Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[CH2:25]([O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:13]1[CH:14]=[C:15]([CH3:16])[C:7]2[CH:6]([CH2:5][C:4]([OH:32])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cccc(OCc4ccccc4)c3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2cccc(OCc3ccccc3)c2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
To a solution of [6-(3-benzyloxy-phenoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (1.0 g, 2.3 mmol) in THF (20 mL) at 0° C. was added a solution of LiOH (0.278 g, 11.5 mmol) in water (10 mL). The solution was allowed to warm to room temperature and stirred for 3 hours then acidified to pH 2 with 6M HCl. The solution was extracted with ethyl acetate (2×50 mL) and the organic extracts washed with water, brine, dried over sodium sulfate and concentrated in vacuo to give [6-(3-benzyloxy-phenoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid as a clear oil (0.85 g, 91%) which was used without further purification. 1H NMR (400 MHz, DMSO): δ 9.13 (s, 1H), 7.42-7.25 (m, 6H), 7.08 (s, 1H), 6.96 (s, 1H), 6.79 (dd, J=8.4, 2.0 Hz, 1H), 6.64 (s, 1H), 6.51 (d, J=6.8 Hz, 1H), 5.48 (d, J=7.6 Hz, 1H), 5.07 (s, 2H), 3.10 (dd, J=15.6, 2.4 Hz, 1H), 2.26 (s, 3H), 2.13-2.07 (m, 1H).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[O:9]1)[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[O:9]1
Reactant: O=[O+][O-]
Reactant: CC=CCC1CC(=O)c2ccc(OC)cc2O1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(CC=O)CC2=O
Reaction time: 1 h
Yield: 49 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted while stirring for 1 hour through a solution, cooled to -70°, of 6.25 g of (RS)-2-(2-buten-1-yl)-7-methoxy-4-chromanone in 90 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 15 minutes. After the addition of 3 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was subsequently evaporated in a vacuum. The residue was treated with 60 ml of dichloromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 100 ml of water and neutralized while stirring by the spatula-wise addition of sodium hydrogen carbonate. An additional 70 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 2.9 g (49%) of 2-(2-oxoethyl)-7-methoxy-4-chromanone were obtained as a yellow oil.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:28][CH2:27]2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)CCCc1cccc2ccccc12
Reactant: CN1CCN(C(CN2CCNCC2)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCN(C(CN2CCN(C(=O)CCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.37 g of 4-Naphthalen-1-yl-butyric acid was dissolved in 5.0 ml of toluene, and 0.35 ml of thionyl chloride and 1 drop of dimethylformamide were added, followed by heating at 70° C. for 30 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give a crude 4-naphthalen-1-yl-butyryl chloride. To the resulting crude 4-naphthalen-1-yl-butyryl chloride was added 2.3 ml of a toluene solution of 0.40 g of 1-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]piperazine, followed by stirring at room temperature for 30 minutes. To the reaction solution was added a saturated aqueous sodium bicarbonate solution and, after extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column chromatography (Wako-gel C-200, chloroform:methanol=10:1) to give 0.58 g of 1-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]-4-(4-naphthalen-1-yl-butyryl)piperazine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][C:12]1[N:16]2[N:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1.[H-].[Na+].I[CH3:30].O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:30])=[CH:4][C:3]=1[CH2:11][C:12]1[N:16]2[N:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1
Reactant: Cn1cc(-c2ccc3ncc(Cc4cc5cn[nH]c5cc4F)n3n2)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3ncc(Cc4cc5cnn(C)c5cc4F)n3n2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-(6-Fluoro-1H-indazol-5-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 167, 18.6 mg, 0.054 mmol) was dissolved in DMF (0.310 mL) and cooled down to 0° C. NaH (1.9 mg, 0.080 mmol) was added and the RM was stirred for 30 min. Then iodomethane (4.02 μL) was introduced and it was allowed to warm up to rt. After 2.5 h of stirring, water was added and it was extracted with EtOAc. Organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound as a white solid (tR 1.0 min (conditions 2), MH+=362).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([N:22]=[N+:23]=[N-:24])=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C=CC(=O)O)ccc1OC(C)=O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc(C=CC(=O)N=[N+]=[N-])ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
34.0 g (0.145 mol) of 4-acetoxy-3-methoxy-cinnamic acid are suspended in 150 ml of benzene and 21 ml (0.290 ml) of thionyl chloride are added. The mixture is then heated to the boil, under a reflux condenser, for 30 minutes; thereafter, the solvent and excess thionyl chloride are removed by distillation under reduced pressure. The crude 4-acetoxy-3-methoxycinnamic acid chloride which remains is dissolved in 150 ml of absolute 1,2-dimethoxyethane, 28.3 g (0.435 mol) of sodium azide are added and the mixture is subsequently stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated under reduced pressure at 30° C., in the course of which colourless crystals separate out. The crystallisation is completed by adding ether. 4-Acetoxy-3-methoxy-cinnamic acid azide of melting point 93°-95° C. (decomposition) is obtained.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.O>[CH2:21]([S:28][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1SCc1ccccc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 97.4 %

