Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]([F:33])([C:29]([F:32])([F:31])[F:30])[CH2:21][NH:22][C:23](=[O:28])[CH2:24][C:25](O)=[O:26]>>[CH3:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:25](=[O:26])[CH2:24][C:23]([NH:22][CH2:21][C:20]([F:33])([F:19])[C:29]([F:30])([F:32])[F:31])=[O:28])[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]1=2
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: O=C(O)CC(=O)NCC(F)(F)C(F)(F)F
Product: CN1C(=O)[C@@H](NC(=O)CC(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
(S)-7-Amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in example 73 to yield N-((S)-5-Methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:25][CH:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NC1CCCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCCCC1)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 92.7 %

Procedure:
Dissolve 4-bromo-benzoyl chloride (2.0 g, 9.1 mmol) in DCM (20 mL). Cool the solution to 0° C. and add triethylamine (2.54 mL, 18.2 mmol) followed by cycloheptylamine (1.24 g, 10.9 mmol). Warm the mixture to room temperature over 1 h. Wash the mixture with saturated NaHCO3 (15 mL). Collect the organic layer, and extract the aqueous layer with DCM. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel (120 g) eluting with hexane/EtOAc (1:1) to obtain the title compound as a solid (2.5 g, 93%). MS (APCI+) m/z: 296 (M)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>COCCOC.O.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:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[C:10]3[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=3[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:3]=2)=[CH:29][CH:28]=1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccn3)c2C1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)CC(=O)c2c(-c3ccc(Cl)cc3)cn(-c3ccccn3)c2C1
Temperature: 100 °C
Yield: 10.7 %

Procedure:
A solution of 3-bromo-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one (50 mg, 0.16 mmol) and tetrakis(triphenylphosphine)palladium (15 mg, 0.01 mmol) in ethylene glycol dimethyl ether (2 mL) at 45° C. was degassed with nitrogen for 30 min. A degassed solution of Cs2CO3 (104 mg, 0.16 mmol) in water (1 mL) was added followed by 4-chlorophenylboronic acid (25 mg, 0. 16 mmol). The solution was heated at 100° C. for 18 h then filtered through celite. The filtrate was partitioned between DCM and water. The organic phase was separated, dried (MgSO4) and evaporated. The residue was purified by column chromatography, eluting with isohexane: EtOAc (3:1) to give the title compound (6 mg, 11%) as a colourless solid. 1H NMR (360 MHz, d6-DMSO) δ 1.05 (6H,s), 2.37 (2H,s), 3.01 (2H,s), 7.38 (2H,d, J=8.5 Hz), 7.46-7.50 (1H,m), 7.56 (1H,s), 7.68-7.74 (3H,m), 8.05-8.09 (1H,m), 8.59-8.63 (1H,m). MS (ES+) 351/353 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][CH2:9][C:10]2=[O:12])=[O:5])[CH3:2].CCN(CC)CC.O([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])S(C(F)(F)F)(=O)=O>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][CH:9]=[C:10]2[O:12][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C2CCC(=O)C21
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1C2CC=C(O[Si](C)(C)C(C)(C)C)C21
Temperature: 22 °C

Procedure:
To a solution of (1RS,5SR,6RS)-2-oxo-bicyclo[3,1,0]hexane-6-carboxylic acid ethyl ester (28.93 g, 172 mmole) in dichloromethane (430 ml) was added at 22° C. NEt3 (36.0 ml, 258 mmole), the mixture was cooled to 0° C. and treated with tert-butyldimethylsilyl triflate (43.5 ml, 189.2 mmole) keeping the temperature below 10° C. The mixture was allowed to warm to 22° C. over 2 h, washed with saturated aqueous NaHCO3, the organic layer was dried, evaporated and the residue purified over aluminiumoxide (100 g) using cyclohexane/AcOEt (9:1) to give the title compound as a yellow oil which was used without further purification in the next step.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:1]([NH:8][C@H:9]([C:17]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCCC1

Procedure:
2.65 g (10 mmol) BOC-L phenylalanine was coupled to 1.48 ml (17.8 mmol) pyrrolidine according to procedure B. Yield of active ester 3.22 g (8.9 mmol, 89%). Yield of crude product 3.33 g. The product was purified with a silica column using 1–2% methanol in dichloromethane as eluent. Yield 1.76 g (5.5 mmol, 55%).
Reaction SMILES: Cl[C:2]1[C:3]([Cl:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([OH:19])C>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([OH:19])[CH2:13][CH2:12]1.[Cl:9][C:3]1[N:4]=[CH:5][N:6]=[CH:7][CH:2]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCO
Reactant: CN1CCNCC1
Product: CN1CCN(O)CC1
Product: Clc1ccncn1
Temperature: 0 °C

