Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]2[C:18](=[O:41])[CH2:19][NH:20][C:21](=[O:40])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]CC3C=CC=CC=3)=[O:31])=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+:42].[Br-]>CO.O>[OH-:31].[K+:42].[C:12]1([C@H:9]2[CH2:10][CH2:11][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]2[C:18](=[O:41])[CH2:19][NH:20][C:21](=[O:40])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:24]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NCC(=O)N1[C@@H](c2ccccc2)CC[C@H]1c1ccccc1)Nc1ccc(CC(=O)OCc2ccccc2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2c2ccccc2)cc1
Product: [OH-]

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 4 g of benzyl cis-4-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetate in solution in 65 cm3 of methanol and 0.61 g of potassium hydroxide in solution in 12 cm3 of water, and after treatment, 1.8 g of cis-4-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetic acid, melting at 221° C., are obtained [proton NMR (200 MHz, DMSO D6, δ in ppm), 1.4 to 2.4 (m, 4H, CH2 --CH2); 3.3 (s, 2H, CH2CO2); 3.2 and 3.8 (ABX, 2H, CH2NH); 5.1 (m, 2H, 2 CHN); 6.1 (t, 1H exchangeable, NH); 6.9 (d, 2H, aromatic in para position); 7.1 to 7.4 (m, 12H, aromatic); 8.6 (s, 1H exchangeable, NH)], [infrared spectrum (KBr), characteristic bands in cm-1 3375, 3095, 3070, 3035, 2980, 2880, 1735, 1700, 1630, 1610, 1515, 1450, 1560, 805, 760, 705].
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6](CN)=[C:5]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:4]=1.FC1C=CC([C:21]#[N:22])=C(N2C=NC=N2)C=1.Cl>C(O)C.[Pd]>[N:11]1([C:5]2[CH:6]=[CH:7][C:8]([C:21]#[N:22])=[C:3]([F:2])[CH:4]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: N#Cc1ccc(F)cc1-n1cncn1
Reactant: NCc1ccc(F)cc1-n1cncn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(-n2cncn2)cc1F
Yield: 99 %

Procedure:
(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride). Intermediate 67, 4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile, (2.46 g, 13.13 mmol) was dissolved in hot ethanol (150 mL). To this was added 1N HCl (15 mL) followed by 10% Pd—C (200 mg). The mixture was treated with H2 at 55 psi for 4 h in a Parr shaker then filtered over Celite and the solvent removed under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The aqueous phase was separated and lyophilized to afford the title compound as a white powder (2.96 g, 99% yield). 1H NMR (500 MHz, CD3OD) δ ppm: 9.51 (1H, s), 8.63 (1H, s), 7.85 (1H, dd, J=8.5, 5.8 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz), 7.49 (1H, td, J=8.3, 2.4 Hz), 4.20 (2H, s). LCMS (M+H) calcd for C9H10N4F: 193.08; found: 193.16.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[OH:21])[CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[N:3]1.ClC1C=C(C=CC=1)C(OO)=[O:47]>C(Cl)Cl>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][N+:14]3([O-:47])[CH2:15][CH2:16][CH:17]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=4)([C:32]4[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=4)[OH:21])[CH2:18][CH2:19]3)=[CH:11][CH:12]=2)=[N:3]1
Reactant: Cn1nnc(-c2ccc(CN3CCC(C(O)(c4ccc(C(F)(F)F)cc4)c4ccc(C(F)(F)F)cc4)CC3)cc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1nnc(-c2ccc(C[N+]3([O-])CCC(C(O)(c4ccc(C(F)(F)F)cc4)c4ccc(C(F)(F)F)cc4)CC3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
A solution of 1.1 grams (0.002 mole) of N-[4-(2-methyl-2H-tetrazol-5-yl)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine (Compound 31—prepared in Example 9) in 100 mL of methylene chloride was stirred, and 0.6 gram (excess) of 50-85% 3-chloroperoxybenzoic acid was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about one hour. After this time the reaction mixture was washed with an aqueous 10% solution of sodium hydroxide. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.0 gram of N-[4-(2-methyl-2H-tetrazol-5-yl)phenyl-methyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine N-oxide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:6]#N.[C:13]1([Mg]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C[O:24]CC1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:24]
