Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:7])[O:2][CH2:3][CH2:4][O:5][CH3:6].[NH2:9][C@@H:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]([Cl:40])=[C:18]([NH:24][C:25]3[N:30]=[C:29]([NH:31][CH:32]4[CH2:34][CH2:33]4)[C:28]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:27]4[N:26]=3)[CH:19]=[C:20]([C:22]#[N:23])[CH:21]=2)[CH2:12][C@H:11]1[O:41][Si:42]([CH:49]([CH3:51])[CH3:50])([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44].C(N(CC)CC)C>ClCCl>[Cl:40][C:17]1[C:18]([NH:24][C:25]2[N:30]=[C:29]([NH:31][CH:32]3[CH2:33][CH2:34]3)[C:28]3=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:27]3[N:26]=2)=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][C@@H:10]([NH:9][C:1](=[O:7])[O:2][CH2:3][CH2:4][O:5][CH3:6])[C@H:11]([O:41][Si:42]([CH:46]([CH3:48])[CH3:47])([CH:49]([CH3:51])[CH3:50])[CH:43]([CH3:44])[CH3:45])[CH2:12]1
Reactant: COCCOC(=O)Cl
Reactant: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
2-methoxyethyl carbonochloridate (5.08 mg, 0.037 mmol) was added to a solution of 2-((3-((3R,4R)-4-amino-3-((triisopropylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 174D, 19 mg, 0.031 mmol) and triethylamine (8.53 μl, 0.061 mmol) in dichloromethane (1 mL) and the reaction solution was stirred at room temperature overnight. More 2-methoxyethyl carbonochloridate (5.08 mg, 0.037 mmol) was added and stirring continued over the weekend, still about 30% SM left. More triethylamine (100 μL) and 2-methoxyethyl carbonochloridate (20 μL) was added and stirred for another day. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 0-40% ethyl acetate/dichloromethane) to give 2-methoxyethyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino) imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate (12 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[O:5][N:4]=1.[N-:16]=[N+]=[N-].[Na+].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH2:16])[N:7]=2)=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2nc(CCl)no2)cc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(CN)no2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-chloromethyl-5-(4-methoxy-phenyl)-[1,2,4]oxadiazole (8.90 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (17.8 mmol). This mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (3×). The combined organic extracts were combined and washed with water (2×), dried over anhydrous sodium sulfate, and evaporated. Then clear oily residue was placed under high vacuum and gently warmed for 18 hours. Upon cooling the material solidified. This solid was dissolved in tetrahydrofuran (15 mL) and treated with triphenylphosphine (9.0 mmol). Bubbling was immediately evident. This mixture was stirred for 16 hours and then treated with water (3.0 mL). This was heated in a 45° C. oil bath for 3 hours. The product was purified by flash chromatography (silica gel; 2:1 ether/dichloromethane), m.p. 66-68° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]([O:11][CH3:23])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)C(c1ccccc1)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(c1ccccc1)c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a solution of compound 2-(4-Bromophenyl)-2-phenylacetic acid, 14-c, (5.6 g, 19.3 mmol) in methanol (200 mL) was added concentrated sulfuric acid (6 mL) and the reaction mixture was stirred at 60° C. for 14 h. The resulting solution was concentrated and ice-water was added. The aqueous layer was extracted by EA. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to yield title compound, 14-d, (5.5 g, 93%). 1H NMR (300 MHz, CDCl3) δ3.73 (s, 3H), 4.96 (s, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.25-7.30 (m, 5H), 7.42 (d, J=8.4 Hz, 2H). LC-MS: (M+H)+ 304, 306.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:17])[C:13]=1[C:14]([NH2:16])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>O>[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:17])[C:13]=1[C:14](=[S:19])[NH2:16]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC(=O)c1c(Cl)cncc1Cl
Solvent: O
Solvent: c1ccncc1
Product: NC(=S)c1c(Cl)cncc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
Into a 3000-mL three-necked round bottom flask equipped with a condenser, mechanical stirrer under an atmosphere of nitrogen was added pyridine (1500 mL), then 3,5-dichloro-4-pyridine-carboxamide (92.9 g., 0.486 mole) (which dissolved), and tetraphosphorus decasulfide (237 g., 0.535 moles)(which had almost dissolved then a bright yellow precipitate formed and an exotherm heated the mixture to 60° C.). The slurry was allowed to stir for 1 hr (temperature had dropped to 45° C.) and then the temperature was then raised and when it reached 100° C. all of the solids had dissolved and continued heating to 118° C. and was maintained at 115° C. for 4 hr. The mixture was poured into water (3750 mL) carefully as gas began to evolve and the temperature of the aqueous solution rose to approximately 45° C. and was allowed to sit at room temperature over two nights. To the resulting mixture was added water (6000 mL) and was extracted with methylene chloride (3×2000 mL), washed with water (3×1000 mL) and the solvent removed in vacuo to give a brownish yellow liquid, with much pyridine present. The vacuum pump was connected to the rotary evaporator to remove the residual pyridine. The residue (brown solid) was triturated with diethyl ether (3×1500 mL), treated with decolorizing carbon and the solvent removed in vacuo to give a solid which contained pyridine. The yellow solid was slurried in water (2×200 mL) and dried in vacuo at 60° C. to give 63.2 g of a light yellow solid (62.8% yield): mp 186-187° C.; TLC[50/50 ethyl acetate/hexanes] showed amide at Rf=0.31 and thioamide Rf=0.53; 1H NMR (DMSO-d6) d 10.6 (s, b, 1H), 10.0 (s, b, 1H), 8.6 (s, 2H).