Procedure:
Trichloropyrimidine is added in portions to an ice cool solution of N-methylpiperazine (40 g) in ethanol (200 ml). The mixture is then heated at 60° for 2 h. The mixture is concentrated and chromatographed on silica gel with 2-5% methanol and methylene chloride to give 2,4-bis[4-methylpiperazinol-6-chloropyrimidine. This material is heated at 130° in water (30 ml) with piperazine (32 g) in a Parr bomb for 20 h. The product is partitioned between methylene chloride and aqueous sodium carbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated to give the title compound, TLC (methylene chloride/methanol/ammonium hydroxide--91.5/8/0.5) Rf =0.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=2)[O:3]1.[I:18]Cl.BrC1C=C(C(O)=O)C=C2C=1OC(C)(C)CC2(C)C>>[I:18][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]2([CH3:12])[CH3:13]
Reactant: ClI
Reactant: CC1(C)CC(C)(C)c2cc(C(=O)O)ccc2O1
Agent: CC1(C)CC(C)(C)c2cc(C(=O)O)cc(Br)c2O1
Product: CC1(C)CC(C)(C)c2cc(C(=O)O)cc(I)c2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
To a solution of 2,2,4,4-tetramethyl-6-chromanoic acid (66 mg, 0.28 mmol) in 0.8 ml of ACOH was added ICl (0.07 ml, 1.4 mmol). The resulting colored solution was stirred at room temperature for overnight. Following the same procedure as for the synthesis of 8-bromo-2,2,4,4-tetramethyl-6-chromanoic acid (Compound P), the reaction gave the title compound (107 mg) as white solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([CH2:13]O)=[CH:6]2.O=S(Cl)[Cl:17]>C(Cl)Cl>[ClH:17].[Cl:17][CH2:13][C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: COc1ccc2ncc(CO)cc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2ncc(CCl)cc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred solution of (6-methoxyquinolin-3-yl)methanol SLA 47088A (0.476 g, 2.5 mmol) in dry CH2Cl2 (25 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (3.65 mL, 50.4 mmol). The mixture was stirred for 2 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was then taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)-6-methoxyquinoline hydrochloride SLA 47088B as a yellow solid (0.60 g, 98% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([C:35]3[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=3)=[CH:31][NH:32]2)=[CH:28][CH:27]=1>CS(C)=O.C(OCC)(=O)C>[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([C:35]3[CH2:36][CH2:37][N:38]([CH2:12][C@H:13]4[CH2:22][CH2:21][C:20]5[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=5)[O:14]4)[CH2:39][CH:40]=3)=[CH:31][NH:32]2)=[CH:28][CH:27]=1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CC2
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1O[C@@H](CN1CC=C(c3c[nH]c4cc(F)ccc34)CC1)CC2
Temperature: 80 °C
Yield: 61.9 %

Procedure:
To a solution of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.348 g, 1.00 mmol) in methyl sulfoxide (20 mL) was added 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.865 g, 4.00 mmol) and the reaction mixture was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 4:1) followed by recrystallization from ethanol provided 0.243 g (62%, 40% ee) of 6-fluoro-3-(1-{[(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole as a tan crystalline powder. [α]D25=−27.14 (c 9.95 in chloroform, 40% ee); Rf=0.47 (silica, ethyl acetate:hexanes 4:1); mp >170° C. dec; Anal. Calcd. for C24H25FN2O2.0.1 H2O: C, 73.11; H, 6.44; N, 7.11. Found: C, 72.81; H, 6.36; N, 7.06.
Reaction SMILES: Cl.[N:2]1([C:8]([O:10][CH2:11][CH:12]2[CH2:17][NH:16][CH2:15][CH2:14][NH:13]2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:23]([N:13]1[CH2:14][CH2:15][N:16]([C:23](=[O:24])[C:22]2[CH:21]=[C:20]([O:19][CH3:18])[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=2)[CH2:17][CH:12]1[CH2:11][O:10][C:8]([N:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])=[O:24]
Reactant: O=C(OCC1CNCCN1)N1CCCCC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C(COC(=O)N3CCCCC3)C2)cc(OC)c1OC
Yield: 68.5 %