Procedure:
Under nitrogen atmosphere, to a mixture of methyl 2-chloro-3-nitrobenzoate (20.8 g, 96.5 mmol) and potassium carbonate (40.0 g, 289 mmol) in N,N-dimethylformamide (300 mL) was added benzyl mercaptan (11.5 mL, 98.0 mmol) at 0° C., and the mixture was stirred at 90° C. for 6 hr, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1→1/2) to give the title compound (28.5 g, yield 97%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[CH2:24]/[CH:25]=[CH:26]/[C:27]1[S:28][C:29]([Cl:32])=[CH:30][CH:31]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:24][CH:25]=[CH:26][C:27]4[S:28][C:29]([Cl:32])=[CH:30][CH:31]=4)[C@@H:15]([CH2:19][O:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1ccc(/C=C/CBr)s1
Reactant: COCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1CC=Cc1ccc(Cl)s1

Procedure:
The title compound is prepared as described in EXAMPLE 278 using 1-(4-amino-quinazoline-7-ylmethyl)-3-methoxymethyl-piperazine-2-one, EXAMPLE 75 and 2-(3-bromo-(E)-propenyl)-5-chloro-thiophene EXAMPLE 17. 1H NMR (d6-DMSO, 300 MHz) δ9.74 (bs, 2H), 8.80 (s, 1H), 8.38 (d, 1H), 7.69 (m, 2H), 7.02 (dd, 1H), 6.84 (d, 1H), 6.02 (m, 1H), 4.76 (AB, 2H), 3.86 (m, 4H), 3.30 (s, 3H), 3.23 (m, 2H), 3.02 (m, 2H). MS (ion spray), m/z, 458, 460, (M+H) (Cl pattern). Elemental analysis, cal C22H24ClN5O2S.2C2HF3O2.1.45H2O % C=43.85, % H=4.09, % N=9.83; found % C=43.92, % H=3.61, % N=9.63.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[C:20]([F:22])[C:19]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[C:18]([F:28])[CH:17]=3)[CH2:11][C:10]([OH:12])=[CH:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:29]([C:31]1[CH:32]=[N:33][C:34]2[N:35]([N:37]=[C:38]([CH:40]=O)[N:39]=2)[CH:36]=1)[CH3:30]>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[C:20]([F:22])[C:19]([C:23]([CH3:26])([CH3:27])[C:24]#[N:25])=[C:18]([F:28])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:40][C:38]3[N:39]=[C:34]4[N:33]=[CH:32][C:31]([CH2:29][CH3:30])=[CH:36][N:35]4[N:37]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cnc2nc(C=O)nn2c1
Reactant: CC(C)(C#N)c1c(F)cc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Solvent: CO
Product: CCc1cnc2nc(CC3=C(O)CC(CCc4cc(F)c(C(C)(C)C#N)c(F)c4)(C4CCCC4)OC3=O)nn2c1
Reaction time: 12 h

