Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:34]([O:41][CH2:42][C@H:43]([C:45]1[C:53]2[C:48](=[N:49][CH:50]=[C:51]([C:54]([CH3:59])([CH3:58])[C:55](O)=[O:56])[CH:52]=2)[NH:47][C:46]=1[C:60]1[CH:65]=[C:64]([CH3:66])[CH:63]=[C:62]([CH3:67])[CH:61]=1)[CH3:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH2:68]([NH:72][CH2:73][CH:74]([CH3:76])[CH3:75])[CH:69]([CH3:71])[CH3:70].O.[Cl-].[Na+].O>C(Cl)Cl.C(N(CC)CC)C>[CH2:68]([N:72]([C:55](=[O:56])[C:54]([C:51]1[CH:52]=[C:53]2[C:45]([C@H:43]([CH3:44])[CH2:42][O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:46]([C:60]3[CH:65]=[C:64]([CH3:66])[CH:63]=[C:62]([CH3:67])[CH:61]=3)[NH:47][C:48]2=[N:49][CH:50]=1)([CH3:59])[CH3:58])[CH2:73][CH:74]([CH3:76])[CH3:75])[CH:69]([CH3:71])[CH3:70]
Reactant: CC(C)CNCC(C)C
Reactant: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)O)cc3c2[C@H](C)COCc2ccccc2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)N(CC(C)C)CC(C)C)cc3c2[C@H](C)COCc2ccccc2)c1

Procedure:
PyBOP is added to a stirred mixture of (S)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-pyrrolo-[2,3-b]pyridin-5-yl]-2-methylpropanoic acid, diisobutylamine and triethylamine in CH2Cl2 at ambient temperature. After approximately 12h, the reaction mixture is poured into water/brine (1:1) and extracted with ethyl acetate. The combined organic extract is washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (gradient elution; 60-75% ethyl acetate/hexanes as eluent) to give the title compound.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH2:11])=[S:10].Br[C:13]1([C:19](OC)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:13]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:19](=[O:20])[N:11]=1
Reactant: NC(=S)NC1CC2CCC1C2
Reactant: COC(=O)C1(Br)CCCCC1
Product: O=C1N=C(NC2CC3CCC2C3)SC12CCCCC2

Procedure:
Synthesis was performed from N-bicyclo[2.2.1]hept-2-ylthiourea and methyl 1-bromocyclohexanecarboxylate according to Method D.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2].N1C=CC=CC=1.[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:40](=[O:41])[CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Temperature: -20 °C
Yield: 107 %

Procedure:
To a solution of 32.6 g of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 750 ml of tetrahydrofuran is dropwise added a solution of 9.5 ml of pyridine and 15.1 ml of phenylacetyl chloride in 144 ml of tetrahydrofuran over a period of 15 minutes while maintaining the temperature at -20° C. and stirring under nitrogen atmosphere. The mixture is stirred for 55 minutes, poured into 700 ml of ice water, stirred for 5 minutes and extracted with ethyl acetate. The extract is washed with an aqueous solution of sodium hydrogencarbonate and water, dried on sodium sulfate, and evaporated under reduced pressure to yield 46.4 g of benzyl α-(3ξ-carbomethoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product in 107% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][C:12]3[CH:17]=[N:16][C:15]([C:18]#[N:19])=[N:14][C:13]=3[N:20]=2)=[CH:5][CH:4]=1)=[O:2].C1C[O:30]CC1.C([O-])([O-])=O.[K+].[K+].C(N)(N)=O.OO>O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][C:12]3[CH:17]=[N:16][C:15]([C:18]([NH2:19])=[O:30])=[N:14][C:13]=3[N:20]=2)=[CH:7][CH:8]=1)=[O:2]
Reactant: N#Cc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: C1CCOC1
Agent: NC(N)=O
Agent: O=C([O-])[O-]
Agent: OO
Solvent: O
Product: NC(=O)c1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 7-(4-formylphenyl)-6-phenylpyrido[2,3-d]pyrimidine-2-carbonitrile (2-5) (0.100 g, 0.297 mmol) in 2:1 THF:H2O (6 mL) was added K2CO3 (16 mg) and urea peroxide (0.112 g, 1.19 mmol). The mixture was stirred for 1 hr at rt when it was concentrated, diluted with 1:1 H2—O:saturated aqueous Na2CO3, and extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The crude material was used directly in the next step. LRMS, calc'd: 355.0, found: 355.0
