Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11](=O)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+].FC(F)(F)C(O)=O>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)[CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1c(C(=O)COc2ccccc2)oc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(COc2ccccc2)c2oc3ccccc3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
To a mixture of 1-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethanone (697 mg) synthesized above, methyl 4-aminobenzoate (399 mg), triethylamine (2.93 mL) and methylene chloride (10 mL) was added titanium (IV) chloride (344 μL) at 0° C. under argon atmosphere, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, methylene chloride was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (20 mL) of the obtained oil in tetrahydrofuran were added acetic acid (2 mL) and sodium cyanoborohydride (329 mg), and the mixture was stirred at room temperature for 15 min. Trifluoroacetic acid (2 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/hexane) to give the title object compound (279 mg, 27%) as a yellow solid.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:12]1[C:13]2[C:9](=[C:8]([O:7][CH3:6])[CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)[CH:3]1[O:5][CH2:4]1
Reactant: BrCC1CO1
Reactant: COc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1ccn2CC1CO1
Temperature: 60 °C

Procedure:
Epibromohydrin (0.64 ml, 7.5 mmole) was added to a stirred solution of 4-methoxyindole (1.0 g, 6.8 mmole) and sodium hydride (0.3 g, 7.8 mmole) in anhydrous DMF (20 ml), and the mixture was heated at 60° C. under nitrogen for two hours. Water (100 ml) was added and the product extracted into CH2Cl2 (3×25 ml). The combined organics were washed with water (25 ml), brine (25 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a yellow colored oil (1.5 g). This was purified by flash silica gel chromatography (30% ethyl acetate in hexane) to afford the titled product as a light oil (1.27 g, 92% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])[CH3:2].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:9])[C:5]([CH3:7])([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10])[CH3:6])[CH3:2]
Reactant: Cc1ccccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Oc1ccccc1C
Temperature: 100 °C

Procedure:
To a mixture of 2-bromo-2-methylpropionic acid ethyl ester (8.27 mL, 64.0 mmol) and 2-methylphenol (7.60 g, 70.2 mmol) in dioxane (100 mL) was added Cs2CO3 (31.3 g, 96.0 mmol). After the mixture was refluxed at 100° C. for 4 hours and allowed to cool down to room temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in Et2O, washed with 1 N NaOH, dried, and concentrated to give 9.69 g (68%) of D1a; 1H NMR (300 MHz, CDCl3) δ 7.13 (d, J=7.3 Hz, 1 H), 7.03 (t, J=7.6 Hz, 1 H), 6.87 (t, J=7.3 Hz, 1 H), 6.66 (d, J=8.2 Hz, 1 H), 4.24 (q, J=7.1 Hz, 2 H), 2.23 (s, 3 H), 1.59 (s, 6 H), 1.25 (t, J=7.1 Hz).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[Br:17][C:18]1[CH:19]=[C:20]([S:26](Cl)(=[O:28])=[O:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].Cl>N1C=CC=CC=1>[Br:17][C:18]1[CH:19]=[C:20]([S:26]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:28])=[O:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1Br
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5.0 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 5.2 g of 3-bromo-4-methoxy-benzene-sulfonyl chloride was stirred for 3 hours with 20 ml of pyridine. The resulting, red colored suspension was poured into 300 ml of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 300 ml of ethanol and 200 ml of 2N sodium hydroxide solution. After the addition of 4.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 4.4 g of 3-bromo-4-methoxy-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide separated as yellow crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([NH2:15])[CH2:11][CH2:12][CH2:13][CH3:14]>O1CCOCC1>[CH3:9][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:15][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=1
Reactant: CCCCCN
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: C1COCCO1
Product: CCCCCNc1cc(C)nc(N)n1

Procedure:
2-Amino-4-chloro-6-methylpyrimidine (10 g) and pentylamine (20 ml) were combined in dioxane (100 mL) and refluxed for 42 h. The solvents were evaporated, the product taken up in DCM, washed with water, sat. sodium bicarbonate solution, brine, dried, and the solvent evaporated to give the subtitle compound 8.3 g.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[C:15]([Sn](CCCC)(CCCC)CCCC)=[C:14]([CH3:29])[O:13][N:12]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[C:3]([C:15]2[C:11]([CH3:10])=[N:12][O:13][C:14]=2[CH3:29])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(C)noc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1nc(Cl)ncc1Br
Temperature: 70 °C
Reaction time: 16.5 h
Yield: 73.1 %

