Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:17])([CH3:16])[CH3:15])[CH2:10][CH2:9]1.[H-].[Na+].[CH3:20]I.O>C1COCC1>[CH3:20][O:17][C:14]([C@H:11]1[CH2:12][CH2:13][C@H:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:9][CH2:10]1)([CH3:15])[CH3:16]
Reactant: CI
Reactant: CC(C)(O)[C@H]1CC[C@H](OC2CCCCO2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(C)(C)[C@H]1CC[C@H](OC2CCCCO2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((trans)-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl)propan-2-ol (1.56 g, 6.5 mmol) in THF (10 mL) was added NaH (300 mg, 13 mmol, 2.0 eq) slowly at r.t. and then CH3I (1.96 g, 13 mmol, 2.0 eq) was added in one portion. The mixture was stirred at 50° C. for 2 h, Water (10 mL) was added and the mixture was extracted with EA (30 mL×3), dried and concentrated to give the title compound as a colorless oil (1.2 g, yield: 72%). 1H NMR (400 MHz, CDCl3) δ: 4.64 (t, 1H), 3.93-3.89 (m, 2H), 3.51-3.47 (m, 1H), 3.17 (s, 3H), 1.97-1.85 (m, 3H), 1.70-1.67 (m, 1H), 1.58-1.43 (m, 9H), 1.34-1.27 (m, 2H), 1.09 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][C:9]1[N:10]=[N:11][NH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17](I)[CH3:18]>CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][C:9]1[N:10]=[N:11][N:12]([CH2:17][CH3:18])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NCc1nn[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nnc(CNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2H-Tetrazol-5-ylmethyl)-carbamic acid tert-butyl ester (0.9 g, 4.5 mmol) is dissolved in dry DMF, NaH (60% dispersed in mineral oil) (0.18 g, 4.5 mmol) is added and the reaction mixture is stirred at room temperature for 5 minutes before ethyl iodide (0.35 ml, 4.5 mmol) is added. The reaction mixture is stirred overnight at room temperature and partitioned between EtOAc and water. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to afford an oil. Purification by flash chromatography on silica eluting with 2:1 iso-hexanes/EtOAc affords the title compound.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]([C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:23]([F:33])=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[NH2:50][OH:51]>C(O)(C)C>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]([C:26](=[N:50][OH:51])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:23]([F:33])=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(Cl)c1F
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CCOC(=O)C(=NO)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(Cl)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 2-(6-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-((2R,6S)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)-2-oxoacetate (Intermediate 121, 13.4 g, 21.85 mmol) was slurried in isopropanol (150 ml), and pyridine (124 ml, 1529.70 mmol) was added to give a yellow solution. Hydroxylamine hydrochloride (1.670 g, 24.04 mmol) was added, and the suspension was stirred at room temperature for approximately 16 hours. The resulting solution was concentrated to an oil. The residue was purified by chromatography on SiO2 using 5-40% EtOAc/hexane. A total of 11.93 g (87%) of the title product as a mixture of oxime isomers was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:13])C(I)=C[O:11][C:6]=2[CH:5]=[C:4]([O:14][CH2:15]OCC[Si](C)(C)C)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[CH:5]=[C:6]([OH:11])[C:7]=1[CH:8]=[O:13]
Reactant: C[Si](C)(C)CCOCOc1cc(Cl)c2c(=O)c(I)coc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)c(C=O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 219.5 %

Procedure:
To a solution of 2-chloro-4,6-dimethoxybenzaldehyde [4] (3.15 g) in dichloromethane (30 mL) cooled at −78° C. was added boron tribromide (1M solution in dichloromethane, 16 mL). The mixture was stirred at −78° C. for 30 min, warmed and stirred at room temperature for 18 h. The mixture was cooled to 0° C., poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. Evaporation of the solvent gave the title compound (2.85 g). 1H NMR (DMSO-d6): 12.15 (s, 1H), 10.14 (s, 1H), 6.74 (d, 1H, J=2.1 Hz), 6.53 (d, 1H, J=2.1 Hz), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][NH2:19].[OH:20][CH:21]([CH2:24]O)[CH:22]=[O:23]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][N:19]=[CH:24][CH:21]([OH:20])[CH2:22][OH:23]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2CON)c1Cl
Reactant: O=CC(O)CO
Product: Cc1ccc(Cl)c(Nc2ccccc2CON=CC(O)CO)c1Cl

Procedure:
The title compound is prepared by the reaction of O-[2-[(2,6-dichloro-3-methylphenyl)amino]phenylmethyl]hydroxylamine, prepared as in Example 1, steps 1-3, with 2,3-dihydroxypropionaldehyde.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Temperature: 150 °C

