Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH2:2][CH3:3].C(N(CC)CC)C.[N+:18]([C:21]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[Cl:44])=[CH:29][C:22]=1[O:23][CH:24]([CH3:28])[C:25](Cl)=[O:26])([O-:20])=[O:19]>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[C:25](=[O:26])[CH:24]([O:23][C:22]1[CH:29]=[C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[Cl:44])[CH:31]=[CH:32][C:21]=1[N+:18]([O-:20])=[O:19])[CH3:28])[CH2:2][CH3:3]
Reactant: CCCNCC1OCCO1
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCN(CC1OCCO1)C(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
N-n-Propyl-N-(1,3-dioxolan-2-ylmethyl)amine (1.33 grams; 0.0092 mole), dry toluene (60 ml) and triethylamine (3.0 ml) were charged into a glass reaction vessel equipped with a magnetic stirrer, thermometer and addition funnel. The reaction mixture was blanketed under nitrogen gas and a solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride (3.9 grams; 0.0092 mole) in toluene (40 ml) was added dropwise with stirring. A slight exotherm was observed. After the addition was completed stirring was continued at room temperature for a period of about 1.5 hours. After this time the reaction mixture was transferred to a separatory funnel and was washed with water and dilute aqueous sodium bicarbonate. The washed solution was then dried and stripped of solvent leaving a viscous oil as the residue. This residue was then chromatographed through clay using ethyl acetate-hexane mixtures with increasing concentrations of ethyl acetate as the eluant. A total of nine fractions were collected. Fractions 5 and 6 were combined and stripped of solvents to yield the desired product N-propyl-N-(1,3-dioxolan-2-ylmethyl)-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionamide as an amber gum.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[C:3]1=O.[N:20]#[C:21][NH2:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)(=O)C.C(N(CC)CC)C>[F:16][C:15]([F:18])([F:17])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH:4]1[CH2:5][CH2:6][CH2:7][N:2]2[N:1]=[C:21]([NH2:22])[N:20]=[C:3]12
Reactant: N#CN
Reactant: NN1CCCC(Cc2ccccc2C(F)(F)F)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc2n(n1)CCCC2Cc1ccccc1C(F)(F)F
Temperature: 80 °C
Yield: 24.5 %

Procedure:
1-Amino-3-(2-trifluoromethylbenzyl)piperidin-2-one (916 mg) and cyanamide (849 mg) were dissolved in ethanol (15 mL). p-Toluenesulfonic acid monohydrate (961 mg) was added and the mixture was heated under reflux at 80° C. for 3.5 hours. After cooling to room temperature, triethylamine (2.3 mL) was added and the mixture was further heated under reflux at 80° C. for four days. A sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the organic layer was concentrated under reduced pressure. The resulting solid was washed with ethyl acetate to obtain the title compound (244 mg). The property values of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O.C(OCC)(=O)C.O>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-Bromophenol (2 g, 0.0116 mol) in acetone (40 ml) was treated with potassium carbonate (1.91 g, 1.2 equivalents) and benzyl bromide (1.44 ml, 1.05 equivalents). The reaction was refluxed under nitrogen. After 5-6 hours of reflux, the reaction was cooled to room temperature and diluted with an equal volume of ethyl acetate. This was diluted further with water and the organic layer was separated, dried over magnesium sulfate and evaporated to dryness to afford a white fluffy powder. Yield=2.36 g (73%).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[C:10]([CH:11]([N:15]([CH3:26])[C:16](=[O:25])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:12]([CH3:14])[CH3:13])=[CH:9][N:8]=[CH:7][N:6]=1)C.Cl>CC(C)=O>[CH:4]([C:5]1[C:10]([CH:11]([N:15]([CH3:26])[C:16](=[O:25])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:12]([CH3:13])[CH3:14])=[CH:9][N:8]=[CH:7][N:6]=1)=[O:3]
Reactant: CCOC(OCC)c1ncncc1C(C(C)C)N(C)C(=O)Cc1ccc(F)cc1
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)C(c1cncnc1C=O)N(C)C(=O)Cc1ccc(F)cc1
Yield: 766.3 %