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]2[NH:8][C:9]([O:11][C:3]=2[CH:2]=1)=[O:10].C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>N([O-])=O.[Na+].O>[Cl:7][C:6]1[C:1]([N+:16]([O-:18])=[O:17])=[CH:2][C:3]2[O:11][C:9](=[O:10])[NH:8][C:4]=2[CH:5]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2o1
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
In a 250-ml flask, place 17.0 g (0.1 m) of chlorzoxazone (1b; X=Cl), 50 ml of acetic acid, and 0.14 g of sodium nitrite. Warm and stir the slurry to 50° C. Add 11.3 g (0.125 m) of concentrated nitric acid (70%) and stir the mixture at 55°-63° C. for 5 hrs. Add 100 ml of hot water, cool to room temperature and let it stand overnight. Collect solid, wash with water, and dry in air to give 18.7 g (87%) of 5-chloro-6-nitro-benzoxazol-2-one (2b; X=Cl) as pale yellow solids.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[N:11]=[C:10]([NH:17][CH:18]2[CH2:20][CH2:19]2)[C:9]=1[F:21]>ClCCl>[CH:18]1([NH:17][C:10]2[C:9]([F:21])=[C:8]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)[N:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]=2)[CH2:20][CH2:19]1
Reactant: C1CSCCN1
Reactant: Fc1c(Cl)nc(C2CC2)nc1NC1CC1
Solvent: ClCCl
Product: Fc1c(NC2CC2)nc(C2CC2)nc1N1CCSCC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
A mixture of thiomorpholine (2.27 g, 22 mmol) and 6-chioro-N,2-dicyclopropyl-5-fluoro-4-pyrimidinamine 31 (1 g, 4.4 mmol) is stirred at 110° C. for 18 hours. After cooling, the brown solution is diluted with dichloromethane, washed two times with a saturated sodium bicarbonate solution. The combined organic layers are dried over magnesium sulfate and concentrated under high vacuum to afford a brown oil. The crude oil is purified by column chromatography (hexane/ethyl acetate: 80/20) to give N,2-dicyclopropyl-5-fluoro-6-(4-thiomorpholinyl)-4-pyrimidinamine 120 (915 mg, 71%) as a yellowish solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(N(CC)CC)C.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][NH2:24]>ClCCl>[Cl:11][C:4]1[N:3]=[C:2]([NH:24][CH2:23][CH2:22][CH2:21][O:20][CH3:19])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COCCCN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91.5 %

Procedure:
2,6-Dichloro-3-nitropyridine (3.29 mmol, 0.635 g) was added to an oven dried 50 mL round-bottomed flask equipped for stirring under nitrogen. Dichlormethane (12 mL) and triethylamine (3.62 mmol, 0.504 mL) were added and the resultant solution was cooled to −15° C. with an acetone/ice bath. 3-methoxypropan-1-amine (3.29 mmol, 0.337 mL) was then added drop-wise via syringe and the resultant solution was stirred at −15° C. for 0.5 hr. The acetone/ice bath was removed and the reaction was allowed to warm to room temperature and stir for 0.5 hr. The reaction solution was poured into water and extracted twice with dichloromethane (50 mL). The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo affording an orange oil. This material was then purified by chromatography on silica gel (20% ethyl acetate/hexanes) to afford 6-chloro-N-(3-methoxypropyl)-3-nitropyridin-2-amine (33A) as a yellow solid (3.01 mmol, 0.740 g, 92% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.89 (m, 2H) 3.00 (s, 3H) 3.43 (t, J=6.06 Hz, 2H) 3.53-3.61 (m, 2H) 6.77 (d, J=8.59 Hz, 1H) 8.42 (d, J=8.08 Hz, 1H). ESI-MS: m/z 246.2 (M+H)+.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([C:9](=O)[C:10](=[CH:32]OCC)[C:11]([C:13]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:15][CH:14]=2)=[O:12])[CH2:8][CH2:7]1.Cl.[NH2:38][OH:39]>C(O)C.C(OCC)(=O)C>[CH:6]1([C:9]2[O:39][N:38]=[CH:32][C:10]=2[C:11]([C:13]2[C:18](=[O:19])[N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:15][CH:14]=2)=[O:12])[CH2:8][CH2:7]1
Reactant: NO
Reactant: CCOC=C(C(=O)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(c1cnoc1C1CC1)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Anhydrous sodium acetate (68 mg, 0.83 mmol) was added to a solution of 1-cyclopropyl-3-(1,6-dihydro-6-oxo-1,2-diphenyl-5-pyrimidinyl)-2-(ethoxymethylene)-1,3-propanedione (i.e. the product from Example 6, Step B) (171 mg, 0.41 mmol) in ethanol (4 mL) at 0° C. Hydroxylamine hydrochloride (29 mg, 0.42 mmol) was added and the resulting suspension was stirred at 0° C. for 30 min and then at ambient temperature for 2 h. The resulting mixture was diluted with ethyl acetate (20 mL) and ethanol (20 mL), concentrated onto 0.8 g silica gel, and the residue purified by medium pressure liquid chromatography using a 12 g silica gel column and eluting with 0 to 100% ethyl acetate in hexanes to obtain 14 mg of the title compound, a compound of the present invention as a yellow glassy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(O)(CC)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Reactant: C1COCCN1
