Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C(NCCNC(C)C)(C)C.[Cl:20][CH2:21][C:22](Cl)=[O:23].CCOC(C)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:22](=[O:23])[CH2:21][Cl:20]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(C)c1O
Agent: CC(C)NCCNC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cccc(C)c1OC(=O)CCl
Temperature: -78 °C
Yield: 94.6 %

Procedure:
Under a nitrogen atmosphere: 2,6-dimethylphenol (1.0 equivalent, 40 mmoles) was dissolved in dichloromethane (40 mL) and diisopropyl ethylene diamine (1.3 equivalents, 53.2 mmoles). This solution was cooled to −78° C. Chloroacetylchloride was added all at once. The reaction was followed by 1TLC (25 EtOAc:75 Hexanes) until reaction was complete (˜10 minutes). The reaction was extracted using water and ether. The ether layer was washed with water and then brine, dried (MgSO4), filtered, rinsed with ether, and concentrated under vacuum. The concentrate was purified by silica gel column chromatography using hexanes as eluant, to afford 10.5 grams (94.6% yield) of chloro-acetic acid 2,6-dimethyl-phenyl ester product as a tan oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:18])[CH:14]=2)[C@H:9]1[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=O)(C)(C)C>CCO.Cl.O1CCOCC1>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[C@@H:9]1[C:10]2[C:15](=[CH:14][C:13]([F:18])=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1)[CH3:32]
Reactant: CCOC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccc(F)cc2CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(Cl)cc1[C@H]1NCCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (640 mg, 1.38 mmol, 1 eq.) in EtOH (2.5 mL), 4M HCl in dioxane (5.5 mL) was added. The resulting solution was stirred at r.t. for 3 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between AcOEt and a sat. aq. NaHCO3 soln. The layers were separated and the aq. phase was extracted with AcOEt. The comb. org. phases were concentrated in vacuo to give the free amine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH2:17]([NH:20][C:21]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])=[O:22])[CH2:18][CH3:19]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([C:21]([NH:20][CH2:17][CH2:18][CH3:19])=[O:22])[CH:24]=2)=[N:3][CH:4]=1
Reactant: CCCNC(=O)c1cccc(N)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: CCCNC(=O)c1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-[(N-propylamino)carbonyl]aniline were reacted to provide 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-propylamino)carbonyl]phenyl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.00 (d, 1H, J=5.4 Hz), 7.84 (t, 1H, 31.8 Hz), 7.69-7.59 (m, 2H), 7.44 (t, 1H, J=7.5 Hz), 7.16-7.05 (m, 3H), 6.67 (td, 1H, J=2.4 and 7.2 Hz), 3.34-3.29 (m, 2H), 1.65-1.56 (m, 2H), 0.96 (t, 3H, J=7.5 Hz); 19F NMR (282 MHz, CD3OD): −46049; LCMS: purity: 94%; MS (m/e): 382 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][O:14][C:13](=[O:16])[C:12]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC(C[AlH]CC(C)C)C.[OH-].[Na+]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[C:12](\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)/[CH2:13][OH:16])/[CH2:15][OH:14])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)OC2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(CO)=C(/CO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a solution of 110 g of 4-(4-methanesulfonyl-phenyl)-3-phenyl-5H-furan-2-one in 1.5 L of dichloromethane stirred at −78° C., 150 mL of DIBAL was added dropwise. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was then cooled to −78° C., and 1.2 L of 1 M aqueous NaOH was added dropwise. After the addition, the resulting mixture was warmed to room temperature and the organic phase was separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined and dried over Na2SO4. 110 g of the titled compound was obtained after evaporation. 1H NMR (acetone-d6, 500 MHz): δ 7.69 (d, 2H), 7.36 (d, 2H), 7.16-7.05 (m, 5H), 4.66 (d, 2H), 4.63 (d, 2H), 4.19 (t, 1H, OH), 4.17 (t, 1H, OH), 3.04 (s, 3H).
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.Br[CH2:24][CH2:25][CH2:26][Cl:27]>O1CCCC1>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:12][CH2:11]1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)NC1CCNCC1
Reactant: ClCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCC(=O)NC1CCN(CCCCl)CC1