Procedure:
8.4 g (2.1 mmol) of N-[1-(4-diethoxymethylpyrimidin-5-yl)-2-methylpropyl]-N-methy4-fluorophenylacetamide was dissolved in 100 ml of acetone, and 13 ml of 6N hydrochloric acid was added and reacted at room temperature for 5 hours. After completion of the reaction, the reaction solution was concentrated, and an aqueous sodium hydrogencarbonate solution was added to alkaline, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous citric acid solution, water and an aqueous sodium chloride solution, in this order, dried and concentrated, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5 to ethyl acetate) to obtain 5.3 g (yield: 77%) of N-[1-(4-formylpyrimidin-5-yl)-2-methylpropyl]-N-methyl-4-fluorophenylacetamide as colorless viscous liquid (nD20=1.5466).
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C.Cl>O1CCCC1>[N:18]1([CH2:2][C:3]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)=[O:4])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Reactant: C1CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CN2CCCC2)CC1
Temperature: 25 °C

Procedure:
Tert-butyl 4-(2-bromoacetyl)piperidinecarboxylate (0.85 g, 2.8 mmol) was dissolved in tetrahydrofuran (8.5 mL), and the solution was mixed with pyrrolidine (0.46 mL, 5.6 mmol) and triethylamine (0.78 mL, 5.6 mmol) with stirring at room temperature, followed by stirring for twenty-four hours. The reaction mixture was mixed with diluted hydrochloric acid (0.5 mol/L, 27 mL) and washed with ethyl acetate. The aqueous layer was adjusted to be basic with an aqueous potassium hydroxide solution added under ice-cooling and was extracted with ethyl acetate. The organic layer was washed with brine, was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was dried under reduced pressure and thereby yielded tert-butyl 4-(2-pyrrolidin-1-ylacetyl)piperidinecarboxylate (0.72 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9]O)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:18]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][Cl:18])[CH:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(CO)ccnc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(CCl)ccnc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(2-Chloro-3-methyl-pyridin-4-yl)-methanol (12-4, impure, 0.200 g) was dissolved in 5 mL anhydrous DCM under N2. Anhydrous DMF (0.098 mL, 1.3 mmol) and POCl3 (0.118 mL, 1.27 mmol) were added and the reaction was stirred at RT for 17 h. The reaction was quenched with sat NaHCO3 (aq) and extracted 3× with DCM. The organic phases were dried over Na2SO4, filtered and concentrated to provide 2-chloro-4-chloromethyl-3-methyl-pyridine still contaminated with a major by-product. 2-Chloro-4-chloromethyl-3-methyl-pyridine (impure, 0.215 g) was stirred in 3 mL DMSO. 1-Acetylpiperazine (0.626 g, 4.88 mmol was added and the reaction was stirred at RT overnight. The solution was purified by directly loading onto a preparative reverse phase column to afford an oil which slowly crystallizes. TFA salt: 1H NMR (CD3OD) δ 8.30 (d, 1H, J=5.0 Hz), 7.53 (d, 1H, J=5.0 Hz), 4.48 (s, 2H), 3.84 (bs, 4H), 3.39-3.30 (m, 4H), 2.14 (s, 3H).
Reaction SMILES: NC1C=CC=CC=1C(F)(F)F.NC1C=CC(Cl)=CC=1C(F)(F)F.[NH2:24][C:25]1[C:30]([Cl:31])=[CH:29][C:28](Cl)=[CH:27][C:26]=1[C:33]([F:36])([F:35])[F:34]>>[NH2:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:33]([F:36])([F:34])[F:35]
Reactant: Nc1c(Cl)cc(Cl)cc1C(F)(F)F
Agent: Nc1ccc(Cl)cc1C(F)(F)F
Agent: Nc1ccccc1C(F)(F)F
Product: Nc1c(Cl)cccc1C(F)(F)F

