Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1.Cl[CH2:15][CH2:16][N:17]([CH2:25][CH2:26]Cl)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>CS(C)=O.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2([C:12]#[N:13])[CH2:26][CH2:25][N:17]([C:18]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:24])[CH2:16][CH2:15]2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(CC#N)c1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cccc(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 87.9 %

Procedure:
This compound is prepared by the procedure described in step A of preparation 1.8, from 16.3 g of sodium hydride at a concentration of 60% in oil in 400 ml of DMSO, 30 g of 3-methoxyphenylacetonitrile in 150 ml of THF and 47 g of tert-butyl bis(2-chloroethyl)carbamate in 100 ml of DMSO. This gives 54 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][C:3]=1[NH2:18].[C:19](Cl)(Cl)=[S:20]>O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][C:3]=1[N:18]=[C:19]=[S:20]
Reactant: Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
To a solution of 4.8 g of 5-(4-chloro-3-aminophenyl)-3-(2-furyl)-1,2,4-oxadiazole in 400 ml of tetrahydrofuran, 5 ml of triethylamine and 2.1 g of thiophosgene are added. After stirring at room temperature for 4 hours, the reaction mixture is filtered and evaporated to dryness in vacuo. The residue is crystallized from petroleum ether to yield 1.5 g (27%) of the title product, m.p. 131°-132° .
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[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][CH3:27].O>CN(C)P(N(C)C)(N(C)C)=O>[F:1][C:2]1[CH:9]=[C:8]([NH:10][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][CH3:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(N)cc1F
Reactant: CCCCCCCCCCCCCCCCBr
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C#N)c(F)c1
Temperature: 120 °C

Procedure:
2-Fluoro-4-aminobenzonitrile (11.8 g) and 1-bromohexadecane (15.3 g) are dissolved in hexamethylphosphoramide (200 ml.) and heated under an atmosphere of nitrogen in an oil bath maintained at 120° C. for 22 hours. The reaction mixture is cooled to room temperature and water is added gradually. The mixture is then chilled in an ice-bath and filtered. The solid is washed thoroughly with water and dried. The solid is recrystallized from ether-hexane to yield 2-fluoro-4-(hexadecylamino)benzonitrile as a pale yellow solid.
Reaction SMILES: [N:1]1[N:2]=[C:3]([CH:10]([NH2:22])[CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([CH3:21])[CH:20]=2)[NH:17][N:16]=[CH:15]3)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:23](C1NC=CN=1)(C1NC=CN=1)=[O:24].[F:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[NH:44][C:43](=[O:46])[N:42]([CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH2:41]2>CN(C)C=O>[N:1]1[N:2]=[C:3]([CH:10]([NH:22][C:23]([N:50]2[CH2:51][CH2:52][CH:47]([N:42]3[CH2:41][C:40]4[C:45](=[C:36]([F:35])[CH:37]=[CH:38][CH:39]=4)[NH:44][C:43]3=[O:46])[CH2:48][CH2:49]2)=[O:24])[CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([CH3:21])[CH:20]=2)[NH:17][N:16]=[CH:15]3)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(CC(N)c2nnc3ccccn23)cc2cn[nH]c12
Reactant: O=C1Nc2c(F)cccc2CN1C1CCNCC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2nnc3ccccn23)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 1-([1,2,4]triazolo[4,3-a]pyridine-3-yl)-2-(7-methyl-1H-indazol-5-yl)ethanamine (30 mg, 0.1 mmol) in dimethylformamide (1.0 mL) at 0° C. was treated with carbonyl diimidazole (17.5 mg, 1.1 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 8-fluoro-3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (26.0 mg, 1.1 equiv). The mixture was then stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 30 mg (53%). 1H-NMR (CD3OD, 300 MHz) δ 1.25-1.60 (m, 5H), 2.50 (s, 3H), 2.67-2.81 (m, 2H), 3.60 (s, 1H), 3.62 (s, 1H), 3.12-4.18 (m, 4H), 4.25-4.45 (m, 1H), 5.80 (dd, J=8.1, 8.1, 1H), 6.08-7.04 (m, 4H), 7.10 (s, 1H), 7.35-7.44 (s, 1H), 7.49 (s, 1H), 7.70 (m, 1H), 7.96 (s, 1H), 8.41 (d, J=7.0, 1H). Mass spec.: 568.10 (MH)+.
Reaction SMILES: [CH:1]1[C:10]2C(=CC=[CH:8][CH:9]=2)C=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16][C@H:15]1[CH2:39][NH2:40])(=[O:13])=[O:12].[C:41]1([CH3:49])[C:42]([CH:47]=O)=[CH:43][CH:44]=[CH:45][CH:46]=1.Cl[Sn]Cl.[BH3-]C#N.[Na+]>CO>[CH3:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[CH2:49][NH:40][CH2:39][C@H:15]1[N:14]([S:11]([C:2]2[CH:3]=[CH:8][C:9]3[C:10](=[CH:10][CH:1]=[CH:2][CH:3]=3)[CH:1]=2)(=[O:13])=[O:12])[CH2:18][C@H:17]([SH:19])[CH2:16]1
Reactant: Cc1ccccc1C=O
Reactant: NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: Cl[Sn]Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1CNC[C@@H]1C[C@@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1