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1.[OH:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][O:17][CH:16]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+].N>CCOCC>[OH:12][CH2:13][CH2:14][N:15]([CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][C:7]1[CH:10]=[CH:11][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)[CH2:19][CH2:18][OH:17]
Reactant: OCCN1CCOC1c1ccccc1
Reactant: COc1ccc(CCl)cc1
Agent: N
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(CC(c2ccccc2)N(CCO)CCO)cc1
Yield: 65.1 %

Procedure:
To a Grignard reagent prepared from magnesium turnings (6.7 g), magnesium powder (6.7 g) and p-methoxybenzyl chloride (18.1 g) in absolute ether (240 ml) is added dropwise a solution of 3-(2-hydroxyethyl)-2-phenyloxazolidine (9.6 g) in absolute ether (24 ml) under stirring, and the mixture is heated under reflux for 3 hours. The reaction mixture is poured onto ice water (100 ml) containing ammonium chloride under vigorously stirring by decantation, and the mixture is made alkaline with ammonia. The ether layer is separated and extracted with an excess amount of 10 % hydrochloric acid. The hydrochloric acid layer is made alkaline with sodium hydroxide and extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate and then the solvent is distilled off to give an oily substance of crude N,N-bis(2-hydroxyethyl)-2-(4-methoxyphenyl)-1-phenylethylamine (10.2 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Br:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:33]=[CH:32][C:24]2[N:25]([CH3:31])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=2[CH:22]=1.Cl>C(O)CCC.O1CCOCC1>[Br:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:33]=[CH:32][C:24]3[N:25]([CH3:31])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Br
Yield: 48.4 %

Procedure:
2-(2-chloro-5-bromo-pyrimidin-4-ylamino)-N-methyl-benzamide (52 mg, 0.15 mmol) and 7-amino-1-methyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (29 mg, 0.15 mmol) were combined in 5 mL n-butanol. A drop of a solution of 4N hydrochloric acid in dioxane was added and the mixture was refluxed for five hours. The mixture was concentrated and triturated with ether. The remaining solid was partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The organic layer was separated, was dried (sodium sulfate), and was concentrated to afford an oil which was purified on silica (methanol:dichloromethane gradient elution) to afford 36 mg (48%) of 2-[5-bromo-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as an off-white solid. Mp: 238-40° C.; MS: 496.61 (M+H); 1H NMR (chloroform-d): δ 10.95 (s, 1H), δ 8.58 (d, J=8 Hz, 1H), δ 8.22 (s, 1H), δ 7.52 (d, J=8 Hz, 1H), δ 7.44 (m, 3H), δ 7.11 (t, J=8 Hz, 1H), δ 7.01 (s, 1H), δ 6.25 (br s, 1H), δ 3.35 (s, 3H), δ 3.06 (s, 3H), δ 2.67 (m, 2H), δ 2.33 (t, J=7 Hz, 2H), δ 2.16 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)Cl.O>[Br:19][CH2:20][C:21]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:22]
Reactant: COc1ccc(N)cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)CBr)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared via a modification of the literature procedure (Vloon, W. J.; Kruk, C.; Pandit, U. K.; Hofs, H. P.; McVie, J. G. J. Med Chem. 1987, 30, 20-4.). To a solution of 4-methoxyaniline (4.93 g, 40.0 mmol) in methylene chloride (200 mL) was added diisopropylethylamine (7.66 mL, 44.0 mmol). The resulting mixture was cooled to -20° C., and bromoacetyl bromide (3.82 mL, 44.0 mmol) was added slowly. The reaction mixture was warmed to room temperature over 20 minutes and stirred additional 30 minutes. The reaction mixture was diluted with water (100 mL), stirred for 30 minutes and the organic layer was separated. The organic layer was washed with water (2×100 mL), brine (100 mL), dried over magnesium sulfate and concentrated in vacuo to afford a beige solid (9.68 g) which was recrystallized from ethyl acetate to provide bromo-N-(4'-methoxyphenyl)acetamide as a whim crystal (6.31 g, 65%).