Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC#N>[CH2:11]([NH:18][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: NCc1ccccc1
Solvent: CC#N
Product: O=C(O)c1cnccc1NCc1ccccc1
Temperature: 80 °C

Procedure:
A mixture of 4-chloronicotinic acid (300 mg, 1.90 mmol) and benzylamine (408 mg, 3.81 mmol) in MeCN (3 mL) was stirred and heated in the microwave (80° C., 200 W) for 1 h. The solution obtained was partitioned between water and EtOAc. The precipitate formed was filtered off, washed with water, EtOAc and dried in vacuo. 4-(benzylamino)nicotinic acid was obtained as a colourless solid (147 mg, 34%). ESI-MS [M+H]+=229.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[CH3:21][O:20][C:19]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[CH2:3][CH2:2][O:1][C:31]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=1)=[O:32]
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]#[N:29].N1CCOCC1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:27][C:28]#[N:29])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: N#CCCl
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCn1c(=O)n(CC#N)c(=O)c2[nH]c(Cl)nc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 26.1 %

Procedure:
To a mixture of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.707 mmol) and Cs2CO3 (254 mg, 0.778 mmol) in anhydrous DMF (5 ml) was added chloroacetonitrile (0.054 ml, 0.85 mmol). The mixture was heated at 50° C. for 18 hours then allowed to cool to rt and degassed under a gentle vacuum then nitrogen introduced. This was repeated twice. Pd(PPh3)4 (82 mg, 0.071 mmol) was added and the mixture degassed once more, before morpholine (0.617 ml, 7.07 mmol) was added and the mixture left to stir for 3 hours at rt. The mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down an amino-propyl SPE (5 g), eluting with MeOH followed by 5-10% AcOH/MeOH. The product fraction was concentrated giving the title compound 52 mg (26%); NMR; δH (400 MHz, d6-DMSO) 0.90 (t, 3H, J=7.5 Hz), 1.26-1.37 (m, 2H), 1.60-1.69 (m, 2H), 3.94 (t, 2H, J=7.5 Hz), 4.87 (s, 2H), 14.72 (br s, 1H); m/z 299.2 [MNH4+].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][N+:19]([O-:22])=[CH:18][CH:17]=1>CN(C=O)C.C(Cl)Cl>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:16]2[CH:21]=[CH:20][N+:19]([O-:22])=[CH:18][CH:17]=2)=[CH:5][CH:4]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [O-][n+]1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
4-Trifluoromethylbenzylalcohol (4.2 g, 23 mmol) was dissolved in DMF (20 mL) and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol) was added. After stirring for 30 minutes, 4-chloropyridine-N-oxide (1.5 g, 11.5 mmol) was added and the reaction mixture was heated for 1 h at 120° C. Upon cooling the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried and concentrated. Purification by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) provided the title compound (0.6 g, 19%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J=7.8 Hz, 2H), 7.68 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.86 (d, J=7.8 Hz, 2H), 5.15 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[C:14]=[O:15].[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH2:19]>C(#N)C>[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH:19][C:14]([NH:13][C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:15]
Reactant: Nc1c(F)cccc1Br
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Solvent: CC#N
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1c(F)cccc1Br
Temperature: 85 °C
Yield: 99 %

Procedure:
2-Methoxy-5-trifluoromethylphenyl isocyanate (274.3 g) is dissolved in acetonitrile (1 l), then 2-bromo-6-fluoroaniline (200 g) is added and rinsed out with acetonitrile (50 ml). The resulting clear solution is stirred under reflux (ca. 85° C.) for 38 h, then concentrated in vacuo at 40° C. to a viscous magma. This is filtered off with suction, washed with acetonitrile (260 ml, cooled to 0-5° C.) and dried overnight at 45° C. in the VDO using entraining nitrogen. A total of 424.3 g of N-(2-bromo-6-fluorophenyl)-N′-[2-methoxy-5-(trifluoromethyl)phenyl]urea are obtained as a solid, corresponding to 99.2% of theory.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNc1ccc(Cl)cn1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCCNc2ccc(Cl)cn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-[(2-aminoethyl)amino]-5-chloropyridine hydrochloride and DBU in DME. ES-MS m/e (%): 356 (M+H+, 100).
Reaction SMILES: BrC1C(CC2(O)C3C(=CC=C(C)C=3)N(CCC(C)C)C2=O)=NC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:31](=[O:44])[C:30]2=[O:45].[CH3:46][O:47][C:48]1[C:49]([CH3:54])=[N:50][CH:51]=[CH:52][CH:53]=1>>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:31](=[O:44])[C:30]2([OH:45])[CH2:54][C:49]1[C:48]([O:47][CH3:46])=[CH:53][CH:52]=[CH:51][N:50]=1
Reactant: COc1cccnc1C
Reactant: O=C1C(=O)N(CCc2ccccc2)c2ccc(Cl)cc21
Agent: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Product: COc1cccnc1CC1(O)C(=O)N(CCc2ccccc2)c2ccc(Cl)cc21