Procedure:
A solution of 2-{4-[2-(2-Cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-2,6-difluoro-phenyl}-2-methyl-propionitrile (272 mg, 0.7 mmol) in anhydrous MeOH (1.5 mL) was treated with 6-ethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (324 mg, 2.0 mmol), followed by borane-dimethylamine complex (191.7 mg, 1.05 mmol) at room temperature. The reaction was stirred for 12 hours. The precipitate was removed by filtration, and the filtrate was concentrated to a crude oil. The crude oil was purified by flash chromatography (25 g SiO2, 1:3:1:0 (93.5% ethyl acetate, 6% methanol, 0.5% acetic acid):(81.5% hexanes, 12% ethyl acetate, 6% methanol, 0.5% acetic acid)) to give product as an oil. It was further purified by preparatory HPLC. Yield: 19.0 mg, 8.0%. 1H NMR (CDCl3) δ: 1.37 (t, J=3.75 Hz, 3H)), 1.48-1.75 (m, 8H), 1.84 (s, 6H), 1.91-2.02 (m, 2H), 2.32-2.49 (m, 3H), 2.61-2.70 (m, 2H), 2.79-2.86 (m, 2H), 4.10 (s, 2H), 6.69 (d, J=10.86 Hz, 2H), 8.62 (s, 1H), 8.73 (s, 1H). MS (ESI): 548 (M−H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-:21].[Na+]>Cl>[O:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:10]2[N:11]=[CH:12][N:13]=[C:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:21])[CH:7]=3)[CH:9]=2)[CH2:16][CH2:17]1
Reactant: [OH-]
Reactant: Fc1cc(-c2cc(NC3CCOCC3)ncn2)ccn1
Agent: Cl
Agent: [Na+]
Product: O=c1cc(-c2cc(NC3CCOCC3)ncn2)cc[nH]1
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
6-(2-Fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine (2.50 g, 9.11 mmol) was dissolved in 1M HCl (50 mL) and heated to 90° C. The mixture was agitated overnight, cooled and neutralized with 1M NaOH (50 mL). The resulting slurry was cooled to 5° C., and the solids were filtered off, washed with ice cold water and dried in vacuo to give 4-(6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (2.46 g, 9.03 mmol, 99.1% yield) as a solid.
Reaction SMILES: C([N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[CH:12]=2)[NH:7][C:6]1=[O:17])(C)(C)C.O([CH2:26][C:27]([F:30])([F:29])[F:28])S(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:26][C:27]([F:30])([F:29])[F:28])[C:6](=[O:17])[NH:5][C:14]2=[O:15]
Reactant: CC(C)(C)n1c(=O)[nH]c2ccc(Cl)cc2c1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1[nH]c(=O)n(CC(F)(F)F)c2ccc(Cl)cc12
Temperature: 50 °C
Reaction time: 48 h
Yield: 99.4 %

Procedure:
To a solution of 3-tert-butyl-6-chloro-1H-quinazoline-2,4-dione (1.0 g, 3.97 mmol) in acetonitrile (40 mL) was added trifluoroethyl triflate (0.736 mL, 4.76 mmol) and potassium carbonate (821 mg, 5.95 mmol). The reaction was heated to 50° C. and stirred 48 hrs. The solution was cooled, concentrated, and dissolved in ethyl acetate. The solution was washed with sodium bicarbonate, brine, dried over Na2SO4, filtered, and concentrated. The crude residue was dissolved in acetic acid and treated with 4 mL HBr solution (30 weight % in AcOH). The reaction was stirred for 3 hours at room temperature, and concentrated to provide 1.1 g of yellow solid. 1H NMR (300 MHz, CD3OD) δ ppm 4.96 (q, J=8.7 Hz, 2H), 7.53 (d, J=9.0 Hz, 1H), 7.75 (dd, J=2.6, 9.1 Hz, 1H), 8.07 (d, J=2.7 Hz, 1H); MS (ESI+Q1MS) m/z 279 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:22]([CH2:26][CH3:27])[C:23](=O)[CH3:24])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:28][NH2:29]>>[OH:1][C:2]1[CH:3]=[C:4]([C:10]2[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[CH:22]([CH2:26][CH3:27])[C:23]([CH3:24])=[N:29][N:28]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: NN
Reactant: CCC(C(C)=O)c1cc(OC)c(OC)cc1C(=O)c1ccc(OC)c(O)c1
Product: CCC1C(C)=NN=C(c2ccc(OC)c(O)c2)c2cc(OC)c(OC)cc21

Procedure:
Annulation of 3-{2-[(3-hydroxy-4-methoxyphenyl)carbonyl]-4,5-dimethoxyphenyl}pentan-2-one by reaction with hydrazine to yield 1-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH:3]=1.[F-:20].[Cs+]>CS(C)=O>[F:20][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH:3]=1
Reactant: O=C(O)c1nn(-c2cc(I)ccn2)c2c1C[C@H]1C[C@@H]21
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(O)c1nn(-c2cc(F)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 200 °C
Yield: 69.8 %