Reactant: C1CCOC1
Reactant: COc1cc(C#N)cc(OC)c1
Reactant: Cl[Mg]c1ccccc1
Agent: Cl
Product: COc1cc(OC)cc(C(=O)c2ccccc2)c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
This compound was previously prepared by a two-step process.v However, we prepared it by a one-step method adapted from another literature procedure.vi Neat 3,5-dimethoxybenzonitrile (16.0 g, 98.1 mmol) was added to a 2.0M solution of phenylmagnesium chloride in THF (98.0 mL, 196.1 mmol). The reaction mixture was refluxed for 24 hours at 70° C. The solution was then transferred into a mixture of concentrated aqueous HCl (100 mL) and ice (300 g). The mixture was allowed to warm up to room temperature and stirred for 24 hours. The product was extracted with ether (3×300 mL) and the combined organic layers were washed with brine (200 mL) and water (150 mL) before being dried with anhydrous magnesium sulfate. The filtrate was dried in vacuo to afford 3,5-dimethoxybenzophenone as a yellow solid in 75% yield. 1H NMR (CDCl3): δ 7.84 (d, 3JH-H=7.2 Hz, 1H), 7.61 (t, 3JH-H=7.6 Hz, 2H), 7.50 (t, 3JH-H=7.6 Hz, 2H), 6.95 (d, 3JH-H=2.4 Hz, 1H), 6.70 (t, 3JH-H=2.4 Hz, 2H), 3.85 (s, 6H).
Reaction SMILES: [Cl-].[NH4+:2].[Al](C)(C)C.[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:2])=[NH:13])=[CH:10][N:9]=1
Reactant: [NH4+]
Reactant: N#Cc1ccc(Cl)nc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N=C(N)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
Suspend ammonium chloride (1.16 g, 21.6 mmol) in toluene (10 mL). Cool to 0° C. and slowly add 2.0 M Al(CH3)3 in toluene (10.8 mL, 21.6 mmol) (see Tetrahedron Lett. 1990, 31(14), 1969-1972). After the gas stops evolving, add a solution of 6-chloronicotinonitrile (1.00 g, 7.22 mmol) in toluene (52 mL). Beat to 80° C. overnight. Cool the reaction mixture, then slowly pour into slurry of silica gel (40 g) in CHCl3 (200 mL). Stir for 10 minutes before filtering. Filter and wash the silica plug with methanol (2×100 mL). Concentrate the filtrate and purify by 10 g SCX column washing with methanol and then eluting with 2.0 M NH3 in methanol to give the title compound (0.458 g. 40.8%): MS ES+ 155.9 (M+H)+: HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.2 min, 97.2% purity.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[C:28]2=[N:29][CH:30]=[C:31]([OH:33])[CH:32]=[C:27]2[CH:26]=[CH:25]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:31]4[CH:32]=[C:27]5[CH:26]=[CH:25][NH:24][C:28]5=[N:29][CH:30]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cnc5[nH]ccc5c4)ncnc32)CC1
Temperature: 160 °C
Yield: 32.1 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 1H-pyrrolo[2,3-B]pyridin-5-ol (Matrix Scientific, Columbia, S.C., USA; 26 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.19 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated under high vacuum to give 4-[4-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (21 mg, 33%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.80-2.15 (m, 4H), 3.02 (br s, 2H), 4.08 (d, 2H, J=12.4 Hz), 4.85-5.10 (m, 1H), 6.45-6.52 (m, 1H), 7.58 (d, 1H, J=2.9 Hz), 7.94 (d, 1H, J=2.5 Hz), 8.20 (d, 1H, J=2.5 Hz), 8.22 (s, 1H), 8.50 (s, 1H), 11.85 (br s, 1H). Mass spectrum (ES) MH+=436. HRMS Calcd. for C22H26N7O3 (MH+): 436.2092. Found: 436.2090.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[C:11]([CH3:17])=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1>>[OH:16][C:12]1[C:11]([CH3:17])=[C:10]([NH:9][C:2]2[CH:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=3[CH3:17])[N:5]=[CH:4][N:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1c(N)cccc1O