Procedure:
VPC assay of the organic product revealed the following composition (15% XE 60 column packing; 120° C-250° C; 4°/min.): o-aminobenzotrifluoride (13.1 wt. %; 25.94 grams; 0.161 mole; 83.9% conversion); 2-amino-5-chlorobenzotrifluoride, 53.5 wt. %; 105.9 grams or 64.5% corrected yield); and, 2-amino-3,5-dichlorobenzotrifluoride, 33.3 wt. %; 65.93 grams or 34.2% corrected yield). A trace of 2-amino-3-chlorobenzotrifluoride was produced.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]([NH:16][NH2:17])=O)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>C(O)CCC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]2[N:16]([C:14]([C:11]3([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH2:13][CH2:12]3)=[N:20][N:21]=2)[N:17]=1
Reactant: NNC(=O)C1(c2ccc3ncccc3c2)CC1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCCCO
Product: Clc1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Temperature: 140 °C
Yield: 27 %

Procedure:
A sealed tube was charged with 1-(quinolin-6-yl)cyclopropanecarbohydrazide (513 mg, 2.26 mmol), 3,6-dichloro-pyridazine (437 mg, 2.93 mmol) and 5 mL of n-butanol. The mixture was heated at 140° C. for 12 h. After cooling, solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound (196 mg, 41%). LCMS (method A): [MH]+=322, tR=4.38 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH2:13]([O:15]/[CH:16]=[CH:17]/B1OC(C)(C)C(C)(C)O1)[CH3:14].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>O.[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.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][CH:5]=[C:6](/[CH:14]=[CH:13]/[O:15][CH2:16][CH3:17])[CH:7]=1
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)c1ncc(Br)cc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCO/C=C/c1cnc(C(F)(F)F)c(Br)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
To a solution of 3,5-dibromo-2-(trifluoromethyl)pyridine (1.11 g, 3.65 mmol) in water (9 mL) were added 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.72 g, 3.65 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.42 g, 0.36 mmol), 1,2-dimethoxyethane (16.7 mL), and sodium carbonate (1.16 g, 11.0 mmol). The resulting mixture was allowed to stir overnight at 60° C. After the reaction was allowed to cool to rt, EtOAc (50 mL) was added. The organic solution was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3-bromo-5-[(E)-2-ethoxyvinyl]-2-(trifluoromethyl)pyridine (0.41 g, 38%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](=[O:7])[CH2:5][Cl:6].Cl[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])O.[Na+]>O.C1(C)C=CC=CC=1>[CH3:19][O:18][C:16]([NH:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](=[O:7])[CH2:5][Cl:6])=[O:17]
Reactant: N[C@@H](Cc1ccccc1)C(=O)CCl
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
(3S)-3-Amino-1-chloro-4-phenyl-2-butanone hydrochloride (2.0 g) was dissolved in water (34 ml). A solution (50 ml) of methyl chloroformate (0.858 ml) in toluene was added to the obtained solution. Further, an aqueous solution (15 ml) of sodium hydrogencarbonate (1.44 g) was added dropwise to the obtained mixture. They were stirred at room temperature for 1 hour to conduct the reaction. After the extraction with toluene twice and with ethyl acetate twice, the organic layers were combined together. The solvents were evaporated under reduced pressure. n-Hexane and 2-propanol were added to the residue. The obtained mixture was heated to 50° C. to obtain a homogeneous solution, which was cooled to 10° C. to form crystals. The crystals were taken by the filtration, washed with cold 2-propanol (6 ml) and then dried to obtain (3S)-3-methoxycarbonylamino-1-chloro-4-phenyl-2-butanone (1.70 g) in a yield of 78%.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:53][OH:54])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:56].[Na+].[Br-].[K+].Cl[O-].[Na+].Cl>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:45][CH:46]=4)[CH:34]=3)[O:32][C@@:10]1([C:53]([OH:56])=[O:54])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl) phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 171 (1.1 g, 1.45 mmol, obtained from the synthetic method described in step 11 of example 17) in dichloromethane (20 mL) were added sodium bicarbonate (1.58 g, 18.85 mmol), potassium bromide (172.0 mg, 1.45 mmol) and 2,2,6,6-tetramethylpiperidinooxy (22.0 mg, 0.14 mmol) in turn at 0° C., and then sodium hypochlorite (10 mL, 11.80 mmol, 3.5% available chlorine) was added dropwise. The mixture was stirred at 0° C. for 30 min and then room temperature for 1.5 hours. The reaction mixture was acidified with aqueous HCl until pH becomes 4 and partitioned. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 18a (0.74 g, 66.0%) as pale yellow oil. This material was not further purified.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Cl:27][CH2:28][C:29]([C:31]1[N:32]=[CH:33][N:34]2[CH:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[S:36][C:35]=12)=[O:30]>>[Cl:27][CH2:28][C:29]([C:31]1[N:32]=[CH:33][N:34]2[CH:38]=[C:37]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[S:36][C:35]=12)=[O:30]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)CCl)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)CCl)c4s3)[C@H](C)[C@H]12
Yield: 54.7 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-(7-chloroacetylimidazo-[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (1.01 g) was prepared in the same manner as in step a) of Example 1, except that 2.85 g of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.66 g of 7-chloroacetyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][CH2:11][Cl:12]>C1(C)C=CC=CC=1>[Cl:12][CH2:11][CH2:10][CH2:9][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCNCC1
Reactant: ClCCCBr
Solvent: Cc1ccccc1
Product: CN1CCN(CCCCl)CC1

