Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:32])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH:30]=[O:31])[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1.Cl>O1CCCC1.O>[CH3:3][O:4][C:5](=[O:32])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH2:30][OH:31])[C:22]([C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4C=O)ccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CO)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaBH4 (18 mg) is added to a solution of {(S)-6-[(R)-4-formyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.20 g) in tetrahydrofuran (4 mL) and water (1 mL) at room temperature. The mixture is stirred at room temperature for 30 min. 1 N aqueous HCl solution is added and the mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (Na2SO4), and concentrated to give the title compound. The crude product is submitted to the next reaction step without further purification. LC (method 4): tR=1.09 min; Mass spectrum (ESI+): m/z=445 [M+Na]+.
Reaction SMILES: C1N2CCN(CC2)C1.[Br:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH:12]=[O:13].CN(C=O)C.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>O>[Br:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH:12]([OH:13])[C:25](=[CH2:26])[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=Cc1cc(F)ccc1Br
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C(=O)OC(C)(C)C)C(O)c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 114.4 %

Procedure:
Alternate Preparation. This procedure uses DABCO as a more economical substitute for (4s)-quinuclidin-3-ol. A 1 L flask was charged with 2-bromo-5-fluorobenzaldehyde (13.4 g, 66.0 mmol), DABCO (14.81 g, 132 mmol), DMF (53.6 mL) and water (13.4 mL). To this reaction mixture was added tert-butyl acrylate (12.68 g, 99.0 mmol). The mixture was then stirred at rt for 12 h. At this time TLC indicated consumption of starting material. The reaction mixture was diluted with 25 mL of water and then extracted with two 100 mL portions of MTBE. The combined organic phases were washed with 0.1N HCl, water and brine. It was then dried over MgSO4, filtered and concentrated to yield 25 g (>100%) of the product as a colorless oil which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH3:11])[N:5]=1)([O-:3])=[O:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][CH:14]=[C:13]2[O:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[N:5][C:6]([CH3:11])=[CH:7][CH:8]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)nc3[N+](=O)[O-])c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
2-Nitro-6-methylpyridin-3-ol (4.1 g), 4-chloro-6,7-dimethoxyquinoline (2 g), and 4-(N,N-dimethylamino)-pyridine (3.3 g) were dissolved in 1,2-dichlorobenzene (90 ml) to prepare a solution which was then stirred at 130° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. A 1 N aqueous sodium hydroxide solution was added to the residue, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give the title compound (732 mg, yield 24%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC[O-].[Na+].[Na].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:21]=[CH:22][CH:23]=1>O.C(O)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:26][CH2:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)OCCCc2cccc(Cl)c2)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCCc1cccc(Cl)c1)C(=O)OCC
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 41.7 %

Procedure:
91.3 g of malonic acid diethyl ester are added dropwise, at 50° C., to a sodium ethylate solution freshly prepared from 13.11 g of sodium and 650 ml of ethanol. The mixture is kept at that temperature for 2.5 hours, and 185 g of p-toluenesulfonic acid [3-(3-chlorophenyl)propyl] ester are then added dropwise. When the addition is complete, the obtained mixture is stirred at 50° C. for 6 hours; 800 ml of water are then added, and the mixture is extracted 3 times with a total of 1 liter of diethyl ether. The combined organic phases are dried over sodium sulfate; the solvent is evaporated off, and the residue is distilled. 74.2 g of 3-(3-chlorophenyl)propylmalonic acid diethyl ester (b.p. 145° to 152° C. under 0.01 mm Hg) are obtained.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH-](O[C:23](=[O:25])[CH3:24])OC(=O)C)(=O)C.[Na+]>>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:6][C:5]3[O:25][C:23]4[C:24](=[N:7][CH:1]=[CH:2][CH:3]=4)[CH:4]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [Na+]
Product: c1ccc(N2CCN(Cc3cc4ncccc4o3)CC2)cc1

