Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].S(O)(O)(=O)=[O:3].[CH2:7]([NH:14][C:15](N)=N)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]C>>[CH2:7]([N:14]=[C:15]=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCNC(=N)N
Reactant: O=S(=O)(O)O
Agent: [Na]
Product: CCCCCCN=C=O

Procedure:
Proceeding in a manner similar to that described above in part A of Example 18, and using 3.44 g. of sodium, 30.9 g. of n-heptylguanidine sulfate, and 19.1 g. of n-hexyl isocyanate, there was obtained 26.2 g. of 1-n-heptylamidino-3-n-hexylurea having the structural formula ##STR63## as a white crystalline solid which melted at 68°-72° C. The solubility of this base in a dilute acidic solution (prepared by mixing 0.36 ml. of N/2 hydrochloric acid and 9.64 ml. of water) at 25° C. was less than 0.25 percent. In 95 percent ethyl alcohol at 25° C. it was soluble to the extent of 5 percent (w/v); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[S:18][CH:19]=[C:20]([C:22](O)=[O:23])[CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:58]1[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]([N:58]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]3)=[O:23])[CH:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1csc(C2CCN(C(=O)OCc3ccccc3)CC2)c1
Reactant: C1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(c2cc(C(=O)N3CCCCCC3)cs2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
4-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid benzyl ester (0.095 g, 0.27 mmol) was dissolved in DMF (2 mL). DIPEA (0.54 mmol), HATU (0.27 mmol) and homopiperidine (0.27 mmol) were added and the reaction stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic solution was separated and dried with magnesium sulphate, filtered and the solvent removed under vacuum. The residue was purified by HPLC, eluting with 40%-90% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.032 g). LCMS m/z 427.29 [M+H]+ RT=12.22 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 7.4-7.35 (m, 4H), 7.35-7.3 (m, 1H), 7.25 (s, 1H), 6.9 (s, 1H), 5.15 (s, 2H), 4.3 (m, 2H), 3.6 (m, 2H), 3.5 (m, 2H), 3.00-2.90 (m, 3H), 2.0 (m, 2H), 1.8 (m, 2H), 1.75-1.5 (m, 8H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][C:49]1[CH:56]=[CH:55][CH:54]=[CH:53][C:50]=1[NH:51][CH3:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:51]([C:50]4[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=4[O:48][CH3:47])[CH3:52])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CNc1ccccc1OC
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)c2ccccc2OC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-methoxy-n-methylaniline (Aldrich) to give the title product. LC-MS (ES+) 784 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:26]([F:29])([F:28])[F:27])=[CH:10]\[C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(=[S:32])C.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([SH:32])([C:26]([F:28])([F:27])[F:29])[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Reactant: CC(O)=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 5-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-[1,2,4]triazol-1-yl-benzonitrile (100 mg) was added thioacetic acid (6 eq.) and triethylamine (4 μL). To dissolve the suspension more thioacetic acid (400 μL) was added. The solution was stirred under argon at room temperature for 20 hours. To this mixture was added a minimum of dichloromethane and then isolute. The suspension was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 5-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-mercapto-butyryl]-2-[1,2,4]triazol-1-yl-benzonitrile (108 mg).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([NH:12][CH2:13][CH2:14][OH:15])[CH:9]=[C:8]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=O.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:15][CH2:14][CH2:13][N:12]1[C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=2[C:9]2[C:8]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[N:7][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:11][C:10]1=2
Reactant: OCCNc1cc(N2CCCC2)nc(N2CCCC2)n1
Reactant: O=C1CCCCC1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: OCCn1c2c(c3c(N4CCCC4)nc(N4CCCC4)nc31)CCCC2

