Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:9][CH2:10][C@@H:11]([CH3:46])[C:12]([N:14]1[CH2:34][CH:33]([O:35][C:36]2[CH:41]=[CH:40][C:39]([CH:42]=[CH:43]OC)=[CH:38][CH:37]=2)[CH2:32][C@H:15]1[C:16]([O:18]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:47][C:48]1[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[C:51]([S:58]([NH2:61])(=[O:60])=[O:59])=[CH:50][C:49]=1[S:62]([NH2:65])(=[O:64])=[O:63].C1(OC)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(#N)C>[NH2:61][S:58]([C:51]1[C:52]([C:54]([F:56])([F:57])[F:55])=[CH:53][C:48]2[NH:47][CH:43]([CH2:42][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH:33]4[CH2:34][N:14]([C:12](=[O:13])[C@H:11]([CH3:46])[CH2:10][S:9][C:1](=[O:8])[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C@H:15]([C:16]([OH:18])=[O:17])[CH2:32]4)=[CH:41][CH:40]=3)[NH:65][S:62](=[O:63])(=[O:64])[C:49]=2[CH:50]=1)(=[O:59])=[O:60]
Reactant: Nc1cc(C(F)(F)F)c(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: COC=Cc1ccc(OC2C[C@@H](C(=O)OC(c3ccccc3)c3ccccc3)N(C(=O)[C@H](C)CSC(=O)c3ccccc3)C2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COc1ccccc1
Solvent: CC#N
Solvent: CO
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1CC(Oc2ccc(CC3Nc4cc(C(F)(F)F)c(S(N)(=O)=O)cc4S(=O)(=O)N3)cc2)C[C@H]1C(=O)O

Procedure:
To a mixture of (S)-1-[(S)-3-(benzoylthio)-2-methyl-1-oxopropyl]-4-[4-(2-methoxyethenyl)phenoxy]-L-proline, diphenylmethyl ester (3.6 g., 5.66 mmole), 4-amino-6-(trifluoromethyl)-1,3-benzenedisulfonamide (1.8 g., 5.7 mmole) and anisole (3.5 ml.) in 80 ml. of acetonitrile is added 120 mg. of p-toluenesulfonic acid. The reaction is essentially complete after refluxing for one hour. The solvent is removed under vacuum and the residue is triturated with diethyl ether to give a solid. The solid is purified by chromatography on an LPS-1 column eluted with ethyl acetate:pyridine:acetic acid:water (2400:50:15:27). After removal of the solvents on a rotary film evaporator using benzene to azeotrope off the acetic acid and pyridine, 3.8 g. of a homogeneous solid is obtained. Approximately half this material is passed through an LH-20 column (methanol) to give an analytically pure sample of (S)-4-[4-[[7-(aminosulfonyl)-3,4-dihydro-1,1-dioxo-6-(trifluoromethyl)-2H-1,2,4-benzothiadiazin-3-yl]methyl]phenoxy]-1-[(S)-3-(benzoylthio)-2-methyl-1-oxopropyl]-L-proline; m.p. 170°-182° (foams); [α]D =-24.6° (c=1.0%, methanol). TLC (silica, methylene chloride:methanol:acetic acid; 8:1:1) Rf =0.47.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[CH:11]=[C:10]3[N:19]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:20](=O)[CH2:21][O:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2].[CH3:29]COCC.CO>C1COCC1.[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[C:12]2[CH:11]=[C:10]3[N:19]([CH2:24][C:25]([F:26])([F:27])[F:28])[C:20](=[CH2:29])[CH2:21][O:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)OCC(=O)N3CC(F)(F)F
Reactant: CCOCC
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C1COc2cc3nc(OC(C)C)cc(C(F)(F)F)c3cc2N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one (EXAMPLE 22) (0.183 g, 0.448 mmol) in 4.8 mL THF was added Tebbe reagent (0.99 mL, 0.49 mmol) at 0° C. After 1 h, ether (22 mL) and MeOH (0.32 mL) were added sequentially and the mixture was allowed to warm to rt. The slurry was filtered through Celite and concentrated, and the resultant residues was filtered through a short plug of basic alumina (4:1 hexanes:EtOAc) to afford 0.20 g of (±)-2,3-dihydro-7-isopropoxy-2-methylene-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline. This residue was dissolved in 2.2 mL THF, and BH3THF solution (1M, 0.49 mL, 0.49 mmol) was added dropwise at 0° C. After 15 min, the mixture was allowed to warm to rt, whereupon 0.1 mL MeOH was added and the solution allowed to stir for 16 h. The solvent was removed in vacuo, and the residue was redissolved in 2.2 mL THF and 0.45 mL MeOH, whereupon 0.10 mL 6N NaOH and a 35% H2O2 solution (0.055 mL, 60.9 mg, 0.63 mmol) was added. A precipitate was formed which was filtered with 20 mL THF. The filtrate was concentrated, and the resultant solid was dissolved in 1 mL MeOH, acidified with 0.05 mL conc. HCl, and the solution concentrated in vacuo. The residue was treated with 0. 1 mL 6N NaOH, and partitioned between water (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. Flash chromatography (2:1 hexanes:EtOAc) afforded 91 mg (48%) of (±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a light amber oil. Data for (±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline: Rf 0.34 (2:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 7.17 (broad s, 1H), 7.01 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.50 (dd, 1H, J=11.1, 1.6), 4.12-4.25 (m, 1H), 3.96-4.09 (m, 1H), 3.78-3.90 (m, 2H), 3.61-3.67 (m, 1H), 1.71 (t, 1H, J=5.1), 1.38 (d,6H, J=6.2).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1nccc2ccccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1nccc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-methyl isoquinoline (Aldrich) in concentrated sulfuric acid at 0° C. was added potassium nitrate (1.1 mmol). Reaction mixture was warmed to room temperature and stirred at room temperature for 5 hours. Reaction mixture was basified. Solid precipitated was column purified.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][C@H:24]([CH2:26][OH:27])[CH3:25]>>[OH:27][CH2:26][C@@H:24]([NH:23][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4])[CH3:25]
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)OC)s1
Reactant: C[C@H](N)CO
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)N[C@@H](C)CO)s1
Yield: 71 %

