Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].O[CH2:11][CH:12]([CH2:14]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:7]([CH:11]=[CH:12][CH:14]=[N:6]2)=[CH:8][CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: COc1ccc2cccnc2c1
Yield: 13.2 %

Procedure:
In a similar fashion using route 10 general procedure 20, 3-methoxyaniline (1.0 g, 8.12 mmol), glycerol (2.32 g, 25.2 mmol), 3-nitrobenzenesulfonic acid sodium salt (2.4 g, 10.6 mmol) and H2SO4/H2O (6 ml, 7:5) gave the title compound (170 mg, 14%) after purification by column chromatography with n-hexane/EtOAc (17:3) as the eluent.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([N:7]1[CH2:12][CH2:11][CH2:10][C:9](NC(OC(C)(C)C)=O)([NH:13]C(OC(C)(C)C)=O)[C:8]1=[O:29])[CH3:6])[CH3:2].C(OC(=O)NC1CCCN(CC2NC(C3C=CC(C4C=CC(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)=CC=4)=CC=3)=CN=2)C1=O)(C)(C)C>>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([NH2:13])[C:8]1=[O:29])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1CCCC(NC(=O)OC(C)(C)C)(NC(=O)OC(C)(C)C)C1=O
Agent: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Product: CCOC(=O)C(C)N1CCCC(N)C1=O

Procedure:
2-(3-Amino-2-oxo-piperidin-1-yl)-propionic acid ethyl ester was prepared using method 804 substituting 2-[3,3-bis(tert-butoxycarbonylamino)-2-oxo-piperidin-1-yl]-propionic acid ethyl ester for {1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester. C10H18N2O3 calculated 214.2 observed [M+1]+ 215.2; rt=1.21 min.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[C:10]=1[OH:19])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:24]>>[NH2:24]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:19])[C:11]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=2[S:13]\1
Reactant: Cc1ccc2c(O)c(C(=O)c3ccccc3)sc2c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: Cc1ccc2c(c1)S/C(=C(/N)c1ccccc1)C2=O
Yield: 57 %

Procedure:
Prepared as in Example 31 from 2-benzoyl-6-methyl-benzo[b]thiophen-3-ol and ammonium acetate with a yield of 57% of theory. M.p. 166°-167° C. (ethyl acetate/petroleum ether 1:1).
Reaction SMILES: [O:1]=[C:2]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH2:16])[CH:11]=2)[CH2:6][CH2:5]1.[H-].[Na+].Cl[C:25]1[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=1>>[O:1]=[C:2]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)[CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:25]3[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=3)[CH:11]=2)[CH2:8][CH2:9]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1cc(N2CCN(CC(=O)N3CCCC3)CC2)ncn1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCN(CC(=O)N4CCCC4)CC3)ncn2)s1

Procedure:
6-[4-(2-Oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]pyrimidin-4-amine 17-2 (0.60 g, 2.07 mmol) and sodium hydride (0.165 g, 4.13 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.299 g, 2.07 mmol) were treated as in Scheme 4 above. The product was purified on a silica column. Hi-Res MS: calc: 399.1710 found: 399.1706. 1NMR (CDCl3): 9.40 ppm (s, 1H); 8.45 ppm (s, 1H); 7.88 ppm (s, 1H); 5.98 ppm (s, 1H); 3.68 ppm (s, 4H); 3.50 ppm (m, 4H); 3.21 ppm (s, 2H); 2.68 ppm (t, 4H); 1.98 ppm (m, 2H); 1.87 ppm (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([NH2:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]2[C:3]=1[C:9](=[O:11])[N:19]1[CH:18]=[C:17]([C:20]([NH2:22])=[O:21])[CH:16]=[CH:15][C:14]1=[N:1]2
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: COC(=O)c1c(C)sc(C)c1N
Solvent: c1ccncc1
Product: Cc1sc(C)c2c(=O)n3cc(C(N)=O)ccc3nc12
Temperature: 180 °C
Yield: 3.2 %