Procedure:
A mixture of 2-[(2,6-di-(1-pyrrolidinyl)pyrimidin-4-yl)amino]ethanol (VI, Example1, 5.55 g), 2-bromocyclohexanone (3.54 g), N,N-diisopropylethylamine (2.65 g) and acetonitrile (60 mL) is heated at reflux for 44 hr. The reaction mixture is cooled to 20°-25° and concentrated under reduced pressure. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered, and concentrated. Chromatography (silica gel, 2.5% acetone/chloroform) gives the title compound, NMR (CDCl3) 7.64, 4.05, 3.91, 3.67, 3.55, 2.72, 2.56, 2.0-1.7 δ; MS (m/z) calc'd=355.2372, found=355.2368.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][NH:6][C:7]([O:9][C@@H:10]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[C@@H:11]1[N:16]2[CH2:17][CH2:18][C@H:13]([C@@H:14]([CH:19]=[CH2:20])[CH2:15]2)[CH2:12]1)=[O:8])C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25]([N:24]=[CH:23][CH:22]=[C:21]2[C@H:10]([O:9][C:7]([NH:6][CH2:5][C:4]([OH:33])=[O:3])=[O:8])[C@@H:11]2[N:16]3[CH2:17][CH2:18][C@H:13]([C@@H:14]([CH:19]=[CH2:20])[CH2:15]3)[CH2:12]2)=[CH:26][CH:27]=1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](OC(=O)NCC(=O)OCC)c1ccnc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](OC(=O)NCC(=O)O)c1ccnc2ccc(OC)cc12
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A solution of 120 mg (0.26 mmol) of (8) in 2 ml of methanol was added 200 mg of potassium carbonate and 0.5 ml of water. The mixture was heated to reflux for 2 h and cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated to remove methanol. The residue was redissolved in 2 ml of water and 1N HCl was added dropwise to the solution until the pH reached 7. The aqueous solution was concentrated, 100 ml of methanol was added and filtered. The filtrate was concentrated and yielded 95 mg (0.22 mmol, 85%) of (9).
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:16])[C@@H:11]([NH2:15])[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:16])[C@@H:11]([NH:15][CH:18]([CH:20]2[CH2:22][CH2:21]2)[CH3:17])[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(C)C)s1
Reactant: CC(=O)C1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC[C@H](NC(C)C1CC1)C(=O)Nc1ncc(C(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(S)-amino-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide (150 mg, 0.54 mmol) and cyclopropyl methyl ketone(45 mg, 0.54 mmol)in 10 mL of methylene chloride and 5 drops of acetic acid was treated with sodium triacetoxyborohydride (172 mg, 0.8 mmol) and stirred at room temperature overnight. The mixture was quenched with dilute ammonium hydroxide and extracted with methylene chloride. The organic layer was separated and concentrated to dryness. The residue was purified by HPLC to give 2-(S)-(1-cyclopropyl-ethylamino)-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide as a colorless oil, LC-MS RT=1.4 min, M+1=310.
Reaction SMILES: Cl/[C:2](/[CH2:16][CH3:17])=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[CH3:42][C:43]([OH:47])(C)[C:44]#C>[Cu]I.[Pd](Cl)Cl.O1CCCC1>[OH:47][C:43]([CH3:44])([CH3:42])[C:17]#[C:16]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7]
Reactant: C#CC(C)(C)O
Reactant: CC/C(Cl)=C\CN(CC)Cc1cccc(O)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCN(C/C=C/C#CC(C)(C)O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78 %

Procedure:
To 7.5 ml tetrahydrofuran were added 1.13 g (5 mmol) of (E)-N-(3-chloro-2-pentenyl)-N-ethyl-3hydroxybenzylamine, 4.76 mg (0.25 mmol) of copper (I) iodide, 18.0 mg (0.1 mmol) of palladium chloride and 52.5 mg (0.2 mmol) of triphenyiphosphine, and further, 0.99 ml (10 mmol) of n-butylamine and 0.58 ml (6 mmol) of 3-methyl-1-butyne-3-ol under ice cooling. The mixture stirred for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate =3/2 ). The desired fractions were put together and concentrated under reduced pressure to obtain 1.07 g (yield: 78%) of the above identified compound as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]=1.O>[N+]([O-])(O)=O>[CH:2]([C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]=1)=[O:1]
Reactant: O=c1c(CO)coc2ccccc12
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=Cc1coc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A quantity of 35.2 g. (0.2 mole) of 3-(hydroxymethyl)chromone is dissolved in 250 ml of concentrated nitric acid with stirring at 25° C. There is no initial heat of reaction. The temperature gradually rises to 30° C over the next several minutes and is kept there for about five minutes with ice-acetone bath cooling. Water, 600 ml, is added to the reaction solution. The separated, pale yellow solid is filtered, washed well with water and dried to give 25 g. of crude aldehyde melting at 145°-148°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[C:4]([N:24]([CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)[CH2:25][CH2:26][CH2:27][O:28][CH3:29])[N:3]=1.[NH2:40][CH2:41][CH2:42][CH2:43][CH:44]([CH2:50][NH2:51])[CH2:45][CH2:46][CH2:47][CH2:48][NH2:49]>>[CH3:29][O:28][CH2:27][CH2:26][CH2:25][N:24]([C:4]1[N:5]=[C:6]([N:8]([CH:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[NH:12][C:11]([CH3:17])([CH3:18])[CH2:10]2)[CH2:19][CH2:20][CH2:21][O:22][CH3:23])[N:7]=[C:2]([NH:40][CH2:41][CH2:42][CH2:43][CH:44]([CH2:50][NH:51][C:2]2[N:7]=[C:6]([N:8]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:17])([CH3:18])[CH2:10]3)[N:5]=[C:4]([N:24]([CH:30]3[CH2:31][C:32]([CH3:39])([CH3:38])[NH:33][C:34]([CH3:36])([CH3:37])[CH2:35]3)[CH2:25][CH2:26][CH2:27][O:28][CH3:29])[N:3]=2)[CH2:45][CH2:46][CH2:47][CH2:48][NH:49][C:2]2[N:3]=[C:4]([N:24]([CH:30]3[CH2:31][C:32]([CH3:38])([CH3:39])[NH:33][C:34]([CH3:37])([CH3:36])[CH2:35]3)[CH2:25][CH2:26][CH2:27][O:28][CH3:29])[N:5]=[C:6]([N:8]([CH:9]3[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12][C:13]([CH3:16])([CH3:15])[CH2:14]3)[CH2:19][CH2:20][CH2:21][O:22][CH3:23])[N:7]=2)[N:3]=1)[CH:30]1[CH2:31][C:32]([CH3:39])([CH3:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH2:35]1
Reactant: COCCCN(c1nc(Cl)nc(N(CCCOC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Reactant: NCCCCC(CN)CCCN
Product: COCCCN(c1nc(NCCCCC(CCCNc2nc(N(CCCOC)C3CC(C)(C)NC(C)(C)C3)nc(N(CCCOC)C3CC(C)(C)NC(C)(C)C3)n2)CNc2nc(N(CCCOC)C3CC(C)(C)NC(C)(C)C3)nc(N(CCCOC)C3CC(C)(C)NC(C)(C)C3)n2)nc(N(CCCOC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1