Procedure:
To a degassed with argon solution of 5-bromo-2,4-dichloropyrimidine (228 mg, 1.0 mmol) and 3,5-dimethyl-4-(tributylstannyl)isoxazole (772 mg, 2.0 mmol) in anhydrous DMF (2 mL), was added Pd(PPh3)2Cl2 (35 mg, 1.04 mmol). The mixture was stirred at 70° C. for 16.5 h. DMF was evaporated. The resulting orange oil was purified on ISCO (hexane/ethyl acetate gradient, 5-25%) to give the title compound (211 mg, 73.0%). 1HNMR (CDCl3): 8.81 (s, 1H), 2.44 (s, 3H), 2.30 (s, 3H). MS (ESI) m/z: Found: 288.0 (M++1), 290.0 (M++3), Calc. 286.9 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([CH:14]=[O:15])=[CH:5][N:4]=1.[O-:16]Cl=O.[Na+]>C(#N)C.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=[O:15])=[CH:5][N:4]=1
Reactant: COc1ncc(C=O)c2c(C)cccc12
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ncc(C(=O)O)c2c(C)cccc12

Procedure:
To a stirred solution of 1-methoxy-5-methylisoquinolin-4-carbaldehyde (Intermediate-7) (2 g, 10 mmol) in ACN—H2O (120 mL, 1:1) was added, NaClO2 (5.4 g, 59.7 mmol), NaH2PO4 (5.5 g, 40 mmol) and the mixture was stirred at RT overnight. It was then extracted with EtOAc (3×150 mL), dried over Na2SO4, filtered and concentrated to give the desired acid derivative (1.2 g, 56%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17]C2CCCCO2)=[CH:13][CH:12]=1)=O.[CH:24]1([Mg]Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:24]1(=[C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1c(F)cccc1F
Reactant: Br[Mg]C1CCCC1
Product: Oc1ccc(C(=C2CCCC2)c2c(F)cccc2F)cc1

Procedure:
Compound 12 was synthesized from ketone 5 (1 mmol) and cyclopentyl magnesium bromide (2 mmol) using procedure B described for synthesis of 6. The THP protection group was cleaved under the acidic conditions used. Yield: 18 mg (16%). 1H-NMR (400 MHz, CDCl3): δ ppm 7.26-7.14 (m, 1H), 7.13-7.12 (m, 2H), 6.89-6.85 (m, 2H), 6.76-6.73 (m, 2H), 4.75 (s, 1H), 2.50 (broad t, J=6.4 Hz, 2H), 2.13 (broad t, J=6.4 Hz, 2H), 1.75-1.58 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)=O)[S:4][N:3]=1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)=[N:16][OH:17])[S:4][N:3]=1
Reactant: O=C(c1ccsc1)c1snc(Cl)c1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccsc1)c1snc(Cl)c1Cl
Yield: 110.6 %