Product: Cc1c(O)cccc1Nc1cc(Nc2cccc(O)c2C)ncn1
Yield: 40 %

Procedure:
This compound was obtained (yield 40%) based on the method described in Production Example 2B using 4,6-dichloropyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine, and using 3-amino-2-methylphenol instead of the 3-aminophenol.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18]Br>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:18][CH2:17][CH2:16][Br:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: Oc1ccccc1Cc1ccccc1
Product: BrCCCOc1ccccc1Cc1ccccc1

Procedure:
By following similar procedure as described in Preparation 89, O-alkylation of 2-benzylphenol with 1,3-dibromopropane gives the title-compound as oil. EIMS: m/z 304 (M+, 79Br), 306 (M+, 81Br).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][OH:9])=[N:6][CH:5]=[N:4]1)[CH3:2].[H-].[Na+].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:21][N:22]2[C:27]=1[CH:26]=[N:25][N:24]=[C:23]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34].O>CN(C)C=O>[CH2:1]([N:3]1[C:7]([CH2:8][O:9][C:20]2[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[F:12])=[C:27]3[N:22]([C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[N:24][N:25]=[CH:26]3)[N:21]=2)=[N:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncnc1CO
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nncc3c2-c2ccccc2F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccccc1F
Reaction time: 0.5 h

Procedure:
The title compound was prepared as part of a rapid analogue library using the following methodology. To a solution of (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol (32 mg, 0.25 mmol) in dry N,N-dimethylformamide (5 ml) in a RADLEYS reaction carousel under nitrogen was added sodium hydride (60% wt in oil) (10 mg, 0.25 mmol) and the suspension was stirred for 30 min. A solution of 3,7-bis(2-fluorophenyl)-2-(p-toluenesulfonyloxy)pyrazolo[1,5-d][1,2,4]triazine (100 mg, 0.21 mmol) in dry N,N-dimethylformamide (2 ml) was then added and the solution was stirred under nitrogen for 1 h. A further amount (4 mg, 0.10 mmol) of sodium hydride (60% wt in oil) was added and the solution was stirred for 18 h. Water (25 ml) was added to quench the reaction and the solid which was precipitated was collected by filtration and washed with water. The solid was dissolved in dichloromethane, filtered and the filtrate was concentrated in vacuo to give a white solid (40 mg). Data for the title compound: mp=164° C.; 1H NMR (360 MHz, CDCl3) δ 1.31 (3H, t), 4.09-4.16 (2H, m), 5.56 (2H, s), 7.21-7.33, (3H, m), 7.37-7.43 (2H, m), 7.58-7.68 (2H, m), 7.82 (1H, m), 7.87 (1H, s), 9.28 (1H, s); MS (ES+) m/e 434 [MH]+; HPLC>97% purity (run on an HP1100, using a Hichrom KR100-5C18, 25 cm column, flow rate of 1 ml/min and 50% acetonitrile/pH 3 phosphate buffer as the mobile phase).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][CH:13]([CH2:19][CH:20]=C)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:10]([Cl:24])[CH:9]=1>C1COCC1.O.O=[Os](=O)(=O)=O>[Br:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][CH:13]([CH2:19][CH:20]=[O:2])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:10]([Cl:24])[CH:9]=1
Reactant: C=CCC(Cc1ccc(Br)cc1Cl)C(=O)OCC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC=O)Cc1ccc(Br)cc1Cl
Reaction time: 2 h
Yield: 75.7 %

Procedure:
Add sodium periodate (41 g, 190 mmol) into a solution of ethyl 2-(4-bromo-2-chlorobenzyl)pent-4-enoate (21 g, 63 mmol), 2.5 wt % OsO4 (64 g, 6.3 mmol) in THF (400 mL) and water (160 mL) and stir for 2 hours. Extract the reaction mixture with ethyl acetate, wash the organic layer with sodium thiosulfate solution and brine. Dry over sodium sulfate, filter and concentrate. Purify the residue with silica gel column to afford the title compound (15.9 g, 75%) as colorless oil.