Procedure:
As described for example 53, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (100 mg, 0.31 mmol) was converted, using L-alaninol instead of 2-amino-1,3-propandiol, to the title compound (80 mg, 71%) which was obtained as an off white oil. MS: m/e=366.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:13][NH:14][C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[Br:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][N:14]([CH2:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1
Reactant: c1ccc(-c2cc(NCc3cccc4ccccc34)on2)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: BrCCCCN(Cc1cccc2ccccc12)c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
Charged flask with a 60% sodium hydride in oil dispersion (64.0 mg, 1.6 mmol) and suspended in DMF (1 ml). A DMF (1 ml) solution of naphthalen-1-ylmethyl-(3-phenyl-isoxazol-5-yl)-amine (300 mg, 1.0 mmol) was added and the mixture stirred under argon at rt for 30 min resulting in a light yellow solution. After adding 1,4-dibromobutane (358 μl, 3.0 mmol), the reaction was stirred at rt for 1 hr, poured into 10% sodium bicarbonate (aq) and extracted with ethyl acetate (3×). The extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude oil (181 mg). Flash chromatography on silica gel (10% ethyl acetate in hexane) gave the product as a colorless oil (114 mg, 26.2%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][C:17]([N:19]([CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH:28]1([N:19]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:17](=[O:18])[CH2:16][NH:14][CH:9]2[CH:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COc1ccc(N(C(=O)CBr)C2CCCC2)cc1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CNC2C=CC=CC2Nc2ccccc2)C2CCCC2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
2.03 g (10.7 mmol) N-Phenyl-o-phenylene diamine, 3.50 g (11.2 mmol, 1.05 equiv) 2-Bromo-N-cyclopentyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, 1.62 g (11.7 mmol, 1.1 equiv) Potassium carbonate, and 177 mg (1.1 mmol, 0.1 equiv) Potassium Iodide were combined in 35 mL DMF and stirred 18 h at 60° C. The reaction mixture is filtered and the solvent removed in vacuo. The residue is taken into EtOAc (150 mL), washed with 1N HCl (2×50 mL), H2O (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by flash chromatography on 50 g silica gel eluted with EtOAc/Hexanes (3:17, 1 L). Appropriate fractions were combined and concentrated in vacuo to give 2.53 g (6.09 mmol) of N-Cyclopentyl-N-(4-methoxy-phenyl)-2-(6-phenylamino-cyclohexa-2,4-dienylamino)-acetamide as a yellow oil: 1H NMR (Acetone-d6, 300 MHz) δ7.26-6.50 (m, 13H), 6.22 (d, 1H, J=7.9), 5.29 (s, br, 1H), 4.82 (m, 1H), 3.87 (s, 3H), 3.41 (d, 2H, J=4.4), 1.83 (m, 2H), 1.48 (m, 4H), 1.33 (m, 2H); TLC Rf =0.14 (EtOAc/Hexanes, 3:17).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:18])[CH:15]=3)[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:9]2)=CC=1.C(O)(C(F)(F)F)=[O:29]>C(Cl)Cl>[CH2:19]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([Cl:18])=[CH:13][CH:12]=2)[CH2:17][NH:8][C:9]1=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CN2Cc3cc(Cl)ccc3N(Cc3ccccc3)C2)cc1
Solvent: ClCCl
Product: O=C1NCc2cc(Cl)ccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirring mixture of 3-(4-methoxybenzyl)-1-benzyl-6-chloro-3,4-dihydroquinazolin-2(1H-one (0.2 g, 0.68 mmol) in DCM (5.0 mL) was added TFA (4.0 mL). The mixture was stirred at RT for 5 h. The reaction was monitored by MS, and upon completion, the reaction was concentrated. The crude residue was purified using flash column chromatography (100% DCM to 2% MeOH in DCM) to obtain the desired product 1-benzyl-6-chloro-3,4-dihydroquinazolin-2(1H)-one as a white solid. MS m/e 273 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1.[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[N:25]=[C:26]=[O:27])([CH3:15])[CH3:14]>C(Cl)(Cl)Cl>[OH:12][CH2:11][CH2:10][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:26]([NH:25][C:17]2[C:16]([CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=[CH:19][C:18]=2[CH:22]([CH3:24])[CH3:23])=[O:27])[CH2:5][CH2:6]1
Reactant: NCCN1CCN(CCO)CC1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: ClC(Cl)Cl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCCN1CCN(CCO)CC1
Reaction time: 0.08 h
Yield: 54 %

