Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][C:8]1[CH:29]=[CH:28][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[CH:10][CH:9]=1.C1C[O:33]CC1>>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:15]([C:1](=[O:5])[C:2]([OH:33])=[O:3])=[CH:14]2)=[CH:28][CH:29]=1
Reactant: C1CCOC1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Cn2ccc3cc(-c4ccccc4)ccc32)cc1
Product: Cc1ccc(Cn2cc(C(=O)C(=O)O)c3cc(-c4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
Oxalyl chloride (0.474 mL, 5.43 mmol) was added dropwise to a stirring solution of 1-(4-methylbenzyl)-5-phenyl-1H-indole (0.46 g, 1.55 mmol) in THF (15 mL) at room temperature over a period of 5 minutes under a nitrogen atmosphere. After the reaction mixture was stirred at room temperature for 4 hours, the reaction was quenched carefully with water. The aqueous mixture was extracted with ethyl acetate. The extract was washed with water, and brine, dried over anhydrous magnesium sulfate, and concentrated to give the title compound as a yellow solid (0.41 g, 72%), m.p: 195-196° C. Mass spectrum (ESI, [M+H]+) m/z 370. 1HNMR (400 MHz, DMSO-d6): δ 13.95 (br s, 1H), 8.68 (s, 1H), 8.41 (s, 1H), 7.63-7.66 (m, 3H), 7.56 (d, 1H, J=10.4 Hz), 7.47 (t, 2H, J=7.5 Hz), 7.35 (t, 1H, J=7.3 Hz), 7.22(d, 2H, J=8.1 Hz), 7.15(d, 2H, J=8.0 Hz), 5.56 (s, 2H), and 2.25 ppm (s, 3H). Elemental Analysis for C24H19NO3.0.3 H2O: Calculated: C, 76.91; H, 5.27; N, 3.74. Found: C, 76.85; H, 5.18; N, 3.61.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][C@H:5]1[C:10]([OH:12])=O)(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.Cl.Cl.[N:40]1([C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:56][C@H:55]([CH2:57][O:58][C:59]4[CH:63]=[CH:62][O:61][N:60]=4)[O:54][C:53]3=[O:64])=[CH:48][C:47]=2[F:65])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[C:1]([N:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][C@H:5]1[C:10]([N:43]1[CH2:42][CH2:41][N:40]([C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:56][C@H:55]([CH2:57][O:58][C:59]4[CH:63]=[CH:62][O:61][N:60]=4)[O:54][C:53]3=[O:64])=[CH:48][C:47]=2[F:65])[CH2:45][CH2:44]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of (2S,4R)-1-acetyl-4-hydroxy-2-pyrrolidinecarboxylic acid (173 mg, 1 mmol) in dichloromethane (10 ml) and DMF (2 ml) under nitrogen was treated successively with dicyclohexylcarbodiimide (227 mg, 1.1 mmol) and 1-hydroxybenzotriazole (149 mg, 1.1 mmol), then stirred at ambient temperature for 1 hour. A solution of 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (435 mg, 1 mmol) and N,N-diisopropylethylamine (258 mg, 2 mmol) in dichloromethane (5 ml) was added, and the mixture stirred for 18 hours. Solid was filtered off, the organic solution evaporated to dryness, and the residue purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 15% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product after trituration with diethyl ether (210 mg).