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:6])[CH2:2][CH3:3]>[Pd].CO>[NH2:17][C:15]1[CH:14]=[C:9]([CH:8]=[C:7]([C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:20][CH2:21][CH3:22])=[O:6])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Reaction time: 3 h

Procedure:
A suspension of methyl 3-[(dipropylamino)carbonyl]-5-nitrobenzoate (XXX, PREPARATION 9, 6.00g, 20.0 mmol) and palladium on carbon (5%, 0.600 g) in methanol (40 mL) is shaken in a hydrogenation apparatus under hydrogen (45 psi) for 3 hours. The mixture is then filtered through diatomaceous earth and concentrated to give the title compound, NMR (300 MHz, CDCl3) delta 7.27, 6.77, 4.10, 3.82, 3.38, 3.10, 1.62, 1.46, 0.91 and 0.68.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=O)[CH3:2].[CH3:8][C:9]([CH:11]=[CH2:12])=[O:10].OS(O)(=O)=O>C(Cl)(Cl)Cl>[CH2:1]([C:3]1([CH2:6][CH3:7])[CH2:4][CH2:8][C:9](=[O:10])[CH:11]=[CH:12]1)[CH3:2]
Reactant: C=CC(C)=O
Reactant: CCC(C=O)CC
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCC1(CC)C=CC(=O)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
A mixture of 2-ethylbutyraldehyde (12.3 mL, 100 mmol), methylvinylketone (5.6 mL, 67.3 mmol) and H2SO4 (0.07 mL) is stirred at 40° C. overnight. Another portion of methylvinylketone (5.6 mL, 67.3 mmol) and H2SO4 is added and stirring is continued at 40° C. for 2 d. The yellow solution is diluted with chloroform and the solvent is removed again under reduced pressure. The crude product is purified by vacuum distillation to give 4,4-diethyl-cyclohex-2-enone (10.7 g) as a colourless oil; Bp11 mbar=88° C.; 1H NMR (CDCl3): δ 6.71 (d, J=10.0 Hz, 1H), 5.92 (d, J=10.5 Hz, 1H), 2.42 (t, J=7.0 Hz, 2H), 1.84 (t, J=7.0 Hz, 2H), 1.57-1.40 (m, 4H), 0.87 (t, J=7.6 Hz, 6H).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Reactant: CN1CCNCC1
Agent: Cl
Product: CN1CCN(C(=O)c2cccc(-c3cccc4cc(C(=O)N[C@@H]5CN6CCC5CC6)oc34)c2)CC1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 23.5 mg (0.23 mmol) of N-methylpiperazine are reacted together by general method E. 9.2 mg (15.4% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]C1C=CC=CC=1B(O)O>>[Cl:21][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[C:7]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=1[C:14]=23
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccccc3Cl)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (210 mg, 0.79 mmol) and 2-chlorophenylboronic acid (136 mg, 0.87 mmol) were coupled to yield 2-(2-chlorophenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 78 mg (33%), as a shiny white solid. mp 275° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 2.76 (m, 2H), 3.38 (m, 2H), 7.23 (app t, 1H, J=7.8 Hz), 7.56 (m, 5H), 7.71 (dd, 1H, J=7.5, 0.9 Hz), 8.07 (br t, 1H), 11.53 (br s, 1H); MS (FAB, MH+) 297; Anal. (C17H13N2OCl.0.15 H2O) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[O:20][CH3:21]>CS(O)(=O)=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:17]1[C:16]([CH3:19])=[CH:15][C:14]([O:20][CH3:21])=[C:13]([O:12][CH3:11])[CH:18]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Br
Reactant: COc1ccc(C)cc1OC
Agent: CS(=O)(=O)O
Product: COc1cc(C)c(C(=O)c2ccccc2Br)cc1OC