Procedure:
A mixture of 4-heptanoylaminopiperidine (7.49 g; preparation 16), triethylamine (9.79 ml) and 1-bromo-3-chloropropane (5.38 ml) in 200 ml of dry tetrahydrofuran was refluxed for 4 hours, then a further 9.79 ml of triethylamine and 5.38 ml of 1-bromo-3-chloropropane were added. The reaction mixture was refluxed overnight, then concentrated to dryness, treated with 100 ml of saturated aqueous potassium carbonate solution and extracted with ethyl acetate (2×100 ml). The organic extracts were pooled, dried over sodium sulfate and concentrated to dryness to give 15 g of an oil which was purified by silica gel chromatography (eluent chloroformlmethanol 9:1) to give, after crystallization from 30 ml of hexane, 6.12 g of the product, m.p. 68-70° C.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:24][C:22]1[S:23][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:21]=1
Reactant: CCOC(=O)C(=NOCc1ccc(C)cc1)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCc1ccc(C)cc1)c1csc(N)n1
Yield: 38.7 %

Procedure:
Ethyl 4-chloro-2-(4-methylbenzyloxyimino)-3-oxobutyrate (syn isomer, 19.88 g.), thiourea (5.59 g.), sodium acetate (9.99 g.), water (45 ml.) and ethanol (45 ml.) were treated in a similar manner to that of Example P-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(4-methylbenzyloxyimino)-acetate (syn isomer, 8.25 g.).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:6]([C:12](=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:7][CH:8]=[C:9]([Cl:11])[CH:10]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:11][C:9]1[CH:10]=[C:5]2[NH:3][N:2]=[C:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]2=[N:7][CH:8]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1F)c1ncc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: Fc1ccccc1Cc1n[nH]c2cc(Cl)cnc12
Temperature: 160 °C