Reaction SMILES: [CH2:1]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:14]([O:16][C:17]1[C:21](OCC)=[N:20][S:19](=[O:26])(=[O:25])[N:18]=1)[CH3:15]>C(O)C>[CH2:8]([N:7]([C:21]1[C:17]([O:16][CH2:14][CH3:15])=[N:18][S:19](=[O:26])(=[O:25])[N:20]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCNCCCCCC
Reactant: CCOC1=NS(=O)(=O)N=C1OCC
Solvent: CCO
Product: CCCCCCN(CCCCCC)C1=NS(=O)(=O)N=C1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
Dihexylamine (90 mg, 0.48 mmol) was added to a solution of 3,4-diethyloxy-1,1-dioxo-1,2,5-thiadiazole (100 mg, 0.48 mmol) in ethanol (5 mL) and the reaction stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue absorbed onto silica gel, and purified by flash column chromatography (silica, hexane:EtOAc 3:1) to yield 4-(N,N-di-n-hexylamino)-3-ethoxy-1,1-dioxo-1,2,5-thiadiazole (120 mg, 72%). MS (EI, m/e 345).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][C:10](=[CH2:12])[C@@H:9]3[C@@H:13]4[C:18]([CH2:19][CH2:20][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][CH2:4]2)=[CH:17][CH2:16][CH2:15][CH2:14]4)[CH3:2].[C-]#[C-].[Li+].[Li+].[CH2:25](N)[CH2:26]N.C(O)(=[O:31])C>CS(C)=O.O>[CH3:2][CH2:1][C@@:3]12[C@:4]([OH:31])([C:25]#[CH:26])[CH2:5][CH2:6][C@H:7]1[C@@H:8]1[CH2:20][CH2:19][C:18]3[C@@H:13]([C@H:9]1[C:10](=[CH2:12])[CH2:11]2)[CH2:14][CH2:15][CH2:16][CH:17]=3
Reactant: CC(=O)O
Reactant: NCCN
Reactant: C=C1C[C@]2(CC)CCC[C@H]2[C@@H]2CCC3=CCCC[C@@H]3[C@@H]12
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CCCC[C@@H]4[C@H]3C(=C)C[C@@]21CC
Temperature: 25 °C
Yield: 89 %

Procedure:
100 g (0.35 moles) of 13-ethyl-11-methylen-gon-4-ene (compound XVIII) were dissolved in anhydrous dimethylsulfoxide (3 liters) under stirring at room temperature. 430 g of lithium acetylide complexed with ethylendiamine were added to the so obtained solution and the stirring at room temperature was carried on for 21 hours. After this period the reaction was spilled in water cooled at a temperature of 2° C. (3 liters) then a 10% aqueous solution of acetic acid was added (7 liters) and the aqueous phase was extracted with dichloromethane (3×2 liters). The organic extracts were subsequently washed with a saturated solution of sodium bicarbonate (2 liters) and then with a saturated solution of sodium chloride. The organic phase was then dehydrated on sodium sulfate, filtered and evaporated to dryness to give 96.24 g (0.31 moles; yields 89%) of Desogestrel.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:26])[C@H:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)[NH:7][C:8](=[O:17])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.[I:38][C:39]1[CH:47]=[C:43]([C:44](O)=[O:45])[C:42]([NH2:48])=[CH:41][CH:40]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH:1]([O:4][C:5](=[O:26])[C@H:6]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:44](=[O:45])[C:43]2[CH:47]=[C:39]([I:38])[CH:40]=[CH:41][C:42]=2[NH2:48])=[CH:23][CH:24]=1)[NH:7][C:8](=[O:17])[C:9]1[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=1[Cl:15])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)OC(=O)[C@H](Cc1ccc(NC(=O)c2cc(I)ccc2N)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-Amino-N-(2,6-dichlorobenzoyl)-L-phenylalanine Isopropylester, 1-hydroxybenzotriazole monohydrate (11.5 g) and 5-iodoanthranilic acid (17.8 g) were dissolved in dimethylformamide (200 mL) and cooled down to 0° C. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.7 g) was added thereto and stirred at room temperature for 16 hours. The organic layer wherein ethyl acetate (1 L) was added was washed with 0.1N sodium hydroxide aqueous solution (200 mL, 100 mL), water (100 mL), 0.1N hydrochloric acid (200 mL) and saturated aqueous solution of sodium chloride (200 mL, 100 mL), respectively. After drying the organic layer over anhydrous sodium sulfate and removing the solvent, a solid material obtained from a mixed solvent of methylene chloride and hexane was filtered to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[NH:24]1[CH2:28][CH2:27][C@H:26]([CH2:29][OH:30])[CH2:25]1>>[Br:1][C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@H:26]([CH2:29][OH:30])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8]
