Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C(N(CC)CC)C.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)[N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:8]1[C:3]([C:1]#[C:2][C:26]2[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH:39]4[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]4)=[CH:35][CH:34]=3)[N:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ncccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 71.6 %

Procedure:
A solution of methyl 2-(2-ethynylpyridin-3-yl)acetate (I120) (43.6 mg, 0.249 mmol) in dimethylformamide (2 mL) and triethylamine (107 μL, 0.765 mmol) were added to a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I45) (87.4 mg, 0.191 mmol), Pd(PPh3)2Cl2 (13 mg, 0.019 mmol), Cu(I)I (5.5 mg, 0.029 mmol) and triphenylphosphine (7.5 mg, 0.017 mmol) in dimethylformamide (2 mL). The reaction mixture was heated under microwave irradiation at 120° C. for 10 minutes. The cooled mixture was diluted with EtOAc and passed through a plug of celite, washing with ethyl acetate (100 mL). The solvent was removed under reduced pressure and the residue partitioned between EtOAc (70 mL) and water (50 mL). The layers separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (70 mL) and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a dark brown residue. The residue was purified by column chromatography on silica gel (0-40% EtOAc in petroleum benzine 40-60° C.) to yield the title compound (I121) (81.5 mg, 72%) as a brown viscous oil which was used without further purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28]>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:28][CH2:27][CH2:26][CH:25]=[CH2:24])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: C=CCCCBr
Solvent: CC#N
Product: C=CCCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 88 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0608 g, 0.207 mmol) and 5-bromo-1-pentene (0.045 mL, 0.380 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0806 g, 88.6%). EI-MS m/z 362(M+) Rt (1.88 min).
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[OH-].[Na+].C(O)(=O)C>CO.O>[OH:18][CH2:19][C@@H:20]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 47.7 %

Procedure:
To a solution of (S)-di-tert-butyl (4-((tert-butyldiphenylsilyl)oxy)butane-1,3-diyl)dicarbamate (6.25 g, 11.51 mmol) in MeOH (100 mL) was added sodium hydroxide (1.38 g, 34.5 mmol) in water (20.0 mL). The mixture was heated to 70° C. for 18 h then cooled to room temperature and partially concentrated in vacuo. DCM was then added and the mixture was cooled to 0° C., whereupon acetic acid (2.31 mL, 40.3 mmol) was added. The organic layer was then separated, washed with saturated NaHCO3 (aq) and brine. The combined aqueous portions were extracted with DCM and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound (1.67 g, 48%). LCMS: Rt=0.67 min, m/z=305.1 (M+1) Method 2m_acidic. 1H NMR (400 MHz, CDCl3) δ ppm 5.06 (br s, 1H) 4.83 (br s, 1H) 3.82-3.64 (m, 2H) 3.61 (dd, J=10.3, 4.9 Hz, 1H) 3.43-3.25 (m, 1H) 3.11-2.93 (m, 1H) 2.18 (br s, 1H) 1.79-1.65 (m, 1H) 1.64-1.58 (m, 1H) 1.51-1.36 (m, 18H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].[NH2-].[Li+].N>O>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Cc1ccccn1
Agent: N
Agent: [Li+]
Agent: [NH2-]
Solvent: O
Product: OC(Cc1ccccn1)(c1ccccc1)c1ccccc1
Temperature: 125 °C
Reaction time: 5 h

Procedure:
Benzophenone, 32.4 kg (177.8 mole), α-picoline, 33.1 kg (355.5 moles), and lithium amide, 4.54 kg (197.4 moles) are charged into a 30 gallon reactor arranged for reflux operation. The mixture is stirred, rapidly heated to 125° C. and maintained at this temperature. The rate of ammonia evolution will gradually increase and after about 3 to 4 hours of reaction time only occasional heating is required to maintain the desired temperature and a rapid evolution of ammonia. After about 5 hours, a vigorous surge of ammonia evolution is noted. Following the ammonia surge, external heating is continued and the reaction maintained at 125° C. for an additional 6 to 8 hours. The reaction mixture is cooled to 70°-80° C. and rapidly added to approximately 230 liters of water at 25° C. Stirring is continued for approximately 30 minutes and the solid removed by filtration. The filter cake is thoroughly washed with water and dried at 60° -70° C. yielding 42-6 kg of α,α-diphenyl-2-pyridineethanol having a m.p. of 147°-51° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][O:12][CH2:11]1.O>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:14](=[O:15])[CH2:13][O:12][CH2:11][C:10]([OH:17])=[O:16]
Reactant: O=C1COCC(=O)O1
Reactant: Cc1cccc(CN)c1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(CNC(=O)COCC(=O)O)c1
Reaction time: 1 h

