Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C@@H:7]2[CH2:12][N:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][C:3]=1[OH:22].C(N(CC)CC)C.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>ClCCl.CN(C)C1C=CN=CC=1>[CH2:13]([N:11]1[CH2:10][CH2:9][NH:8][C@H:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([O:22][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:4]=2)[CH2:12]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2)ccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of (2R)-2-(4-chloro-3-hydroxybenzyl)-4-benzylpiperazine (3.78 g) and triethylamine (5.71 ml) in dichloromethane was added 4-dimethylaminopyridine (0.29 g) and tert-butyldimethylsilyl chloride (5.30 g) successively with ice bath cooling under nitrogen atmosphere. After stirring overnight at room temperature, water (50 ml) was added to the mixture and the organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of dichloromethane and methanol (10:1) as eluent to give (2R)-4-benzyl-2-[4-chloro-3-(tert-butyldimethylsilyloxy)benzyl]piperazine (4.11 g) as an oil.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:21]=3)[C:10]=2[O:9]1
Reactant: COc1cccc(B(O)O)c1
Reactant: CNCC1Cc2cccc(Br)c2O1
Product: CNCC1Cc2cccc(-c3cccc(OC)c3)c2O1

Procedure:
The title compound was prepared (0.41 g, 49%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 3-methoxyphenylboronic acid (0.188 g, 1.24 mmol). mp 148-151° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8](Br)[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[O:6].[OH:20][C:21]1C=C(C=CC=1)C=O>>[CH3:21][O:20][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCCCCCCOc1c(Br)cc(C=O)cc1Br
Product: CCCCCCCCOc1ccc(C=O)cc1OC

Procedure:
The title compound was prepared using a procedure analogous to Aldehyde 3 substituting 3-methoxy-4-hydroxybenzaldehyde for 3-hydroxybenzaldehyde: ESI-MS 265.2 (M+H)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C([S:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])C1C=CC=CC=1.[OH-].[Na+].Cl>C1C=CC=CC=1>[SH:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccccc1SCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: N#Cc1ccccc1S
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
In a 3-neck round bottom flask that contained an addition funnel was added benzene (40 mL). The flask was placed under N2 atmosphere and cooled in an ice water bath (0° C.). Aluminum chloride (4.88 g, 36.61 mmol) was added to the benzene solution. A solution of 2-(benzylthio)benzonitrile (5.0 g, 22.19 mmol) from Step 1(A) in benzene (40 mL) was added to the addition funnel. The solution was added dropwise over forty minutes and the reaction mixture was stirred at 0° C. for one hour and then stirred at room temperature for 48 hours. The reaction was worked up by pouring the crude mixture into ice water (200 mL) and stirring for 30 minutes. 10% NaOH (100 mL) solution was added and the mixture was stirred for 10 minutes. The solution was acidified (pH=2) by addition of 6N hydrochloric acid (HCl). The solution was placed in a separatory funnel and extracted with dichloromethane (3×100 mL). The combined organics were dried over Na2SO4 and then concentrated under reduced pressure to afford a brown oil. The product was purified by flash silica column chromatography. Elution through an 80-g Silicycle® flash silica cartridge with 5% ethyl acetate in heptanes afforded the title compound as a brown oil (2.55 g, 85%); Rf of 0.56″ with 70:30 v/v heptanes: ethyl acetate; 1H-NMR (400 MHz; CDCl3) δ 7.52 (d, 1H), 7.39-7.32 (m, 2H), 7.19-7.14 (m, 1H), 4.01 (s, 1H); MS (ESI−) m/z 134.05 (Mz−1).
Reaction SMILES: [CH2:1]([N:4]([CH2:15][C:16]#[CH:17])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].C1C[O:21][CH2:20]C1>>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([S:5]([N:4]2[CH2:1][CH:2]3[CH2:3][C:20](=[O:21])[CH:17]=[C:16]3[CH2:15]2)(=[O:7])=[O:6])=[CH:13][CH:12]=1
Reactant: C1CCOC1
Reactant: C#CCN(CC=C)S(=O)(=O)c1ccc(C)cc1
Product: Cc1ccc(S(=O)(=O)N2CC3=CC(=O)CC3C2)cc1
Temperature: 65 °C
Yield: 33 %