Procedure:
N-Methyl piperazine (0.2 mol) and 1-bromo-3-chloropropane (0.1 mol) in toluene (100 mL) were heated at 80° C. for 3 hr. The precipitate was collected and the remaining filtrate extracted with HCl (1N, 2×50 mL). The aqueous layer was made basic with NaOH (1N) and extracted with ether (3×100 mL). The combined ether layers were washed with water, dried (MgSO4), filtered and evaporated to afford product as a pale yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[C:12]([N:16]=[C:17]=[S:18])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([NH:16][C:17]([NH:1][C@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4])=[S:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: N[C@@H](CO)Cc1ccccc1
Reactant: CC(C)(C)N=C=S
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccccc1
Yield: 98.8 %

Procedure:
The process is performed as in Example 2, starting with 5 g of (R)-(+)2-amino-3-phenyl-1-propanol in 50 cm3 of ethanol and 5.7 g of tert-butyl isothiocyanate at a temperature in the region of 20° C. for 16 hours. After an identical work-up, 8.7 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(phenylmethyl)ethyl]thiourea are obtained in the form of a white solid melting at 107° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C:35]1([CH2:40][OH:41])[CH2:39][CH2:38][CH2:37][CH2:36]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C:35]4([CH2:40][OH:41])[CH2:39][CH2:38][CH2:37][CH2:36]4)(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(NC1(CO)CCCC1)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)NC3(CO)CCCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 584 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromo-N-(1-(hydroxymethyl)-cyclopentyl)benzene-sulfonamide in Step B. MS (ESI): mass calcd. for C22H23FN4O3S, 442.15; m/z found, 443.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.42 (s, 1H), 8.39 (s, 1H), 8.18 (d, J=7.3, 1H), 8.08 (m, 1H), 7.66-7.60 (m, 1H), 7.58-7.52 (m, 1H), 7.43 (dd, J=8.1, 1.8, 1H), 7.38-7.32 (m, 2H), 4.12 (s, 1H), 3.49 (s, 2H), 1.64-1.39 (m, 8H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[C:12]([F:19])=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O.FC(F)(F)C([N:31]1[CH2:36][C:35]2([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[O:34][CH2:33][CH2:32]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCCC[N+](CCCC)(CCCC)CCCC.[F-].N>CN1CCCC1=O.C1COCC1.CO.C(O)(=O)C>[O:34]1[C:35]2([CH2:41][CH2:40][N:39]([CH2:14][C:13]3[C:12]([F:19])=[C:11]([CH2:10][CH2:9][OH:8])[CH:18]=[CH:17][CH:16]=3)[CH2:38][CH2:37]2)[CH2:36][NH:31][CH2:32][CH2:33]1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(C=O)c1F
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reaction time: 0.25 h