Procedure:
A little DMAP and 238 mg (4.75 mmol) of hydrazine hydrate are added to a solution of 1.35 g (4.75 mmol) of 1-(3,5-dichloropyridin-2-yl)-2-(2-fluorophenyl)ethanone from example 2A in 12 ml of pyridine. The mixture is heated in a closed vessel in a microwave at 160° C. for 20 min and then concentrated in vacuo, and the residue is purified by chromatography on silica gel (eluent: dichloromethane/methanol 100:3). 507 mg (41% of theory) of the title compound and 388 mg of the uncyclized hydrazone are obtained. The latter is heated anew in 5 ml of DMF in the microwave at 200° C. for 1.5 h. The solution is concentrated and the residue is purified by preparative HPLC. A further 176 mg (12% of theory) of the title compound are obtained in this way.
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19].Cl>>[CH3:21][O:20][C:18]([NH:1][C@@H:2]([CH:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)[C:3]([OH:5])=[O:4])=[O:19]
Reactant: N[C@H](C(=O)O)C1CCOCC1
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
A solution of (S)-amino-(tetrahydro-pyran-4-yl)-acetic acid (200 mg, 1.26 mmol) in saturated aqueous sodium bicarbonate solution (2.46 mL, 25.13 mmol) was stirred until all solids were dissolved. Methyl chloroformate (0.19 mL, 2.51 mmol) was added dropwise, the reaction mixture was stirred for 30 min, and 1N HCl was added to adjust pH to 1. The reaction mixture was extracted with ethyl acetate (3×5 mL) and the organic extracts were dried over sodium sulfate, filtered, concentrated and dried overnight under vacuum to give the title intermediate (248 mg, 91% yield) as a white, sticky solid. (m/z): [M+H]+ calcd for C9H15NO5 218.10. found 218.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)=[CH:11][C:10]([CH:21]=O)=[N:9]1.[CH3:23][NH2:24].CO.CO.[BH4-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)=[CH:11][C:10]([CH2:21][NH:24][CH3:23])=[N:9]1
Reactant: Cc1cccc(Sc2cc(C=O)nn2-c2ccccc2Cl)n1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc(Sc2cccc(C)n2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2-chlorophenyl)-5-[(6-methylpyridin-2-yl)thio]-1H-pyrazole-3-carbaldehyde (415 mg) in tetrahydrofuran (4 mL) were added 40% methylamine-methanol solution (1.5 mL) and methanol (4 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. Sodium borohydride (905 mg) was added to the reaction mixture at 0° C. and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 450 mg, yield quantitative).
Reaction SMILES: [CH:1]1([CH2:4][S:5][C:6]2[CH:7]=[C:8]([O:28][C:29]3[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=3)[C:9]([NH:12][C:13]3[S:17][N:16]=[C:15]([C@H:18]4[CH2:22][O:21]C5(CCCCC5)[O:19]4)[N:14]=3)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.Cl>C(O)C>[CH:1]1([CH2:4][S:5][C:6]2[CH:7]=[C:8]([O:28][C:29]3[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=3)[C:9]([NH:12][C:13]3[S:17][N:16]=[C:15]([C@H:18]([OH:19])[CH2:22][OH:21])[N:14]=3)=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Cc1ncccc1Oc1cc(SCC2CC2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Oc1cc(SCC2CC2)cnc1Nc1nc([C@H](O)CO)ns1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
To a solution of (S)-N-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)-pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decane-2-yl)-1,2,4-thiadiazol-5-amine (0.30 g, 0.586 mmol) in ethanol (20 mL) was added 1 M HCl (0.87 mL) and the reaction heated to 80° C. for 2 hours. The reaction was cooled and concentrated in vacuo and the solid triturated with ethanol The solid was dried in vacuo to afford (S)-1-(5-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)-pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol (0.146 g, 0.338 mmol, 57.7% yield) as the mono HCl salt. Mass Spectrum (apci) m/z=432.0 (M+H−HCl).
Reaction SMILES: [CH3:1][C:2]1CC[CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:40])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:39])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](\[CH3:38])/[CH:22]=[CH:23]/[CH:24]=[C:25](\[CH3:37])/[CH:26]=[CH:27]/[C:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][CH2:30][C:29]=1[CH3:36].C(Cl)(Cl)Cl.[OH2:45].[CH2:46]([OH:48])[CH3:47]>>[CH3:1][C:2]1[C:46](=[O:48])[CH2:47][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:40])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:39])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](\[CH3:38])/[CH:22]=[CH:23]/[CH:24]=[C:25](\[CH3:37])/[CH:26]=[CH:27]/[C:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][C:30](=[O:45])[C:29]=1[CH3:36]
Reactant: O
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Reactant: CCO
Solvent: ClC(Cl)Cl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)CCC2(C)C)C(C)(C)CCC1=O
Yield: 85 %