Solvent: CCC(C)O
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 105 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
In a 500 mL volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 95.0 g (0.354 mol) of 6-methoxy-7-(3-chloropropoxy)-quinazolin-4-one, 154.2 g (1.77 mol) of morpholine, and 380 mL of sec-butyl alcohol. The resulting mixture was heated to 105° C. under stirring for 18 hours. After the reaction was complete, 380 mL of methanol was added to the reaction mixture. The resulting mixture was stirred at 70° C. for 30 minutes, and cooled to room temperature. The mixture was then stirred for 30 minutes at room temperature. The precipitated crystalline product was filtered, placed in 190 mL of methanol and stirred for washing, again filtered, and dried at 60° C. under reduced pressure to give 104 g (isolated yield: 92%, purity: 98.81% in terms of area percentage determined by high performance liquid chromatography) of 6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-one as a white crystalline product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.F[C:15]1[N:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.O>CS(C)=O>[O:13]([C:15]1[N:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ncccc1-c1ccc(F)nc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncccc1-c1ccc(Oc2ccccc2)nc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A mixture of potassium carbonate (3287 mg), phenol (821 mg) and 6′-fluoro-3,3′-bipyridin-2-amine (1500 mg) in DMSO (15 mL) was stirred for 1 hr at 150° C. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (1750 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19](O)=[O:20])[O:16][C:15]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.Cl.[CH3:24][O:25][NH2:26].Cl.CN(C)CCCN=C=NCC>O1CCCC1.O.O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19]([NH:26][O:25][CH3:24])=[O:20])[O:16][C:15]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: O=C(O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CONC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (5R)-(−)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid (EXAMPLE 1, Step 1, 150 mg, 0.483 mmol) and O-methylhydroxylamine hydrochloride (61 mg, 0.724 mmol) in tetrahydrofuran/water (1/1, 4.8 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (278 mg, 1.45 mmol), and the resulting mixture was stirred at ambient temperature for 30 minutes and was then diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with methanol/methylene chloride (2.5/97.5). Pooling and concentration of those fractions with an Rf=0.53 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 206-208° C. (decomp.); MS (ESI+) for C15H18FN3O5 m/z 340 (M+H)+; [α]25D=−56° (c 0.92, DMSO).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[Cl:6][C:7]1[CH:17]=[CH:16][C:10]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1.C(N(CC)CC)C.S(=O)(=O)(O)O>O1CCOCC1>[C:3]([CH2:2][S:1][CH:11]([C:10]1[CH:9]=[CH:8][C:7]([Cl:6])=[CH:17][CH:16]=1)[CH2:12][C:13]([OH:15])=[O:14])([OH:5])=[O:4]
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: O=C(O)CS
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(O)CSC(CC(=O)O)c1ccc(Cl)cc1

Procedure:
To a stirred mixture of mercaptoacetic acid (5.04 g, 3.8 ml, 54.7 mmol) and 4-chlorocinnamic acid (10.0 g, 54.7 mmol) in 20 ml of dioxane is added dropwise a solution of triethylamine (6.90 g, 9.53 ml, 68.0 mmol) in 20 ml of dioxane. The mixture is heated under reflux for 5 hours, then cooled and poured into ice, acidified with conc. sulfuric acid and extracted with ether. The combined ether extracts are washed with water and with brine, dried and stripped of the solvent. The residue is washed with chloroform to give 3-carboxymethylthio-3-(4-chlorophenyl)propionic acid, a yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[CH3:21][C:17]1([CH3:22])[CH2:18][CH2:19][CH2:20][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:16]1
