Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]([CH2:24][C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[C:7]2[C:12]([C:13]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:11][CH:10]=[C:9]([C:20]([O:22]C)=[O:21])[CH:8]=2)=O.[C:33]([NH:37][C:38]([NH2:40])=[S:39])([CH3:36])([CH3:35])[CH3:34].[OH-].[Na+].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>CS(C)=O>[C:33]([NH:37][C:38]1[S:39][CH:2]=[C:3]([C:5]2[N:6]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[C:7]3[C:12]([C:13]=2[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:11][CH:10]=[C:9]([C:20]([OH:22])=[O:21])[CH:8]=3)[N:40]=1)([CH3:36])([CH3:35])[CH3:34].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(C(=O)CBr)n(CC(=O)N3CCOCC3)c2c1
Reactant: CC(C)(C)NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)(C)Nc1nc(-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2CC(=O)N2CCOCC2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The bromomethylketone of example 11 (39.6 mg, 0.078 mmol, 1 equiv.) was dissolved in DMSO (1 mL) and N-tertbutylthiourea (12.4 mg, 0.094 mmol, 1.2 equiv.) was added. The mixture was stirred for 2 h at room temperature. 10 N NaOH (24 μL) was added and after stirring for 4 h at room temperature, another portion of 10 N NaOH (24 μL) was added and the mixture stirred 24 h at room temperature to complete the hydrolysis. The reaction mixture was then neutralized by addition of TFA and the title product of example 12 isolated directly from the reaction mixture by preparative HPLC as a white amorphous TFA salt (21 mg).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>CCOCC>[CH3:24][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35](=[O:36])[CH2:14][C:13](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:23]
Reactant: CC(=O)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
To a cooled (-78° C.) solution of diisopropylamine (2.48 g, 0.024 mol) in 100 mL ether, n-BuLi (0.024 mol) was added dropwise followed by 50 mL ether. After stirring for 5 minutes at -78° C. under a nitrogen atmosphere, a solution of acetophenone (2.95 g, 0.024 mol) in 25 mL ether was added dropwise and the resulting solution was stirred for 20 minutes at -78° C. A solution of 2,6-diisopropylphenyl isocyanate in 25 ML Et2O was then added dropwise and the reaction mixture was allowed to gradually warm to room temperature and stir for 16 hours under a nitrogen atmosphere (J. F. Wolfe, et al, Synthetic Communications 17, 13 (1987)). The reaction mixture was then quenched with a saturated solution of ammonium chloride and extracted with methylene chloride. The layers were separated and the organic layer was washed two times with water, dried (Na2SO4) and concentrated in vacuo (30° C.) to afford a yellow residue. This residue was washed with hexane, filtered, and oven-dried (40° C.) to yield a pale yellow solid, 4.3 g (0.013 mol, 54%) of the title compound, mp 124°-126° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:35].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:23]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH3:35])[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(CNc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccc(F)cc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
5,6-bis(Benzyloxy)-N-[(4-fluorophenyl)methyl]pyridazin-3-amine (Intermediate 45; 0.7 g, 1.68 mmol) was dissolved in N,N-dimethylformamide (8 ml) and the solution was cooled to 0° C. before sodium hydride (60% by weight in paraffin; 0.101 g, 2.53 mmol, 1.5 equiv.) was added under nitrogen atmosphere. The reaction mixture was allowed to warm at room temperature for approximately 30 minutes and iodomethane (1.189 g, 8.43 mmol, 5 equiv.) was added. The reaction was allowed to stir at room temperature for one hour before being poured into water (100 ml) and the organic materials were extracted into ethyl acetate (50 ml×2). The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude compound was purified by column chromatography (silica gel, eluting with 0-50% ethyl acetate in hexane) to yield 5,6-bis(benzyloxy)-N-(4-fluorobenzyl)-N-methylpyridazin-3-amine (0.51 g, 64% yield).
Reaction SMILES: [N+]([O-])([O-])=[O:2].[NH4+].[Ce].CO[C:9]1([CH3:29])[C:14]([CH3:15])=[C:13]([O:16]C)[C:12]([CH3:18])=[C:11]([CH2:19][CH2:20][C@@:21]2([CH3:28])[CH2:25][O:24]C(C)(C)[O:22]2)[CH2:10]1>O.C(#N)C>[OH:22][C@:21]([CH3:28])([CH2:25][OH:24])[CH2:20][CH2:19][C:11]1[C:10](=[O:2])[C:9]([CH3:29])=[C:14]([CH3:15])[C:13](=[O:16])[C:12]=1[CH3:18]
Reactant: O=[N+]([O-])[O-]
Reactant: COC1=C(C)C(C)(OC)CC(CC[C@@]2(C)COC(C)(C)O2)=C1C
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC1=C(C)C(=O)C(CC[C@](C)(O)CO)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 41.4 %