Procedure:
A mixture consisting of 0.5 g of 1-benzyl-4-[2-(4-fluorobenzoyl)ethyl]piperidine and 2 ml of pyrrolidine was heated at 150° C. for 24 hours and the reaction mixture was subjected to distribution between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried and the solvent was distilled off. The residue was recrystallized from ethyl acetate to give 0.7 g of colorless crystals melting at 144°-145° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH3:1][N:2]([CH2:5][CH2:6][CH2:7][CH:8]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:3]
Reactant: CNC
Reactant: BrCCCC=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CN(C)CCCC=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Next, an aqueous solution (40%) of dimethyl amine (25 equivalents) is added slowly to a THF solution of 1.0 equivalent of 5-bromo-1,1-diphenyl-1-pentene that has been obtained in the previous step. The mixture is then stirred at room temperature for 24 hours, and worked up in the usual manner to yield 5-(N,N-dimethyl)amino-1,1-diphenyl-1-pentene as a yellow oil.
Reaction SMILES: Cl.[C:2]1([C:8]#[C:9][C:10]2[S:14][C:13]([C:15]3[N:16]=[C:17]4[CH:22]=[N:21][CH:20]=[CH:19][N:18]4C=3N)=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.CC(=O)OCC.[CH3:35][N:36]([CH:38]=O)[CH3:37]>>[CH3:35][N:36]([CH3:37])[C:38]1[N:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:17]2=[N:16][C:15]=1[C:13]1[S:14][C:10]([C:9]#[C:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:12]=1
Reactant: Nc1c(-c2ccc(C#Cc3ccccc3)s2)nc2cnccn12
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C)c1c(-c2ccc(C#Cc3ccccc3)s2)nc2cnccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
790 mg (2.5 mmol) of 2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-ylamine hydrochloride (Example 83) were dissolved in DMF (8 ml). After addition of 300 mg (7.5 mmol) of sodium hydride (60% dispersion in mineral oil) in portions, the mixture was stirred at RT for 30 min. 0.3 ml (5.0 mmol) of methyl iodide dissolved in DMF (2 ml) was then added dropwise. The reaction solution was stirred at RT for a further 4 h and then quenched with water (20 ml) and extracted with EA (2×50 ml). The combined organic phases were dried over MgSO4, filtered and evaporated under a vacuum. 351 mg (1.0 mmol, 40% of theoretical) of dimethyl-[2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine were obtained from the group by crystallisation (EA).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[S:12][CH:11]2[N:8]([C:9](=[O:16])[C@@H:10]2[C@H:13]([OH:15])[CH3:14])[C:7]=1[C:17]([O-:19])=[O:18].[K+].[C:24]([O:30][CH2:31]I)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[S:12][CH:11]2[N:8]([C:9](=[O:16])[C@@H:10]2[C@H:13]([OH:15])[CH3:14])[C:7]=1[C:17]([O:19][CH2:31][O:30][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:18]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Oc3cccc(F)c3)SC12
Reactant: CC(C)(C)C(=O)OCI
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(Oc3cccc(F)c3)SC12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 100 mg of potassium 3-(3-fluorophenoxy)-6(S)-{1-(R)-hydroxyethyl}-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in 1 ml of dimethylformamide were added 98 μl of pivaloyloxymethyl iodide and the mixture was stirred at room temperature for 90 minutes. The mixture was partitioned between ethyl acetate and water, the organic layer was washed with water and brine, dried over magnesium sulphate and evaporated in vacuo to dryness. Chromatography over silica gel and elution with hexane-ethylacetate afforded 50 mg of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:10]2[N:11]([CH:18]=[C:19]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=3)[CH:20]=2)[N:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])[CH3:2].[C:34]([C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1)#[N:35].CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:34]([C:36]1([C:39]([N:6]2[CH2:7][C@H:3]([CH2:1][CH3:2])[C@H:4]([NH:8][C:9]3[C:10]4[N:11]([CH:18]=[C:19]([C:21]5[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=5)[CH:20]=4)[N:12]=[CH:13][C:14]=3[C:15]([NH2:17])=[O:16])[CH2:5]2)=[O:40])[CH2:38][CH2:37]1)#[N:35]
Reactant: N#CC1(C(=O)O)CC1
Reactant: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, 2hydroiodide (26 mg, 0.037 mmol), 1-cyanocyclopropanecarboxylic acid (12.25 mg, 0.110 mmol), BOP-reagent (48.8 mg, 0.110 mmol) and Hunig's Base (0.045 mL, 0.257 mmol) in DMF (1 mL) was stirred at rt overnight. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 7-minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (6 mg, 0.011 mmol, 30% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.78 (dd, J=11.9, 2.0 Hz, 1H), 8.19-8.10 (m, 1H), 8.07-7.90 (m, 2H), 7.38 (dd, J=8.2, 3.7 Hz, 1H), 7.20-7.06 (m, 1H), 5.05 (t, J=4.2 Hz, 0.5H), 4.91 (t, J=4.5 Hz, 0.5H), 4.57 (s, 2H), 4.37-4.25 (m, 1.5H), 4.18 (d, J=11.4 Hz, 0.5H), 3.97 (s, 2H), 3.94-3.75 (m, 1.5H), 3.49-3.37 (m, 3.5H), 2.69-2.59 (m, 0.5H), 2.58-2.46 (m, 0.5H), 1.83-1.32 (m, 6H), 1.08-0.96 (m, 3H) fractional peaks are due to the presence of amide rotomers. MS (ES+) m/z: 545.1 (M+H); LC retention time: 1.15 min (analytical LCMS Method H).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.C(OCC)(=O)C.[C:25](#[N:27])[CH3:26]>>[NH2:27][C:25]1[CH:26]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[C:4](=[CH:17][CH:16]=[C:15]([Cl:18])[CH:14]=2)[N:3]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC#N
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Reaction time: 0.5 h