Procedure:
A mixture of 5 g (0.0226 mol) of 4-amino-2,5-dimethyl-3-thiophene-carboxylic acid, methyl ester and 3.5 g (0.0226 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) is heated in an oil bath at 180° C. for thirty minutes. The mixture is cooled, dissolved in hot pyridine, cooled, the precipitate collected and dissolved in hot methanol, activated charcoal (Darco-G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Manville). The filtrate is cooled to give 0.2 g of 1,3-dimethyl-10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide with methanol (1:0.125); mp 272°-275° C. after recrystallization from methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:37])[N:24]=[C:23]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=2[N:20]([CH3:35])[C:19]1=[O:36])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:37])[N:24]=[C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]3[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=3[N:20]([CH3:35])[C:19]2=[O:36])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)N=C(C2CCCCC2)c2ccccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(C2CCCCC2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-5-cylcohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one (Example 8-G), the title compound was prepared as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.ClC(Cl)C>C(O)(=O)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=4)[CH2:6][CH2:7]3)[CH2:20][CH2:19]2)=[CH:25][CH:26]=1
Reactant: O=C1CCN(CCc2ccc(F)cc2)CC1
Reactant: Brc1ccc2c(c1)NCC2
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Reaction time: 2 h
Yield: 58 %

Procedure:
Triacetoxylated sodium borohydride (298 g) was added over 30 min to a mixture of 6-bromoindoline (175 g), 1-(4-fluorophenethyl)-4-piperidone (194 g), acetic acid (250 ml) and dichloroethane (2.5 l) followed by stirring 2 hr. Then the reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (2 l), an 8 N aqueous solution of sodium hydroxide (1 l) and water (500 ml) and the layers were separated. The organic layer was washed successively with water (0.5 l) and brine (0.5 l), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in hot ethyl acetate (500 ml) and then cooled with ice water. The resulting crystalline precipitates were collected by filtration to give the title compound (205 g) (yield: 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@H:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:26][C:27]1[NH:28][C:29](=[O:37])[C:30]2[CH2:36][O:35][CH2:34][CH2:33][C:31]=2[N:32]=1.[NH4+].[Cl-]>C1COCC1.ClCCl.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@H:15]3[CH2:19][CH2:18][N:17]([CH2:26][C:27]4[NH:28][C:29](=[O:37])[C:30]5[CH2:36][O:35][CH2:34][CH2:33][C:31]=5[N:32]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Reactant: COc1ccc(C(=O)C2CCN([C@H]3CCNC3=O)CC2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(=O)C2CCN([C@H]3CCN(Cc4nc5c(c(=O)[nH]4)COCC5)C3=O)CC2)cc1
Temperature: 1.7000000476837158 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A solution of (S)-3-(4-(4-methoxybenzoyl)piperidin-1-yl)pyrrolidin-2-one (25.66 g, 85 mmol) in THF (283 mL) was cooled to −1.7° C. and to this was slowly added NaH (10.18 g, 255 mmol) and 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (89 mmol, 17.88 g) maintaining the temperature below 5° C. The reaction vessel was immersed into an ice-water bath and allowed bath to expire overnight. When reaction was complete by LCMS (approximately 15 h), the reaction was cooled to 1.7° C. and saturated NH4Cl was slowly added, keeping the internal temperature below 10° C. The mixture was diluted with dichloromethane (500 mL) and 1 N NaOH (500 mL) and split into two batches that were processed identically. Additional 1 N NaOH (500 mL) was added and the aqueous layer was washed with dichloromethane (2×500 mL). The aqueous layer was adjusted to pH 7 using approximately 250 mL 3 N HCl and extracted with dichloromethane (4×500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was taken up in dichloromethane (500 mL) and ethyl acetate (500 mL) was added. The resulting solution was concentrated to an approximate volume of 300 mL and seeded with pure title compound and concentrated further in vacuo. To this stirred solution was added ethyl acetate (500 mL) and a seed of pure title compound. Filtration of the suspension provided the title compound as a white solid (32.87 g, 70.5 mmol).
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:16](=[O:17])[CH2:15][CH2:14][C@@H:13]2[C:18]([OH:20])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:23]([OH:27])[C:24]([NH2:26])=[O:25].O[NH-].O=[N-]>>[NH2:26][C:24](=[O:25])[C:23](=[O:27])[CH:22]([NH:21][C:18]([C@H:13]1[CH2:14][CH2:15][C:16](=[O:17])[N:12]1[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:20])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1cccc2ccccc12
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1cccc2ccccc12