Procedure:
N-(3-methylbenzyl)-diglycolic acid, monoamide was prepared as follows: 2.4 g (0.02 moles) of 3-methylbenzylamine (Aldrich Chemical) was added to 3.0 g (0.026 mole) of diglycolic anhydride (Aldrich) dissolved in 15 mL dioxane. The solution was warmed, with stirring, at 70°-80° C. for 60 min. After cooling slightly, water was added to near the cloud point. After standing 60 minutes at room temperature, the crystals were filtered by suction, washed with water, and air dried. Recrystallized from water-ethanol.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.O=S(Cl)[Cl:14]>C1C=CC=CC=1>[Cl:14][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2c(c1)OCO2
Solvent: c1ccccc1
Product: ClCc1ccc2c(c1)OCO2

Procedure:
Piperonyl alcohol (45.64 g, 300 mmol) was dissolved in 340 ml of dry benzene, and SOCl2 (37 ml) was added dropwise with stirring. The solution was refluxed for 1 h, cooled and evaporated on the rotary evaporator (bath temperature less than 50° C.!). The resulting dark green residue was used without further purification.
Reaction SMILES: Br[CH:2]([CH2:18][CH3:19])[C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:17])[NH:10]2)=[O:4].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[O:23]1[CH2:24][CH2:25][N:20]([CH:2]([CH2:18][CH3:19])[C:3]([C:5]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]3[C:6]=2[CH2:7][CH2:8][C:9](=[O:17])[NH:10]3)=[O:4])[CH2:21][CH2:22]1
Reactant: C1COCCN1
Reactant: CCC(Br)C(=O)c1ccc(OC)c2c1CCC(=O)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCC(C(=O)c1ccc(O)c2c1CCC(=O)N2)N1CCOCC1

Procedure:
g of 5-(α-bromobutyl)-8-hydroxy-3,4-dihydrocarbostyril (IV) was suspended in 30 ml of benzene, and 4.2 ml of morpholine (III) was added to the suspension followed by allowing the mixture to react for 4 hours while heating under refluxing. The reaction mixture was filtered and the filtrate was washed with water followed by concentration under reduced pressure to remove any remaining water. The resulting residue was dissolved in 50 ml of isopropanol, and the solution was adjusted to a pH of 2-3 with concentrated hydrochloric acid. The viscous precipitate formed upon ice-cooling was separated and dissolved in acetone by heating. After allowing the solution to cool, the precipitate formed was dissolved in 30 ml of water and adjusted to a pH of 7.5-8 with sodium bicarbonate. The precipitate formed upon ice-cooling was filtered and dissolved in 10 ml of a 47% aqueous hydrobromic acid followed by concentration under reduced pressure. The residue thus obtained was washed with 10 ml of ethanol and recrystallized from ethanol to obtain 2.8 g of white amorphous 5-(α-morpholinobutyryl)-8-hydroxy-3,4-dihydrocarbostyril (IIb) hydrobromide monohydrate. The structure of the material thus obtained was confirmed by NMR and IR spectra and elemental analysis.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]1([S:12](Cl)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:6]1([S:12]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of imidazole (27.2 g, 0.4 mol), and benzenesulphonyl chloride (35.3 g, 0.2 mol) in dry tetrahydrofuran (200 ml) was stirred at ambient temperature for 1 h, when the resulting precipitate was removed by filtration. The filtrate was evaporated under reduced pressure and the resulting solid was recrystallised from benzene/petroleum ether (b.p. 40°-60°), to afford 1-(benzenesulphonyl)imidazole, m.p. 82°-83°.
Reaction SMILES: Cl.[CH3:2][C@:3]1([N:8]2[C:12]3[N:13]=[C:14]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36].O>C(Cl)Cl>[NH2:23][C:20]1[N:19]=[CH:18][C:17]([C:16]2[C:11]3[CH2:10][CH2:9][N:8]([C@@:3]4([CH3:2])[CH2:7][CH2:6][N:5]([CH:31]5[CH2:35][CH2:34][NH:33][C:32]5=[O:36])[CH2:4]4)[C:12]=3[N:13]=[C:14]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:22][N:21]=1
Reactant: C[C@]1(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)CCNC1
Reactant: O=C1NCCC1Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C[C@]1(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)CCN(C2CCNC2=O)C1
Yield: 47.8 %