Procedure:
A suspension of 1.4 g of powdered KOH in 25 ml of anhydrous acetonitrile stirred under an argon atmosphere was heated to boiling under reflux conditions for 30 minutes and then a solution of 1.15 g of 2-amino-5-chlorobenzophenone in 5 ml of anhydrous acetonitrile was added. The mixture was boiled with a reflux condenser for 12 hours. Cooling was followed by pouring into ice, extraction with ethyl acetate, washing with water and removal of the solvent by distillation.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10].[CH3:11][C:12]#[C:13][N:14]1[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][C:22](=[O:35])[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]1>C(N(CC)CC)C.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>[F:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[C:11]#[C:12][CH2:13][N:14]1[CH2:19][CH2:18][C@@H:17]([CH2:20][CH2:21][C:22](=[O:35])[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[C@@H:16]([C:36]([O:38][CH3:39])=[O:37])[CH2:15]1
Reactant: CC#CN1CC[C@@H](CCC(=O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Reactant: Fc1cc(F)c(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 80 °C

Procedure:
4.05 g of tetrakis(triphenylphosphine)palladium, 0.834 g of cuprous iodide and 7.9 cm3 of 1-bromo-2,3,5-trifluorobenzene are added at a temperature in the region of 20° C., with stirring and under an inert atmosphere, to a solution of 17.28 g of methyl (3R,4R)-1-(3-prop-2-ynyl)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 173 cm3 of triethylamine. After heating for 2 hours at a temperature in the region of 80° C., the reaction mixture is cooled to approximately 20° C., diluted with 100 cm3 of water and then extracted with 4 times 150 cm3 of ethyl acetate. The organic extracts are combined, washed with 5 times 100 cm3 of water, dried over sodium sulfate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue is purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45μ; diameter 7 cm; mass 600 g), elution being carried out with ethyl acetate. Fractions 3 to 11 are combined and then concentrated under the above conditions. 18.4 g of methyl (3R,4R)-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate are obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]>[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]3=[O:33])[C:10]([OH:17])([C:13]([F:14])([F:16])[F:15])[CH2:9][C:8]2([CH3:19])[CH3:18]
Reactant: Cn1ncc2c(N)cccc2c1=O
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)n(C)ncc12
Yield: 4 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 114 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 3, 50 mg of imine is reacted by reaction with 0.23 ml of titanium tetrachloride, and 12 mg of the title compound is obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:11]3[O:19][C@H:20]4[CH2:25][CH2:24][CH2:23][C@H:21]4[NH:22][C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2].C=O.[BH3-][C:29]#N.[Na+]>C(O)(=O)C>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[C:12]2[C:11]3[O:19][C@H:20]4[CH2:25][CH2:24][CH2:23][C@H:21]4[N:22]([CH3:29])[C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@@H]1CCC[C@@H]1O3
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(C)[C@@H]1CCC[C@@H]1O3
Yield: 97.5 %