Reaction SMILES: [Na].[CH:2]1([CH2:8][CH2:9][CH2:10]Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.[CH2:13]([OH:16])[CH2:14][OH:15]>C1(C)C(C)=CC=CC=1>[CH:2]1([CH2:8][CH2:9][CH2:10][O:15][CH2:14][CH2:13][OH:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OCCO
Reactant: BrCCCC1CCCCC1
Agent: [Na]
Solvent: Cc1ccccc1C
Solvent: O
Product: OCCOCCCC1CCCCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
85 ml of xylene are added to a solution of 15.75 g of sodium in 182.2 g of ethylene glycol. The mixture is heated to 100° C., and a solution of 140.5 g of 3-cyclohexylpropyl bromide in 70 ml of xylene is added dropwise within 3 hours. When the addition has ended, the mixture is boiled for 4 hours under reflux, cooled, and then 500 ml of water are added. The mixture is extracted with twice 500 ml of petroleum ether, the combined organic phases are dried over sodium sulphate and the remaining oil is purified by chromatography on silica gel (migrating agent: 80:20 petroleum ether/ethyl acetate). 105.3 g of 2-(3-cyclohexylpropyloxy)-ethanol are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][CH:12]=[CH:13][N:14]=1)([O-:3])=[O:2].[H-].[Na+].N#N.[CH3:19]I>O.O1CCCC1.CN(C)C=O>[CH3:19][N:14]1[CH:13]=[CH:12][N:11]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CI
Reactant: O=[N+]([O-])c1ccccc1-c1ncc[nH]1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccnc1-c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under N2, 9.5 g of 2-(2-nitrophenyl)-1H-imidazole in a solution of 100 ml dimethylformamide and 25 ml of anhydrous tetrahydrofuran cooled to 0°-5° C., was treated with 2.3 g of a 50% mineral oil dispersion of NaH. After the N2 evolution ceased, 8.5 g of CH3I was added dropwise over a period of 15 minutes maintaining the temperature at 0°-5°. The reaction mixture was allowed to warm to ambient temperature and then stirred for two hours. The reaction mixture was then poured into water. The aqueous suspension of the product was extracted several times with CH2Cl2. The extracts were combined and dried with anhydrous Na2SO4. The solvent was removed on a rotary evaporator. The last traces of dimethylformamide were removed under high vacuum; a waxy solid remained. The crude product was crystallized from CH3CN. Two crops totaling 3.6 g were obtained. The m.p. was 89°-90°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C@H:6]([CH3:13])[CH2:5]2.[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:16])[C@H:6]([CH3:13])[CH2:5]2
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1Cc2cc(Br)ccc2C(=O)N1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
426 mg (1.7 mmol) (R)-6-bromo-3-methyl-3,4-dihydro-2H-isoquinolin-1-one are dissolved in 3 ml DMF and at 0° C. combined with 80 mg (2 mmol) sodium hydride (60% in mineral oildispersion). After 10 minutes 122 μl (1.9 mmol) methyl iodide are added dropwise, and the mixture is stirred for 16 hours at RT. Then the reaction mixture is mixed with water and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The residue is purified by flash chromatography on silica gel (eluant DCM/MeOH 20:1).
