ml of trifluoroacetic acid at 0° C. and subsequently stirred at room temperature for 5 hours; the mixture was subsequently evaporated and the residue was treated with methylene chloride/ether (1:1). The precipitate which formed was filtered off. There was obtained N,N'-bis-(4-aminomethyl-benzyl)-D-tartaramide di(trifluoroacetate), MS: m/z 387.4 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10]([NH:17][CH2:18][C:19](O)=[O:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:13]([O:12][C:10]([NH:17][CH2:18][C:19]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)=[O:20])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccc(CO)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-aminobenzylalcohol (300 mg, 2.43 mmol), N-Boc-glycine (426 mg, 2.43 mmol), and 1-hydroxybenzotriazole (344 mg, 2.55 mmol) in 4.8 mL of dry N,N-dimethylformamide was added N,N-diisopropylethylamine (0.42 mL, 2.9 mmol). After addition of 1-ethyl-3-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochlorde (489 mg, 2.55 mmol) at 0° C., the solution was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain crude 4-[2-(tert-butoxycarbonylamino)acetylamino]benzylalcohol.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH:17]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:24]([CH3:27])([O-:26])=[O:25]>CO>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH:17]=[CH:27][N+:24]([O-:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1[nH]c2ccccc2c1Cc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: O=[N+]([O-])C=Cc1[nH]c2ccccc2c1Cc1ccccc1

Procedure:
A mixture of 3-benzyl-2-indolecarbaldehyde (7.06 g), ammonium acetate (462 mg) and nitromethane (10.5 ml) in methanol (30 ml) was refluxed for 2 hours. After cooling, precipitates formed were collected and washed two times with chilled methanol (5 ml) to give 3-benzyl-2-(2-nitrovinyl)indole.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]=1[F:23].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]=1[F:23])(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCOC(=O)C(C)c1ccc(N)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)c1ccc(NS(=O)(=O)CCCCl)c(F)c1
Reaction time: 1 h
Yield: 90.1 %

Procedure:
Chloropropanesulfonyl chloride (0.576 mL, 4.73 mmol) was added to a solution of ethyl 2-(4-amino-3-fluorophenyl)propanoate (1 g, 4.735 mmol) and pyridine (0.382 mL, 4.735 mmol) in DCM (18 mL) at 0° C. The reaction mixture was stirred for 1 h, after it was partitioned between DCM (10 mL) and 1N hydrochloric acid (10 mL). The organic phase was separated and dried over magnesium sulfate, filtered and concentrated in vacuo to afford ethyl 2-(4-(3-chloropropylsulfonamido)-3-fluorophenyl)propanoate as an oil (1.5 g).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13](=[O:19])[N:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:6][C:5]=1[NH2:26])(=[O:3])[CH3:2].[BH4-].[Na+].Cl.O>C1COCC1.CO.CCOC(C)=O>[NH2:26][C:5]1[N:6]=[C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]([C:10]2[CH:11]=[CH:12][C:13](=[O:19])[N:14]([CH:16]([CH3:17])[CH3:18])[CH:15]=2)=[N:9][C:4]=1[CH:1]([OH:3])[CH3:2]
Reactant: CC(=O)c1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 19.4 %

Procedure:
To a solution of 5-(6-acetyl-5-amino-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (82 mg) in THF-MeOH (1:1, 2.0 ml), was added sodium borohydride (8.9 mg). The mixture was stirred st room temperature for 4 hours. 1N HCl (0.05 ml) was poured into the mixtre. Water and EtOAc were poured into the mixture and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography. The desired product was recrystallized from EtOH and dried in vacuo to give 5-[5-amino-6-(1-hydroxyethyl)-3-phenyl-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (16 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH2:18][CH2:17]1.[OH-].[Na+]>C(O)CCC.O>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH2:20][CH2:21]1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: Nc1ccccc1OC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: COc1ccccc1N1CCN(CCNc2ccccc2OC(F)(F)F)CC1

Procedure:
A solution of 2.09 g of 2-trifluoromethoxyaniline and 3.15 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine in 20 mL of n-butanol was stirred at 100° C. for 2 hrs. The mixture was then cooled, diluted with H2O, alkalinized with 2 N NaOH and extracted with CHCl3. The organic phase was dried on anhydrous Na2SO4, evaporated until dry and the crude purified via flash chromatography (EtOAc-petrolium ether 3:7) and subsequently crystallized from EtOH giving 0.55 g (12%) of the title compound. Melting point: 69.5-71° C.