Procedure:
To a stirred solution of the product of Example 4, Step 2, 5-{7-[(3S)-3-methylpyrrolidin-3-yl]-2-(morpholin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}pyrimidin-2-amine hydrochloride (320 mg, 0.764 mmol) and TEA (232 mg, 2.29 mmol) in DCM (16 mL) was added 3-bromo-pyrrolidin-2-one (188 mg, 1.15 mmol) at 25° C. The mixture was stirred at 40° C. for 3 days, whereupon water (10 mL) was added. The mixture was extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated to give a crude product (400 mg) as a yellow solid. The residue was purified by preparative TLC (silica gel, 10:1 DCM/MeOH) to give the racemic title compound (170 mg, 48%) as a yellow solid. This material was separated by preparative SFC column (AS, 250 mm×30 mm, 10 μm), mobile phase: 45% MeOH and NH3 in H2O, with a flowrate of 80 mL/min) to give the title compounds: Enantiomer 1 (Example 6), retention time 6.23 min (50 mg, 29%) as a yellow solid and enantiomer 2, retention time 6.21 min (19 mg) as a yellow solid. Enantiomer 1: SFC Retention time: 6.23 min; 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 2 H), 3.76-3.68 (m, 10 H), 3.43-3.33 (m, 5 H), 3.14-3.12 (m, 2 H), 3.05-3.00 (m, 1 H), 2.89-2.85 (m, 1 H), 2.56-2.53 (m, 1 H), 2.35-2.30 (m, 1 H), 2.14-2.10 (m, 1H), 2.00-1.95 (m, 1 H), 1.44 (s, 3 H). m/z (APCI+) for C23H31N9O2 466.2 (M+H)+. Enantiomer 2 (Example 7): SFC Retention time 6.21 min; 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 2 H), 3.82-3.68 (m, 12 H), 3.46-3.40 (m, 1 H), 3.36-3.33 (m, 1 H), 3.14-3.10 (m, 3 H), 3.03-3.00 (m, 1 H), 2.95-2.90 (m, 1 H), 2.54-2.51 (m, 1 H), 2.40-2.35 (m, 1 H), 2.14-2.11 (m, 1 H), 2.04-2.02 (m, 1 H), 1.44 (s, 3 H). m/z (APCI+) for C23H31N9O2 466.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:17][C@@H:18]([CH3:23])[C:19]([CH3:22])([OH:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>[Cu]I.CCOC(C)=O.O>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]2[C:9]=1[CH:10]=[CH:11][N:17]2[C@H:18]([C:19]([OH:21])([CH3:22])[CH3:20])[CH3:23]
Reactant: C[C@H](N)C(C)(C)O
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](n1ccc2c(Cl)c(C#N)ccc21)C(C)(C)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
A mixture of 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile, (0.229 g, 0.91 mmol), (S)-3-amino-2-methylbutan-2-ol (Example 21E) (0.113 g, 1.092 mmol), and K2CO3 (0.252 g, 1.820 mmol) in anhyd NMP (3 mL) was stirred in a heating block at 60° C. under N2 for 2 h. CuI (0.017 g; 0.091 mmol) was added and the mixture was subjected to microwave heating (140° C.) for 30 min. The reaction mixture was poured into EtOAc/water and the whole was filtered through a pad of Celite. Layers of the filtrate were separated and the aqueous layer was extracted with EtOAc (×2). Combined organics were filtered (Whatman #2), washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (S)-4-chloro-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-5-carbonitrile (0.148 g, 62% yield) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.50 (d, 1H), 7.42-7.39 (m, 1H), 7.39-7.34 (m, 1H), 6.74 (d, J=3.3 Hz, 1H), 4.41 (q, J=7.0 Hz, 1H), 1.60 (d, J=7.1 Hz, 3H), 1.41 (s, 1H), 1.33 (s, 3H), 1.09 (s, 3H); MS (LCMS ES+) m/z 263 ([M+H]+, 88%), 304 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: F[C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:9]=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>CN1C(=O)CCC1.O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:8]2[C:6]3=[N:7][C:2]([NH:34][CH2:33][C:32]4[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[CH:3][CH:4]=[C:5]3[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:9]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1ccc(Cn2nc(C(=O)OC(C)(C)C)c3ccc(F)nc32)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2ccc3c(C(=O)OC(C)(C)C)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 80 °C