Procedure:
This compound was prepared in an analogous manner to 3-((3-bromopyridin-2-yl)methyl)-3-hydroxy-1-isopentyl-5-methylindolin-2-one using 5-chloro-1-phenethylindoline-2,3-dione and 3-methoxy-2-methylpyridine. 1H-NMR δ 8.21 (dd, 1H), 7.33-7.17 (m, 8H), 6.95 (d, 1H), 6.62 (d, 1H), 5.5 (bs, OH), 3.98 (m, 1H), 3.86 (m, 1H), 3.78 (s, 3H), 3.37 (d, 1H), 3.09 (d, 1H), 2.96 (t, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:12]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)#[N:36].CO>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C@H:12]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[CH3:13])[CH:3]=2)=[CH:39][CH:38]=1)#[N:36]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@@H](OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(-c2ccc(C#N)cc2)cc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
(R)-tert-Butyl 4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (0.35 g, 0.65 mmol), 4-cyanophenylboronic acid (284 mg, 1.93 mmol), and tetrakis(triphenylphosphine) palladium(0) (75 mg, 0.07 mmol) were combined in dry tetrahydrofuran (5 mL) in a microwave tube and sealed. After flushing with nitrogen, 2.3 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography on silica gel (15% ethyl acetate/hexanes) to afford 300 mg (82%) as an oil. LC/MS: tR=3.51 min, 565.23 (MH)+. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]2)=[N:6][CH:7]=1.Cl.[F:19][C@@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([N:22]3[CH2:23][CH2:24][C@@H:20]([F:19])[CH2:21]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2ccc(Br)cn2)C1
Reactant: F[C@@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: F[C@@H]1CCN([C@H]2CCN(c3ccc(Br)cn3)C2)C1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
Dissolve methanesulfonic acid (R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl ester (0.23 g, 0.71 mmol) and (R)-3-fluoro-pyrrolidine hydrochloride (107 mg, 0.85 mmol) in DMF (5 mL) and add Cs2CO3 (0.69 g, 2.13 mmol). Warm to 70° C. overnight. Dilute with EtOAc (100 mL) and wash with H2O (3×100 mL). Dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 75-100% EtOAc/hexane to give 0.22g (100%) of the title compound. 1H-NMR (CDCl3), δ 1.87-2.00 (m, 1H), 2.00-2.09 (m, 1H), 2.18-2.30 (m, 2H), 3.40-3.80 (m, 9H), 5.10-5.28 (m, 1H), 5.34-5.40 (m, 1H), 6.28 (d, J=9.0 Hz, 1H), 7.51 (dd, J=9.0, 2.4 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH:8]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][C:28](=[C:31]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH2:35][CH2:34][N:33]3[CH:42]=[CH:43][N:44]=[C:32]23)[CH2:27][CH2:26]1.S1C=CC=C1>CO.[Pd]>[N:44]1[CH:43]=[CH:42][N:33]2[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:31](=[C:28]3[CH2:27][CH2:26][N:25]([C@H:10]4[CH2:11][CH2:12][N:7]([C:5](=[O:6])[C:4]5[CH:3]=[C:2]([CH3:1])[CH:23]=[C:22]([CH3:24])[CH:21]=5)[C@@H:8]([CH2:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:9]4)[CH2:30][CH2:29]3)[C:32]=12
Reactant: c1ccc2c(c1)CCn1ccnc1C2=C1CCNCC1
Reactant: Cc1cc(C)cc(C(=O)N2CCC(=O)CC2Cc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: Cc1cc(C)cc(C(=O)N2CC[C@H](N3CCC(=C4c5ccccc5CCn5ccnc54)CC3)C[C@@H]2Cc2ccccc2)c1
Yield: 12.2 %

Procedure:
A mixture of (±)-1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinone (2.5 g) and 6,11-dihydro-11-(4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine (2.1 g) in methanol (150 ml) and a solution of thiophene (4%; 1 ml) was hydrogenated at 50° C. overnight with palladium on activated carbon (10%; 2 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/ (CH3OH/ NH3) 98/2 to 95/5). The desired fraction was collected, the solvent evaporated, yielding 0.54 g (12.3%) of (±)-cis-4-[4-(5,6-dihydro-11H-imidazo [2,1-b][3]benzazepin-11-ylidene)-1-piperidinyl]-1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)piperidine (comp. 1; mp. 138.7° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]>ClCCl.CO>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH3:24])[CH3:25])=[CH:18][CH:17]=2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 122.7 %