Procedure:
250 mg (0.56 mmol) (2S,4R)-C-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methylamine and 58 μl (0.5 mmol) o-tolualdehyde in 1 ml MeOH were treated with a solution of 57 mg (0.3 mmol, 0.6 eq) SnCl2 and 38 mg (0.6 mmol, 1.2 eq) NaBH3CN in 1 ml MeOH at room temperature and subsequent cleavage of the protecting group (Method 3) gave (3R,5S)-5-[(2-methyl-benzylamino)-methyl]-1-(naphthalene-2-sulfonyl)-pyrrolidine-3-thiol as white solid, mp 122° C., MS: 427 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:5][CH:4]=1.[OH-].[Na+].Cl.C(=O)([O-])[O-:21].[Na+].[Na+].[Br:26][C:27]1[CH:28]=[CH:29][C:30](F)=[C:31]([CH:34]=1)[CH:32]=[O:33]>CS(C)=O>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([OH:21])=[O:14])=[C:31]([CH:32]=[O:33])[CH:34]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COc1ccc(CN2CCCCC2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc(CN(CCCCC(=O)O)c2ccc(Br)cc2C=O)cc1
Temperature: 0 °C
Yield: 96.6 %

Procedure:
To 1-(4-methoxybenzyl)piperidin-2-one (50.0 g) was added aqueous 4N sodium hydroxide solution (228 ml) and then the mixture was refluxed for a day. The mixture was cooled to 0° C. and concentrated hydrochloric acid (76 ml) was added thereto. The mixture was neutralized. Then, after adding sodium carbonate (53.8 g) and dimethyl sulfoxide (600 ml), 5-bromo-2-fluorobenzaldehyde (38.6 g) was added dropwise at 135° C. to the mixture. After refluxing for 5 hours, the mixture was neutralized with 3N hydrochloric acid at 0° C., and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, after which it was dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give 5-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)pentanoic acid (77.2 g) as a brown oily material.
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C1(C)C=CC=CC=1>[S:14]([O:5][CH2:4][C@H:2]1[O:3][CH2:1]1)([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CO1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC[C@@H]1CO1
Temperature: 0 °C
Yield: 80 %

Procedure:
To an ice-cooled solution of (R)-glycidol (5.0 g, 0.068 m) and triethylamine (8.1 g, 0.080 m) in toluene (100 ml) was added, over 15 minutes, methanesulfonyl chloride (8.0 g, 0.070 ml) in toluene (25 ml). Stirring was continued with cooling for 1 hour. The solution was filtered and concentrated to give an 80-85% yield of the crude (S)-3-mesyloxy-1,2-epoxypropane; this material could be used without further purification. Distillation gave 7 (61%); bp 92°-95° C./0.1 mm; [α]D22 =23.7° (c=5.16, CH3OH); 1H NMR (CDCl3) 4.5 (1H, d of d, J=12, J=3), 4.1 (1H, d of d, J=12, J=6), 3.3 (1H, m), 3.1 (3H, s), 2.8 (2H, m).
Reaction SMILES: [OH-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[CH2:35]1[O:51][C:50]2[CH:49]=[CH:48][C:39]([C:40]([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=O)=[CH:38][C:37]=2[O:36]1>O1CCCC1.O>[CH2:35]1[O:51][C:50]2[CH:49]=[CH:48][C:39](/[C:40](/[C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[CH:15]/[CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])=[CH:38][C:37]=2[O:36]1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1cccnc1)c1ccc2c(c1)OCO2
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCC/C=C(\c1cccnc1)c1ccc2c(c1)OCO2
Temperature: 85 °C
Yield: 11.2 %