Procedure:
Working again according to a protocol identical to the one used in step 1.3 of Example 1, followed by treating, under the same conditions as those of step 1.4 of Example 1, 0.5 g of 2-(1′-piperidinocarbonyloxymethyl)piperazine hydrochloride with 1.1 g of 3,4,5-trimethoxybenzoyl chloride, 0.8 g of 1,4-bis(3′,4′,5′-trimethoxybenzoyl)-2-(1′-piperidinocarbonyloxymethyl)piperazine is obtained. Yield: 56%. Melting point: 146.7° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5](OC)=[O:6].O.[NH2:14][NH2:15].Cl>O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:14][NH2:15])=[O:6]
Reactant: NN
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: Cl
Solvent: O
Product: NNC(=O)c1ccc(O)c(F)c1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
10.00 g (58.8 mM) of methyl 3-fluoro-4-hydroxybenzoate and 17.5 ml of 80%-hydrazine hydrate were mixed and stirred for 1 hour and 20 minutes at 100° C., followed by cooling to room temperature. The resultant mixture was poured into 150 ml of iced water and 16.8 ml of concentrated hydrochloric acid was added thereto (pH=about 8), followed by addition of common salt and stirring at room temperature to precipitate a crystal. The crystal was recovered by filtration and stirred in methanol at room temperature. The resultant crystal was recovered from the above mixture by filtration to obtain 9.26 g of 3-fluoro-4-hydroxybenzohydrazide (Yield: 92.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:36][CH2:37][CH2:38][CH2:39]I.Cl>CN(C)C=O>[Cl:36][CH2:37][CH2:38][CH2:39][N:16]1[C:17]2[C:12](=[N:11][CH:10]=[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:18]=2)[C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]1=[O:19]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: ClCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCCl)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (40 mg, 0.117 mmol) in N,N-dimethylformamide was added lithium bis(trimethylsilyl)amide (234 μL, 1.0 M in tetrahydrofuran, 0.234 mmol) dropwise. 1-Chloro-3-iodopropane (50 μL, 0.468 mmol) was added dropwise and stirred 4 hours at room temperature. The reaction mixture was acidified with cold 1 N aqueous hydrochloric acid and extracted with toluene. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration provided ethyl 1-(3-chloropropyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J=1.1 Hz, 1 H), 7.50 (s, 1 H), 7.18 (dd, J=8.6, 5.3 Hz, 2 H), 7.03 (t, J=8.6 Hz, 2 H), 4.50 (q, J=7.1 Hz, 2 H), 4.27 (t, J=7.6 Hz, 2 H), 4.13 (s, 2 H), 3.61 (t, J=5.9 Hz, 2 H), 2.09 (m, 2 H), 1.47 (t, J=7.3 Hz, 3 H); MS m/z 417 (M−H)−.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=2[O:14][CH3:15])[CH2:3][CH2:2]1.[Br:16]Br.[NH4+].[OH-]>CO.C(Cl)Cl.O>[Br:16][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[C:6]([O:14][CH3:15])[CH:7]=1
Reactant: BrBr
Reactant: COc1cccc([N+](=O)[O-])c1NC1CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1cc(Br)cc([N+](=O)[O-])c1NC1CC1
Reaction time: 1 h

Procedure:
N-cyclopropyl-2-methoxy-6-nitroaniline (1.05 g, 5.04 mmol) was dissolved in MeOH (25 mL). Bromine (0.27 mL, 5.2 mmol) was added dropwise over 1 min, and the resulting mixture was stirred 1 h. Additional bromine (0.05 mL, 0.98 mmol) was then added and the resulting mixture was stirred for an additional 30 min. The mixture was then diluted with DCM (75 mL) and H2O (50 mL), and the aqueous phase was basified with saturated aqueous NH4OH (2 mL). The phases were separated, and the aqueous phase was extracted with DCM (30 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-25% EtOAc in hexanes) to afford 4-bromo-N-cyclopropyl-2-methoxy-6-nitroaniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C10H12BrN2O3: 287.0; found: 286.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: NCCc1nc(-c2ccc(Cl)cc2)cs1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1nc(-c2ccc(Cl)cc2)cs1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 16 %

Procedure:
This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (30 mg, yield 16%). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.81 (d, J=8.6 Hz, 2H), 7.64-7.60 (m, 2H), 7.39 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 4.02-3.97 (q, J=5.8 Hz, 2H), 3.39-3.36 (t, J=5.9 Hz, 2H). MS (ESI) m/z: Calculated for C21H14ClF3N4O2S: 478.05. found: 479.0 (M+H)+.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:22]([NH:24][N:25]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:26](=[O:40])[CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:22]([NH:24][N:25]([CH2:41][CH:42]([CH3:43])[CH3:44])[C:26](=[O:40])[CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCN1C(=O)c2ccccc2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCN1C(=O)c2ccccc2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
A solution of 0.050 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(3-phthalimidopropionyl)valerohydrazide in 5 ml of methanol was treated with 0.005 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 1 hr at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.009 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(3-phthalimidopropionyl)valerohydrazide in the form of an off-white solid.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([CH3:15])=[C:9]([C:13]#[N:14])[NH:10][C:11]=1[CH3:12])=O.[N+]([O-])(O)=O.[N+:21]([C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH2:33])=[NH:32])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>COCCO>[CH3:15][C:8]1[C:7]([C:5]2[CH:4]=[CH:3][N:33]=[C:31]([NH:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)[N:32]=2)=[C:11]([CH3:12])[NH:10][C:9]=1[C:13]#[N:14]
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Reactant: Cc1[nH]c(C#N)c(C)c1C(=O)C=CN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1[nH]c(C#N)c(C)c1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Temperature: 120 °C