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 g of bisphosphorus pentoxide in 200 ml of methanesulfonic acid is poured over 20.7 g (0.1 mol) of 2-bromobenzoic acid and 15.2 g (0.1 mol) of 1,2-dimethoxy-4-methylbenzene, and the mixture is heated, with stirring, for 30 minutes at 70° C. The mixture is then poured into ice-water and extracted with ether. After concentration by evaporation, the ether extracts yield (2-bromophenyl)-(3,4-dimethoxy-6-methylphenyl)-methanone as a brown product of honey-like consistency.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C@@H:11]1[NH:29][C:28](=[O:30])[C@@H:27]([NH:31]C(OC(C)(C)C)=O)[CH2:26][C:25]2[CH:39]=[C:21]([CH:22]=[CH:23][C:24]=2[OH:40])[C:20]2=[CH:41][C:16](=[C:17]([OH:42])[CH:18]=[CH:19]2)[CH2:15][C@@H:14]([C:43]([NH:45][C@H:46]([C:54]([NH:56][CH2:57][CH2:58][NH2:59])=[O:55])[CH2:47][CH2:48][CH2:49][NH:50][C:51]([NH2:53])=[NH:52])=[O:44])[NH:13][C:12]1=[O:60])(C)(C)C.[ClH:62]>O1CCOCC1>[ClH:62].[ClH:62].[ClH:62].[ClH:62].[ClH:62].[NH2:31][C@H:27]1[CH2:26][C:25]2[CH:39]=[C:21]([CH:22]=[CH:23][C:24]=2[OH:40])[C:20]2=[CH:41][C:16](=[C:17]([OH:42])[CH:18]=[CH:19]2)[CH2:15][C@@H:14]([C:43]([NH:45][C@H:46]([C:54]([NH:56][CH2:57][CH2:58][NH2:59])=[O:55])[CH2:47][CH2:48][CH2:49][NH:50][C:51]([NH2:53])=[NH:52])=[O:44])[NH:13][C:12](=[O:60])[C@H:11]([CH2:10][CH2:9][CH2:8][NH2:7])[NH:29][C:28]1=[O:30]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)N[C@@H](CCCNC(=N)N)C(=O)NCCN)NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](N)C(=O)N[C@@H](CCCN)C(=O)N1)C(=O)NCCN
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.3 mg (0.005 mmol) of tert-butyl{3-[(8S,11S,14S)-8-{[((1S)-1-{[(2-aminoethyl)amino]carbonyl}-4-{[amino(imino)methyl]amino}butyl)amino]carbonyl}-14-[(tert-butoxycarbonyl)amino]-5,17-dihydroxy-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-11-yl]propyl}carbamate di(hydrotrifluoroacetate) (Example 209A) are added into 0.4 ml of a 4N solution of hydrogen chloride in dioxane and stirred at RT for 30 min. The reaction solution is concentrated, coevaporated with dichloromethane several times and dried under high vacuum.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].[CH:6]([C:8]1[C@H:13]([C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:12]2[C:30](=[O:42])[C@@H:31]([NH:32][C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:11]2[S:10][CH:9]=1)=[O:7].[Cl-].[Li+].Cl>O1CCCC1.C(OCC)(=O)C>[OH:7][CH:6]([C:8]1[C@H:13]([C:14]([O:16][CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[N:12]2[C:30](=[O:42])[C@@H:31]([NH:32][C:33](=[O:41])[CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:11]2[S:10][CH:9]=1)[CH2:3][CH:2]=[CH2:1]
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: C=CC[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC(O)C1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
Allylmagnesium chloride (2M in diethyl ether, 4.0 ml, 8 mmol) was added to a solution containing diphenylmethyl (4R, 6R, 7R)-3-formyl-7-phenylacetamidoceph-2-em-4-carboxylate (0.5 g, 1.0 mmol) and lithium chloride (0.35 g, 8 mmol) in tetrahydrofuran (5 ml) at −70° C. After 20 minutes at −70° C., hydrochloric acid (1M, 10 ml, 10 mmol) was added. Ethyl acetate was added and the organic layer was separated, washed with brine, dried (MgSO4), and evaporated. The resulting oil was purified by chromatography (20% to 60% ethyl acetate in hexane, silica gel) giving; first the title compound S-diastereomer, 90 mg (17%), dH (CDCl3) 2.18 (1H, dt, J 15 Hz and 8 Hz), 2.36 (1H, dt, J 17 and 5 Hz), 3.45 (2H, ABq), 4.18 (1H, m), 4.95-5.15 (4H, m), 5.55-5.7 (2H, m), 6.11 (1H, d, J 9 Hz), 6.36 (1H, s), 6.89 (1H, s), 7.3-7.4 (15H, m), and second; the title compound R-diastereomer, 250 mg (45%), dH (CDCl3) 2.28 (2H, t, J 7 Hz), 3.62 (2H, ABq), 4.15 (1H, t, J 7 Hz), 4.95-5.2 (4H, m), 5.5-5.65 (2H, m), 6.16 (1H, d, J 9 Hz), 6.20 (1H, s), 6.89 (1H, s), 7.3-7.4 (15H, m).