Procedure:
Compound 133 was prepared according to General Method 5 (EXAMPLE 2) from (7aR,10aS)-7,7a,8,9,10,10a-hexahydro-3-isopropoxy-1-(trifluoromethyl)-cyclopenta[5,6][1,4]oxazino[2,3-f]quinoline (5 mg, 0.014 mmol), 37% aqueous formaldehyde solution (0.01 mL, 0.14 mmol) and NaBH3CN (9 mg, 0.14 mmol) in 1 mL acetic acid to afford 5 mg of (7aR,10aS)-7,7a,8,9,10,10a-hexahydro-3-isopropoxy-7-methyl-1-(trifluoromethyl)-cyclopenta[5,6][1,4]oxazino[2,3-f]quinoline. This material (5 mg, 0.01 mmol) carried on according to General Method 4 (EXAMPLE 1) by treatment with 4 mL of 1:1 acetic acid:concentrated HCl (3 mM) heated at 90° C. for 4 h to afford 3.9 mg (90%) of Compound 133, a yellow solid, after column chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 10.58 (bs, 1H), 7.10 (s, 1H), 7.00 (d, J=8.8, 1H), 6.87 (d, J=8.8, 1H), 4.15 (m, 1H), 3.53 (m, 1H), 2.98 (s, 3H), 2.02 (m, 4H), 1.64 (m, 2H), 0.88 (t, J=6.8, 3H).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:11]([NH2:25])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:33][C:14]1[N:15]([CH2:18][CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:16]2[C:12]([N:13]=1)=[C:11]([NH2:25])[N:10]=[C:9]([NH:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[N:17]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(NCC2CCCCC2)nc2c1ncn2CC1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1nc(NCC2CCCCC2)nc2c1nc(Br)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N2-(cyclohexylmethyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purine-2,6-diamine (90 mg) in dry chloroform (1 mL) at room temperature was added NBS (46 mg) in one go. The dark brown reaction was stirred at RT for 1 hour. The reaction was diluted with DCM (15 mL) and washed with water (5 mL). The organics were passed through a hydrophobic frit and concentrated in vacuo.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][CH2:6][NH2:7].[CH3:11]O>>[ClH:1].[CH3:11][O:9][C:8](=[O:10])[C@H:3]([CH2:4][CH2:5][CH2:6][NH2:7])[NH2:2]
Reactant: CO
Reactant: NCCC[C@H](N)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](N)CCCN
Reaction time: 8 h
Yield: 97 %

Procedure:
Into a stirred suspension of L-(+)-ornithine hydrochloride (Aldrich) in methanol was bubbled anhydrous hydrochloric acid gas until the solution was saturated. The reaction mixture was capped with a rubber septum and stirring was continued overnight at room temperature. The solvent was then stripped under reduced pressure and the residue triturated with ether. The resulting solid was dried under reduced pressure to afford L-(+)-ornithine methyl ester hydrochloride as a white solid (97% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([F:23])[CH:11]=2)=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[OH:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CC(C)=O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([F:23])[CH:11]=2)=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: Oc1ccc(F)c(NCc2cc(F)cc(-c3cccc(F)c3)c2)c1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(F)cc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[3-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenol (350 mg, 1.0 mmol, 1.0 eq) in acetone (5 mL) was added Cs2CO3 (492.5 mg, 1.5 mmol, 1.5 eq). The resulting mixture was stirred for 30 min at room temperature then ethyl bromoacetate (202 mg, 1.21 mmol, 1.2 eq) was added. The resulting mixture was stirred 1 h then water added and the mixture extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as an oil (385 mg, 88%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[C:21]([OH:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].[CH:25]1(O)[CH2:30][CH2:29][CH2:28][CH:27]=[CH:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C1COCC1>[Br:13][C:14]1[C:21]([O:22][CH:30]2[CH2:29][CH2:28][CH2:27][CH:26]=[CH:25]2)=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: COc1ccc(C=O)c(Br)c1O
Reactant: OC1C=CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C=O)c(Br)c1OC1C=CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl azodicarboxylate (2.7 ml) was dropwise added to a mixture of 2-bromo-3-hydroxy-4-methoxy-benzaldehyde (4.0 g), THF (80 ml), 2-cyclohexen-1-ol (1.2 ml), and triphenylphosphine (4.5 g) under ice-cooling, followed by stirring at room temperature for 2 hours. The mixture was poured into water followed by extraction with ether. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and with a saturated saline, and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (hexane:ethyl acetate=10:1 and 5:1) to give Compound IIn-a (1.8 g, 47%) as a pale-yellow oily substance.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[F:8][C:9]([F:27])([F:26])[C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=1)[O:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>C1C=CC=CC=1>[F:8][C:9]([F:27])([F:26])[C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=1)[O:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:4]([CH2:5][CH:6]=[CH2:7])[CH2:1][CH:2]=[CH2:3])=[O:17]
Reactant: C=CCNCC=C
Reactant: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Product: C=CCN(CC=C)C(=O)c1cccnc1Oc1cccc(C(F)(F)F)c1

Procedure:
In the same manner as in Example 1(a), 1.6 grams (0.016 mole) diallylamine and 2.5 grams (0.008 mole) 2-(3-trifluoromethylphenoxy)nicotinoyl chloride were mixed in 100 milliliters benzene to yield 1.6 grams (55.2% of theoretical yield) of the desired product, nD30 1.5003. The structure of this compound was confirmed by mass spectrometry.