Procedure:
Coupling of (R)-1-naphthalen-1-ylmethyl-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[CH3:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>N1C=CC=CC=1>[O:5]=[C:4]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[CH3:8])[CH:3]=[C:2]([CH3:7])[CH3:1]
Reactant: Cc1ccccc1N
Reactant: CC(C)=CC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)=CC(=O)Nc1ccccc1C

Procedure:
3-Methylbut-2-en-oylchloride (24.2 g) was added dropwise to a stirred solution of 2-methylaniline (20 g) in anhydrous pyridine (200 cm3) cooled to 0°. After 1 hour solvent was evaporated in vacuo to yield a solid which was recrystallised from ether/petroleum ether (boiling range 40-60) to afford the title compound, m.p. 105 (29.5 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:19]1[CH2:31][CH2:32][CH2:33][OH:34])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:29])([CH3:28])[CH3:30])([CH3:26])[CH3:25])[CH2:20][C@H:19]1[CH2:31][CH2:32][CH:33]=[O:34])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCC=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 110.7 %

Procedure:
A solution of methylene chloride (80 ml) and dimethyl sulfoxide (2.98 ml, 40 mmol) was cooled to -78° C., and oxalyl chloride (1.85 ml, 21.2 mmol) was dropwise added thereto. The mixture was stirred for 15 minutes at the same temperature, and then a solution of (2R,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(3-hydroxypropyl)pyrrolidine (5 g, 13.9 mmol) in methylene chloride (70 ml) was dropwise added thereto over a period of 10 minutes. The mixture was stirred for 30 minutes, and then triethylamine (9.66 ml, 69.3 mmol) was added thereto. The mixture was heated to room temperature and stirred for 15 minutes. The reaction solution was concentrated in vacuo, and ethyl acetate (70 ml) was added thereto. The mixture was washed twice with 10% aqueous citric acid (30 ml) and further with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to obtain (2R,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2-formylethyl)pyrrolidine (5.5 g, yield: 100%) as crude product. This compound was used for the subsequent reaction without purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[CH:5]([NH2:15])[CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(N(CC)C(C)C)(C)C.C1(C[C@H](N2[CH2:51][C:50]([O:52][C:53]3[C:58]([F:59])=[CH:57][CH:56]=[CH:55][C:54]=3[F:60])=[CH:49][C:48]2=[O:61])C(NC2C=CN(CC(O)(C)C)N=2)=O)CCCCC1>C(#N)C>[CH3:2][O:3][C:4](=[O:16])[CH:5]([N:15]1[CH2:51][C:50]([O:52][C:53]2[C:58]([F:59])=[CH:57][CH:56]=[CH:55][C:54]=2[F:60])=[CH:49][C:48]1=[O:61])[CH2:6][C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COC(=O)C(N)Cc1c(Cl)cccc1Cl
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(Cc1c(Cl)cccc1Cl)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
In a flask was placed 2-amino-3-(2,6-dichloro-phenyl)-propionic acid methyl ester hydrochloride salt (313 mg, 1.10 mmol), acetonitrile (5 mL) and N,N-diisopropylethylamine (200 μL, 1.23 mmol). This mixture was stirred at 60° C. for 1 h and then cooled to 25° C. The mixture was then treated with N,N-diisopropylethylamine (200 μL, 1.23 mmol) and heated at 80° C. and a solution of 4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 36, 321 mg, 1.00 mmol) in acetonitrile (1 mL) was added slowly. The mixture was heated at 100° C. for 16 h and then placed in a sealed microwave tube and heated at 140° C. for 1 h in the microwave. The mixture was then concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 10% ethyl acetate/hexanes to 100% ethyl acetate) afforded 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (58 mg, 12%) as a gold oil: HR-ES-MS m/z calculated for C20H15NO4Cl2F2 [M+H]+ 442.0419, observed 442.0420.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[CH:12][N+:13]([O-])=O)=[CH:4][CH:3]=1>CO.[Ni]>[NH2:13][CH2:12][CH:8]1[CH2:9][CH2:10][CH2:11][N:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])C=C1CCCN1Cc1ccc(F)cc1
Agent: [Ni]
Solvent: CO
Product: NCC1CCCN1Cc1ccc(F)cc1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A solution of 27 g (0.114 mol) of 1-p-fluorobenzyl-2-nitromethylene-pyrrolidine in 600 ml of methanol is hydrogenated at ambient temperature and atmospheric pressure in the presence of Raney nickel. When the theoretical amount of hydrogen has been absorbed, which requires about one hour, the catalyst is filtered off and the methanol is evaporated from the filtrate. The product which remains is distilled under reduced pressure. 17.2 g (yield: 72%) of 2-aminomethyl-1-p-fluorobenzyl-pyrrolidine are collected as a colourless liquid distilling at 80°-82° under a pressure of 0.01 mm of mercury; this product is used, without further purification, in the next stage of the synthesis.
Reaction SMILES: C(OC(CCC([O:10][C:11]1[C:12]([CH3:29])=[C:13]([CH3:28])[C:14]2[O:18][CH:17]([CH2:19][CH2:20][C:21](OCC)=[O:22])[S:16][C:15]=2[C:26]=1[CH3:27])=O)=O)C.C(OC1C(C)=C(C)C2OC(C)SC=2C=1C)(=O)C>>[OH:10][C:11]1[C:12]([CH3:29])=[C:13]([CH3:28])[C:14]2[O:18][CH:17]([CH2:19][CH2:20][CH2:21][OH:22])[S:16][C:15]=2[C:26]=1[CH3:27]
Reactant: CCOC(=O)CCC(=O)Oc1c(C)c(C)c2c(c1C)SC(CCC(=O)OCC)O2
Agent: CC(=O)Oc1c(C)c(C)c2c(c1C)SC(C)O2
Product: Cc1c(C)c2c(c(C)c1O)SC(CCCO)O2