Procedure:
To a solution of tert-butyl 6-fluoro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (2.55 g, 7.14 mmol) in NMP (30 mL) was added 4-methoxybenzylamine (2.80 mL, 21.41 mmol). The resulting mixture was then heated to 80° C. for 2 hours, after which the mixture was diluted with water (200 mL) and extracted with EtOAc (2×200 mL). The combined extracts were washed with water (100 mL), dried with MgSO4, filtered, absorbed onto silica gel (17 g) and removed the solvent in vacuo. This solid was purified on silica gel (80 g) column (0-100% EtOAc/CH2Cl2 to give the title compound. LRMS (M+1)=474.0
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[S:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16]([O:18][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1csc(N2CC(O)C2)n1)N1CCSCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCSCC3)cs2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
To a solution of 1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (599 g, 2.50 mmol) (obtained as described in Reference Example 25(2)) in methylene chloride (30 ml) were added methanesulfonyl chloride (0.49 ml, 6.30 mmol) and triethylamine (0.88 ml, 6.30 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 40 minutes. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using 5% methanol in ethyl acetate as the eluant to afford 1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (709 mg, yield 93%) as a pale yellow solid.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[C@@H:16]([C:17](=[O:25])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:9]2[S:8][C:7]=1[NH2:27])(=O)C.[C:28]1(C)C=C[CH:31]=[CH:30][CH:29]=1.FC(F)(F)C(O)=[O:38]>>[CH2:5]([C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[C@@H:16]([C:17](=[O:25])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:9]2[S:8][C:7]=1[NH2:27])[C:28]1[O:38][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccccc1
Reactant: CC(=O)OCC1=C(N)S[C@@H]2[C@H](C(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Product: NC1=C(Cc2ccco2)C(C(=O)O)N2C(=O)[C@@H](C(=O)Cc3ccccc3)[C@H]2S1
Reaction time: 1 h

Procedure:
A solution of 7.8 g of 3-acetyloxymethyl-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid in 60 ml of trifluoroacetic acid, prepared at room temperature within 15 minutes, is treated with an equal volume of toluene and evaporated to dryness. The residue, which contains the 7β-phenylacetyl-amino-3-trifluoroacetyloxymethyl-ceph-2-em-4ξ-carboxylic acid, is dissolved in 200 ml of dry formamide and treated with 5.80 ml of furan. After reacting for 1 hour at 50° under nitrogen, the reaction mixture is cooled and treated with ethyl acetate and 10% aqueous dipotassium hydrogen phosphate solution (pH 7.5). The aqueous solution is separated and washed several times with ethyl acetate. The aqueous phase is adjusted to pH 2.5 with 20% aqueous phosphoric acid and extracted with ethyl acetate. The resulting organic extract is washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The solid residue is crystallised from ethal acetate to yield the almost pure 3-furfuryl-7β-phenylacetyl-amino-ceph- 2-em-4ξ-carboxylic acid, which after repeated recrystallisation from ethyl acetate melts at 188°-190°: thin-layer chromatogram (silica gel): Rf = 0.75 (system n-butanol/acetic acid/water 67:10: 23) and Rf = 0.53 (system n-butanol/ethanol/water 40:10:50); ultraviolet absorption spectrum (in methanol): strong terminal absorption; infrared absorption spectrum (in mineral oil); characteristic bands at 3,01μ, 5,66μ, 5,75μ, 6,02μ and 6,54μ.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][CH:3]=1.C([O-])(=O)C1C=CC(C([O-])=O)=CC=1.[NH4+:25].[NH4+:26]>[Ti].O>[C:1](#[N:26])[C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:25])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: [Ti]
Agent: O=C([O-])c1ccc(C(=O)[O-])cc1
Solvent: O
Product: N#Cc1ccc(C#N)cc1
Temperature: 280 °C
Reaction time: 1 h

Procedure:
To a two-liter all-titanium stirred autoclave is added 146.19 g. (0.88 moles) of terephthalic acid, 24.02 g. (0.12 moles) of diammonium terephthalate and 1000 ml. of water. This mixture is heated with stirring to 280° C and held at this temperature for approximately one hour. The resultant equilibrated mixture represents the hydrolyzate obtained by the non-catalytic hydrolysis of terephthalonitrile which would result from the removal, as ammonia, of 88 percent of the total available nitrogen from a one molal solution of terephthalonitrile. That this is so is clearly evident from the hydrolysis equilibria of a terephthalonitrile hydrolysis system which are discussed above. The reactor is then rapidly cooled to ambient temperature and sufficient NaOH is added to the contents of the reactor to effect complete solution at room temperature. An excess of H2SO4 is then added to effect precipitation of the terephthalic acid product. After filtration, thorough washing and drying, a sample of the acid is submitted for determination of parts per million (by weight) of nitrogen. The value of 2400 ppm corresponds to 2.84 mole percent terephthalamic acid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([N:13]2[C:14]3[C:10](=[CH:9][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1cccc(-n2ccc3ccccc32)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 74.2 %

Procedure:
To a mixture of 4 (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)1H-indole (3, 2.43 g, 10 mmol), and 1,4-dibromobenzene (11.8 g, 50 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes-EtOAc (9:1) to provide 2.02 g (74%) of the product 4 (3-bromo-phenyl)-1H-indole as a white solid.