Procedure:
Into a solution of 4-(aminoethyl)piperazine-1-ethanol in chloroform (20 ml) was dropped a solution of 2,6-diisopropylphenyl isocyanate (2.03 g, 10 mmol) in chloroform (20 ml) followed by stirring for 5 minutes. The reaction solution was concentrated in vacuo and the residue was purified by a silica gel column chromatography (100 g of silica gel; developing solvents, chloroform→chloroform:ammonia-saturated methanol =20:1) to provide 2.03 g (yield 54%) of N-[2-[4-(2-hydroxyethyl)piperazin-1-yl]ethyl]-N′-(2,6-di-isopropylphenyl)urea.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH2:18][CH2:17]1
Reactant: O=C1Cc2cc(O)ccc2N1
Reactant: COCCN1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCN1CCC(Oc2ccc3c(c2)CC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an oven dried, nitrogen flushed 100 ml round bottom flask was added 5-hydroxyoxindole (10 mmol), 1-(2-methoxyethyl)-piperidin-4-ol (11 mmol), triphenylphosphine (15 mmol), Anhydrous tetrahydrofuran (35 ml) and a stirrer bar. Diethyl azodicarboxylate (15 mmol) was added slowly to the mixture and stirred at room temperature overnight. The reaction was concentrated in vacuo and flash chromatography (silica, 5% methanol in ethyl acetate). Upon concentration a reddish oil (470 mg) was obtained with a 75% purity by H-NMR and LC/MS.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7](=O)[CH3:8].C(O)C.Cl.[NH2:17][OH:18]>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7](=[N:17][OH:18])[CH3:8]
Reactant: CC(=O)COc1cccc(C)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(COc1cccc(C)c1)=NO

Procedure:
1-(3-Methylphenoxy)propan-2-one (24.9 g.) and ethanol (100 ml.) were added to a solution of hydroxylamine hydrochloride (25 g.) and fused sodium acetate (25 g.) in water (110 ml.). The resulting solution was refluxed for 31/2 hours and evaporated to near dryness under reduced pressure. The residue was partitioned between water and ether. The ether extract was washed with water, dried over anhydrous potassium carbonate and evaporated. The residue was distilled to give a fraction, b.p. 159°-163°/12 mm. Redistillation gave 1-(3-methylphenoxy)propan-2-one oxime, b.p. 165°-167°/13 mm.
Reaction SMILES: P(=O)(O)(O)O.[CH:6]([NH:8][CH:9]([C@@H:11]([C@H:13]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])[OH:12])O)=[O:7]>O>[CH:6]([NH:8][CH2:9][C@H:11]([OH:12])[C@@H:13]([OH:14])[C@H:15]([OH:16])[C:17](=[O:18])[CH2:19][OH:20])=[O:7]
Reactant: O=CNC(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P(O)(O)O
Solvent: O
Product: O=CNC[C@H](O)[C@@H](O)[C@H](O)C(=O)CO
Reaction time: 22 h