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].[N:27]1[CH:32]=[C:31]([C:33]([C:35]2[N:36]=[CH:37][N:38]3[CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[S:40][C:39]=23)=[O:34])[CH:30]=[N:29][CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C: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]([C:41]3[S:40][C:39]4=[C:35]([C:33]([C:31]5[CH:30]=[N:29][CH:28]=[N:27][CH:32]=5)=[O:34])[N:36]=[CH:37][N:38]4[CH:42]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncnc3)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)c5cncnc5)c4s3)[C@H](C)[C@H]12
Yield: 73.9 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyrimidin-5-yl)carbonylimidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (144 mg) was prepared in substantially the same manner as in step a) of Example 1, except that 180 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 176 mg of 7-(pyrimidin-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29])[CH:10]([OH:21])[CH2:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.CO[C:41](OC)([CH3:43])[CH3:42]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[C@H:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:10]([CH2:11][C:12]2[N:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])[O:21][C:41]1([CH3:43])[CH3:42])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1F)C(O)Cc1ncccc1C(=O)O
Reactant: COC(C)(C)OC
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2F)C(Cc2ncccc2C(=O)O)OC1(C)C
Temperature: 40 °C

Procedure:
To a solution of 2-[3-tert-Butoxycarbonylamino-4-(2-fluoro-phenyl)-2-hydroxy-butyl]-nicotinic acid (13 g, 32 mmol) in 500 mL of 2,2-dimethoxypropane and 500 mL of acetone at 0° C. is added boron trifluoride diethyl etherate (3.2 mL, 25 mmol). The reaction is heated at 40° C. overnight after which time the solvent is removed under reduced pressure. The resultant residue is then partitioned between dichloromethane and water and extracted with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:14]1([C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCO
Reactant: BrCC=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Product: OCCOCC=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of n-butyllithium in hexanes (7.3 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to ethylene glycol (20 ml) at 10° C. When addition was complete the mixture was stirred for 0.5 h at room temperature. 3-Bromo-1,1-diphenyl-1-propene (5.0 g, 18.3 mmol) was added and the reaction mixture was stirred at room temperature for 1 h, at 80° C. for 0.5 h and finally at room temperature for 3 h. Water (100 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The phases were separated and the organic phase was washed with water (2×50 ml), dried over sodium sulphate and the solvent was evaporated in vacuo. Flash chromatography of the residue on silica gel (150 g) using n-heptane and THF (4:1) as eluent provided 2.9 g (62%) of 2-(3,3-diphenyl-2-propen-1-yloxy)ethanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7](C1C=CC=C(O)C=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].S([O:39][CH2:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[CH2:43][CH2:42]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:39][CH2:40][CH:41]1[CH2:42][CH2:43][N:44]([C:47]([O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[O:48])[CH2:45][CH2:46]1)=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a stirred solution of tert-butyl(3-hydroxyphenyl)(phenyl)methylcarbamate. (the second eluting isomer from Chiral Example 1 Step 4, 1.00 g, 3.34 mmol) in DMF (15 mL), was added potassium carbonate (0.554 g, 4.01 mmol). The reaction mixture was stirred for 10 minutes, and benzyl 4-((tosyloxy)methyl)piperidine-1-carboxylate (prepared according to Bioorganic & Medicinal Chemistry Letters, 20(1), 380-382; 2010, which is incorporated herein by reference in its entirety, 1.48 g, 3.67 mmol) added. The reaction mixture was heated at 60° C. for 2 days followed by 80° C. for 5 days. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine (×2). The organic phase was dried with anhydrous magnesium sulfate, and the solvent evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 50% ethyl acetate in iso-hexane to afford the title compound (1.12 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:5].[N:13](OCCC(C)C)=O.C(O)(=O)C>C1C=CC=CC=1>[N+:5](=[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:3]([O:2][CH3:1])=[O:12])=[N-:13]
Reactant: CC(C)CCON=O
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)CCC(=[N+]=[N-])C(=O)OC

Procedure:
Part A. A solution of L-glutamic acid dimethyl ester (2.6 g, 14.8 mmol), isoamyl nitrite (2.13 mL, 15.9 mmol) and acetic acid (0.22 mL) in benzene (150 mL) is heated to reflux for one hour. The solution is washed with 1N aqueous sulfuric acid, water, saturated sodium hydrogen carbonate solution, water and brine (50 mL each). The solvent is removed in vacuo to yield dimethyl 2-diazopentane-1,5-dioate which can be further purified by column chromatography.