Reactant: OC[C@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.2 using 5-bromo-6-chloro-N-(3-fluoro-4-(trifluoromethoxy)phenyl)nicotinamide (Stage 13.3) and (S)-1-pyrrolidin-3-yl-methanol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.99 min, UPLC-MS (Condition 3) tR=1.18 min, m/z=478.1/480.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][Br:46])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[C@H](CCCO)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[C@H](CCCBr)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
To a solution of 4-chloro-N-[5-chloro-2-fluorophenyl]-N-[(R)-1-methyl-4-hydroxybutyl]-benzenesulfonamide (336 mg, 0.827 mmol) in acetonitrile (4 mL) was added triphenylphosphine (433 mg, 1.65 mmol) and carbon tetrabromide (548 mg, 1.65 mmol) at 0° C. The resulting mixture was allowed to stir at 22° C. for 12 h followed by the addition of 25 mL of sat. ammonium chloride. The product was extracted with ether (2×25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:4 ethyl acetate:hexanes) of the concentrate afforded 349 mg of 4-chloro-N-[5-chloro-2-fluorophenyl]-N-[(R)-1-methyl-4-bromobutyl]benzenesulfonamide as a yellow oil in 88% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(C#N)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 5-cyano-2-hydroxybenzoate (may be prepared as described in Description 12; 531 mg, 3 mmol), potassium carbonate (1037 mg, 7.50 mmol) and (bromomethyl)benzene (1026 mg, 6.00 mmol) in acetone (60 ml) was stirred at 50° C. overnight. The mixture was cooled and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate (10:1) to yield the title compound as a white solid. 480 mg.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:12][NH2:13])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].O[Li].O>CO>[NH2:13][CH2:12][C:5]1([C:3]([OH:4])=[O:2])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1
Reactant: COC(=O)C1(CN)CC12CCCC2
Agent: [Li]O
Solvent: CO
Solvent: O
Product: NCC1(C(=O)O)CC12CCCC2
Yield: 38.8 %

Procedure:
To a solution of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid methyl ester (3.40 g, 18.6 mmol) was added methanol (75 mL) and LiOH—H2O (1.55 g, 37.1 mmol). The mixture was heated to reflux under nitrogen for 48 hours. The solvent was removed by evaporation under reduced pressure and the residue was dissolved in water (50 mL). With ice bath cooling, concentrated HCl (˜2.5 mL) was added until the pH was adjusted to 6. A white precipitate was isolated by filtration and dried under vacuum to yield 1.22 g (39%) of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid as an off-white solid: mp 231-235° C. (decomposition); 1H NMR (300 MHz, D2O) δ 0.78 (d, J=4.7 Hz, 1H), 1.32 (d, J=4.7 Hz, 1H), 1.40 (m, 1H), 1.54-1.77 (m, 7H), 2.86 (d, J=13.2 Hz, 1H), 3.43 (d, J=13.2 Hz, 1H); MS (APCI) m/z 170 [M+H]+. Anal. Calcd. For C9H15NO2-1.1H2O: C, 57.18; H, 9.17; N, 7.41. Found: C, 57.38; H, 8.82; N, 7.09.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:5][N:6]=1.[CH2:11]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>N1C=CC=CC=1>[C:7]([C:4]1[S:3][C:2]([NH:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=2)(=[O:31])=[O:30])=[N:6][N:5]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(C(C)(C)C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
2-Amino-5-tert-butyl-1,3,4-thiadiazole (204 mg, 1.3 mmol) was suspended in pyridine (0.5 mL). p-Dodecylbenzenesulfonyl chloride (300 mg, 0.87 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred at this temperature for 1 h. The reaction mixture was then added to aqueous 10% HCl (5 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and volatiles evaporated to yield a solid mass. Chromatography on silica gel (70-230 mesh) eluted with 2% MeOH in CH2Cl2 gave the product (350 mg, 0.75 mmol, 87%). Recrystallization from hexanes:ethyl acetate (3:7) gave an analytical sample, mp 117-118° C.; 1H NMR (500 MHz, CDCl3) δ 0.88 (3, t, J=6.5 Hz), 1.20-1.36 (18, m), 1.38 (9, s), 1.56-1.64 (2, m), 2.63 (2, t, J=7.5 Hz), 7.25 (2, d, J=8.0 Hz), 7.86 (2, d, J=8.0 Hz), 12.24 (1, br s); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 31.1, 31.8, 35.8, 36.5, 126.5, 128.7, 138.5, 148.1, 167.8, 168.0; MS (ESI+, m/z) Calcd for C24H40N3O2S2 466.3. found 466.2 (M+H)+; HRMS (ESI+, m/z) Calcd for C24H40N3O2S2 466.2562. found 466.2562 (M+H)+.