Procedure:
To a suspension of the catalyst A precursor resin, shown above {24 mg, 0.025 mmol[Co2(CO)m]} in anhydrous THF(5 cm3) was added N-(2-propenyl)-N-(2-propynyl)-4-methylphenylsulfonamide (125 mg, 0.5 mmol) and the resulting mixture was heated to 65° C. under an atmosphere of CO (50 mbar). After 48 h the mixture was filtered, the resin was washed with THF (2×1 cm3) and the combined filtrates were concentrated in vacuo. 1H-NMR spectroscopy of the pale yellow residue indicated a 1:1 mixture of starting material and product and no by-products. Purification by flash chromatography (SiO2, 20% EtOAc/hexane) gave the title compound (46 mg, 0.167 mmol, 33%) as a white solid; mp 147-149° C.; vmax(CH2Cl2)/cm−1 3058, 1716, 1651, 1350, 1164, 1094, 673; δH (360 MHz)(CDCl3) 1.96-2.02 (1 H, m), 2.32 (3 H, s, CH3), 2.48-2.58 (2 H, m), 3.01-3.36 (1 H, m), 3.93-3.98 (2 H, m), 4.27 (1 H, d, J 16.5), 5.92 (1 H, s, C═CH), 7.28 (2 H, d, J 8, Ar-H), 7.66 (2 H, d, J 8, Ar-H); δC{1H} (90 MHz)(CDCl3) 21.6 (CH3), 39.8 (CH2), 44.0 (CH), 47.7 (CH2), 52.5 (CH2), 126.2 (CH), 127.5 (CH), 130.1 (CH), 133.7 (C), 144.2 (C), 178.6 (C), 207.2 (C═O).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][CH:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH3:6].[OH-].[K+].S(OC)(O[CH3:24])(=O)=O>CS(C)=O>[CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][CH:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:24])[CH:8]=1)[CH3:6]
Reactant: COC(CC(C)c1c[nH]c2ccccc12)OC
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(CC(C)c1cn(C)c2ccccc12)OC
Temperature: 25 °C

Procedure:
(R)-3-(1H-Indol-3-yl)-butanal (236 mg, 1.26 mmol) was dissolved in methanol (15 mL) and treated with trimethyl orthoformate (275 μl, 2.50 mmol) and a catalytic amount of p-TSA. The reaction was stirred at room temperature for 3 hours, at which time H2O (10 mL) was added and the reaction was extracted with ether (3×20 mL). The collected organics were rinsed with brine, dried over Na2SO4, and concentrated in vacuo to provide 3-(3,3-dimethoxy-1-methyl-propyl)-1H-indole (228 mg, 1.17 mmol). 3-(3,3-dimethoxy-1-methyl-propyl)-1H-indole (39.9 mg, 0.171 mmol) was dissolved in a KOH (38.4 mg, 0.684 mmol)/DMSO (2 mL) solution and allowed to stir at 0° C. for 10 min, at which time dimethyl sulfate (32.5 μl, 0.340 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was left to stir at room temperature until it appeared done by TLC. The reaction was quenched with H2O (1 mL) and brought to a neutral pH with dropwise addition of 1M HCl. The solution was extracted with Et2O (3×5 mL), and the collected organics were rinsed with brine, dried over Na2SO4, and concentrated in vacuo to provide 3-(3,3-dimethoxy-1-methyl-propyl)-1-methyl-indole. This crude residual material was dissolved in THF (5 mL) and 1M HCl (1 mL) to give (R)-3-(1-methyl-1H-indol-3-yl)-butanal (1.9 mg, 0.0094 mmol) after preparative TLC (25:75 EtOAc/hexanes). [α]D=−4.1 (c=1.0, CHCl3); reported rotation for (R)-3-(1-methyl-1H-indol-3-yl)-butanal [α]D=−4.2 (c=1.0, CHCl3).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH3:10])([O-:9])=[O:8].[Br:11][C:12]1[CH:13]=[C:14]([Cl:19])[C:15](Cl)=[N:16][CH:17]=1.[Cl-].[NH4+]>CS(C)=O.O>[Br:11][C:12]1[CH:13]=[C:14]([Cl:19])[C:15]([CH2:10][N+:7]([O-:9])=[O:8])=[N:16][CH:17]=1
Reactant: C[N+](=O)[O-]
Reactant: Clc1cc(Br)cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])Cc1ncc(Br)cc1Cl
Temperature: 25 °C
Yield: 28.3 %

