Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)[CH3:20].[OH-].[Na+].C(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH:16][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([CH2:19][CH3:20])=[CH:22][CH:23]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(C(=O)Nc2ncc3c(n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 501 mg (2.0 mmol) was added at 0° C. to a solution of 4-ethylbenzoic acid chloride 296 μl (2.0 mmol) in pyridine (25 ml) and stirring was performed for 2 h at 0° C. and then overnight at RT under nitrogen as inert gas. After the addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes, CH2Cl2 (50 ml) was added and the aqueous phase extracted with CH2Cl2 (3×20 ml). The combined organic phases were dried over Na2SO4. After filtration and removal of the solvent, purification was performed by means of column chromatography and the product 2-(4-ethyl-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 640 mg (1.67 mmol, 84% of theoretical) was obtained.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:24]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:27][C:26](=[O:42])[NH:25]2)[CH:17]=[C:18]([O:21][CH2:22][CH3:23])[C:19]=1[OH:20].O>C1COCC1>[CH2:22]([O:21][C:18]1[C:19]2[O:20][C:6](=[O:7])[NH:13][C:14]=2[CH:15]=[C:16]([CH:24]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:27][C:26](=[O:42])[NH:25]2)[CH:17]=1)[CH3:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(N)c1O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc2[nH]c(=O)oc12
Yield: 26.8 %

Procedure:
To a solution of CDI (243 mg, 1.50 mmol) in THF (3 mL) was added 4-(3-amino-5-ethoxy-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one (386 mg, 0.96 mmol) and the resultant mixture was heated to reflux for 1.0 h. The reaction mixture was added water (10 mL) and filtered. The filtered mass was washed with methanol (3 mL) and dried to afford Compound 72 as a yellow solid (110 mg, 30%). 1H NMR (DMSO-d6 500 MHz): δ 11.56 (s, 1H), 8.69 (s, 1H), 7.49 (s, 1H), 7.21 (s, 3H), 7.20 (s, 2H), 6.99-7.04 (m, 3H), 6.81 (d, J=6.0 Hz, 2H), 6.74 (d, J=6.0 Hz, 2H), 5.12 (s, 1H), 4.11 (q, J=6.8 Hz, 2H), 1.31 (t, J=7.0 Hz, 3H); MS (ESI): m/z 428.1 [M+1]+.
Reaction SMILES: NC1C=CC=CC=1[S:8][C:9]1[CH:28]=[CH:27][C:26]2C3=C4[C:25]5[C:16]([C:17](=[O:53])[N:18]([C:41]6[C:46]([CH:47]([CH3:49])[CH3:48])=[CH:45][CH:44]=[CH:43][C:42]=6[CH:50]([CH3:52])[CH3:51])[C:19](=[O:40])[C:20]=5C=C3OC3C=CC(C(C)(C)C)=CC=3)=[CH:15][C:14]([O:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:57][CH:56]=3)=[C:13]4[C:12]3=[CH:65][CH:66]=[CH:67][C:10]=1[C:11]=23.N([O-])=O.[Na+].CC(O[CH2:76][C:77]1[C:90]2[C:85](=[CH:86][CH:87]=[CH:88][CH:89]=2)C(COC(C)=O)=C2[C:78]=1[CH:79]=CC=C2)=O>O>[C:61]([C:58]1[CH:57]=[CH:56][C:55]([O:54][C:78]2[C:77]3[C:90]4[CH:89]=[CH:88][C:87]5[S:8][C:9]6[C:10](=[CH:11][CH:26]=[CH:27][CH:28]=6)[C:67]6=[CH:66][CH:65]=[C:12]([C:13]7[C:76]=3[C:25]3[C:16](=[CH:15][C:14]=7[O:54][C:55]7[CH:60]=[CH:59][C:58]([C:61]([CH3:63])([CH3:64])[CH3:62])=[CH:57][CH:56]=7)[C:17](=[O:53])[N:18]([C:41]7[C:42]([CH:50]([CH3:51])[CH3:52])=[CH:43][CH:44]=[CH:45][C:46]=7[CH:47]([CH3:48])[CH3:49])[C:19](=[O:40])[C:20]=3[CH:79]=2)[C:85]=4[C:86]=56)=[CH:60][CH:59]=1)([CH3:64])([CH3:62])[CH3:63]