Procedure:
Sodium hydroxide (1 g, 60% in oil) was added to dimethyl sulfoxide (25 ml) under nitrogen and the mixture was heated at 85° C. with stirring for an hour. The reaction mixture was cooled to room temperature and 5-carboxypentyltriphenylphosphonium bromide (5.2 g, 11 mmoles) was added gradually. The mixture was stirred for 10 minutes and a solution of 3-(3,4-methylenedioxybenzoyl)pyridine (2.5 g, 0.11 mole) in tetrahydrofuran (10 ml) was added dropwise thereto. After completion of addition, the mixture was further stirred at room temperature for 30 minutes. After completion of the reaction, water (100 ml) was added and the neutral substance was extracted twice with toluene (50 ml). The aqueous layer was adjusted to pH 5.5 with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate as the eluent. The eluant was concentrated and the residue was crystallized from ethyl acetate-isopropyl ether to give (Z)-7-(3,4-methylenedioxyphenyl)-7-(3-pyridyl)-6-heptenoic acid (0.4 g, 24.6%). Mp 90°-91° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]ccc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 43 %

Procedure:
The title compound is prepared from 1H-indole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 43% of theory; LC (method 4): tR=1.97 min; Mass spectrum (ESI+): m/z=317 [M+H]+.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[CH3:11][N:12]([CH3:25])[C:13]1(C#N)[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1.[Cl-].[NH4+]>C(OCC)C>[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:13]1([N:12]([CH3:25])[CH3:11])[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1
Reactant: Fc1ccccc1CCl
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C1(Cc2ccccc2F)CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
1.16 g magnesium were stirred into 20 ml analytical grade diethyl ether under a nitrogen atmosphere and approximately one third of the solution of 6.19 g 2-fluorobenzyl chloride in 25 ml analytical grade diethyl ether was added. The remainder of the solution was rapidly added dropwise after the Grignard formation had started, and when the addition had ended the mixture was subsequently stirred for one hour, a solution of 5.00 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 25 ml analytical grade diethyl ether was then added dropwise and the reaction mixture was stirred overnight. For working up, 36 ml ammonium chloride solution (20 per cent by weight) were added, while cooling with ice, the phases were separated, the aqueous phase was extracted twice with 50 ml diethyl ether each time and the combined organic phases were washed successively with 20 ml water and 20 ml saturated sodium chloride solution. The crude [8-(2-fluorobenzyl)-1,4-dioxaspiro[4.5]dec-8-yl]dimethylamine obtained (7.34 g) was stirred, without further purification, with a mixture of 18 ml conc. hydrochloric acid (32 per cent by weight) and 10 ml water for 24 hours at room temperature. The reaction mixture was then first washed three times with 50 ml diethyl ether each time and then adjusted to pH 9 by addition of aqueous ammonia (25 per cent by weight), while cooling with ice, and extracted three times with 50 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 5.80 g 4-dimethylamino-4-(2-fluorobenzyl)cyclohexanone were obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([CH3:17])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=2)[CH2:5][CH2:6][N:7]=1.[BH4-].[Na+].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>CO.O.C(O)C>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]2[C:8]([CH3:17])=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:10]=[C:3]12
Reactant: CC1=NCCn2c1cc(-c1ccccc1)c2C
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: Cc1c(-c2ccccc2)cc2n1CCNC2C
Yield: 66 %