Procedure:
To 12.4 g of potassium tert-butoxide in 79 ml of dimethylsulfoxide, 6.7 g of nitromethane was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 1 hour. Then, the reaction mixture was added dropwise to 25.0 g of 5-bromo-2,3-dichloropyridine in 20 ml of dimethylsulfoxide with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for 23 hours and at 50° C. for 6 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 100 ml of water and 100 ml of saturated aqueous ammonium chloride and extracted with ethyl acetate (200 ml×2). The resulting organic layers were combined, washed with water (100 ml×3) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 30:70) as the eluent to obtain 7.8 g of the desired product as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH:10]([C:13]([OH:15])=[O:14])[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C=C(C(=O)O)CO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cccc2c1CC(C(=O)O)CO2
Reaction time: 1 h

Procedure:
A mixture of 5-methoxy-2H-1-benzopyran-3-carboxylic acid (12.25 g, prepared in a similar manner to that described above), 10% palladium-on-carbon catalyst (3 g) and ethanol (250 ml) was hydrogenated at 1 atmosphere for 1 hour. Hydrogen uptake was slow, so further catalyst (3 g) was added, and hydrogenation continued for 5 hours. The mixture was filtered and the solvent removed in vacuo to leave a semisolid which crystallised from 2-propanol to give a mass of pale yellow crystals which was broken up, collected by filtration, washed with ice-cold 2-propanol, dried in vacuo, ground to a powder, and redried in vacuo to give 5-methoxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid as a buff powder (7.4 g), m.p. 147°-150° C.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>N1CCCCC1.C(OCC)C>[CH2:13]([C:19]1[CH:26]=[CH:25][C:22](/[CH:23]=[C:9](/[C:10](=[O:12])[CH3:11])\[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCc1ccc(C=O)cc1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CCCCCCc1ccc(/C=C(/C(C)=O)C(=O)c2ccccc2)cc1
Reaction time: 48 h

Procedure:
Benzoylacetone (0.65g, 0.004 moles), parahexylbenzaldehyde (0.76g, 0.004 moles) and piperidine (3 drops) were stirred in ethyl ether (10ml) for 20 hrs. An additional 200mg benzoylacetone was added and the solution stirred for 48 hrs. The solution was concentrated to an oil with a gentle stream of Nitrogen. The product was purified by silica gel chromatography. The structure assignment was supported by NMR, infrared and uv spectra and elemental analysis (334.5).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>C(OCC)(=O)C>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][CH2:9][CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: BrCCCCCCBr
Reactant: Cc1cccc(CCO)n1
Solvent: CCOC(C)=O
Product: Cc1cccc(CCOCCCCCCBr)n1
Yield: 82.2 %