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cc(Oc3ccc(C(C)(C)C)cc3)c3c4cccc5c(Sc6ccccc6N)ccc(c6c(Oc7ccc(C(C)(C)C)cc7)cc(c2c36)C1=O)c54
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1-n1c(=O)c2cc(Oc3ccc(C(C)(C)C)cc3)c3c4ccc5sc6ccccc6c6ccc(c7c(Oc8ccc(C(C)(C)C)cc8)cc(c1=O)c2c37)c4c56
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Compound 8-bromo-5,12-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (3.0 g), 2-aminobenzenthiol (0.48 g, 10% excess) and anhydrous potassium carbonate (0.24 g) were added to 30 mL of N-methyl-2-pyrrolidinone (NMP). The solution was heated rapidly and refluxed for 30 min. After a minute the liquor was added to 2% aqueous hydrochloride acid (250 ml) and after standing overnight, filtered and dried at 105° C. to give a red-blue solid of 8-((2-aminophenyl)thio)-5,12-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (2.06 g) with a nominal yield of 60.0%. 8-((2-aminophenyl)thio)-5,12-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (2.06 g) was dissolved in warm glacial acetic (12 mL) and concentration hydrochloride acid (1.3 mL) giving a fine suspension. The suspension was cooled to 0° C. and a solution of sodium nitrite (0.16 g) in water (3.6 mL) added and stirred continuously till clear. The prepared solution was added to a boiling solution of hydrated cupric sulphate (2.6 g) in water (60 mL) with good stirring within 1 hour. After boiling a further 1 hour, the solution was cooled, filtered and a blue-red solid was given. The solid was washed with a warm solution of sodium hydroxide (20 mL, 3%) three times and purified on Chromatography Column to eliminate by-products. The blue solid of 5,15-bis(4-(tert-butyl)phenoxy)-2-(2,6-diisopropylphenyl)-1H-thioxantheno[2′,1′,9′:10,5,6]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (0.69 g) was given with a nominal yield of 34.2%. MS: base peak 884.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[Br:17][CH:18](Br)[CH3:19]>CC(C)=O>[Br:17][CH2:18][CH2:19][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCBr)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
A mixture of 4-hydroxyacetophenone (20 g, 147 mmol) and potassium carbonate (81 g, 588 mmol) was placed into 2 L round bottomed flask and acetone (1 L) was added. To this reaction mixture dibromoethane (38 mL) was added in one portion, and then the reaction mixture was allowed to reflux for 36 hours, under nitrogen atmosphere. The reaction mixture was cooled to room temp, and filtered off, residue was washed with acetone (2×100 mL), and the filtrates were combined and concentrated under reduced pressure. The crude was chromatographed over silica gel by using 10-15% ethyl acetate/pet. ether (2 L), affording the title compound 7 g (20%) as a white solid. Mp. 58-61° C.