Reaction SMILES: [CH2:1]([B:5]([OH:7])[OH:6])[CH2:2][CH2:3][CH3:4].O[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]O.O[C@H]([C@@H](O)C(N(C)C)=O)C(N(C)C)=O>ClCCl.[Cl-].[Na+].O>[CH2:1]([B:5]1[O:7][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCB(O)O
Reactant: OCCNCCO
Agent: CN(C)C(=O)[C@H](O)[C@@H](O)C(=O)N(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCB1OCCNCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(But-1-yl)-tetrahydro-4H-1,3,6,2-dioxazaborocine [CAS 92527-13-4] (3 g, 17.5 mmol), which was prepared from n-butylboronic acid and 2-(2-hydroxy-ethylamino)-ethanol [CAS 111-42-2] as reported in Organic Synthesis, 1998, 76, 86-96, and (2R,3R)-2,3-dihydroxy-N,N,N′,N′-tetramethyl-butanediamide [CAS 26549-65-5] (9.85 g) were dissolved in anhydrous dichloromethane (160 mL) under N2. Brine (25 mL) was added. The resulting mixture was stirred at room temperature for about 16 hours. The two layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with 50 mL brine, dried over MgSO4, filtered and concentrated in vacuo to provide the title compound as an oil.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[C:10]=2[CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[C:41]1([CH:47]([CH3:51])[CH2:48][CH:49]=O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOC(C)=O>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[C:10]=2[CH:15]=[CH:49][CH2:48][CH:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:51])=[CH:7][CH:8]=1
Reactant: CC(CC=O)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1C=CCC(C)c1ccccc1
Reaction time: 0.25 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-triphenyl-phosphonium bromide (0.2678 g, 0.451 mmol) was dissolved in THF (2.7 mL) at 0° C. Potassium tert-butoxide (1 M in THF, 0.5 mL, 0.50 mmol) was added and after stirring 15 minutes 3-phenyl-butyraldehyde (0.074 mL, 0.50 mmol) was added and the ice bath was removed. After 15 minutes, analytical LCMS indicated complete reaction. Standard aqueous workup followed by silica gel chromatography (0-20% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: ClCCl.C[C:5]([O:7][CH2:8][C:9]1[CH2:18][S:17][C@@H:12]2[C@H:13]([NH2:16])[C:14](=[O:15])[N:11]2[C:10]=1[C:19]([OH:21])=[O:20])=O.CS(O)(=O)=O.[OH-].[Na+]>CO>[NH2:16][CH:13]1[C:14](=[O:15])[N:11]2[C:10]([C:19]([OH:21])=[O:20])=[C:9]([CH2:8][O:7][CH3:5])[CH2:18][S:17][C@H:12]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To 10 ml of dichloromethane were added 1.41 g of 7-ACA, 5.1 ml of methanesulfonic acid and 1.23 ml of methanol. The reaction was conducted at 0° C. for 6 hours. After completion of the reaction, the reaction mixture was poured into ice water. Then, the resultant mixture was adjusted to pH 3.5 with 10% aqueous sodium hydroxide to form a precipitate. The precipitate was collected by filtration, and then washed with water and dried to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.14 g. The yield of the desired product was 65%.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.Br[CH2:21][CH2:22][CH3:23].CN(C)C=O>O>[CH2:21]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH2:22][CH3:23]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCBr
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCON1C(=O)c2ccccc2C1=O
Reaction time: 2 h

Procedure:
A mixture of 212 g. of N-hydroxyphthalimide, 132 g. of triethylamine, 160 g. of 1-bromopropane and 500 ml. of dimethylformamide is stirred overnight. The reaction mixture is poured into 4.5 liters of water and is stirred at ice temperature for 11/2 hours. The solid is removed by filtration, washed with water and dried in vacuo to give N-propxyphthalimide, m.p. 51°-3° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1)(=[O:36])=[O:35].N1CCCCC1>CO>[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](/[CH:46]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:38]1)(=[O:36])=[O:35]
Reactant: O=Cc1cn(S(=O)(=O)c2cccc(Cl)c2Cl)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4cccc(Cl)c4Cl)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1.2 mL) was added with 1-(2,3-dichlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.102 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-[(2-{[1-(2,3-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.159 g, 80%).
Reaction SMILES: BrC1N=[C:4]([O:18]C)[C:5](NS(C2S[C:14](Cl)=[CH:15][CH:16]=2)(=O)=O)=NC=1.C(N([CH:26]([CH3:28])[CH3:27])CC)(C)C.ClC[O:31]CC[Si](C)(C)C>ClCCl>[C:4]([O:18][CH2:26][CH3:28])(=[O:31])[CH3:5].[CH3:14][CH2:15][CH2:16][CH:26]([CH3:27])[CH3:28]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1nc(Br)cnc1NS(=O)(=O)c1ccc(Cl)s1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(C)C
Product: CCOC(C)=O
Reaction time: 2 h

Procedure:
A mixture N-(5-Bromo-3-methoxy-2-pyrazinyl)-5-chloro-2-thiophenesulphonamide (Example 1) (0.40 g), diisopropylethylamine (0.26 g) and [2-(chloromethoxy)ethyl]trimethylsilane (0.25 g) in dichloromethane (50 mL) was stirred at room temperature. After 2 h, the solution was washed with water, dried (MgSO4) and evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compounds a white solid (0.40 g).
Reaction SMILES: [Cl:1]C1C=C(C=CC=1)C(OO)=O.[Cl:12][C:13]1[CH:32]=[CH:31][C:30]([S:33][CH2:34][C:35]2(C(OC(C)(C)C)=O)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:16].[OH-:48].[Ca+2].[OH-:50]>C(Cl)(Cl)Cl>[ClH:1].[Cl:12][C:13]1[CH:32]=[CH:31][C:30]([S:33]([CH2:34][CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)(=[O:50])=[O:48])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)C1(CSc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CCNCC1
Reactant: [OH-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(S(=O)(=O)CC2CCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.3 %

Procedure:
m-Chloroperoxybenzoic acid (0.19 g) was added to a solution 2-chloro-5-(4-[{1,1-dimethylethyl}oxycarbonyl]piperidin-4-ylmethylsulfanyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.165 g, Example 58a) in chloroform (10 ml). After 5 h calcium hydroxide (120 mg) was added and 30 min. later the salts removed by filtration. The reaction mixture was concentrated, then dissolved in methanol (10 ml) and hydrochloric acid (1.0 ml of a 4N solution in dioxane) added. After stirring at room temperature for 14 h, concentration under reduced pressure yielded the title compound (0.075 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15]>>[CH2:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH3:15]
Reactant: O=C1CCNCC1
Reactant: CCOCCCCCl
Product: CCOCCCCN1CCC(=O)CC1

Procedure:
1-(4-Ethoxybutyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-4-ethoxybutane essentially as described above in Example 38, Scheme C, step a.