Procedure:
From 6-methyl-2-pyridineethanol (5 g) and 1,6-dibromohexane (26 g), stirring the reaction mixture under nitrogen for 18 h, and using ethyl acetate for extraction. FCC eluting with cyclohexane→cyclohexane-ethyl acetate (92:8) gave the title compound as a yellow oil (9 g), t.l.c. (System A 80:20:1) Rf 0.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]([C:33]1[C:34]([CH:39]=O)=[N:35][CH:36]=[CH:37][CH:38]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:39][C:34]2[C:33]([C:25]([CH3:26])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:24])=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: CC(C)(c1ccccc1)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester and 3-(1-Methyl-1-phenyl-ethyl)-pyridine-2-carbaldehyde with NaBH(OAc)3 in CH2Cl2 gave 4-{(3,5-Dimethyl-pyridin-2-ylmethyl)-[3-(1-methyl-1-phenyl-ethyl)-pyridin-2-ylmethyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a white solid. Deprotection with TFA using General Procedure F gave (3,5-Dimethyl-pyridin-2-ylmethyl)-[3-(1-methyl-1-phenyl-ethyl)-pyridin-2-ylmethyl]-piperidin-4-yl-amine as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].N12CCN(CC1)CC2.C(OCC)(=O)C>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:15]([N:14]([CH3:18])[CH3:13])=[S:16])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1O
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Br)cc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
4-Bromosalicylic acid (15.5 g, 71 mmol) was dissolved in methanol (500 ml), and concentrated sulfuric acid (9.7 g, 99 mmol) was added thereto. The reaction mixture was refluxed for 24 hrs, and the solvent was evaporated. The residue was neutralized with 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:20, v/v) were collected and concentrated to give methyl 4-bromosalicylate (8.7 g, 52%). Methyl 4-bromosalicylate (8.7 g, 37 mmol) and N,N-dimethylthiocarbamoyl chloride (6.0 g, 48 mmol) were dissolved in DMF (80 ml), and 1,4-diazabicyclo[2.2.2]octane (5.5 g, 49 mmol) was added thereto. The reaction mixture was stirred at room temperature for 24 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:4, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (10.6 g, 88%) as white crystals.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][S:7][CH2:6][NH:5]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([N:5]2[C:4](=[O:3])[CH2:8][S:7][CH2:6]2)(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: O=C1CSCN1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CSCC2=O)cc1
Yield: 41.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (0.58 g) was added portionwise to a solution of 4-oxothiazolidine (1.50 g) and 4-methoxybenzenesulfonyl chloride (3.01 g) in tetrahydrofuran (30 ml) at 0° C. with stirring and the mixture was stirred for 1 hour at the same temperature. After the solvent was evaporated in vacuo, the residue was mixed with ethyl acetate (10 ml) and water (50 ml) and the resultant precipitate was collected by filtration. The cake was washed with water and diisopropyl ether and recrystallized from a mixture of ethanol and ethyl acetate to give 3-(4-methoxybenzenesulfonyl)-4-oxothiazolidine (1.65 g) as slightly brown prisms.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([N:15]4[CH2:20][CH2:19][N:18](C(OCC)=O)[CH2:17][CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:27])[C:6]([C:28]([O:30]CC)=[O:29])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>>[N:15]1([C:11]2[C:12]([CH3:14])=[C:13]3[C:8]([C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:26])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 48.4 %

Procedure:
To ethyl 1-cyclopropyl-7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.8 g) is added 10% aqueous sodium hydroxide (7 ml), and the mixture is refluxed for 5 hours. After cooling, the mixture is acidified with diluted hydrochloric acid and is extracted with dichloromethane. The aqueous layer is adjusted to about pH 7.5 with sodium hydrogen carbonate, and the resulting precipitates are separated by filtration to give 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.3 g), m.p. 291°-295° C. (decomp.).
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:24]([OH:26])=[O:25])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:15]4[N:14]=[C:13]([CH2:22][OH:23])[CH:12]=3)[CH2:7][S:8][C@H:3]12.CO.[C:31]1([C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N+]=[N-])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=NN)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl.CCOCC.CCCCCC>[NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:24]([O:26][CH:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:25])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:15]4[N:14]=[C:13]([CH2:22][OH:23])[CH:12]=3)[CH2:7][S:8][C@H:3]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cc(CO)nc4nc(CO)nn34)CS[C@H]12
Agent: NN=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3cc(CO)nc4nc(CO)nn34)CS[C@H]12