Reaction SMILES: ClC1C=CC(O)=C(C=1)C(C1C=CC=CC=1)=O.[BH4-].[Na+].N1C=CN=C1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH:32]([N:39]2[CH:43]=[CH:42][N:41]=[CH:40]2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1.[H-].[Na+].[Cl:46][C:47]1[CH:54]=[C:53]([Cl:55])[CH:52]=[CH:51][C:48]=1[CH2:49]Cl>CO.C(O)C.CN(C)C=O.O.C1C=CC=CC=1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:49][C:48]2[CH:51]=[CH:52][C:53]([Cl:55])=[CH:54][C:47]=2[Cl:46])=[C:27]([CH:32]([N:39]2[CH:43]=[CH:42][N:41]=[CH:40]2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:26]=1
Reactant: Oc1ccc(Cl)cc1C(c1ccccc1)n1ccnc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C(c1ccccc1)c1cc(Cl)ccc1O
Agent: [BH4-]
Agent: [H-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Product: Clc1ccc(COc2ccc(Cl)cc2C(c2ccccc2)n2ccnc2)c(Cl)c1

Procedure:
23 g. of 5-chloro-2-hydroxybenzophenone is reduced with an excess of sodium borohydride in methanol, thus obtaining 10.5 g. of 5-chloro-2-hydroxybenzohydrol, m.p. 132°-134° (from benzene). 2.3 g. of this product is heated with 670 mg. of imidazole for 2.5 hours to 200°. The reaction mixture is then dissolved in ethanol, a small amount of water is added, and this yields 500 mg. of 4-chloro-2-[α-(1-imidazolyl)-benzyl]-phenol, m.p. 228°-232°. The product is stirred in 7.5 ml. of dimethylformamide with 65 mg. of sodium hydride suspension (80%) for 1.5 hours at room temperature and then combined with 440 mg. of 2,4-dichlorobenzyl chloride. After the mixture has been worked up as set forth in Example 1, it is recrystallized from benzene/cyclohexane, thus obtaining 430 mg. of {4-chloro-2-[α-(1-imidazolyl)-benzyl[-phenyl}-(2,4-dichlorobenzyl)-ether, m.p. 115°-120°.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]3[C:10](=[O:21])[NH:11][CH2:12][CH:13]=[C:14]([Sn](C)(C)C)[C:15]=3[N:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:33])[C:25]1[CH:30]=[C:29](Br)[CH:28]=[CH:27][C:26]=1[Cl:32].[F-].[Cs+]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:32][C:26]1[CH:27]=[CH:28][C:29]([C:14]2[C:15]3[N:16]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[S:8][C:9]=3[C:10](=[O:21])[NH:11][CH2:12][CH:13]=2)=[CH:30][C:25]=1[C:24]([O:23][CH3:22])=[O:33]
Reactant: COC(=O)c1cc(Br)ccc1Cl
Reactant: C[Sn](C)(C)C1=CCNC(=O)c2sc(N3CCOCC3)nc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C2=CCNC(=O)c3sc(N4CCOCC4)nc32)ccc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A solution of 2-(morpholin-4-yl)-8-(trimethylstannyl)-5,6-dihydro-4H-[1,3]thiazolo[5,4-c]azepin-4-one (0.160 g, 0.386 mmol) and methyl-5-bromo-2-chlorobenzoate (0.116 g, 0.464 mmol) in DMF (3.74 mL) was purged with argon, and then cesium fluoride (0.205 g, 1.35 mmol), copper(I) iodide (0.0184 g, 0.0966 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0446 g, 0.0386 mmol) were added. The mixture was stirred at 80° C. for 2 hours. The solution was cooled to room temperature and some of the solvent was removed in vacuo. The residue was diluted with EA and water. The layers were separated and the aqueous layer was extracted twice more with EA. The combined organic layer was then washed with water and brine then dried over anhydrous sodium sulfate and concentrated. The residue was purified using column chromatography on silica gel (12 gr Analogix column, gradient DCM to 60% EA in DCM over 15 minutes) to give the product (0.129 g, 80%). LCMS: (AA) ES+ 420, 422. 1H NMR (400 MHz, d6-DMSO) δ: 8.05 (t, J=5.0 Hz, 1H), 7.80 (d, J=2.1 Hz, 1H), 7.61-7.44 (m, 2H), 6.48 (t, J=7.1 Hz, 1H), 3.84 (s, 3H), 3.70-3.62 (m, 4H), 3.61-3.53 (m, 2H), 3.42-3.34 (m, 4H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([CH2:19][CH2:20][C:21](OCC)=[O:22])[CH:14]=[C:15]([CH3:18])[C:16]=1[OH:17])([CH3:10])[CH3:9]>O1CCCC1>[CH3:10][C:8]([C:11]1[CH:12]=[C:13]([CH2:19][CH2:20][CH2:21][OH:22])[CH:14]=[C:15]([CH3:18])[C:16]=1[OH:17])([CH3:7])[CH3:9]
Reactant: CCOC(=O)CCc1cc(C)c(O)c(C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CCCO)cc(C(C)(C)C)c1O
Yield: 59.5 %

Procedure:
To a suspension lithium aluminum hydride (15.2 g) in tetrahydrofuran (500 mL) is added over a period of 60 minutes ethyl 3-[3-(1,1-dimethylethyl)-4-hydroxy-5-methylphenyl]propionate (80.0 g) in tetrahydrofuran (100 mL). The mixture is heated at reflux for 2 hours and then quenched by the sequential addition of water (17 mL), 10% aqueous sodium hydroxide (17 mL) and water (51 mL). The resulting suspension is washed with tetrahydrofuran and the filtrate is concentrated to give 40 g of crude 3-[3-(1,1-dimethylethyl)-4-hydroxy-5-methylphenyl]propanol. The crude intermediate is crystallized from heptane/toluene to give 38 g of light yellow crystals. The 1H NMR and field desorption spectra are consistent with the above-specified product.
Reaction SMILES: [OH-:1].[Na+].CN(C)[C:5](=[O:34])[CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([NH:28][CH2:29][CH2:30][O:31][CH3:32])=[O:27])[C:8]1=[O:33]>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:14]2[CH:15]=[C:16]3[C:11]([C:10]([OH:25])=[C:9]([C:26]([NH:28][CH2:29][CH2:30][O:31][CH3:32])=[O:27])[C:8](=[O:33])[N:7]3[CH2:6][C:5]([OH:34])=[O:1])=[N:12][CH:13]=2)=[CH:23][CH:22]=1
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: [OH-]
Agent: [Na+]
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O

Procedure:
A 4N NaOH solution (22 mL) was added dropwise to a 100° C. suspension of 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (5 g, 11 mmol; the title compound in Example 89) in DMSO (50 mL). The mixture was stirred for 1 h at 100° C., cooled to 10° C., diluted with H2O (10 mL), acidified by dropwise addition of conc. HCl (7 mL), diluted with EtOH and filtered to give the product as a white solid: 1H NMR (d6-DMSO) δ 13.22 (1H, br s), 10.18 (1H, m), 8.55 (1H, s), 8.03 (1H, s), 7.35 (2H, m), 7.11 (2H, m), 4.98 (2H, s), 4.11 (2H, s), 3.52 (4H, m), 3.28 (3H, s).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[NH2:14][CH2:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]3[CH:27]=[CH:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1>>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:14][CH2:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]3[CH:27]=[CH:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1)#[N:2]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: NCCc1nc2ccc(-c3ccc(=O)[nH]n3)cc2[nH]1
Product: N#Cc1ccccc1OCC(O)CNCCc1nc2ccc(-c3ccc(=O)[nH]n3)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1)=[O:4]>C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccco2)cnc1N
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1nc(C2CCCO2)cnc1N
Yield: 30.8 %

Procedure:
A solution of 3-amino-6-furan-2-yl-pyrazine-2-carboxylic acid methyl ester (1.94 g, 8.9 mmol) was dissolved in THF (80 ml) and hydrogenated over night at rt in the presence of 10% Pd/C (1.0 g). The catalyst was filtered and washed with THF. The filtrate was again hydrogenated in the presence of Pd/C 10% (1.0 g) overnight. The catalyst was filtered and washed with THF. The filtrate was concentrated. The crude product was purified by column chromatography using a CH2Cl2/MeOH gradient for elution, providing the title compound (611 mg, 31%) as yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18].C(N(CC)CC)C>C(Cl)Cl>[C:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a 100 mL round-bottomed flask equipped with a magnetic stirrer bar and an addition funnel was added 4-hydroxybenzophenone (1 g, 5.04 mmol) and CH2Cl2 (35 mL). The mixture was cooled to 0° C. and methacryloyl chloride (0.39 mL, 4.04 mmol) was added in one portion. After 30 minutes, triethylamine (0.7 mL, 5.04 mmol) dissolved in CH2Cl2 (10 mL) was added dropwise over 30 minutes. The reaction mixture was allowed to stir for a further 1 hour at 0° C. and then at room temperature for 3 hours. After this time, the organic mixture was washed with 0.1% NaOH (3×100 mL) and water (5×100 mL). The combined organic layers were dried over MgSO4 and then concentrated in vacuo to afford a crude product. The crude product was purified by column chromatography (100% CH2Cl2) to provide the compound as a white solid (yield=75%, 1 g).