Procedure:
To a mixture of 4-(3-dimethylamino-acryloyl)-3,5-dimethyl-1H-pyrrole-2-carbonitrile (1.0 mmol, 0.22 g) and 3-nitrophenyl guanidine nitrate (1.5 mmol, 0.36 g) in 2-methoxyethanol (5 mL) was added K2CO3 (138 mg, 1.0 mmol). The reaction mixture was heated at 120° C. under N2 for 18 h. The solvent was evaporated to dryness and the residue was purified by flash chromatography (1:2 EtOAc/heptane) to afford the title compound as a light-yellow solid. M.p. 258–259° C. MS: [M+H]+=336.1 (C17H14N6O2 requires 334.3). 1H-NMR (CD3OD) δ: 2.39 (s, 3H, CH3), 2.49 (s, 3H, CH3), 6.94 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.50 (t, 1H, J=8.3 Hz, Ph-H), 7.81 (m, 1H, Ph-H), 7.94 (m, 1H, Ph-H), 8.45 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 8.94 (t, 1H, J=2.2 Hz, Ph-H).
Reaction SMILES: [CH3:1][C:2]([NH2:25])([CH3:24])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]2[CH2:35][O:34]2)[CH:28]=1>C(O)C>[CH3:1][C:2]([NH:25][CH2:35][C@@H:33]([C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1)[OH:34])([CH3:24])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: C[C@H](Oc1cccc2c(CC(C)(C)N)c[nH]c12)C(=O)N1CCOCC1
Reactant: c1cncc([C@@H]2CO2)c1
Solvent: CCO
Solvent: O
Product: C[C@H](Oc1cccc2c(CC(C)(C)NC[C@H](O)c3cccnc3)c[nH]c12)C(=O)N1CCOCC1
Temperature: 10 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To a solution of 2-methyl-1-{7-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethoxy]-1H-indol-3-yl}propan-2-amine (68.4 mg, 0.198 mmol) in ethanol (4 mL)- water (0.4 mL) is added (R)-(pyridin-3-yl)oxirane (36.0 mg, 0.297 mmol), and the mixture is refluxed for 8 hours. To the reaction solution is added (R)-(pyridin-3-yl)oxirane (144.0 mg, 1.19 mmol) in 4 portions, and the mixture is heated with stirring at 100 to 1 10° C. in a sealed tube for 18 hours. After the reaction is completed, the solvent is evaporated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (chloroform/methanol=20/1→10/1→chloroform/a saturated ammonia methanol=10/1) to give (1R)-2-[(1,1-dimethyl-2-{7-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethoxy]-1H-indol-3-yl}ethyl)amino]-1-pyridin-3-ylethanol (23.1 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O>CN(C=O)C>[CH2:30]([O:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH:9]=[O:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOc1ccc([N+](=O)[O-])cc1C=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
5-Nitrosalicylaldehyde (1.7 g, 10 mm) was dissolved in 20 ml dry DMF and K2CO3 (2.2 g, 16 mm) was added cautiously. The reaction was stirred at room temperature for 20 minutes and 1-bromoundecane (2.6 g, 11 mm), in 20 ml dry DMF, was added dropwise to the mixture. The reaction was heated at 89° C. for 3 days, cooled and poured into 100 ml H2O. The product was extracted with diethyl ether, washed with 5% aqueous Na2CO3 and brine, and dried over MgSO4. Filtration and evaporation of the solvent yielded an oil which was chromatographed over silica gel using 10% ethylacetate/hexane. This yielded an oil which crystallized upon scratching. The resulting white solid melted at 47°-48° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[N:12]([CH3:19])[N:13]=[C:14]([OH:18])[C:15](=[O:17])[N:16]=3)[CH2:7][S:8][C@H:3]12.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH:25](=[N:1][C@@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[N:12]([CH3:19])[N:13]=[C:14]([OH:18])[C:15](=[O:17])[N:16]=3)[CH2:7][S:8][C@H:3]12)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: Cn1nc(O)c(=O)nc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CN(C)C=O
Product: Cn1nc(O)c(=O)nc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N=Cc3ccccc3)[C@H]2SC1
Yield: 93.2 %

Procedure:
A suspension of 7β-amino-3-[(2,5-dihydro-6- hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thiomethyl]ceph-3-em-4-carboxylic acid (see EP 65748) (3.71 g) in dimethylformamide (50 ml) was treated with benzaldehyde (4.24 g) and the mixture was sonicated in an ultrasound bath at 25° for 0.5 hours, by which time a clear solution had resulted. After evaporation to dryness in vacuo the residue was triturated with ether to give the title compound, (4.28 g).