Procedure:
While stirring for 2 minutes at room temperature, 2.01 g of cerium ammonium nitrate in 7.5 ml of water were added dropwise to a solution of 550 mg of (S)-4-(3,5-dimethoxy-3,4,6-trimethyl-phenylethyl)-2,2,4-trimethyl-1,3-dioxolan in 7.5 ml of acetonitrile. After 2 minutes of additional stirring, the reaction mixture was extracted three times with 20 ml of chloroform each time. The combined organic extracts were dried over sodium sulfate, whereafter the solvent was removed. After chromatography of the obtained residue on silica gel with benzene/ethyl acetate (2:1 parts by volume) and ethyl acetate, there were obtained 266 mg of (S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolan-4-ethyl)-p-benzoquinone and 177 mg of (S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethyl-p-benzoquinone in the form of yellow needles with a melting point of 111°-112°.
Reaction SMILES: IC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[F:33].[I:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[I:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:38]2[CH:39]=[CH:40][C:35]([I:34])=[CH:36][CH:37]=2)=[S:45])=[CH:28][C:27]=1[F:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccc(I)cc1
Agent: O=C(N=C=S)c1ccc(I)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(I)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
4-Iodo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-iodo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-iodo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (84 mg, yield 88%).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C(C(CC)(CC)CN)C.C(OCC)(=O)C>O>[N:12]1([CH:2]([CH3:11])[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: c1c[nH]cn1
Agent: CCC(CC)(CC)CN
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C(=O)c1ccccc1)n1ccnc1
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of 2-bromopropiophenone (21.3 g, 0.1M), imidazole (20.4 g, 0.3M), triethylethylamine (30.3 g, 0.3M) and ethyl acetate (300 ml) was refluxed overnight, cooled to room temperature and treated with water. The organic phase was separated, dried over MgSO4 and evaporated to give 2-(imidazol-1-yl)propiophenone as a viscous oil (12.95 g,
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12]O.[Br:14]P(Br)Br.C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][Br:14]
Reactant: BrP(Br)Br
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Br)c(CBr)c1
Yield: 60.1 %

Procedure:
To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (1.6 g, 6.27 mmol) in dichloromethane (10 mL) at 0° C. was added tribromophosphine (1.698 g, 6.27 mmol) over 2 hours. To the reaction mixture was added saturated NaHCO3 and the organic layers was separated, dried with NaSO4, filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% EtOAc in hexane) to afford the title compound (1.2 g, 3.77 mmol, 60.2% yield). 1H NMR (300 MHz, CDCl3) δ ppm 4.60 (s, 2H) 7.53-7.61 (m, 2H) 7.84 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][CH:29]=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:31]([Mg]Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][CH:29]([OH:30])[CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Br[Mg]Cc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC=O)cc3)cc2)CC1
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(O)Cc4ccccc4)cc3)cc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1-{4′-[3-Methyl-4-(3-oxo-propyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.250 g, 0.62 mmol) was dissolved in THF and cooled to 0° C. under N2 atmosphere. Benzylmagnesium bromide (19% in THF, 0.62 mL, 0.62 mmol) was added and the reaction was allowed to slowly warm to room temperature. After 1.5 hours, the reaction was cooled to 0° C. and additional benzylmagnesium bromide (19% in THF, 0.1 mL, 0.10 mmol) was added, and the reaction was stirred for 30 minutes. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried and concentrated and the residue was purified by silica gel chromatography (0-60% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](O)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:31])=O>>[F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([Cl:31])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 59.2 %