Reaction SMILES: O=[C:2]1[C:11]2[C:6]3[C:7](=[CH:12][CH:13]=[CH:14][C:5]=3[C:4](=O)[N:3]1[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:8]=[CH:9][CH:10]=2.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)C>C1COCC1>[CH2:2]1[C:11]2[C:6]3[C:7](=[CH:12][CH:13]=[CH:14][C:5]=3[CH2:4][N:3]1[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:8]=[CH:9][CH:10]=2
Reactant: NCCCCN1C(=O)c2cccc3cccc(c23)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: NCCCCN1Cc2cccc3cccc(c23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.0 g (18.6 mmol) 4-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-butylamine are dissolved in 200 ml THF and 6.1 g (160.7 mmol) LiAlH4 are added in portions under cooling. The suspension is stirred for 24 hours at RT and for 8 hours under reflux. After cooling, ethanol is carefully added dropwise until no more foam appears. The mixture is filtered and the filtrate is concentrated under vacuum. The residue is distributed between chloroform and water. The organic phase is dried over sodium sulfate and, after withdraw of the solvent, chromatographically purified over silica gel with CHCl3/CH3OH/NH4OH (90/10/0.5 to 90/10/1): Yield 2.2 g (49%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:19]2[CH2:18][CH2:17][CH:16]([O:15][C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[C:12]([F:11])([F:26])[F:27])[CH2:21][CH2:20]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Temperature: 82.5 °C

Procedure:
A mixture of 2-chloro-5-nitropyridine (1.6 g, 6.5 mmol), 4-[2-(trifluoromethyl)phenoxy]piperidine (1.2 g, 7.6 mmol), and DBU (2 mL, 13 mmol) in DMF (25 mL) was heated at 80-85° C. for 2 h. The EtOAc extract was washed three times with water, dried (MgSO4) and concentrated. CombiFlash chromatography (120 g, 20-40% EtOAc in hexanes in 20 min, 70 mL/min, 18 mL/fraction) gave the desired product as a yellow powder.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:21]=[C:20]([CH3:22])[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4].[CH2:31]1N2CN3CN(C2)C[N:32]1C3.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:22][C:20]1[N:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:18]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([N:5]4[C:3](=[O:4])[CH2:2][NH:32][CH2:31]4)=[CH:7][CH:8]=3)[N:16]=2)[CH:21]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(NC(=O)CBr)cc4)no3)cc2C)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N5CNCC5=O)cc4)no3)cc2C)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-N-(4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}phenyl)acetamide (Step 2, 190 mg, 0.407 mmol) in ethanol (4 mL) was added hexamethylenetetramine (286 mg, 2.04 mmol). The reaction mixture was stirred and heated at reflux for 2.5 h. After being cooled to rt, the solvent was evaporated, and the residue was subjected to preparative HPLC. The crude product thus obtained was treated with a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate. Subsequent filtration and evaporation of the solvent yielded the title compound which was obtained in pure form after stirring with cyclohexane (84 mg, 50%): 1H NMR (400 MHz, CDCl3) δ 8.23 (d, 2H), 7.70 (d, 2H), 7.13 (d, 2H), 7.07 (d, 2H), 6.79 (s, 1H), 5.40 (s, 2H), 4.92 (s, 2H), 3.69 (s, 2H), 2.32 (s, 3H), 2.25 (s, 3H); ES-MS m/z 415, HPLC RT (Method E) 1.62 min.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]([N:11]=[C:12]2[NH:16][CH2:15][CH2:14][NH:13]2)[CH:6]=[CH:7][C:8]=1[O:9]C.Br>>[BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]([N:11]=[C:12]2[NH:13][CH2:14][CH2:15][NH:16]2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(N=C2NCCN2)cc1Cl
Agent: Br
Product: Oc1ccc(N=C2NCCN2)cc1Cl
Yield: 73.6 %

Procedure:
A mixture of 8 gm of 2-(3-chloro-4-methoxy-phenylimino)-imidazolidine hydrobromide (0.026 mol) and 125 ml of 48% hydrobromic acid was refluxed on an oil bath for five hours. Thereafter, the hydrobromic acid was evaporated in vacuo, the residue was dissolved in methanol, and the solution was purified by treatment with activated charcoal and filtration. Ether was added to the filtrate, whereby an amorphous product separated out which was collected and dried, yielding 5.60 gm (73.6% of theory) of 2-(3-chloro-4-hydroxy-phenylimino)-imidazolidine hydrobromide, m.p. 224°-225° C., Rf -value 0.4 in mobile phase consisting of 75 parts sec.butanol, 15 parts formic acid and 10 parts water. Carrier: Silicagel; visualization: ultraviolet light and potassium iodoplatinate.