Procedure:
Following general procedure F, 1-(6-bromo-4-(4-((dimethylamino)methyl)phenylamino)quinolin-3-yl)ethanone (2.0 g, 5.09 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.2 g, 7.6 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (1:1, 40 mL) and HBr gas was bubbled through the suspension until a solution formed. The solution was concentrated to dryness and the resultant solid was triturated with diethyl ether. The mixture was filtered, washed with diethyl ether, and dried to obtain desired product (3.0 g, 94% over two steps) as a yellow solid: 1H NMR (300 MHz, DMSO) δ 11.93 (s, 1H), 10.59 (s, 1H), 9.81 (s, 1H), 9.24 (s, 1H), 8.37 (m, 2H), 8.11 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.5 Hz, 2H), 7.56 (s, 2H), 7.51 (d, J=8.5 Hz, 2H), 4.39 (d, J=4.0 Hz, 2H), 2.74 (d, J=4.0 Hz, 6H), 2.54 (s, 3H). APCI MS m/z 480 [C26H23Cl2N3O2+H]+; HPLC>99% (AUC), tR=4.79 min.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:21])=[C:16]([CH2:18][CH2:19]O)[N:17]=2)=[CH:9][CH:8]=1.C([N:24]([CH2:27][CH3:28])[CH2:25]C)C.BrC1C=CC(C2OC(C)=C(CCOS(C)(=O)=O)N=2)=CC=1.N1CCC1>ClCCl.O1CCCC1>[N:24]1([CH2:19][CH2:18][C:16]2[N:17]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=3)[O:14][C:15]=2[CH3:21])[CH2:25][CH2:28][CH2:27]1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCO
Reactant: CCN(CC)CC
Agent: C1CNC1
Agent: CS(=O)(=O)Cl
Agent: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Add methanesulfonyl chloride (0.745 g, 6.50 mmol) to a cool (0° C.) solution of 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol (1.4 g, 5.0 mmol) and triethylamine (1.26 g, 12.5 mmol) in dichloromethane (20 mL). Warm to room temperature and stir for 1 hour. Remove solvents, transfer crude of methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester residue to a sealed tube, add tetrahydrofuran (30 mL), azetidine (2.0 g, 35.5 mmol), and heat at 60° C. overnight. Wash the crude organic material with 1N HCl. Separate layers and add 5N NaOH to the aqueous layer until it is basic. Extract the aqueous layer with diethyl ether (2×50 mL), dry the organic extracts over Na2SO4, filter, and concentrate. Purify on silica gel eluting with 10% ammoniated methanol in dichloromethane to give 4-(2-azetidin-1-yl-ethyl)-2-(4-bromo-phenyl)-5-methyl-oxazole (1.22 g, 72%): mass spectrum (m/e): 323 (M+1).
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[NH:24][C:25]([NH:27][S:28]([N:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])(=[O:30])=[O:29])=[O:26])[CH3:14].CI>C(#N)C>[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25](=[O:26])[N:27]([S:28]([N:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])(=[O:30])=[O:29])[CH3:2])[CH3:14]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCN(CCCC)S(=O)(=O)NC(=O)Nc1c(C(C)C)cccc1C(C)C
Solvent: CC#N
Solvent: CI
Product: CCCCN(CCCC)S(=O)(=O)N(C)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.6 mL, 10.7 mmol) was added dropwise to a solution of N-[2,6-bis(1-methylethyl)phenyl]-N'-[(dibutylamino)sulfonyl]urea (4.0 g, 9.7 mmol) and methyl iodide (1.52 g, 10.7 mmol) in 100 mL acetonitrile at -15° C. The resulting mixture was warmed to room temperature and stirred for 16 hours. Concentrated in vacuo and partitioned between 1N HCl and ethyl acetate. The organic layer was dried with MgSO4, filtered, and concentrated to give an orange oil. Chromatography gave the title compound as a clear oil; 1H NMR (DMSO-d6) θ 8.57 (s, 1H), 7.31-7.15 (m, 3H), 3.33-3.21 (m, 7H), 3.05 (heptet, 2H), 1.57-1.46 (m, 4H), 1.35-1.20 (m, 4H), 1.13 (d, 12H), 0.90 (t, 6H). ##STR14##
Reaction SMILES: O[C:2]1([CH2:11]Cl)[CH2:6][S:5][C:4]([CH2:7][N:8]([CH3:10])[CH3:9])=[N:3]1.C[OH:14].[OH-].[K+]>O>[CH3:9][N:8]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH2:11][OH:14])[N:3]=1)[CH3:10]
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN(C)Cc1nc(CO)cs1
Temperature: 25 °C