Procedure:
Ethyl 3-[5-(3-ethoxycarbonylpropionyloxy)-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propionate (prepared as described in Example 32) was used in the same process as described in (1) above, to give the title compound, whose melting point, infrared absorption spectrum and mass spectrum were the same as those of the product described in (a) above.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClN1[C:42](=[O:43])CCC1=O>CO.C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:20])=[C:15]([CH3:18])[C@@H:16]([O:43][CH3:42])[S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: ClCCl
Product: CO[C@H]1S[C@@H]2[C@@H](NC(=O)Cc3ccccc3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
To a solution of diphenylmethyl 7α-phenylacetamido-3-methyl-3-cephem-4-carboxylate (2.88 g, 5.8 mmole) in 40 ml of methanol and 60 ml of methylene chloride, was added N-chlorosuccinimide (882 mg, 6.6 mmol) and the mixture was stirred for 90 minutes at room temperature. The reaction solution was then washed with brine (2X) and dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resultant yellow foam (2.84 g) was chromatographed over 100 grams of silica gel employing 10-15% of ethyl acetate in toluene as the eluting solvent. The first fraction to elute from the column was the desired 2α-methoxy cephem compound which was subsequently recrystallized from a mixture of ethyl acetate and cyclohexane to give pure diphenylmethyl 7α-phenylacetamido-2α-methoxy-3-methyl-3-cephem-4-carboxylate. (638 mg, 21% yield) (mp 144°-145° C.) i.r. (CHCl3) 1780, 1725 and 1680 cm-1 ; n.m.r. (CDCl3) δ1.95 (s, 3, CH3) 3.35 (s, 3, OCH3), 3.45 (s, 2, CH2Ph), 4.60 (s, 1, C2 --H), 4.70 (d, J=2 and 8 Hz, 1, C7 --H), 4.85 (d, J=2 Hz, 1, C6 --H), 6.95 (s, 1, CH2Ph), 7.3 (m, 16, aromatic H and N--H); u.v. (CHCl3) λmax 264 nm (ε=9726).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][Si](C)(C)C)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)#[CH:21]
Reactant: CN1CCN(C2CCN(c3ccc(C#C[Si](C)(C)C)cc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N2CCC(N3CCN(C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
A solution of 1-methyl-4-(1-{4-[(trimethylsilyl)ethynyl]phenyl}piperidin-4-yl)piperazine (2.55 g, 7.179 mmol) in anhydrous methanol (25 mL) was treated with powdered anhydrous potassium carbonate (99.2 mg, 0.718 mmol) under stirring at room temperature for 3 h. After removing the solvent under vacuum the residue was taken up with DCM (50 mL) and water (5 mL). The phases were separated, the organic phase was washed with a saturated solution of sodium hydrogencarbonate (3×10 mL), brine (3×10 mL), water (10 mL), dried over sodium sulfate and the solvent removed under vacuum. The yellowish solid obtained was purified by chromatography on silica gel (DCM/MeOH/TEA 90/10/0.2) to give the title compound as yellow solid (1.534 g, 76%).
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12]1)[CH2:10][C:9]2=[O:28].[OH-].[Na+]>>[CH2:17]([N:13]1[CH2:14][CH2:15][CH2:16][C:11]2([CH2:10][C:9](=[O:28])[C:8]3[C:25](=[CH:26][CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=3)[O:24]2)[CH2:12]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2
Yield: 86 %