Procedure:
3,4-Dihydro-1,6-dimethyl-7-phenylpyrrolo[1,2-a]pyrazine (0.5 g) was dissolved in a mixture of 20 ml of methanol and 2 ml of water under argon. The solution was treated portionwise with 0.25 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 50 ml of methylene chloride and washed with 50 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 30 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 0.6 g of yellow oil, was dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.5 g (66%) of 1,2,3,4-tetrahydro-1,6-dimethyl-7-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 196°-197° C. (dec.).
Reaction SMILES: CS[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[Mn]([O-])(=O)(=O)=O.[K+].[OH:17][S:18]([O-:20])=O.[Na+].[CH3:22]C(O)=O>>[CH3:22][S:18]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)(=[O:20])=[O:17]
Reactant: CC(=O)O
Reactant: CSc1ccc(C#N)cc1
Reactant: O=S([O-])O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
4-Methylsulfanyl-benzonitrile (250 mg, 1.68 mmol) was dissolved in 12 mL of HOAc. Potassium permanganate (531 mg, 3.36 mmol) was added as an aqueous solution (7-8 mL). After stirring 30 min at RT, NaHSO3 was added with stirring until the brown color of the solution disappeared. The mixture was concentrated and diluted with water. The precipitate was filtered and dried in vacuo to yield 4-methanesulfonyl-benzonitrile (250 mg, 82%) which was used without further purification.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>[Pd].C(Cl)Cl>[C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Oc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1cccc(N)c1
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To 60 mL anhydrous CH2Cl2 was added O-pivaloyl-3-nitrophenol (5.0 g, 22.4 mmol) and a catalytic amount (50 mg) of 10% Pd on C. The flask was repeatedly evacuated and flushed with N2. The reaction flask was again evacuated and H2 was introduced by balloon. After stirring under an atmosphere of H2 for 3 h, the reaction flask was flushed twice with N2. The suspension was then filtered through a bed of Celite™ and concentrated to give 4.15 g (96%) of O-pivaloyl-3-aminophenol as a viscous amber oil. Data for O-pivaloyl-3-aminophenol: Rf 0.21 (silica gel, hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3) 7.12 (dd, J=8.0, 8.0, 1H), 6.52 (dd, J=7.8, 2.7, 1H), 6.44 (ddd, J=8.0, 2.4, 1.4, 1H), 6.38 (t, J=2.2, 1H), 3.81 (br s, 2H), 1.34 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:18].[C:19]1([CH2:25][C:26](=[NH:30])OCC)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[ClH:18].[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1c(F)cccc1F
Yield: 5.5 %

Procedure:
A mixture of 2-amino-3-(2,6-difluorobenzyloxy)pyridine (4.72 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) to obtain the product as a hygroscopic glass (0.43 g), m.p. 45°-50° C.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:5]=1[C:6]([NH:8][CH2:9][CH:10]=[O:11])=[O:7])([O-])=O.[C:20](C1C=CC2C(=O)NCC=NC=2C=1)(C)(C)C>CO.[Pd]>[C:16]([C:14]1[CH:13]=[CH:12][C:5]2[C:6](=[O:7])[NH:8][CH2:9][CH:10]([O:11][CH3:20])[NH:1][C:4]=2[CH:15]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1ccc2c(c1)N=CCNC2=O
Reactant: CC(C)(C)c1ccc(C(=O)NCC=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC1CNC(=O)c2ccc(C(C)(C)C)cc2N1
Reaction time: 3 h

Procedure:
70 mg 10 wt % Pd on carbon was wetted with a small amount of methanol under argon. To this was added 717 mg (3 mmol) 2-nitro-4-tert-butyl-N-(2-oxo-ethyl)-benzamide dissolved in 20 mL methanol. The flask was evacuated and the atmosphere replaced with hydrogen gas using a balloon as ballast, and the mixture was hydrogenated for 3 hours. The reaction was filtered through celite under argon, the celite washed with ethyl acetate. Solvent was removed under vacuum to give a solid. NMR and LC/MS shows this to be a mixture of the title compound and 8-tert-Butyl-3,4-dihydro-benzo[e][1,4]diazepin-5-one as a one to one mixture, which was used without purification.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:12]([O:14][C@H:15]([O:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH3:16])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@@H:3]12.[NH2:26][C:27]1[S:28][CH:29]=[C:30](/[C:32](=[N:45]/[O:46]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:33]([O:35]C2SC3C=CC=CC=3N=2)=S)[N:31]=1.O.[C:67]1([CH3:77])[CH:72]=[CH:71][C:70]([S:73]([OH:76])(=[O:75])=[O:74])=[CH:69][CH:68]=1>CN(C)C=O.C(O)CC>[C:67]1([CH3:77])[CH:68]=[CH:69][C:70]([S:73]([OH:76])(=[O:74])=[O:75])=[CH:71][CH:72]=1.[NH2:26][C:27]1[S:28][CH:29]=[C:30](/[C:32](=[N:45]/[OH:46])/[C:33]([NH:1][CH:2]2[C:24](=[O:25])[N:4]3[C:5]([C:12]([O:14][C@H:15]([O:17][C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])[CH3:16])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@@H:3]23)=[O:35])[N:31]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=S)Oc2nc3ccccc3s2)cs1
Reactant: COCC1=C(C(=O)O[C@@H](C)OC(=O)OC(C)C)N2C(=O)C(N)[C@@H]2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Solvent: CN(C)C=O
Solvent: O
Product: COCC1=C(C(=O)O[C@@H](C)OC(=O)OC(C)C)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@@H]2SC1