Procedure:
To a solution of (1aR,5aR)-2-(4-iodo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (174 mg, 0.47 mmol) in DMSO (2.5 mL) was added cesium fluoride (500 mg, 3.29 mmol). The mixture was heated under microwave irradiation at 200° C. for 60 min. The mixture was purified by preparative HPLC to give the title compound as a white solid (85 mg). LCMS m/z=260.1 [M+H]+.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([CH2:6]/[C:7](/[CH3:10])=[CH:8]/[F:9])[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[Br:17]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl>[F:9]/[CH:8]=[C:7](\[CH2:10][Br:17])/[CH2:6][N:5]1[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]2[C:1]1=[O:16]
Reactant: NC(=O)CCC(=O)NBr
Reactant: C/C(=C\F)CN1C(=O)c2ccccc2C1=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1C/C(=C/F)CBr

Procedure:
A mixture of 1-phthalimido-2-methyl-3-fluoro-2-propene (prepared in Step E) (2.09 g) and N-bromosuccinamide (1.78 g) in carbon tetrachloride (100 ml) was refluxed for 45 min. The cooled mixture is filtered and the filtrate is washed with water, dried and evaporated to leave an almost colorless oil. Chromatography (silica; 20% ether in light petroleum) followed by recrystallization of the major fractions from EtOAc/light petroleum gives:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10].[CH:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([C:17]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:10])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NCCc1ccccc1Cl
Reactant: O=C(Cl)C1CCCCC1
Product: O=C(NCCc1ccccc1Cl)C1CCCCC1

Procedure:
1-Amino-2-(2-chlorophenyl)ethane and cyclohexanecarbonyl chloride was reacted in the same way as in step (a) of Example 13 to afford 1-cyclohexylcarbonylamino-2-(2-chlorophenyl)ethane having a melting point of 93.5° to 93.9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22].[NH2:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:35])[NH:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:34][C:32]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28](=[O:35])[NH:29]2)=[C:24]([N:23]=[CH:11][C@@:10]([OH:17])([C:13]([F:14])([F:16])[F:15])[CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:22])[C:4]=2[O:20][CH3:21])[CH2:18][CH3:19])[CH:33]=1
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(C)c1OC
Reactant: Nc1cc(F)cc2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cc(F)cc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(C)c1OC

Procedure:
In the same way as in Example 130, 271 mg (0.51 mmol) of (2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 90 mg (0.51 mmol) of 5-amino-7-fluoroquinolin-2(1H)-one and 0.32 ml (1.02 mmol) of titanium tert-butoxide are reacted to give 7-fluoro-5-{[(2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]-amino}quinolin-2(1H)-one. 320 mg of crude imine are cyclized in the same way as in Example 130 at −30° C. with 4.1 ml (4.1 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) yields 165 mg of desired product.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12].[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:17]([O:15][C:14](=[O:16])[C@H:6]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])[NH2:5])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCO
Solvent: O=S(Cl)Cl
Product: CCCCCCCCOC(=O)[C@@H](N)CCCNC(=N)N
Temperature: 90 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
One millimole thionyl chloride was added to a stirred suspension of one millimole L-arginine free base in 50 mL of octanol under nitrogen. The mixture was heated to 90° C, and the temperature was maintained with stirring for 2 hours. The mixture was cooled to 60° C, one more equivalent of thionyl chloride was added, and the mixture was stirred at 60° C. for an additional 2 hours, at which time the reaction was seen to be complete by TLC (performed as described in Example 33). Excess thionyl chloride was allowed to evaporate. Then, the solution was cooled to room temperature, and 250 ml diethyl ether was added. Washing of the resultant soft white precipitate with saturated sodium bicarbonate solution gave a white solid. Filtration of this suspension and washing of the filtrate with saturated sodium bicarbonate solution (3× with 20 ml), water (3× with 20 ml), acetone (3× with 20 ml) and diethyl ether (3× with 20 ml) gave arginine octyl ester. The yield was 85%. FAB mass spectrometry gave the expected parameters for arginine octyl ester.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][Cl:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][Cl:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCCCl)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCCCl)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 82.8 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.8 g.), conc. hydrochloric acid 1.6 g.), methanol (27 ml.) and tetrahydrofuran (40 ml.) were treated in a similar manner to that of Example 15-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.4 g.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH:13]=O)[C:4](=[O:15])[CH:3]=1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:13][CH2:12][N:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([Cl:1])=[CH:3][C:4]4=[O:15])[CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: O=CCn1c(=O)cc(Cl)c2ccccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To 20 mL of a chloroform solution containing 179 mg of (4-chloro-2-oxoquinolin-1(2H)-yl)acetaldehyde and 286 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 47 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 269 mg of sodium triacetoxyborohydride was added and stirred for 1 hour. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography[Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=50:1], to give 177 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-chloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.