Procedure:
To a 100 ml, three-necked, flask equipped with an agitator and a condensor were added 3.0 g (0.014 mol) of 4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline (prepared as in Example 1), 45 ml of methanol and 4 ml of water. Potassium hydroxide [1.8 ml of a 45% (weight percent) aqueous solution] was added dropwise to the reaction solution at a rate such that the reaction temperature was maintained at room temperature. Once potassium hydroxide addition was completed, the reaction mixture was stirred at room temperature for an additional hour. A 1 ml sample of the reaction mixture was then removed from the flask, placed into a 50 ml volumetric flask and then diluted to volume with a 4:1 (v:v) acetonitrile/water solution. One milliliter of the diluted sample solution was then placed in a 25 ml volumetric flask and further diluted to volume with a 4:1 (v:v) acetonitrile/water solution. Ten microliters of this solution were then assayed using the HPLC assay technique described in Example 3. Such HPLC assay indicated that 85.5% of the thiazoline substrate had converted to the desired titled product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][NH:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([NH:28][C@@H:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30]O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.CO>[NH2:28][C@@H:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][O:20][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[C:13]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:12][N:11]=1
Reactant: Cc1cccc(-c2cc(=O)[nH]cc2-c2ccncc2)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(-c2cc(OC[C@@H](N)Cc3ccccc3)ncc2-c2ccncc2)c1

Procedure:
To a stirred mixture of 4-(3-methylphenyl)-5-(4-pyridyl)-1H-pyrid-2-one (12 mg, 0.05 mmole), (S)-2-tert-butoxycarbonylamino-3-phenylpropanol (15 mg, 0.06 mmole), triphenylphosphine (18 mg, 0.07 mmole), in methylene chloride (1 mL) at room temperature was added diethyl azodicarboxylate (12 mg, 0.07 mmol). When the reaction was complete (monitored by TLC), methanol was added (1 mL) and the reaction was concentrated and treated with 1 mL of 1:1 TFA/methanol for 30 minutes. The mixture was concentrated, neutralized with 1 drop conc NH4OH, and purified (SiO2, 10% methanol/methylene chloride) to give the title compound: MS (m/z): Calcd. C26H25N3O (M+): 395, found (M+H)+: 396.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:17][NH2:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:18][CH3:17])=[O:10])[CH2:6]1
Reactant: CN
Reactant: Cc1cccc(Cl)c1OC1CN(C(=O)Cl)C1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2c(C)cccc2Cl)C1
Reaction time: 72 h
Yield: 146.6 %

Procedure:
A stirred solution of 3.9 g (0.015 mole) of 3-(2-chloro-6-methylphenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated all at once with 3.5 mL (0.045 mole) of 40% aqueous monomethylamine. After stirring for 72 h the reaction mixture was diluted with 200 mL of water and the precipitated solid collected by filtration to give 5.6 g of wet white product. The crude product was recrystallized (after drying) from benzene/ligroin, yielding 2.9 g (75.9%) of white crystalline product, mp 119°-121° C.
Reaction SMILES: [O:1]([C:8](Cl)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][CH2:12][C:13]1([CH3:17])[CH2:16][O:15][CH2:14]1.CN1CCOCC1>C(Cl)Cl>[C:2]1([O:1][C:8]([O:11][CH2:12][C:13]2([CH3:17])[CH2:16][O:15][CH2:14]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(CO)COC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC1(COC(=O)Oc2ccccc2)COC1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A 0.552 mL (4.42 mmol) sample of phenoxycarbonylchloride in 2 mL of methylene chloride was added to a solution of 376 mg (3.68 mmol) of 3-hydroxymethyl-3-methyloxetane and 60.7 mL (5.52 mmol) of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The mixture was stirred at 0° C. for 3.5 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.582 g of the title compound, which was taken directly to the next step.
Reaction SMILES: [N+](C1C=CC(COC([NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]3[CH2:24][C@H:23]([S:25][C:26]4[C@H:27]([CH3:50])[C@@H:28]5[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]5[C:30]=4[C:31]([O:33]CC4C=CC([N+]([O-])=O)=CC=4)=[O:32])[CH2:22][N:21]3[CH3:51])=[O:19])[CH2:14]2)=O)=CC=1)([O-])=O.[ClH:54]>O1CCCC1.O>[ClH:54].[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]2[CH2:24][C@H:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([OH:33])=[O:32])[CH2:22][N:21]2[CH3:51])=[O:19])[CH2:14]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](N)C4)N(C)C3)[C@H](C)[C@H]12

Procedure:
1.0 g of 4-nitrobenzyl (1R, 5S ,6S)-2-{(2S, 4S)-2-[(3S)-3-(4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-ylcarbonyl]-1-methylpyrrolidin-4ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] was dissolved in 30 ml of a 2:1 by volume mixture of tetrahydrofuran and water, after which 1.04 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 1.5 g of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 18(b), to give 175 mg of the title compound as a powder.