Procedure:
A solution of (3,4-dichloro-1,2-thiazol-5-yl)(3-thienyl)methanone (3.00 g, 10.2 mmol) and hydroxylamine hydrochloride (844 mg, 25.5 mmol) in pyridine (30 mL) was stirred 4 h at 50° C. then overnight at room temperature. After removal of the solvent in vacuo, addition of water (50 mL) and extraction with ethyl acetate (3×40 mL), the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on silica gel to afford 1-(3,4-dichloro-1,2-thiazol-5-yl)-N-hydroxy-1-(3-thienyl)methanimine [3.15 g, yield 99%; HPLC/MS: m/z=279 (M+H); log P(HCOOH)=3.04].
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[F:17][C:18]([F:37])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:33][N:32]=[C:31]([CH2:34]Cl)[N:30]=2)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[F:37][C:18]([F:17])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:33][N:32]=[C:31]([CH2:34][N:3]3[C:4]4[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=4)[CH:10]=[C:2]3[CH3:1])[N:30]=2)[CH:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 2H), 8.09 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 6.65 (s, 1H), 5.50 (s, 2H), 2.68 (s, 3H); MS (ES) m/z 519 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][CH2:9][C:10](=S)[NH:11][C:5]=2[CH:4]=1)#[N:2].[C:25]([NH:30][NH2:31])(=O)[CH2:26][CH2:27][CH3:28]>C(O)C>[C:1]([C:3]1[CH:24]=[CH:23][C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][CH2:9][C:10]3[N:11]([C:25]([CH2:26][CH2:27][CH3:28])=[N:30][N:31]=3)[C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)NC(=S)CN=C2c1ccc(C(F)(F)F)cc1
Reactant: CCCC(=O)NN
Solvent: CCO
Product: CCCc1nnc2n1-c1cc(C#N)ccc1C(c1ccc(C(F)(F)F)cc1)=NC2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 8-cyano-1,3-dihydro-5-[p-(trifluoromethyl)phenyl]-2H-1,4-benzodiazepine-2-thione is heated in ethanol with butyric acid hydrazide and the resulting product heated to 250° C. to give 9-cyano-1-propyl-6-[p-(trifluoromethyl)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.O.O[N:22]1[C:26]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>ClCCl>[CH3:26][NH:22][C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CNC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-[(benzyloxy)carbonyl]-β-alanine (10 g, 44.8 mmol), methylamine hydrochloride (3.33 g, 49.28 mmol), 1-hydroxybenzotriazole hydrate (6.05 g, 44.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.3 g, 53.76 mmol) and N-methylmorpholine (11.33 ml, 103 mmol) in dichioromethane (200 ml) was stirred at room temperature for 18 hours. The resulting precipitate was filtered off to give the desired product as a colourless foam, and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:hexane (90:10 to 100:0) to give additional product, 7.96 g, 75% in total; 1H NMR (CDCl3, 300 MHz) δ: 2.42 (t, 2H), 2.80 (s, 3H), 3.50 (m, 2H), 5.21 (s, 2H), 5.49 (bs, 1H), 5.63 (bs, 1H), 7.36 (m, 5H); Anal. Found: C, 60.68; H, 7.00; N, 11 .95. C12H16N2O3 requires C, 61.00; H, 6.83; N, 11.86%.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6](=[O:18])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])[CH3:3].[Cl:25][C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[C:30](Cl)[CH:29]=[CH:28][N:27]=1.C(N(CC)CC)C>CCO>[Cl:25][C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[C:30]([NH:1][C@H:2]([C:4]2[N:5]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:6](=[O:18])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[C:14]([F:15])([F:16])[F:17])[CH3:3])[CH:29]=[CH:28][N:27]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Reactant: C[C@H](N)c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](Nc1ccnc(Cl)c1[N+](=O)[O-])c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of (S)-3-(1-aminoethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-1 (1.0 g, 3.0 mmol, 1.0 eq) and 2,4-dichloro-3-nitropyridine (578 mg, 3.0 mmol, 1.0 eq) in EtOH (10 mL), triethylamine (608 mg, 6.0 mmol, 2.0 eq) was added and the resulting mixture was stirred at reflux overnight. The mixture was allowed to cool to RT and then concentrated in vacuo. The resultant residue was purified by flash column chromatography on silica gel (1% MeOH-DCM) to afford the product, (S)-3-(1-(2-chloro-3-nitropyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-33.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O>[CH2:11]([C:5]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])([CH2:4][CH2:3][CH2:2][C:1]([OH:10])=[O:9])[C:6]([OH:8])=[O:7])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C(O)CCCCC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCC(CCCCCCCCCCCCCCCCCC)(CCCC(=O)O)C(=O)O

Procedure:
64 parts by mass of adipic acid, 236 parts by mass of stearyl alcohol and 0.5 part by mass of dihydroxy bis titanium (triethanolaminate) serving as a condensation catalyst were put into a reaction container provided with a cooling tube, a thermometer, an agitator, a dehydration device and a nitrogen introduction tube were caused to react for 2 hours while generated water was evaporated away and were further caused to react under a reduced pressure of 5 to 20 mm Hg for 3 hours, with the result that distearyl adipic acid was obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([Cl:18])[CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[C:5]([OH:7])=O.ClCl.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH2:43][CH:44]1[C:55](=[O:56])[N:46]2[C:47]([C:52]([OH:54])=[O:53])=[C:48]([CH3:51])[CH2:49][S:50][C@H:45]12.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C>ClCCl.CO>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([Cl:18])[CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[C:5]([NH:43][CH:44]1[C:55](=[O:56])[N:46]2[C:47]([C:52]([OH:54])=[O:53])=[C:48]([CH3:51])[CH2:49][S:50][C@H:45]12)=[O:7]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1ccc2cccc(Cl)c2c1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: ClCl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)CS[C@H]12)c1ccc2cccc(Cl)c2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Four hundred twenty milligrams of α-methoxyimino-α-(8-chloro-2-naphthyl)acetic acid were converted to the acid chloride by reaction with excess chlorine and 500 mg of triphenyl phosphite in 20 ml of dichloromethane. The reaction mixture was added in one portion to a stirred solution of 350 mg of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 5 ml of dichloromethane containing 2 ml of bis(trimethylsilyl)trifluoroacetamide. The reaction mixture was stirred at 25° C. for six hours and then diluted by addition of 20 ml of methanol. The solvent was removed by evaporation under reduced pressure to provide 7-[α-methoxyimino-α-(8-chloro-2-naphthyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid. The product thus formed is dissolved in formic acid containing zinc metal dust to give, following isolation and purification, 7-(8-chloro-2-naphthyl)glycylamido-3-methyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[H-].[Na+].Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:1][N:2]([CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CNc1nc(-c2ccccc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C)c2nc(-c3ccccc3)cs2)cc1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of N-methyl-4-phenyl-1,3-thiazol-2-amine (1.67 g, 8.8 mmol) in N,N-dimethylformamide (25 mL) was added 60% sodium hydride (350 mg, 8.8 mmol), and the mixture was stirred for 30 min. Methyl 4-(bromomethyl)benzoate (2.1 g, 9.2 mmol) was added and the mixture was stirred at room temperature for 1.5 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to give the title compound (2.6 g, yield 86%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].ClC1C=CC=C(C(OO)=[O:19])C=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[O:19]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])/[CH:10]=[CH:9]/[CH:8]=[O:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCc1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCC(=O)/C=C/C=O
Yield: 72.6 %