Procedure:
The product from Example 35B, 1-phenylpiperazine, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.78 (br, 4H), 3.28 (br, 4H), 3.85 (s, 2H), 6.89 (m, 4H), 7.20 (dd, J=4.75, 8.14 Hz, 1H), 7.26 (m, 2H), 7.73 (d, J=8.14 Hz, 1H), 8.54 (br, 1H); MS (DCI/NH3) m/z 294.2 (M+H)+; Anal Calcd for C18H19N3O: C, 73.69; H, 6.53; N, 14.32. Found: C, 72.19; H, 6.43; N, 14.09.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Cl)[N:14]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:11][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][N:7]=2)[CH3:10])[CH:16]=[CH:17][CH:18]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: Clc1cccc(Cl)n1
Agent: Cl
Product: C[C@H](Nc1cccc(Cl)n1)c1ccc(F)cn1
Yield: 36.8 %

Procedure:
(S)-1-(5-Fluoropyridin-2-yl)ethanamine hydrochloride (prepared as described in WO2006/123113, 0.291 g, 1.37 mmol) was added to a solution of 2,6-dichloropyridine (0.203 g, 1.38 mmol) in NN-diisopropylethylamine (1.2 mL, 6.89 mmol) and the resulting mixture was stirred and heated to reflux for two days. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (0-10% ethyl acetate in hexanes) to yield the title compound (127 mg, 36%) as a yellow solid.
Reaction SMILES: [Na].[C:2]([C:6]1[CH:7]=[C:8]([C:17]2[N:18]=[C:19]([SH:22])[S:20][CH:21]=2)[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:5])([CH3:4])[CH3:3].[CH3:23]I.O>CO>[C:2]([C:6]1[CH:7]=[C:8]([C:17]2[N:18]=[C:19]([S:22][CH3:23])[S:20][CH:21]=2)[CH:9]=[C:10]([C:13]([CH3:15])([CH3:16])[CH3:14])[C:11]=1[OH:12])([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1cc(-c2csc(S)n2)cc(C(C)(C)C)c1O
Reactant: CI
Agent: [Na]
Solvent: CO
Solvent: O
Product: CSc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cs1
Yield: 73 %

Procedure:
In 30 ml of methanol was dissolved 0.18 g of metallic sodium and after adding thereto 2.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-mercaptothiazole, 1.15 g of methyl iodide was added dropwise to the solution at 0°-5° C. After allowing to stand the mixture for 30 minutes at room temperature, 60 ml of iced water was added to the reaction mixture. The crystals thus precipitated were recovered by filtration and recrystallized from n-hexane to provide 1.6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthiothiazole.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:46])[CH2:31][CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH2:25]2)=[O:23])[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.CO>C(OCC)(=O)C.[Pd]>[C:42]([O:41][C:39]([N:36]1[CH2:35][CH2:34][CH:33]([CH2:32][CH2:31][C:30]([N:26]2[CH2:27][CH2:28][CH2:29][C@@H:24]([C:22](=[O:23])[NH:21][C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:25]2)=[O:46])[CH2:38][CH2:37]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(O)c1
Reaction time: 16 h
Yield: 75.8 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-({(1S)-1-[3-(benzyloxy)phenyl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (650 mg, 1.02 mmol) was dissolved in ethyl acetate (45 mL) and methanol (7.4 mL) and palladium on charcoal (65 mg, 10%) was added. The mixture was shaken under a hydrogen atmosphere for 16 hours filtrated through celite which were washed with methanol. The filtrate was concentrated and purified by chromatography on silica gel (methanol in ethyl acetate 0% to 25%) to yield 422 mg of tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(3-hydroxyphenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][S:24]([CH3:23])(=[O:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cnccc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cnccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution containing 4-(benzyloxy)pyridin-3-amine (6.2 g, 15.8 mmol), triethylamine (11 mL, 79 mmol), and dichloromethane (163 mL) was added methanesufonylchloride (1.2 mL, 15.8 mmol) in dichloromethane (100 mL) drop wise over 90 min. The solution was maintained at room temperature for 6 h and concentrated to afford N-(4-(benzyloxy)pyridin-3-yl)methanesulfonamide which was used without further purification. LCMS: retention time: 1.305 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Xterra, 5 micron, C18, 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 279 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)(Cl)Cl>[Cl:24][CH2:25][C:26]([NH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]([OH:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: NC(c1ccccc1)C(O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCl)NC(c1ccccc1)C(O)c1ccccc1
Yield: 76.8 %