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH3:15])[CH2:10][CH2:9]1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([N:14]([CH3:15])[S:25]([C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)(=[O:26])=[O:27])[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN[C@H]1CC[C@H](OCCCCBr)CC1
Agent: Cl
Product: CN([C@H]1CC[C@H](OCCCCBr)CC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
In analogy to example 11.9, trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-amine hydrochloride and 4-nitro-benzenesulfonyl chloride (with 2.1 eq N,N-diisopropylethylamine) were reacted to yield trans-N-[4-(4-Bromo-butoxy)-cyclohexyl]-N-methyl-4-nitro-benzenesulfonamide, MS: 451 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C:16](=[O:32])[CH2:17][C@@H:18]([O:24][Si](C(C)(C)C)(C)C)[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:12]([CH:33]([CH3:35])[CH3:34])[N:11]=[C:10]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:9]=2)=[CH:4][CH:3]=1.F.C(=O)(O)[O-].[Na+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[C:16](=[O:32])[CH2:17][C@@H:18]([OH:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:12]([CH:33]([CH3:35])[CH3:34])[N:11]=[C:10]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@@H](CC(=O)/C=C/c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C[C@H](O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
To a solution of 16 g of the compound 6 in 100 ml of acetonitrile is added dropwise a solution of 48% hydrogen flouride in 400 ml of acetonitrile (1:19) under ice-cooling, and the mixture is warmed to room temperature and stirred for 1.5 hours. The reaction mixture is neutralized with sodium bicarbonate and extracted with ether. The organic layer is washed with sodium chloride, dried and evaporated under reduced pressure to distil ether to give 13 g (Yield: 100%) of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate 7 as syrup. ##STR12##
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[C:7](Cl)([Cl:9])=[O:8].C(N(CC)CC)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>O1CCCC1.C(Cl)Cl>[O:6]=[C:2]1[N:3]([C:7]([Cl:9])=[O:8])[CH2:4][CH2:5][O:1]1
Reactant: O=C(Cl)Cl
Reactant: O=C1NCCO1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cl)N1CCOC1=O

Procedure:
In a similar manner to that of Example 1-9), 2-oxo-3-oxazolidinecarbonyl chloride, which was prepared from 2-oxazolidinone (1.04 g), phosgene (0.018 mole) and triethylamine (3.0 g) in tetrahydrofuran was treated with a solution of 7-(D-2-phenylglycinamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3.0 g) and bis(trimethylsilyl) acetamide (4.8 g) in methylene chloride (60 ml). The reaction mixture was worked up in a similar manner to that of Example 1--1) to give powder (1.92 g). This powder was dissolved into acetone and water was added thereto. The resultant mixture was concentrated, and a precipitated solid was collected by filtration to give powder (1.55 g) of 7-[D-2-(2-oxo-3-oxazolidinecarboxamido)-2-phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, mp 165° to 170° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:9]([OH:11])=O)[C:4](=[O:16])[CH:3]=1.[NH2:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:9]([NH:17][C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[CH:20][CH:19]=2)=[O:11])[C:4](=[O:16])[CH:3]=1