Reactant: CC1(C)C=C(c2ccc(OCc3ccccc3)cc2)CCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)CCCC(c2ccc(O)cc2)C1
Reaction time: 8 h
Yield: 102.4 %

Procedure:
To 1-benzyloxy-4-(3,3-dimethyl-cyclohex-1-enyl)-benzene (4.3 g, 16.4 mmol) in MeOH (50 mL) and EtOAc (50 mL) was added 10% Pd/C (0.67 g) under N2. This mixture was stirred under H2 (1 atm) overnight. The reaction mixture was filtered through celite. The filtrate was concentrated to give the title compound as a white solid (3.43 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=[O:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH:23]=O>N1CCCCC1.C(O)C>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH:23]=[C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.5 %

Procedure:
A mixture of 5-carboxy-2-oxindole (88.5 mg), indole-2-carbaldehyde (87 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (1 drop) in ethanol (3 mL) was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was filtered and acidified with 2N hydrochloric acid. The resulting solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven to give 60 mg (40% yield) of 3-(1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid as a mustard-colored solid.
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:34][C:35]#[N:36].O>C1COCC1>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:34][C:35]#[N:36])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(O)cc1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OCC#N)cc1
Yield: 52.6 %

Procedure:
To the phenol prepared in example 91 (608 mg, 1.5 mmol) in THF (20 mL) at 0° C. was addded sodium hydride (66 mg of a 60% dispersion in oil, 1.66 mmol). After ten minutes bromoacetonitrile (199 mg, 1.66 mmol) was added. The suspension was stirred at room temperature whereupon another portion of bromoacetonitrile (360 mg, 3 mmol) was added and stirring continued until the reaction was complete by TLC. Water (50 mL) was added to the reaction and the two layers separated. The aqueous phase was extracted with ether (2×40 mL) and the combined organic phases dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 10% MeOH/CHCl3 to provide 350 mg (53%) of product. Anal. Calcd for C27H30N3O3: C, 67.56; H 6.30; N, 8.75. Found: C, 67.39; H, 6.51; N, 8.49.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[C:18]([O:20][CH3:21])=[O:19])[C:3]1=[O:22].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([C:18]([O:20][CH3:21])=[O:19])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Yield: 38.8 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate (50 mg, 0.16 mmol), 3-(trifluoromethyl)benzoic acid (38 mg, 0.20 mol), EDCI (38 mg, 0.20 mmol), HOBT (27 mg, 0.20 mmol), and Et3N (20 mg 0.20 mmol) in CH2Cl2 was stirred overnight at room temperature. The solution was washed with water and brine, concentrated in vacuo and the residue chromatographed on silica gel (3%-5%-10% (NH4OH/MeOH)/CH2Cl2) to give 30 mg of the title product as a white solid. MS found: (M+H)+=484.25
Reaction SMILES: ClC(Cl)C(O[CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C>O>[CH:32]1[CH:31]=[CH:30][N+:29]([CH2:6][C:7]2[CH2:8][S:9][C@@H:10]3[C@H:17]([NH:18][C:19]([CH2:20][C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[O:26])[C:16](=[O:27])[N:11]3[C:12]=2[C:13]([O-:15])=[O:14])=[CH:34][CH:33]=1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)C(Cl)Cl)CS[C@H]12
Reactant: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12

Procedure:
3-Dichloroacetoxymethyl-7β-(2'-thienylacetamido)ceph-3-em-4-carboxylic acid (0.1 g., 2.15 mmole.) was suspended in water (4 ml.), and pyridine (0.352 ml., 4.3 mmole.) was added. The solution was heated at 50° for 1 hour, acidified to pH 4.5 with acetic acid, and washed with ethyl acetate and finally with petrol. The aqueous solution was freed from dissolved organic solvents and applied to a column comprising (from top to bottom) layers of deactivated neutral alumina (8 ml.), Dowex 1 (AcO-) (20 ml.) and Zeokarb 226 (H+) (5 ml.). Elution with water was carried out until the eluate showed no optical rotation; the total eluate was freeze-dried and the residue triturated with methanol to give a white solid (296 mg.), [α]D23 +48.8° (c 0.8, water), λλmax (water) 238nm (E1cm1% = 351), 255 nm (E1cm1% = 324).