Procedure:
3-(2-(tert-Butyldimethylsilyloxy)ethyl)-2-fluorobenzaldehyde [Aromatic Intermediate 5] (5.0 g) was added to a solution of 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate [Example 9, step a] (9.3 g) and acetic acid (1.0 mL) in N-methyl-2-pyrrolidinone (50 mL). The resulting mixture was stirred for 15 min, then cooled in an ice bath. Sodium triacetoxyborohydride (5.64 g) was then added and the mixture was stirred overnight. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution:brine (1:5) and extracted four times with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to afford an oil. The oil was dissolved in THF (100 mL) and treated with TBAF (1M in THF, 18.0 mL). The resulting solution was stirred at room temperature for 50 minutes, then more TBAF (1M in THF, 18.0 mL) was added and the mixture was stirred for a further 100 minutes. The solution was then concentrated in vacuo to afford an oil. The oil was dissolved in methanol (100 mL), the solution was treated with ‘880’ aqueous ammonia (20 mL), stirred at room temperature for 50 minutes, then concentrated in vacuo to give an oil. The oil was dissolved in methanol and concentrated onto flash silica in vacuo. The resulting powder was purified by flash chromatography on silica eluted with ‘880’ aqueous ammonia:methanol:dichloromethane (1:10:89) to afford the subtitled compound as a yellow oil. Yield 5.8 g, 60% pure. Used crude.
Reaction SMILES: C[Si](C)(C)Cl.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH:10]=[O:11].[CH2:16](O)[CH2:17][OH:18]>C1(C)C=CC=CC=1>[CH2:17]1[O:18][CH:10]([C:9]2[CH:12]=[CH:13][C:14]([F:15])=[C:7]([Br:6])[CH:8]=2)[O:11][CH2:16]1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: OCCO
Agent: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Product: Fc1ccc(C2OCCO2)cc1Br
Temperature: 100 °C
Yield: 85 %

Procedure:
26 g (0.24 mol) of trimethylchlorosilane were added to a mixture of 20.3 g (0.1 mol) of 3-bromo-4-fluoro-benzaldehyde and 6.8 g (0.11 mol) of ethane-1,2-diol and the mixture was heated to 100° C. for 3 hours. After cooling to room temperature, 100 ml of toluene were added and the mixture was shaken twice with 50 ml of ice-water each time. The organic phase was dried over sodium sulphate and evaporated in vacuo. The residue was distilled in vacuo. 21 g (85% of theory) of 3-bromo-4-fluoro-benzaldehyde ethyleneacetal were thus obtained in the form of a colorless oil with a boiling point of 79°-81° C./0.1 mm Hg.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22]C)[C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:5][CH2:4]1.Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[CH3:2][N:3]1[CH2:4][CH2:5][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:7][CH2:8]1
Reactant: COc1cccc2c1Oc1ccccc1C21CCN(C)CC1
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CN1CCC2(CC1)c1ccccc1Oc1c(O)cccc12

Procedure:
1'-Methyl-4-methoxyxanthene-9-spiro-4'-piperidine hydrochloride (1.0 g.) in a solution of 45% w/v hydrobromic acid in glacial acetic acid (10 ml.) is heated under reflux for 2 hours. The solution is basified with sodium bicarbonate, diluted with water and extracted with chloroform. The chloroform extract is washed with water, dried over MgSO4, and evaporated to dryness. The residue is recrystallised from toluene-petroleum ether (b.p. 60°-80° C.) to give 1'-methyl-4-hydroxyxanthene-9-spiro-4'-piperidine, m.p. 171°-173° C.