Reactant: O=C(O)C(CC1CC1)n1ccc(Br)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(CC2CC2)n2ccc(Br)cc2=O)cc1

Procedure:
290 mg (purity 94%, 0.95 mmol) of 2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 114 mg (purity 80%, 21% of theory)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Cl:10].ClCCCCCC(Cl)=[O:19].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Cl:10]
Reactant: O=C(CCCl)CCCCCCl
Reactant: O=C(Cl)CCCCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCl)CCCCCCCl
Yield: 43 %

Procedure:
1,8 dichloro-3-octanone: A well stirred, ice-cooled solution of 30.35 g (179.6 mmol) of 6-chlorohexanoyl chloride in 300 ml of dry CCl4 was degassed with nitrogen for 1/2 hr. AlCl3 (26.34 g, 179.6 mmol) was added in portions, then ethylene was bubbled in at a rate so that no excess ethylene escaped from the reaction vessel. Ethylene was allowed to bubble through the reaction mixture at 0° C. for 2 hrs. and at ambient temperature overnight. The reaction mixture was poured into 800 ml ice-water and extracted with chloroform (2×400 ml). The combined chloroform extracted were washed with sat'd aq. NaHCO3 (500 ml), H2O (500 ml), sat'd NaCl (500 ml) and dried over MgSO4. After the removal of the solvent, 15.2 g (43%) of crude 1,8-dichlorooctanone was obtained, which was used without further purification. NMR(CDCl3): δ1.44 (6H, m, --CH2 --), δ2.34 (2H, t, ##STR19## J=3.0 Hz), δ2.85 (2H, t, ##STR20## J=3.0 Hz), δ3.52 (2H, t, --CH2Cl, J=3 Hz) δ3.74 (2H, t, --CH2Cl, J=3.0 Hz).
Reaction SMILES: O(CCCCCCC(C1OC(C)=NN=1)=O)C1C=CC=CC=1.[CH2:22]([O:29][C:30]1[CH:50]=[CH:49][C:33]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]([C:43]2[O:44][C:45]([CH3:48])=[N:46][N:47]=2)[OH:42])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:22]([O:29][C:30]1[CH:50]=[CH:49][C:33]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([C:43]2[O:44][C:45]([CH3:48])=[N:46][N:47]=2)=[O:42])=[CH:32][CH:31]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1nnc(C(O)CCCCCCOc2ccc(OCc3ccccc3)cc2)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: Cc1nnc(C(=O)CCCCCCOc2ccccc2)o1
Solvent: ClCCl
Product: Cc1nnc(C(=O)CCCCCCOc2ccc(OCc3ccccc3)cc2)o1
Yield: 80.3 %

Procedure:
The synthesis was carried out analogous to the preparation of 65.1 using 64.2 (60 mg, 0.15 mmol) and Dess-Martin periodinane (0.127 g, 0.3 mmol) in wet CH2Cl2 (5 mL). Purification by flash column chromatography on silica gel gave pure compound 65.2 (47.5 mg, 80% yield) as a white solid (m p 118-120° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1)[NH2:23]
Reactant: NN
Reactant: Clc1cnc(-c2ccc(Oc3ccccc3)cc2)cn1
Solvent: O
Solvent: CCO
Product: NNc1cnc(-c2ccc(Oc3ccccc3)cc2)cn1

Procedure:
To a solution of 2-chloro-5-(4-phenoxyphenyl)pyrazine in 2 mL of ethanol was added hydrazine monohydrate (2 mL). The reaction mixture was heated at 110 C for 2 hours and evaporated in vacuo. The residue was dissolved in dichloromethane, washed with water, dried over Na2SO4, and evaporated in vacuo to afford 2-hydrazinyl-5-(4-phenoxyphenyl)pyrazine.