Procedure:
(−)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (525 mg, 1.34 mmol) was hydrolyzed with 1 M NaOH following the experimental procedure described for Example 16 STEP B, to give (−)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid (435 mg).
Reaction SMILES: CC1C(C)=CC=CC=1OCCCC(N1C2C(=C(C3C=CC(COC(NCC(OC)=O)=O)=CC=3)C=CC=2)CCC1)=O.C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)OCC1C=CC(C2C=CC=C3C=2CCCN3C(=O)CCCOC2C=CC=C(C)C=2C)=CC=1.[C:85](=[O:105])(OC1C=CC([N+]([O-])=O)=CC=1)[O:86][CH2:87][C:88]1[CH:93]=[CH:92][C:91]([Br:94])=[CH:90][N:89]=1.Cl.NCC(OC)=O.Cl.[NH2:114][CH2:115][CH2:116][C:117]([O:119][CH3:120])=[O:118]>>[Br:94][C:91]1[CH:92]=[CH:93][C:88]([CH2:87][O:86][C:85]([NH:114][CH2:115][CH2:116][C:117]([O:119][CH3:120])=[O:118])=[O:105])=[N:89][CH:90]=1
Reactant: COC(=O)CCN
Reactant: O=C(OCc1ccc(Br)cn1)Oc1ccc([N+](=O)[O-])cc1
Agent: COC(=O)CN
Agent: COC(=O)CNC(=O)OCc1ccc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)cc1
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(COC(=O)Oc5ccc([N+](=O)[O-])cc5)cc4)cccc32)c1C
Product: COC(=O)CCNC(=O)OCc1ccc(Br)cn1

Procedure:
The title compound was prepared using a procedure analogous to methyl 2-((4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzyloxy)carbonylamino)acetate except that 4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzyl 4-nitrophenyl carbonate was replaced with (5-bromopyridin-2-yl)methyl 4-nitrophenyl carbonate and methyl 2-aminoacetate hydrochloride was replaced with methyl 3-aminopropanoate hydrochloride. LCMS, [M+H]+=317.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25]1[CH2:31][S:28](=[O:30])(=[O:29])[O:27][CH2:26]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:26][CH2:25][CH2:31][S:28]([OH:30])(=[O:29])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCCO1
Reactant: Oc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(O)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Temperature: 25 °C

Procedure:
The crude 1-[1-(4-chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (3.5 g, 11.22 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 471 mg, 11.79 mmol) in dimethylformamide (25 mL). After stirring for 30 min at room temperature 1,3-propanesultone (1.44 g, 11.79 mmol) was added dropwise. The reaction mixture was stirred over night at room temperature. The dimethylformamide was removed in vacuo. The crude product (8.4 g) was used for the next step without further purification.