Procedure:
Following the procedure described in Example 1, 2-chloro-4,6-bis[N-(3-methoxypropyl)-N-(2,2,6,6-tetramethyl-4-piperidyl)amino]-1,3,5-triazine [prepared as described in Preparation 6(b)] and 1,8-diamino-4-aminomethyloctane were reacted together and the reaction mixture treated to yield a residue, which was purified by column chromatography through silica gel, eluted with 4:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine, to give the desired Compound No. 32, in the form of crystals melting at 96°-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:16][CH2:17][C:18]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([Cl:1])[CH:3]=1)=[O:19]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CCl)Nc1ccc(F)c(Cl)c1
Temperature: 0 °C
Yield: 89 %

Procedure:
To 130 ml of toluene was added, with stirring, 24.0 g (0.0.165 mole) of 3-chloro-4-fluoroaniline and 13.5 ml (0.166 mole) of pyridine. The resulting solution was cooled to ca. 0° C. and 13.2 ml (0.166 mole) of 2-chloroacetyl chloride was added. The reaction mixture was stirred at room temperature for 5 hours and then it was extracted twice with 100 ml of 1N hydrochloric acid, followed by 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried using magnesium sulfate, and then it was concentrated in vacuo to give 32.6 g (88% yield) of N-(2-chloroacetyl)-3-chloro-4-fluoroaniline.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH2:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1>>[OH:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]([NH:38][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:30]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: NC(c1ccccc1)c1ccc(O)cc1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccc(O)cc1
Yield: 77 %

Procedure:
The title compound was prepared in a yield of 77% in a similar manner to that described in Example 37 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and α-(4-hydroxyphenyl)benzylamine.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[N:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([CH2:27][NH:28][CH2:29][CH2:30][CH3:31])[CH:19]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1>CO.[Pt]>[CH2:1]([O:8][C:9](=[O:38])[N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH2:27][NH:28][CH2:29][CH2:30][CH3:31])[CH:19]=2)[CH:12]=1)[CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCc1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: c1ccsc1
Product: CCCNCc1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1N

Procedure:
A mixture of cyclohexyl-[3-(4-nitro-3-propylaminomethyl-phenoxy)-phenyl]-carbamic acid benzyl ester (0.00181 mol) in methanol (50 mL) was hydrogenated with 5% Pt/C (0.5 g) as a catalyst in the presence of thiophene solution (1 mL). After uptake of H2 (3 equiv), the catalyst was filtered off and the filtrate was evaporated to yield the title compound as a residue. which was used in subsequent reactions without further purification.
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.C([Li])CCC.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1.O>[OH:18][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([OH:12])=[CH:14][CH:15]=1)[C:5]#[CH:6]
Reactant: O=Cc1ccc(O)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(O)c1ccc(O)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of trimethylsilylacetylene (1.00 g, 10 mmol) (Aldrich) in dry THF (100 mL) under argon at −78° C. was added n-butyllithium (4.4 mL, 11 mmol, 2.5 M solution in hexanes) (Aldrich) dropwise. The reaction was stirred for 30 min at −78° C., after which time 4-hydroxybenzaldehyde (0.50 g, 4 mmol) (Aldrich) was added and the reaction was allowed to slowly warm to room temperature. A saturated solution of ammonium chloride (5 mL) was then added and the reaction was stirred at room temperature for 2 h. The solution was then diluted by the addition of 30 mL water, and THF was removed in vacuo. The product was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give clean 3-hydroxy-3-(4-hydroxyphenyl)-1-propyne which was used directly, without further purification. (Yield 501 mg, 84%).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH3:12][O-:13].[Na+]>>[CH3:12][O:13][C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=1[CH3:11]
Reactant: C[O-]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Cl
Agent: [Na+]
Product: COc1c(C)c[n+]([O-])c(C)c1C
Yield: 92 %