Procedure:
Into a flask was charged 0.5 gm of β-carotene and 10 ml of chloroform. The mixture is stirred to form a solution. Into this solution was charged 1.6 ml of the oxidant solution described in example 1. The mixture was stirred for 1.5 hours to complete the reaction. The phases were separated and the organic phase was washed with water once and evaporated to yield a residue that was dissolved in 10 ml of warm ethanol. This ethanol solution was added slowly to 50 ml of water to form a precipitate which was filtered and dried to yield 85% yield of canthaxanthin of approximately 80% purity.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br>C(Cl)(Cl)Cl.CC(O)=O>[Br:15][CH2:13][C:12]([C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][O:9][CH:10]=1)=[O:14]
Reactant: CC(=O)c1conc1-c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1conc1-c1ccccc1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
To a solution of 1-(3-phenyl-isoxazoi-4-yl)-ethanone (6.35 g, 34 mmol) in chloroform (50 mL) and AcOH (1 mL) at 48° C. was added a solution of bromine (1.83 mL, 36 mmol) in chloroform (15 mL) over 10 min keeping the temperature below 50° C. After addition the reaction mixture was allowed to cool down to room temperature and poured into ice-water (200 mL). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate: 100:0 to 7:3) afforded the title compound (3.72 g, 41%) which was obtained as a light yellow solid. MS m/e (EI): 265.0/267.0 [M].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([O-])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[NH4+:12].[CH:13]([O-])([O-])OC>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:13][NH:12][C:7]2=[O:8]
Reactant: [NH4+]
Reactant: COC([O-])[O-]
Reactant: Nc1ccc(Cl)cc1C(=O)[O-]
Solvent: CC#N
Product: O=c1[nH]cnc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
In a 2-mL volume stainless steel pressure-resistant vessel were placed 340 mg (1.8 mmol) of ammonium 5-chloroanthranilate (prepared in the same manner as in Reference Example 3), 400 mg (3.6 mmol) of methyl orthoformate, and 1.5 mL of acetonitrile. The reaction was carried out at 120° C. for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and analyzed (according to absolute quantitative analysis) by high performance liquid chromatography. There was produced 303 mg (reaction yield: 93%) of 6-chloroquinazolin-4-one.
Reaction SMILES: S(O[CH2:6][CH2:7][CH:8]=[C:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]1=2)(C)(=O)=O.C(OC(=O)C(OCC)CC1C=CC(O)=CC=1)C.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1C=CC=CC=1>[CH:8](=[C:9]1[C:10]2[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=2[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2)[CH:7]=[CH2:6]
Reactant: CS(=O)(=O)OCCC=C1c2ccccc2CCc2ccccc21
Agent: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: C=CC=C1c2ccccc2CCc2ccccc21
Temperature: 100 °C
Yield: 70.8 %

Procedure:
A mixture of 5-(3-mesyloxypropylidene)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten (5.0 g, 15.2 mmol), ethyl -3-(4-hydroxyphenyl)-2-ethoxypropanoate (3.7 g, 15.5 mmol), potassium carbonate (2.9 g, 21 mmol) and dimethylformamide (10 ml) was heated at 100° C. for 5 h. Benzene (200 ml) and water (200 ml) were added and the phases were separated. The organic phase was dried and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with benzene/chloroform, to give first 2.5 g of 5-propenylidene-10,11-dihydro-5H-dibenzo(a,d)cyclohepten and then 1.5 g (21%) of the title compound as an oil. 1H NMR (250 MHz, CDCl3) δ7.10-7.35 (m, 10 H); 6.85 (d, 2 H); 6.06 (t, 1 H); 4.27 (q, 2 H); 4.07 (m, 3 H); 3.68 (m, 1 H); 3.45 (m, 1 H); 3.17 (bs, 4 H); 3.06 (d, 2 H); 2.69 (q, 2 H); 1.27 (t, 3 H); 0.99 (t, 3 H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:17]([N:18]=[N+:19]=[N-:20])[C@@H:16]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[O:14][C@H:6]1SC1C=CC=CC=1)(=[O:3])[CH3:2].[Br:30]Br.CCCCCCC.C1CCCC=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:17]([N:18]=[N+:19]=[N-:20])[C@@H:16]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[O:14][C@@H:6]1[Br:30])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(C)=O)[C@@H](N=[N+]=[N-])[C@H]1OC(C)=O
Reactant: BrBr
Agent: C1=CCCC1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](N=[N+]=[N-])[C@H]1OC(C)=O

Procedure:
Compound 7 (237.4 mg, 560 μmol) was dissolved in dry CH2Cl2 (2 mL), and bromine (32 μl, 620 μmol) was added. The reaction was monitored by TLC (heptane:EtOAc, 1:1). When the reaction was complete, a small amount of cyclopentene was added to the reaction mixture to remove the rests of Br2. The mixture was concentrated under reduced pressure and purified by quick Flash chromatography (Eluent: 500 mL heptane:EtOAc, 2:1).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[O:4]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1>[N:32]1([CH2:2][CH:3]2[CH2:7][O:6][C:5]3([CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:11][CH2:12]3)[O:4]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: OCC1COC2(CCN(CCc3ccccc3)CC2)O1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc(CCN2CCC3(CC2)OCC(CN2CCOCC2)O3)cc1