Procedure:
905 mg (2.42 mmol) of 1-(1R,S)-(isopropyloxycarbonyloxy)ethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate and 1.5 g (2.6 mmol) of 2-benzothiazolyl (Z)-2-(2-aminothiazol-4-yl)-2-trityloxyiminothioacetate are reacted in 10 ml of N,N-dimethylformamide analogously to Example 5. The trityl-protected title compound is heated at 90° C. for 25 minutes with 475 mg (2.5 mmol) of p-toluenesulfonic acid hydrate in 10 ml of n-propanol. After cooling, 900 mg (52% of theory) of the title compound crystallize. If the trityl group is first removed with formic acid and the tosylate is then formed analogously to Example 5, the yield is 231 mg (13% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[NH2:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8])=[CH:5][CH:4]=1.C(#N)C.C(Cl)(Cl)Cl.C(N(CC)CC)C.[C:37]([C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]>C(#N)C>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[NH:20][C:45](=[O:46])[C:44]2[CH:48]=[CH:49][C:41]([C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:42][CH:43]=2)[C:13]([O:15][CH3:16])=[O:14])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(N)c(NC(=O)c2ccc(OC)cc2)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c(NC(=O)c2ccc(OC)cc2)c1
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of methyl 3-[(4-methoxybenzoyl)amino]-4-aminobenzoate (0.800 g, 2.67 mmol) in 1:1 acetonitrile/chloroform (100 mL) was cooled to 0° C. and treated with triethylamine (0.41 mL, 2.9 mmol), and a solution of 4-tert-butylbenzoyl chloride (0.58 mL) in acetonitrile (25 μL). The reaction mixture was allowed to warm to room temperature over 16 h, concentrated in vacuo, diluted with ethyl acetate, washed with cold dilute aqueous hydrochloric acid and cold saturated aqueous sodium bicarbonate solution. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Crystallization of the residue from methylene chloride/hexane provided 1.0 g (81%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:13](=O)[CH3:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)=O.C([NH2:21])=O.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][CH:13]([NH2:21])[CH3:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CC1(c2ccc(Cl)cc2)CCC1
Reactant: NC=O
Agent: Cl
Solvent: O=CO
Solvent: O
Product: CC(N)CC1(c2ccc(Cl)cc2)CCC1
Temperature: 180 °C

Procedure:
A mixture of 1-[1-(4-chlorophenyl)cyclobutyl]propan-2-one prepared as described in Example 3 (15 g) and 98% formic acid (4 ml) was added dropwise to formamide (12 ml) at 160° C. The temperature was raised to 180° C. and maintained at this temperature for ten hours. The mixture was cooled, diluted with water and extracted with dichloromethane. The extract was washed, dried and evaporated to yield a yellow oil which was hydrolysed with concentrated hydrochloric acid under reflux. The resulting aqueous solution after dilution with water was washed with ether, aqueous NaOH was added and the aqueous solution extracted with ether. The extracts were washed, dried and evaporated to yield a residue which on distillation gave 2-[1-(4-chlorophenyl)cyclobutyl]-1-methylethylamine (b.p. 105°-107°/0.7 mm Hg).