Procedure:
To a stirred solution of 2-hydroxy-1,2-diphenylethylamine (95.5 g, 0.39 m) (obtained by catalytic reduction of benzoin oxime) and triethylamine (43.3 g, 0.429 m) in chloroform (1 liter) maintained under nitrogen was added dropwise chloroacetylchloride (46.2 g, 0.41 m) and the mixture heated to reflux for 1 hour. After cooling, the mixture was washed with 10% HCl (1 liter) and water and the organic phase dried over MgSO4. The solvent was evaporated to a solid residue which was recrystallized from methanol to give 91.0 g of N-chloroacetyl-2-hydroxy-1,2-diphenylethylamine, m.p. 166°-169°.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[CH3:27][S:28]([NH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:30])=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([NH:31][S:28]([CH3:27])(=[O:29])=[O:30])[CH:37]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(NS(C)(=O)=O)c4)cc23)CC1
Temperature: 160 °C

Procedure:
A mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (30 mg, 0.07 mmols), {3-[(methylsulfonyl)amino]phenyl}boronic acid (46 mg, 0.21 mmols), cesium carbonate (150 mg), and Pd(PPh3)4 (10 mg) in dioxane/water (3/1, 4 mL) was heated at 160° C. for 2700 secs. (microwave irradiation). The resulting mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11](=O)[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][CH:11]([CH3:12])[CH3:10]
Reactant: Nc1cc(F)ccc1Br
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)Nc1cc(F)ccc1Br
Temperature: 20 °C

Procedure:
2-bromo-5-fluoroaniline E-1.7″″″ (2.00 g; 10.53 mmol) is suspended in 20 ml DCM and propan-2-one (1.55 ml; 21.05) is added and the reaction mixture is stirred for 16 at 20° C. Afterwards sodium triacetoxyborohydride (4.69 g; 21.05 mmol) is added and the reaction mixture is stirred for 48 h at 20° C. The reaction mixture is poured into water and extracted with DCM. The combined organic layer is dried over MgSO4 the solid materials are filtered off and HCl in dioxane is added until the pH value is below 2. The solvents are concentrated under reduced pressure. The crude product is purified using reversed phase chromatography (Method: prep. HPLC1). Product containing fractions are combined and extracted with DCM. To the organic layer HCl in dioxane is added until the pH value is below 2. The solvents are concentrated under reduced pressure.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([C:13]1([CH2:17][OH:18])[CH2:16][O:15][CH2:14]1)[CH3:12].N1C=CC=CC=1>CCOCC>[CH2:11]([C:13]1([CH2:17][O:18][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[CH2:16][O:15][CH2:14]1)[CH3:12]
Reactant: CCC1(CO)COC1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC1(COC(=O)c2ccc(I)cc2)COC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-iodobenzoyl chloride (11.5 gms) in dry ether (50 ml) was added to a stirred solution of 3-ethyl-3-hydroxymethyloxetane (5 gms) and pyridine (3.5 mls) in ether (100 ml) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 24 hours. After this time the mixture was washed with water and brine. The organic extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was purified by column chromatography on silica (preeluted with 1% triethylamine in hexane) and eluted with 5% ethyl acetate in hexane. 3-Ethyl-3-(4-iodobenzoyloxymethyl) oxetane was obtained as a colourless oil (8.1 gms).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@@H:12]2[CH2:16][C@H:15]([S:17][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25]CC3C=CC([N+]([O-])=O)=CC=3)=[O:24])[CH2:14][N:13]2[CH3:43])=[O:11])[CH2:6][CH2:5]1.O1CCCC1.[ClH:49]>O>[ClH:49].[OH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]([C@@H:12]2[CH2:16][C@H:15]([S:17][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([OH:25])=[O:24])[CH2:14][N:13]2[CH3:43])=[O:11])[CH2:8][CH2:9]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)N4CCN(CCO)CC4)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)N4CCN(CCO)CC4)N(C)C3)[C@H](C)[C@H]12