Procedure:
A 500 ml round bottom flask equipped with nitrogen inlet and magnetic stirrer is charged with 40 g (0.132 mol) of product from Example 2 and 24.97 g (0.233 mol) of 2.6-lutidine. To this is slowly added (exothermic) 185 ml (1.98 mol) of phosphorous oxychloride. The flask is fitted with a condenser and the mixture is heated to reflux. After refluxing for 18 hours the material is cooled, concentrated, and the mixture was poured into 150 g of ice slowly. The ice mixture was then poured into 200 ml of 10% HCl (aqueous) and extracted twice with ether. The combined ether layers were washed with 10% NaOH (aqueous), dried (MgSO4), and concentrated in vacuo affording a black oil. The residue was kugelrohr distilled at 67 Pa. The earlier fraction (pot temperature 50° C.) was discarded. The later fraction (pot temperature 85° C.) afforded 25.15 g (60%) of product, nD25 1.4185.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>CN(C)C=O>[CH2:3]([N:12]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(NCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N(CC(=O)c2ccccc2)Cc2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Suspend sodium hydride (42 mg of a 60% dispersion, 1.39 mmol) in dimethylformamide, place under nitrogen atmosphere and cool to -10°C. Add, by dropwise addition, a solution of 3-[(phenacyl)amino]-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole (0.6 g, 1.26 mmol) in dimethylformamide. Stir at -10° C. for 30 minutes and add, by dropwise addition, benzyl bromide (0.24 g, 1.39 mmol).Stir for 5 hours, pour into 1N hydrochloric acid and extract into ethyl acetate. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1.CN(C=O)C>C1COCC1>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][N:16]=[C:15]2[CH:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C1Cc2ccc(F)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3C(=O)Nc4cc(F)ccc43)c2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
A solution of 6-fluorooxindole (264 mg, 1.75 mmol), (prepared according to Synthesis 1993, 51), in THF (3 ml) was added dropwise under nitrogen to sodium hydride (42 mg, 1.75 mmol, pre-washed with hexane). After stirring the resulting mixture for 20 minutes at ambient temperature, 4-chloro-6,7-dimethoxyquinazoline (210 mg, 0.93 mmol), (prepared as described for the starting material in Example 1), was added as a solid, followed by DMF (4 ml). The reaction mixture was then heated at 85° C. for 1 hour, the solvent was removed by evaporation and the residue partitioned between ether and water. The aqueous layer was separated and neutralised with 2M hydrochloric acid and the solid was collected by filtration, washed with ether and dried under vacuum to give 6,7-dimethoxy4-(6-fluorooxindol-3-yl)quinazoline (255 mg, 81%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=O.[C:14](#[N:17])[CH:15]=C.C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[CH:4]=[CH:15][C:14]#[N:17]
Reactant: C=CC#N
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: Cc1ccc([N+](=O)[O-])cc1C=CC#N

Procedure:
0.336 g (1.5 millimols) of palladium acetate, 29.93 g (150 millimols) of 2-methyl-5-nitrobenzoyl chloride, 9.94 g (187.5 millimols) of acrylonitrile and 27.80 g (150 millimols) of tri-n-butylamine, in 150 ml of p-xylene, are stirred for 80 minutes at 130°. The mixture is then extracted, and dried, as described in Example 68. The crude product is chromatographed on silica gel in toluene and is then recrystallised from carbon tetrachloride/cyclohexane. 6.3 g (22% of theory) of white crystals, of melting point 115.6° C., are obtained. Analysis for C10H8N2O2 : calculated C 63.83%, H 4.29%, N 14.89%; found C 63.8%, H 4.2%, N 15.1%.
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9])(=[O:5])[CH:3]=O.C1(P(=[CH:31][C:32]2[CH2:33][S:34][C@@H:35]3[C@H:55]([NH:56][C:57](=[O:64])[CH2:58][C:59]4[S:60][CH:61]=[CH:62][CH:63]=4)[C:54](=[O:65])[N:36]3[C:37]=2[C:38]([O:40][CH:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:11][C:8]([Cl:9])([Cl:10])[CH2:7][O:6][C:2]([CH:3]=[CH:31][C:32]1[CH2:33][S:34][C@@H:35]2[C@H:55]([NH:56][C:57](=[O:64])[CH2:58][C:59]3[S:60][CH:61]=[CH:62][CH:63]=3)[C:54](=[O:65])[N:36]2[C:37]=1[C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])=[O:5]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: O=CC(=O)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CC(=O)OCC(Cl)(Cl)Cl)CS[C@H]12
Yield: 47 %