Procedure:
In a suspension of 5.3 g of 7-amino-3-[(2,5-bis(hydroxy- methyl)-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylic acid, 35 ml of methanol and 100 ml of methylene chloride was added dropwise, while stirring, diphenyldiazomethane synthesized from 6.9 g of benzophenonehydrazone, 7.6 g of mercuric oxide (yellow) and 70 ml of n-hexane, in 30 ml of methylene chloride solution, and the mixture was stirred at room temperature overnight. After the reaction mixture was condensed, ether was added thereto to crystalize, and crystal was collected by filtration and dried to obtain 7.28 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1)[N:8]([CH:17]1[CH2:19][CH2:18]1)[C:7]2=[O:20].[CH3:21][C@@H:22]1[C:26]2[NH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[C:24](=[O:39])[NH:23]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH:17]1([N:8]2[C:7](=[O:20])[C:6]3[C:11](=[C:2]([C:28]4[NH:27][C:26]5[CH:22]([CH3:21])[NH:23][C:24](=[O:39])[C:25]=5[CH:29]=4)[CH:3]=[CH:4][CH:5]=3)[NH:10][C@H:9]2[NH:12][C:13]2([CH3:16])[CH2:15][CH2:14]2)[CH2:19][CH2:18]1
Reactant: CC1(Nc2nc3c(Br)cccc3c(=O)n2C2CC2)CC1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Product: CC1NC(=O)c2cc(-c3cccc4c3N[C@@H](NC3(C)CC3)N(C3CC3)C4=O)[nH]c21
Temperature: 45 °C
Yield: 58.8 %

Procedure:
A microwave tube was charged with 8-bromo-3-cyclopropyl-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (492a; 170 mg, 0.51 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705; 167 mg, 0.64 mmol), X-Phos pre-catalyst II generation (Sigma-Aldrich; 20 mg, 0.025 mmol) and K3PO4 (Sigma-Aldrich; 324 mg, 1.53 mmol). The tube was sealed and purged with argon for 5 min. 1,4-Dioxane (1.4 mL) and water (0.35 mL) were added and Ar (g) was bubbled through the mixture for 5 min. The tube was sealed and heated in an oil bath at 45° C. for 90 min. The reaction was then cooled to RT and EtOAc and water were added. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-10% MeOH in CH2Cl2), to provide (R)-3-cyclopropyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(1H)-one (492) (117 mg, 0.30 mmol, 59% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.01 (s, 1H), 8.09 (dd, J=7.63, 1.37 Hz, 1H), 7.77 (dd, J=7.73, 1.27 Hz, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.13 (t, J=7.73 Hz, 1H), 6.93 (d, J=0.98 Hz, 1H), 4.63 (q, J=6.46 Hz, 1H), 2.67-2.74 (m, 1H), 1.55 (s, 3H), 1.36 (d, J=6.65 Hz, 3H), 1.19-1.27 (m, 2H), 0.99-1.04 (m, 2H), 0.83-0.88 (m, 2H), 0.73 (dd, J=3.91, 2.54 Hz, 2H). m/z (ES, +ve) 390.0 (M+H)+.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].C([NH:20][CH2:21][C:22](O)=[O:23])(OC(C)(C)C)=O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:7]([C:6]1[CH:5]=[CH:4][C:2]([O:3][C:22](=[O:23])[CH2:21][NH2:20])=[C:1]([O:11][CH3:12])[CH:10]=1)[CH:8]=[CH2:9]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CCc1ccc(OC(=O)CN)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.5 %

Procedure:
To a solution of Eugenol (0.3 g, 1.82 mmol) in DCM (20 mL), was added Boc-glycine (0.35 g, 2.01 mmol), N-methyl morpholine (0.65 mL, 6.00 mmol), EDC.HCl (0.76 g, 4.0 mmol) and DMAP at ice temperature. The mixture was allowed to stir at room temperature (25° C.) over a period of 12 h. The resulting mixture was diluted with DCM (100 mL), washed with water (2×50 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was purified by silica gel column chromatography to obtain resulting product as pale yellow oil (300 mg, 46.9%)