Procedure:
A solution of 700 mg of 4-nitrobenzyl (1R,5S,6S)-2-{(2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-1-methylpyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] in 60 ml of a 1:1 by volume mixture of tetrahydrofuran and water was mixed with 1.15 ml of 1N aqueous hydrochloric acid, and the mixture was hydrogented by bubbling hydrogen through it at room temperature for 2 hours in the presence of 1000 mg of 10% w/w palladium-on-charcoal. At the end of this time, the catalyst was removed by filtration, and the filtrate was extracted with diethyl ether. The remaining aqueous layer was concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through a Lobar column (Merck, LiChroprep RP-8, size B). The column was eluted with 1.5% v/v aqueous methanol and those fractions containing the title compound were combined, concentrated by evaporation under reduced pressure and lyophilized, to give 300 mg of the title compound as a colorless powder.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C>C(Cl)(Cl)Cl>[CH2:2]([O:9][N:10]1[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=[C:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Nc1cnc2ccccc2c1Cl)c1ccccc1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: c1ccc(COn2c(-c3ccccc3)nc3cnc4ccccc4c32)cc1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
O-Benzylhydroxylamine hydrochloride (10.2 g, 63.7 mmol), N-(4-chloroquinolin-3-yl)benzamide (6.00 g, 21.2 mmol), and isopropanol (200 mL) were combined and heated at 80° C. After 18 hours the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the solution was washed sequentially with saturated aqueous potassium carbonate and water and then concentrated under reduced pressure. This material was purified by column chromatography (320 g of silica gel, eluting with a gradient of 1-2% methanol in dichloromethane). The resulting solid was triturated with hexanes to provide a tan solid that was isolated by filtration. The solid was mixed with chloroform and isolated by filtration to provide 0.951 g of 1-(benzyloxy)-2-phenyl-1H-imidazo[4,5-c]quinoline as a reddish-brown solid. 2-Phenyl-1H-imidazo[4,5-c]quinolin-1-ol (2.39 g) was recovered from the aqueous washings.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[N:5]([CH2:8][C@@H:9]([NH:14][C:15]1[C:20]([F:21])=[CH:19][N:18]=[C:17]([Cl:22])[N:16]=1)[C:10]([CH3:13])([CH3:12])[CH3:11])=[N+:6]=[N-:7]>C1COCC1.C1(C)C=CC=CC=1>[Cl:22][C:17]1[N:16]=[C:15]([NH:14][C@@H:9]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:8][N:5]2[CH:3]=[C:2]([CH2:1][OH:4])[N:7]=[N:6]2)[C:20]([F:21])=[CH:19][N:18]=1
Reactant: C#CCO
Reactant: CC(C)(C)[C@@H](CN=[N+]=[N-])Nc1nc(Cl)ncc1F
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](Cn1cc(CO)nn1)Nc1nc(Cl)ncc1F
Temperature: 120 °C

Procedure:
A mixture of prop-2-yn-1-ol (0.22 g, 3.85 mmol) and (S)—N-(1-azido-3,3-dimethylbutan-2-yl)-2-chloro-5-fluoropyrimidin-4-amine, 216a, (0.21 g, 0.77 mmol) in THF (4 mL) and toluene (4 mL) was heated in a pressure vial at 120° C. for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product which contained two regioisomers was purified by silica gel chromatography (0-5% MeOH/CH2Cl2 gradient) to afford 100 mg of desired regioisomer, 217a, as well as 70 mg of the minor regioisomer (5-hydroxymethyl triazole).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])=[O:8].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:33])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]([F:21])([F:22])[F:23])=[O:8]
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Br)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Br)ccc1OC(=O)N1CCOCC1
Yield: 89.4 %

Procedure:
Using 5-bromo-2-hydroxy-N-[2,5-bis(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[F:17])[CH:10]=[C:9]([CH3:18])[C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>C1C=CC=CC=1>[C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[F:17])[CH:10]=[C:9]([CH2:18][Br:20])[C:8]2=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2cccc(F)c2n(-c2ccccc2)c1=O
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: c1ccccc1
Product: O=c1c(CBr)cc2cccc(F)c2n1-c1ccccc1

Procedure:
Reflux a solution of 1-phenyl-8-fluoro-3-methyl-2(1H)-quinolone (0.54 g), N-bromosuccinimide (0.38 g) and benzyl peroxide (0.04 g) in dry benzene (11 mL) for 6 hours. Evaporate, partition between dichloromethane and water, dry and evaporate the organic phase, and dry the residue at room temperature and high vacuum to obtain 1-phenyl-8-fluoro-3-bromomethyl-2(1H)-quinolone, suitable for further reactions (see example 32).