Procedure:
A suspension of 2,2,2-trichloroethyl glyoxylate monohydrate (435 mg., 1.86 mmole) in dry methylene chloride (25 ml.) was stirred at 23° and treated, over 10 minutes, with diphenylmethyl 3-(triphenylphosphoranylidenemethyl)-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (765 mg., 1 mmole). After stirring for 45 minutes, the solvent was removed in vacuo and the residue was extracted with ethyl acetate (50 ml.); the insoluble material was filtered off and the filtrate was washed well with water (2 × 50 ml.) and brine (50 ml.), dried, and evaporated to an oil (1.07 g.). This material was purified by chromatography on 0.05-0.2mm. Kieselgel, with benzene; ethyl acetate = 10:1 as eluent. Combination of similar fractions (as judged by t.l.c.) gave the title compound (325 mg., 47%), as an amorphous white solid, m.p. 70° to 81° (decomp.), [α] - 72.2° (CHCl3), λmax. 313 nm (ε 9,300) with an inflexion at 237 nm. (ε 14,900), νmax. (CHBr3) 3415 (NH), 1789 (β-lactam), 1728 (--CO2R), and 1682 and 1510 cm.-1 (CONH); the p.m.r. spectrum (CDCl3) indicated that this compound was mainly the cis-isomer, with signals at τ 3.50 (NH, d, J 9 Hz.); 4.08 and ca. 2.60 (CH=CH), two d, JAB 12 Hz.), 4.09 (C(7) --H, dd, J 5, 9 Hz.); 4.93 (C(6) --H, d, J 5 Hz.); 5.33 (--CH2CCl3, s); 6.16 (--CH2CONH--, s); and 6.29 and 6.61 (C(2) --CH2, AB-q J 18 Hz.), together with the trans-isomer (10 to 15%) with signals at τ 3.88 and 1.96 (CH=CH, two d, J 16 Hz.) [Found: C, 53.4; H, 3.6; N, 3.8; S, 9.1; Cl, 15.25; C31H25Cl3N2O6S2 (692.0) requires C, 53.8; H, 3.6; N, 4.05; S, 9.3; Cl, 15.4%]. Rf 0.54 (Merck GF254 + 266 plates, with benzene: ethyl acetate = 5:1 for development).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(OC(F)(F)F)cc4)cc3CC[C@@H]12
Reaction time: 24 h
Yield: 54.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 4-trifluoromethoxyphenylboronic acid (161 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was healed at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 137 mg (56%) of the title compound as a waxy solid. FDMS: m/e=389. α[D]589 =+48.95 (c=0.96, chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>O1CCOCC1.O>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)CCC2
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.9 %

Procedure:
To a solution of 5.2 g (39 mmol) of 5-aminoindan in 15 mL of dioxane kept in an ice-bath was added dropwise 8 mL (8.6 g, 84 mmol) of acetic anhydride. The solution was stirred at room temperature for 16 h. It was diluted with 70 mL of water. The mixture was filtered, washed with water, and dried to leave a gray solid 6.21 g (91%). 1H NMR (CDCl3), 2.069 (m, 2), 2.165 (s, 3), 2.879 (m, 4), 7.20 (mb, 1), 7.145 (s, 2), 7.441 (s, 1).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[N:33]1([CH2:39][C:40](O)=[O:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:40](=[O:41])[CH2:39][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:31][CH2:32]2)[N:10]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=C(O)CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(=O)CN3CCOCC3)CC2)nc1N

Procedure:
The same procedure as described in Example 81 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and morpholin-4-yl-acetic acid (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-2-morpholin-4-yl-ethanone. MS (M+H)+: 473.