Procedure:
2.0 g (14.47 mmol) of 2-pentylfuran was dissolved in 60 ml of dichloromethane, and 3.84 g (14.47 mmol) of 65% m-chloroperbenzoic acid was added dropwise thereto with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature. To the reaction solution was added saturated aqueous sodium carbonate and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure to give 1.62 g of the title compound as a yellow oil (yield: 73%).
Reaction SMILES: [OH:1][B:2]1[C@@H:7]([NH:8][C:9](=[O:22])[CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][NH:20]C)[CH2:13][CH2:12]2)[CH2:6][C:5]2[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([OH:29])=[O:28])[C:4]=2[O:3]1.C1COCC1.C([O-])(O)=O.[Na+].Cl[C:41]([O:43][CH3:44])=[O:42]>O.CO>[OH:1][B:2]1[C@@H:7]([NH:8][C:9](=[O:22])[CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][NH:20][C:41]([O:43][CH3:44])=[O:42])[CH2:13][CH2:12]2)[CH2:6][C:5]2[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([OH:29])=[O:28])[C:4]=2[O:3]1
Reactant: COC(=O)Cl
Reactant: CNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-2-hydroxy-3-(2-(trans-4-(2-(methylamino)ethylamino)cyclohexyl)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 51 (39 mg) in a mixture of H2O (1 mL), THF (1 mL) and MeOH (1 mL) was added NaHCO3 (200 mg), followed by methyl chloroformate (1.2 eq). The reaction mixture was stirred at RT overnight. The solvent was then removed in vacuo and the crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 448 (MH)+.
Reaction SMILES: [OH-].[K+].[CH3:3][P:4]([C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])(=[O:8])[O:5][CH2:6][CH3:7].[CH2:19]([OH:21])[CH3:20]>>[CH3:3][P:4]([C:9]1[CH:14]=[C:13]([O:21][CH2:19][CH3:20])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])(=[O:8])[O:5][CH2:6][CH3:7]
Reactant: CCO
Reactant: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: CCOc1ccc([N+](=O)[O-])c(P(C)(=O)OCC)c1
Reaction time: 48 h

Procedure:
To a solution of potassium hydroxide pellets (10.0 mmol) dissolved in ethanol (B 50 ml) is added ethyl P-methyl-2-nitro-5-chlorophenylphosphinate (20.0 mmol). The mixture is boiled for 48 hours and is then concentrated to a slurry. The residue is diluted with water, acidified with 10% HCl and extracted with ethyl acetate (2×). The combined extracts are washed with brine, dried and evaporated to yield ethyl P-methyl-2-nitro-5-ethoxyphenylphosphinate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[C:24][C:25]([O:27][CH3:28])=[O:26])=[C:10]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[H][H]>O1CCOCC1.[Pd]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:10]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C1=C(COCC#CC(=O)OC)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCCCC(=O)OC)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 39.7 %

Procedure:
A solution of methyl 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}but-2-ynoate (1.00 g) in dioxane (30 ml) was stirred under one atmosphere (1.0333 kg.cm.-2) of hydrogen at room temperature in the presence of 5% palladium on barium sulphate. When the uptake of hydrogen had ceased the mixture was filtered and evaporated. The residue was purified by chromatography on silica (6 g) using toluene plus 0→50% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated and the residue crystallised from diisopropyl ether to give the title compound (0.40 g), m.p. 78°-80°.