Procedure:
0.86 g (5 mmol) 4-chloro-2,3,5-trimethylpyridine N-oxide and 8.5 ml 2M sodium methoxide was heated in a closed vessel to 70° C. for 16 hrs. Gave after work up 92% yield of 4-methoxy-2,3,5-trimethylpyridine N-oxide. Addition of 20% dimethylsulfoxide to the solvent increases the reaction rate but complicates the work up. The product was obtained as a waxy solid. NMR: 2×3H, 2,25; 3H, 2,5(s); 3H, 3,80(s); 1H, 8,2(s). (CDCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[N:17]=1)=[O:9]
Reactant: Nc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1nc(-c2ccc(Cl)c(Cl)c2)cs1)c1cc(Cl)ccc1O
Yield: 15.1 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-(3,4-dichlorophenyl)thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:15]1[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[C:4]([CH:14]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccccc1CNC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
6.04 g of t-butyl N-(2-methoxybenzyl)carbamate was dissolved in 50 ml of acetonitrile, and 4.6 g of N-bromosuccinimide was added. After stirring for 3 hours at room temperature, the solvent was evaporated. The residue was dissolved in ethyl acetate, and successively washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was washed with mixture solution of methyl t-butylmethyl ether and hexane, to give 6.97 g of t-butyl N-(5-bromo-2-methoxybenzyl)carbamate.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1[F:34])=O>O>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([F:34])[C:27]=1[C:25]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:24]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1c(F)cccc1F
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3c(F)cccc3F)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 16 %

Procedure:
4-[4-(2,6-Difluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (45 mg, 16%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-2′,6′-difluoroacetophenone (available from SynQuest Laboratories, Inc.) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J=1.9 Hz, 1H), 7.94-8.04 (m, 3H), 7.50-7.70 (m, 3H), 7.19-7.32 (m, 4H).
Reaction SMILES: N[C@@H]1C(=O)N2C(C(OC(C3C=CC=CC=3)C3C=CC=CC=3)=[O:12])=C(C=C)CS[C@H]12.[CH:29]1([N:35]=[C:36]=[N:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.CN(C)C=O>[C:36]([NH:35][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)([NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:12]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
A solution of diphenylmethyl 7βamino-3-vinylceph-3-em-4-carboxylate (1.57 g., 4 mmole) in methylene dichloride (25 ml.) with dicyclohexylcarbodiimide (907 mg., 4.4 mmole) was treated slowly (over 10 minutes) with a solution of D-2-t-butoxycarbonylamino-2-phenylacetic acid (1.1 g., 4.4 mmole) in N,N-dimethylformamide (10 ml.). The mixture was stirred at 23° for 30 minutes and dicyclohexylurea removed by filtration. The filtrate was washed with water and dried and evaporated in vacuo to give a pale yellow solid. This material was crystallised from methanol, and the isolated material washed with ether, to give the crude title cpompound (2.2 g.) (contaminated with dicyclohexylurea). The crude compound in benzene :ethyl acetate (2:5) was filtered through a short column of Kieselgel 0.02 - 0.5 mm., 10 cm. × 2.5 cm.). Evaporation of the solvent in vacuo and washing the crystalline residue with ether gave the pure title compound (1.6 g., 64%) as small needles m.p. 200°-202°, [α]D - 129° (CHCl3), λmax 294.5 nm. (ε 14,400), νmax. 3395 (NH), 1780 (β-lactam), 1712 (CO2R), 1690 and 1500 (CONH) and 912 cm.-1 (CH=CH2),τ(CDCl3) 3.05 (CHPh2),3.03 (CH=CH2, dd, J 17 and 11 Hz). 3.08 (NH, d, J 9 Hz) 4.23 (C(7) -H, dd, J 9 and 4.5 Hz), 4.28 (CH-NH, d, J 7 Hz), 4.65 and 4.79 (CH=CH2, two d, J 17 and 11 Hz resp.), 4.77 (CH-NH, d, J 7 Hz), 5.10 (C(6) -H, d, J 4.5 Hz), 6.46 and 6.70 (C(2) -CH, AB-q, J 18 Hz) 8.58 (C[CH3 ]3). (Found: C, 66.6; H, 5.6; N, 6.4; S, 5.1. C35H35N3O6S requires C, 67.2; H, 5.65; N, 6.7; S, 5.1%).