Procedure:
2-hydroxymethyl-8-phenethyl-1,4-dioxa-8-azaspiro[4,5]decane (Compound 1.50 gm, 0.18 mole), Para Toluenesulfonic Acid (PTSA, 3.5 gms) was dissolved in toluene (300 ml) at 28° C. To this was added 18.5 gm of morpholine drop wise with continuous stirring, continued the stirring for 13 hrs at reflux temperature. Toluene was distilled under vacuum to get a semi-solid with brick red color. The yield of the product was 90%.
Reaction SMILES: [F:1][C:2]1[C:24]([S:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]2)=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.C(O)(C(F)(F)F)=[O:39].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[C:24]([S:25]([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]2)=[O:39])=[CH:23][C:5]2[C:6]3[N:10]([CH:9]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[N:7]=3)[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)(C)C(N)=O)CC4)c(F)cc2OCC3)n(C(C)C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)(C)C(N)=O)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To an ice-cooled solution of 2-{4-[8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}isobutyramide from Example 8 (96 mg, 0.183 mmol) in DCM (10 mL) was added TFA (42 μL, 0.548 mmol) followed by a solution of m-CPBA (35 mg, 0.201 mmol) in DCM (2 mL). The resulting mixture was stirred for 30 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 10-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3 in MeOH. The product containing fractions were concentrated in vacuo and further purified by column chromatography (Si-PCC, gradient 2-12% MeOH in DCM) affording 220 as a white solid (59 mg, 60%). LCMS: RT 2.54 min [M+H]+ 544.1. 1H NMR (DMSO, 400 MHz): δ 8.72 (1H, d, J=7.98 Hz), 7.93 (1H, s), 7.17-7.09 (2H, m), 6.86 (1H, s), 5.68-5.56 (1H, m), 4.67-4.50 (4H, m), 2.88-2.74 (3H, m), 2.26 (3H, s), 2.19-2.04 (2H, m), 1.92-1.84 (1H, m), 1.76-1.51 (3H, m), 1.50-1.42 (6H, m), 1.03 (6H, d, J=4.44 Hz)
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.[C:26](OC(=N)N(C(C)C)C(C)C)([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([O:22][C:21]([C:5]1[N:4]2[C:24](=[O:25])[CH:2]([NH2:1])[C@H:3]2[S:8][CH2:7][C:6]=1[CH:9]([S:15][C:16]1[NH:17][N:18]=[N:19][N:20]=1)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:23])([CH3:29])([CH3:28])[CH3:27]
Reactant: NC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(C(CCC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12

Procedure:
To a suspension of 19.3 g. (0.05 mol.) of 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 500 ml. of dry methylene chloride is added in one portion 30.0 g. (0.15 mol.) of O-t-butyldiisopropylpseudourea in 50 ml. of methylene chloride and the mixture is stirred at ambient temperature for 24 hours. The precipitate is removed by filtration and the filtrate is evaporated to give a residue which is taken up in 200 ml. of benzene and filtered again. The filtrate is extracted with three 100 ml. portions of cold 1N hydrochloric acid. The aqueous extracts are layered with ethyl acetate and the pH is adjusted to 7.5 by addition of solid sodium bicarbonate. The organic layer is separated and the aqueous phase is extracted with two 150 ml. portions of ethyl acetate. The combined extracts are dried (MgSO4), filtered and evaporated to dryness to give 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.B(O)O.[C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C([O-])([O-])=O.[K+].[K+]>>[C:26]([O:25][C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:34][CH:33]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)CCCNc1ccc2ncc(Br)n2n1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [K+]
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cnc3ccc(NCCCC(=O)O)nn23)cc1

Procedure:
The ethyl 4-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)butanoate was subjected to Suzuki coupling with N-Boc-benzyl amine boronic acid, using 4.0 equivalents of K2CO3 as the base and procedure described in example 5.6.19 to give the titled compound.