Procedure:
To a suspension of 40 g of Gluconobacter oxidans spp. suboxidans (DSM 50049) in 1 l of tap water, brought to pH 4.5 with phosphoric acid, are added at 32° C. and 700 rpm with venting of 3 l of air/hour 200 g of N-formylaminosorbitol, followed 4 hours later by a further 200 g of N-formylaminosorbitol. After 22 hours the reaction has ended, the cells are centrifuged off and discarded. The product is isolated as an oil by concentrating in vacuo.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[Cl:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]2[C:15]=1[CH:16]=[C:17]([C:25]1[C:26]([NH2:40])=[N:27][CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=1)[N:18]=[CH:19]2.C(=O)([O-])[O-].[K+].[K+].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.C1COCC1.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.COCCOC.O>[Cl:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]2[C:15]=1[CH:16]=[C:17]([C:25]1[C:26]([NH2:40])=[N:27][CH:28]=[C:29]([C:2]3[S:6][C:5]([N:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)=[N:4][CH:3]=3)[CH:30]=1)[N:18]=[CH:19]2
Reactant: Brc1cnc(N2CCOCC2)s1
Reactant: CC1(C)OB(c2cnc(N)c(-c3cc4c(Cl)ccc(F)c4cn3)c2)OC1(C)C
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: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ncc(-c2cnc(N3CCOCC3)s2)cc1-c1cc2c(Cl)ccc(F)c2cn1
Temperature: 100 °C

Procedure:
A solution of 4-(5-bromo-thiazol-2-yl)-morpholine (52.4 mg, 0.210 mmol), 3-(5-chloro-8-fluoroisoquinolin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB5) (70 mg, 0.18 mmol), potassium carbonate (77.5 mg, 0.560 mmol), and Pd(PPh3)4 (0.01 g, 0.01 mmol) in previously degassed DME/water (4:1) (1.95 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 45 min. The reaction mixture was partitioned between CHCl3 and H2O, and the layers were separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 1.5% MeOH in CHCl3] resulting in a yellow solid slightly contaminated with triphenylphosphine oxide. Therefore, this material was dissolved in MeOH/THF and passed through a prewashed 5 g SCX column. The column was washed with 2 volumes of MeOH and 2 volumes of THF then was washed with 1M NH4OH in MeOH upon which the product was released from the resin. The filtrate was concentrated in vacuo, and the resulting material was chromatographed on silica gel [eluting with 0.5% MeOH in CHCl3] resulting in the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=3.37-3.49 (m, 4H), 3.68-3.81 (m, 4H), 7.05 (s, 2H), 7.51-7.62 (m, 2H), 8.03 (dd, J=8.4, 4.8 Hz, 1H), 8.07 (d, J=2.2 Hz, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.36 (s, 1H), 9.64 (s, 1H). MS (ES+): m/z=442.06/444.03 (76/24) [MH+]. HPLC: tR=3.06 min (ZQ2, polar—5 min).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:19]S(C)=O>>[CH3:19][N:16]1[CH:14]2[CH2:13][CH2:12][CH:11]1[CH:10]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][CH:7]=1)[CH2:15]2
Reactant: FC(F)(F)c1ccc(C2=CC3CCC(C2)N3)cc1
Reactant: CS(C)=O
Product: CN1C2C=C(c3ccc(C(F)(F)F)cc3)CC1CC2
Temperature: 130 °C

Procedure:
(±)-3-(4-trifluoromethylphenyl)-8-azabicyclo[3.2.1]oct-2-ene in the form of a free amine (1 mg) was dissolved in anhydrous dimethyl sulphoxide (DMSO; 300 ml), and then reacted with [11C]-methyl iodide and heated for 5 min at 130° C. The resulting N-[11C]-methyl labelled [11C]-compound was subsequently purified by HPLC. Removal of the HPLC solvent was achieved by heating the [11C]-labelled (±)8-methyl-3-(4-trifluoromethylphenyl)-8-azabicyclo[3.2.1]oct-2-ene containing fraction under reduced pressure. The labelled product was then formulated in saline or water (10 ml) and passed over a 0.22 mm membrane filter into a sterile vial.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[C:18]([CH2:25][CH3:26])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]2[N:35]=[C:36]([CH:38]=O)[N:37]=[C:30]2[N:29]=1>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[C:18]([CH2:25][CH3:26])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:38][C:36]3[N:37]=[C:30]4[N:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]4[N:35]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1CC#N
Solvent: CO
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1CC#N
Reaction time: 0.08 h
Yield: 20.5 %

Procedure:
To a solution of {4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-ethylphenyl}acetonitrile (200 mg, 0.57 mmol, example A(102)) in anhydrous MeOH (6 mL) at room temperature was added 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (120 mg, 0.68 mmol). The mixture was stirred for 5 min before borane-dimethylamine complex (37 mg, 0.62 mmol) was added. The reaction was stirred at that temperature for 15 hours before it was quenched by the addition of 1.0 N HCl. The solvent was removed and the residue was purified by HPLC to obtain the desired product (60 mg, 21% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.03 (t, J=7.5 Hz, 3 H), 1.32-1.64 (m, 8 H), 2.06 (m, 2 H), 2.36-2.55 (m, 12 H), 2.73 (d, J=17.9 Hz, 1 H), 3.64 (d, J=16.1 Hz, 1 H), 3.77 (d, J=16.4 Hz, 1 H), 3.89 (s, 2 H), 6.95 (s, 1 H), 7.00 (s, 1 H), 7.04 (d, J=7.7 Hz, 1 H), 7.17 (d, J=7.7 Hz, 1 H), 10.81 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:31]([CH3:33])[CH3:32])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:34][CH3:35])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:31]([CH3:32])[CH3:33])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:34][CH3:35])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(c(N(C)C)n2)CCC3c2ccc(F)c(F)c2)ccc1-n1cnc(Cl)c1
Agent: O=C=O
Solvent: CO
Product: COc1cc(Nc2nc3c(c(N(C)C)n2)CC[C@@H]3c2ccc(F)c(F)c2)ccc1-n1cnc(Cl)c1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N4,N4-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (139 mg, 0.28 mmol from Example 95) was purified using chiral SFC to afford 47.6 mg of peak A (Example 95A) and 47.3 mg of peak B (Example 95B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 35% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 8 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=4.6 min, tR (peak B) 6.3 min. The absolute stereochemistry of individual enantiomers (Examples 95A and 95B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 95).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][N:7]=[C:8]([C:35]1([O:40][CH2:39][CH2:38][O:37]1)[CH3:36])[C:9]([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[C:15]([C:30]([OH:32])=[O:31])=[C:16]([CH2:19]SC3SC4C=CC=CC=4N=3)[CH2:17][S:18][C@H:13]12)=[O:10].CON=C(C1(OCCO1)C)C(NC1C(=O)N2C(C(O)=O)=C(C)CS[C@H]12)=O>O1CCCC1.O.[Zn]>[CH3:5][O:6][N:7]=[C:8]([C:35]1([O:40][CH2:39][CH2:38][O:37]1)[CH3:36])[C:9]([NH:11][CH:12]1[C:33](=[O:34])[N:14]2[CH:15]([C:30]([OH:32])=[O:31])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12)=[O:10]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nc4ccccc4s3)CS[C@H]12)C1(C)OCCO1
Agent: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)CS[C@H]12)C1(C)OCCO1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C=C1CS[C@@H]2C(NC(=O)C(=NOC)C3(C)OCCO3)C(=O)N2C1C(=O)O
Reaction time: 2 h
Yield: 34.3 %

Procedure:
Acetic acid (1 ml.) was added to a solution of 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-(benzothiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 500 mg.) in tetrahydrofuran (6 ml.) and water (2 ml.). Zinc powder (500 mg.) and copper sulfate 5-hydrate (50 mg.) were added to the solution at room temperature, and stirred at the same temperature for 2 hours. The resultant mixture was treated in a similar manner to that of Example 10-(3) Method A to give a mixture (120 mg.) of 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-methylenecepham-4-carboxylic acid (syn isomer) and 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-methyl-3-cephem-4-carboxylic acid (syn isomer) (5:1).